Post on 08-Mar-2021
b13.13 Product Class 13:
1,2,3-Triazoles
A. C. Tom�
General Introduction
Previously published information regarding this product class can be found in Houben–Weyl, Vol. E 8d, pp 305–405 (1,2,3-triazoles)[1] and pp 406–478 (benzotriazoles).[2] Other im-portant reviews on the chemistry of 1,2,3-triazoles and their benzo derivatives are alsoavailable.[3–9]
1,2,3-Triazoles and benzotriazoles are important types of heterocyclic compounds.They find numerous applications in industry, namely as dyestuffs, fluorescent whiteners,photostabilizers of polymers, optical brightening agents, corrosion inhibitors and as pho-tographic photoreceptors.[6,7] Also, due to their extensive biological activities, they findsuccessful application in medicine and as agrochemicals.[6,7] Beyond this, these com-pounds are intensively studied by many research groups due to their theoretical interestand synthetic usefulness.
The 1,2,3-triazoles can be divided in three main groups: monocyclic 1,2,3-triazoles,benzotriazoles, and 1,2,3-triazolium salts. As indicated in Scheme 1, for monocyclic1,2,3-triazoles three subclasses can be recognized, depending on the position of the sub-stituents in the ring. While 1H- and 2H-1,2,3-triazoles are aromatic compounds their 4H-isomers are not. This fact is reflected in the abundance of examples of 1H- and 2H-1,2,3-triazoles and the rarity of 4H-1,2,3-triazoles.[3] In the literature, the 1,2,3-triazole system issometimes named as “v-triazole” in order to distinguish it from “s-triazole”, the 1,2,4-tri-azole system.
Scheme 1 Classes of 1,2,3-Triazoles
1H-1,2,3-triazoles
N
NN
R1
R1
1
5
4 3
2
2H-1,2,3-triazoles
N
NNR1
R1
R1
1
5
4 3
2
4H-1,2,3-triazoles
N
NNR1
1
5
4 3
2
R1
R1
R1
1H-benzotriazoles
1
5
4 3
2
NN
N
6
7
2H-benzotriazoles
1
5
4 3
2NNR1
N
6
7R1
1
2
NNR1
N
1,2,3-triazolium salts
N
NNR1
R1
R1
1
2NR1
NN
R1
R1
1
2
benzotriazolium salts
+ ++
1
2
NN
R1
N
+
R1 R1 R1 R1
415
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bN-Unsubstituted 1,2,3-triazoles can be regarded either as 1H- or as 2H-derivatives sincethese two tautomeric forms are in equilibrium, both in solution and in the gas phase(Scheme 2). In this article, for simplification, this type of compound will be representedas 1H-triazoles, independently of the predominant tautomer.
Scheme 2 Tautomerism in 1,2,3-Triazoles
1
2
N
NH
N
1
2N
NNH
1H-1,2,3-triazole 2H-1,2,3-triazole
1
2
1H-benzotriazole 2H-benzotriazole
NH
NN
NNH
N
1
2
The two tautomeric forms of 1,2,3-triazole and benzotriazole are in equilibrium, both insolution and in the gas phase (Scheme 2). However there is an extraordinary difference instability between 1,2,3-triazole and benzotriazole tautomers. In the gas phase, the 2H-tau-tomer of 1,2,3-triazole represents more than 99.9% of the equilibrium mixture, whereasin benzotriazole the 1H-tautomer is the predominant one (more than 99.99% at equilibri-um).[10] In solution, the much higher dipole moment of 1H-tautomers favor these struc-tures and, as a consequence, mixtures of 1H- and 2H-1,2,3-triazole are observed in solu-tion whereas the higher stability of 1H-benzotriazole is reinforced.[10] In the solid state,1,2,3-triazole exists as a 1:1 mixture of 1H- and 2H-tautomers, while 4-phenyl-1,2,3-tria-zole and 4-nitro-1,2,3-triazole are, respectively, in the 2H- and 1H- tautomeric forms.[11]
The experimental dipole moment in benzene for the tautomeric mixture of 1H- and 2H-1,2,3-triazole is 1.85 D at 25 8C and 2.08 D at 45 8C. The experimental dipole moments areas follows: 1H-1,2,3-triazole 4.38 D, 2H-1,2,3-triazole 0.22 D, 1H-benzotriazole 4.15 D, and2-methyl-2H-benzotriazole 0.49 D.[7]
1H-1,2,3-Triazole is both a weak base (pKa 1.17) and a weak acid (pKa 9.4) of compara-ble strength to phenol. 1H-1,2,3-Triazole-4,5-dicarbonitrile (pKa 2.53), 4,5-dibromo-1H-1,2,3-triazole (pKa 5.37), and 4-nitro-1H-1,2,3-triazole (pKa 4.80) are much more acidic com-pounds. 1-Methyl-1H-1,2,3-triazole (pKa 1.25) shows a basicity comparable to 1H-1,2,3-tria-zole, but 2-methyl-2H-1,2,3-triazole is a much weaker base.[12–14] The basicity of N-unsub-stituted and N-methyl-1,2,3-triazoles in the gas phase, in solution, and in the solid statehas been determined.[11] The fused benzene ring in benzotriazole (pKa 8.2) is base-weaken-ing and acid-strengthening. Substitution of hydrogen atoms by chlorine in the benzenering results in increased acidity: 5-chlorobenzotriazole, pKa 7.7; 4,5,6,7-tetrachlorobenzo-triazole, pKa 5.5.[15,16]
The application of semi-empirical and ab initio methods in theoretical calculationsfor 1,2,3-triazoles and benzotriazoles and the description of a number of instrumentaltechniques used in the characterization of these systems have been reviewed.[7]
1,2,3-Triazoles with a strong electron-withdrawing group at N1 (e.g., cyano, nitro, orarylsulfonyl groups) undergo ready and reversible ring opening to Æ-diazoimine tauto-mers (Scheme 3). This ring–chain tautomerism, also observed in some benzotriazole de-rivatives, is markedly temperature dependent.[17–20]
416 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 3 Ring–Chain Tautomerism in 1,2,3-Triazoles and Benzotriazoles
N
NX
NR1
R2
R1 NX
R2 N2
X = CN, SO2Ar1
X = CN, SO2Ar1, NO2
NX
NN N2
NX
This type of tautomerism is also involved, for example, in the interconversion of 1-aryl-1,2,3-triazol-5-amines and 5-anilino-1,2,3-triazoles (R1 = aryl) (Scheme 4). This isomeriza-tion is known as the Dimroth rearrangement. It is also observed in the interconversionof triazoles with other substituents at position 5 (or 4) and in the conversion of 1,2,3-tri-azoles into other ring systems. The equilibrium is established thermally, but its positionis influenced by the basicity of the solvent. In pyridine, for example, the equilibrium po-sition is shifted to the more acidic NH triazoles. It is also observed that electron-withdraw-ing groups and large, rigid groups tend to favor the exocyclic nitrogen while alkyl groupstend to favor the cyclic nitrogen. This subject has been reviewed.[21]
Scheme 4 Dimroth Rearrangement in 1,2,3-Triazoles
R1 = Me
N
NN
R2
H2N
R1 H2N NR1
R2 N2
R1HN NH
R2 N2 N
NH
N
R2
R1HN R1 = aryl
In terms of stability, monocyclic 1,2,3-triazoles and benzotriazoles are remarkably stablecompounds. The triazole ring is not normally cleaved by hydrolysis or oxidation and re-ductive cleavage only occurs under forcing conditions. The presence of substituents thathave a destabilizing effect on the ring system can facilitate the cleavage. When subjectedto pyrolysis or photolysis, 1,2,3-triazoles and benzotriazoles extrude nitrogen and pro-duce very reactive species which react further to form a range of stable compounds: ni-triles, ketenimines, azirines, pyrazines, indoles, etc. The thermal or photochemical extru-sion of nitrogen from 1-arylbenzotriazoles leads to the formation of carbazoles (Scheme5).
General Introduction 417
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 5 Photolysis of 5-Chloro-1-(4-chlorophenyl)-1H-benzotriazole
NN
N
Cl
Cl
Cl
N
Cl
NH
Cl Cl
MeCN, hν
− N2
•
•
Both monocyclic 1,2,3-triazoles and benzotriazoles are readily alkylated on nitrogen byalkyl halides, dimethyl sulfate, diazoalkanes, methyl sulfonates, and other alkylatingagents; generally mixtures of all possible N-alkyl isomers are obtained. With more reac-tive reagents, or under forcing reaction conditions, triazolium salts are obtained. N-Aryla-tion is also possible if activated aryl halides are used. 1,2,3-Triazoles and benzotriazolesalso react with acyl halides and anhydrides to furnish the corresponding N-acyl deriva-tives. These compounds also react with sulfonyl chlorides, isocyanates, chlorotrimethyl-silane, etc. to give the corresponding N-substituted derivatives. Electrophilic substitutionat CH positions is also possible: halogenation and nitration are examples of such transfor-mations. Lithiation of triazoles followed by addition of electrophilic reagents is anotherversatile approach to functionalization of these compounds at CH positions. Triazoles canalso be activated toward electrophiles by introduction of an N-oxide group.
All these types of reactions, and many others that produce new 1,2,3-triazole deriva-tives, are described in this section. Also, the synthetic methods available for the construc-tion of the 1,2,3-triazole ring are reviewed.
13.13.1 Product Subclass 1:Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles
13.13.1.1 Synthesis by Ring-Closure Reactions
13.13.1.1.1 By Formation of One N-N and One N-C Bond
13.13.1.1.1.1 Fragments C-C-N-N and N
13.13.1.1.1.1.1 Method 1:From 2-Diazo-1,3-dicarbonyl Compounds and Amine Derivatives
The cyclocondensation reaction of 2-diazo-1,3-dicarbonyl compounds with amine deriva-tives is an old but versatile, simple, and completely regioselective method for the prepa-ration of 1H-1,2,3-triazoles. This method was developed by Wolff at the beginning of the20th century; he reported the synthesis of triazoles 3 by the reaction of ethyl 2-diazo-3-oxobutanoate (1) with phenylhydrazine, semicarbazide, hydroxylamine, aniline, or am-monia (Scheme 6).[22,23,246] The mechanism of the reaction involves the in situ formationof Æ-diazoimines of type 2 followed by ring closure. Several variations of this method ap-peared since then and a range of 2-diazo-1,3-dicarbonyl compounds can be used: Æ-diazo-�-oxo esters, Æ-diazo-�-formyl esters, Æ-diazo-�-oxoaldehydes, diazomalonaldehyde, anddiazomalonates.
418 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 6 Reaction of Ethyl 2-Diazo-3-oxobutanoate with Amine Derivatives[22–24,246]
ZNH2 N
NZ
N
EtO2C
3
N2
O
EtO
O
1
N2
O
EtO
NZ
2
Z = H, Ph, NHPh, OH, NHCONH2
The 1H-1,2,3-triazol-1-ol 3 (Z = OH) is obtained in 53% yield by reaction of 1 with an excessof hydroxylamine (EtOH/H2O 1:1, 80 8C, 5 h).[24]
The method described by Wolff can be extended to Æ-diazo-�-oxo esters with bulkysubstituents. For example, the 5-(1-adamantyl)-1H-1,2,3-triazoles 5 are prepared by the re-action of the diazo compound 4 with aniline and methylamine, respectively (Scheme7).[25] In this case titanium(IV) chloride is used as catalyst to promote the formation ofthe intermediate imine and thus facilitate the formation of the triazole.
Scheme 7 Reaction of Ethyl 3-(1-Adamantyl)-2-diazo-3-oxopropanoate with Amines[25]
N
NN
EtO2C
5
N2
O
EtO
O
4
+ R1NH2
TlCl4, ClCl
reflux, 15 h
R1R1 = Ph 74%
R1 = Me 51%
Ethyl 5-(1-Adamantyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylate (5, R1 = Ph);Typical Procedure:[25]
A soln of 4 (28 mg, 0.1 mmol), PhNH2 (13 mg, 0.14 mmol), and TiCl4 (19 mg, 0.1 mmol) indry 1,2-dichloroethane (2 mL) was refluxed for 15 h, and the resulting mixture was basi-fied with 1 M NaOH (1 mL). After adding Et2O/H2O (1:1, 10 mL) and shaking, the organiclayer was separated, washed with H2O and dried (Na2SO4). Evaporation of the solvent lefta residue, which was chromatographed to give 5 (R1 = Ph) as crystals; yield: 26 mg (74%);mp 134–138 8C.
13.13.1.1.1.1.1.1 Variation 1:From 2-Diazo-3-oxopropanoates and Amine Derivatives
Ethyl 2-diazo-3-oxopropanoate (6) reacts with a range of amine derivatives to give the cor-responding triazoles 7 (R1 = H, alkyl, aryl, OH, NHPh, NHCONH2) (Scheme 8).[26–28] Theyields of the reactions are highly dependent on the amine derivative used. The reactionof compound 6 with 2-aminoethanol gives triazole 7 (R1 = CH2CH2OH), which is used asprecursor to several 1,2,3-triazole-containing antibiotics.[29,30]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 419
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 8 Reaction of Ethyl 2-Diazo-3-oxopropanoate with Amine Derivatives[26–28]
N
NN
EtO2C
N2
O
EtO
O
6
+ R1NH2
R1H
7
R1 R1NH2 Conditions Yield (%) Ref
H NH3 AcOH, 100 8C, 3–4 h 50 [27]
H NH2OH H2O, rt, 48 h 7 [27]
NHCONH2 H2NNHCONH2 H2O, rt, 48 h 35 [27]
Ph PhNH2 EtOH, AcOH, rt, 30 min 74 [26]
Ph PhNH2 EtOH, AcOH, rt, 16 h 70 [28]
NH
N
But
NH
NH2N
But
EtOH, AcOH, rt, 16 h 81 [28]
Ethyl 1-Phenyl-1H-1,2,3-triazole-4-carboxylate (7, R1 = Ph); Typical Procedure:[28]
Ethyl 2-diazo-3-oxopropanoate (6; 0.426 g, 3 mmol) was dissolved in EtOH (3 mL). A soln ofPhNH2 (0.27 g, 2.9 mmol) in EtOH (1.8 mL) and AcOH (0.6 mL) was added and the mixturewas stirred at rt for 16 h. On removal of the solvent a solid was obtained, and crystalliza-tion (EtOH) gave white needles of the triazole 7 (R1 = Ph); yield: 0.45 g (70%); mp 86–87 8C.
13.13.1.1.1.1.1.2 Variation 2:From 2-Diazo-3-oxoaldehydes and Amine Derivatives
2-Diazo-3-oxoaldehydes 8 react with anilines, hydroxylamine, or semicarbazide yielding4-acyl-1-substituted 1H-1,2,3-triazoles 9 in moderate to good yields (Scheme 9).[26,27] Theyalso react with ammonia to give N-unsubstituted 1,2,3-triazoles in 20–26% yield. In thecondensations with hydroxylamine and semicarbazide the reaction goes further and theketone functions are converted into oximes and semicarbazones, respectively.[27] A newermethod for the preparation of a wide range of the required 2-diazo-3-oxoaldehydes hasbeen published.[31] Diazomalonaldehyde (8, R1 = H) reacts with aniline hydrochloride, inwater and at room temperature to yield 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (9,R1 = H; R2 = Ph) in 96% yield.[32]
Scheme 9 Reaction of 2-Diazo-3-oxoaldehydes with Amine Derivatives[26–28]
N
NNN2
O
H
O
R1
+ R2NH2
R1 = H, alkyl, aryl; R2 = H, aryl, OH, NHCONH2
8 9
R2
O
R1
420 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bCondensation of 2-Diazo-3-oxoaldehydes with Aniline; General Procedure:[27]
A soln of the 2-diazo-3-oxoaldehyde 8 (10 mmol) in EtOH (6 mL) and a mixture of PhNH2
(10.7 mmol) and AcOH (1.25 mL) were mixed. The mixture was stirred at rt for 30 min. Inmost cases during this time the triazoles precipitated and were obtained pure after recrys-tallization (EtOH). The yields were within the range of 26–87%.
13.13.1.1.1.1.1.3 Variation 3:From Dimethyl Diazomalonate and Amines
Dimethyl diazomalonate (10) undergoes reaction with primary alkylamines to generatethe corresponding primary ammonium salts of methyl 1-alkyl-5-hydroxy-1H-1,2,3-tria-zole-4-carboxylates 12 in 66–98% yield (Scheme 10).[33] The probable mechanism of this re-action involves the formation of the intermediate diazoamide 11, which then undergoesbase-catalyzed cyclization to the 1,2,3-triazole salt 12. Acidification of an aqueous solu-tion of 12 and extraction with dichloromethane gives the free triazolols. However, sincetriazol-5-ols undergo facile isomerization to the corresponding diazoamides, care must betaken during their formation and purification. The major limitation of this reaction is thefact that aromatic amines, e.g. aniline, fail to react. This is consistent with the reducednucleophilicity of the nitrogen in aromatic amines.[33]
Scheme 10 Reaction of Dimethyl Diazomalonate with Amines[33]
N
NNN2
O
MeO
O
MeO R1NH2
10 12
R1
MeO2C
N2
O
MeO
NHR1
O
11
R1NH2
−OR1NH3+
R1 Amine Time (d) Yield (%) mp (8C) Ref
Bu BuNH2 3 82 111–113 [33]
(CH2)4Me Me(CH2)4NH2 5 85 110–113 [33]
(CH2)5Me Me(CH2)5NH2 3 70 120–122 [33]
Cy CyNH2 3 66 154–157 [33]
(CH2)2OH HO(CH2)2NH2 3 98 119–124 [33]
Bn BnNH2 3 84 153–156 [33]
2-thienyl 2-thienylamine 3 67 160–161 [33]
3-thienyl 3-thienylamine 6 72 160–162 [33]
1,2,3-Triazole Salts 12; General Procedure:[33]
Dimethyl diazomalonate (10 mmol) was added to a large excess of the amine and the mix-ture was stirred at rt and monitored by IR spectroscopy until the diazo ester was com-pletely consumed (3–6 d). At this point the resultant salt had crystallized from soln andwas isolated by filtration and recrystallized. Alternatively, the reaction could be per-formed in toluene using 2–5 equiv of amine; yield: 66–98%.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 421
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.1.1.2 Method 2:
From Vinyldiazonium Salts and Amine Derivatives
Vinyldiazonium salts 13 react with ammonia and amine derivatives (primary amines, hy-drazines, hydroxylamine ethers) to give 1-substituted 1,2,3-triazoles 14 (Scheme 11).[34–36]
A probable mechanism for this reaction is represented in Scheme 11.[36] The reaction ofvinyldiazonium salts 13 with ø,ø¢-diaminoalkanes leads to ø,ø¢-bis(1H-1,2,3-triazol-1-yl)alkanes.[37]
Scheme 11 Reaction of Vinyldiazonium Salts with Amine Derivatives[36]
N
NN
R4NH2
13
R4
R1
− HX
N
R1
R3
R2
N
••
X−
+
N
R1••
NHR4
R2R3
N+
R2
R3
N
NN
R4
R1
14
R5
R5 = R2, R3
− R2H or R3H
−
R1 R2 R3 X R4 R5 Yield (%) Ref
H OEt OEt SbCl6 H OEt 65 [36]
H OEt OEt SbCl6 3-morpholinopropyl OEt 54 [36]
H OEt OEt SbCl6 Cy OEt 62 [36]
H OMe 4-MeOC6H4 SbCl6 furfuryl 4-MeOC6H4 63 [36]
4-O2NC6H4 OEt piperidino SbCl6 H piperidino 48 [36]
4-O2NC6H4 OEt piperidino SbCl6 furfuryl piperidino 80 [36]
4-O2NC6H4 OEt piperidino SbCl6 3-morpholinopropyl piperidino 65 [36]
4-O2NC6H4 OEt piperidino BF4 4-MeOC6H4 OEt 51 [36]
4-O2NC6H4 OEt piperidino BF4 NH2 OEt 24 [36]
2-(Benzoyloxy)alk-1-enediazonium trifluoromethanesulfonates 17 [generated in situ fromthe reaction of Æ-diazo ketones 15 and benzoyl trifluoromethanesulfonate (16)] reactwith isopropylamine to give the corresponding 1-isopropyl-1H-1,2,3-triazoles 18 in highyields (Scheme 12).[38]
422 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 12 Reaction of 2-(Benzoyloxy)alk-1-enediazonium Trifluoromethanesulfonateswith Isopropylamine[38]
• •
+
N
NN
Pri
R1
18
R1
A: R1 = Me 77%
B: R1 = Ph 80%
R1
O
R1
N2
+ BzOTfOBz
R1
N
R1
N
1715 16
OTf−
A: 1. CH2Cl2, −70 to −50 oC, 2 h
2. iPrNH2, −70 oC to rt, 2 h
B: 1. CH2Cl2, −95 oC, 2 h
2. iPrNH2, −95 oC, 0.5 h; −75 oC, 2 h
1-Isopropyl-4,5-dimethyl-1H-1,2,3-triazole (18, R1 = Me); Typical Procedure:[38]
A soln of benzoyl trifluoromethanesulfonate (5.20 g, 20.4 mmol) in CH2Cl2 (50 mL) wascooled to –70 8C and a soln of 15 (R1 = Me; 2.00 g, 20.4 mmol) in CH2Cl2 (50 mL) was addeddropwise. After the addition, the suspension was stirred at –70 8C for 1 h and at –50 8C for3 h. iPrNH2 (6.00 g, 102 mmol) was gradually added after cooling to –70 8C. A homogene-ous soln was formed and after 2 h at rt it was extracted with H2O (4 �). The organic layerwas dried (MgSO4) and the solvent was removed at 15 Torr. Distillation (90 8C/0.05 Torr, Ku-gelrohr apparatus) gave triazole 18 (R1 = Me); yield: 2.19 g (77%).
13.13.1.1.1.1.3 Method 3:From Dichloro- or Trichloroacetaldehyde Sulfonylhydrazones andPrimary Amines
Tosyl and mesyl hydrazones of dichloroacetaldehyde and trichloroacetaldehyde reactwith ammonia and primary amines to produce 1H-1,2,3-triazoles 20 and 22, respectively,in good yields (Scheme 13).[39,40] This is a much more convenient and secure reaction sys-tem, especially for large-scale production of triazoles, than some alternative methodswhere thermally unstable, or explosive, starting materials are used, namely diazo and azi-do derivatives. For example, 1H-1,2,3-triazole itself can be prepared in 75% yield from thereaction of dichloroacetaldehyde tosylhydrazone (19, X = Ts) with ammonia.[40] The samehydrazone can be converted into 1-benzyl-1H-1,2,3-triazole, 1-phenyl-1H-1,2,3-triazole, or1H-1,2,3-triazol-1-amine in similar yields. These triazoles can also be prepared from themesylhydrazone 19 (X = Ms) in almost the same yields (60–85%). When trichloroacetalde-hyde tosylhydrazone (21) is treated with aqueous ammonia only unidentified materialsare obtained, but the reaction with methylamine or benzylamine gives the 1,5-disubsti-tuted triazoles 22.[39]
Scheme 13 Reaction of Dichloro- and TrichloroacetaldehydeSulfonylhydrazones with Ammonia and Primary Amines[39,40]
R1NH2, MeOH
0−40 oC, 4 h
20
X = Ts, Ms; R1 = H, Ph, Bn, NH2
N
NN
R1H N
HCl
Cl
NHX
19
70−83%
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 423
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bR1 = Me: MeNH2, MeOH, 0 oC to rt, 19 h
R1 = Bn: BnNH2, MeOH, 0 oC, 2.5 h
22
N
NN
R1H N
ClCl
Cl
NHTs
21
R1 = Me 25%
R1 = Bn 30%
R1HN
Æ,Æ-Dichloro ketone tosylhydrazones can also be used as precursors of 1H-1,2,3-triazoles.For example, 1,1-dichloroacetone tosylhydrazone (23) is converted into 1-benzyl- and 1-al-lyl-4-methyl-1H-1,2,3-triazoles 24 in good yields (Scheme 14).[39] Also, an attempted syn-thesis of tosylhydrazone 26 from 2,2-dichloro-1-phenylethanone 25 gives the triazole di-rectly 27.[39]
Scheme 14 Reaction of Æ,Æ-Dichloro Ketone Tosylhydrazones with Primary Amines[39]
24
N
NN
R1O
HCl
Cl
R1 = Bn 84%
R1 =
TsNHNH2
N
HCl
Cl
NHTs
23
R1NH2
CH2CH CH2 83%
27 20%
N
NN
Ph O
HCl
Cl Ph
Ph N
HCl
Cl
NHTs
2625
NHTs
TsNHNH2 TsNHNH2
1H-1,2,3-Triazole (20, R1 = H); Typical Procedure:[40]
To a soln of NH3/H2O (8.9 g, 523 mmol) in MeOH (40 mL) under ice-cooling was added slow-ly dichloroacetaldehyde tosylhydrazone (19, X = Ts; 4.4 g, 15.7 mmol) in MeOH (60 mL).The mixture was stirred at 22 8C for 9 h and then it was filtered to remove NH4Cl. The fil-trate was concentrated and chromatographed (silica gel, EtOAc/hexane 1:1) to give 1H-1,2,3-triazole as a colorless oil; yield: 0.81 g (75%); bp 208–210 8C.
13.13.1.1.1.2 Fragments C-C-N and N-N
13.13.1.1.1.2.1 Method 1:From Enaminones and Diazo Transfer Reagents
Enaminones react with a range of diazo transfer reagents to give 1H-1,2,3-triazoles. 3-Di-azo-1,3-dihydro-2H-indol-2-one derivatives and sulfonyl azides are particularly useful inthese reactions.
13.13.1.1.1.2.1.1 Variation 1:From Enaminones and 3-Diazo-1,3-dihydro-2H-indol-2-one Derivatives
�-Amino-Æ,�-unsaturated ketones (enamino ketones) 28 (R2 = Me) and �-amino-Æ,�-unsat-urated esters (enamino esters) 28 (R2 = OEt) react with 3-diazo-1,3-dihydro-2H-indol-2-onederivatives to give 1H-1,2,3-triazoles of type 30 in good to excellent yields (Scheme15).[41,42] Various 3-diazo-1,3-dihydro-2H-indol-2-ones can be used but the best results areobtained with the nitro derivatives 29 and 31.[41] When cyclic enaminones 33 or 34 areused, carbocyclic fused 1,2,3-triazoles of types 33 and 35 are obtained in good yields (49–
424 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b83%).[42] The 3-diazobenzo[b]thiophen-2-one also reacts with enaminones to give 1,2,3-tri-azoles.[41] In these reactions, compounds 29, 31, and 3-diazobenzo[b]thiophen-2-one act asdiazo transfer reagents; a probable mechanism has been described.[41]
Scheme 15 Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones[41,42]
30
N
NN
R1
O
R2
NH
O
N2
O2N
NO2
+
H
R1HN
O
R2
2928
R1 = Me, t-Bu; R2 = Me, OEt
55−81%
30
N
NN
R1
O
R2
NO
N2
O2N
+
H
R1HN
O
R2
3128
R1 = Me, t-Bu; R2 = Me, OEt
Me
55−82%
+
32
NH
O
N2
O2N
NO2
29
O
NHMeR1
R1
NN
N
33
R1
R1 Me
O
R1 = H 49%
R1 = Me 50%
+
34
NH
O
N2
O2N
NO2
29
N NN
35
CO2Et
( )
n = 1, 2, 3
nNH
CO2Et
H
( )n
73−83%
Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones; General Procedure:[41]
A mixture of the diazocarbonyl compound (1 mmol) and the enaminone (1 mmol) in drytoluene (30 mL) was refluxed until the disappearance of the N2 absorption band at2100 cm–1 in the IR spectrum. The solvent was evaporated and the residue was submittedto column chromatography (Florisil, hexane/CH2Cl2/MeOH mixtures). The products werefurther purified by preparative TLC (silica gel, CHCl3/MeOH 100:1).
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 425
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.1.2.1.2 Variation 2:
From Enaminones and Sulfonyl Azides
Mesyl and tosyl azides can act as diazo transfer reagents to enaminones yielding triazoles36 in good yields (Scheme 16).[43] For this purpose, mesyl azide is a much better reagentthan tosyl azide (yields of 20–97% and 2–50%, respectively). The reaction works betterwith N-alkyl-substituted enaminones (72–97%) than N-aryl-substituted enaminones (20–37%).
Scheme 16 Reaction of Enaminones with Sulfonyl Azides[43]
TsN3 or MsN3, NaH N
NN
R1
R1 = alkyl, aryl; R2 = Me, OEt
O
R2
H
R1HN
O
R2
36
Reaction of Enaminones with Sulfonyl Azides; General Procedure:[43]
To a stirred mixture of NaH (6.67 mmol; free of oil) in anhyd MeCN (4 mL), under N2 at rt,was added a soln of the enaminone (1.85 mmol) in anhyd MeCN (4 mL). The stirring wascontinued for 30 min, followed by dropwise addition of mesyl azide (5 mmol) in anhydMeCN (1 mL). Stirring was maintained for 24 h and the reaction was quenched withNaOH soln (10%). The separated organic layer was dried (MgSO4) and the solvent was re-moved under reduced pressure to give a residue that was extracted with CH2Cl2
(3 � 10 mL). The crude 1,2,3-triazoles were purified by column chromatography (silicagel, hexane/EtOAc 9:1).
13.13.1.1.2 By Formation of One N-N and One C-C Bond
13.13.1.1.2.1 Fragments C-N-N and C-N
13.13.1.1.2.1.1 Method 1:From Diazoalkanes and Nitriles
Diazoalkanes react with activated nitriles such as cyanogen, cyanogen halides, methyl cy-anoformate, aryl cyanates, sulfonyl cyanides, and others to give 1,2,3-triazoles (Scheme17). These reactions can formally be regarded as 1,3-dipolar cycloadditions.[3] If an excessof diazoalkane is used the triazoles may be N-alkylated; generally mixtures of the threepossible N-alkyl-1,2,3-triazoles are obtained. For example, cyanogen bromide reacts withexcess diazomethane to give a mixture of the 4-bromo-2-methyl-2H-1,2,3-triazole (21%), 5-bromo-1-methyl-1H-1,2,3-triazole (6.4%), and 4-bromo-1-methyl-1H-1,2,3-triazole (5.5%).[44]
Tosyl cyanide reacts with 1 equivalent of diazomethane to afford 4-tosyl-1H-1,2,3-triazole(37, R1 = H; X = Ts) in 68% yield. With excess diazomethane it gives a mixture (95%) of thethree isomeric N-monomethylated triazoles 38 (R1 = H; X = Ts).[45] Similarly, 4-oxo-4H-1-benzopyran-2-carbonitriles react with diazomethane to yield mixtures of three isomericN-methyl-1,2,3-triazoles.[46]
426 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 17 Reaction of Activated Nitriles with Excess Diazoalkanes[44,45]
37
N
NN
X
R1
N
NN
X
R1
H
38
R1CHN2XCN
R1
R1CHN2
The importance of the nature of electron-withdrawing groups in nitriles with respect totheir reactivity toward diazomethane is demonstrated by the relative yields of N-methyl-triazoles 39–41 given in Table 1.[47] For example, 1-methyl-1H-imidazole-4,5-dicarbonitrilereacts with diazomethane only at the 5-cyano group.
Table 1 Examples of N-Methyltriazoles Obtained by Reaction of Diazomethanewith Activated Nitriles[47]
R1CN + CH2N2
N
NNMe
R1
+N
NN +
N
NN
R1
R1
4039 41
Me Me
R1 Ratio Ref
39 40 41
CCl3 88.6 9.8 1.6 [47]
CO2Et 23.6 74.8 1.6 [47]
Bz 62.2 34.5 3.3 [47]
O
O
91.5 3.1 5.4 [47]
N
NMe
NC
55.7 42.2 2.1 [47]
Diazomethane also undergoes addition to the C”N bond of chloro(fluoroimino)acetoni-trile (42) to yield triazole 43 (Scheme 18). Two equivalents of diazomethane are consumedin this reaction; the insertion of a methylene group is observed in the final product.[48]
Scheme 18 Reaction of Diazomethane withChloro(fluoroimino)acetonitrile[48]
N
NH
N
42
NF
Cl CN
NFCl
43
19.5%
CH2N2 (2 equiv)
Et2O, −78 oC
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 427
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bReaction of Activated Nitriles with Diazomethane; General Procedure:[47]
CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhala-tion.
A soln of CH2N2 (0.13 mol) in Et2O (600 mL) was added to the nitrile (0.02 mol). The reac-tion was monitored by TLC until the nitrile was completely consumed (several days). Thesolvent was evaporated and the residue was submitted to column chromatography (silicagel). The isomeric N-methyltriazoles were separated using appropriate eluents.
13.13.1.1.2.1.1.1 Variation 1:From Diazoalkanes and Aryl Cyanates
Aryl cyanates 44 react with diazoalkanes in a 2:1 proportion to yield the aryl 4-(aryloxy)-1H-1,2,3-triazole-1-carboximidates 45 (44–83%), which after hydrolysis give the corre-sponding N-unsubstituted triazoles 46 (Scheme 19).[49]
Scheme 19 Reaction of Aryl Cyanates with Diazoalkanes[49]
44
Ar1OCNN
NH
N
Ar1O
R1
N
NN
Ar1O
R1
HN OAr1
45
N
NH
N
Ar1O
R1
46
H2O
Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4; R1 = H, CO2Et
R1CHN2 Ar1OCN
13.13.1.1.2.1.1.2 Variation 2:From Diazoalkanes and Unactivated Nitriles
Unactivated nitriles generally do not react with diazomethane or other diazoalkanes,however, reaction can occur in the presence of a catalyst. Aluminum trichloride, triethyl-aluminum, and other aluminum complexes can be used as catalysts in the reaction of di-azomethane with benzonitrile.[50] Aryldiazomethanes also react with benzonitriles in thepresence of potassium tert-butoxide (molar ratio 1:1:1), in toluene, to give 4,5-diaryl-1H-1,2,3-triazoles, mostly in good to satisfactory yields (26–75%).[51] A plausible mechanismfor this reaction is shown in Scheme 20. The reaction can be carried out at room temper-ature or in refluxing toluene.
428 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 20 Synthesis of 4,5-Diaryl-1H-1,2,3-triazoles by Reaction of Aryldiazomethaneswith Benzonitriles in the Presence of Potassium tert-Butoxide[51]
Ar1CN + Ar2CHN2
N
NNAr1
t-BuOK
N
NH
N
Ar2
Ar1
47
H3O+N
NN
Ar2
Ar1− K+
Ar2
H
Ar1 Ar2 Conditions Yield (%) Ref
Ph Ph rt, 24 h 69 [51]
Ph Ph 110 8C, 2 h 75 [51]
4-ClC6H4 4-ClC6H4 110 8C, 2 h 70 [51]
4-ClC6H4 Ph 110 8C, 2 h 44 [51]
4-BrC6H4 Ph rt, 24 h 66 [51]
4-Tol Ph 110 8C, 2 h 26 [51]
13.13.1.1.2.1.1.3 Variation 3:From [Diazo(trimethylsilyl)methyl]lithium and Nitriles
[Diazo(trimethylsilyl)methyl]lithium (48) [generated in situ from the reaction of diazo(tri-methylsilyl)methane and butyllithium] reacts smoothly with nitriles to give 4-substituted5-(trimethylsilyl)-1,2,3-triazoles 49 in excellent yields (Scheme 21).[52,53] Various nitriles,including aromatic, heteroaromatic, and aliphatic nitriles, react efficiently with 48 togive 4-(trimethylsilyl)triazoles 49. Since treatment of diazo(trimethylsilyl)methane withbutyllithium followed by protonation gives 4,5-bis(trimethylsilyl)-1H-1,2,3-triazole,[54]
the generation of 48 needs to be carefully controlled.
Scheme 21 Reaction of Nitriles with [Diazo(trimethylsilyl)methyl]lithium[52,53]
R1CNEt2O, 0 oC, 3 h N
NH
N
TMS
R1
48
R1 = Pr, t-Bu, Bn, 3,7-dimethylocta-2,6-dienyl, Ph, 1-naphthyl, 2-pyridyl, 1-isoquinolyl, SEt, OPh, PO(OEt)2, TMS
+44−96%
TMS
N2
Li
49
Triazoles 49; General Procedure:[52]
15% BuLi in hexane (0.76 mL, 1.2 mmol) was added dropwise to a soln of TMSCHN2
(0.55 mL, 1.2 mmol) in Et2O (10 mL) at 0 8C under argon and the mixture was stirred for20 min at 0 8C. To the resulting soln was added dropwise a soln of a nitrile (1 mmol) inEt2O (3 mL) at 0 8C, then the mixture was stirred at 0 8C for 3 h. The mixture was treatedwith sat. aq NH4Cl and extracted with Et2O. The Et2O extracts were washed with H2O anddried (MgSO4). Concentration of the solvent gave a residue, which was purified by prepar-ative layer chromatography to give the triazole.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 429
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.2.1.2 Method 2:
From Diazoalkanes and Imines, Oximes, or Diarylazines
The 1,3-dipolar cycloaddition of diazoalkanes to C=N bonds is a general method for thesynthesis of 4,5-dihydro-1H-1,2,3-triazoles and 1H-1,2,3-triazoles (Scheme 22).[4] It is an es-pecially useful method for the regioselective preparation of 1H-1,2,3-triazoles with bulkysubstituents in positions 1 and 5. Imines are the most versatile C=N system to be used inthis method, but oximes and diarylazines can also be used.
Scheme 22 Addition of Diazoalkanes to Imines[55,56]
NR3
R2
R1
50
+ R4CHN2
N
NN
R4
R3
R2
R1
51
13.13.1.1.2.1.2.1 Variation 1:From Diazoalkanes and Imines
4,5-Dihydro-1H-1,2,3-triazoles 51 are the expected products from the cycloaddition reac-tion of imines 50 with diazoalkanes but in some cases they spontaneously aromatize tothe corresponding triazoles. When the 4,5-dihydro-1H-1,2,3-triazoles are the isolatedproducts they can be converted into triazoles by a large number of alternative procedures(see Section 13.13.1.3).
The addition of diazoalkanes (especially diazomethane) to imines, to give 4,5-dihy-dro-1H-1,2,3-triazoles 51, is very well studied.[4] In general it is favored by the presence ofelectron-withdrawing substituents in the imine, especially on an N-aryl moiety.[55,56]
Though kinetic investigations of this reaction show that it follows essentially a concertedprocess and is not generally dependent on solvent polarity, a sizable increase in rate isnoticed in the presence of protic solvents such as water or alcohols.[57] For example, whilereaction of diazomethane with N-benzylideneaniline (52, Ar1 = Ar2 = Ph) does not occur indry ether, it does occur in aqueous dioxane giving the 4,5-dihydro-1H-1,2,3-triazole 53(Ar1 = Ar2 = Ph) in 53% after eight days (Scheme 23).[55] This solvent system can be success-fully used for the preparation of 5-hetaryl-substituted 4,5-dihydro-1H-1,2,3-triazoles oftype 53 (Ar1 = 2- or 3-pyridyl, 2-quinolyl).[58,59] Triethylaluminum and other aluminumcomplexes have been used as catalysts in the reaction of diazomethane with imines.[50]
Scheme 23 Addition of Diazomethane to Diarylimines[58]
N
Ar1
52
+ CH2N2
N
NN
53
dioxane, H2O (cat.)
rt, 2−8 d
Ar1
Ar2
Ar2
Diazomethane undergoes addition to hexafluoroacetone imines 54 to give 4,5-dihydro-1H-1,2,3-triazoles 55 as the sole product or to give mixtures of 4,5-dihydro-1H-1,2,3-tria-zoles 55 and 56 (the latter produced as a result of the addition of diazomethane to theC=C bond) (Scheme 24).[60]
430 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 24 Addition of Diazomethane to Hexafluoroacetone Imines[60]
54
+ CH2N2
N
NNEt2O, rt
R2
R1
N
F3C
F3C
R1
R2
N
NN
N
N
R1
R2
+
55 56
F3C F3C
F3C F3C
R1 R2 Yield (%) Ref
55 56
Me Me 91 – [60]
Ph H 88 – [60]
Me H 30 32 [60]
iPr H 42 51 [60]
Diazomethanes of the types 57, 58, and 59 react with formimidamides 60 to give directlythe corresponding triazoles 61 in 11–62% yields (Scheme 25).[61]
Scheme 25 Addition of Substituted Diazomethanes to Formimidamides[61]
R1 = Me, Et, t-Bu
N
NN
R1O2C N2
N2
(R1O)2P N2
57
58
59
R1 = Me, t-Bu, Ph
R1 = Me, Et
11−62%
, MeCN, 81 oC, 24 hNBut
Me2NX
But
61
60R1
O
O
13.13.1.1.2.1.2.2 Variation 2:From Diazoalkanes and Oximes
Diazomethane undergoes addition to oximes to give 4,5-dihydro-1H-1,2,3-triazoles. The O-methyl oxime 62 reacts with diazomethane to yield the unstable 4,5-dihydro-1H-1,2,3-tri-azole 63 (87%) that on treatment with piperidine gives the triazole 64 in 50% yield(Scheme 26).[62]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 431
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 26 Reaction of Diazomethane with Dimesylmethanone O-Methyloxime[62]
N
Ms
Ms
62
+ CH2N2
N
NN
Ms
Ms
OMe
OMe
63
dioxane, EtOAc
0 oC, 30 min
87%
N
NN
OMe
64
Ms
piperidine, dioxane, EtOAc
−10 to 50 oC, 3 h
50%
13.13.1.1.2.1.2.3 Variation 3:From Diazoalkanes and Diarylazines
Aromatic aldehyde azines 65 react with aryldiazomethanes in the presence of potassiumtert-butoxide to give N-unsubstituted 4,5-diaryl-1H-1,2,3-triazoles 66 (Scheme 27).[51] Thescope of this method has yet to be demonstrated since only two symmetrical triazoles66 are prepared by this way. The mechanism of this reaction seems to involve one 1,3-di-polar cycloaddition followed by base elimination of an aromatic imide anion. However itshould be noted that even in the absence of the aryldiazomethanes, the aromatic alde-hyde azines (DMSO, rt) in the presence of potassium tert-butoxide (1 equiv), give thesame 4,5-diaryl-1H-1,2,3-triazoles, although in much lower yields.[51]
Scheme 27 Reaction of Aromatic Aldehyde Azines with Aryldiazomethanes in the Presenceof Potassium tert-Butoxide[51]
65
+ Ar1CHN2
DMSO, rt, 24 h
N
NNH
N Ar1
Ar1
N
NH
N
Ar1
Ar1
N
N
Ar1CH
CHAr1
t-BuOKAr1
H
N
NN
N Ar1
Ar1
H
Ar1
H
66 Ar1 = Ph 92%
Ar1 = 4-ClC6H4 38%
13.13.1.1.2.1.3 Method 3:From Diazoalkanes and Heterocumulenes
The reaction of diazoalkanes (or their organometallic derivatives) with heterocumulenesis a versatile method for the synthesis of 1H-1,2,3-triazoles. The reactions with keten-imines, carbodiimides, isocyanates, and isothiocyanates are performed under very mildconditions and generally they give the desired triazoles in moderate to excellent yields.
432 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.2.1.3.1 Variation 1:
From Diazoalkanes and Ketenimines
Diazomethane reacts with ketenimines 67 (rt, 4 d) to give triazoles of type 68 in moderateyields (Scheme 28).[63,64] Other diazoalkanes fail to react with ketenimines 67 to give thecorresponding 1,2,3-triazoles.[64]
Scheme 28 Reaction of Ketenimines with Diazomethane[63,64]
Et2O
rt, 4 d• NAr1
Ph
Ph
67
N
NN
Ar1
Ph
Ph31−43%
N
NN
Ar1
Ph
Ph
68
Ar1 = Ph, 4-Tol, 4-ClC6H4, 4-BrC6H4
+ CH2N2
Better yields of triazoles are obtained if [diazo(trimethylsilyl)methyl]lithium (48) is used(Scheme 29). For example, alkyl and aryl ketenimines 69, (R1 = R2 = X = alkyl, aryl) reactsmoothly with 48 [prepared from diazo(trimethylsilyl)methane and butyllithium] to give4-(trimethylsilyl)-1,2,3-triazoles 71 in good yields.[65] Since desilylation of 71 is readilyachieved in almost quantitative yields (10% aq KOH/MeOH, reflux, 6 h),[65] reagent 48 canbe used, with better results, as a diazomethane equivalent.
The reaction of 48 with ketenimines bearing electron-withdrawing groups (69,X = EWG) also gives 1,2,3-triazoles but in some cases only pyrazoles are obtained: it cangive either 1H-1,2,3-triazoles 71 or pyrazoles 72 as the sole product or mixtures of thesecompounds (Scheme 29).[66] The nature and the yields of the products change with the sol-vent used in the reaction. The betaines 70 are likely to be intermediates in these reac-tions: the triazoles are formed by the attack of the nitrogen anion on the diazonium nitro-gen.[66]
Scheme 29 Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium[65,66]
Et2O, 0 oC, 2 h
NZ
N
R2HN
R1
72
N2
TMS
Li
• NR2
R1
X
+
48 69
X
R1 NR2
N2LiTMS
+−
TMS
N
NN
TMS
71
R2
X
R1
X = alkyl, aryl, EWG
X = EWG
Z = X, H
70
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 433
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bR1 X R2 Solvent Yield (%) Ref
71 72
Ph Ph 4-Tol Et2O 74 [65]
Ph Ph Bu Et2O 67 [65]
Me Me 4-Tol Et2O 82 [65]
Et Bu Bu Et2O 82 [65]
Me PO(OEt)2 Et Et2O 73a [66]
Me PO(OEt)2 Ph Et2O 68 2a [66]
Me Ac Ph Et2O 76 [66]
Me Ac Ph THF 58 [66]
Me Ac Ph hexane 46 14b [66]
Me CN Et Et2O 43 [66]
a Z = PO(OEt)2.b Z = H.
Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium;General Procedure:[65]
To 1.87 M TMSCHN2 in hexane (0.64 mL, 1.2 mmol) in Et2O (10 mL) was added, dropwise15% BuLi in hexane (0.76 mL, 1.2 mmol) at 0 8C under argon. The mixture was stirred atthis temperature for 20 min. A soln of an alkyl or aryl ketenimine (1 mmol) in Et2O(2 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h. After addi-tion of cold H2O, the mixture was extracted with benzene (CAUTION: carcinogen). The or-ganic layer was washed with H2O, dried (MgSO4), and concentrated in vacuo. The residuewas purified by column chromatography (silica gel) to give triazoles 71.
13.13.1.1.2.1.3.2 Variation 2:From Diazoalkanes and Carbodiimides
Carbodiimides 73 react with diazoalkanes to give 1H-1,2,3-triazoles 74 (Scheme 30). Forexample, reaction of diazomethane with di(1- or 2-naphthyl)carbodiimides[67] or withbis(4-X-phenyl)carbodiimides (X = H, NMe2, OMe, Me, Cl, Br, Ac) gives triazoles 74 (R1 = H)in low to moderate yields.[63,68,69]
Scheme 30 Reaction of Carbodiimides with Diazoalkanes[63,67–69]
• NAr1Ar1NN
NNAr1N
R1
Ar1
Et2O, rt, 4 d N
NNAr1HN
R1
Ar1
7473
+ R1CHN2
Organometallic diazomethanes also react with carbodiimides to form 1,2,3-triazoles, forexample diazo(trimethylsilyl)methane and diazobis(trimethylstannyl)methane give, re-spectively, compounds 75 (19%) and 76 (96%) by reaction with 73 (Ar1 = 4-Tol) (Scheme31).[68]
434 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 31 Reaction of Organometallic Diazoalkanes with Carbodiimides[68]
N
NNAr1HN
TMS
75
73
Et2O
35 oC, 2 h
N
NNN
Me3Sn
76
Ar1
Me3Sn
TMSCHN2
(Me3Sn)2CN2
Ar1
Ar1
Ar1N • NAr1
19%
96%
Ar1 = 4-Tol
Reaction of Carbodiimides with Diazomethane; General Procedure:[63]
CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhalation.
A freshly prepared ethereal soln of CH2N2 (12 mmol) was added to the carbodiimide(10 mmol) dissolved in a sufficient quantity of Et2O. The mixture was allowed to stand atrt for 4 d. The separated crystals were collected by filtration and washed with Et2O. Thetriazoles 74 were then recrystallized (MeOH or aq acetone).
13.13.1.1.2.1.3.3 Variation 3:From Diazoalkanes and Isocyanates
Alkyl and aryl isocyanates react with [diazo(trimethylsilyl)methyl]lithium (48) to give 1-substituted 1H-1,2,3-triazol-5-ols 77 in good yields (Scheme 32).[70] Experimental data indi-cate that these reactions proceed by a stepwise process, not by a concerted 1,3-dipolar cy-cloaddition process.[70]
Scheme 32 Reaction of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium[70]
N
NNLiO
TMS
77
48
N2
TMS
Li
+ R1NCOEt2O
R1N
O−
LiN2TMS
+
R1
N
NNHO
R1
H2O
− TMSOH
R1 Conditions Yield (%) mp (8C) Ref
Bu Et2O, –78 8C, 1,5 h; rt, 3.5 h 63 132–133 [70]
t-Bu Et2O, 0 8C, 1 h; reflux, 6h 53 126–131 (dec) [70]
Cy Et2O, 0 8C, 1 h; rt, 1.7 h 71 148 [70]
Ph Et2O, 0 8C, 2 h 79 113–115 (dec) [70]
4-ClC6H4 Et2O, 0 8C, 2 h 83 111 (dec) [70]
1-naphthyl Et2O, 0 8C, 1 h 83 125 (dec) [70]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 435
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bBenzoyl isocyanate reacts with ethyl diazoacetate, in refluxing xylene, to give ethyl 1-ben-zoyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate in 60% yield (Scheme 33).[71]
Scheme 33 Reaction of Benzoyl Isocyanate with Ethyl Diazoacetate[71]
xylene, reflux N
NNHO
BzNCO + EtO2CCHN2
Bz
EtO2C
60%
1-(4-Chlorophenyl)-1H-1,2,3-triazole (77, R1 = 4-ClC6H4); Typical Procedure for the Reac-tion of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium:[70]
To 2 M TMSCHN2 in hexane (0.6 mL, 1.2 mmol) in Et2O (10 mL) was added dropwise, 15%BuLi in hexane (0.76 mL, 1.2 mmol) at 0 8C under argon. The mixture was stirred at thistemperature for 20 min. A soln of 4-chlorophenyl isocyanate (154 mg, 1 mmol) in Et2O(3 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h and ice wa-ter was then added. The aqueous layer was separated and the organic phase was extractedwith H2O. The combined aqueous layer was acidified with 2 M HCl. The resulting whiteprecipitates were collected by filtration, dried in vacuo, and purified by column chroma-tography (silica gel) to give 77 (R1 = 4-ClC6H4); yield: 162 mg (83%).
13.13.1.1.2.1.3.4 Variation 4:From Diazoalkanes and Isothiocyanates
Treatment of isothiocyanates with [diazo(trimethylsilyl)methyl]lithium (48) in tetrahy-drofuran, followed by quenching with alkyl halides, gives 1-substituted 5-(alkylsulfanyl)-4-(trimethylsilyl)-1H-1,2,3-triazoles 78 in excellent yields (Scheme 34).[72] A dramatic sol-vent effect is observed in this reaction: changing tetrahydrofuran for diethyl ether leadsto the exclusive formation of 1,3,4-thiadiazol-2-amines in good yields.[73] This is in con-trast to the results observed with isocyanates (Scheme 32). Removal of the trimethylsilylgroup from 78 is readily carried out with 10% aqueous potassium hydroxide in boilingmethanol to give triazoles 79 in almost quantitative yields.[72]
Scheme 34 Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium[72]
N
NNLi+ −S
TMS
79
48
N2
TMS
Li
+ R1NCSTHF
R1N
S−
LiN2
TMS+
R1
N
NNR2S
R1
OH−
78
N
NNR2S
R1
TMS
R2X
436 Science of Synthesis 13.13 1,2,3-Triazoles
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bR1 R2X Yield (%) Ref
78 79
Ph MeI 98 94 [72]
Ph BnBr 99 97 [72]
Me MeI 96 100 [72]
Me BnBr 90 98 [72]
Bu BnBr 97 95 [72]
Cy BnBr 98 96 [72]
Bn BnBr 91 99 [72]
CH2=CHCH2 BnBr 91 83 [72]
Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium;General Procedure:[72]
To a soln of 2 M TMSCHN2 in hexane (0.6 mL, 1.2 mmol) in THF (10 mL) was added drop-wise 15% BuLi in hexane (0.76 mL, 1.2 mmol) at –78 8C under argon. The mixture wasstirred at this temperature for 20 min. A soln of the isothiocyanate (1 mmol) in THF(3 mL) was then added dropwise at –78 8C. After 1 h at –78 8C, the alkyl halide (1.2 mmol)was added and the mixture was stirred at –78 8C for 1 h, then at 0 8C for 2 h. After additionof ice water, the mixture was extracted with benzene (CAUTION: carcinogen). The organiclayer was washed with H2O, dried (MgSO4), and concentrated in vacuo. The residue waspurified by column chromatography (silica gel) to give triazoles 78.
13.13.1.1.2.1.4 Method 4:From N-Alkyl-N-nitrosoamines and Nitriles
Lithium salts of N-alkyl-N-nitrosoamines react with aryl cyanides to form triazoles 80 in40–70% yield (Scheme 35).[74] The main limitation of this method is the fact that enolizablenitriles cannot be used.
Scheme 35 Reaction of Lithium Salts of N-Alkyl-N-nitrosoamines withAryl Cyanides[74]
80
+THF, −78 oC, 10 h N
NNR2
R1
Ar1CN NNO
Li+R1 40−72%
Ar1
Ar1 = Ph, 4-Tol, 2-naphthyl; R1 = Me, iPr, t-Bu; R2 = H; R1,R2 = (CH2)3
R2−
1-Methyl-4-phenyl-1H-1,2,3-triazole (80, R1 = Me; R2 = H; Ar1 = Ph); Typical Procedure:[74]
CAUTION: N-Methyl-N-nitrosomethylamine (N,N-dimethylnitrosamine) is a probable humancarcinogen and an eye and skin irritant. It is hepatotoxic and an exp. carcinogen and teratogen.All operations should be performed in a well-ventilated fume hood using appropriate safety pre-cautions and procedures.
Pure N-methyl-N-nitrosomethylamine (1.62 mL, 22 mmol) was added with stirring to asoln of LDA (23 mmol) in anhyd THF (70 mL) [from iPr2NH (3.22 mL) and 1.6 M BuLi in hex-ane (14.2 mL)] at –78 8C and after 10 min the mixture was treated with PhCN (1.03 mL,10 mmol). The mixture was maintained at the temperature of dry ice for 10 h and the mix-ture was treated with a soln of glacial AcOH (1.32 mL, 23 mmol) in THF (5 mL). Working up
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 437
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bwith CH2Cl2 afforded a crystalline crude product that was recrystallized (CCl4); yield:1.15 g (72%); mp 122 8C.
13.13.1.1.3 By Formation of Two N-C Bonds
13.13.1.1.3.1 Fragments N-N-N and C-C
The most important and general approach to the synthesis of the 1,2,3-triazole ring sys-tem involves azides. A wide variety of azides (organic or inorganic) can be used: alkyl,aryl, hetaryl, acyl, alkoxycarbonyl and sulfonyl azides, azidotrimethylsilane, hydrazoicacid, sodium azide, etc. All are suitable reagents for triazole synthesis.
Azides react with various types of compounds to yield 1,2,3-triazoles or their imme-diate precursors. The most used are: (i) compounds with C”C bonds (here referred to asalkynes, irrespectively of other functional groups), (ii) compounds with C=C bonds (herereferred to as alkenes, and including allenes, enamines, enol ethers, etc.), and (iii) activat-ed methylene compounds.
In spite of the great usefulness of the azides in the triazole synthesis, if the reactionconditions (especially the temperature) are not well controlled, the products obtainedmay be not the expected triazoles. This is because of the thermal instability of the azidesand of some of the intermediates (dihydrotriazoles) formed during the triazole synthe-sis.[75] It is very important to always consider that most organic azides undergo thermalor photochemical decomposition to nitrenes. The decomposition temperature is depen-dent on the azide type (Table 2) and some azides, especially cyanogen azide and the loweralkyl azides, are unpredictably explosive. When the decomposition is carried out in thepresence of an alkene the corresponding aziridine is usually obtained.[75]
Table 2 Decomposition Temperature of Azides[76]
Azide Type Decomposition Temp (8C) Ref
alkyl azides 180–200 [76]
aryl azides 140–170 [76]
sulfonyl azides 120–150 [76]
alkoxycarbonyl azides 100–130 [76]
acyl azides 25–80 [76]
13.13.1.1.3.1.1 Addition of Azides to Alkynes
The thermal 1,3-dipolar cycloaddition of azides to alkynes is often the method of choicefor the synthesis of 1,2,3-triazoles since it gives directly the desired product. However,when unsymmetrical alkynes are used, mixtures of the two possible regioisomers areusually obtained. In general, addition to unsymmetrical alkynes tends to give mainly theisomers with the electron-withdrawing groups at the 4-position and the electron-releas-ing groups at 5-position.[3] The low regioselectivity of these reactions is the major disad-vantage of this method as a preparative procedure. The accepted mechanism for these re-actions is a concerted 1,3-dipolar cycloaddition. Kinetic data and the regio- and stereose-lectivity of these reactions strongly support this mechanism. However, the reactions in-volving ionic azides (e.g., sodium azide) follow a nonconcerted ionic mechanism. Thesemechanisms have been discussed and documented in reviews.[76,77]
N-Unsubstituted 1,2,3-triazoles are prepared by the direct addition of hydrazoic acidor an azide ion to alkynes but it is often more convenient to obtain these compounds byremoval of a N-substituent from a 1H- or 2H-triazole.
438 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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b13.13.1.1.3.1.1.1 Method 1:
Addition of Hydrazoic Acid to Alkynes
Hydrazoic acid reacts with alkynes to give the corresponding N-unsubstituted triazoles 81(Scheme 36). This method was originally performed by Dimroth and Fester who preparedthe parent compound by heating an alcoholic solution of hydrazoic acid with an acetonesolution of acetylene at 100 8C for 70 hours.[78] With alk-1-ynes the reaction is generallycarried out in benzene in a closed vessel at temperatures ranging from 90 to 135 8C for30–48 hours.[79] The triazoles are obtained in low to moderate yields. Reactions involvingalkynes with electron-withdrawing or donating groups are faster and the yields are high-er.
Scheme 36 Addition of Hydrazoic Acid to Alkynes[44,79–83]
81
N
NH
NR1
R2
R2R1 + HN3
R1 R2 Yield (%) mp (8C) bp (8C)/Torr Ref
H Me 14 35–36 108–109/25 [79]
H Bu 56 – 103–105/1 [79]
H (CH2)5Me 63 27 120–122/2 [79]
H (CH2)9Me 29 59 148–149/0.6 [79]
H Ph 48 148 – [79,80]
H CHO 50 141–142 – [81]
H CO2H 71 222–224 – [44]
Ph CHO 90 186–188 – [82]
TMS CHO 83 171–183 – [83]
TMS Ac 88 159–160 – [83]
TMS CO-t-Bu 79 84–85 – [83]
TMS Bz 85 102 – [83]
4-Phenyl-1H-1,2,3-triazole (81, R1 = H; R2 = Ph):[79]
CAUTION: Hydrazoic acid is highly toxic and explosive. Adequate protection and shielding arenecessary during the preparation and handling of this reagent.
A combustion tube containing phenylacetylene (14.7 g, 0.144 mol) and a soln of HN3 inbenzene (50 mL of 14.2% HN3 in benzene, 0.165 mol) (CAUTION: carcinogen) was sealedand heated in a bath at 110–115 8C for 40 h. After cooling to rt almost the entire contentscrystallized. The solid was collected by filtration, washed with benzene, and recrystal-lized twice (benzene). Decolorizing charcoal was used during the first crystallization;yield: 10 g (48%); mp 148 8C.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 439
for references see p 587
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b13.13.1.1.3.1.1.2 Method 2:
Addition of the Azide Ion to Alkynes
The azide ion undergoes addition to alkynes to give triazoles 82 in low to moderate yields(Scheme 37). Better yields are obtained with alkynes bearing electron-withdrawinggroups. Almost quantitative yields (>98%) of 5-substituted 1H-1,2,3-triazole-4-carbalde-hydes are obtained from the reaction of alk-2-ynals with sodium azide in dimethyl sulfox-ide, at room temperature.[84] Generally the reaction is carried out in dimethyl sulfoxide ordimethylformamide; sodium azide[84–87] is frequently used as the azide ion source but lith-ium azide[88] and aluminum azide[89] have also been used. The mechanism of the reactionprobably involves the nucleophilic addition of the azide ion to the triple bond followed by1,5-dipolar cyclization of the resulting vinyl anion. Addition of sodium azide to 1-aryl-5-phenylpent-4-yne-1,3-diones in refluxing dimethylformamide gives the corresponding 4-(3-aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R1 = Ph; R2 = COCH2Bz, COCH2CO-4-Tol, 4-MeOC6H4COCH2CO) in good yields.[86]
Scheme 37 Addition of Sodium Azide to Alkynes[84–86]
R2R1 + NaN3DMSO N
NNR1
R2
−
+
−
82
N
NH
NR1
R2
−
H3O+
NN
NR2
R1
R1 R2 Yield (%) mp (8C) Ref
H H 11 – [85]
H Ph 40 148 [85]
Ph Ph 16 140 [85]
H CO2Me 49 145 [85]
CO2Me CO2Me 54 132 [85]
Ph CHO >98 – [84]
Bu CHO >98 – [84]
Ph COCH2Bz 72 87 [86]
Ph COCH2CO-4-Tol 72 122 [86]
Ph 4-MeOC6H4COCH2CO 60 79 [86]
The reaction of propynenitrile with aluminum azide (THF, reflux, 24 h) gives a mixture ofthe triazoles 83 (32%) and 84 (47%) (Scheme 38).[89] The formation of the tetrazole ring re-sults from the addition of an azide ion to the cyano group.
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bScheme 38 Addition of Aluminum Azide to Propynenitrile[89]
CNH + Al(N3)3
THF, reflux
24 h N
NH
NNC
84 47%
N
NH
N
HNN
N N+
83 32%
Addition of sodium azide to (arylethynyl)triphenylphosphonium halides 85 gives 4-aryl-5-triphenylphosphonio-1,2,3-triazolide ylides 86 in high yields (Scheme 39).[87] These ylidesare readily hydrolyzed in aqueous basic solution to give quantitatively triazoles 87 andtriphenylphosphine oxide.
Scheme 39 Addition of Sodium Azide to (Arylethynyl)triphenylphosphonium Halides[87]
PPh3 X−Ar1
NaN3, DMF
60 oC, 3 h N
NH
N
86
+
NN
N−
Ph3P
Ar1
+
Ar1
87
NaOH
EtOH/H2O (1:2)
reflux, 2 h
85
Ar1 = Ph 93%
Ar1 = 4-ClC6H4 94%
− Ph3PO
100%
Propargyl sulfonates 88 react with lithium azide/copper(I) chloride complex (THF/DMF,–60 8C) to give, after acidification, the 5-(1-azidoalkyl)-1H-1,2,3-triazoles 89 in low yields(4–24%); 50–70% of the starting material is recovered (Scheme 40).[88]
Scheme 40 Addition of Lithium Azide to Propargyl Sulfonates[88]
N
NH
N
R3
89
LiN3, CuCl
THF/DMF (1:1)
−60 oC, 10 h
88
MsO
R3
R1 R2
N3
R2R1
4−24%
R1 = t-Bu, Ph, 3-O2NC6H4; R2 = H, Ph; R3 = t-Bu, Ph
4-(3-Aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R1 = Ph; R2 = COCH2Bz,4-TolCOCH2CO, 4-MeOC6H4COCH2CO); General Procedure:[86]
CAUTION: Sodium azide can explode on heating and is highly toxic.
A soln of 1-aryl-5-phenylpent-4-yne-1,3-dione (4 mmol) in DMF (20 mL) was refluxed withNaN3 (4.6 mmol) for 3 h. The mixture was then poured into cold H2O (200 mL), acidifiedwith dil H2SO4, and the precipitated triazole 82 was collected by filtration, washed withH2O several times, dried, and recrystallized [benzene/petroleum ether (bp 60–80 8C)] asyellow needles.
13.13.1.1.3.1.1.3 Method 3:Addition of Alkyl, Aryl, or Hetaryl Azides to Alkynes
The addition of alkyl, aryl, and hetaryl azides to alkynes is the most popular method forthe synthesis of 1,2,3-triazoles. The number of publications related to this method is soimpressive that, although no substantial differences are found in the experimental proce-dures, for easier systematization of the information available, several variations of themethod will be presented according to the type of alkyne used. Once again, it should beemphasized that azides are dangerous compounds, especially alkyl azides which are
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 441
for references see p 587
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btreacherously explosive and should be treated with extreme caution. Wherever possiblethese compounds should only be handled as solutions.
13.13.1.1.3.1.1.3.1 Variation 1:Addition of Azides to Acetylene and to Symmetrically Substituted Alkynes
Azides undergo addition to acetylene and to symmetrically substituted alkynes 90 to giveonly one 1-substituted 1H-1,2,3-triazole 91, which simplifies the purification step(Scheme 41); this is a general method for the preparation of triazoles 91 and in some casesthe yields are excellent. Addition of phenyl azide,[78] arylmethyl azides[90–92] or other alkylazides[90] to acetylene yields the corresponding 4,5-unsubstituted triazoles 91 (R2 = H). Thismethod has also been used for the preparation of dendrimers containing various 1,2,3-tri-azole rings.[93] The addition of dimethyl acetylenedicarboxylate to per(6-azido-6-deoxy-2,3-di-O-methyl)cyclodextrins yields the corresponding per(4,5-dicarboxy-1,2,3-triazol-1-yl)derivatives.[94] 1,4-Diazidobuta-1,3-dienes react with cyclooctyne at room temperature togive the corresponding bis(triazolyl) derivatives in high yields (86–99%).[95] 1,2-, 1,3-, and1,4-Bis(azidomethyl)benzenes react with dimethyl, diethyl, and di-tert-butyl acetylenedi-carboxylates to afford the corresponding benzobis(triazoles) in good yields.[96] Other inter-esting bis(triazolyl) derivatives have been prepared by reacting dimethyl acetylenedicar-boxylate and bis-azides (produced from the reaction of sodium azide and bis-epoxides).[97]
Scheme 41 Addition of Azides to Symmetrically Substituted Alkynes[92,98–115]
R1N3 +N
NNR2
91
R2R2
R2
R1
90
R1 R2 Conditions Yield (%) Ref
Me Ph benzene, 60 8C, 2 months 30 [98]
CF2CHFCF3 Ph 180 8C, 18 h 88 [99]
(CF2)2CO2Me CO2Me 130 8C, 6 h 94 [99]
Ph CH2OH benzene, 80 8C, 12 h 73 [100]
Ph CH(OEt)2 EtOH, 100 8C, 28 h 82 [101]
Ph CO2Me EtOH, reflux, 20 h 92 [102]
(CH2)5Me CH(OEt)2 EtOH, 100 8C, 43 h 90 [101]
4-MeOC6H4 CO2Me benzene, reflux, 24 h 97 [103]
4-O2NC6H4 CO2Me benzene, reflux, 24 h 87 [103]
4-O2NC6H4 CO2Me benzene, reflux, 24 h 80 [104]
2-AcOC6H4 Bz toluene, reflux, 2–30 h 82 [92]
Bn CO2H acetone, rt to reflux, 1 h 93 [105]
1-naphthyl Bz benzene, reflux, 48 h 70 [106]
1-naphthyl CO2Me benzene, reflux, 5 h 95 [106]
1-naphthyl TMS CHCl3, reflux, 96 h 37 [106]
1-adamantyl CO2Me toluene, reflux, 24 h 77 [107]
1-adamantyl CH2OH toluene, reflux, 90 h 32 [107]
1-adamantyl Ph toluene, reflux, 500 h 17 [107]
442 Science of Synthesis 13.13 1,2,3-Triazoles
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bR1 R2 Conditions Yield (%) Ref
(E)-CPH=CHMe CO2Me rt 70 [108]
cyclohepta-2,4,6-trienyl CO2Me CCl4, reflux, 1 h 73 [109]
cyclohepta-2,4,6-trienyl Bz benzene, 100 8C, 2 h 58 [109]
CH2PO(OEt)2 CO2Me toluene, reflux, 30–40 h 92 [110]
CH2PO(OEt)2 Bz toluene, reflux, 30–40 h 85 [110]
OAcOAcO
AcO
OAc
CH2OH toluene/pyridine, reflux, 18 h 38 [111]
S
O
OO
Pri
CO2Me benzene, reflux, 6 h 84 [112]
N−O+
CO2Me toluene, 80 8C, 1.5 h 7 [113]
O O
Ph 80 8C, 120 h 51 [114]
O O
CH2OH 80 8C, 30 h 66 [114]
NH
CO2Et
EtO2CCO2Me benzene, rt, 12 h 95 [115]
13.13.1.1.3.1.1.3.2 Variation 2:Addition of Azides to Alk-1-ynes
Azides undergo addition to alk-1-ynes to give mixtures of 1,4- and 1,5-disubstituted 1H-1,2,3-triazoles (Scheme 42). The ratio of the two products is mainly dependent on thestructure of alkyne: when R2 is an electron-withdrawing group it goes preferentially toposition 4 (triazoles 93), however isomers 94 are predominant when R2 is an electron-re-leasing group. The mechanism and kinetics of the cycloaddition of phenyl azide to vari-ous 4-substituted phenylacetylenes has been reported.[116] Phenyl azide reacts regioselec-tively with trifluoromethyl-substituted alkynyl Æ-amino acids to give the 1,4-disubstitut-ed triazole.[117] It has been shown that cucurbituril substantially accelerates (ca. 105-fold)the reaction of azide-substituted ammonium ions with alkyne-derived ammonium ions.The reaction is regioselective, affording only the 1,4-disubstituted triazole derivatives.[118]
This method has been used for the preparation of oligo-1,2,3-triazoles and [n]rotax-
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 443
for references see p 587
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banes.[119,120] A catalytic effect is also observed for zinc chloride doped natural phosphatefor the cycloaddition of alkyl azides with alk-1-ynes.[121] With this catalyst a significant re-duction in the reaction time is observed but the yields and the 1,4-/1,5-substitution ratioof the triazole are not improved. The enzyme acetylcholinesterase, which plays a key rolein neurotransmitter hydrolysis in the central and peripheral nervous systems, has beenused as a catalyst for the reaction of a tacrine-substituted alkyl azide with a phenanthridi-nium-substituted terminal alkyne. The 1,5-disubstituted triazole is the predominant iso-mer.[122] A high-yielding and simple copper(I)-catalyzed reaction sequence leading exclu-sively to 1,4-disubstituted 1,2,3-triazoles has been described.[123] It involves the reactionof organic azides with alk-1-ynes in the presence of the catalyst (0.25–2 mol%) preparedin situ by reduction of copper sulfate with ascorbic acid and/or sodium ascorbate. The re-action proceeds to completion in 6 to 36 hours at room temperature in a variety of sol-vents, including aqueous tert-butyl alcohol or ethanol and, very importantly, water withno organic cosolvent. The use of microwave-induced 1,3-dipolar cycloaddition of organicazides to alk-1-ynes under solvent-free conditions is also another important develop-ment.[124,125] It allows a substantial decrease in reaction times, reduced pollution, lowcost, and simplicity in processing and handling. The addition of O-propargyl glycosidesand propargyloxy-calixarenes to a calixarene diazide leads to the formation of interesting1,2,3-triazole derivatives having glycosyl and calixarene moieties.[126]
Scheme 42 Addition of Azides to Alk-1-ynes[99,103,104,106–108,112,124,125,127–132]
R1N3 +N
NN
93
H R2
R2
R1
92
N
NNR2
94
R1
+
R1 R2 Conditions Yield (%) Ref
93 94
Ph Ph toluene, reflux, 17 h 43 52 [127]
Ph (CH2)3OH 100 8C, 15 h 63 31 [128]
Ph CO2Me rt, 12 d; 60 8C, 34 h 88 12 [103]
Bn Ph toluene, reflux, 17 h 39 55 [127]
Bn CONHBn microwave irradiation,55 8C, 30 min
65 22 [125]
(CH2)3Ph piperidino-carbonyl
microwave irradiation,55 8C, 30 min
65 22 [125]
CH2CO2Et Ph toluene, reflux, 48 h 41 36 [129]
1-adamantyl Ph toluene, reflux, 35 h 60 21 [107]
1-adamantyl 1-adamantyl toluene, reflux, 30 h 67 0 [107]
1-adamantyl CO2Me toluene, reflux, 11 h 84 0 [107]
CH2PO(OEt)2 Ph microwave irradiation,120 8C, 30 min
45 54 [124]
CH2PO(OEt)2 CH2OH microwave irradiation,100 8C, 30 min
30 69 [124]
CH2PO(OEt)2 CO2Et microwave irradiation,100 8C, 5 min
61 31 [124]
CF2CFHCF3 Ph steel bomb, 130 8C, 6 h 32 62 [99]
CF2CFHCF3 Bu steel bomb, 120 8C, 6 h 37 58 [99]
444 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bR1 R2 Conditions Yield (%) Ref
93 94
CF2CFHCF3 CO2Me steel bomb, 120 8C, 6 h 70 18 [99]
CF2CFHCF3 TMS steel bomb, 90 8C, 6 h 50 – [99]
CH2C(NO2)2Me CO2H CHCl3, rt, 3 d 89a [130]
CH=CH-t-Bu CO2Me rt 54 13 [108]
4-O2NC6H4 CO2Et benzene, reflux, 48 h 60 25 [104]
CH2CH2CO2Et Bz benzene, reflux, 22 h 48 30 [131]
Cy Bz benzene, reflux, 48 h 26 10 [131]
4-Tol Bz benzene, reflux, 26 h 60 11 [131]
1-naphthyl Bz benzene, reflux, 24 h 44 14 [131]
1-naphthyl CO2Et 100 8C, 8 h 71 12 [106]
S
O
OO
Pri
CO2Me benzene, reflux, 18 h 66 23 [112]
S
O
OO
Pri
TMSbenzene, reflux, 7 d
81 – [112]
S
O
OO
Pri
SO2Ph benzene, reflux, 16 h 72 5 [112]
NN
N
Ph toluene, reflux, 2 h 40 60 [132]
a Combined yield of 93 and 94.
The 1,3-dipolar cycloaddition of aryl azides to (trimethylsilyl)acetylene is regioselectiveand gives, after several days at 25 8C, almost quantitative yields of the 1-aryl-4-(trimethyl-silyl)-1,2,3-triazoles 96 (Scheme 43).[133] A study has shown that the rate of these cyclo-additions increases logarithmically with pressure.[134] For example, the reaction of 4-methoxyphenyl azide with 95 takes 55 days, at atmospheric pressure, to complete con-sumption of the azide. The same reaction is complete in 1.5 hours if it is conducted atroom temperature but under pressure (0.3 GPa). At pressures of about 1 GPa these reac-tions are almost instantaneous and quantitative.[134]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 445
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 43 Addition of Aryl Azides to (Trimethylsilyl)acetylene[133]
Ar1N3 +N
NN
96
TMSH
TMS
Ar1
95
sealed tube
25 oC
Ar1 Time (d) Yield (%) Ref
Ph 35 96 [133]
4-Tol 40 95 [133]
4-MeOC6H4 55 95 [133]
4-ClC6H4 25 95 [133]
4-O2NC6H4 20 95 [133]
4-NCC6H4 26 96 [133]
benzo[b]thien-2-yl 9 93 [133]
benzo[b]thien-3-yl 28 95 [133]
13.13.1.1.3.1.1.3.3 Variation 3:Addition of Azides to Unsymmetrical Disubstituted Alkynes
Azides add to unsymmetrical disubstituted alkynes to give mixtures of isomeric triazoles97 and 98 (Scheme 44). The relative proportions of the two products are strongly depen-dent on the nature of R2 and R3.
Scheme 44 Addition of Azides to Unsymmetrical Disubstituted Alkynes[103,124,135–137]
R1N3 +N
NN
97
R3R2
R2
R1
N
NNR2
98
R3
R1
+R3
R1 R2 R3 Conditions Yield (%) Ref
97 98
Ph CH2OH CO2Me toluene, 55 8C, 14 d 8 49 [135]
4-MeOC6H4 CH2OH CO2Me benzene, rt, 60 d 31 59 [136]
Ph Ph Bz benzene, 80 8C, 19 h 0 86 [103]
1-naphthyl Me CO2Me 100 8C, 8 h 9 72 [106]
CH2CO2-t-Bu CF3 PO(OiPr)2 Et2O, rt, 20 h 68 22 [137]
CH2PO(OEt)2 Me PO(OEt)2 100 8C, 60 h 73 23 [124]
CH2PO(OEt)2 Ph CO2Et 160 8C, 10 min 58 42 [124]
A recognition-mediated reaction between 4-(azidomethyl)benzo-15-crown-5 99 and theasymmetric alkyne 100 shows that the regioselectivity of the cycloaddition can be con-trolled. The mutual recognition between the ammonium cation and the crown etherleads to the formation of triazole 101 and its regioisomer in the ratio of 97:3 (Scheme45).[138]
446 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 45 Recognition-Mediated Reaction between Azides and UnsymmetricalDisubstituted Alkynes[138]
99
N
NN
101
O
H3N
But
+
+
CF3CO2−
O
O
O
O
O
N3
O
OO
OO
H3N
O
But
+
CF3CO2−
100
Azido sugars have been extensively used to prepare carbohydrate-derived 1,2,3-tria-zoles.[139] For example, the �-D-galactopyranosyl azide 102 reacts with alkyne 103 to yieldmixtures of the nucleoside triazole analogues 104/105 (30%/49%) (Scheme 46).[139] Analo-gously, the 5-azido-5-deoxy-Æ-D-xylofuranose 106 reacts with a range of alkynes to givemixtures of 5-(1H-1,2,3-triazol-1-yl)-Æ-D-xylofuranoses 107/108.[140,141] 2,3,5-Tri-O-benzoyl-�-D-ribofuranosyl azide reacts with methyl 4-hydroxybut-2-ynoate to yield a mixture ofthe two expected isomeric triazoles in 75% yield.[142]
Scheme 46 Addition of Azido Sugars to Alkynes[139–141]
102
N
NNF3C
105 49%
Ph
OAcO
AcOAcO
OAc
O
OAcAcO
AcO
OAc
N3+ Ph CF3
toluene
reflux, 14 h
N
NNPh
104 30%
F3C
OAcO
AcOAcO
OAc
+
103
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 447
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b108
+ R1 H
toluene
reflux
107
+O
N3
OH
OO
O
N
OH
OO
NN
R1
O
N
OH
OO
NN
R1
R1 = Ph, CH2OH, CO2Et
106
13.13.1.1.3.1.1.3.4 Variation 4:Using Polymer-Supported Methods
The use of polymer-supported methods to prepare carbohydrate-derived 1,2,3-triazoles isalready established. Addition of azidodeoxy carbohydrate derivatives to the monomethylether derivative of polyethylene glycol 109 (a soluble polymer-supported alkyne) yieldsthe polymer-supported triazoles 110/111 in a proportion of approximately 2:1 (Scheme47). Treatment of these polymers with sodium borohydride in hot ethanol gives the cor-responding “free” triazoles 112/113 in greater than 75% yield.[143] In a variation of this pro-cedure a succinate ester linkage (instead of an oxalyl ester) is also successfully used to pre-pare polymer-supported glycosyl triazoles. In this procedure, the “free” glycosyl triazolescan be obtained in high yields (>90%) and high purity by treatment of the polymer with anexcess of ammonia in methanol solution, followed by precipitation of the polymer withether and filtration.[141]
Scheme 47 Addition of Azido Sugars to Soluble Polymer-Supported Alkynes[143]
toluene
reflux, 12 h
O
N3
OH
OO
MeO
O
O
O
On
109
sugar N3+
N
NN
110sugar
O
OO
O
O
Me
n
N
NN
111sugar
nO
O
O
OOMe
N
NN
sugar
HON
NN
sugar
HO
112 113
+
NaBH4, EtOH
heat, 3 h
sugar N3 =
N3O
O
OO
O
N3
AcOAcO
OMeAcO
, ,
+
448 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bThe complementary method, i.e. reaction of a polymer-supported azido sugar with al-kynes, can also be used (Scheme 48). Azide 114 reacts with alkynes to give mixtures ofthe two regioisomers 115/116 in high yields (R1 = Ph; R2 = H, 50%; R1 = CO2Et; R2 = H,>95%; R1 = CH2OH; R2 = H, >95%). Treatment of these compounds with ammonia in meth-anol solution, followed by precipitation of the polymer with diethyl ether and filtrationgives the corresponding “free” triazoles 117/118.[141]
Scheme 48 Addition of Alkynes to Soluble Polymer-Supported Azido Sugars[141]
toluene
reflux, 2 d
114
+
n
NH3, MeOH
rt, 10 h O
N
OH
OO
NN
R2
R1
O
N
OH
OO
NN
R1
R2
+
117 118
O
N
O
OO
NN
R1
R2
O
O
O
OMe
nO
N
O
OO
NN
R2
R1
O
O
O
OMe
n O
N3
O
OO
O
O
O
OMe
R2R1
115 116
+
A solid-phase synthesis of functionalized 1,2,3-triazoles from the reaction of resin-boundazides 119 and terminal alkynes has been reported (Scheme 49).[144] The reaction withmethyl propynoate occurs in dimethylacetamide at 60 8C and, after cleavage in trifluoro-acetic acid, provides the free acids 120 (R2 = CO2Me), as single isomers, in moderate yields(17–27%). The reaction with phenylacetylene requires higher temperatures (120 8C) andprovides 1:1 mixtures (22–25%) of the possible regioisomers 120 (R2 = Ph) and 121(R2 = Ph) after trifluoroacetic acid cleavage.
Scheme 49 Solid-Phase Synthesis of 1H-1,2,3-Triazoles Using Resin-Bound Azides andTerminal Alkynes[144]
N
NN
120
H1. R2
R2
N
NNR2
121
+
R1 CO2H R1 CO2H
DMA, 60 or 120 oC, 3 d
2. TFA, CH2Cl2, rt, 18 h
O
O
N3
R1
R1 = H, Me, Et, (CH2)5Me; R2 = CO2Me, Ph
17−27%
119 1:1
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 449
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bA solid-phase, regioselective, copper(I)-catalyzed, 1,3-dipolar cycloaddition of terminal al-kynes to azides has been used to prepare peptido-1,2,3-triazoles.[145] Copper(I) salts areused as catalysts in the reaction of resin-bound terminal alkynes to primary, secondary,and tertiary alkyl azides, aryl azides, and an azido sugar at 25 8C, affording selectively 1,4-disubstituted 1H-1,2,3-triazoles with quantitative conversions and purities ranging from75 to 99%.[145]
13.13.1.1.3.1.1.3.5 Variation 5:Intramolecular 1,3-Dipolar Cycloadditions
The intramolecular 1,3-dipolar cycloaddition of an azido group onto a C”C bond givespolycyclic triazoles. Azides 122 and 124, for example, give triazoles 123 (52%) and 125(59%), respectively, when heated in refluxing toluene (Scheme 50).[146]
Scheme 50 Synthesis of 1,2,3-Triazoles via Intramolecular1,3-Dipolar Cycloadditions[146]
123
toluene, reflux, 36 h
N3
OH
N NN
OH
122
52%
125
toluene, reflux, 24 h
N3
OTBDMS
N NN
OTBDMS
124
HO HO
59%
Propargyl azides 127 undergo intramolecular cycloaddition reactions yielding N-unsub-stituted 1H-1,2,3-triazoles 130 (Scheme 51). The reaction must be carried out in nucleo-philic solvents, such as methanol or ethanol, or in the presence of nucleophiles such asazide ion, amines, or thiols, if not, then only polymeric triazole products are obtained.The mechanism of this transformation involves the rearrangement of the propargyl azideto allenyl azide 128 that gives by rapid ring closure the triazafulvene 129. This short-livedintermediate is trapped by nucleophiles to give triazoles 130 in good yields.[147,148] Sincepropargyl azides can be prepared from propargyl halides or propargyl tosylates 126(X = halogen, OTs) and sodium azide, various substituted 1,2,3-triazoles can be synthe-sized in good yields in one-pot procedure from these precursors without the necessity toisolate the potentially hazardous propargyl azides. In the presence of sodium hydroxidethe propargyl azides 127 undergo base-catalyzed (prototropic) rearrangement to allenylazides 131. The immediate cyclization of this intermediate leads to the triazafulvene132, which can be trapped by nucleophiles to give triazoles 133 in good yields (Scheme51).[148]
450 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 51 Synthesis of 1H-1,2,3-Triazoles from Propargyl Azides or Their Precursors[148]
128
N
NH
N
130
126
R2
X
R1
N3
127
R2
N3
R1
•R2
N3
R1
NuH
R2
Nu
R1
129
131
N
NH
N
133
•R2
R1
NuH
132
20−70 oC
NaOHN3
R1
R2
Nu
N
NN
R2
R1
N
NNR1
R2
R1 R2 X Conditions Nu Yield (%)of 130
Ref
Me H OTs NaN3, MeOH, H2O, 20–40 8C OMe 82 [148]
Ph H Br NaN3, MeOH, H2O, reflux OMe 87 [148]
H H Br 1. NaN3, dioxane, H2O, rt, 1 h S-iPr 31 [148]
2. iPrSH, 70 8C, 3 h
H H OTs 1. NaN3, dioxane, H2O, rt NH2 77 [148]
2. NH3, H2O, 50–60 8C
H MOM OSO2Ph 1. NaN3, MeOH, H2O, rt, 24 h OMe 88 [148]
2. MeOH, reflux, 6 h
H Ph OTs 1. NaN3, MeOH, H2O, 35 8C OMe 73 [148]
2. MeOH, reflux, 45 h
Depending on the reaction conditions, propargyl azides 127 can be selectively convertedinto triazoles 130 or 133. For example, azide 134 can produce triazole 135 or triazole 136depending only on the presence or absence of sodium hydroxide (Scheme 52).[148]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 451
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 52 Selective Synthesis of Isomeric 1H-1,2,3-Triazoles from Propargyl Azides[148]
N
NH
N
135
134
H2N
NH3, NaOH
NH3
62%
MeO
N
NH
N
136
H2N
MeO
75%
N3
MeO
The intramolecular 1,3-dipolar cycloaddition of an azide group with a C”C bond has beenused extensively for the synthesis of nonclassical polycyclic �-lactams.[149–154]
13.13.1.1.3.1.1.3.6 Variation 6:Addition of Azides to Alkoxyalkynes
Nitrophenyl azides 138 undergo cycloaddition reactions with 1-methoxyalk-1-ynes 137 atroom temperature to give 1H-1,2,3-triazoles 139 in low yields (R1 = Et; X = H, 22%) or thecorresponding ring-opened isomeric Æ-diazocarboximidates 140 (R1 = Me, 52%; R1 = Et,75%) (Scheme 53).[155] The reaction of ethoxyacetylene with 4-methxoyphenyl azide and4-nitrophenyl azide also gives the corresponding 1-aryl-5-ethoxy-1H-1,2,3-triazoles.[103]
Scheme 53 Addition of Aryl Azides to 1-Methoxyalk-1-ynes[155]
N
NNMeO
139
R1
OMeR1
N3
O2N
NO2
X
+
CHCl3, rt
3−10 d
NO2
O2N X
N
140
NO2
O2N X
MeO
R1 N2
138137
R1 = Me, Et; X = H, NO2
X = NO2
Similarly, 5-ethoxy-1H-1,2,3-triazoles 143 are obtained from the reaction of ethoxyacety-lene (141) with phenyl azide, substituted phenyl azides[156] and hetaryl azides[114] 142(Scheme 54). The best yield is obtained with phenyl azide (87%). With 2-nitrophenyl azide,and 4-nitrophenyl azide the yields are very low (6–12%).
452 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 54 Addition of Azides to Ethoxyacetylene[114,156]
N
NNEtO
143
OEtH + R1N36−87%
142141
R1 = aryl,
R1
O O
5-Ethoxy-1-(6-methyl-2-oxo-2H-pyran-4-yl)-1H-1,2,3-triazole (143, R1 = 6-methyl-2-oxo-2H-pyran-4-yl); Typical Procedure:[114]
A mixture of 4-azido-6-methyl-2H-pyran-2-one (0.77 g, 5.09 mmol), ethoxyacetylene(7.13 mmol, from a 50% soln in hexanes) and anhyd THF (18 mL) was left in a closed reac-tor for 7 d. The resulting precipitate of the product was collected by filtration and the fil-trate was left 7 d more at 30 8C to give a second crop. The combined precipitates werewashed with hexane to afford the pure product; yield: 24% (57% with respect to consumedazide 142); mp 159–161 8C.
13.13.1.1.3.1.1.4 Method 4:Addition of Ethyl Azidoformate and Cyanogen Azide to Alkynes
Ethyl azidoformate (144) undergoes addition to phenylacetylene to give 1,2,3-triazoles. Ifthe reaction is carried out at 50 8C (3 weeks) a mixture of the 1,4- and 1,5-disubstituted tri-azoles is obtained in a ratio of about 53:47 and an overall yield of 36% (Scheme 55).[157] Ifthe reaction is performed at 130 8C the two initially formed triazoles 145/146 isomerize toethyl 4-phenyl-2H-1,2,3-triazole-2-carboxylate (147) and this is the isolated triazole prod-uct (16%). Under these reaction conditions, 2-ethoxy-4(or 5)-phenyloxazole 148 (16%) isalso obtained.[157,158] The formation of this compound is due to the addition of (ethoxycar-bonyl)nitrene (generated by thermal decomposition of the azide) to phenylacetylene. Thereaction of ethyl azidoformate with dimethyl acetylenedicarboxylate and methyl propyn-oate also gives the corresponding triazoles (23 and 50% yield, respectively) and 2-ethoxy-oxazoles (3%).[158]
Scheme 55 Addition of Ethyl Azidoformate to Phenylacetylene[157,158]
N
NN
145
144
Ph
130 oC
50 oC
N
NN
147 16%
Ph
CO2Et
N
NN
146
CO2Et
Ph+
CO2Et
N
O
Ph
OEt+
148 or isomer 16%
HPh N3CO2Et+ 53:47
36%
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 453
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bEthyl azidoformate reacts with N,N-diethylprop-1-yn-1-amine (149, R1 = Me) in carbon tet-rachloride at room temperature to yield only triazole 150 (R1 = Me) (Scheme 56).[159] How-ever, if an excess of the ynamine is used, the initially formed triazole isomerizes to ethyl5-(diethylamino)-4-methyl-2H-1,2,3-triazole-2-carboxylate.[159] Ethyl azidoformate alsoadds to ynamines 149 (R1 = Ac, CO2Me) to give the corresponding triazoles 150 in goodyields.[160] Benzoyl azide also adds readily to ynamines.[159,161] Addition of ethyl azido-formate to ethoxyacetylene (no solvent, rt, 35 d) gives a mixture of three isomeric tri-azoles: ethyl 5-ethoxy-1H-1,2,3-triazole-1-carboxylate, ethyl 4-ethoxy-1H-1,2,3-triazole-1-carboxylate, and ethyl 4-ethoxy-2H-1,2,3-triazole-2-carboxylate in a ratio of 54.5:42:3.5(by NMR). Addition of 1,4-diazabicyclo[2.2.2]octane converts 1-ethoxycarbonyl isomersinto the 2-ethoxycarbonyl derivative.[159]
Scheme 56 Addition of Ethyl Azidoformate to Ynamines[159,160]
N
NN
150144
R1
CO2Et
R1Me2NN3CO2Et +
CCl4, rt, 20 min, or
THF, 65 oC, 3 h
Me2N
149
R1 = Me 100%
R1 = Ac 82%
R1 = CO2Me 70%
Cyanogen azide (N3CN) reacts with acetylene at 45 8C to give 77% of a 1:1 adduct that iscolorless below its melting point (33 8C) but is yellow in the melt or in solution. The ad-duct is a tautomeric mixture of 1H-1,2,3-triazole-1-carbonitrile and N-cyano-Æ-diazoethyl-idenimine (see Scheme 3).[20] The cyanogen azide adducts of prop-1-yne, but-2-yne, andhex-1-yne are also tautomeric mixtures of the corresponding triazoles and N-cyano-Æ-di-azoimines.[20] Cyanogen azide reacts with ethoxyacetylene[20] and N,N-diphenylacetyl-amine[162] to afford only the diazo derivatives, resulting from ring opening of the initiallyformed 1H-1,2,3-triazole-1-carbonitriles.
13.13.1.1.3.1.1.5 Method 5:Addition of Sulfonyl Azides to Alkynes
Sulfonyl azides 151 undergo addition to electron-rich alkynes (ynamines and alkoxyal-kynes 152) to yield 1-sulfonyl-1H-1,2,3-triazoles 153 (Scheme 57).[103,155,163–167] However,these compounds are very labile and, in solution, exist in equilibrium with open-chain di-azo tautomers. In many cases the diazo tautomer is the sole product. As an example, ad-dition of arenesulfonyl azides 151 (R1 = aryl) to ynamine 152 (R2 = Me; Y = NEt2) givesmainly 1,2,3-triazoles 153 while the reaction of this type of azides with ynamine 152(R2 = Ph; Y = NMe2) gives the Æ-diazoamidines 154 (Scheme 57).[166]
454 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 57 Addition of Sulfonyl Azides to Electron-Rich Alkynes[166]
N
NN
153151
R2
SO2R1
YR2
Y
152
R1SO2N3 +
N
SO2R1
Y
R2 N2
154
R1 R2 Y Yield (%) mp (8C) Ref
153 154
Ph Me NEt2 62 – 84–85 [166]
4-MeOC6H4 Me NEt2 58 – 54–56 [166]
4-Tol Me NEt2 65 – 49–52 [166]
4-AcHNC6H4 Me NEt2 78 – 131–132 [166]
4-O2NC6H4 Me NEt2 – 81 97–98 [166]
2,4-Cl2C6H3 Me NEt2 – 62 87–88 [166]
4-MeOC6H4 Ph NMe2 – 79 95–96 [166]
4-O2NC6H4 Ph NMe2 – 70 106–107 [166]
4-BrC6H4 Ph NMe2 – 65 102–103 [166]
3-O2NC6H4 Ph NMe2 – 78 104–105 [166]
2,5-Cl2C6H3 Ph NMe2 – 83 112–113 [166]
Tosyl azide reacts with 3-aminoprop-2-ynimidamides 155 to yield 1H-1,2,3-triazole-4-carboximidamide 156 in good yields (Scheme 58).[168]
Scheme 58 Addition of Tosyl Azide to 3-Aminoprop-2-ynimidamides[168]
NTs
NN
155
MeNMeNPh
NAr1Ar1HN
+ TsN3
CHCl3rt, 20 d
Ph
Ar1HN
Ar1N
N
NN
NTs
MeNPh
Ar1HN
Ar1
156 65−74%
Ar1 = Ph, 4-Tol
Reaction of Arenesulfonyl Azides 151 with Ynamines 152 (Y = Dialkylamino);General Procedure:[166]
A soln of the sulfonyl azide (0.01 mol) in THF (10 mL) was added to a soln of the ynamine(0.01 mol) in THF (5 mL) at –78 8C (cooled in dry ice/acetone bath) over 1 h. The soln wasthen allowed to warm to rt, filtered through anhyd alumina, and the solvent was removedby evaporation under reduced pressure. The resulting solid (or oil) was crystallized (Et2O/petroleum ether) to afford the appropriate triazole or Æ-diazoamidine.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 455
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.3.1.1.6 Method 6:
Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes
Azidotrimethylsilane can be successfully used as a safe synthetic equivalent of the highlyexplosive hydrazoic acid.[169,170] It undergoes addition to alkynes to give the corresponding2-(trimethylsilyl)-2H-1,2,3-triazoles 158 [via the 1-(trimethylsilyl)-1H-isomers 157] in goodyields (Scheme 59). For example, the reaction of azidotrimethylsilane with but-2-yne gives4,5-dimethyl-2-(trimethylsilyl)-2H-1,2,3-triazole (158, R1 = R2 = Me) in 78–87% yield. Sim-ilar results are obtained with other alkynes.[171] The trimethylsilyl group can be subse-quently replaced by a proton under very mild conditions.[171–173] In some cases, the N-un-substituted triazole 159 is the isolated product of the cycloaddition reaction.[174,175] A relat-ed silyl azide, (trimethylsilyl)methyl azide (TMSCH2N3), also reacts with alkynes to givequantitative yields of the corresponding 1-[(trimethylsilyl)methyl]-1H-1,2,3-triazoles.[176]
Scheme 59 Addition of Azidotrimethylsilane to Alkynes
N
NN
R2
TMSN3 +
120−150 oC
10−20 hR2R1
R1
TMS
N
NNTMS
R2
R1
H2O or
EtOH N
NH
N
R2
R1
159158 50−90%
157
100%
Azidotributylstannane (160) is another synthetic equivalent of hydrazoic acid. It gives 2-substituted triazoles 162 by reaction with mono- and disubstituted alkynes by a 1,3-dipo-lar cycloaddition to give initially the 1-substituted triazoles 161 (Scheme 60).[177–179]
Triazoles 162 can be converted into the N-unsubstituted derivatives by treatment with hy-drogen chloride. As an example, phenylacetylene reacts with 160 (neat, 140 8C, 12 h) togive triazole 162 (R1 = H; R2 = Ph) in 61% yield. On treatment with hydrogen chloride thiscompound is converted into triazole 163 (R1 = H; R2 = Ph) in 75% yield.
Scheme 60 Addition of Azidotributylstannane to Alkynes[177–179]
N
NN
R2
Bu3SnN3 +
140−180 oC
12−70 hR2R1
R1
N
NN
R2
R1
N
NH
N
R2
R1
163162
161
SnBu3
SnBu3
HCl, Et2O
160
456 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.3.1.1.7 Method 7:
Addition of Azides to Metal Acetylides
Alkyl,[180,427] aryl,[180,181,425,427] and sulfonyl[182–184] azides form triazole derivatives with lith-ium, magnesium, and sodium derivatives of terminal alkynes. The mildness of the condi-tions required for the additions (0 8C or below) suggests that the mechanism of the reac-tion may be different from that of normal azide addition to alkynes. A plausible mecha-nism (Scheme 61) involves nucleophilic attack of the acetylenic anion 164 on the termi-nal nitrogen of the azide, followed by 1,5-anionic cyclization to give the triazolyl anion165.[3] The total regioselectivity of the reaction supports this interpretation. The triazolylanion so formed can be protonated (to give 166), carboxylated (to give 167) or can reactwith more azide to give a linear triazene 168 which, in turn, can be hydrolyzed to the tri-azolamine 169.[182]
Scheme 61 Addition of Azides to Metal Acetylides[182]
N
NN
NN NR2
R1
165
H3O+
164
R1 +− −+
R2
−NN
NR1
R2
N
NNR1
166
R2
CO2N
NNR1
167
R2
HO2C
R2N3N
NNR1
168
R2
NN
R2N− H3O+ N
NNR1
169
R2
H2N
−
Sodium phenylacetylide reacts with tosyl azide (1 equiv) to yield, after acidification, tria-zole 170. If an excess of tosyl azide is used, the 4-azidotriazole 171 is obtained (Scheme62). In both cases the yields are very low.[184] A copper(I)-catalyzed reaction of resin-boundterminal alkynes (probably involving the corresponding copper acetylides) with a rangeof organic azides has been reported.[145]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 457
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 62 Addition of Sodium Phenylacetylide to Tosyl Azide[184]
N
NN
170
Ph
Ph Na+−
1. TsN3 (1 equiv)
2. H3O+
Ts
N
NN
171
Ph
Ts
N31. TsN3 (excess)
2. H3O+
16%
9%
4-Azido-5-phenyl-1-tosyl-1H-1,2,3-triazole (171); Typical Procedure:[184]
A slurry of sodium phenylacetylide [prepared from PhC”CH (0.05 mol) and Na (0.05 mol)]in dry Et2O (25 mL) was added slowly to a stirred soln of tosyl azide (19.7 g, 0.10 mol) in dryEt2O (50 mL) at a rate which maintained the solvent at reflux. As the mixture was stirredfor 24 h a brown solid separated (15.2 g, 58%), which corresponds to a sodium salt of anintermediate compound. Part of this compound (5.0 g) was treated with hot glacial AcOH(10 mL) and a light yellow solid was obtained upon cooling. Two recrystallizations (glacialAcOH) afforded pure triazole 171; yield: 0.52 g (16%); mp 170–171 8C (dec).
13.13.1.1.3.1.2 Addition of Azides to C=C Bonds
The thermal cycloaddition of azides to alkenes is an important route to 1H-1,2,3-triazoles.Azides undergo addition to a wide range of angle strained, unstrained, and unactivateddouble bonds; to electron-rich double bonds such as enamines, enamides, enol ethers,and ketene acetals; and to alkenes bearing one or two electron-withdrawing groups.[7] Inthese reactions, 4,5-dihydro-1H-1,2,3-triazoles (D2-1,2,3-triazolines) are the addition prod-ucts but they can be aromatized to the corresponding triazoles by elimination of suitablegroups or by oxidation. In some cases the dihydrotriazoles aromatize spontaneously. Un-like the case of alkynes, the reaction of azides with alkenes is highly regioselective. Be-cause of this, it may be convenient to prepare a triazole via the dihydrotriazole since atthe end the separation of regioisomers is not needed.
The synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of azides to alkenes re-quires patience. It may take weeks to months to obtain reasonable yields of the desiredcompound, especially if the C=C bond is not activated by electron-withdrawing or elec-tron-donating substituents. Increasing the reaction temperature is not always a solutionsince it is restricted by the thermal lability of most dihydrotriazoles (they readily extrudeN2).
13.13.1.1.3.1.2.1 Method 1:Addition of Sodium Azide to Activated Alkenes
Sodium azide undergoes addition to alkenes with strongly electron-withdrawing substitu-ents to give N-unsubstituted 1,2,3-triazoles in good yields (Scheme 63). The mechanismseems to involve the conjugate addition of the azide ion to the double bond, cyclizationof the resulting anion, and aromatization. The synthesis of triazoles 173 by the reactionof sodium azide with Æ-nitroacrylic ester 172 (Y = CO2Et) and Æ-nitro ketone 172 (Y = Bz)are examples of this method.[185] Other nitroalkenes are converted into 1,2,3-triazoles inthe same way.[186] Similarly, triazole 175 is obtained, along with two minor dihydrotri-azoles, from the reaction of diethyl (4-nitrobenzylidene)malonate (174) with sodium
458 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bazide.[187] Ethyl 3-(4-nitrophenyl)acrylate reacts with sodium azide, in aprotic solvents, togive triazole 175 in moderate yields.[188] The reaction of �-aryl-Æ-(phenylsulfinyl)acrylates176 with sodium azide gives triazoles 177 in good yields.[189] 5-Tosyl-1H-1,2,3-triazole(179) is prepared in 50% yield from the reaction of 1,2-ditoylacetylene (178) with sodiumazide.[190,191] It has been shown that (E)-2-azidovinyl 4-methylphenyl sulfone is an inter-mediate in this transformation. Another example of synthesis of 1,2,3-triazoles from theaddition of sodium azide to activated alkenes is found in the preparation of (4-oxo-4H-1-benzopyran-2-yl)-1,2,3-triazoles 181 from 2-(2-arylvinyl)-4H-1-benzopyran-4-ones 180.[192]
Using 180 (X = H) as starting compounds, triazoles 181 are the only isolated products;the yields are in the range of 48–59%. When 2-(2-aryl-1-bromovinyl)-4H-1-benzopyran-4-ones 180 (X = Br) are used the triazoles 181 (38–40%) are obtained together with unexpect-ed 1-aryl-5-[(4-oxo-4H-1-benzopyran-2-yl)methyl]tetrazoles (10–12%).
Scheme 63 Addition of Sodium Azide to Activated Alkenes
HN
NO2
Y
172
+ NaN3
DMF, rt, 120 h
173
Y = CO2Et 70%
Y = Bz 54%
HN
NH
N
NY
174
+ NaN3
DMSO, 25 oC, 2 h
N
N
NH
175
41%
4-O2NC6H4 H
EtO2C CO2Et
4-O2NC6H4
EtO2C
176
+ NaN3
DMF, AcOH, rt, 24 h
N
N
NH
177
57−73%
Ar1 H
EtO2C SOPh
Ar1
EtO2C
Ar1 = Ph, 1-naphthyl, 2-furyl
178
+ NaN3DMSO, rt, 24 h
N
N
NH
179
50% TsTs
Ts
180
+ NaN3
DMF, reflux
181
O
O
X
Ar1
O
O
NH
NN
Ar1
X = H 48−59%
X = Br 38−40%
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 459
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bSodium azide also adds to Æ-chloroenamines 182 (NR2R3 = NMe2, pyrrolidinyl, morpholi-no) to give 1,2,3-triazoles 184 (via the Æ-azidoenamines 183) in good yields (Scheme64).[193,194] However, with less basic Æ-chloroenamines (NR2R3 = NMePh), azirines 185 arethe sole reaction products.
Scheme 64 Addition of Sodium Azide to Æ-Chloroenamines[193,194]
182
+ NaN3
NR2R3
ClR1MeCN, CCl4
NR2R3
N3R1
N
NNR1
R3R2NN
NH
NR1
R3R2N
183
184 58−84%
N
NR2R3R1
185
R1 = Me, t-Bu, Ph
The addition of sodium azide to (1- and 2-acylvinyl)triphenylphosphonium salts 186 and189 gives, respectively, acyl or alkoxycarbonyl-1,2,3-triazoles 188 and 191 (via the ylides187 and 190) (Scheme 65).[195,196]
Scheme 65 Addition of Sodium Azide to (1- and 2-Acylvinyl)triphenylphosphoniumSalts[195,196]
186
NaN3, MeOH
H2O N
NH
N
R2
188 15−50%
R1 = iPr, t-Bu, Cy, cyclopropyl; R2 = H, Et
R1
O
Ph3P
R2
+
Cl−R1
O
Ph3P
R2
+
−
N3
187
− PPh3 R1
O
189
NaN3, H2O
1 h N
NH
N
191 30−95%
R1 = Me, Et, Pr, iPr, Ph, OMe
Ph3P+
X−
Ph3P+
−
N3
190
− PPh3 R1
O
R1
O O
R1
Ethyl 5-(4-Nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (175); Typical Procedure:[187]
CAUTION: Sodium azide can explode on heating and is highly toxic.
Diethyl (4-nitrobenzylidene)malonate (174; 2.0 g, 6.82 mmol) was added in one portion toa soln of NaN3 (443 mg, 6.82 mmol) in dry DMSO (10 mL) at 25 8C. The mixture immediate-ly became deep orange-brown in color and heat was evolved. After stirring for 2 h, themixture was poured onto an ice/water slurry (40 g). The resultant mixture was extracted
460 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bwith Et2O (two minor dihydrotriazoles could be obtained from this fraction), the aqueouslayer was acidified with dil HCl to pH 1 and extracted with Et2O. These ethereal extractswere dried (MgSO4) and evaporated to give a yellow amorphous solid (800 mg) which wasrecrystallized (CH2Cl2) to give pale yellow crystals; yield: 730 mg (41%); mp 174–176 8C.
13.13.1.1.3.1.2.2 Method 2:Addition of Azides to Activated Alkenes
Azides undergo addition to alkenes with strongly electron-withdrawing substituents togive 4,5-dihydro-1H-1,2,3-triazoles. Frequently these 4,5-dihydro-1H-triazoles are unstableand, by elimination of a stable fragment, aromatize to 1,2,3-triazoles[197–199] or are convert-ed into aziridines by elimination of nitrogen.[200] Generally the addition of azides to thesealkenes is regioselective and only one triazole is obtained. However, in some cases mix-tures of triazoles are formed. For example, 1-nitroalk-1-enes 192 react with phenyl ormethyl azide to give mixtures of the triazoles 193, 194, and 195 (Scheme 66).[197] The rel-ative proportions of these compounds are dependent of the experimental conditions.Nitrotriazoles 195 are obtained by air oxidation of the corresponding 4,5-dihydro-1H-tria-zoles. The formation of the two regioisomeric triazoles 193 and 194 is explained by theisomerization of the 1-nitroalk-1-enes to 2-nitroalk-1-enes.[197]
Scheme 66 Reaction of Azides with 1-Nitroalk-1-enes[197]
192
R1 = Me, Ph; R2 = Me, Ph, CO2Me
H
R2
H
NO2
R1N3 +
benzene
30−70 oC
4−15 d N
NNR2
193
R1
N
NN
194
R1
N
NNR2
195
R1
R2 O2N
+ +
Phenyl azide adds to 1-bromoethenesulfonyl chloride (196), in refluxing chloroform, toyield 4-bromo-1-phenyl-1H-1,2,3-triazole (198) in 45% yield (Scheme 67).[198] The unstable4,5-dihydro-1H-triazole 197 aromatizes promptly by losing sulfur dioxide and hydrogenchloride.
Scheme 67 Addition of Phenyl Azide to 1-Bromoethenesulfonyl Chloride[198]
196
H
H
Br
SO2ClPhN3 +
CHCl3reflux, 1 h N
NN
197
Ph
H
H
ClO2SBr
− SO2
− HCl
N
NN
198 45%
Ph
Br
Several perfluoroalkyl-substituted 1,2,3-triazoles linked to C6 of D-galactose and D-altroseare synthesized by this method.[199] For example, addition of the monosaccharide azide199 to the perfluoroalkyl-substituted phenyl vinyl sulfones 200 yields the reversed nu-cleosides 201 in good yields (Scheme 68). Only a single 1,2,3-triazole derivative is formedin each of these reactions.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 461
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 68 Addition of Monosaccharide Azides to Perfluoroalkyl-SubstitutedPhenyl Vinyl Sulfones[199]
199
OO
O
OO
N3
R1
SO2Ph
+
toluene, reflux
17−21 h
72−75%
OO
O
OO
NN
N
R1
200 201
R1 = CF3, (CF2)3CF3, (CF2)5CF3
Other sugar-derived 1,2,3-triazoles are prepared by a one-pot substitution–cyclization–ox-idation procedure starting from D-arabinose and L-fucose. The key step in this process isan intramolecular 1,3-dipolar cycloaddition of an azide to the C=C bond of an Æ,�-unsat-urated carboxylic ester. The resulting 4,5-dihydro-1H-triazole is readily aromatized by airoxidation.[201] Analogous sugar-derived 4,5-dihydro-1H-1,2,3-triazoles (related to D-glucoseand D-galactose) are stable but can be aromatized in good yields to the corresponding tri-azoles by oxidation with bromine.[202]
Maleimides and quinones have also been used as dipolarophiles in reactions witharyl azides,[203–206] silyl azides,[207] (azidoalkyl)indoles,[208] glycosyl azides,[209] (1-azidoalkyl)-phosphonates[210] and Æ-azidocarboxylic esters.[210]
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-Æ-D-galactopyranose, (201, R1 = CF3); Typical Procedure:[199]
A soln of azide 199 (0.85 g, 3.0 mmol) and sulfone 200 (R1 = CF3; 0.57 g, 2.40 mmol) in tol-uene (15 mL) was refluxed under argon for 17 h (TLC control). Then the solvent was evapo-rated under reduced pressure and the residue was purified by column chromatography(toluene/EtOAc 20:1); yield: 0.64 g (72%); mp 128–130 8C; [Æ]D –49.2 (CHCl3).
13.13.1.1.3.1.2.3 Method 3:Addition of Azides to Strained Alkenes
Azides react with alkenes to yield 4,5-dihydro-1H-1,2,3-triazoles. Whereas unactivated al-kenes are sluggish in their reaction with aryl azides, in contrast strained bicyclic alkenesare particularly reactive.[76] For example, the reaction of 4-bromophenyl azide with hex-1-ene (in excess) affords the corresponding 4,5-dihydro-1H-1,2,3-triazole in 89% yield after5.5 months at room temperature. At elevated temperatures (>80 8C), extensive decompo-sition of the 4,5-dihydro-1H-1,2,3-triazole is observed.[211] No detectable addition productis observed when the same azide and cyclohexene are left for three months at room tem-perature. Conjugated dienes are, however, much more reactive than the correspondingmono-unsaturated alkenes. For example, the adduct from the reaction of cyclohexa-1,3-diene and 4-bromophenyl azide begins to crystallize after three days at room temperatureand, after 18 days, a 77% yield of the corresponding 4,5-dihydro-1H-1,2,3-triazole is ob-tained.[211] On the other hand, phenyl azide and substituted phenyl azides react with nor-bornene, in refluxing petroleum ether (60–90 8C) for three to four hours, to give the cor-responding 1-aryl-4,5-dihydro-1H-1,2,3-triazoles in 51–93% yield.[212,213] Norbornene andother strained alkenes also react with azidotrimethylsilane to give the corresponding 1-(trimethylsilyl)-4,5-dihydro-1H-1,2,3-triazole adducts in high yields.[214] The reaction ofnorbornene and dicyclopentadiene with several heterarylmethyl azides has been stud-ied.[132]
462 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bThe reaction of azides with norbornadiene is particularly interesting since it allows
the synthesis of 4,5-unsubstituted triazoles 204 (Scheme 69). The thermolysis of the inter-mediate 4,5-dihydro-1H-1,2,3-triazole 203 gives the triazole and cyclopentadiene (via aretro-Diels–Alder reaction). For example, the reaction of norbornadiene with diethyl (azi-domethyl)phosphonate [202, X = PO(OEt)2] in tetrahydrofuran at room temperature givesthe 4,5-dihydro-1H-1,2,3-triazole [203, X = PO(OEt)2] in 92% yield. Thermolysis of this com-pound at 60 8C yields the corresponding triazole in 74% yield.[249] Similarly, Æ-alkoxy- andÆ-alkylsulfanyl-substituted azides, on reaction with norbornadiene in refluxing 1,4-diox-ane, also give the corresponding triazoles in high yields.[215] Phenyl azide and substitutedphenyl azides also react with norbornadiene to give the corresponding 4,5-dihydro-1H-1,2,3-triazoles which, by thermolysis, yield the corresponding 1-aryl-1H-1,2,3-tria-zoles.[213,216,217] In the reaction of norbornadiene with azidotrimethylsilane the initiallyformed 4,5-dihydro-1H-1,2,3-triazole is converted, spontaneously, into 2-(trimethylsilyl)-2H-1,2,3-triazole.[214] Addition of a range of hetaroyl azides to the strained 5-methylenebi-cyclo[2.2.1]hept-2-ene, at room temperature, afforded carbonyl aziridines as the majorproduct. These compounds are formed by loss of molecular nitrogen from the 4,5-dihy-dro-1H-1,2,3-triazole adducts.[218]
Scheme 69 Reaction of Azides with Norbornadiene[215,249]
202
THF, rt
203
X = PO(OEt)2, OR1, SR1
X N3+ N
NN
X 60 oC
−
204
N
X
N
N
The oxa and aza analogues of norbornadiene 205 (X = O, NCO2Et) also react with phenylazide to give 1,2,3-triazoles (Scheme 70). While triazole 207 is obtained in quantitativeyield from 205 (X = O), the reaction with 205 (X = NCO2Et) gives two triazoles: 207 (64%)and 1-phenyl-1H-1,2,3-triazole (36%).[219,220]
Scheme 70 Reaction of Phenyl Azide with 7-Oxa- and 7-Azabicyclo[2.2.1]hepta-2,5-dienes[219,220]
205 206
X = O, NCO2Et
X X
NPh
NN
CO2Me
CO2Me
PhN3
CO2Me
MeO2C−
207
NN
N
X PhMeO2C
MeO2C
Methylenecyclopropane is another interesting strained system that reacts readily withphenyl azide to give stable 4,5-dihydro-1H-1,2,3-triazoles.[221] However, the equivalent re-action with alkyl 2-methylenecyclopropane-1-carboxylates 208 yields 1,2,3-triazoles 210(Scheme 71).[128] A probable mechanism for the rearrangement of the intermediate 4,5-di-hydro-1H-1,2,3-triazoles 209 is shown in Scheme 71.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 463
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 71 Reaction of Phenyl Azide with Alkyl 2-Methylenecyclopropane-1-carboxylates[128]
209
+ PhN3
R3
R1O2C
R2
100 oC
12−24 h
208
210 R1 = Me; R2 = H; R3 = CO2Me 91%
R1 = Et; R2 = R3 = H 50%
R1 = Et; R2 = Me; R3 = H
NN
N
Ph
R3R2
R1O2C
N
NN
R3
R2
R1O
O HPh
Dimethyl 2-(1-Phenyl-1H-triazol-4-yl)butanedioate (210, R1 = Me; R2 = H; R3 = CO2Me);Typical Procedure:[128]
A mixture of 208 (R1 = Me; R2 = H; R3 = CO2Me; 2 g) and phenyl azide (10 mL) was heated ona steam bath for 12 h. The mixture was cooled and hexane was added to dissolve the re-maining phenyl azide. The supernatant layer was decanted and the resulting brown solidwas recrystallized (acetone/cyclohexane) to give triazole 210 (R1 = Me; R2 = H; R3 = CO2Me);yield: 3.1 g (91%). A pure sample was obtained by recrystallization (EtOAc); mp 114–115 8C.
13.13.1.1.3.1.2.4 Method 4:Addition of Azides to Allenes
Aryl azides undergo addition to allenes to give 4-alkylidene-4,5-dihydro-1H-1,2,3-triazolesin reasonable yields. 4,5-Dihydro-1H-1,2,3-triazoles 212, for example, are obtained in 29–73% yield from the reaction of 2,4-dimethylpenta-2,3-diene (211) (tetramethylallene) withphenyl azide and nitrophenyl azides (Scheme 72).[222]
Scheme 72 Addition of Aryl Azides to Tetramethylallene[222]
+ Ar1N3
212
Ar1 = Ph 29%
Ar1 = 4-O2NC6H4 73%
Ar1 = 2,4,6-(O2N)3C6H2 72%
•
211
NN
N
Ar1
When it is possible, the 4-alkylidene-4,5-dihydro-1H-1,2,3-triazoles aromatize spontane-ously to 1,2,3-triazoles, as observed in the reaction of propa-1,2-diene with phenyl azide.In this case a mixture of 5-methyl-1-phenyl-1H-1,2,3-triazole (0.6%), 4-methyl-1-phenyl-1H-1,2,3-triazole (1%), and a diamine (18%) is obtained.[223] Similarly, addition of phenyl azideto methyl buta-2,3-dienoate (213) gives a mixture of the triazoles 214 and 215 (9:1) in 67%yield (Scheme 73);[224] the addition occurs exclusively at the Æ,�-double bond.
464 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 73 Addition of Phenyl Azide to Methyl Buta-2,3-dienoate[224]
+ PhN3
214
67%•
CO2Me
213
74 oC, 24 h
215
+
NN
N
Ph
MeO2C
NN
N
PhMeO2C
9:1
Phenyl azide adds to cyclonona-1,2-diene (216) to give selectively the 4,5-dihydro-1H-1,2,3-triazole 217 (Scheme 74). This stable compound can be isomerized to the corre-sponding triazole 218 by treatment with a strong base.[223] When optically active (+)-(R)-cy-clonona-1,2-diene is used the (+)-(S)-4,5-dihydro-1H-1,2,3-triazole 217 is obtained, suggest-ing a concerted cycloaddition mechanism.
Scheme 74 Addition of Phenyl Azide to Cyclonona-1,2-diene[223]
+ PhN3
217
21%•
216
toluene
reflux, 10 h
NN
N
Ph
70%
NaOEt, EtOH
reflux, 3 d
218
NN
N
Ph
2,4,6-Trinitrophenyl azide (220) (picryl azide) adds to (aryloxy)allenes 219 to give triazoles222 or 223, depending on the substituents R1 and R5 (Scheme 75). The reactions proceedvia the unisolated 4,5-dihydro-1H-1,2,3-triazoles 221, which undergo an exceptionally fac-ile Claisen rearrangement to triazoles 222.[225] These compounds, unless blocked by a sub-stituent at R1, rapidly tautomerize to the isomeric compounds 223. When R1 and R5 arechloro or methyl the cyclohexadienone derivatives 222 are isolated in 66–85% yield.When R1 or R5 is hydrogen, triazoles 223 are isolated in 67–79% yield.
Scheme 75 Addition of 2,4,6-Trinitrophenyl Azide to (Aryloxy)allenes[225]
+ Ar1N3
219
CHCl3, rt
24 h to 3 weeks
O
•R1
R2
R3
R4
R5
221
R2
R3
R4
R5
O
R1
NN
N
220
222 R1 = R5 = Cl, Me 66−85% 223 R1 or R5 = H 67−79%
R2
R3
R4
R5
Ar1 = 2,4,6-(O2N)3C6H2
N
NN
OH
Ar1
Ar1
R2
R3
R4
R5
N
NN
O Ar1
R1
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 465
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bAn interesting one-pot procedure for the conversion of allenyl derivatives into 4,5-unsub-stituted 1,2,3-triazoles has been described.[226,227] The method involves a sequential andcascade palladium-catalyzed azide formation (from aryl/hetaryl/vinyl iodides, allene, andsodium azide) followed by a 1,3-dipolar cycloaddition to norbornadiene and finally a ret-ro-Diels–Alder reaction.
1-Phenyl-1,4,5,6,7,8,9,10-octahydrocyclonona[d][1,2,3]triazole (218); Typical Procedure:[223]
A soln of cyclonona-1,2-diene (216; 1.22 g, 0.01 mol) and phenyl azide (1.19 g, 0.01 mol) intoluene (15 mL) was refluxed for 10 h. The viscous yellow oil, obtained upon solvent evap-oration, crystallized when stored at rt for several days. Recrystallization [petroleum ether(bp 60–110 8C)] gave 4,5-dihydro-1H-1,2,3-triazole 217; yield: 0.51 g (21%). A soln of the 4,5-dihydro-1H-triazole (1.00 g, 4.14 mmol) in 0.75 M NaOEt in EtOH (40 mL) was refluxed for3 d. After solvent evaporation, the residue was extracted with Et2O and the ether extractwas washed with H2O until the aqueous washes were neutral. The Et2O layer was dried(MgSO4) and evaporated to give 0.81 g of crude product. Crystallization (petroleumether/benzene 3:1) afforded white crystalline triazole 218; yield: 0.70 g (70%); mp 77–78 8C.
13.13.1.1.3.1.2.5 Method 5:Addition of Azides to Æ-Acylphosphorus Ylides
The addition of azides to Æ-acylphosphorus ylides is a versatile method for the synthesisof 1,2,3-triazoles. Combining different Æ-acyl- or Æ-alkoxycarbonyl phosphorus ylides 224with azides of various types gives a range of substituted triazoles 226 (Scheme 76). Thereaction is regioselective, it requires mild conditions (room temperature or refluxing ben-zene) and generally the triazoles are obtained in good to very good yields.
Æ-Acylphosphorus ylides are commonly represented in the three resonance forms224A, 224B, and 224C. However, it has been demonstrated that they exist essentially orexclusively in the cis-enolate configuration 224C. The reaction of these ylides with azidesis accelerated by electron-releasing substituents on the ylide and electron-withdrawingsubstituents on the azide. The polarity of the solvent has only a small effect on the reac-tion rate. Low entropies of activation are obtained for these reactions. All these kineticdata indicate that the mechanism of these reactions involves a concerted 1,3-dipolar cy-cloaddition of the azide to the C=C bond in 224C.[228] The resulting 4,5-dihydro-1H-1,2,3-triazoles 225 are converted into triazoles 226 by spontaneous elimination of triphenyl-phosphine oxide. When acyl or alkoxycarbonyl azides are used, the initially formed 1-sub-stituted triazoles 226 (R1 = COX) isomerize to the corresponding 2-substituted triazoles227.[229,231] This synthetic method is, however, not general; with some phosphorus ylides,especially Æ-ethoxycarbonyl phosphorus ylides (224, R2 = OEt), diazo compounds and oth-er products are obtained rather than triazoles.[230–232] With these compounds, in the caseswhere 1,2,3-triazoles are formed the yields are moderate (when R3 = Me) or very low(when R3 = Ph).
466 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 76 Addition of Azides to Æ-Acylphosphorus Ylides[228–230,233,234]a
+ R1N3
224A
R1 = COX
R1 = alkyl, aryl, COR4, CO2Et, SO2Ar1
R2 O
R3 PPh3
R2 O
R3 PPh3+−
R2 O−
R3 PPh3+
224B 224C
N
N
N
R3
Ph3P
−O
R2
+
− Ph3PO
R1
225 226 227
NN
N
R1
R3
R2N
NR1
NR3
R2
R1 R2 Conditions Yield (%) Ref226 227
O
OO
O(MeO)3C6H2
Mebenzene, reflux,14–16 h
63 – [233]
O
OO
O(MeO)3C6H2
Phbenzene, reflux,14–16 h
52 – [233]
acridin-9-yl CH2NMe2 benzene, reflux, 2 h 49 – [234]
acridin9-yl N benzene, reflux, 2 h 73 – [234]
Ph Ph benzene, reflux, 48 h 80 – [228]
Ph 4-O2NC6H4 benzene, reflux, 6 d 67 – [228]
4-O2NC6H4 Me benzene, reflux, 0.5 h 73 – [228]
4-O2NC6H4 4-O2NC6H4 benzene, reflux, 48 h 98 – [228]
4-MeOC6H4 Ph benzene, reflux, 72 h 54 – [228]
4-MeOC6H4 4-O2NC6H4 benzene, reflux, 10 d 70 – [228]
Ts Me CH2Cl2, rt, 0.25 h 98 – [230]
Ts Ph CH2Cl2, rt, 1 h 98 – [230]
Ts 4-O2NC6H4 CH2Cl2, rt, 10 h 87 – [230]
Bz Me CH2Cl2, rt, 48 h – 50 [229]
4-O2NC6H4CO Me CH2Cl2, rt, 24 h – 65 [229]
4-O2NC6H4CO Ph CH2Cl2, rt, 24 h – 68 [229]
4-MeOC6H4CO Me CH2Cl2, rt, 7 d – 24 [229]
4-MeOC6H4CO Ph CH2Cl2, rt, 14 d – 75 [229]
3-O2NC6H4CO 4-O2NC6H4 CH2Cl2, rt, 20 d – 43 [229]
CO2Et Ph CH2Cl2, rt, 48 h – 46 [229]
CO2Et 4-O2NC6H4 CH2Cl2, rt, 14 d – 76 [229]
a Note: R3 = H for all examples in the table.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 467
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bThe reaction of a quinuclidin-3-yl Æ-acylphosphorus ylide with 3-nitrobenzoyl azide in re-fluxing acetonitrile, followed by column chromatography on basic alumina, affords thecorresponding N-unsubstituted 1,2,3-triazole in 52%.[235] The reaction of vinyl azides withÆ-acylphosphorus ylides is a convenient method for the synthesis of 1-vinyl-1H-1,2,3-tria-zoles.[236] The reaction of Æ-acylphosphorus ylides with azides has been used to prepare arange of 1-[(diethoxyphosphoryl)methyl]-1H-1,2,3-triazoles 230[237] and 1,2,3-triazole nu-cleosides 231[238] and 232[239] (Scheme 77). Addition of acetyl azide to Æ-acyl-Æ-alkylphos-phorus ylides or acetylation of those phosphorus ylides and subsequent treatment withsodium azide gives the same 1,2,3-triazoles.[240]
Scheme 77 Addition of (Diethoxyphosphoryl)methyl Azides and Glycosyl Azides toÆ-Acylphosphorus Ylides[237–239]
R1 = H, Ph; R2 = Me, Ph, CO2Et
R2 O−
PPh3+
229 230
(EtO)2P N3
R1
+
toluene
110 oC, 5−27 h
228
61−83%
O
NN
N
R2
R1 P(OEt)2
O
O−
PPh3+
231
+O
BzON3
OBzBzO
Br
toluene
110 oC, 45 min
38%
O
BzON
OBzBzO
N
NBr
R2 O−
PPh3+
232
+O
N3
OAcAcO
toluene
80 oC, 60 h
59−82%
ON
OAcAcO
N
N R2BzO BzO
R2 = Me, Et, iPr, CO2Et
1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3,-triazoles 230; General Procedure:[237]
A soln of diethyl (azidomethyl)phosphonate 228 (2 mmol) and Æ-acylphosphorus ylide229 (2–2.3 mmol) in dry toluene (15 mL) was refluxed for 5–27 h. The solvent was thenevaporated in vacuo. The product was separated from the Ph3PO by flash chromatographyto give analytically pure triazole 230.
13.13.1.1.3.1.2.6 Method 6:Addition of Azides to Enamines or Enol Ethers
Azides undergo addition to enamines 233 (R1 = amino)[241] and to enol ethers 233 (R1 = alk-oxy)[242,243] under mild conditions, frequently at room temperature, to yield 4,5-dihydro-1H-1,2,3-triazoles 234 (Scheme 78). These reactions are completely regioselective; theamino or alkoxy group in the resulting 4,5-dihydro-1H-1,2,3-triazoles is in the 5-position.In some cases the 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to 1,2,3-tria-zoles 235, in others the aromatization is effected by heating the compound alone (forenol ether adducts) or by treatment with acid or base (Scheme 78).
468 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 78 Addition of Azides to Enamines or Enol Ethers[241–243]
R3 H
Y
234
H+ or OH−
Y = NR42, OR4
R2
R1N3 +N
NN
R1
Y
R2
− HY
235
N
NN
R1
R3
R2
233
HR3
The thermal elimination of nitrogen from the 4,5-dihydro-1H-1,2,3-triazoles is a possiblecompeting reaction. Some dihydrotriazoles derived from cyclic enol ethers and enaminesfail to give triazoles for this reason.[242,244,245] In general, however, yields are very good. Thereaction is most effective with azides bearing electron-withdrawing groups such as nitro-phenyl, phenylsulfonyl, or ethoxycarbonyl. Sulfonyl azide adducts give N-unsubstitutedtriazoles, the substituent being lost on aromatization.[13]
13.13.1.1.3.1.2.6.1 Variation 1:Addition of Azides to Enamines
There are substantial differences in the products obtained from the reactions of enamineswith aryl azides or sulfonyl azides. Nitroenamine 236 (X = NO2), for example, reacts witharyl azides to yield the expected triazoles 237 while with tosyl azide it gives the N-unsub-stituted triazole 238 (X = NO2) (Scheme 79).[13] With sulfonylenamines 236 (X = SO2Ph, 4-O2NC6H4SO2) the corresponding triazoles 238 are also obtained. Similar results are ob-served in the reaction of methyl (E)-3-pyrrolidin-1-ylprop-2-enoate (239) with hetaroylazides 240 (Scheme 79). In all cases methyl 1H-1,2,3-triazole-4-carboxylate is formed in ap-proximately 90% yield.[218] Dienamines also react with 4-nitrophenyl azide to give 1,2,3-tri-azoles but with tosyl azide only amidines are obtained (formed by decomposition of theintermediate 4,5-dihydro-1H-1,2,3-triazoles).[247]
Scheme 79 Addition of Aryl, Sulfonyl, and Hetaroyl Azides to Enamines[13,218]
X = NO2, SO2Ph, 4-O2NC6H4SO2; Ar1 = Ph, 4-O2NC6H4
237
N
NN
Ar1
O2N
O N
238
N
NH
N
XTsN3, EtOH
reflux, 12−24 h
Ar1N3
X = NO2
O NTs+
236
50−80%
X
R1 = 2-furyl, 2-thienyl, 2-selanylphenyl,
N
NH
N
MeO2CCHCl3rt, 20−25 d
239
90%
MeO2C
N
+R1 N3
O
R1 N
O
240
S
S
+
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 469
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bAn interesting difference in chemical behavior is observed with the two isomeric cyano-enamines 241 and 244 (Scheme 80). Both react with aryl azides to give 4,5-dihydro-1H-1,2,3-triazoles (242 and 245, respectively), which spontaneously aromatize to 1,2,3-tria-zoles 243 and 246.[248] However, under identical experimental conditions, in one casethe elimination of hydrogen cyanide is the favorable process while in the other onlyamine is eliminated. Both reactions are completely regioselective. The elimination of hy-drogen cyanide or amine is independent of the structure of the amine; the process de-pends only on the relative positions of the amino and cyano groups. These reactions canbe done without solvent, at 62–65 8C, and the yields, in both cases, are very good (75–95%).
Scheme 80 Addition of Aryl Azides to Cyanoenamines[248]
NC
R1R2N
H
H+ Ar1N3
242
N
NN
Ar1
− HCN
N
NNR1R2N
Ar1
243241
NC
R1R2N
H
R1R2N
CN
H+ Ar1N3
245
N
NN
Ar1
R1R2N
H− HNR1R2
N
NN
Ar1
246244
NCHNC
The synthetic versatility of this method is exemplified in Scheme 81: a range of 1,2,3-tri-azoles 249 are obtained in good yields from the reaction of (azidomethyl)phosphonates247 with enamines 248.[124,249,250]
Scheme 81 Reaction of (Azidomethyl)phosphonates with Enamines
R4
R3R2N
R5
H
56−77%
N
NN
249248
R5
(EtO)2P N3
R1
+
toluene, reflux
48 h R4
R1 P(OEt)2
247
R1 = H, Me, Ph; NR2R3 = piperidino, morpholino; R4,R5 = (CH2)4; R4 = H, Me; R5 = CO2Me, CO2Et, POPh2, PO(OEt)2
O
O
The synthesis of 4-(aminomethyl)-1H-1,2,3-triazoles (Scheme 82) is another interesting ap-plication of this method. Enamines 250 (resulting from the reaction of propenal with 2equivalents of secondary amines) react with aryl azides to give 4,5-dihydro-1H-1,2,3-tria-zoles 251[251,252] which, upon treatment with base,[251] are converted into triazoles 252. In asimilar process, reaction of propenal with benzenethiol, followed by the addition of a sec-ondary amine and an aryl azide gives 4-[(phenylsulfanyl)methyl]-4,5-dihydro-1H-1,2,3-tri-azoles which, after treatment with base, give mixtures of three triazoles, resulting fromthe elimination of the amine or the phenylsulfanyl group.[253] Thiopyrano[3,4-d]-1,2,3-tria-zoles can also be prepared in moderate yields from the reaction of enamines, derivedfrom tetrahydrothiopyran-4-one, and aryl azides.[254]
470 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 82 Synthesis of 4-(Aminomethyl)-1H-1,2,3-triazoles[251,252]
250
R12NH
NR12 = NMe2, morpholino, piperidino, pyrrolidin-1-yl; X = H, Cl, CN, NO2
H
O
R12N NR1
2
X N3
251
N
NNR1
2N
H
H
X
R12N NaOH or
NaOMe
252
N
NN
X
R12N
The reactions of azides with enamines in which tautomerism is possible give mixtures oftriazoles (Scheme 83).[255]
Scheme 83 Addition of Azides to Enamines in Which Tautomerism Is Possible[255]
− R12NH
N
NN
H
H
R12N
R2
R12N
R2
H
+ R3N3
+ R3N3− R1
2NH
R2
R3
N
NN
R3
R2
Imines with an Æ-methylene group can also react with azides via their enamine tauto-mers.[256] This method has been extended to the solid-phase synthesis of 1,2,3-triazoles.The resin-bound 3-oxobutanamide 253 reacts with primary aliphatic amines yielding 3-aminobut-2-enamides which react with tosyl azide to give the polymer supported tria-zoles 254 (Scheme 84). Upon treatment with trifluoroacetic acid, the “free” triazoles (astrifluoroacetates) 255 are obtained in purities of up to 82% (1H NMR, HPLC).[257]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 471
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 84 Solid-Phase Synthesis of Triazoles via Enamines[257]
O N
O
N
O O
R1NH2, DMF
HC(OEt)3 O N
O
N
O NHR1
TsN3, DMF
iPr2NEt O N
O
N
O
NN
NR1TFA H2N
N
O
NN
NR1+
253
254 255CF3CO2
−
Enamides 256, despite being less reactive than enamines, also react with aryl azides atroom temperature (3 days to 10 months) to give 4,5-dihydro-1H-1,2,3-triazoles 257 as sta-ble crystalline products (Scheme 85). In refluxing ethanol, however, the reaction yieldsthe corresponding triazoles as the major product. The reaction of the 4,5-dihydro-1H-1,2,3-triazoles 257 with potassium hydroxide in refluxing methanol yields triazoles258.[258]
Scheme 85 Reaction of Aryl Azides with Enamides[258]
Y = 2-oxopyrrolidin-1-yl, NMeAc
257
N
NN
X
Y
258
N
NN
X
KOH, MeOH
reflux, 30 min
EtOH, reflux
24−90 h
17−66%
rt, 3 d to 10 months
44−91%
N3
+
X
Y
70−84%256
1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3-triazoles 249; General Procedure:[249]
To the (azidomethyl)phosphonate 247 (5 mmol) dissolved in toluene (20 mL) was addedthe enamine 248 (5 mmol). The resulting mixture was refluxed for 48 h, with stirring.The soln was concentrated and the residue was then purified by flash chromatography(silica gel, hexane/Et2O 1:1).
472 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.3.1.2.6.2 Variation 2:
Addition of Azides to Enol Ethers
As indicated in Section 13.13.1.1.3.1.2.6, azides react very readily with enol ethers to af-ford 4,5-dihydro-1H-1,2,3-triazoles in good yields;[242,243] these reactions are completelyregioselective. As an example, 2-ethoxypropene reacts with 4-nitrophenyl azide to givethe 4,5-dihydro-1H-1,2,3-triazole 259 in 99% yield; when heated at 150 8C it eliminates eth-anol and the corresponding 1,2,3-triazole 260 is formed in quantitative yield (Scheme86).[242] Cyclic enol ethers, like 2,3-dihydrofuran or 3,4-dihydro-2H-pyran, also react withazides to give the corresponding 4,5-dihydro-1H-1,2,3-triazoles 261. However, when thesecompounds are heated, nitrogen is evolved and the imino ethers 262 are formed.[242,259]
The reaction of enol ethers with heterocyclic azides gives similar results.[114]
Scheme 86 Reaction of Aryl Azides with Enol Ethers[242]
259
N
NN
50 oC, 90 h
99%
N3
NO2
OEt+
NO2
EtO
150 oC
100%
260
N
NN
NO2
261
20 oC
72−98%Ar1N3 +
O( )n
NN
N
O
( )n 100−130 oC
O NAr1
Ar1
262
( )n
n = 1, 2
Aryl azides containing no electron-withdrawing groups add to the enolate ion of acetalde-hyde (formed by cycloreversion of tetrahydrofuran in the presence of butyllithium) togive 1-aryl-4,5-dihydro-1H-1,2,3-triazol-5-ols 263 in very good yields (Scheme 87).[260] Thesecompounds are converted into the corresponding 1-aryl-1H-1,2,3-triazoles 264 in good tonearly quantitative yields by treatment with sodium methoxide in methanol or withpotassium tert-butoxide in tert-butyl alcohol.[260] In a similar process, benzyl azide andphenyl azide react with the enolate ions of methyl ketones to give mixtures of triazolederivatives.[261,262] For example, benzyl azide reacts with acetone, in the presence of potas-sium tert-butoxide, to give a mixture (ca. 1:1) of 1-benzyl-5-methyl-1H-1,2,3-triazole (265)and 1-benzyl-4-isopropenyl-5-methyl-1H-1,2,3-triazole (266) (Scheme 87). When phenylazide is used, triazole 267 is the main product.[262] Under similar reaction conditions,phenylacetone reacts with organic azides to give triazoles 268 in high yields.[263]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 473
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 87 Reaction of Azides with Enolates[260]
X = H, 2-SMe, 2-SEt, 4-Me, 2-OMe, 3-OMe, 4-OMe
263
N
NN
X
HO
264
N
NN
X
NaOR1, R1OH
rt, 0.5−60 h
THF
rt, 1−24 h
70−99%
N3
+
X
O−
65−100%
265
N
NN
t-BuOK, t-BuOH
rt, 3.5 h
77%BnN3 +
O
Bn
+
266
N
NN
Bn
t-BuOK, t-BuOH
rt, 40 min
74%PhN3 +
O
267
N
NN
Ph
NHNO
t-BuOK, t-BuOH
rt, 0.5−4 h
79−92%R1N3 +
O
268
N
NN
R1
Ph
Ph
R1 = Me, Bn, Ph
1-Benzyl-5-methyl-4-phenyl-1H-1,2,3-triazole (268, R1 = Bn); Typical Procedure:[263]
Benzyl azide (2.48 mL, 0.02 mol) and phenylacetone (2.67 mL, 0.02 mol) were added to t-BuOK stock soln (20 mL). The mixture turned red and heat evolution was observed aftera few min. After 2 h, the mixture was poured into ice water (150 mL). The crystalline prod-uct was washed with H2O and pentane; crude product yield: 4.22 g (85%). Recrystallization(EtOAc/pentane) gave the pure product; mp 93–94 8C.
13.13.1.1.3.1.2.7 Method 7:Addition of Azides to Vinyl Acetate
Azides undergo addition to vinyl esters of lower (C1–C4) carboxylic acids to yield 1-substi-tuted 1,2,3-triazoles 269 in good yields (Scheme 88). Vinyl acetate is the most readily avail-able and is the preferred vinyl ester substrate. Generally vinyl acetate is also used as sol-vent and the reaction takes place at 50–150 8C. This method has been frequently used forthe preparation of 1-aryl- and 1-benzyl-1H-1,2,3-triazoles with biological activities.[264–268]
Heteraryl azides also add to vinyl acetate to give the corresponding triazoles.[114] Similarreaction with isopropenyl acetate yields the 5-methyl-1-substituted 1H-1,2,3-triazoles.[114]
474 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 88 Reaction of Azides with Vinyl Acetate[114,264–268]
50−150 oCR1N3 +
269
N
NN
R1
AcO
1-(4-Acetylphenyl)-1H-1,2,3-triazole (269, R1 = 4-AcC6H4); Typical Procedure:[267]
A soln of 4-azidoacetophenone (4.0 g, 24.8 mmol) and vinyl acetate (6 mL) in a closed tubewas heated at 80 8C for 24 h. After evaporation of the solvent, the residue was dissolved inCHCl3 and the soln was washed with 2 M NaOH and 2 M HCl. The CHCl3 layer was evapo-rated in vacuo and the crude residue was recrystallized [benzene (CAUTION: carcinogen)];yield: 2.86 g (61%); mp 169–171 8C.
13.13.1.1.3.1.2.8 Method 8:Addition of Azides to Ketene Acetals
Ketene N,N-, S,S-, S,N-, O,O-, and O,N-acetals react with organic azides or sodium azide toyield 1,2,3-triazoles. These reactions are completely regioselective but the yields arestrongly dependent on the structure of the ketene acetal.
Aryl azides undergo 1,3-dipolar cycloaddition to 1,1-dimorpholinoethenes 270 togive 4,5-dihydro-1H-1,2,3-triazoles 271 (Scheme 89). When R1 = Me the 4,5-dihydro-1H-1,2,3-triazoles 271 are stable and can be isolated.[253] These compounds are deaminatedin almost quantitative yields (95–98%) to the corresponding triazoles 272 by treatmentwith acetic acid (60 8C, 30 min).[253] When R1 is an electron-withdrawing group (COR2,CO2R
2, SO2R2, NO2) the 4,5-dihydro-1H-1,2,3-triazoles 271 cannot be isolated or detected;
the deamination process to 272 proceeds so rapidly that NMR monitoring of the reactionmixture does not allow detection of signals unequivocally associated with the structure271.[269]
Scheme 89 Reaction of Aryl Azides with 1,1-Dimorpholinoethenes[253]
Ar1N3, toluene
rt or reflux, 4−50 h
271
N
NN
Ar1N N
R1 H
O O
N
N
O
O
O NH−
N
NN
Ar1
R1
NO
272
270
16−73%
R1
Cyclic ethene-1,1-diamines 273 react readily with 4-nitrophenyl azide to yield exclusively1,2,3-triazoles 274 in excellent yields (Scheme 90). However, when phenyl azide or othersubstituted phenyl azides are used the reaction proceeds much more slowly and mixturesof triazoles 274 and 275 are obtained.[270] The formation of triazoles 274 can be explainedby a mechanism where the ethene-1,1-diamines act as nucleophiles and attack the termi-nal nitrogen of the azide. Cyclization and elimination of one molecule of water yields the
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 475
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
btriazoles. The formation of triazoles 275 can be explained by a 1,3-dipolar cycloadditionof the azide to the ethene-1,1-diamine, followed by Dimroth rearrangement of the inter-mediate dihydrotriazole and finally aromatization by deamination.[270]
Scheme 90 Reaction of Aryl Azides with Cyclic Ethene-1,1-diamines[270]
n = 1, 2; Y = H, Cl, Me, OMe, NO2
274
N
NN
1,4-dioxane
rt to 80 oC, 5 h to 5 d
N3
+
Y
X
NH
N
( )n
Y
HN NH
O
X
( )n
NN
N
NH
O
X
( )n
+
275
273
2-Nitroethene-1,1-diamines of types 276 or 280, with at least one free NH group, reactwith 4-chlorobenzenesulfonyl azide to give 4-nitro-1,2,3-triazoles 279 and 281, respec-tively, in low to moderate yields (Scheme 91). The mechanism of formation of these com-pounds is likely to involve Dimroth rearrangement of the 4,5-dihydro-1H-triazoles 277,resulting from 1,3-dipolar cycloaddition, to 278 followed by elimination of the arylsulfo-namide as show in Scheme 91.[271]
Scheme 91 Reaction of 4-Chlorobenzenesulfonyl Azide with2-Nitroethene-1,1-diamines[271]
4-ClC6H4SO2N3
MeCN, rt, 7 dHN NH
H
( )n
NN
N
NH
( )n
+
277
NO2
N
NN
SO2Ar1
HN
NH NHAr1O2S
NN
N
NH
NO2
( )n
279
278276
( )n
35−65%
NO2
NO2
n = 1, 2
4-ClC6H4SO2N3
dioxane, 80 oC, 15 h
281
N
NHMe
NO2
H
12%N
N
NN
O2N
Me
280
476 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bAroylketene dithioacetals 282 react with sodium azide via intermediates 283 to afford N-unsubstituted 1,2,3-triazoles 284 in good yields (Scheme 92).[272] Under similar conditions,the reaction with 4,4-bis(methylsulfanyl)but-3-en-2-one does not yield the correspondingtriazole.
Scheme 92 Reaction of Aroylketene Dithioacetals with Sodium Azide[272]
NaN3, DMSO
110 oC, 12−25 h
65−75%
O
Ar1
H
MeS SMe
N
NN
−
Na+− NaSMe
N
NH
N
MeS
Ar1
O
282 283 284
Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4, 3,4-Cl2C6H3
O
Ar1
MeS
MeS
Tosyl azide reacts smoothly with acylketene S,N-acetals 285 in ethanolic sodium hydrox-ide solutions to give 1,2,3-triazoles 286 in good yields (Scheme 93).[273] Under similar con-ditions, the reaction of tosyl azide with cyclic ketene S,N-acetals 288 results in intractabletar, however, in dioxane, at higher temperature, the fused thiazolo[3,2-c][1,2,3]triazole de-rivatives 289 are obtained in good yields.[273] Detosylation of compounds 286 with concen-trated sulfuric acid leads to the corresponding 4-acyl-1,2,3-triazol-5-amines 287.
Scheme 93 Reaction of Acylketene S,N-Acetals with Tosyl Azide[273]
NaOH, EtOH
0 oC to rt, 10 h
44−75%
O
R1H
MeS NHR2
N
NN
285
287
R1 = Me, Ph, 4-ClC6H4, 4-Tol; R2 = Me, Et, Pr, iPr, Bu, Cy, CH2CH(OEt)2, Bn, Ph
+ TsN3TsHN
O
R1
R2
concd H2SO4
rt, 25 min
75−95%
N
NNH2N
O
R1
R2
286
dioxane
95−100 oC, 15 h
60−69%
O
R1H
288
R1 = Ph, 4-ClC6H4, 4-MeOC6H4
+ TsN3N N
NS
R1
O
S NH
289
Ketene O,O-acetals (1,1-bis-enol ethers) 290 react with aryl azides to give triazoles 291 invarying yields (Scheme 94).[6,156,274] With temperature control and in the presence of an ex-cess of the ketene acetal, the intermediate 4,5-dihydro-1H-1,2,3-triazole is obtained.[275,276]
The intermediate 4,5-dihydro-1H-1,2,3-triazole obtained from the reaction of ethyl azido-formate and ketene acetals decomposes readily at room temperature, the reaction path-
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 477
for references see p 587
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FOR PERSONAL USE ONLY
bway depending on the presence of the substituents on the 4-position.[276] With benzoylazide the main products are oxazole derivatives.[275]
Scheme 94 Reaction of Ketene O,O-Acetals with Azides[156,274]
290
+ Ar1N3
EtO OEt
R1 HN
NN
Ar1
− EtOH
N
NN
Ar1
R1
EtO
291
R1
EtO
EtO
4-Acyl-5-(tosylamino)-1H-1,2,3-triazoles 286; General Procedure for Reaction ofAcylketene S,N-Acetals with Tosyl Azide:[273]
A soln of NaOH (4.80 g, 0.12 mol) in EtOH (10 mL) was added slowly (5 min) to an ice-cooledand stirred suspension of the ketene S,N-acetal 285 (0.01 mol) and tosyl azide (2.36 g,0.012 mol) in EtOH (10 mL), and the mixture was further stirred at rt for 10 h. It was thenpoured over crushed ice (150 g), acidified with 20% AcOH (30 mL), and extracted withCHCl3 (3 � 50 mL). The organic extract was washed with H2O (3 � 50 mL), dried (Na2SO4),and evaporated to give crude triazoles 286, which were further purified by recrystalliza-tion (EtOH).
13.13.1.1.3.1.3 Reaction of Azides with Active Methylene Compounds
The base-catalyzed condensation of azides with active methylene compounds (the Dim-roth reaction) is a versatile method for the preparation of 1H-1,2,3-triazoles. It was firstdescribed by Dimroth in 1902.[277,426] Depending on the functional groups present in theactive methylene compound used, the substituent in the 5-position of the triazole can bean alkyl or aryl group, a hydroxy group, an alkoxycarbonyl group, or an amino group. Al-though the reactions are stepwise,[278] they are completely regioselective. The mechanismof the Dimroth reaction can be envisaged as a nucleophilic attack by the carbanion on theterminal nitrogen of the azide, followed by cyclization to a dihydrotriazole and aromati-zation. In accord with this mechanism, the reaction goes least readily with azides bearingelectron-releasing groups. The reactions are generally carried out with alkoxides in alco-hols at room temperature or under reflux. However, in some cases better results are ob-tained using potassium tert-butoxide in tetrahydrofuran,[279] sodium amide in diisopropylether,[280] or potassium carbonate in dimethyl sulfoxide.[281]
13.13.1.1.3.1.3.1 Method 1:Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxoamides
Organic azides react with 1,3-diketones, 3-oxo esters, or 3-oxoamides to yield, generally ingood yields, 1H-1,2,3-triazoles with a carbonyl group in position 4 (Scheme 95). The reac-tion with aryl or hetaryl azides gives better yields. With simple vinyl azides[282] and 2-azi-dovinyl ketones[283] the expected 1-vinyl-1,2,3-triazoles are obtained. However, when 1-azidovinyl ketones are reacted with 3-oxo esters in the presence of triethylamine the ini-tially formed 1-vinyl-1,2,3-triazoles undergo further reaction with another molecule ofthe oxo ester.[284] In hexamethylphosphoric triamide, 4-nitrophenyl azide reacts smoothlywith acyclic 1,3-diketones and 3-oxo esters to afford the corresponding triazoles 293 inalmost quantitative yields.[285] However, with five- and six-membered cyclic 1,3-diones itgives mainly the corresponding diazo derivatives. 1,3-Dicarbonyl compounds react withtosyl azide in hexamethylphosphoric triamide to give only the corresponding diazo com-pounds, usually in high yields.[285]
478 Science of Synthesis 13.13 1,2,3-Triazoles
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FOR PERSONAL USE ONLY
bScheme 95 Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxo-amides[135,267,281,286–295]
R1N3 +N
NN
R1
base
N
NNR2
293
R2 R3
O ON
−NN
R1
R1
R2 = alkyl, aryl; R3 = alkyl, aryl, OR4, NR4R5
−O
R2
O
R2
O
R3
O
R3
O
R3
R1 R2 R3 Conditions Yielda (%) Ref
4-O2NC6H4 Me Me NaOEt, EtOH, rt, 5 h 83 [267]
3-HO-4-MeO2CC6H3 Ph Ph Et3N, MeOH, reflux, 15 h 60 [286]
2-O2NC6H4 Me OEt NaOEt, EtOH, 0 8C, 2 h 56 [287]
Ph Me OMe Et3N, MeOH, 70 8C, 10 d 68 [135]
3,5-Cl2C6H3CH2 Me OEt K2CO3, DMSO, 35 8C, 18 h 89 [281]
2-O2N-4-ClC6H3 Me NHPh NaOEt, EtOH, rt, 18 h 80 [287]
4-(HO2CCH2O)C6H4 Me NEt2 NaOEt, EtOH, reflux, 16 h 65 [288]
4-pyridyl 4-O2NC6H4 OEt NaOEt, EtOH, rt, 24 h 86 [289]
N N
Me Me NaOEt, EtOH, rt, 4 h 90 [290]
N N Ph
Ph OEt NaOEt, EtOH, rt, 4 h 71 [291]
N
MeO4-O2NC6H4 OEt NaOEt, EtOH, 0–3 8C, 6 h n.r. [292]
NCl
Me NHPh NaOEt, EtOH, 0 8C to rt, 6 h n.r. [293]
acridin-9-yl Me Me NaOMe, MeOH, rt, 24 h 62 [294]
acridin-9-yl Me OMe KOH, MeOH, rt, 12 h 75 [294]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 479
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bR1 R2 R3 Conditions Yielda (%) Ref
S
HO
MeO2CMe Me MeOH, Et3N, rt, 2 d 67 [295]
S
HO
MeO2CMe OEt MeOH, Et3N, rt, 2 d 62 [295]
a n.r. = not reported.
Aryl azides react with 2-substituted 1H-indane-1,3(2H)-diones to give fairly stable tricyclic4-acyl-4,5-dihydro-1H-triazol-5-ols in good yields.[296] With tosyl azide the isolated prod-ucts are isoquinolinediones.[296] Ethyl 2-oxocyclododecanecarboxylate (294) reacts withphenyl azide, in the presence of 1 equivalent of sodium ethoxide, to give the 1H-1,2,3-tri-azol-5-ol 295 in 48% yield (Scheme 96).[297]
Scheme 96 Reaction of Ethyl 2-Oxocyclododecanecarboxylate with Phenyl Azides[297]
+ PhN3N
NNHO
295
EtO2C
Ph
NaOEt, EtOH, THF
rt, 3 d
CO2Et
O
294
48%
( )10
3-Oxoamides react with sulfonyl azides in a different way than with alkyl or aryl azides. Inthis case, the sulfonyl azide acts as a diazo transfer agent and the nitrogen of the amidefunction is involved in the formation of the 1,2,3-triazole ring. As indicated in Scheme 97,in the presence of sodium ethoxide, tosyl azide reacts with 3-oxoamides 296 to give thesodium salts of 4-acyl-1H-1,2,3-triazol-5-ols in almost quantitative yields. However, at-tempts to convert salts 297 into the corresponding hydroxy derivatives leads to the for-mation of diazoamides 298.[298]
Scheme 97 Reaction of Tosyl Azide with 3-Oxoamides[298]
+ TsN3
NaOEt
EtOH
N
NN
R1OC
−O
297
R1 NHPh
O O
R1 = Me, Ph
97−100%
Na+
296
NaOEt
H+
R1 NHPh
O O
298
N2Ph
Dimethyl 3-oxopentanedioate (299) reacts with aryl[299] and glycosyl azides[300] to yield se-lectively triazoles 300 (Scheme 98).
480 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 98 Reaction of Dimethyl 3-Oxopentanedioate with Azides
+ R1N3base N
NNMeO2C
300
MeO
O O
299
OMe
O
R1
MeO2C
R1 Conditions Yield (%) Ref
Ph Et3N, MeOH, reflux, 4 d 62 [299]
4-ClC6H4 Et3N, MeOH, reflux, 1 d 76 [299]
4-O2NC6H4 Et3N, MeOH, reflux, 1 d 94 [299]
4-AcC6H4 Et3N, MeOH, reflux, 1 d 82 [299]
O
BzO OBz
BzO
K2CO3, DMSO, rt, 15 h 95 [300]
O
OBz
BzOOBz
K2CO3, DMSO, rt, 24 h 93 [300]
O
BnOOBn
OBn
K2CO3, DMSO, 45 8C, 24 h 80 [300]
Diethyl 2-oxobutanedioate, ethyl 2,4-dioxo-4-phenylbutanoate, and ethyl 4-(2-furyl)-2,4-dioxobutanoate, all as sodium salts 301, react with aryl azides to afford triazoles 302 inlow yields (Scheme 99).[301]
Scheme 99 Reaction of 2-Oxobutanedioate and 2,4-Dioxobutanoate Derivativeswith Azides[301]
N
NN
Ar1
EtO2CAr1N3+
THF, 50 oC, 7 h
302
O
X
X = OEt, Ph, 2-furyl
O O
XOEt
O
−
301
Na+17−26%
13.13.1.1.3.1.3.2 Method 2:Reaction of Azides with Malonic Esters, Malonamides, or Acetamides
The base-catalyzed reaction of organic azides with malonic acid derivatives is one of thebest methods for the synthesis of 1H-1,2,3-triazol-5-ols 303 with an alkyloxy (or aryloxy)carbonyl or carbamoyl functions in the 4-position (Scheme 100). As observed with otheractive methylene compounds, these reactions are stepwise and completely regioselective.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 481
for references see p 587
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bScheme 100 Reaction of Azides with Diethyl Malonate[281,302–304]
N
NN
R1
EtO2C
HO
R1N3 EtO2C CO2Et+base
N
O OEt
NNR1
EtO2C
H
303
−
R1 Conditions Yield (%) Ref
Bn K2CO3, DMSO, 35 8C, 44 h 77 [281]
Bn NaOMe, MeOH, reflux, 15 h 88 [302]
3,5-Cl2C6H3CH2 K2CO3, DMSO, 40 8C, 72 h 96 [281]
4-MeOC6H4CH2 K2CO3, DMSO, 35 8C, 72 h 92 [281]
4-MeOC6H4CH2 NaOEt, EtOH, reflux, 18 h 67 [303]
4-pyridyl NaOMe, MeOH, rt, 24 h 75 [304]
Malonamides 304 (X = CONHR1) give an unusual reaction with phenyl azide from which1H-1,2,3-triazol-5-ols 306 are isolated; aniline is also formed (Scheme 101).[305] A mecha-nism has been suggested involving cyclization of the triazene intermediate 305 with dis-placement of aniline. Similar behavior is observed in the reaction of N-methylphenylacet-amide (304, X = Ph; R1 = Me) with phenyl azide.[305] However, with phenylacetamide (304,X = Ph; R1 = H) a mixture of two triazoles is obtained: the corresponding triazole 306(R1 = H; X = Ph) and 1,4-diphenyl-1H-1,2,3-triazol-5-ol. With malonic esters and amides sub-stituted at the central carbon, triazole formation is accompanied by decarboxylation and4-alkyl- or 4-aryl-1H-1,2,3-triazol-5-ols are obtained.[305,306]
Scheme 101 Reaction of Phenyl Azide with Malonamides and Phenylacetamide[305]
N
NN
R1
X
305
HO
R1 = H, Me; X = CONHR1, Ph
− PhNH2PhN3 X+
NaOEtN
O NHR1
NNHPhX
306
NHR1
O
304
N-Arylsulfonylmalonamide derivatives 307 and malonohydrazides 309 react with tosylazide to give selectively 1-(arylsulfonyl)- and 1-(arylmethyleneamino)-1H-1,2,3-triazol-5-ols 308 and 310, respectively, in moderate to good yields (Scheme 102).[307] The mecha-nism of the reaction involves a diazo group transfer followed by subsequent cyclizationof the intermediate diazomalonate derivative.
482 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 102 Reaction of Tosyl Azide with Malonohydrazides and N-Tosylmalonamides[307]
N
NNNa+ −O
R1 = H, Me; R2 = Ts, 4-O2NC6H4; Ar1 = 4-Tol, Ph
62−68%
TsN3, NaOEt, EtOHO
R1R2N NH
O
SO2Ar1
308
SO2Ar1
O
R1R2N
307
N
NNNa+ −OAr1 = 4-MeOC6H4 52%
Ar1 = 4-FC6H4 82%
O
BnHN NH
O
N
310
N
O
BnHN
309
Ar1
TsN3, NaOEt, EtOH
0−5 oC to rt, 2 h
Ar1
The reaction of phosphonyl and phosphinyl acetamides 311 with tosyl azide, in the pres-ence of potassium tert-butoxide, yields 1H-1,2,3-triazolols 313, presumably via diazo de-rivatives 312 (Scheme 103).[308,309]
Scheme 103 Reaction of Tosyl Azide with Phosphonyl and Phosphinyl Acetamides[308,309]
N
NH
N
HO
R12P
R1 = OEt 56%
R1 = Ph 70%
313311
R12P CONH2
OTsN3, t-BuOK
R12P CONH2
O
N2 O
312
1-(Arylmethyleneamino)-1H-1,2,3-triazol-5-ol Sodium Salts 310; General Procedure:[307]
The malonohydrazide 309 (2 mmol) was suspended in a soln of NaOEt (0.136 g, 2 mmol) inEtOH (12 mL) and tosyl azide (0.40 g, 2 mmol) was added dropwise at 0–5 8C. The mixturewas stirred for 2 h after which the precipitate 310 was collected by filtration and dried.
13.13.1.1.3.1.3.3 Method 3:Reaction of Azides with Acetonitrile Derivatives
Organic azides react with acetonitrile derivatives 314 to give 1-substituted 1H-1,2,3-tri-azol-5-amines 315 in good yields (Scheme 104). However, to avoid Dimroth rearrange-ment of the products, the reactions must be carried out at low temperatures (0–20 8C).[304]
In the reactions of acetonitrile derivatives with 2-substituted aryl azides (e.g., 2-nitrophen-yl azide, 2-azidobenzoic acid, or 2-azidobenzonitrile), the 1H-1,2,3-triazol-5-amine can re-act further by condensation of the amino group with the ortho substituent on the 1-phenylgroup, resulting in the formation of fused 1,2,3-triazoles.[310–313,317] Best yields are obtainedwith aryl, hetaryl, and benzyl azides but some good results have also been obtained withalkyl azides.[279,314]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 483
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 104 Reaction of Azides with Acetonitrile Derivatives[279–282,291,294,304,315–324]
N
NN
R2
H2N
R2 = aryl, CN, CO2R3, CONR3R4, PO(OEt)2
315
314
R2 CNbase
R1N3 +
R1
N
NN
R1
HN
R2H
N
NN
NR1−R2
H
R1 R2 Conditions Yield (%) Ref
(CH2)5Me Ph t-BuOK, THF, rt, 12 h 98 [279]
Me t-Bu LDA, Et2O, –78 to 08 C, 1 d 35 [315]
Bn Bn NaNH2, iPr2O, reflux, 7 d 24 [280]
CH2SPh 2-FC6H4 K2CO3, DMSO, rt, 16 h 29 [316]
Ph Ph NaOMe, MeOH, 0 8C to rt, 24 h 99 [317,318]
4-pyridyl Ph NaOMe, MeOH, rt, 24 h 82 [304]
4-O2NC6H4 CO2Me NaOMe, MeOH, rt, 24 h 89 [304]
Bn Ph K2CO3, DMSO, rt to 40 8C, 24 h 84 [281]
Bn Ph t-BuOK, THF, rt, 12 h 78 [279]
Bn CN K2CO3, DMSO, rt to 40 8C, 18 h 48 [281]
Bn CONH2 K2CO3, DMSO, rt to 40 8C, 5 h 84 [281]
Bn CONH2 NaOEt, EtOH, reflux, 1 h 81 [319]
Bn CO2Et NaOEt, EtOH, reflux, 3 h 25 [319]
Bn CO2H NaOEt, EtOH, reflux, 4 h 20 [319]
Ph CONH2 NaOMe, MeOH, rt, 24 h 88 [320]
Ph CONMe2 Et2O, NaOMe, MeOH, 0 8C, 24 h 74 [321]
4-HO2CC6H4 CONH2 NaOMe, MeOH, rt, 7 d 61 [320]
2-O2NC6H4 CONH2 NaOEt, EtOH, 0 8C to rt, 23 h 55 [322]
3,3-dimethylbut-1-enyl CONH2 NaOMe, MeOH, reflux, 30 min 62 [282]
1-naphthyl CO2Et NaOEt, EtOH, 0 8C to rt, 6 h 94 [323]
4-pyridyl CO2Et NaOEt, EtOH, 0 8C to rt, 16 h 86 [323]
4-quinolyl CONH2 NaOEt, EtOH, 0 8C to rt, 21 h 91 [323]
4-quinolyl CO2Et NaOEt, EtOH, 0 8C to rt, 21 h 79 [323]
N N Ph
CN NaOEt, EtOH, rt, 4 h 69 [291]
484 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bR1 R2 Conditions Yield (%) Ref
N N Ph
Ph NaOEt, EtOH, rt, 4 h 81 [291]
acridin-9-yl 2-pyridyl NaOMe, MeOH, rt, 24 h 70 [294]
acridin-9-yl piperidino-carbonyl
NaOMe, MeOH, rt, 24 h 26 [294]
acridin-9-yl 4-ClC6H4NHCO NaOMe, MeOH, rt, 24 h 15 [294]
Ph PO(OEt)2 NaOEt, EtOH, rt, 3 h 76 [324]
The reaction of cyanoacetamide with glycosyl azides, in aqueous dimethylformamidewith potassium hydroxide and at room temperature gives 5-amino-1-glycosyl-1H-1,2,3-tri-azole-4-carboxamide shows that this type of cycloaddition has a two-step mechanism.[278]
Also using cyanoacetamide and gycosyl azides, a study of the influence of the reactionconditions (the nature of the solvent and base) on the retention or inversion of the config-uration of the anomeric carbon has been described.[325] A range of 1-(substituted benzyl)-5-amino-1H-1,2,3-triazole-4-carboxamides has been prepared from the reaction of cyano-acetamide with benzyl azides.[326]
Treatment of 2-oxocyclododecanecarbonitrile (316) with phenyl azide in the pres-ence of a catalytic amount of sodium ethoxide for four days at room temperature leadsto the formation of 1H-1,2,3-triazol-5-amine 317 and lactam 318 in 60 and 10% yield, re-spectively (Scheme 105).[297] A mechanism for the formation of these two compounds hasbeen proposed.
Scheme 105 Reaction of 2-Oxocyclododecanecarbonitrile with Phenyl Azide[297]
N
NNH2N
316
+
O
CN
NaOEt
EtOH, THF
rt, 4 d
Ph
EtO2C ( )10
317 60%
HN
O
NN
N
Ph+
318 10%
PhN3
Sulfonyl azides do not generally give triazoles with activated methylene compounds.However, in aqueous alkaline solutions, sulfonyl azides, and also azidoformates andN,N-dimethylcarbamoyl azide, react with malononitrile to yield N-unsubstituted 1,2,3-tri-azoles 319, 320, and 321, respectively, in good to excellent yields, as indicated in Scheme106.[327]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 485
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 106 Reaction of Malononitrile with Sulfonyl and Carbonyl Azides[327]
CN
CN
OH−, H2O
5 oC, 1 hCN
CN
−N
NH
N
NC
H2N
320
N
NH
N
NC
NH
319
SR1OO
N
NH
N
NC
NH
321
Me2N
OO
Me2N N3
O
R2O N3
R1SO2N3
71−96%
58−60%
63%
R1 = Me, Ph, 4-Tol, 4-MeOC6H4, 4-O2NC6H4; R2 = Et, t-Bu
13.13.1.1.3.1.3.4 Method 4:Reaction of Aryl Azides with Alkoxides
Aryl azides react with sodium ethoxide or propoxide to afford 1-aryl-1H-1,2,3-triazoles322 in moderate yields (Scheme 107).[328] Two equivalents of azide are required, the sec-ond being reduced to aniline. The mechanism[3] of this reaction probably involves the for-mation of an aldehyde by hydride transfer from the alkoxide to one mole of aryl azide.The attack of the carbanion of the aldehyde so produced on a second mole of the azideleads to the triazole. The reaction of tosyl azide with sodium butoxide yields only butyltoluenesulfonate.[184]
Scheme 107 Reaction of Aryl Azides with Alkoxides[328]
N
NN
322
R1
R1 = H, Me; X = H, Cl, Br, Me, NO2
reflux, 1−5 d2 X N3 NaO
R1+
X
− 4-XC6H4NH2
30−70%
1-Aryl-4-methyl-1H-1,2,3-triazoles 322 (R1 = H); Typical Procedure for Condensation ofAryl Azides with Sodium Propoxide:[328]
The appropriate aryl azide (0.03 mol) was added to a cold soln of NaOPr (0.04 mol) and themixture was refluxed on a water bath for 24 h. The brownish product was acidified withconcd HCl, steam-distilled, made alkaline, and steam-distilled again. The residual solnwas extracted with Et2O; when the extract was evaporated, the 1-aryl-4-methyl-1H-1,2,3-triazole 322 (R1 = Me) separated and was crystallized (petroleum ether or EtOH/H2O).
486 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.1.4 By Formation of One N-N Bond
13.13.1.1.4.1 Fragment N-N-C-C-N
13.13.1.1.4.1.1 Method 1:Cyclization of Æ-Diazoamides
Æ-Diazoamides can be cyclized to 1H-1,2,3-triazoles by treatment with base[298,308,309,329] orby other methods. Some reactive Æ-diazoamides cyclize spontaneously to the correspond-ing triazoles; one example is indicated in Scheme 108. The intermediate Æ-diazoamides324, generated in situ from the reaction of ethyl N-(diazoacetyl)glycinate (323) with ben-zoyl bromides, cyclize spontaneously to triazoles 325.[330]
Scheme 108 Cyclization of Ethyl N-(3-Aryl-2-diazo-3-oxopropanoyl)glycinates[330]
325
CH2Cl2rt, 76−91 h
R1 = H 50%
R1 = Br 15%
NH
O
H
N2
CO2Et
R1
Br
O
+
R1
O
NH
O
N2
CO2Et
O
N
NN
HO
324
323
R1
CO2Et
Reaction of Æ-diazoamide 326 with phosphorus pentachloride gives methyl 1-benzyl-5-chloro-1H-1,2,3-triazole-4-carboxylate (328) through the intermediate imidoyl chloride327 (Scheme 109).[331] N-Unsubstituted 5-halo-1H-1,2,3-triazoles are also obtained in goodto excellent yields by treatment of diazomalononitrile derivatives with hydrogen ha-lides.[1]
Scheme 109 Cyclization of a Diazomalonamide[331]
N
NN
326
MeO2CPCl5
80 oC, 3 hMeO2C N2
O NHBn
MeO2C N2
Cl NBn
327 328
BnCl
13.13.1.1.4.1.2 Method 2:Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones
Æ-Azidoacetophenone (phenylsulfonyl)hydrazones 330, prepared by the reaction of thecorresponding Æ-bromoacetophenone (phenylsulfonyl)hydrazones with sodium azide,are converted into 4-aryl-1H-1,2,3-triazoles 332, in good yields on heating in refluxingbenzene (Scheme 110). The reaction proceeds probably via the elimination of benzene-sulfinic acid from the intermediate 2-(phenylsulfonyl)-2,5-dihydro-1H-1,2,3-triazoles331.[332] The Æ-bromoacetophenone (phenylsulfonyl)hydrazones 329 react with benzyl-
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 487
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bideneaniline to yield 4-aryl-1-phenyl-1H-1,2,3-triazoles (19–25%) and substituted 2,3,4,5-tetrahydro-1,2,4-triazines (20–45%).[333]
Scheme 110 Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones[332,333]
N
NH
N
329
332
Ar1− PhSO2H
71−96%
NH
NNAr1 SO2PhAr1 N
HN
N
••
Ar1 N
HN
BrNaN3, DMF
82−94%
330
Ar1 N
HN
N3
− N2
benzene
reflux, 2 h
331
SO2Ph SO2Ph
SO2Ph
Ar1 = 4-XC6H4; X = H, Br, Cl, NO2, Me, Ph, N NPh
13.13.1.1.4.1.3 Method 3:Cyclization of Æ-Hydroxyimino Hydrazones
Cyclic Æ-hydroxyimino hydrazones 334 and 337 (prepared from Æ-hydroxyimino ketones333 and 336, respectively) on heating at 170–190 8C for three hours in diethylene glycolcontaining potassium hydroxide yield the N-unsubstituted 1,2,3-triazoles 335 and 338(Scheme 111). The yield of triazole significantly decreases as the size of the ketone ringincreases from five- to six- to seven-membered, that is as the rings become more flexibleand the hydrazone and oxime groups less coplanar.[334,335] Under the same conditions, acy-clic Æ-hydroxyimino hydrazones do not give triazoles; in this case, the normal Wolff–Kish-ner reduction products are obtained.
Scheme 111 Cyclization of Æ-Hydroxyimino Hydrazones[334,335]
O
N
( )n
333
H2NNH2
N
N( )n
334
15−52%
KOH
diethylene glycol
170−190 oC, 3 h( )n
335
NH
N
N
n = 1−3
OH OH
NH2
336
H2NNH2
32%
KOH
diethylene glycol
170−190 oC, 3 h
338
O
N
337
N
N
NN
NHOH OH
NH2
Glyoxal O-benzyloxime hydrazone 340, generated in situ by addition of glyoxal O-benzyl-oxime 339 to a 10-fold excess of hydrazine, gives 1-(benzyloxy)-1H-1,2,3-triazole 341 byoxidative cyclization (Scheme 112). Copper(II) sulfate is the best oxidant but manganesedioxide and nickel peroxide can also be used.[336]
488 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 112 Cyclization of Æ-Hydroxyimino Hydrazone Derivatives[336]
N
NN
H2NNH2, MeOH
0 oC, 45 min
341
OBn
N
O
OBn
N
N
OBn
340339
CuSO4•5H2O, py
100 oC, 30 min
52−63%
NH2
3,8-Dihydroindeno[1,2-d][1,2,3]triazole (335, n = 1); Typical Procedure:[335]
1H-Indene-1,2(3H)-dione 1-hydrazone 2-oxime (334, n = 1; 930 mg, 5.3 mmol) and KOH(1.23 g, 22 mmol) in purified diethylene glycol (50 mL) was heated, with a stream of N2
bubbling through it, until the temperature reached 170–190 8C (ca. 30 min). Heating wasmaintained at this temperature for 3 h and N2 was bubbled through the soln for the entiretime. The mixture was then cooled, diluted with 1 M aq KOH (400 mL), and extracted withCH2Cl2 (4 � 200 mL). The alkaline soln was acidified with HCl and the pH was adjusted to 7with NaHCO3. The soln was again extracted with CH2Cl2 (4 � 200 mL). Each extract wasback-washed with sat. aq NaCl (2 � 100 mL). These organic extracts were combined, dried(Na2SO4), filtered, and evaporated in vacuo to yield a weakly acidic fraction (584 mg)which was sublimed (100 8C/0.2 Torr) to yield triazole 335 (n = 1); yield: 432 mg (52%); mp144 8C.
13.13.1.1.4.1.4 Method 4:Cyclization of Æ-Hydroxyimino Aroyl- or Arylsulfonylhydrazones
Oxidation of Æ-hydroxyimino aroylhydrazones 342 with lead(IV) acetate in acetic acidgives 1-(aroyloxy)-4,5-dimethyl-1H-1,2,3-triazoles 344 in moderate yields (Scheme 113).This transformation probably involves an intramolecular [1,3]-aroyl migration in the in-termediate 343.[337]
Scheme 113 Oxidation of Æ-Hydroxyimino Aroylhydrazones with Lead(IV) Acetate[337]
N
NN
Pb(OAc)4, AcOH
CH2Cl20 oC, 30 min
344
O
N
N
342
NH
Ar1
O
35−48%
N
NN
O−
Ar1
O
O
Ar1+
343
Ar1 = 4-XC6H4; X = H, Me, OMe, Cl, NO2
OH
Æ-Hydroxyimino tosylhydrazones 345 are converted into 4-aryl-5-methyl-1H-1,2,3-triazol-1-ols 347 in good yields by thermal cyclization of salts 346 (Scheme 114).[24] The Æ-diazooximes 348 are probable intermediates in this transformation. Attempts to prepare 4,5-dimethyl-1H-1,2,3-triazol-1-ol by this method failed.[24]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 489
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 114 Cyclization of Æ-Hydroxyimino Tosylhydrazones[24]
N
NN
NaOEt, EtOH
DME
rt, 30 min
347
OH
N
N
345
Ar1
NHTs
75−77%
Ar1
Ar1 = Ph, 4-MeOC6H4
N
N
346
Ar1
NHTs
O− Na+
diglyme
reflux, 45−90 min
N
NAr1
NTs
− Na+
NOH
NAr1
N−+
OH
OH
348
1-(Aryloxy)-4,5-dimethyl-1H-1,2,3-triazole 344 by Oxidation of Æ-Hydroxyimino Aroyl-hydrazones; General Procedure:[337]
A soln of 342 (1 mmol) in AcOH/CH2Cl2 (1:5, 30 mL) was added over 20 min to a stirred solnof Pb(OAc)4 (4 mmol) in dry CH2Cl2 (30 mL). The soln was stirred at 0 8C for 30 min and then10% aq Na2S2O3 was added. The organic layer was separated, washed with brine, dried, andevaporated. The resulting residue was either chromatographed or recrystallized from theappropriate solvent.
13.13.1.1.4.1.5 Method 5:Cyclization of 1,2-Diketone Bis(hydrazone) Derivatives
1,2-Diketone bis(hydrazones) and some of their derivatives such as bis(semicarbazones),bis(arylsulfonylhydrazones), and bis(acylhydrazones) are converted into 1H-1,2,3-triazol-1-amines. The cyclization of these compounds is carried out by oxidation or by treatmentwith acids or bases.
13.13.1.1.4.1.5.1 Variation 1:Cyclization of 1,2-Diketone Bis(hydrazones)
Oxidation of bis(hydrazones) 349 with manganese dioxide or mercury(II) oxide gives 1H-1,2,3-triazol-1-amines 350 (Scheme 115). Although two isomeric triazoles would be ex-pected from unsymmetrical bis(hydrazones), compounds 349 give only the 4-aryl-1,2,3-triazol-1-amines.[338] Other vicinal bis(hydrazones) have been converted into 1H-1,2,3-tri-azol-1-amines.[339–342] The major disadvantage of this method is that unless the conditionsare carefully controlled, complete oxidation of the bis(hydrazones) occurs and the isolat-ed products are alkynes. Pyrolysis of cyclooctane-1,2-dione bis(hydrazone) yields the cor-responding N-unsubstituted 1H-1,2,3-triazole.[342]
490 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 115 Cyclization of 1,2-Diketone Bis(hydrazones)[338]
MnO2 or HgO
N
N
349
Ar1
H
Ar1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4, 2-naphthyl
N
NN
NH2
H
Ar1
350
NH2
NH2
13.13.1.1.4.1.5.2 Variation 2:Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones)
Vicinal bis(arylsulfonylhydrazones) 351 can be cyclized using either acid or base to give 1-(arylsulfonylamino)-1H-1,2,3-triazoles.[343,344] When unsymmetrical 1,2-diketones areused, the two possible triazoles 352 and 353 are obtained (Scheme 116).[345,346] Benzil bis-(tosylhydrazone) cyclizes to 4,5-diphenyl-1-(tosylamino)-1H-1,2,3-triazole by oxidationwith either mercury(II) or lead(IV) acetates in acetic acid.[347] This type of triazole is alsoobtained by thermal[348] or photochemical[349] decomposition of the dianions of thebis(tosylhydrazones) of 1,2-diketones. The 1-(arylsulfonylamino)-1H-1,2,3-triazoles areconverted into 1H-1,2,3-triazol-1-amines by treatment with sulfuric acid.
Scheme 116 Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones)[345,346]
H+ or OH−
heat
351
N
NN
HN
R2
R1
352
N
NN
HN
R1
R2
353
+
NHN
NH
NSO2Ar1
SO2Ar1
R1
R2
SO2Ar1 SO2Ar1
4,5-Diphenyl-1-(tosylamino)-1H-1,2,3-triazole (352, R1 = R2 = Ph; Ar1 = 4-Tol);Typical Procedure:[345]
Benzil bis(tosylhydrazone) (74 g, 0.14 mol) was added rapidly to a stirred soln of KOH (9 g,0.16 mol) in ethylene glycol (400 mL) at 120 8C. After 10 min the soln was cooled to 40 8Cand H2O was added slowly, with rapid stirring, until a precipitate began to appear. Themixture was then acidified with 2 M HCl and more H2O was added until the total volumewas 1 L. The precipitate was then collected by filtration, dried, and washed well withpetroleum ether to leave the triazole; yield: 43 g (81%); mp 232–233 8C (EtOH).
13.13.1.1.4.1.5.3 Variation 3:Cyclization of 1,2-Diketone Bis(semicarbazones)
The 1,2-diketone bis(semicarbazones) 354 undergo cyclization on treatment with lead(IV)acetate to give 1-ureido-1H-1,2,3-triazoles 355 (Scheme 117). These compounds are hy-drolyzed with concentrated hydrochloric acid to give the corresponding 1H-1,2,3-triazol-1-amines 356.[350]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 491
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 117 Cyclization of 1,2-Diketone Bis(semicarbazones)[350]
Pb(OAc)4
CH2Cl2rt, 3 h
354
N
NN
HN
R2
R1
355
N
NN
NH2
R2
R1
356
30−40%
HCl, reflux, 2 h
50−65%
NHN
NH
NCONH2
CONH2
R1
R2
CONH2
R1 R2 1-Ureido-1H-1,2,3-triazole 355 1H-1,2,3-Triazol-1-amine 356 Ref
Yield (%) mp (8C) Yield (%) mp (8C) [350]
Me Me 30 225–226 65 89–91 [350]
Ph Ph 40 209–211 55 126–128 [350]
Ph Me 34 207–208 55 142–144 [350]
4-Tol Me 40 203–204 58 164–165 [350]
4-BrC6H4 Me 38 204–205 50 169–171 [350]
4-Tol H 32 224–226 52 123–124 [350]
1-Ureido-1H-1,2,3-triazoles 355; General Procedure:[350]
Pb(OAc)4 (0.021 mol) was added to a suspension of bis(semicarbazone) 354 (0.02 mol) inCH2Cl2 (100 mL) and the mixture was stirred at rt for 3 h. The mixture was filtered andthe precipitate was treated with MeOH. The methanolic soln upon evaporation gave the1-ureido-triazole which was recrystallized (MeOH or EtOH).
13.13.1.1.4.1.5.4 Variation 4:Cyclization of 1,2-Diketone Bis(acylhydrazones)
1,2-Diketone Bis(acylhydrazones) undergo oxidative cyclization to 1H-1,2,3-triazol-1-amine derivatives 360–362 (via intermediate 358/359) (Scheme 118). Lead(IV) acetate isthe oxidant most used for this transformation. With bis(aroylhydrazones) 357 (R2 = aryl)the principal products are imides 360 and amides 361.[351–355] On the other hand, oxida-tion of bis(arylacetylhydrazones) 357 (R2 = arylmethyl) yields mainly 1-(arylacetylamino)-1,2,3-triazoles 362 (R2 = arylmethyl) in moderate yields.[356] Oxidation of bis(acetylhydra-zones) 357 (R2 = Me) with lead(IV) acetate gives amides 361 (R2 = Me) as the primary prod-ucts but partial hydrolysis to monoacetylamino derivatives 362 may occur in some casesduring the workup.[357] Lead(IV) acetate oxidation of mixed aroylhydrazones of biacetyl af-fords pairs of isomeric triazoles (of the imide 360 type) in different proportions.[358]
492 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 118 Cyclization of 1,2-Diketone Bis(acylhydrazones)[357]
Pb(OAc)4
CH2Cl2rt, 1−2 h
357
N
NN
−N
R1
R1
358
N
NN
HN
R1
R1
COR2
COR2
+N
NN
N
R1
R1
359
COR2+
N
NN
N
R1
R1
360
OCOR2
R2
N
NN
N
R1
R1
+ +
361 362
R2
O−N
HN
NH
NCOR2
COR2
R1
R1
R2OC COR2 COR2
Lead(IV) Acetate Oxidation of Bis(acylhydrazones) 357; General Procedure:[357]
To a stirred suspension of the bis(acylhydrazone) (2 mmol) in CH2Cl2 (20 mL) was addedPb(OAc)4 (2.4 mmol) dissolved in CH2Cl2 (20 mL). The slight excess of the oxidant waschecked throughout the experiment by the use of KI/starch paper and maintained, if nec-essary, by the addition of extra amounts of Pb(OAc)4. When all the starting material wasconsumed the mixture was filtered and the filtrate was extracted successively with aqNa2S2O3 and Na2CO3. The dried soln was evaporated under reduced pressure and the resi-due was chromatographed (medium pressure, silica gel, petroleum ether/EtOAc, gradientelution). The isolated products were further purified by recrystallization.
13.13.1.1.4.1.6 Method 6:Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene)
(1,2-Diphenylethene-1,2-diyl)bis(trityldiazene) (363) cyclizes readily to the 1H-1,2,3-tri-azol-1-amine derivative 365 when treated with acetic acid or left in suspension in ordina-ry unpurified chloroform for several days (Scheme 119).[359] The dipolar compound 364 isa probable intermediate in this transformation. Treatment of compound 365 with benzo-yl chloride yields 1-benzoylamino)-4,5-diphenyl-1H-1,2,3-triazole. The synthetic useful-ness of this method is still to be demonstrated. See also Section 13.13.2.1.3.1.2 for the cy-clization of 1,2-diketone bis(arylhydrazones) to 2H-triazoles.
Scheme 119 Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene)[359]
N
N
363
Ph
Ph
N
NN
−N
Ph
Ph
NTr
NTr
364
N
NN
NHTr
Ph
Ph
Tr
Tr
+AcOH
365
90%
4,5-Diphenyl-N-trityl-1H-1,2,3-triazol-1-amine (365):[359]
A suspension of (1,2-diphenylethene-1,2-diyl)bis(trityldiazene) (363; 0.5 g, 0.69 mmol) in90% AcOH (10 mL) was evaporated to one half of the original volume on a hot plate. Thesolid dissolved with disappearance of the red color in a few minutes. Upon cooling, the
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 493
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bwhite crystalline triazolamine 365 was separated; yield: 0.30 g (90%). Recrystallization(petroleum ether/benzene) gave crystals; mp 265–267 8C.
13.13.1.1.5 By Formation of One N-C Bond
13.13.1.1.5.1 Fragment N-N-N-C-C
13.13.1.1.5.1.1 Method 1:Cyclization of Linear Triazenes and Tetrazenes
Triazenes are a recognized intermediate in the synthesis of 1,2,3-triazoles starting froman azide and an activated methylene compound (see Section 13.13.1.1.3.1.3, Scheme 95).Stable triazene compounds can also be cyclized to 1,2,3-triazoles.[360–364] For example, 1-aryl-3-(cyanomethyl)triazenes 366 cyclize in aprotic media with Lewis base catalysis togive 1-aryl-1H-1,2,3-triazol-5-amines 367 (Scheme 120). If the reaction is carried out inprotic media the cyclization is followed by Dimroth rearrangement and the isolated prod-ucts are the isomeric N-aryl-1H-1,2,3-triazol-5-amines 368.[363] Treatment of chloroform so-lutions of triazenes 366 with suspended basic alumina for several days yields the 1H-1,2,3-triazol-5-amines 367 essentially free from isomers 368. However, refluxing the triazenes(X = 4-NO2 or 4-CN) in absolute ethanol for 1–2 hours gives triazoles 368 with no trace ofthe isomeric triazoles 367. In a similar process, 1-aryl-1H-1,2,3-triazol-5-ols are preparedby cyclization of 1-aryl-3-(ethoxycarbonylmethyl)triazenes.[364]
Scheme 120 Cyclization of Linear Triazenes[363]
367N
NH
NHN
N
N NH
CN
X
alumina, CHCl3rt, 7 d
N
NNH2N
X
X
Dimroth
rearrangement
366
368
X = NO2, CN, CO2Me, CONH2
36−92%
The 1,2,3-triazole system can also be formed by the isomerization of 1-(arylazo)aziridines369 (Scheme 121). This isomerization is catalyzed by iodide ions and the product is a 1-aryl-4,5-dihydro-1H-1,2,3-triazole 371.[365] The isomerizations probably occur by a nucleo-philic attack of iodide ion on the aziridinyl carbon to yield the ion 370, which subse-quently displaces an iodide ion by the negatively charged nitrogen. Although the 4,5-dihy-dro-1H-1,2,3-triazoles 371 are obtained in high yields, this is a dangerous method sincesome 1-(arylazo)aziridines 369 explode violently on standing at room temperature for20–30 minutes.[365]
494 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 121 Isomerization of 1-(Arylazo)aziridines[365]
N
NN
NaI, acetone
rt, 30 min
or reflux, 1 h
369
371
64−98%
Ar1
N
NAr1N
−N
NAr1N
I
N
NAr1N
I
370
−
Anodic oxidation of 1-aryl-3,3-dimethyltriazenes in acetonitrile gives 2-aryl-5-methyl-2H-1,2,3-triazole-4-carbonitriles in low yields.[366] Methyl 1-benzyl-1H-1,2,3-triazole-4-carbox-ylate is obtained in 2% yield, together with several other products, by photolysis of a tet-raz-2-ene;[367] this method has very limited synthetic interest.
1-Aryl-1H-1,2,3-triazol-5-amines 367 by Cyclization of 1-Aryl-3-(cyanomethyl)triazenes;General Procedure:[363]
The triazene 366 (250 mg) was dissolved in the minimum volume of CHCl3 (25–50 mL) andbasic alumina (2.5 g) was added. The suspension was stirred at rt for 7 d. The mixture wasfiltered to remove alumina and the filtrate evaporated to dryness in vacuo. The residuewas the 1H-1,2,3-triazol-5-amine 367.
13.13.1.1.5.1.2 Method 2:Cyclization of Vinyl Azides
In the presence of a base, vinyl azides (e.g., 372) cyclize to 1H-1,2,3-triazoles, such as 374(Scheme 122).[85,190] A probable mechanism for such transformation involves the forma-tion of the anion of the vinyl azide, which then cyclizes to the aromatic triazole anion(e.g., 373). Protonation affords the final product.
Scheme 122 Cyclization of 2-Tosylvinyl Azides[85,190]
N
NH
N
NaTs, DMSO
>24 h
372
374
TsH2O
H N3
Ts H Ts
NN
N
+−
−−
N
NN
Ts
373
Methyl 3,3-diazido-2-cyanoacrylate (375) reacts with amines to give vinyl azides 376,which undergo 1,5-cyclization to form triazoles 378 (via 4H-1,2,3-triazoles 377) in goodyields (Scheme 123).[368] Under controlled reaction conditions (catalytic amount of theamine and absence of moisture) vinyl azides 376 are converted into methyl 1,2,3-tri-azole-2-carboxylates 379.[369]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 495
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 123 Reaction of Methyl 3,3-Diazido-2-cyanoacrylate with Amines[368,369]
N
NH
N
R1R2NH, CH2Cl20 oC to rt, 12 h
375
378
R1R2N
NC CO2Me
N3 N3
− HN3
376
NC CO2Me
R1R2N N3
N
NN
R1R2N
NC
MeO2C
377
NC
N
NN
379
R1R2N
NC CO2Me
61−84%
NR1R2 = pyrrolidin-1-yl 90%
NR1R2 = piperidino 68%
NR1R2 = NEt2, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl
13.13.1.1.5.1.3 Method 3:Cyclization of 2-(Formyloxy)vinyl Azides
(Z)-2-(Formyloxy)vinyl azides are converted into 1H-1,2,3-triazoles by using triethyl phos-phite (Scheme 124).[370] Addition of triethyl phosphite to formate 380 immediately initi-ates an exothermic reaction producing a deep orange solution. Evaporation of the solventand purification by silica gel chromatography gives triazole 382. It has been shown byNMR that N-formyltriazole 381 (which can be isolated) is the initial product of cyclization.4-Phenyl-1H-1,2,3-triazole is prepared by cyclization of formate 383 following the samemethodology.[370]
Scheme 124 Cyclization of (Z)-2-(Formyloxy)vinyl Azides[370]
P(OEt)3
CHCl3rt, 24 h silica gel
380
O
OH
N3
381
NN
NCHO
382 46%
NH
NN
H N3
Ph O O
H
1. P(OEt)3, CHCl3, 10 min
2. silica gel
62%
N
NH
N
Ph
383
496 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.2 Synthesis by Ring Transformation
There are several heterocyclic compounds that, by chemical modification or just by isom-erization, are converted into 1H-1,2,3-triazoles or 2H-1,2,3-triazoles (see also Section13.13.2.2). Despite some synthetically interesting exceptions, in most cases the startingheterocycles are not readily available and the routes are unlikely to be general. Thefollowing are examples of transformations of this type that lead to 1H-1,2,3-triazole deriv-atives: (a) diazotization of isoxazol-4-amines to give triazol-1-ols,[371,372] (b) diazotization of5-aminothiazol-2-ols to give triazol-4-ols,[373] (c) diazotization of 3-aminopyridinium saltsto give 4-(3-oxoprop-1-enyl)-1,2,3-triazole derivatives,[374,375] (d) base-induced rearrange-ment of sydnoneimines to give triazol-4-ols,[376] (e) reaction of ethyl 2-amino-4,5-dihydro-furan-3-carboxylates with phenyl azide to give 1H-1,2,3-triazol-5-amines,[377] (f ) thermoly-sis of 5-diazo-6-methoxyuracils results in the formation of 4-acyl-1,2,3-triazole deriva-tives,[378–380] (g) reaction of 1,2,4-triazin-3-ones with N-chlorinating agents,[381] (h) treat-ment of 1,2,4-triazin-3-one 2-oxides with acetic anhydride,[382] (i) reduction or oxidationof triazolotriazoles,[383,384] (j) diazotization of 7�-amino cephalosporin sulfones,[385] (k)thermolysis of mesoionic oxatriazolones in the presence of alkynes,[386] (l) reaction of1,3,3-trimethyl-2-methylene-2,3-dihydro-1H-indole with aryl azides,[387] (m) reaction ofisothiazole dioxides with sodium azide,[388] (n) reaction of triazolo[1,5-a]pyridines withaniline,[389] (o) permanganate oxidation of substituted benzotriazoles,[390–392] (p) hydrolyticcleavage of 1,2,3-triazolo[4,5-d]pyrimidines,[393–395] and (q) reaction of 4-oxo-4H-pyridi-no[1,2-a]pyrimidine-3-diazonium salts with primary alcohols.[396]
The chemical transformation of 1,2,3-thiadiazoles into 1H-1,2,3-triazoles is a synthet-ically useful method. For example, base-catalyzed isomerization of 1,2,3-thiadiazol-5-amine derivatives affords 1H-1,2,3-triazole-5-thiols in high yields.[397–401] Also, thermolysisof 5-[alkyl- or 5-[allyl(alkoxycarbonyl)amino]-1,2,3-thiadiazoles 384 in a sealed glass tubein the absence of solvent gives 5-(alkylsulfanyl)-1H-1,2,3-triazoles 385 (Scheme 125).[402]
Scheme 125 Thermolysis of 5-(Alkoxycarbonylamino)-1,2,3-thiadiazoles[402]
− CO2
43−92%
N
NNR2S
R1
220 oC, 15 minN
SNN
R2O2C
R1
384 385
R1 = Me, Et, CH2CH CH2; R2 = Me, Et
Another example of this approach is the conversion of 5-chloro-1,2,3-thiadiazole-4-carbal-dehyde 386 into 1H-1,2,3-triazole-4-carbothioamides 390 (Scheme 126).[403] A wide varietyof amine derivatives can be used in this method. A probable mechanism for this transfor-mation involves intermediates 387–389 and is indicated in Scheme 126. Other examplesof conversion of 5-chloro-1,2,3-thiadiazole derivatives into 1H-1,2,3-triazoles are report-ed.[404,405]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 497
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 126 Reaction of 5-Chloro-1,2,3-thiadiazole-4-carbaldehyde with Amines[403]
50−93%
N
SNCl
386
OHC
R1 = Me, Et, Bn, Ph, 4-MeOC6H4, 4-ClC6H4, NH2, NHPh, morpholino, OH
R1NH2, MeOH
rt, 30 min to 8 h
N
SNCl
387
H
R1NN2
NR1
Cl
S
N
NN
R1
S
R1HN
390
R1NH2
N
NN
R1
S
Cl
389388
The reaction of diazoalkanes with 3,5-dichloro-2H-1,4-oxazin-2-ones 391 and 3-chloro-2H-1,4-benzoxazin-2-ones 395 is another interesting method for the synthesis of 1H-1,2,3-tri-azole derivatives (Schemes 127 and 128).[406,407] The intermediate bicyclic or tricyclic tri-azolo-fused compounds 393 and 396 are converted into the monocyclic 1H-1,2,3-triazoles394 or 397 by reaction with nucleophiles (amines, methanol, water). The first step of thisprocedure involves the selective attack of the diazoalkane to the imidoyl chloride func-tion (e.g., giving 392) followed by ring closure. Reactions with diazomethane give higheryields (68–91%) of the fused triazoles than reactions with diazoethane or diazopropane(41–52%). The reaction conditions required for the ring cleavage of the lactone functionin compounds 393 are dependent on the nucleophile: with propylamine or diethylamineit takes one hour at room temperature, with aniline it requires three hours at reflux andwith methanol or water it takes 12 hours at reflux. The triazoles 394 obtained from thistwo-step procedure have the interesting Æ-chloro ketone substituent at N1, which may beused for the elaboration of other heterocycles.
498 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 127 Reaction of Diazoalkanes with 3,5-Dichloro-2H-1,4-oxazin-2-ones[406,407]
Et2O
0 oC, 3 d
N
NNNuH
N
O O
ClCl
R1
R2
Nu
OCl
R1
O
394
+ R2CHN2
N
O O
Cl
R1
392
N
R2
N
−
+
391
393
O
N NN
Cl
R1
O R2
Compound R1 R2 Nu Yielda,b (%) Ref
393 Me H – 91 [407]
393 Ph H – 81 [407]
393 2,6-Cl2C6H3 H – 72 [407]
393 2,6-Cl2C6H3 Me – n.r. [407]
393 Me Et – n.r. [407]
394 Me H OMe 95 [407]
394 Ph H OMe 80 [407]
394 Me H NEt2 87 [407]
394 Me Et OMe 28c [407]
394 2,6-Cl2C6H3 Me OMe 25c [407]
394 2,6-Cl2C6H3 H NHPh 84 [407]
394 Me H OH 55 [407]
a n.r. = not reported.b Yield of 394 from 393 or 393 from 391 unless otherwise stated.c Yield of 394 from 391.
Scheme 128 Reaction of Diazoalkanes with 3-Chloro-2H-1,4-benzoxazin-2-ones[406,407]
Et2O
0 oC, 3 d
N
NN
N
O O
Cl
R2
Nu
O
397
+ R2CHN2
395 396
OH
R1
R1
O
N NN
O R2
R1
NuH
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 499
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bCompound R1 R2 Nu Yielda (%) Ref
396 H H – 75 [407]
396 Me H – 71 [407]
396 Cl H – 68 [407]
396 H Me – 52 [407]
396 Cl Et – 41 [407]
397 Cl H OMe 75 [407]
397 Cl Et OMe 60 [407]
397 Cl Et NHPr 76 [407]
397 Me H NHPh 59 [407]
397 H H NEt2 60 [407]
397 H H OH 58 [407]
a Yield of 397 from 396 or 396 from 395.
Methyl 1H-1,2,3-Triazole-5-carboxylates 394 and 397 (Nu = OMe); General Procedure:[407]
CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhala-tion.
Compound 391 or 395 (10 mmol) was slowly added to a Et2O soln of CH2N2 (40 mmol) at0 8C. In the cases of MeCHN2 and EtCHN2, iPr2O was used as solvent and, to avoid violentreactions, the initial temperature was –78 8C. Afterwards the temperature was brought to4 8C and, after stirring for 3 d, the excess of diazo compound and the solvent was evapo-rated. Then the residue was recrystallized (CHCl3/hexane) yielding 393 or 395. This com-pound (10 mmol) was dissolved in MeOH (50 mL), the soln was brought to reflux temper-ature, and the solvent was evaporated after 15 min (for 393) or 12 h (for 396). The residuewas recrystallized (CHCl3/hexane) yielding 394 or 397.
13.13.1.3 Aromatization
4,5-Dihydro-1H-1,2,3-triazoles (triazolines) are intermediates of 1,2,3-triazoles in manysynthetic methods, especially those involving the addition of azides to C=C bonds. Inmost cases 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to the correspondingtriazoles but when they are stable compounds they can be aromatized by oxidation, elim-ination, or isomerization reactions. This subject is discussed in a review.[4] Some illustra-tive examples are described below.
13.13.1.3.1 Method 1:By Oxidation Reactions
The oxidative dehydrogenation of 4,5-dihydro-1H-1,2,3-triazoles 398 to triazoles 399 iscarried out mainly with potassium permanganate or nickel peroxide (Scheme 129). Verygood results are obtained when the reaction is carried out with potassium permanganatein a two-phase system (benzene/water) using tetrabutylammonium chloride as a phase-transfer catalyst.[59,408,409] If the reaction is run in a single phase in anhydrous benzenealone, the products are not triazoles but imines.[410] The oxidation of 4,5-dihydro-1H-1,2,3-triazoles bearing sterically crowded ortho-substituted phenyl groups in the 5-posi-tion with potassium permanganate gives low yields of the corresponding triazoles. Inthese cases much better results are obtained with nickel peroxide.[58,411]
500 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 129 Oxidative Dehydrogenation of 4,5-Dihydro-1H-1,2,3-triazoles[58,408]
N
NN
399
R2
R1
N
NN
398
R2
R1
A: KMnO4, TBACl, benzene, H2O, reflux, 2−8 h
B: NiO2, benzene, reflux, 3−4 h
R1 R2 Method Time (h) Yield (%) Ref
4-pyridyl Ph A 2 65 [408]
4-pyridyl 4-Tol A 2 73 [408]
4-pyridyl 4-ClC6H4 A 3 72 [408]
3-pyridyl 3-O2NC6H4 A 8 58 [408]
2-quinolyl Ph A 7 40 [408]
2-quinolyl 4-ClC6H4 A 5.5 57 [408]
4-O2NC6H4 4-O2NC6H4 A 8 38 [408]
2-ClC6H4 4-MeOC6H4 B 4 63 [58]
2-ClC6H4 3,4-Cl2C6H3 B 3 63 [58]
2,4-Cl2C6H3 Ph B 4 65 [58]
2,4-Cl2C6H3 4-F3CC6H4 B 4 70 [58]
2,6-Cl2C6H3 Ph B 4 50 [58]
2,6-Cl2C6H3 3-ClC6H4 B 3 52 [58]
2,6-Cl2C6H3 4-BrC6H4 B 3 74 [58]
The oxidation of 1-aryl-4-methylene-5-morpholino-4,5-dihydro-1H-1,2,3-triazoles 400with 3-chloroperoxybenzoic acid affords 1-aryl-1H-1,2,3-triazole-4-carbaldehydes 401(Scheme 130). The corresponding carboxylic acids are also produced as byproducts.[412]
4,5-Dihydro-1H-1,2,3-triazoles 400 also react with halomethyl radicals to yield 1,2,3-tria-zole derivatives.[413] Oxidation of 4,5-dihydro-1H-triazole 402 with bromine gives triazole403 in 83% yield (Scheme 130).[202]
Scheme 130 Oxidation of 4,5-Dihydro-1H-1,2,3-triazoles with3-Chloroperoxybenzoic Acid[412] or Bromine[202]
N
NN
401
MCPBA, CHCl3rt, 30 min
OHC
R1
R2
38−70%
N
NN
400
R1
R2
NO
R1 = CO2Et, Me, NO2, Cl, H; R2 = H, CF3
Br2, NaOAc
MeCCl3rt, 8 h
83%N
NNMeO2C
TBDMSO
OHTBDMSO
OTBDMS
402
N
NNMeO2C
TBDMSO
OHTBDMSO
OTBDMS
403
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 501
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b1,5-Disubstituted 1H-1,2,3-Triazoles 399 by Nickel Peroxide Oxidation;General Procedure:[58]
To a soln of the 4,5-dihydro-1H-1,2,3-triazole 398 (5 mmol) in benzene (100 mL) (CAU-TION: carcinogen) was added dried, finely powdered NiO2 (0.06 mol) and the mixture wasrefluxed with vigorous magnetic stirring for 3–4 h. The mixture was then allowed to coolto rt and filtered under gravity. The residual NiO2 was washed with hot CHCl3, and thecombined filtrates were subjected to rotary evaporation. The resulting oily residue wascooled and triturated with petroleum ether, or an Et2O/petroleum ether mixture, whenit solidified to a clean, crystalline mass, and the colored impurities remained in soln.Many of the triazoles at this point were quite pure, giving reasonably sharp meltingpoints. Recrystallization (acetone/petroleum ether) gave analytically pure samples.
13.13.1.3.2 Method 2:By Elimination Reactions
Several methods for the synthesis of 1,2,3-triazoles involve spontaneous or induced elim-ination reactions. Typical examples are the reactions of azides with enamines, enolethers, or enolates, and the thermal elimination of stable molecules from 4,5-dihydro-1H-1,2,3-triazoles via retro-Diels–Alder reactions (see, for example, Schemes 69 and70).[213,214,217,220,414] The elimination of morpholine from compound 404 on heating in for-mic acid (Scheme 131) is another example. In this process the piperidine ring is cleavedreductively, with carbon dioxide evolution, and the triazole 405 is obtained.[415] In somecases the elimination reaction corresponds to an isomerization, as exemplified in theconversion of 4,5-dihydro-1H-triazole 406 into triazole 407 (Scheme 131).[387] The base-cat-alyzed dehydration of 4,5-dihydro-1H-1,2,3-triazol-5-ols (by treatment with hot methano-lic potassium hydroxide) also gives high yields of the corresponding triazoles.[263] In arelated method, 1-benzyl-4,5-difluoro-4,5-bis(trifluoromethyl)-4,5-dihydro-1H-1,2,3-tria-zole is converted into 1-benzyl-4,5-bis(trifluoromethyl)-1H-1,2,3-triazole in 69% yield bydefluorination with tetrakis(dimethylamino)ethene.[416]
Scheme 131 Aromatization of 4,5-Dihydro-1H-1,2,3-triazoles byElimination Reactions[387,415]
− CO2
404
HCO2HMeN NN
NN
O
Ph
N
NNMe2N
Ph
+
O
HN
405
67%
KOH, EtOH
406
N N
NN
O2N
Me
407
N
NN
NO2
NHMe
502 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.4 Synthesis by Substituent Modification
13.13.1.4.1 Substitution of Existing Substituents
13.13.1.4.1.1 Of Hydrogen
13.13.1.4.1.1.1 Method 1:Lithiation
1-Substituted 1,2,3-triazoles undergo lithiation with butyllithium or lithium diisopropyl-amide preferentially at the 5-position at –20 to –78 8C. The resulting lithiated species reactwith carbon, silicon, halogen, and sulfur electrophiles to yield a range of 1,5-disubstituted1,2,3-triazoles. This subject has been reviewed comprehensively.[417] At room tempera-ture, the lithiated species rapidly undergo fragmentation to nitrogen and lithium keten-imines.[418,424]
The lithiation of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,3-triazole (408, R1 = SEM)followed by addition of an electrophile, gives moderate yields of 1,5-disubstituted 1,2,3-triazoles 410 (R1 = SEM) (Scheme 132).[419] The 2-(trimethylsilyl)ethoxymethyl (SEM) groupis a particularly interesting N1 protecting group for lithiation: it is readily attached to thetriazole, it helps the stabilization of the intermediate triazol-5-yllithium species by intra-molecular coordination, and it is removed under very mild conditions (by heating withdilute hydrochloric acid or by treatment with tetrabutylammonium fluoride in refluxingtetrahydrofuran). In a similar way, 5-substituted 1-benzyloxy-1H-1,2,3-triazoles 410(R1 = OBn) are obtained in excellent yields from lithiation of 1-(benzyloxy)-1H-1,2,3-tria-zole (408, R1 = OBn), followed by reaction with an electrophile.[336] Removal of the benzylgroup by catalytic hydrogenation affords the corresponding 1H-1,2,3-triazol-1-ols in 98–100% yield. Compound 408 (R1 = OBn) is also converted into 5-acyl- and 5-aryl-1,2,3-tria-zoles through a lithiation–transmetalation strategy.[420] Lithiation of 1-methyl-1H-1,2,3-tri-azole with butyllithium or lithium 2,2,6,6-tetramethylpiperidide, followed by addition ofan electrophile gives moderate yields of 5-alkyl- or 5-acyl-1-methyl-1,2,3-triazoles.[421] Lith-iation of 1-methyl-5-(phenylsulfanyl)-1H-1,2,3-triazole with lithium 2,2,6,6-tetra-methylpiperidide occurs at the 4-position and after quenching with aldehydes and car-boxylic amides the corresponding 4-(1-hydroxyalkyl) and 4-acyl derivatives are obtainedin good yields (71–86%).[421]
Scheme 132 Lithiation of 1H-1,2,3-Triazoles and Quenching with Electrophiles[336,419]
N
NN
R1
BuLi, THF
−78 oC, 5−30 min
408
N
NN
R1
409
Li
electrophile, THF
−78 oC to rt, 1−4 h N
NN
R1
410
R2
R1 R2 Electrophile Yield (%) Ref
SEM CH(OH)Ph PhCHO 45 [419]
SEM Bz EtOBz 21 [419]
SEM Me MeI 30 [419]
SEM SPh PhSSPh 80 [419]
SEM Cl Cl3CCCl3 50 [419]
SEM TMS TMSCl 37 [419]
OBn D D2O 90 [336]
OBn Me MeI 93 [336]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 503
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bR1 R2 Electrophile Yield (%) Ref
OBn CHO DMF 87 [336]
OBn CO2Me ClCO2Me 76 [336]
OBn CONMe2 ClCONMe2 97 [336]
OBn Cl Cl3CCCl3 88 [336]
OBn Br Br2 86 [336]
OBn I I2 96 [336]
OBn SMe MeSSMe 67 [336]
OBn TMS TMSCl 93 [336]
OBn SnBu3 Bu3SnCl 91 [336]
The lithiation of 1,2,3-triazoles is also carried out with 4,5-dibromotriazoles (both 1H- and2H-) via a bromine–lithium exchange reaction.[462] For example, 4,5-dibromo-1-(methoxy-methyl)-1H-1,2,3-triazole (411) reacts with butyllithium, in diethyl ether or tetrahydrofu-ran at –80 to –70 8C, at position 5 and the resulting lithiated derivative 412 is quenchedwith aqueous ammonium chloride, carbon dioxide, methyl chloroformate, benzophe-none, or dimethyl or diphenyl disulfide to give high yields of the corresponding 5-substi-tuted 1,2,3-triazoles 413 (Scheme 133).
Scheme 133 Lithiation of 4,5-Dibromo-1-(methoxymethyl)-1H-1,2,3-triazole[462]
N
NN
BuLi, Et2O
−80 oC, 20 min
411
electrophile
−80 to −70 oC
20−60 min
OMe
Br
BrN
NN
412
OMe
Li
BrN
NN
413
OMe
R1
Br
R1 Electrophile Yield (%) Ref
H NH4Cl 84 [462]
CO2H CO2 72 [462]
C(OH)Ph2 Ph2CO 93 [462]
SMe MeSSMe 87 [462]
SPh PhSSPh 71 [462]
5-Substituted 1-Benzyloxy-1H-1,2,3-triazoles 410 (R1 = OBn) by Lithiation Followed byReaction with an Electrophile; General Procedure:[336]
Under N2 at –78 8C, a 0.1 M soln of 408 (R1 = OBn) in dry THF was treated dropwise with1.6 M BuLi in hexane (1.2 equiv). After 5 min the electrophile was added (neat or dissolvedin THF) and stirring was continued at –78 8C for 1 h and at rt 1 h. The mixture was thenquenched with sat. NH4Cl and the product was extracted with CH2Cl2. The organic phasewas washed with H2O, dried (MgSO4), concentrated, and purified by flash chromatogra-phy (EtOAc/heptane 1:2).
504 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.4.1.1.2 Method 2:
N-Trimethylsilylation
1H-1,2,3-Triazole (414, R1 = H)[421,430] and 4-methyl-1H-1,2,3-triazole (414, R1 = Me)[430] reactwith chlorotrimethylsilane to give selectively 2-trimethylsilyl derivatives 415 (Scheme134). Refluxing a mixture of 1H-1,2,3-triazole and hexamethyldisilazane for six hoursgives an 81% yield of 1-(trimethylsilyl)-1H-1,2,3-triazole (416) and 2-(trimethylsilyl)-2H-1,2,3-triazole (417) in a 1:5 ratio.[422] 1,2,3-Triazole N-oxides are C-silylated at ring and exo-cyclic Æ-positions in high yields in a one-pot procedure involving treatment with trimeth-ylsilyl trifluoromethanesulfonate, iodotrimethylsilane, or tert-butyldimethylsilyl trifluo-romethanesulfonate in the presence of 1,2,2,6,6-pentamethylpiperidine, diisopropyleth-ylamine, or lithium tetramethylpiperidide.[423]
Scheme 134 N-Trimethylsilylation of 1H-1,2,3-Triazoles[421,430]
N
NH
N
TMSCl, benzene, Et3N
0 oC, 30 min, then reflux, 2 h
414
R1
N
NNTMS
415 R1 = H, Me
R1
N
NN
416
TMS
N
NNTMS
417
+(TMS)2NH, reflux, 6 h
81−96%
R1 = H 81%
1:5
2-(Trimethylsilyl)-2H-1,2,3-triazole (415, R1 = H):[421]
TMSCl (10.7 mL, 84 mmol) was added to a soln of 1H-1,2,3-triazole (4.7 mL, 80 mmol) andEt3N (12.1 mL, 87 mmol) in benzene (80 mL) (CAUTION: carcinogen) under N2 with ice cool-ing, and the mixture was stirred for 30 min and then refluxed at 80 8C for 2 h. After filtra-tion, the filtrate was evaporated to afford a residue, which was distilled under atmospher-ic pressure to give a colorless oil; yield: 9.72 g (86%); bp 148 8C; 1H NMR (CDCl3, �): 7.73 (s,2H, hetaryl), 0.51 (s, 9H, TMS).
13.13.1.4.1.1.3 Method 3:Carboxylation
Carboxylation of C-lithio[424,425] or Grignard[180,181] derivatives of triazoles gives the corre-sponding carboxylic acids (Scheme 135). The lithiated species 412 (Scheme 133) isquenched with carbon dioxide to give 4-bromo-1-(methoxymethyl)-1H-1,2,3-triazole-5-car-boxylic acid in 72% yield.[462] The 2-methoxymethyl analogue of 412 yields methyl 4-bro-mo-2-(methoxymethyl)-2H-1,2,3-triazole-3-carboxylate in 71% when quenched with meth-yl chloroformate.[462] Similarly, lithiation of 1-benzyloxy-1H-1,2,3-triazole and quenchingthe resulting 5-lithiated species with methyl chloroformate or dimethylcarbamoyl chlo-ride yields the corresponding 5-carboxylate (76%) or N,N-dimethyl carboxamide (97%)(see Scheme 132).[336]
5-Amino-1H-1,2,3-triazole-4-carboxylic acid is obtained in low yield (14%) by heating1H-1,2,3-triazol-4-amine with aqueous potassium hydrogen carbonate for 16 hours at100 8C.[428]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 505
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 135 Carboxylation of 1,4-Diphenyl-1H-1,2,3-triazole[424]
N
NN
1. BuLi
2. CO2
418
Ph
62%
Ph
N
NN
419
Ph
PhHO2C
1,4-Diphenyl-1H-1,2,3-triazole-5-carboxylic Acid (419); Typical Procedure:[424]
To a stirred soln of 1,4-diphenyl-1H-1,2,3-triazole (418; 0.04 mol) in anhyd THF (80 mL) wasadded dropwise over 15 min, 1.6 M BuLi in hexane (26 mL) at –20 to –60 8C under N2. Whenthe addition was completed the mixture was stirred and cooled for an additional 0.5–1 hand then the mixture was poured onto solid CO2. Acidification of an aqueous soln of thesalt yielded the carboxylic acid 419; yield: 62%; mp 169–170 8C (dec).
13.13.1.4.1.1.4 Method 4:Acylation
N-Unsubstituted 1,2,3-triazoles can be N-acylated by acyl halides and anhydrides with drybenzene or pyridine as the solvent. Substitution takes place at the 1-position but the acylgroup may migrate to the 2-position on heating or on treatment with base.[173,429,430] Thus,acetylation with acetyl chloride gives 1-acetyl derivatives that rearrange to the 2-isomersabove 120 8C; acetylation by heating the triazoles with acetic anhydride gives the 2-acetylderivatives directly. An alternative route to 1-acetyl-1H-1,2,3-triazoles is the reaction of 2-trimethylsilyl derivatives (e.g., 420) with acetyl chloride, giving products such as 421(R1 = Me) (Scheme 136).[173,430] This method can be used to prepare a range of 1-acyl-1H-1,2,3-triazoles, intermediates in the synthesis of oxazoles.[431]
Scheme 136 Acylation of 2-(Trimethylsilyl)-2H-1,2,3-triazole[173,430]
benzene, rt
R1 = Me, aryl
N
NNTMS
420
+ R1COClN
NN
421
O R1
+ TMSCl
Reaction of 4,5-diphenyl-1H-1,2,3-triazole with benzoyl chloride in pyridine gives the cor-responding 1-benzoyl derivative.[432] The 1H-1,2,3-triazol-4-ols 422 react with benzoylchloride in pyridine to yield the dibenzoyl derivatives 423 in high yields (Scheme 137).[433]
Scheme 137 Benzoylation of 1H-1,2,3-Triazol-4-ols[433]
BzCl, py, 5 oC, 1 d
R1 = H 80%
R1 = Ph 92%
N
NH
N
422
N
NNBz
423
BzO
R1
HO
R1
The reaction of 1,2,3-triazole with thiobenzoyl chloride (CCl4, Et3N, rt) yields a mixture of1- and 2-thiobenzoyl-1,2,3-triazoles (22:78).[434] Similar results are obtained if the sodiumsalt of 1,2,3-triazole is used. However, only 1-(thiobenzoyl)-1,2,3-triazole is formed in 40%yield in the reaction of thiobenzoyl chloride with 2-(trimethylsilyl)-2H-1,2,3-triazole (CCl4,
506 Science of Synthesis 13.13 1,2,3-Triazoles
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b08C).[434] Reaction of 1,2,3-triazole with isocyanates affords the corresponding urea deriva-tives.[435]
1,2,3-Triazoles are also C-acylated. In this case, the corresponding lithiated speciesare reacted with appropriate electrophiles (acyl halides, esters, amides) (see Section13.13.1.4.1.1.1).
13.13.1.4.1.1.5 Method 5:Formylation
As shown in Scheme 132, C-lithiated 1,2,3-triazole species are quenched with dimethyl-formamide to afford the corresponding formyl derivatives in excellent yields;[336] howeverother attempts to quench 1,2,3-triazolyllithium compounds with dimethylformamidehave failed.[419,462] The Vilsmeier–Haack formylation of 1H-1,2,3-triazol-5-amines 424 givesthe corresponding 1H-1,2,3-triazole-4-carbaldehydes 425 in good yields (Scheme 138).These compounds are hydrolyzed by dilute hydrochloric acid to the corresponding 5-ami-no derivatives 426.[436] The Vilsmeier–Haack formylation of 1-benzyl-1,2,3-triazol-5-ols af-fords the corresponding 5-chloro-1H-1,2,3-triazole-4-carbaldehydes in 60–94% yields.[302]
1H-1,2,3-Triazole-4-carbaldehydes are also prepared from the corresponding carbonitrilesby catalytic hydrogenation (10% Pd/C, aq 0.1 M HCl)[437] or by Raney nickel/formic acid re-duction.[438]
Scheme 138 Vilsmeier–Haack Formylation of 1H-1,2,3-Triazol-5-amines[436]
R1 = Me, Bn
N
NN
424
H2N
R1
DMF, POCl385 oC, 1 h
75−85%
N
NN
425
N
R1
1 M HCl
reflux, 20 min
65%
OHC
Me2N
N
NN
426
H2N
R1
OHC
5-Amino-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (426, R1 = Me); Typical Procedure:[436]
POCl3 (0.16 g, 1 mmol) was added to 1-methyl-1H-1,2,3-triazol-5-amine (424, R1 = Me;0.05 g, 0.5 mmol) in DMF (1 mL) at 0 8C. The mixture was then heated at 85 8C for 1 h,cooled, and poured onto ice (15 g). The mixture was adjusted to pH 7 and extracted withCHCl3 (3 � 20 mL). The extract was dried (K2CO3) and the solvent was removed in vacuo.The residue was recrystallized (benzene/cyclohexane 1:4) (CAUTION: carcinogen) to give5-{[(dimethylamino)methylene]amino}-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (425,R1 = Me); yield: 75%; mp 136 8C. This compound was refluxed for 20 min with 1 M HCl (16equiv). The soln was neutralized and extracted with CHCl3. Evaporation of the dried(K2CO3) extract gave 426 (R1 = Me); yield: 65%.
13.13.1.4.1.1.6 Method 6:Arylation
1,2,3-Triazoles can be N-arylated by reaction with activated aryl halides. Reaction of 1H-1,2,3-triazole with 1-fluoro-2-nitrobenzene[439] or 1-fluoro-4-nitrobenzene[440] gives mix-tures of the corresponding 1- and 2-nitrophenyl-1,2,3-triazoles. However, with 1-fluoro-2,4-dinitrobenzene and 2-chloro-1,3,5-trinitrobenzene only the 1-substituted derivativesare obtained (Scheme 139).[440] Reaction of 1H-1,2,3-triazole with 2-chloro-1,3,5-trinitro-benzene (427, X = Cl), 2-fluoro-1,3,5-trinitrobenzene (427, X = F) or 1,2,3,5-tetranitroben-zene (427, X = NO2) in dioxane, dimethylformamide, or dimethyl sulfoxide for two daysat room temperature gives 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole (428) exclusively, ex-cept in one case.[471] When the reaction is carried out with 2-fluoro-1,3,5-trinitrobenzene
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 507
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b(427, X = F) in dimethyl sulfoxide, the 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is alsoformed; the final product composition depends on the way in which the reagents aremixed.
Scheme 139 Arylation of 1H-1,2,3-Triazole with 2,4,6-Trinitrophenyl Derivatives[440]
X = Cl, F, NO2
N
NH
N
dioxane
DMF or DMSO
rt, 2 d
58−96%+ X NO2
O2N
O2N
N
NN
NO2O2N
NO2
428427
1-(4-Tolyl)-1H-1,2,3-triazole is obtained in 11% yield from the reaction of 1H-1,2,3-triazoleand 4-tolylboronic acid in the presence of anhydrous copper(II) acetate and pyridine.[441] Amixture of 9-(1H-1,2,3-triazol-1-yl)acridine (429) (49%) and 9-(2H-1,2,3-triazol-2-yl)acridine(430) (26%) is obtained from the reaction of the anion of 1H-1,2,3-triazole, generated usingsodium hydride in dry dimethylformamide, with 9-chloroacridine (Scheme 140).[442] De-protonation of triazole 431 with potassium hexamethyldisilazanide followed by the addi-tion of pentafluoropyridine gives the 2-(4-pyridyl)-substituted triazole 432 in 49% yield(Scheme 140).[174]
Scheme 140 Arylation of 1H-1,2,3-Triazoles with 9-Chloroacridine[442] andPentafluoropyridine[174]
N
NH
N
NaH, DMF
9-chloroacridine
60 oC, 2 h
N
NN
N
N
NNN
+
429 49% 430 26%
N
NH
N
KHDMS
pentafluoropyridine, THF
0 oC to rt, 20 min
N
N
NN
N N
F
F
F
F
432431
F F
49%
1,2,3-Triazoles are also C-arylated. The palladium-catalyzed reaction of the 1,2,3-triazol-5-ylzinc iodide species 433 with appropriate aryl and hetaryl iodides gives the 5-aryl-1- or 5-hetaryl-1H-1,2,3-triazoles 434 (Scheme 141).[420]
508 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 141 Arylation of 1-Benzyloxy-1H-1,2,3-triazol-5-ylzinc Iodide[420]
N
NN
BuLi, THF
−78 oC, 5 min
433
OBn
N
NN
ZnI2−78 oC, 30 min
OBn
Li
N
NN
OBn
IZn
Ar1I, DMF
Pd(PPh3)4
−78 oC to rt
then 80 oC, 1 hN
NN
OBn
Ar1
434 Ar1 = aryl 30−87%
Ar1 = 2-pyridyl 80%
Ar1 = 2-thienyl 63%
Ar1 = 49%NN
OBn
1-(2,4,6-Trinitrophenyl)-1H-1,2,3-triazole (428):[471]
A soln of 1H-1,2,3-triazole (4.20 g, 60 mmol), 2-fluoro-1,3,5-trinitrobenzene (427, X = F;13.40 g, 60 mmol) and dry DMF (100 mL), protected from atmospheric moisture, wasstirred at rt for 3 d. This soln was then poured with stirring into H2O (2 L). The precipitatedproduct was collected by filtration, washed with H2O, and dried. The product was thendissolved in a minimal amount of acetone (~400 mL), and to this stirred soln was addedH2O (1.5 L), dropwise at first, until crystallization was induced, at which time the flowwas increased to a slow, steady stream. The precipitated product was again collected byfiltration, washed with H2O, and dried to give white crystals; yield: 14.6 g (90%); mp214 8C (dec).
13.13.1.4.1.1.7 Method 7:Alkylation
1,2,3-Triazoles can be N- and C-alkylated. N-alkylation is readily achieved by one of thefollowing methods: (i) reaction with alkyl halides,[443] dimethyl sulfate,[50,444–446,460] diazo-methane,[44,46,47,50,447] methyl tosylate,[448,449] or methyl fluorosulfonate[450] (ii) by reactionwith alcohols in acidic media,[451] (iii) by addition to aziridines,[90] (iv) by conjugate addi-tion to activated alkenes[90,198,445,452] and alkynes,[87,443] and (v) by the Mannich reaction.[453]
Alkylation with alkyl halides requires the use of a base; generally a sodium alkoxide, so-dium hydride, or sodium hydroxide are employed.
Alkylation of N-unsubstituted 1,2,3-triazoles under basic, neutral or weakly acidicconditions generally affords mixtures of the N-alkyl derivatives. The 1,2,3-triazole itselfand the symmetrical 4,5-disubstituted triazoles give mixtures of 1- and 2-alkyl isomerswhile unsymmetrical 4,5-substituted triazoles frequently give all the three possiblemonoalkyl derivatives. Some selectivity for 1-alkylation is observed when silver or thalli-um salts of the triazoles are reacted with iodoalkanes.[454] Selective alkylation at N1 is ob-tained by reaction of a 2-(trimethylsilyl)-2H-1,2,3-triazole with primary alkyl halides inthe presence of tetrabutylammonium fluoride.[421]
It has been shown that 1H-1,2,3-triazole reacts with propan-2-ol in concentrated sul-furic acid to yield 1-isopropyl-1H-1,2,3-triazole (80%) as the sole reaction product.[451] Thescope of this method is still to be demonstrated.
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 509
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bAlkylation of 1-methyl- and 1-benzyl-1H-1,2,3-triazole gives only the 1,3-disubstituted
triazolium salts.[455] The 2-alkyl-2H-1,2,3-triazole 1-oxides are quantitatively methylated atthe N-oxygen by trimethyloxonium tetrafluoroborate to yield the corresponding 1-meth-oxytriazolium tetrafluoroborates.[456] 1-Alkyl-1H-1,2,3-triazol-5-ols on reaction with diazo-methane or iodomethane are alkylated at the alcohol oxygen, N2, and N3.[306,331] 1H-1,2,3-Triazole-4-thiol is converted selectively into the 4-(methylsulfanyl) derivative by reactionwith a small excess iodomethane, in the presence of an equimolar amount of ethanolicpotassium hydroxide (1.8 M).[447] Addition of diazomethane to the 4-(methylsulfanyl)tri-azole gives a mixture of the three possible N-methylated 4-(methylsulfanyl)triazoles.[447]
The alkylation of ethyl 4-(4-hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate (435)under alkaline conditions exclusively yields the N2 and N3 alkylation products (Scheme142). Alkylation at N1 or at the hydroxy group is not observed.[457] While alkylation of 435with benzyl or 4-methoxybenzyl chlorides gives a 1:1 mixture of the two isomers, with 4-bromophenacyl bromide preferential substitution at N2 is observed (14% and 65% respec-tively to 436 and 437). Alkylation with trityl chloride shows a marked steric preferencefor the less hindered N2 position, with isomer 437 (R1 = Tr) being formed almost exclu-sively.
Scheme 142 Alkylation of Ethyl 4-(4-Hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate[457]
1. K2CO3, DMF
2. R1X, 20−40 oC
N
NNR1
EtO2C
OHO
N
NH
NEtO2C
OHO
435
N
NNEtO2C
OHO
436
R1
437
+
R1 = CH2Ar1, CH2COAr1, Tr; X = Cl, Br
N-Unsubstituted triazoles also react with compounds of other types to yield N-substitutedderivatives. For example, they react with nitrilimines (gererated in situ) to yield a mixtureof 1- and 2-(benzohydrazonoyl)-1,2,3-triazoles, as illustrated in Scheme 143,[458] and reactwith 1-O-acetyl ribofuranose derivatives (by an acid-catalyzed fusion procedure) to affordmixtures of triazole nucleosides 438 and 439 (Scheme 144).[459]
Scheme 143 Reaction of Triazoles with Nitrilimines[458]
benzene
reflux, 10 hN
NN
N
NH
NN
N
NN
Ph NPh
41% 33%
+N NPhPhC++ −
NHPh
NHPh
510 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 144 Reaction of Triazoles with 1-O-Acetyl Ribofuranose Derivatives[459]
heatN
NH
N
X
N
NN
X
+O
OR1OR1
OAcR1O
O
OR1OR1
R1ON
NN
X
O
OR1OR1
R1O
+
438 439
R1 = Bz, Ac; X = H, CO2Me, CN, NO2
C-Alkylation of triazoles is achieved by lithiation followed by addition of an alkyl halide.For example, reaction of 1-phenyl-1H-1,2,3-triazole with butyllithium and addition ofiodomethane gives 5-methyl-1-phenyl-1H-1,2,3-triazole (440, R1 = H) in 94% yield (Scheme145).[424] It is interesting to note that under similar reaction conditions, 4-methyl-1-phenyl-1H-1,2,3-triazole yields 4,5-dimethyl-1-phenyl-1H-1,2,3-triazole (440, R1 = Me), while itsisomer 5-methyl-1-phenyl-1H-1,2,3-triazole gives only the 5-ethyl derivative 441. Lithia-tion of 1,4-diphenyl- and 1,5-diphenyl-1H-1,2,3-triazole, followed by iodomethanequench, gives the corresponding derivatives 440 (R1 = Ph) and 442 in 78 and 99% yield, re-spectively, reflecting the higher steric hindrance in the 1,4-diphenyl isomer. For other ex-amples of C-alkylation of triazoles see Section 13.13.1.4.1.1.1.
Scheme 145 C-Methylation of 1-Phenyl-1H-1,2,3-triazoles[424]
BuLi, THF, MeΙ−60 to −20 oCN
NN
R1
440
R1 = H, Me, Ph
Ph
78−94%
N
NN
R1
Ph
BuLi, THF, MeΙ−20 to −60 oCN
NN
441
R1 = Me, Ph
Ph
N
NN
PhEtR1 = Me 42%
442
N
NN
PhPhR1 = Ph 99%
R1
13.13.1.4.1.1.8 Method 8:Halogenation
The reaction of 1,2,3-triazole, 1-methyl-, 2-methyl-, 4-methyl-, and 4,5-dimethyl-1,2,3-tri-azole with chlorine, bromine, iodine, hypochlorite, hypobromite, and hypoiodite hasbeen studied.[460] 1H-1,2,3-Triazole reacts with bromine to afford 4,5-dibromo-1H-1,2,3-tri-azole (443) in almost quantitative yield (Scheme 146).[461,462] The intermediate monobro-
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bmotriazole cannot be trapped; apparently it is brominated faster than the starting mate-rial. The 4,5-dibromo-1H-1,2,3-triazole is also obtained in 90–95% yield by bromodecar-boxylation of 1,2,3-triazole-4-carboxylic acid.[462]
Scheme 146 Bromination of 1H-1,2,3-Triazole[461,462]
N
NH
N
443
97%+ Br2
H2O, 40−45 oC, 1 h N
NH
NBr
Br
1-Methyl- and 4-methyl-1H-1,2,3-triazole react with bromine to give, respectively, the 4-bromo-1-methyl- and 5-bromo-4-methyl-1H-1,2,3-triazole in good yields. The isomeric 2-methyl-2H-1,2,3-triazole, less reactive toward halogenation, reacts with bromine only inthe presence of a catalyst (iron filings) and yields 4,5-dibromo-2-methyl-2H-1,2,3-triazole;the monobrominated product is not obtained.[460] 4-Bromo- and 5-bromo-1H-1,2,3-tria-zoles are obtained indirectly by bromination of a triazole with a removable group at N1,as shown in Scheme 147.[463]
Scheme 147 Bromination of 1H-1,2,3-Triazoles with a Removable Substituent at N1[463]
N
NN
OMe
Br2, Na2CO3
20 oC
N
NN
OMe
Br
Br
NMe
NN
OMe
Br
Br
+
X−N
NN
Me
concd H2SO4
120 oC, 1 h
N
NH
N
Brconcd H2SO4
120 oC, 1 h
MeX
Br
2- and 3-Substituted 1,2,3-triazole 1-oxides 444 and 447 are halogenated selectively in po-sition 5 in excellent yields (Scheme 148).[456,464,465] Since compounds 445 and 448 are deox-ygenated almost quantitatively (see Section 13.13.1.4.1.4.4), this is a useful route for thesynthesis of 1- and 2-substituted 4-halo-1,2,3-triazoles. The chlorination/deoxygenation of2-(4-tolyl)-2H-1,2,3-triazole 1-oxides to give 446 is carried out in one step by reaction withgaseous hydrogen chloride.[466]
512 Science of Synthesis 13.13 1,2,3-Triazoles
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bScheme 148 Halogenation of 1,2,3-Triazole 1-Oxides[456,464–466]
NaOCl, Cl2, or Br2
rt
72−100%
444 445
R1 = Me, Bn, Ph; R2 = H, Me; X = Cl, Br
N+
O−
NR1
NR2
N+
O−
NR1
NR2
X
HCl, dioxane
68%
446
R1 = Ph, OMe
N+
O−
N
NR1
4-Tol NN
NR1
4-TolCl
NaOCl or Br2
rt
78−100%
R1 = Me, Bn, Ph; X = Cl, Br
447
N+
O−
N
NR1
448
N+
O−
N
NR1
X
1-Methoxy-2-phenyl-2H-1,2,3-triazol-1-ium tetrafluoroborates 449 react with potassiumhydrogen fluoride to yield 4-fluoro-2-phenyl-2H-1,2,3-triazoles 450 (Scheme 149).[465]
Scheme 149 Fluorination of 1-Methoxy-2-phenyl-2H-1,2,3-triazol-1-ium Tetrafluoroborates[465]
KHF2, MeCN, rt, 3 d
61−64%
R1 = H, Me
BF4−
449
N+
OMe
NPh
NR1
450
NNPh
NR1
F
Mesoionic compound 451 reacts with bromine in acetic acid to give the 5-bromo deriva-tive 452 (Scheme 150).[362]
Scheme 150 Bromination of Mesoionic Triazole Compounds[362]
Br2, AcOH, rt, 2 h
68%
451
NMe
N
N
−O 4 -Tol
+
452
NMe
N
N
−O 4 -Tol
+Br
C-Lithiated 1,2,3-triazole species are quenched with bromine or iodine to afford the corre-sponding halogenated derivatives in excellent yields.[336] Using hexachloroethane as theelectrophile, the chlorinated derivatives are obtained.[336,419]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 513
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bReaction of 1H-1,2,3-triazole with iodine monochloride yields 1-iodo-1H-1,2,3-tria-
zole (453). Melting a mixture of this compound with 3,5-dimethyl-2H-1,2,4-triazole for5–10 minutes gives 4,5-diiodo-1H-1,2,3-triazole (454) (Scheme 151).[467] 1H-1,2,3-Triazolegives 1,4,5-tribromo-1H-1,2,3-triazole when treated with an excess of sodium hypobro-mite.[460]
Scheme 151 Iodination of 1H-1,2,3-Triazole[467]
N
NH
N
ICl, NaOEt
EtOH, rt
60−80%
453
N
NN
I
110 oC, 5−10 min
75%
454
N
NH
NI
I
N
NH
N
2-Phenyl-2H-1,2,3-triazol-4-ol reacts with bromine to give the corresponding 5-bromo de-rivative in high yield.[474] A method for the selective conversion of 2,4,5-triphenyl-2H-1,2,3-triazole into 2-(2-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole has been reported.[468]
4,5-Dibromo-1H-1,2,3-triazole (443); Typical Procedure:[462]
Br2 (15 mL, an excess) was added dropwise to a stirred soln of 1H-1,2,3-triazole (15.0 g,217 mmol) in H2O (100 mL) warmed to 40–45 8C and the resulting soln was stirred for afurther 1 h. The precipitate was collected by filtration and further Br2 (10 mL) was addedto the filtrate, then it was kept at rt overnight, after which a second crop of product hadprecipitated. The combined amounts of product were washed with H2O (3 � 50 mL), dried,and recrystallized (aq MeOH) to give the product; yield: 47.8 g (97%); mp 192–194 8C.
13.13.1.4.1.1.9 Method 9:N-Amination
4,5-Diphenyl-1H-1,2,3-triazole is aminated by reaction with hydroxylamine-O-sulfonicacid yielding the corresponding triazol-1-amines and triazol-2-amines in approximatelyequal amounts (Scheme 152).[3]
Scheme 152 N-Amination of 4,5-Diphenyl-1H-1,2,3-triazole[3]
N
NH
N
N
NN
Ph
Ph
Ph
Ph
NH2
H2NOSO3H N
NN
Ph
Ph+
NH2
13.13.1.4.1.1.10 Method 10:N-Hydroxylation
1H-1,2,3-Triazole is oxidized by peracids to 1H-1,2,3-triazol-1-ol (Scheme 153). Best yieldsare obtained with 3-chloroperoxybenzoic acid or hydrogen peroxide plus formicacid.[336,469] Yields of 65% are obtained by adding the oxidant (hydrogen peroxide/formicacid) portionwise over 30 days followed by continuous extraction of the triazolol with di-ethyl ether over three weeks.[336] The autoxidation of an N-unsubstituted 1,2,3-triazole tothe corresponding triazol-2-ol has been reported.[342]
514 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 153 N-Hydroxylation of 1H-1,2,3-Triazole[336,469]
N
NH
N
N
NN
OH
A: HCO2H, H2O2, 20 oC, 30 d
B: MCPBA, EtOAc, rt, 7 d
A: 65%
13.13.1.4.1.1.11 Method 11:Nitration
Direct nitration of 1H-1,2,3-triazole to give 4-nitro-1H-1,2,3-triazole is not possible.[470]
However, this compound is obtained in moderate yield from the reaction of 1-morpholi-no-2-nitroethene and tosyl azide.[471] Attempts to introduce a nitro group in the triazolering of 1-phenyl- and 4-phenyl-1H-1,2,3-triazole are unsuccessful since nitration occursonly in the phenyl ring. For example, the reaction of 4-phenyl-1H-1,2,3-triazole with amixture of nitric acid and sulfuric acid at 0 8C gives the 4-(4-nitrophenyl) derivative in50% yield; at 90 8C the 4-(2,4-dinitrophenyl) derivative is obtained in 35% yield.[471] Similar-ly, the 3-phenyl-1,2,3-triazole 1-oxide is nitrated with fuming nitric acid, at room temper-ature, at the para phenyl position.[464]
The nitration of 2-phenyl-2H-1,2,3-triazole with a mixture of fuming nitric acid andconcentrated sulfuric acid at 20 8C gives a mixture of 2-(4-nitrophenyl)-2H-1,2,3-triazole(454) and 4-nitro-2-(4-nitrophenyl)-2H-1,2,3-triazole (455) (Scheme 154).[472,473] However,if the nitration is carried out with nitric acid in acetic anhydride at 15 8C, only triazole454 is obtained.[473]
Scheme 154 Nitration of 2-Phenyl-2H-1,2,3-triazole[472,473]
N
NN
A: HNO3, H2SO4
20 oC, 1 h
B: HNO3, Ac2O
15 oC N
NN
NO2
N
NN
NO2
O2N
+
454 455
A: 69%; (454/455) 20:3
B: 81% (454 only)
While 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is nitrated at C4 of the triazole ring, theisomeric 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole is resistant to nitration, even underforcing conditions.[471] Nitration of 2-phenyl-2H-1,2,3-triazol-4-ol with nitric acid in glacialacetic acid affords 5-nitro-2-phenyl-2H-1,2,3-triazol-4-ol in 60% yield.[474] Under similarconditions, 2-phenyl-2H-1,2,3-triazol-4-ol 1-oxide also gives the corresponding 5-nitro de-rivative.[474] Nitration of 4-(2,4,6-trinitroanilino)-1H-1,2,3-triazole with a mixture of nitricacid and sulfuric acid, at 20–25 8C, affords the corresponding 5-nitro derivative in 30%yield.[475]
Nitration of 2-methyl-2H-1,2,3-triazole with a mixture of fuming nitric acid and con-centrated sulfuric acid, at room temperature, affords 2-methyl-4-nitro-2H-1,2,3-triazole(456) in 98% yield (Scheme 155). Under more vigorous conditions (10 h at 100 8C) this com-pound is further nitrated to 2-methyl-4,5-dinitro-2H-1,2,3-triazole (457) (97%).[456] Nitra-tion of 2-methyl-2H-1,2,3-triazole 1-oxide at room temperature gives a mixture of the 4-and 5-nitro derivatives. At 100 8C both compounds are further nitrated to 2-methyl-4,5-di-nitro-2H-1,2,3-triazole 1-oxide.[456] Nitration of 2-phenyl-2H-1,2,3-triazole 1-oxide at roomtemperature gives initially (detectable after 1 min of reaction time) a mixture of 2-(4-nitro-phenyl)-2H-1,2,3-triazole 1-oxide, 5-nitro-2-phenyl-2H-1,2,3-triazole 1-oxide, and 5-nitro-2-
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 515
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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b(4-nitrophenyl)-2H-1,2,3-triazole 1-oxide. The final product, 2-(2,4-dinitrophenyl)-5-nitro-2H-1,2,3-triazole 1-oxide, is formed after approximately two hours.[465]
Scheme 155 Nitration of 2-Methyl-2H-1,2,3-triazole[456]
N
NNMe
HNO3, H2SO4
rt, 3 h
456
N
NNMe
O2N HNO3, H2SO4
100 oC, 10 h
457
N
NNMe
O2N
O2N98% 97%
2-Methyl-4-nitro-2H-1,2,3-triazole (456); Typical Procedure:[456]
2-Methyl-2H-1,2,3-triazole (1 mmol), concd H2SO4 (1.02 mL), and fuming HNO3 (d 1.55;0.51 mL) were stirred at rt for 3 h. H2O (5 mL) was added. Extraction with CH2Cl2 (5 mL,2 � 3 mL), drying (K2CO3), and removal of the solvent gave the crude product (98%). Recrys-tallization (ligroin) gave crystals; mp 99–101 8C.
13.13.1.4.1.2 Of Metals
13.13.1.4.1.2.1 Method 1:Desilylation
N-Trimethylsilyl substituents are readily removed under very mild conditions: treatmentwith aqueous methanol, ethanol, or aqueous acid.[172,173,476] Triazole derivatives contain-ing both N- and C-trimethylsilyl substituents, such as 458, are selectively desilylated:methanol cleaves N-Si bonds (e.g., to give 459), while methanol/hydrochloric acidcleaves Si-C bonds as well, both with protonation (Scheme 156).[172]
Scheme 156 Selective Desilylation of 4-Phenyl-2,5-bis(trimethylsilyl)-2H-1,2,3-triazole[172]
458
N
NN
Ph
459
N
NH
N
Ph
TMSTMS TMS
MeOH N
NH
N
Ph
MeOH, HCl
Removal of the trimethylsilyl group from 460 is readily carried out with 10% aqueous po-tassium hydroxide in boiling methanol to give triazoles 461 in almost quantitative yields(Scheme 157).[72] Heating 4-substituted 5-(trimethylsilyl)-1H-1,2,3-triazoles with potassiumfluoride and concentrated hydrochloric acid (2 drops) in refluxing ethanol gives the 4-sub-stituted 1H-1,2,3-triazoles in high yields.[52]
Scheme 157 Desilylation of 5-(Alkylsulfanyl)-5-(trimethylsilyl)-1,2,3-triazoles[72]
460
N
NN
TMS
R2S
KOH, H2O, MeOH, reflux
R1
461
N
NNR2S
R1
R1 = Me, Bu, Cy, CH2CH CH2, Bn, Ph; R2 = Me, Bn
~100%
516 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.1.4.1.3 Of Carbon Functionalities
13.13.1.4.1.3.1 Method 1:Decarboxylation
Most 1,2,3-triazolecarboxylic acids lose carbon dioxide when heated above their meltingpoint. This reaction has been known since the 19th century.[477–479] A reasonable numberof examples of this transformation are found in the literature.[23,105,282,331,430,480] 1H-1,2,3-Triazole (464, R1 = H) is obtained in 93% by heating 1H-1,2,3-triazole-4-carboxylic acid(462, R1 = H) in an oil bath at 220 8C for a few minutes (Scheme 158).[44] 1,5-Disubstituted1,2,3-triazole-4-carboxylic acids decarboxylate slowly in boiling benzene[481] or toluene.[482]
5-Amino-1-benzyl-1H-1,2,3-triazole-4-carboxylic acid is decarboxylated to the correspond-ing triazolamine, in 60–84% yield, by refluxing in N,N-dimethylaniline for 15 min-utes.[319,428] 5-Amino-1-methyl-1H-1,2,3-triazole-4-carboxylic acid decarboxylates in reflux-ing butan-1-ol (3 h, 65% yield)[393] while 5-amino-1H-1,2,3-triazole-4-carboxylic acid and 5-amino-1-cyclohexyl-1H-1,2,3-triazole-4-carboxylic acid are decarboxylated to the corre-sponding triazolamines, in 57 and 63% yield, respectively, by heating in 1 M hydrochloricacid for one hour.[428] 1H-1,2,3-Triazole-4,5-dicarboxylic acids 463 generally lose two molesof carbon dioxide on heating above their melting point (Scheme 158).[105,478] For example,1-benzyl-1H-1,2,3-triazole is obtained in essentially quantitative yield by thermal decar-boxylation of 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylic acid.[105] However 1-phenyl-1H-1,2,3-triazole-4,5-dicarboxylic acid preferentially decarboxylates at the 5-position, givingthe corresponding 4-carboxylic acid.[479] 1-(1-Naphthyl)-1H-1,2,3-triazole-4,5-dicarboxylicacid decarboxylates in refluxing toluene (24 h) to give 1-(1-naphthyl)-1H-1,2,3-triazole in90% yield.[106]
Scheme 158 Decarboxylation of 1H-Triazolecarboxylic Acids[44,105,478]
462
N
NNHO2C
210−240 oC
R1
464
N
NN
R1
R1 = H, alkyl, aryl
463
N
NNHO2C
R1
HO2C
− CO2
200 oC
− 2CO2
1H-1,2,3-Triazole (464, R1 = H); Typical Procedure:[44]
1H-1,2,3-Triazole-4-carboxylic acid (462, R1 = H; 40 g, 0.35 mol) was heated in an oil bath.At a bath temperature of 220 8C a vigorous evolution of CO2 took place. The reaction wasover in a few min and the 1,2,3-triazole was distilled; yield: 22.8 g (93%); bp 205–206 8C/760 Torr.
13.13.1.4.1.3.2 Method 2:Deformylation
1,4-Diphenyl-1H-1,2,3-triazole-5-carbaldehyde (465) is deformylated in almost quantita-tive yield by treatment with sodium methoxide in refluxing methanol (Scheme 159). Un-der the same conditions, the isomer 1,5-diphenyl-1H-1,2,3-triazole-4-carbaldehyde is re-
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 517
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bcovered quantitatively.[438] Alternatively, quantitative deformylation of 465 is accom-plished, on treatment with a large excess of hydrazine (100-fold) in refluxing ethanol togive 1,4-diphenyl-1H-1,2,3-triazole (466) via hydrazone 467 (Scheme 159).[438]
Scheme 159 Deformylation of 1,4-Diphenyl-1H-1,2,3-triazole-4-carbaldehyde[438]
465
N
NNOHC 93%
Ph
Ph
NaOMe, MeOH, reflux, 12 h
466
N
NN
Ph
Ph
467
N
NN
Ph
Ph
H2NN100%
H2NNH2, EtOH
reflux, 4 h H2NNH2
1,4-Diphenyl-1H-1,2,3-triazole (466); Typical Procedure:[438]
A soln of freshly cut Na (0.23 g, 10 mmol) and 1,4-diphenyl-1H-1,2,3-triazole-5-carbalde-hyde (465; 1.00 g, 4 mmol) in anhyd MeOH (50 mL) was refluxed for 12 h in a vessel provid-ed with a dry ice condenser, after which time 25–30 mL of liquid was distilled. On coolingthe soln remaining in the reaction vessel the product was obtained; yield: 0.83 g (93%).
13.13.1.4.1.3.3 Method 3:Deacylation
1- and 2-Acyltriazoles are readily hydrolyzed in water or dilute acid; the rate constants forhydrolysis and aminolysis of several N-acetyl-1,2,3-triazoles have been measured.[429] 2-Benzoyl-4-(benzoyloxy)-2H-1,2,3-triazoles 468 are hydrolyzed selectively to the corre-sponding 4-benzoyloxy derivatives 469 (Scheme 160).[433]
Scheme 160 Selective Hydrolysis of 2-Benzoyl-4-(benzoyloxy)-2H-1,2,3-triazoles[433]
468
N
NNBzR1
BzOH2O, acetone
reflux, 4−11 h
469
N
NH
N
BzO
R1R1 = H 89%
R1 = Ph 89%
O-Aryl-1H-1,2,3-triazole-1-carboximidates 470 are hydrolyzed to the corresponding N-un-substituted derivatives 471 by reaction with concentrated hydrochloric acid at room tem-perature (Scheme 161);[49] they are also hydrolyzed in aqueous sodium hydroxide (100 8C,15 min).
518 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 161 Hydrolysis of O-Aryl-1H-1,2,3-triazole-1-carboximidates[49]
HCl, 20 oC, 5 h
471
N
NH
N
Ar1O
R143−91%
470
N
NN
Ar1O
R1
HN OAr1
R1 = H, CO2Et; Ar1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4
13.13.1.4.1.3.4 Method 4:Dearylation
N-Aryl substituents that are activated by nitro groups are removed by nucleophilic dis-placement by hydrazine[483] or by potassium hydroxide.[484] Oxidative removal of a 4-ami-nophenyl substituent at N1 by potassium permanganate has also been reported.[485] Oxi-dation of 2,4-bis(2,4-diaminophenyl)-2H-1,2,3-triazole (472) gives 1H-1,2,3-triazole-4-car-boxylic acid (Scheme 162).[486]
Scheme 162 Oxidative Dearylation of 2,4-Bis(2,4-diaminophenyl)-2H-1,2,3-triazole[486]
KMnO4, NaOH
100 oC N
NH
N
HO2C
80%
472
N
NN
H2NNH2
NH2
H2N
13.13.1.4.1.3.5 Method 5:Dealkylation
N-Benzyl-1,2,3-triazoles are frequently used as precursors of N-unsubstituted triazoles.The benzyl group is removed by reduction with sodium in liquid ammonia,[105,319,432,487]
catalytic hydrogenation,[90,105,457,488] or chromic acid oxidation.[280] The 4-methoxybenzylgroup is readily removed by solvolysis in trifluoroacetic acid[303] at 65 8C or with 47% hy-drobromic acid[336] at 120 8C (Scheme 163). The related 3-bromo-4-methoxybenzyl groupis removed by treatment with concentrated sulfuric acid at 120 8C.[463] Triazoles having a2-acetoxybenzyl group in N1 are dealkylated, in low yield, simply by refluxing in piperi-dine or in diethanolamine.[92] 2-Benzyl-2H-1,2,3-triazole and 1-benzyl-1H-1,2,3-triazole 3-oxides are N-debenzylated by treatment with iodotrimethylsilane, concentrated hydro-bromic acid, or concentrated sulfuric acid.[489]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 519
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 163 Removal of a 4-Methoxybenzyl Group from1-(4-Methoxybenzyl)-1H-1,2,3-triazoles[303,336]
TFA, 60−65 oC, 1−7 h
or 47% HBr, 120 oC, 3 h N
NH
N
R2
52−100%
473
R1
N
NN
R2
R1
OMe
R1 = H, CO2Et; R2 = H, OH, Cl, CN, Ph, OPh, 4-MeOC6H4
Triazoles having a 2-(trimethylsilyl)ethoxymethyl group at N1 (e.g., 474) are dealkylatedin good yields under mild conditions, namely by action of dilute aqueous hydrochloricacid or by treatment with tetrabutylammonium fluoride in tetrahydrofuran (Scheme164).[419] The cleavage of 1-cycloheptatrienyltriazoles 475 is carried out by passing hydro-gen chloride through a solution of the triazole in diethyl ether (Scheme 165).[109] Thecleavage is probably facilitated by the stability of the tropylium ion.
Scheme 164 N-Dealkylation of 1-{[(2-Trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazoles[419]
2 M HCl, EtOH, reflux, 2 h
or 1 M TBAF/THF, reflux, 4 h N
NH
N71−89%
474
R1
N
NNR1
R1 = H, Bz, SPh
OTMS
Scheme 165 Cleavage of 1-Cycloheptatrienyl-1H-1,2,3-triazoles[109]
HCl, EtOH
rt, 30 min to 1 h
475
N
NNR1
R1 = CO2Me 34%
R1 = Bz 100%
R1
NH
NNR1
R1
+
N
NH
NR1
R1
Cl+
1-Benzyloxy-1H-1,2,3-triazoles (e.g., 476) are debenzylated in almost quantitative yields tothe corresponding 1,2,3-triazol-1-ols by catalytic hydrogenation (Scheme 166).[490]
520 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 166 Catalytic Hydrogenation of 1-Benzyloxy-1,2,3-triazoles[490]
H2, Pd/C, 0 oC, 30 minN
NNR1
R1 = MOM, Ac
OBn
93−99%
N
NNR1
OH476
1H-1,2,3-Triazoles by Removal of the 4-Methoxybenzyl Group from Triazoles 473;General Procedure:[303]
A soln of the N-protected triazole (ca. 1 g) in TFA (15–30 mL) was stirred at 60–65 8C for 1–7 h; the course of the reaction was monitored by RP–HPLC. The TFA was removed in vacuoand H2O was added to the residue. The product was isolated from the water-insoluble ma-terial by column chromatography (CHCl3). In the case of compounds 473 (R1 = CO2Et;R2 = OH, CN) the product was obtained by evaporation of the filtered aqueous phase.
13.13.1.4.1.4 Of Heteroatoms
13.13.1.4.1.4.1 Method 1:Substitution of Halogens by Nucleophiles
Heating 5-bromo-1-methyl-1H-1,2,3-triazole with ethanolic ammonia for 10 hours at100 8C in a sealed tube affords the corresponding 5-amino derivative in low yield (22% ofthe hydrochloride). The 4-bromo-1-methyl-1H- and 4-bromo-2-methyl-2H-1,2,3-triazolesdo not react with ammonia under the same conditions.[44] 5-Bromo-1-methyl-1H-1,2,3-tri-azole also reacts with aniline to yield the corresponding 5-anilino derivative in 54%.[44] Thedisplacement of the chloro group in triazoles 477 (R1 = Bn)[457,491,756] and 477 (R1 = 4-MeOC6H4CH2)
[303,491,756] by nucleophiles, such as cyanide, aryloxide, and arenethiolate,gives good yields of the corresponding derivatives 478 (Scheme 167). Similarly, 1,4-di-phenyl-1H-1,2,3-triazole-5-carbonitrile is prepared in 75% yield from the reaction of thecorresponding 5-chloro derivative with sodium cyanide in dimethyl sulfoxide (140 8C,4 h).[438]
Scheme 167 Displacement of a Chlorine by Nucleophiles[303,457,491,756]
Nu−, DMF, 70−80 oC, 18−24 hN
NNCl
R1 = Bn, 4-MeOC6H4CH2; Nu = CN, OPh, 4-MeOC6H4S, 2-thienylsulfanyl
66−82%
EtO2C
R1
477
N
NNNu
EtO2C
R1
478
Heating 1-aryl-5-chloro-1H-1,2,3-triazoles 479 with hydrazine gives directly 5-(substitutedamino) 1H-1,2,3-triazol-1,5-diamines 481 (Scheme 168). The 5-hydrazinotriazoles 480 arepresumably formed first but rearrange spontaneously under the reaction conditions.[492]
Heating 5-chloro-1-phenyl-1H-1,2,3-triazole with an aqueous solution of sodium hydrosul-fide at 100 8C in a sealed tube produces a bis(1-phenyl-1H-1,2,3-triazol-5-yl) sulfide.[404] Cu-riously, when the same reaction is carried out at room temperature the product is N-phen-yl-1,2,3-thiadiazol-5-amine.[404]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 521
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 168 Reaction of 1-Aryl-5-chloro-1H-1,2,3-triazoles with Hydrazine[492]
H2NNH2
60−130 oC, 2−24 hN
NNCl
R1 = H, Ph; Ar1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-pyridyl
R1
479
Ar1
47−80%
N
NNH2NHN
R1
480
Ar1
N
NNAr1HN
R1
481
NH2
Attempted displacement of bromine from 4,5-dibromo-1H-1,2,3-triazole by dimethyl-amine under vigorous conditions (sealed tube, 260 8C, 140 h) yields only the dimethyl-amine salt of the dibromotriazole.[445] The halo group in 4-chloro- and 4-bromo-3-substi-tuted 1H-1,2,3-triazole 1-oxides is readily displaced by methoxide ions at 20 8C while the 5-chloro analogues require heating at 140 8C.[464] The displacement of bromine from bromo-and dibromo-1,3-disubstituted 1,2,3-triazolium salts by methoxide, hydroxide, and sul-fide has been studied extensively.[449,493–495] The 5-bromo-1,2-disubstituted 1,2,3-triazo-lium fluorosulfonates react with hydroxide or methoxide ions to form 1,2-disubstituted1,2,3-triazol-5-ones.[450] Intramolecular displacement of chlorine in 4-acyl-5-chloro-1H-1,2,3-triazoles gives access to interesting polycyclic triazole derivatives.[496,497]
13.13.1.4.1.4.2 Method 2:Substitution of Hydroxy Groups by Halogens
Reaction of the 1H-1,2,3-triazol-5-ol 482 with phosphorus pentachloride in toluene at40 8C gives the 5-chloro derivative 483 in 65% yield (Scheme 169).[303]
Scheme 169 Reaction of a 1H-1,2,3-Triazol-5-ol with Phosphorus Pentachloride[303]
PCl5, toluene
40 oC, 90 minN
NNHO
EtO2C
482
OMe
65%
N
NNCl
EtO2C
483
OMe
13.13.1.4.1.4.3 Method 3:Substitution of Diazonium Groups by Nucleophiles
Displacement of nitrogen from diazonium salts derived from 1,2,3-triazol-4-amines and1,2,3-triazol-5-amines is achieved in the same manner as for other aromatic diazoniumsalts. For example, a range of 4-substituted 5-azido-1-phenyl-1H-1,2,3-triazoles 486 is pre-pared in high yield by diazotization of the corresponding 5-amino derivatives 484 fol-lowed by addition of excess sodium azide to the diazonium ions 485 (Scheme 170).[498,499]
In a similar process, 5-amino-1H-1,2,3-triazole-4-carboxamide is converted into the 5-iododerivative in 33%.[500] Diazotization of 1-methyl-1H-1,2,3-triazol-4-amine with sodium ni-trite/hydrobromic acid gives directly the 4-bromo derivative in 41% yield.[44]
522 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 170 Substitution of Diazonium Groups by Nucleophiles[498,499]
NaNO2, H2O, HCl
−5 to 0 oCN
NNH2N
R1
R1 = Ph, XC6H4, CHO, CONH2, CN, PO(OEt)2, SO2Ph
Ph
484
NaN3, H2O
−30 or 0 oCN
NN+N2
R1
Ph
485
N
NNN3
R1
Ph
486
5-Azido-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (486, R1 = CHO); Typical Procedure:[499]
CAUTION: Sodium azide can explode on heating and is highly toxic.
An aqueous soln of NaNO2 (0.76 g, 11 mmol) was added slowly to a well stirred soln of 5-amino-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (484, R1 = CHO; 1.88 g, 10 mmol) inconcd HCl (120 mL) at –5 to 0 8C. Then, a 10-fold excess of NaN3 in H2O was added dropwiseat about –30 8C. After dilution with H2O, the mixture was extracted with Et2O and thecombined extracts were dried (MgSO4). The solvent was evaporated and the residue waschromatographed (silica gel, CH2Cl2). Crystallization (CHCl3/Et2O) gave pure compound;yield: 62%; mp 97 8C (dec).
13.13.1.4.1.4.4 Method 4:Deoxygenation
Triazole N-oxides, such as 487, 489, and 491, are deoxygenated to triazoles (e.g., 488, 490,and 492) in almost quantitative yield by refluxing in phosphorus trichloride (Scheme171)[456,464,465] or by reduction with zinc in acidic media (Scheme 172).[466,501] 2-Aryl-2H-1,2,3-triazole 1-oxides are converted directly into 2-aryl-4-chloro-2H-1,2,3-triazoles by re-action with gaseous hydrogen chloride[466] or by heating with concentrated hydrochloricacid in a sealed tube.[465]
Scheme 171 Deoxygenation of Triazole N-Oxideswith Phosphorus Trichloride[456,464,465]
X = Cl, Br
N
NNR1
487
X
PCl3reflux, 1 h
83−99%
488
O−+
N
NNR1
X
X = Cl, Br
NR1
NN
489
X
PCl3reflux, 1 h
90−97%
490
O−+
NR1
NNX
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 523
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 172 Reductive Deoxygenation of 2H-1,2,3-Triazole 1-Oxides[466,501]
Ar1 = Ph, 3-ClC6H4, 4-ClC6H4, 4-EtO2CC6H4
N
NNAr1
491
Zn, AcOH
0 oC to rt, 12 h
80−95%
492
O−+
N
NNAr1
HO HO
13.13.1.4.1.4.5 Method 5:Dehalogenation
1-Substituted 5-bromo-1H-1,2,3-triazole 3-oxides 493 are debrominated in virtually quan-titative yield when heated at 100 8C for 1 hour with sodium sulfite (Scheme 173).[464]
Scheme 173 Debromination of 5-Bromo-1H-1,2,3-triazole 3-Oxides[464]
R1 = Me, Ph, Bn
Na2SO3, H2O
reflux, 1 h
97−100%
493
N+
O−
N
NR1
494
N+
O−
N
NR1
Br
1-Methyl-1H-1,2,3-triazole 3-Oxide (494, R1 = Me); Typical Procedure:[464]
5-Bromo-1-methyl-1H-1,2,3-triazole 3-oxide (493, R1 = Me; 0.56 g, 3.1 mmol), Na2SO3
(1.19 g, 9.4 mmol), and H2O (5.6 mL) were refluxed for 1 h. The H2O was removed and theresidue was extracted with boiling MeCN (3 � 10 mL). Removal of the MeCN afforded 494(R1 = Me); yield: ~100%; mp 123–124 8C.
13.13.1.4.2 Addition Reactions
13.13.1.4.2.1 Method 1:Conversion into N-Oxides
1-Substituted 1,2,3-triazole 3-oxides 496 are prepared by oxidation of 1-substituted tria-zoles 495 with 3-chloroperoxybenzoic acid (Scheme 174). The yields are good but de-crease when electron-withdrawing substituents are present, particularly if situated adja-cent to the nitrogen to be oxidized. Phenyl groups at this position also lead to decreasedyields. The low yield in these cases is not a serious drawback since unchanged startingmaterial is readily recovered.[464,489] Oxidation of 1-(arylmethyl)-1H-1,2,3-triazoles withperacetic acid does not give the expected N-oxides but 1-arylmethyloxy derivatives.[91] At-tempts to obtain 2-phenyl-2H-1,2,3-triazole 1-oxide by oxidation of 2-phenyl-2H-1,2,3-tria-zole with a range of oxygen donators are unsuccessful.[465]
524 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 174 Preparation of 1-Substituted 1H-1,2,3-Triazole 3-Oxides[464,489]
R1 = Me, Ph, Bn, 4-MeOC6H4CH2; R2 = H, Me, Cl; R3 = H, Me, Ph, Cl, Br, OMe
MCPBA, EtOAc
rt, 5 d
6−85%
495
NN
NR1R2
R3
496
N+
O−
N
NR1R2
R3
1-Substituted 1H-1,2,3-Triazole 3-Oxides 496; General Procedure:[464]
The 1-substituted triazole 495 (1.0 g) was dissolved with heating in EtOAc (1 mL). Aftercooling to 20 8C, MCPBA (1.2 molar equiv) was added. The mixture was stirred for 120 h,diluted with CH2Cl2 (10 mL) and washed with aq 1 M NaOH (8 mL). The aqueous soln wasextracted with CH2Cl2 (2 � 8 mL). The combined organic phase was dried, the CH2Cl2 wasremoved, EtOAc (10 mL) was added, and the suspension was filtered through silica gel(2 g). Washing with further EtOAc (2 � 10 mL) and removal of the solvent gave unchangedstarting material. Subsequent extraction of the silica gel (EtOAc/MeOH 1:1; 5 � 10 mL) andremoval of the solvents gave the crude product.
13.13.1.4.3 Rearrangement of Substituents
Appropriately substituted 1,2,3-triazoles may undergo thermal, photochemical, acid-cat-alyzed, or base-catalyzed isomerizations. As shown in many of the previous methods, fre-quently these isomerizations occur spontaneously during the synthesis of the triazolering. Isomerizations are also observed during reactions involving substitution or modifi-cation of substituents on a 1,2,3-triazole (see, for example, Scheme 168). The most impor-tant isomerization reaction in 1,2,3-triazoles is the Dimroth rearrangement, illustrated inScheme 175 for 1H-1,2,3-triazol-5-amines. This type of isomerization is also observed inother heterocyclic systems. The interconversion of compounds 497 and 498 is mainlycontrolled by the nature of R1, but it is also influenced by the basicity of the solventused. Isomers 498 are favored when R1 is an aryl group, a large rigid group, or an elec-tron-withdrawing group. Isomers 497 are favored when R1 is an alkyl group.[21]
Scheme 175 Dimroth Rearrangement in 1H-1,2,3-Triazol-5-amines
N
NN
497 498
N
NH
NH2NR1
R2
R1HN
R2
R2 N2
H2N NR1
R2 N2
R1HN NH
This type of isomerization is also observed in 1-substituted 4-(iminomethyl)-1H-1,2,3-tria-zoles (Scheme 176). For example, imines 500 and 501 (R1 = H) are interconvertible whenheated in dimethyl sulfoxide at 80 8C. The equilibrium position depends on the electronicproperties of the R2 substituent, favoring 501 when R2 is alkyl, benzyl, and 4-methoxy-phenyl, and 500 when R2 is 4-chlorophenyl and 4-nitrophenyl.[502] An interesting applica-tion of this isomerization is the synthesis of 1-alkyl-1H-1,2,3-triazole-4-carbaldehydes 502from 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (499, R1 = H).[502] This type of isomeriza-tion is also applied to the conversion of 1-phenyl-1H-1,2,3-triazole-4-carbaldehydes 499(R1 = Me, Ph) into 4-oxo-substituted 1-alkyl-1H-1,2,3-triazoles 502 (R1 = Me, Ph).[503]
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 525
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 176 Isomerization of 1-Substituted 4-(Iminomethyl)-1H-1,2,3-triazoles[502,503]
N
NN
500 501
N
NNR1
N2
R1 NPhPh
H
R2N
80−130 oC R2N
H
R2
R1
PhN
R2NH2
H2O
HCO2H or silica gel
502
N
NN
R2
R1
ON
NN
499
R1
Ph
H
O
R1 = H, Me, Ph; R2 = Me, Et, iPr, t-Bu, Bn, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4
Despite the failure of hydrazone and oxime derivatives 500 (R1 = H; R2 = NH2, NHPh, OH)to isomerize to 501,[502] phenylhydrazone 504 (prepared from aldehyde 503) are convert-ed into derivative 505 (Scheme 177). Similarly, phenylhydrazone 507 (R1 = NHPh) and ox-ime 507 (R1 = OH) are converted into amides 508.[504] Triazole 506 [and 1-benzyl, 1-(4-chlo-robenzyl), and 1-(4-methoxybenzyl) analogues] are converted into carboxamides of type508 (R1 = Me, Et) by reaction with methylamine or ethylamine followed by rearrangementof the resulting imines on heating above their melting points.[302]
Scheme 177 Isomerization of 1-Phenyl-1H-1,2,3-triazoles Bearing a Hydrazone orOxime Function at the 4-Position[504]
N
NN
503 505
N
NNH2N
Ph
H
OPhNHNH2
EtOH
NH2
PhN
86%
N
NN
504
H2NPh
H
NPhHN
CHCl3reflux, 2 d
52%
NHPh
N
NN
506 508
N
NNCl
Ph
H
O
R1NH2
NHPh
O
R1 = NHPh 53%
R1 = OH 56%
N
NN
507
ClPh
H
R1NDMSO
70 oC, 2−3 d
R1 = NHPh 69%
R1 = OH 59% R1
Another interesting type of isomerization in 1,2,3-triazoles corresponds to the migrationof alkyl groups between nitrogens. This is not a very common transformation, but someexamples have been reported.[505,506,757] Triazole 509, for example, isomerizes to 510 whentreated with boron trifluoride (Scheme 178).[506,757]
526 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 178 Isomerization of 1-Alkyl-1H-1,2,3-triazoles to2-Alkyl-2H-1,2,3-triazoles[506,757]
N
NN
509
MeO2C
MeO2CBF3•OEt2, Et2O
20 oC, 36 h
82%
N
NN
510
MeO2C
MeO2C
BOM
BOM
Migration of alkyl groups is also observed in 1,3-disubstituted 1,2,3-triazolium-4-thiolates511. Heating these compounds in an organic solvent at 180 8C results in transfer of alkylgroups with the formation of (alkylsulfanyl)-1,2,3-triazoles (Scheme 179).[495,507] When R1
and R2 are different alkyl groups, four compounds 512–515 are obtained. The formationof compounds 514 and 515 clearly indicates that this is an intermolecular reaction. If 511has only one alkyl group, only one product is formed. For example, 1-methyl-3-phenyl-1,2,3-triazolium-4-thiolate (511, R1 = Me; R2 = Ph) is quantitatively converted into 5-(meth-ylsulfanyl)-1-phenyl-1H-1,2,3-triazole (513, R1 = Me; R2 = Ph).[495]
Scheme 179 Migration of Alkyl Groups in 1,3-Disubstituted 1,2,3-Triazolium-4-thiolates[495,507]
NR2
NN
511
−S
180 oC
R1
+N
NN
512
R2S
R1
+NR2
NN
513
R1S
+N
NN
514
R1S
R1
+NR2
NN
515
R2S
1-Ethyl-1H-1,2,3-triazole-4-carbaldehyde (502, R1 = H; R2 = Et); Typical Procedure:[502]
To a soln of 499 (R1 = H; 1 g, 5.8 mmol) in MeOH (20 mL), was added 70% aq EtNH2 (0.57 mL,1.5 equiv), and the whole was stirred overnight at rt. The soln was concentrated and theresulting precipitate 500 (R1 = H; R2 = Et) was collected by filtration and dried; yield: 0.6 g(52%); mp 35 8C. This compound (0.6 g, 3 mmol) was heated overnight in DMSO (2 mL) at80 8C. The soln was poured into ice water and the precipitate 501 (R1 = H; R2 = Et) was col-lected; yield: 0.5 g (83%); mp 83 8C. Compound 501 (0.5 g, 2.5 mmol) was dissolved in amixture of H2O/MeOH (1:1; 20 mL) containing 10% of HCO2H and the soln was heated over-night at 80 8C. After addition of H2O (20 mL), the soln was extracted with CHCl3, and theextracts were washed with H2O and dried (MgSO4). The solvent was removed and the re-sulting oil (0.3 g) was chromatographed (silica gel, CH2Cl2/Et2O 9:1) to give 502 (R1 = H;R2 = Et); yield: 0.15 g (48%).
13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 527
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.2 Product Subclass 2:
Monocyclic 2-Substituted 1,2,3-Triazoles
13.13.2.1 Synthesis by Ring-Closure Reactions
13.13.2.1.1 By Formation of One N-N and One N-C Bond
13.13.2.1.1.1 Fragments C-C-N-N and N
13.13.2.1.1.1.1 Method 1:From N-Aminophthalimide and Conjugated Azoalkenes
2-(Phenylazo)propene (517, R1 = Me; R2 = H) and 1-(phenylazo)cyclopentene [517,R1,R2 = (CH2)3] react with N-aminophthalimide (516), in the presence of lead(IV) acetate,to give 2-phenyl-2H-1,2,3-triazoles 520 in moderate yields (Scheme 180).[508] A probablemechanism for this reaction involves the initial formation of the azimine intermediate518, 1,5-electrocyclization to the 2,5-dihydro-1H-triazole 519, and, finally, 1,2-elimina-tion of phthalimide.
Scheme 180 2H-1,2,3-Triazoles from N-Aminophthalimide and Conjugated Azoalkenes[508]
N
NNPh
520
R1
+N
O
O
NH2
R1
N
R2
HN
PhPb(OAc)4
K2CO3, CH2Cl2−10 oC, 40 min
R2NH
O
O
+
R1 = Me; R2 = H 41%
R1,R2 = (CH2)3 70%516 517
NN
N
518
N
NNPhR1
N
O
O
Ph
N
O
O+
−
519
R2R2
H
R1
13.13.2.1.2 By Formation of Two N-C Bonds
13.13.2.1.2.1 Fragments N-N-N and C-C
13.13.2.1.2.1.1 Method 1:Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes
Azidotrimethylsilane and azidotributylstannane undergo addition to alkynes to give 2-(trimethylsilyl)- or 2-(tributylstannyl)-2H-1,2,3-triazoles, resulting from the isomerizationof the initially formed 1-substituted derivatives These reactions are discussed in Section13.13.1.1.3.1.1.6 (Schemes 59 and 60). A palladium-catalyzed three-component couplingreaction of azidotrimethylsilane, alkynes, and allyl methyl carbonate has been de-scribed.[509] It affords selectively 2-allyl-2H-1,2,3-triazoles 521 in low to moderate yields(Scheme 181). A �-allylpalladium azide complex, which undergoes the 1,3-dipolar cyclo-addition with the alkyne, has been proposed as a key intermediate in this reaction.
528 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 181 2-Allyl-2H-1,2,3-triazoles from Azidotrimethylsilane, Alkynes, andAllyl Methyl Carbonate[509]
N
NN
R12.5 mol% Pd2(dba)3, CHCl310 mol% dppp, EtOAc
100 oC, 2−24 h
R2+
521
TMSN3 +
R2
R1
OCO2Me
R1 = H, Et, t-Bu, cyclohex-1-enyl; R2 = Ac
R1 = H, (CH2)5Me, CO2Me; R2 = CO2Me
R1 = (CH2)4Me; R2 = CHO
R1 = Ph; R2 = CN, CHO, Ac, CO2Me, PO(OEt)2, SO2Ph, NEt2
15−66%
13.13.2.1.2.1.2 Method 2:Addition of Acyl or Alkoxycarbonyl Azides to Æ-Acylphosphorus Ylides
Acyl and alkoxycarbonyl azides undergo addition to Æ-acylphosphorus ylides 522 to yield2-substituted 2H-1,2,3-triazoles, which result from the spontaneous isomerization of theinitially formed 1-substituted triazoles (Scheme 182). For the discussion of this type of re-action and examples see Section 13.13.1.1.3.1.2.5 (Scheme 76).
Scheme 182 2H-1,2,3-Triazoles from Acyl or Alkoxycarbonyl Azides andÆ-Acylphosphorus Ylides[229,231]
N
NN
R3
R2
522
R1N3 +
R1 = acyl, CO2Et
− Ph3POR2 O−
R3 PPh3
+
R1
N
NNR1
R3
R2
13.13.2.1.3 By Formation of One N-N Bond
13.13.2.1.3.1 Fragment N-N-C-C-N
13.13.2.1.3.1.1 Method 1:Cyclization of Æ-Hydroxyimino Hydrazones
The intramolecular elimination of water from Æ-hydroxyimino hydrazones is a generalmethod for the synthesis of 2H-1,2,3-triazoles (Scheme 183). Generally acetic anhy-dride[510–514] is the reagent of choice, but other reagents are also used, namely phosphoruspentachloride,[515] urea,[516] or bromine.[513] As an example, 2H-1,2,3-triazole 524(R1 = R2 = Ph; R3 = 4-O2NC6H4) is obtained in 57% yield by refluxing the corresponding hy-droxyimino hydrazone 523 with acetic anhydride for 40 minutes.[289]
Scheme 183 Cyclization of Æ-Hydroxyimino Hydrazones[289]
523
Ac2O, heat or PCl5, heat
or urea, heat or Br2, heat
R1 NOH
R2 NN
NNR3
R2
R1
NHR3
524
This method has been applied to the synthesis of a range of 2,2¢-diaryl-5,5¢-dimethyl-4,4¢-bi-2H-1,2,3-triazoles 526 from Æ-hydroxyimino hydrazones 525 (Scheme 184).[517]
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 529
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 184 Synthesis of 4,4¢-Bi-2H-1,2,3-triazoles[517]
525
NN
N
NPhN
N
X
PCl5, CHCl3rt, 1 h
526
X = H, 2-Cl, 3-Cl, 4-Cl, 4-NO2, 2-Br, 3-Br, 4-Br
55−68%NOH
NN
PhN
N
NH
X
Another interesting example of the application of this method is the synthesis of 2-aryl-2H-1,2,3-triazoles starting from dehydro-ascorbic acid 527 (Scheme 185). On boiling withacetic anhydride, the dehydro-ascorbic acid 3-(hydroxyimino)-2-arylhydrazones 528 areconverted into the acetylated triazole derivatives 529, whereas the unacetylated triazolederivatives 530 are obtained upon reaction with bromine in water.[512] Treatment of tria-zole 529 (Ar1 = Ph) with ammonia gives the 2H-1,2,3-triazole-4-carboxamide 531 in quan-titative yield.[512] Compound 529 (Ar1 = 3-BrC6H4) is obtained in 85% yield by treating thecorresponding 3-(hydroxyimino)-2-arylhydrazone 528 with acetic anhydride in pyridineovernight at room temperature.[514]
Scheme 185 Cyclization of Dehydro-ascorbic Acid 3-(Hydroxyimino)-2-arylhydrazones[512,514]
527
Ac2O
reflux, 1 h
Ar1 = Ph, 4-ClC6H4, 3-BrC6H4, 4-Tol, 4-MeOC6H4
O O
OO
HO
HO
2 steps
528
O O
NHON
HO
HO
Ar1HN
NN
N
O OAcO
AcO
Ar1
530
NN
N
O OHO
HO
Ar1
Br2, H2O
rt, 3 h
NH3, MeOH
rt, overnight
NN
N
CONH2HO
OHHO
Ph
529 531
Ar1 = Ph
100%
If the Æ-hydroxyimino hydrazone is N-unsubstituted, dehydration with acetic anhydridegives a 2-acetyl-2H-1,2,3-triazole, which is readily hydrolyzed to the corresponding N-un-substituted triazole (Scheme 186) (see also Section 13.13.1.1.4.1.3).[510]
530 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 186 Cyclization of N-Unsubstituted Æ-Hydroxyimino Hydrazones[510]
R2 NOH
R1 NN
NNAc
R1
R2
NH2 Ac2O N
NH
N
R1
R2
H2O
Dehydration of amide derivatives 532 in refluxing thionyl chloride gives 2-phenyl-2H-1,2,3-triazole-4-carboxamides 533 in good yields (Scheme 187).[518]
Scheme 187 Cyclization of Æ-Hydroxyimino Hydrazones with Thionyl Chloride[518]
NOH
Ar2 N
N
NNPh
Ar2NHPh
SOCl2
reflux, 3 h
Ar1HN
O
532
Ar1HN
O
533
Ar1 = Ph, 4-Tol, 2-MeOC6H4, 2-ClC6H4, 4-ClC6H4, 2,4-Me2C6H3; Ar2 = Ph, 4-ClC6H4, 4-O2NC6H4
60−80%
In acetic acid, the nitro(arylhydrazono)acetaldehyde oximes 534 are converted into the 2-aryl-2H-1,2,3-triazol-4-ol 1-oxides 536, probably via the intermediate 535 (Scheme188).[466,501]
Scheme 188 Cyclization of Nitro(arylhydrazono)acetaldehyde Oximes[466,501]
NOH
O2N NN
NNAr1
NHAr1AcOH
rt, 12 h
534 536
Ar1 = Ph, 4-Tol, 4-MeOC6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 4-EtO2CC6H4
50−62%
O−+
HOO N
NAr1
NO• •
535
Oxidation of (arylhydrazono)acetaldehyde oximes 537 with copper(II) sulfate[465,466,519] inaqueous pyridine, with mercury(II) oxide,[520] or with N-iodosuccinimide[521] leads to theformation of 2-aryl-2H-1,2,3-triazole 1-oxides 538 (Scheme 189).
Scheme 189 Oxidation of (Arylhydrazono)acetaldehyde Oximes with Copper(II) Sulfate[519]
NOH
R1 NN
NNAr1
NHAr1CuSO4, py, H2O
reflux, 30 min or rt, overnight
537 538
O−+
R1
R1 = H; Ar1 = Ph 80%
R1 = Me; Ar1 = Ph 90%
R1 = Me; Ar1 = 2,6-Cl2-4-F3CC6H2 90%
Cyclization of the oxomalonaldehyde derivatives 540 and 541 [produced from bis(oxyimi-no) hydrazone 539] with cesium carbonate in tetrahydrofuran affords 2-aryl-2H-1,2,3-tria-zoles 542 and 543 in moderate to excellent yields (Scheme 190).[519,522,523] These triazolesare hydrolyzed to the 4-formyl derivative or converted into a range of other interesting 4-substituted 2-aryltriazoles.
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 531
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 190 Oxidation of Æ-Acetyloxyimino Arylhydrazones withCesium Carbonate[519,522,523]
N
NNAr1
Ac2O, rt
30 min
539
540H
NOH
NNHAr1
NOHH
H
NOAc
NNHAr1
NOHH
Ac2O, heat
5−10 min H
NOAc
NNHAr1
NOAcH
541
HON
N
NNAr1AcON
Cs2CO3
THF, rt
542
543
Ar1 = Ph, 2-FC6H4, 2-ClC6H4, 4-ClC6H4, 2-BrC6H4, 2,6-Cl2C6H3, 3,4-Cl2C6H3, 2,4,6-Cl3C6H2, 2,6-Cl2-4-F3CC6H2
26−82%
72−95%
Cs2CO3
THF
rt, 1 h
Oxidation of both hydroxyimino arylhydrazones 544 and 545 with lead(IV) acetate yields2-aryl-2H-1,2,3-triazole 1-oxides 546 in moderate to excellent yields (Scheme 191).[524]
Scheme 191 Oxidation of Æ-Hydroxyimino Arylhydrazones with Lead(IV) Acetate[524]
Ar1NHNH2, MeOH, H2O
AcOH (cat.), 0 oC, 20−30 min
544
R2
N
NOH
OR1
N
NNAr1
546
R1 = R2 = Me, Ph; Ar1 = Ph, 4-Tol, 4-ClC6H4, 4-O2NC6H4
NHAr1
R2
N
NOH
NR1
NHAr1
NHAr1
545
23−98%
45−72%
O−+
R2
Pb(OAc)4
CH2Cl2, rt
Pb(OAc)4
CH2Cl2, rtR1
O
13.13.2.1.3.1.2 Method 2:Cyclization of 1,2-Diketone Bis(arylhydrazones)
The oxidation of 1,2-diketone bis(arylhydrazones) to 2-aryl-2H-1,2,3-triazoles (Scheme192) is a very general reaction and it has been used extensively for the preparation of sug-ar “osotriazoles” from osazones. This subject has been reviewed.[525] The nitrogen elimi-nated is that attached to the 1-position for sugar osazones; a possible mechanism for thereaction is shown in Scheme 192.[3] Many oxidizing agents have been used, especially cop-per sulfate and other copper(II) salts,[526–529] and nitrous acid.[530,531] As an example, oxida-tion of the phenyl-D-glucosazone [547, R1 = H; R2 = (CHOH)3CH2OH] with copper(II) sulfategives the corresponding triazole 550 in 59% yield.[526–528] In a similar way, glyoxal is con-verted into 2-phenyl-2H-1,2,3-triazole in 59% overall yield via osazone 547 (R1 = R2 = H).[472]
Oxidation of the tetra-O-acetylphenylosazones from D-glucose, D-galactose, and L-sorbose
532 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bwith nitrous acid gives the corresponding 2-phenyl-2H-1,2,3-triazole tetraacetates in ap-proximately 80% yield.[530]
Scheme 192 Oxidation of 1,2-Diketone Bis(phenylhydrazones)[525]
N
R2 NN
NNPh
NHPh oxidant
547 549
R1 = R2 = H, alkyl, aryl
NPh+
R2
R2 NNPh
NNPh
548
R1NHPh
R1 R1
−
N
NNPh
550
R2
R1
This type of reaction can be extended to 1,2-diketone bis(phenylhydrazones) 547(R1 = R2 = alkyl or aryl). Oxidation of these compounds with potassium dichromate in ace-tic acid,[532] nickel peroxide,[533] manganese(IV) oxide,[534] or with other oxidants yields avariety of products; the products formed depend upon the reaction conditions. In somecases, 2-substituted 2H-1,2,3-triazoles are obtained in low to moderate yields. As indicatedin Scheme 192, a probable mechanism for the formation of triazoles involves the oxida-tion of the bis(phenylhydrazones) to bis(phenylazo)ethene derivatives 548, which can ex-ist in the mesoionic form 549.[535,536] Loss of phenylnitrene from this species yields tria-zoles 550. The bis(phenylazo)ethene derivatives 548 are isolated in high yields,[533] andcan be converted into 2-phenyl-2H-1,2,3-triazoles by acid treatment[537] or by irradiationwith UV light.[538] Mesoionic species 549 have been trapped by dipolarophiles in 1,3-dipo-lar cycloadditions to yield new interesting 1,2,3-triazole derivatives.[535,539,540] N-Benzoylanalogues of mesoionic species 549 are isolated in good yields as stable crystalline com-pounds.[541] 1,2-Bis(arylazo)cycloalkenes (548, R1,R2 = ring with six or more carbons) whenheated or treated with acid undergo intramolecular rearrangements, via 1,2,3-triazoliumimide 1,3-dipoles of type 549, to yield 2-aryl-2H-1,2,3-triazoles bearing a 2-aminoarylgroup in the cycloalkene ring.[542]
1,2-Diketone bis(hydrazones) also cyclize to 1,2,3-triazoles solely by thermolysis:heating biacetyl bis(hydrazone) at 170 8C gives 4,5-dimethyl-1H-1,2,3-triazole (25%) andheating biacetyl bis(phenylhydrazone) at 300 8C yields 2-phenyl-4,5-dimethyl-2H-1,2,3-tri-azole in 51% yield.[543]
Oxidation of phenylhydrazones of aromatic aldehydes 551 with manganese(IV) ox-ide in refluxing benzene also affords triazoles 553 and other isolated products (Scheme193).[534] The dimerization of the phenylhydrazones to 552 appears to be the key step inthis transformation. Triazoles 553 are obtained in low to moderate yields. The oxidationof arylhydrazones derived from 2-acetylpyridine and 2-benzoylpyridine with lead(IV) ace-tate leads to the formation of fused 1,2,3-triazolium systems.[544]
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 533
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 193 Oxidation of Phenylhydrazones of Aromatic Aldehydes[534]
551
N
NNPh
553 Ar1 = Ph 44%
Ar1 = 4-Tol 15%
Ar1 = 4-MeOC6H4 7%
Ar1
Ar1
Ar1
H
N NHPh MnO2, benzene
reflux, 4−6 hAr1
H
N NPh•
Ar1
H
N NPh•
Ar1
N
N
Ar1
NPh
NPh
Ar1
N
N
Ar1
NHPh
NHPh
7−44%
552
13.13.2.1.3.1.3 Method 3:Cyclization of Æ-Imino Hydrazones
The oxidative cyclization of 1,2-diketone imine hydrazones 554 with ammoniacal coppersulfate yields 2H-1,2,3-triazoles 555.[545] N-Substituted imines 556 give 1,2-disubstitutedtriazolium salts 557 when N-bromosuccinimide is used as the oxidant (Scheme 194).[546]
Scheme 194 Oxidative Cyclization of Æ-Imino Hydrazones[545,546]
R1 = R3 = alkyl, aryl; R2 = Ac, aroyl, CO2Et, CN
N
NNR3
555
R2
R1
R2
NH
N
R1
554
NHR3 CuSO4, NH3
R1 = alkyl, aryl; R2 = alkyl, CN
N
NNAr1
557
R2
R1
R2
NPh
N
R1
556
NHAr1NBS
Ph+
Br−
A related reaction is the oxidative cyclization of (carbamimidoyl)(phenylazo)acetamide558 (X = O) and (phenylazo)malonimidamide 558 (X = NH) to triazoles 559 (Scheme195).[547]
Scheme 195 Oxidative Cyclization of (Carbamimidoyl)(phenylazo)acetamide and(Phenylazo)malonimidamide[547]
H2N
X
N
HN NH2
NPh
CuSO4, NH4OH, rt, 24 h, then 100 oC, 3 h
or CuSO4, py, 100 oC, 18 h N
NNPh
559
H2N
X
H2N
X = O 64%
X = NH 24%
558
534 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.2.1.3.1.4 Method 4:
Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines)
1,2-Bis(N-alkoxy-N-nitrosoamines) 560 are smoothly converted into 1-alkoxy-4,5-dihydro-1H-1,2,3-triazole 2-oxides 561, in high yields, under reflux in methanol. Reaction of thesecompounds with sodium methoxide affords 4H-1,2,3-triazole 2-oxides 562 or 2H-1,2,3-tri-azol-2-ols 563 (Scheme 196).[548,549]
Scheme 196 Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines)[548,549]
MeOH, reflux
0.5−5.5 h
NNO
NON
OR5
OR5
R1
R2
R3
R4
N
NN
561
O−+
OR5
R1
R2
R3
R4
560
NaOMe
MeOH
rt, 48 h N
NN
562
O−+
R2
N
NNOH
563
R2
R3
NaOMe
MeOH
rt, 3 h
78−98%
R1 = H
13−35%
R1 = R4 = H
65−86%
R3
R4
13.13.2.2 Synthesis by Ring Transformation
Thermal or basic treatment of arylhydrazones 565 of 3-acylisoxazoles 564 affords 4-acyl-2-aryl-2H-1,2,3-triazoles 566 (Scheme 197). For example, hydrazone 565 (R1 = R2 = Me;Ar1 = 2-ClC6H4) is converted into the corresponding triazole 566 by warming it to fusionin a test tube plunged in a silicone oil bath at ca. 240 8C.[517] Hydrazone 565 (R1 = R2 = Ph;Ar1 = 4-O2NC6H4) is converted quantitatively into the corresponding triazole 566 when itis melted in the presence of copper powder or by treatment with ammonia.[550] Copper(II)acetate can also be used as catalyst for this transformation.[551] The kinetics of the trans-formation of hydrazones 565 into triazoles 566 catalyzed by amines[552] or in the presenceof borate buffers,[553] has been studied.
Scheme 197 Synthesis of 2-Aryl-2H-1,2,3-triazoles from Arylhydrazones of3-Acylisoxazoles[517,550]
564
N
NNAr1
566
R2
ON
O
R2
R1
Ar1NHNH2
ON
R2
N
R1
NHAr1
565
R1
O
4-(Arylazo)isoxazol-5-ones 568 (produced from 4-arylisoxazol-5-ones 567) are convertedinto 2-aryl-2H-1,2,3-triazoles 569 when refluxed in propan-2-ol, in the presence of a tertia-ry amine, or in 1-(dimethylamino)propan-2-ol (Scheme 198).[554]
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 535
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 198 Synthesis of 2-Aryl-2H-1,2,3-triazoles from 4-(Arylazo)isoxazol-5(4H)-ones[554]
567
N
NNAr1
569
R2
R1NO
Ar1N2 Cl−
568
R1 R2
O NO
R1
O
NR2
NAr1
Et3N, iPrOH
reflux, 3 h
R1 = Me, Ph, XC6H4; R2 = Me, Bn; Ar1 = XC6H4, naphthyl, heteroaryl
+
Arylhydrazones of 3-acyl-1,2,4-oxadiazoles yield 4-(acylamino)-2-aryl-2H-1,2,3-triazoles571 by thermal or basic rearrangement (Scheme 199). For example, hydrazone 570(R1 = 3-O2NC6H4; Ar1 = 4-O2NC6H4) is converted into the corresponding triazole in 60% yieldwhen it is melted in the presence of copper powder.[550] The same triazole is obtained in90% yield by treatment of hydrazone 570 (R1 = 3-O2NC6H4; Ar1 = 4-O2NC6H4) with ammo-nia.[550] Phenylhydrazone 570 (R1 = Ar1 = Ph) gives the corresponding triazole 571 in almostquantitative yield when treated with either equimolar or catalytic amounts of copper(II)acetate monohydrate in methanol at room temperature for two hours.[551] A kinetic studyof the rearrangement of arylhydrazones 570 (R1 = Ph; Ar1 = XC6H4) into triazoles 571 hasbeen reported.[555] The effect of �-cyclodextrin on the mononuclear rearrangement of 570(R1 = Ar1 = Ph) into 571 (R1 = Ar1 = Ph), in aqueous borate buffer at pH = 9.6, at temperaturesranging from 293.15 to 313.15 K, has also been reported.[556] The 2,4-dinitrophenylhydra-zone of 3-benzoyl-1,2,4-oxadiazol-5-amine 570 [R1 = NH2; Ar1 = 2,4-(O2N)2C6H3] is convertedrapidly into the 4-ureido-2H-1,2,3-triazole 571 [R1 = NH2; Ar1 = 2,4-(O2N)2C6H3], in dimethylsulfoxide at room temperature or by heating above its melting point.[557]
Scheme 199 Synthesis of 4-(Acylamino)-2-aryl-1,2,3-triazoles fromArylhydrazones of 3-Acyl-1,2,4-oxadiazoles[550,551]
N
NNAr1
571
Ph
NH
N
ON
R1 = NH2, Ph, 3-O2NC6H4; Ar1 = Ph, 4-O2NC6H4, 2,4-(O2N)2C6H3
R1
Ph
N
NHAr1
R1
O
570
When refluxed in ethanol, in the presence of sodium ethoxide, the 1,2,5-oxadiazole phen-ylhydrazone 572 rearranges to triazoles 573 and 574 (Scheme 200). The two isomeric ox-imes 573 (E, 80%) and 574 (Z, 10%) can be separated by column chromatography.[551]
Scheme 200 Synthesis of 2H-1,2,3-Triazoles from the Phenylhydrazone of3-Benzoyl-4-methyl-1,2,5-oxadiazole[551]
N
NNPh
573 80%
Ph
572
NaOEt, EtOH
reflux, 6 h
N
N
NNPh
574 10%
Ph
NHOOH
+
NO
N
Ph
N
NHPh
4-(Alkylamino)-3-nitro-1,2,5-oxadiazole 2-oxides 575 react with primary aliphatic aminesto afford 2-alkyl-4-(alkylamino)-5-nitro-2H-1,2,3-triazole 1-oxides 577, via intermediates576, in low to moderate yields (Scheme 201). Compounds 577 are also prepared in aone-pot procedure from 3,4-dinitro-1,2,5-oxadiazole 2-oxide.[558–560]
536 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 201 Synthesis of 2-Alkyl-5-nitro-2H-1,2,3-triazole 1-Oxides from 4-(Alkylamino)-3-nitro-1,2,5-oxadiazole 2-Oxides[558–560]
576
N
NOO2N
575
R1HN R2NH2
CH2Cl2, rt N
NNR2
577 30−40%
R1HN
O2N
O−+
R1HN NOH
O2N NNHR2
O−+
− H2O
O−+
Oxidation of 4-(arylhydrazono)-4H-pyrazole-3,5-diamines 578 with lead(IV) acetate (2equiv) provides 2-aryl-2H-1,2,3-triazole-4-carbonitriles 579 in moderate yields (Scheme202). Plausible mechanisms for this transformation have been proposed.[561]
Scheme 202 Synthesis of 2-Aryl-2H-1,2,3-Triazoles from4-(Arylhydrazono)-4H-pyrazole-3,5-diamines[561]
578
N
NNAr1
NC
N
N NNHAr1
NH2
NH2 Pb(OAc)4, DMF, MeCN
0−5 oC, 1.5−2 h
41−58%
579
Ar1 = Ph, 4-Tol, 4-BrC6H4, 4-O2NC6H4, 4-MeOC6H4, 3-O2NC6H4, 3-MeOC6H4
2-Methyl-4-nitro-1-phenyl-1H-imidazole (580) reacts with hydroxylamine, in the presenceof potassium hydroxide, to yield 4-(acetylamino)-2-phenyl-2H-1,2,3-triazole 1-oxide (581)(Scheme 203). A mechanism for this transformation was suggested.[562]
Scheme 203 Synthesis of 2H-1,2,3-Triazole 1-Oxides from2-Methyl-4-nitro-1-phenyl-1H-imidazole[562]
KOH, MeOH
−5 oC, 3 h
57%
581
N
N
O2N
Ph
+ NH2OHN
NNPh
AcHN
O−+
580
Photolysis of 2-methyl-5-phenyl-2H-tetrazole (582) produces, among other minor prod-ucts, 2-methyl-4,5-diphenyl-2H-1,2,3-triazole (583) in low yield (Scheme 204).[563]
Scheme 204 Synthesis of 2H-1,2,3-Triazoles from 2-Methyl-5-phenyl-2H-tetrazole[563]
benzene, hν, 3 h
583 27%
NN
NNMe
N
NNMe
Ph
582
Ph+ other products
Ph
4,6-Disubstituted 2-methyl-2,5-dihydro-1,2,3-triazines 584 are oxidized by 3-chloroper-oxybenzoic acid (2 equiv) to give 4-substituted 2-methyl-2H-1,2,3-triazoles 585 in goodyields if at least one of the substituents is a phenyl group (Scheme 205).[564,565]
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 537
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 205 Synthesis of 2H-1,2,3-Triazoles from2-Methyl-2,5-dihydro-1,2,3-triazines[564,565]
MCPBA (2 equiv)
CH2Cl2, 0 oC, 12 h
585
N
NNMe
R1
584
+ R2CO2H
N
N
NMe
R1
R2
R1 = R2 = Me trace
R1 = R2 = Ph 69%
R1 = Ph; R2 = Me 68%
The 1,2,3,4-tetrazine 587, generated from the reaction of an (alkylazo)alkene 586 and di-methyl azodicarboxylate, is unstable and on workup yields 2,5-dihydro-1H-1,2,3-triazole588 (Scheme 206). This isomerization is probably acid catalyzed since by addition of tri-fluoroacetic acid 587 is converted in near quantitative yield into triazole 589.[566] Thesame triazole is also obtained cleanly when 588 alone is treated with trifluoroacetic acidunder the same conditions.
Scheme 206 Synthesis of 2H-1,2,3-Triazoles from 1,2,3,4-Tetrazines[566]
benzene
rt, 12 h
588
N
NNMe
586
O
NHPh
NNMe N
N CO2Me
CO2Me+
NN
NMeN
CO2Me
CO2Me
PhHN
O
75%
CO2MeNHMeO2C
PhHN
O
587
589
N
NNMe
PhHN
O
TFA
TFA, CH2Cl2rt, 6 h
80%
[1,2,3]Triazolo[1,5-b]pyridazinium salts 590, when treated with morpholine, undergoopening of the pyridazine ring to yield mixtures of the triazoles 591 and 592 (Scheme207).[567] The ratio of these products varies significantly depending on whether R1 is analkyl or an aryl group. Reaction of triazolopyridazinium salts 590 with alkoxides or thio-lates affords the 4-vinyl-2H-1,2,3-triazoles 593 and 594, respectively, as the sole prod-ucts.[567]
538 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 207 Synthesis of 2H-1,2,3-Triazoles from Triazolopyridazinium Salts[567]
morpholine
MeCN, rt
591
N
NNAr1
R1
NN N
N
R1
+Ar1
BF4−
CN
N
O592
N
NNAr1
R1
N
O
+
590
84%
R1 = Me (591/592) 3:2
R1 = 4-ClC6H4 (591/592) 1:10
R1 = Me, 4-ClC6H4; Ar1= 4-BrC6H4
NaOMe, MeOH, rt
593
N
NNAr1
R1
NN N
N
R1
+Ar1
BF4− MeO
590
R1 = Me 72%
R1 = 4-ClC6H4 82%
BnSH, KOH, EtOH, 5−10 oC
594
N
NNAr1
R1
NN N
N
R1
+Ar1
BF4− BnS
590
R1 = Me 95%
R1 = 4-ClC6H4 90%
Irradiation of 2-aryl-2H-benzotriazoles 595 with UV light, in an aerated solvent, results inthe oxidation of the benzo ring and formation of 2-aryl-2H-1,2,3-triazole-4,5-dicarboxylicacids 597 (Scheme 208).[568] The 2-aryl-2H-benzotriazole-4,7-diones 596 are plausible inter-mediates since photooxidation of compound 596 (R1 = R2 = H), obtained by oxidation of595 (R1 = R2 = H) with potassium dichromate, also leads to 597 (R1 = R2 = H). Oxidation of2-phenyl-2H-benzotriazole (595, R1 = R2 = H) with potassium permanganate also gives thedicarboxylic acid 597 (R1 = R2 = H) (in 50% yield) but oxidation of 595 (R1 = OMe; R2 = Me)under similar conditions, results in the formation of a tricarboxylic acid 597 (R1 = OMe;R2 = CO2H) in 48% yield.[568]
13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 539
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 208 Photooxidation of 2-Aryl-2H-benzotriazoles[568]
O2, EtOH
hν, rt, 12.5 d
597 R1 = R2 = H 93%
N
NN
HO2C
NN
N
HO2C
595
R1
R2
NN
N
596
R1
R2
O
O
R1
R2
oxidation
R1 = H, OMe; R2 = H, Me
13.13.2.3 Synthesis by Substituent Modification
Since substituent modification reactions in 1H- and 2H-1,2,3-triazoles are, in many cases,very similar, the synthesis of new 2H-1,2,3-triazoles by substituent modification of mono-cyclic 2-substituted 2H-1,2,3-triazoles is covered in Section 13.13.1.4.
13.13.3 Product Subclass 3:N-Unsubstituted and 1-Substituted Benzotriazoles
13.13.3.1 Synthesis by Ring-Closure Reactions
13.13.3.1.1 By Formation of Two N-N Bonds
13.13.3.1.1.1 Fragments N-C-C-N and N
13.13.3.1.1.1.1 Method 1:From Benzene-1,2-diamines and Nitrous Acid
The diazotization of benzene-1,2-diamine derivatives is the most common synthetic routeto benzotriazoles. This is a very general method, which can also be applied to the cycliza-tion of other 1,2-diaminocarbocycles[569] and 1,2-diaminoheterocycles.[570–574] In almost allthe cases the diazotization is carried out with nitrous acid (generated in situ from sodiumnitrite and a mineral acid) but other reagents can also be used. Esters of nitrous acid withprimary or secondary alcohols, preferentially methyl nitrite[575] or diphenylnitros-amine,[576] also react with benzene-1,2-diamine derivatives to afford benzotriazoles inhigh yields. Molecules consisting of a benzene-1,2-diamine group linked to a fluorophoremoiety are used as probes for nitric oxide (NO) detection; fluorescent benzotriazoles areformed in this reaction.[577–579]
The structure of the products obtained from the action of nitrous acid on an aromatic1,2-diamine, or on one of its alkyl, aryl, or acyl derivatives, was the subject of a very inter-esting scientific dispute, which occurred between the 1870s and 1910. The symmetricalstructure 598 (Scheme 209), proposed by Griess,[580,581] was shown to be incorrect andstructure 599, suggested by Kekul�, was confirmed as the correct one.[582,583]
540 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 209 Proposed Structures for the Product ofthe Reaction of Nitrous Acid on Benzene-1,2-diamine
NN
N
599
R1
598
N
NNR1
A range of diversely substituted benzotriazole derivatives 601 is prepared by diazo-tization of the corresponding benzene-1,2-diamine derivatives 600, a few examples areshown in Scheme 210.
Scheme 210 Diazotization of Benzene-1,2-diamine Derivatives[322,579,584–594]
NN
N
601
R1
600
NHR1
NH2
R2NaNO2, H3O+
R2
R1 = H, alkyl, aryl, acyl, sulfonyl
R1 R2 Conditions Yield (%) Ref
H H NaNO2, AcOH, H2O, 5–80 8C, 1 h 75–81 [584]
H 5,6-Cl2 NaNO2, HCl, H2O, 0 8C 50 [585]
H 5,6-(NO2)2 NaNO2, HCl, H2O, 5–25 8C, 1 h 83 [586]
Me 6-Cl NaNO2, HCl, H2O, 10 8C 29 [585]
2,4,6-(O2N)3C6H2 4,6-(NO2)2 NaNO2, H2SO4, H2O, 5–25 8C, 1 h 63 [586]
Ac 5,6-Me2 NaNO2, AcOH, H2O, 10–50 8C 63 [587]
Ac 5-NHAc-6-OMe NaNO2, HCl, H2O, 5 8C, 2 h 97 [588]
CSCHMeNHBoc 6-NO2 NaNO2, AcOH, H2O, 0 8C, 30 min 79 [589]
S
H NaNO2, AcOH, H2O >90 [590]
CO2Et 7-Cl-4-OEt-5-CO2Me NaNO2, H2SO4, H2O, 5 8C, 15 min 68 [591]
SO2Ph 5-Me NaNO2, HCl, H2O, rt 100 [592]
NN
HNNH2
O
H NaNO2, HCl, H2O, 0 8C to rt, 2 h 96 [322]
benzotriazol-2-yl H NaNO2, HCl, H2O, 0 8C 63 [593]
6-methyl-3-pyridyl H NaNO2, HCl, H2O, 0 8C, 1 h 84 [594]
acridin-9-yl 5,6-Me2 NaNO2, HCl, H2O, 0 8C, 1 h 85 [579]
Benzo[1,2-d:4,5-d¢]bistriazoles are synthesized, in one step, by diazotization of benzene-1,2,4,5-tetraamine derivatives (Scheme 211). 1,7-Bis(2,4,6-trinitrophenyl)benzobistriazole603 is obtained in 60% yield from the bis(acetylamino) derivative 602,[595] while the 1,7-di-acetyl analogue 605 is prepared in 93% from 1,5-bis(acetylamino)-2,4-dinitrobenzene(604).[596,597]
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 541
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 211 Diazotization of Benzene-1,2,4,5-tetraamine Derivatives[595–597]
603 60%
602
H2SO4, H2O
100 oC, 20 min
Ar1 = 2,4,6-(O2N)3C6H2
Ar1HN
AcHN NHAc
NHAr1 Ar1HN
H2N NH2
NHAr1
NaNO2
5−10 oC
NN
NNN
NAr1 Ar1
605 93%
604
H2, Pd/C, EtOH
rt, 3100 Torr, 3 h
NaNO2, HCl
0 oC, 30 min
AcHN
O2N NO2
NHAc AcHN
H2N NH2
NHAc
NN
NNN
NAc Ac
An alternative method for the conversion of benzene-1,2-diamine derivatives into benzo-triazoles consists of their reaction with benzonitrile oxide, followed by diazotization ofthe resulting N-substituted benzamide oximes 607 to 1-benzohydroximoyl-1H-benzotri-azoles 608 (Scheme 212). These compounds are hydrolyzed in refluxing concentrated hy-drochloric acid to afford benzotriazoles 609 in quantitative yields.[598,758] There is no obvi-ous advantage of this method over direct diazotization of diamines 606, except the factthat compounds 607 can also be converted into benzimidazoles by treatment with hydro-chloric acid.
Scheme 212 Synthesis of Benzotriazoles via N-Substituted Benzamide Oximes[598,758]
606
benzene
reflux, 1 h
R1
R2 NH2
NH2
NaNO2, H2O, HCl
0 oC to rt, 1 h
NN
N
NPh O−++
607
R1
R2 NH2
NH
NOHPh
100%R1
R2
PhNOH
concd HCl
reflux, 2 h
NH
NN
100%R1
R2
609608
CH)2; R2 = H, Me, ClR1 = H, Me, CO2Me; R1,R2 = (CH
70−82%
542 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b5,6-Dinitro-1H-benzotriazole [601, R1 = H; R2 = 5,6-(NO2)2]; Typical Procedure:[586]
A slurry of 4,5-dinitrobenzene-1,2-diamine (7.0 g, 35 mmol) in concd HCl (300 mL) wastreated dropwise with a 10% aq NaNO2 (90 mL) at 5–10 8C. After the resulting mixturehad stirred at 25 8C for 1 h it was chilled to 0 8C and the product was collected by filtration,washed with H2O, and air-dried to provide analytically pure crystals of the monohydrateof 5,6-dinitrobenzotriazole; yield: 6.6 g (83%); mp 144 8C. Anhyd product was obtainedwhen the monohydrate was dried in an oven at 80 8C overnight.
13.13.3.1.2 By Formation of One N-N and One N-C Bond
13.13.3.1.2.1 Fragments C-C-N and N-N
13.13.3.1.2.1.1 Method 1:From Arylamines and 2-Azido-3-ethyl-1,3-benzothiazoliumTetrafluoroborate
The benzothiazolium tetrafluoroborate 610 reacts with 2-naphthylamine to afford naph-tho[1,2-d]triazole 612 in 70% yield (Scheme 213).[599] Since salt 610 is a good diazo-transferreagent,[600] diazoamino derivative 611 is a probable intermediate in this reaction. Com-pound 610 also reacts with amino-heterocycles to yield heterocycle-fused 1,2,3-triazolesin good yields.[599]
Scheme 213 Synthesis of 1H-Naphtho[1,2-d][1,2,3]triazole from 2-Naphthylamine[599]
N
S+
0.4 M HCl, EtOH
rt, 1 h
NH
NN
612 70%
610
N3
Et+
BF4−
NH2 NH2
N2+
611
1H-Naphtho[1,2-d][1,2,3]triazole (612); Typical Procedure:[599]
To a soln of 2-naphthylamine (0.615 g, 5 mmol) in 0.4 M HCl in EtOH (40 mL) at rt wasadded 2-azido-3-ethyl-1,3-benzothiazolium tetrafluoroborate (610; 1.5 g, 5.1 mmol) inone portion and the mixture was stirred for 1 h. The solvent was evaporated and aq 2 MNH3 (20 mL) was added to the residue. The mixture was stirred, filtered, and extractedwith CHCl3 (2 � 5 mL). The organic phase was discharged. The aqueous phase was neutral-ized and the resulting solid was filtered, washed with H2O, and dried; yield: 0.60 g (70%);mp 175–180 8C.
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 543
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.3.1.2.2 Fragments C-C-N-N and N
13.13.3.1.2.2.1 Method 1:From Æ-Diazo Ketones and Amines
Benzoyl trifluoromethanesulfonate (614) smoothly transforms 10-diazophenanthren-9(10H)-one (613) into diazonium salt 615, which reacts with isopropylamine to give thephenanthrotriazole 616 in 86% overall yield (Scheme 214).[38]
Scheme 214 Synthesis of Phenanthro[9,10-d][1,2,3]triazole froma Æ-Diazo Phenanthrenone[38]
+
616 86%
613
O
N2Ph OTf
OCH2Cl2−70 to −40 oC, 3 h
OBz
N2 OTf−
+
615614
NN
NiPrNH2, CH2Cl2−70 oC, 5 h
Pri
13.13.3.1.3 By Formation of Two N-C Bonds
13.13.3.1.3.1 Fragments N-N-N and C-C
13.13.3.1.3.1.1 Method 1:From Azides and Dehydrobenzene
Dehydrobenzene (benzyne) reacts with alkyl, aryl, glycosyl, acyl, or sulfonyl azides toyield 1-substituted benzotriazoles 617 (Scheme 215). The benzyne is generated in situ byslow addition of 2-aminobenzoic acid to a solution of the azide and an alkyl nitrite (gen-erally butyl, pentyl, or isopentyl nitrite).[601]
544 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 215 Synthesis of Benzotriazoles from Azides and Dehydrobenzene[601–604]
617 50−78%
CO2H
NH2
BuONO R1N3
NN
N
R1
R1 = alkyl, aryl, glycosyl, acyl, sulfonyl
R1 Conditions Yield (%) Ref
(CH2)5Me CH2Cl2, acetone, reflux, 2 h 70 [601]
Ph CH2Cl2, acetone, reflux, 2 h 52 [601]
4-OHCC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601]
4-AcC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601]
4-O2NC6H4 CH2Cl2, reflux, 1.5 h 62 [602]
1-napthyla CH2Cl2, acetone, reflux, 3 h 75 [603]
acridin-9-yl CH2Cl2, acetone, reflux, 2 h 47 [601]
OH
HAcOH
AcO
H
AcO
H
OAc
CH2Cl2, acetone, reflux, 2.5 h 73 [604]
Bz CH2Cl2, reflux, 1.5 h 63 [602]
4-MeOC6H4CO CH2Cl2, reflux, 1.5 h 60 [602]
SO2Ph CH2Cl2, reflux, 1.5 h 52 [602]
4-ClC6H4SO2 CH2Cl2, reflux, 1.5 h 78 [602]
a Isopentyl nitrite was used.
The synthesis of 1-(2-methyl-1-naphthyl)-1H-naphtho[2,3-d][1,2,3]triazole (620) from thereaction of a naphthyl azide with 2,3-dehydronaphthalene (619), produced from 3-ami-no-2-naphthoic acid (618), is an interesting extension of this method (Scheme 216).[603]
Scheme 216 Synthesis of Naphthotriazoles from Azides and 2,3-Dehydronaphthalene[603]
620 21%
Me(CH2)4ONO
DME, reflux, 1.5 h R1N3
NN
N
R1
CO2H
NH2
618 619
R1 =
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 545
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b1-(1-Naphthyl)-1H-benzotriazole (617, R1 = 1-naphthyl); Typical Procedure:[603]
A stirred soln of 1-naphthylazide (8.45 g, 50 mmol) and isopentyl nitrite (13.5 mL,100 mmol) in CH2Cl2 (400 mL) was refluxed and treated with a soln of 2-aminobenzoicacid (13.7 g, 100 mmol) in acetone (100 mL) over 2 h. Heating was continued for a further1 h, after which the mixture was cooled and evaporated under reduced pressure to leave abrown oil. Chromatography (silica gel) afforded the benzotriazole as a white crystallinesolid; yield: 9.15 g (75%); mp 114–115 8C.
13.13.3.1.3.1.2 Method 2:From Azides and Quinones
As described in Section 13.13.1.1.3.1.2.3, organic azides undergo addition to alkenes withelectron-withdrawing groups to yield dihydrotriazoles or triazoles. When benzoquinonesor naphthoquinones are used, benzotriazole derivatives are obtained. From the reactionof benzo-1,4-quinone and phenyl azide, mono- or bis-addition products 621, and 622 and623, respectively, are formed, depending on the number of equivalents of azide used(Scheme 217).[203,605,759] Phenyl azide adds to 2-methylbenzo-1,4-quinone to give only onemonoadduct.[204]
Scheme 217 Reaction of Benzo-1,4-quinone with Phenyl Azide[203,605,759]
621
PhN3 (1 equiv)
NN
N
O
O
O
OPh
622
PhN3 (2 equiv)
NN
N
O
O
O
OPh
NN
NPh
623
NN
N
O
OPh
NN
N
Ph
+
Naphtho-1,4-quinone reacts with methyl azide (sealed tube, 105 8C, 20 h) to afford triazole624 (R1 = Me) in 48% yield.[205,605,759] Similar reactions of naphtho-1,2-quinone and 6-bro-monaphtho-1,2-quinone with methyl azide or phenyl azide do not give any triazole deriv-atives.[205] Naphtho-1,4-quinone reacts with (azidoalkyl)phosphonates and with ethyl azi-doacetate to afford triazole derivatives 624 in good yields (Scheme 218).[210]
Scheme 218 Reaction of Naphtho-1,4-quinone with Alkyl Azides[210]
624
NN
N
O
O
O
OR1
R1N3, THF
reflux, 20 h
R1 = CH2PO(OEt)2 75%
R1 = CHMePO(OEt)2 70%
R1 = CHPhPO(OEt)2 76%
R1 = CH2CO2Et 80%
1-Substituted 1H-Naphtho[2,3-d][1,2,3]triazole-4,9-diones 624; General Procedure:[210]
A soln of naphtho-1,4-quinone (0.47 g, 3 mmol) in THF was added dropwise, with stirring,to a soln of diethyl (1-azidoalkyl)phosphonate or ethyl azidoacetate (3 mmol) in THF
546 Science of Synthesis 13.13 1,2,3-Triazoles
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b(15 mL) and the mixture was refluxed for 20 h. The solvent was evaporated and the resi-due was purified by flash chromatography (silica gel, Et2O/hexane) to give the triazole.
13.13.3.1.4 By Formation of One N-N Bond
13.13.3.1.4.1 Fragment N-N-C-C-N
13.13.3.1.4.1.1 Method 1:Cyclization of 2-Nitrophenylhydrazines
When treated with a base, 2-nitrophenylhydrazines cyclize to benzotriazol-1-ols (Scheme219).[606–610] Benzotriazol-1-ol exists in tautomeric equilibrium with 1H-benzotriazole 3-ox-ide. The position of the equilibrium depends on the solvent; e.g. in water the N-oxide formpredominates.[611–613] In some circumstances, the use of 2,4-dinitrophenylhydrazine toprepare 2,4-dinitrophenylhydrazones may lead to the formation of 6-nitrobenzotriazol-1-ol.[614] The cyclization of 2-nitrophenylhydrazines can also be carried out with polyphos-phoric acid (e.g., conversion of 625 into 626, Scheme 220).[615] Benzotriazol-1-ols are pow-erful explosives[617] and decompose violently at 200–210 8C to carbonaceous material.[619]
A large variety of benzotriazol-1-ol derivatives are used extensively as coupling re-agents.[616,621]
Scheme 219 Cyclization of 2-Nitrophenylhydrazines in Alkaline Media
NO2
NHNH2
R1NaOH
− H2OR1
NN
N
OH
R1
HN
NN+
O−
Scheme 220 Cyclization of 2-Nitrophenylhydrazines with Polyphosphoric Acid[615]
NO2
NHNH2PPA, 10 min N
NN+
O−
NO2 Me
− H2O
41%
NO2Me
625 626
1-Methyl-7-nitro-1H-benzotriazole 3-Oxide (626); Typical Procedure:[615]
A mixture of 1-(2,6-dinitrophenyl)-1-methylhydrazine (0.4 g, 1.9 mmol) and PPA (15 g) wasgently warmed and stirred for 10 min. The resulting brown soln was cooled and pouredinto H2O (100 mL). The soln was extracted with CHCl3 (3 � 30 mL) and the yellow organicextract was chromatographed (basic alumina, 100–200 mesh, 100 g). The unchanged hy-drazine was eluted with CHCl3. A second fraction was collected, concentrated under re-duced pressure, and recrystallized (EtOH) to give 626 as yellow plates; yield: 0.15 g (41%);mp 242–243 8C.
13.13.3.1.4.1.1.1 Variation 1:Reaction of 1-Chloro-2-nitrobenzenes or1,2-Dinitrobenzenes with Hydrazine
1,2-Dinitrobenzenes 627 (X = NO2)[609,617] and 1-chloro-2-nitrobenzenes 627 (X = Cl)[618–621]
react with hydrazine to yield benzotriazol-1-ols 629 via the 2-nitrophenylhydrazines 628(Scheme 221). The yields of the reactions are highly dependent on the substituents on the
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 547
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bstarting material. In some cases the substitution of the nitro group is the most favorableprocess, the corresponding arylhydrazines are then the main products.[619] The synthesisof benzotriazol-1-ols from 1-methoxy-2-nitrobenzenes (627, X = OMe) has also been de-scribed.[609,617]
Scheme 221 Benzotriazol-1-ols from 1,2-Dinitrobenzenes or 1-Chloro-2-nitrobenzenesand Aqueous Hydrazine[617,619–621]
NO2
X
R1 R1 R1N
NN
OH
aq H2NNH2
EtOH
reflux, 3−5 h
NO2
NHNH2
− H2O
627 628 629
X R1 Yield (%) Ref
NO2 4,6-Cl2 60 [617]
NO2 4,6-Br2 –a [617]
Cl H 90 [619]
Cl 4,5-Cl2 85 [619]
Cl 4,5,6-Cl3 67 [619]
Cl 4,5,6,7-Cl4 40 [619]
Cl 6-CF3 90 [620]
Cl 6-OMe 6 [620]
Cl 6-CONH2 39 [620]
Cl 6-SO2NHMe 79 [620]
Cl 6-SO2NHBn 96 [621]
a Yield not reported.
Polymer-supported benzotriazol-1-ol derivatives 633[621] and 637[622] are prepared, respec-tively, from the reaction of polymer-supported 1-chloro-2-nitrobenzenes 632 and 636 andhydrazine (Scheme 222). Precursor 632 is obtained from the reaction of the aminometh-ylated polystyrene 630 and the benzenesulfonyl chloride 631 while 636 is prepared byFriedel–Crafts alkylation of polystyrene 634, using 4-chloro-3-nitrobenzyl alcohol (635).The polymeric reagent 633 is highly efficient for the synthesis of amides.[621,623]
Scheme 222 Polymer-Supported Benzotriazol-1-ol Derivatives[621,622]
100%
Et3N, CH2Cl2rt, 5 h
630
NH2 + ClO2S
NO2
Cl
70−80%
1. aq H2NNH2, EtOH, reflux, 5 h
2. HCl, dioxane
S
NO2
Cl
NH
OO
632631
S
HN
O O
633
NN
N
OH
548 Science of Synthesis 13.13 1,2,3-Triazoles
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FOR PERSONAL USE ONLY
bAlCl3, PhNO2
70 oC, 3 d
634
+
NO2
Cl
2. concd HCl, dioxane, reflux, 20 h
636635
637
NN
N
OH
H
HO
NO2
Cl
MeOOH1. H2NNH2, , reflux, 20 h
Benzotriazol-1-ols 629; General Procedure:[619]
The appropriate 1-chloro-2-nitrobenzene (5 g) was dissolved in hot EtOH (15–20 mL) and85% aq hydrazine (5 g) was added. The mixture was refluxed for 3 h and cooled. The pre-cipitate was collected by filtration, dissolved in hot H2O, and the benzotriazol-1-ol deriva-tive was precipitated with aq HCl. The crude product was decolorized with charcoal andrecrystallized (EtOH/MeOH 1:1).
13.13.3.1.4.1.2 Method 2:Cyclization of (2-Aminophenyl)hydrazine Derivatives
Oxidative cyclization of 1-(acetylamino)-2-hydrazino-3-nitrobenzene with chlorine af-fords 4-nitro-1H-benzotriazole in 80% yield (Scheme 223).[624]
Scheme 223 Cyclization of 1-(Acetylamino)-2-hydrazino-3-nitrobenzene[624]
NO2
NHNH2
NHAc80%
Cl2, EtOH
NH
NN
NO2
13.13.3.1.4.1.3 Method 3:Cyclization of (2-Aminophenyl)triazene Derivatives
Polymer-bound 1-(2-aminophenyl)triazenes 638 are cleaved smoothly with trifluoroaceticacid in dichloromethane at room temperature within minutes to give 1-substituted ben-zotriazoles 639 in excellent yields (Scheme 224).[625]
Scheme 224 Benzotriazoles from Polymer-Bound 1-(2-Aminophenyl)triazenes[625]
up to 95%
TFA, CH2Cl2, rtO2N
NN
N
639638
R1
N
NHR1
O2NN
NBn
CH2, cyclopropyl, cyclopentyl, 4-MeOC6H4CH2R1 = CH2CH
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 549
for references see p 587
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FOR PERSONAL USE ONLY
b13.13.3.2 Synthesis by RIng Transformation
13.13.3.2.1 Method 1:From 4,5-Dimethylene-4,5-dihydro-1H-triazoles
4,5-Dimethyl-4,5-dihydro-1H-triazoles 641, generated from 640 by 1,4-elimination of bro-mine, are trapped in low to moderate yields by dienophiles in Diels–Alder reactions(Scheme 225).[626] Benzotriazole 642 is obtained when 641 is generated in the presenceof dimethyl acetylenedicarboxylate; adduct 643 is formed when N-methylmaleimide isused as the dienophile. This adduct is converted into the benzotriazole derivative 644 bytreatment with N-bromosuccinimide.
Scheme 225 Benzotriazoles from 4,5-Dimethyl-4,5-dihydro-1H-triazoles[626]
N
NN
Br
Br
Ph
NaI, DMF
115 oC N
NN
Ph
DMAD
− 2H
27%N
NNMeO2C
MeO2C
641640
642Ph
NMM
38%N
NN
MeN
O
OPh
643
50%N
NN
MeN
O
OPh
644
NBS, CCl4heat
13.13.3.2.2 Method 2:Transformation of 1,3-Dihydro-2H-benzimidazol-2-ones
The reaction of 1,3-dihydro-2H-benzimidazol-2-one (645) with sodium nitrite and water,in a autoclave at high temperature, gives the sodium salt of benzotriazole, which, by acid-ification gives 1H-benzotriazole in high yield (Scheme 226).[627] This reaction can be ex-tended to 1,3-dihydro-2H-benzimidazol-2-ones with substituents on positions 4–7.
Scheme 226 Benzotriazoles from 1,3-Dihydro-2H-benzimidazol-2-ones[627]
61−93%
NN
N
NaNO2, H2O
190−300 oC
pressure
15−75 min
NH
HN
645
O− Na+ N
H
NNH3O+
550 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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b13.13.3.2.3 Method 3:
Transformation of 1,2,4-Benzotriazin-3(2H)-ones
1,2,4-Benzotriazin-3(2H)-one (646) and phenanthrotriazin-3-one 647 are converted into1H-benzotriazole and phenanthrotriazole 648, respectively, on treatment with etherealchloramine at room temperature (Scheme 227).[381] Treatment of benzotriazin-3-one 646with lead(IV) acetate in refluxing benzene affords 1-acetyl-1H-benzotriazole in goodyield.[381]
Scheme 227 Benzotriazoles from 1,2,4-Benzotriazin-3(2H)-ones[381]
65%
NH2Cl, CH2Cl2, DMF
rt, 14 h
646
NH
NN
NNH
N O
86%
Pb(OAc)4, benzene
reflux, 2 h
NN
N
Ac
92%
NH2Cl, Et2O, DMF
rt, 48 h
647
NH
NN
NNH
N O
648
13.13.3.2.4 Method 4:Transformation of 1,2,3,4-Benzotetrazine 1,3-Dioxides
The reduction of 1,2,3,4-benzotetrazine 1,3-dioxides 649 with sodium hydrosulfite ortin(II) chloride affords benzotriazoles 651 in almost quantitative yields (Scheme 228).[628]
It has been suggested that this transformation proceeds via the intermediate N-nitroso-benzotriazoles 650.
Scheme 228 Benzotriazoles from 1,2,3,4-Benzotetrazine 1,3-Dioxides[628]
NN
NN
R1
R2
O−
O−
+
+
649
Na2S2O4 (4 equiv) or
SnCl2•2H2O (4 equiv)
EtOAc, H2O
rt, 3 min
R1
R2
650
NN
N
N O
R1
R2
651 95−98%
NH
NN
− HNO2
R1 = H, Br; R2 = H, Br, NO2
H2O
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 551
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.3.3 Synthesis by Substituent Modification
13.13.3.3.1 Substitution of Existing Substituents
13.13.3.3.1.1 Of Hydrogen
13.13.3.3.1.1.1 Method 1:N-Trimethylsilylation
Benzotriazole reacts with hexamethyldisilazane to give 1-(trimethylsilyl)-1H-benzotria-zole (652) in 95% yield (Scheme 229).[169,434,629,630]
Scheme 229 N-Trimethylsilylation of 1H-Benzotriazole[169]
652
NN
N
95%
heat
TMS
NH
NN
+ (TMS)2NH
13.13.3.3.1.1.2 Method 2:Carboxylation
Heating an intimate mixture of 1H-benzotriazol-5-ol with a large excess of anhydrous po-tassium carbonate in a nickel-lined steel autoclave, with carbon dioxide under pressure,affords 5-hydroxy-1H-1,2,3-benzotriazole-4-carboxylic acid (653) in 49% yield (Scheme230).[631,632]
Scheme 230 Carboxylation of 1H-Benzotriazol-5-ol[631,632]
653
NH
NN
49%
K2CO3, CO2
180−190 oC, 16 h
NH
NNHO HO
CO2H
Benzotriazole reacts with chloroformates 654, in alkaline solutions, to afford selectivelythe corresponding alkyl 1H-benzotriazole-1-carboxylates 655 (Scheme 231).[633–635]
Scheme 231 N-Alkoxycarbonylation of 1H-Benzotriazole[633–635]
655
NN
N
58−100%
aq NaOH
NH
NN
+ ClCO2R1
654
CO2R1
R1 = Me, Et, Ph, Bn
Ethyl 1H-1,2,3-Benzotriazole-1-carboxylate (655, R1 = Et); Typical Procedure:[634]
Ethyl chloroformate (6.0 g, 0.056 mol) was slowly added to a stirred and cooled aqueoussoln of 1H-benzotriazole (6.0 g, 0.05 mol) and NaOH (2.0 g, 0.05 mol). After completion ofthe addition, the mixture was stirred for an additional 15 min, and the precipitated whitesolid was then collected by filtration, washed with H2O, dried, and recrystallized (Et2O);yield: 9.1 g (95%); mp 70–71 8C.
552 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.3.3.1.1.3 Method 3:
Acylation
Benzotriazoles react with acyl chlorides and anhydrides to afford the 1-acyl derivatives656 (Scheme 232).[587]
Scheme 232 Acylation of 1H-Benzotriazole[587]
656
NN
NR1COCl or (R1CO)2O
NH
NN
COR1
1-Acyl-1H-benzotriazoles 656 (R1 = aryl, 2-arylvinyl) are prepared in moderate to goodyields from the reaction of 1H-benzotriazole and acyl chlorides in pyridine or in aqueoussodium hydroxide.[634] Other benzotriazole derivatives 656 (R1 = alkyl, aryl) are obtainedin high yields (87–99%) from the reaction of 1H-benzotriazole and acyl chlorides in anhy-drous dichloromethane and triethylamine at 0 8C.[636,637] 1-Acyl-1H-benzotriazoles 656(R1 = Me, Et, Bu, Ph) are prepared in good yields by fusion of 1H-benzotriazole and acylchlorides at 80–100 8C.[630] When the acyl chlorides are not available, 1-acyl-1H-benzotria-zoles are also conveniently prepared from 1-mesyl-1H-benzotriazole and the respectivecarboxylic acids in yields of 80–95%.[630] 1-Acyl-1H-benzotriazoles are also prepared in ex-cellent yields (94–95%) from the reaction of 1-(trimethylsilyl)-1H-benzotriazole and acylchlorides.[629]
5,6-Dimethyl-1H-benzotriazole reacts with acetic anhydride (reflux for 30 min) togive the 1-acetyl derivative in 93% yield.[587] The same compound also reacts with benzoylchloride and 4-nitrobenzoyl chloride, in the presence of aqueous sodium hydroxide, toyield the 1-acyl derivatives in 82 and 50% yield, respectively.[587]
1H-Benzotriazole reacts with trifluoroacetic anhydride in tetrahydrofuran, at roomtemperature, to give 1-(trifluoroacetyl)-1H-benzotriazole (656, R1 = CF3) in almost quanti-tative yield.[638] This compound is a convenient trifluoroacetylating reagent for aminesand alcohols. 1H-Benzotriazol-5-amine reacts with trifluoroacetic anhydride in dimethyl-formamide, at room temperature, to give selectively 5-[(trifluoroacetyl)amino]benzotri-azole in 85% yield.[639]
Thiobenzoyl chloride reacts with benzotriazole or 1-(trimethylsilyl)-1H-benzotri-azole to yield 1-(thiobenzoyl)-1H-benzotriazole in 64 and 44% yield, respectively.[434]
1H-Benzotriazole reacts with aryl isocyanates to yield 1-(arylaminocarbonyl)-1H-ben-zotriazoles.[640]
13.13.3.3.1.1.4 Method 4:N-Formylation
1H-1,2,3-Benzotriazole-1-carbaldehyde (657) is conveniently prepared from 1H-benzotri-azole and formic acid in the presence of dicyclohexylcarbodiimide (Scheme 233).[641] Thiscompound is a stable N- and O-formylating agent for a variety of amines and alcohols. Thediethyl acetal of compound 657 is prepared directly in 90% yield from the reaction of 1H-benzotriazole and triethyl orthoformate.[642]
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 553
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 233 N-Formylation of 1H-Benzotriazole[641]
657
NN
NDCC, CH2Cl2, rt, 15 h
NH
NN
CHO
+ HCO2H71%
1H-1,2,3-Benzotriazole-1-carbaldehyde (657); Typical Procedure:[641]
To a mixture of 1H-benzotriazole (14.85 g, 0.125 mol) and HCO2H (6.9 g, 0.15 mol) in anhydCH2Cl2 (250 mL) was added DCC (36.05 g, 0.175 mol). The mixture was stirred at rt for 15 h,the precipitate filtered and the solvent removed in vacuo. Recrystallization of the residuegave pure 657 as white needles; yield: 13 g (71%); mp 94–96 8C.
13.13.3.3.1.1.5 Method 5:Arylation
1H-Benzotriazole reacts with activated aryl halides and hetaryl halides to yield the 1-aryl-or 1-hetaryl-1H-benzotriazole derivatives as the main (or sole) products. With 1-chloro-2-nitrobenzene (658, R1 = R2 = H) it gives a mixture of 659 (R1 = R2 = H; 39%) and 660(R1 = R2 = H; 16%), which can be separated by column chromatography (Scheme 234).[643]
The reaction with 1-chloro-2,4-dinitrobenzene (658, R1 = NO2; R2 = H) in refluxing toluene,in the absence of any added base, affords exclusively the 1H-isomer 659 (R1 = NO2; R2 = H)in 96% yield[644] but if it is carried out in refluxing ethanol, in the presence of anhydroussodium acetate, it gives a mixture of 659 (R1 = NO2; R2 = H) and 660 (R1 = NO2; R2 = H) in theratio of approximately 23:10.[645] With 2-chloro-1,3,5-trinitrobenzene (658, R1 = R2 = NO2)or 2-fluoro-1,3,5-trinitrobenzene the 1H-isomer 659 (R1 = R2 = NO2) is the sole product.[586]
2-Fluoro-1,3,5-trinitrobenzene reacts with mono- and dinitrobenzotriazoles[586] to affordthe corresponding 1-(2,4,6-trinitrophenyl) derivatives; with benzo[1,2-d:4,5-d¢]bistriazoleit gives a mixture of 1,5- and 1,7-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistria-zoles.[595]
Scheme 234 N-Arylation of 1H-Benzotriazole[643,644]
NH
NN
+ Cl
O2N
R2
R1N
NN
O2N
R1
R2
659
NN
N
R2
O2N
R1
660
+
R1 = R2 = H, NO2
658
1H-Benzotriazole reacts with 2-bromopyridine and 2-bromopyrimidine, in the absence ofadded base, to give the corresponding 1-substituted benzotriazole derivatives in highyields.[642,644] The reaction of 1H-benzotriazole with 2-chloro-3-nitropyridine and 4-chlo-
554 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bro-3-nitropyridine in dimethyl sulfoxide at 80 8C, in the presence of sodium carbonate,also affords the corresponding 1-substituted benzotriazole derivatives.[646] Under micro-wave irradiation, benzo- and naphthotriazoles 661 react with 4-chloropyridine and 4-chloroquinoline derivatives 662 to give the 1-substituted derivatives 663 in good yields(Scheme 235).[647]
Scheme 235 N-Arylation of Benzotriazoles under Microwave Irradiation[647]
NH
NN
+
R3
R3
661
N
R2
R2
Cl
R1
microwave irradiation
no solvent, 7−10 min NN
NR3
R3
663
N
R2
R2
R1
662
R1 = R3 = H, Me; R2 = H; R2,R2 = R3,R3 = (CH CH)2
A palladium(0)-catalyzed N-arylation of benzotriazole with aryl iodides with both elec-tron-donating and electron-withdrawing groups and hetaryl halides has been report-ed.[648] The reaction is carried out in dimethylformamide at 150 8C, under phase-transferconditions, in the presence of potassium carbonate and copper salts. The 1-aryl-1H-benzo-triazole derivatives are obtained in excellent yields (75–98%). 1H-Benzotriazole is also N-arylated in water by diaryliodonium salts (Ar1
2IBF4) yielding the 1-aryl derivatives in al-most quantitative yields.[649] This is also a palladium- and copper-catalyzed reaction.
The benzotriazole anion reacts with triacetoxy(4-tolyl)lead [4-TolPb(OAc)3] in thepresence of copper(II) acetate to afford a mixture of 1-(4-tolyl)- and 2-(4-tolyl)benzotri-azoles in 23 and 6% yield, respectively.[650]
The polymer-supported benzotriazole 664 reacts with 4-tolylboronic acid in the pres-ence of copper(II) acetate and pyridine, under microwave irradiation, to yield the corre-sponding N-tolyl derivatives. Cleavage of these products with trifluoroacetic acid givesthe two regioisomeric benzotriazoles 665 and 666 (1:1) in 55% yield (Scheme 236).[651]
Scheme 236 N-Arylation of a Polymer-Supported Benzotriazole[651]
NH
NN
+ 4-TolB(OH)2
664
1. Cu(OAc)2, py
2. TFAHN
O
55%
NN
N
665
H2N
O 4-Tol
NN
N
666
4-Tol
H2N
O
+
1:1
1-(2,4-Dinitrophenyl)-1H-benzotriazole (659, R1 = NO2; R2 = H); Typical Procedure:[644]
A mixture of 1-chloro-2,4-dinitrobenzene (658, R1 = NO2; R2 = H; 6.08 g, 30 mmol), 1H-ben-zotriazole (21.44 g, 180 mmol), and toluene (30 mL) was refluxed for 9 d. The mixture wastreated with 20% KOH (200 mL), extracted with CHCl3 (5 � 500 mL), dried (MgSO4), andevaporated to afford a yellow solid; yield: 8.20 g (96%); mp 182–184 8C.
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 555
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.3.3.1.1.6 Method 6:
Alkynylation
Potassium benzotriazol-1-ide, prepared from 1H-benzotriazole and potassium tert-butox-ide, reacts with alkynyl(phenyl)iodonium tosylates 667 to give 1-(2-arylethynyl)-1H-ben-zotriazoles 668 in good yields (Scheme 237).[652,653] The reaction with oct-1-ynyl(phenyl)-iodonium tosylate [667, R1 = (CH2)5Me] affords a mixture of two 1-(alk-1-enyl)-1H-benzotri-azole derivatives. An alternative one-pot synthesis of 1-(substituted ethynyl)-1H-benzotri-azoles 668 (R1 = alkyl or aryl) has been published.[654,655]
Scheme 237 N-Alkynylation of Potassium Benzotriazol-1-ide with Alkynyl(phenyl)-iodonium Tosylates[652,653]
NN
N
+
THF, t-BuOH, CH2Cl2rt, 24 h
45−62%−
K+ OTs−
667
NN
N
R1
668
R1 = Ph, 4-ClC6H4, 4-Tol, 4-MeOC6H4
I+
Ph
R1
13.13.3.3.1.1.7 Method 7:Alkenylation
A simple and convenient method for the stereoselective synthesis of 1-(alk-1-enyl)-1H-ben-zotriazole derivatives, directly from benzotriazole, has been reported.[656] It involves thereaction of alkenyl(phenyl)iodonium salts with 1H-benzotriazole in the presence of abase (Scheme 238). In the reaction with alkenyl(phenyl)iodonium salts 669 (R1 = Ph) and671, retention of configuration is observed in the products 670 and 672, but with 669(R1 = Bu) complete inversion of configuration occurs. This method is particularly efficientfor the preparation of 1-(alk-1-enyl)-1H-benzotriazoles with amino-, acyl-, and alkoxycar-bonyl substituents, which are difficult to prepare by other methods. Other nonselectiveor less convenient methods for the synthesis of 1-(alk-1-enyl)-1H-benzotriazoles are alsoknown.[656]
Scheme 238 N-Alkenylation of 1H-Benzotriazole with Alkenyl(phenyl)iodonium Salts[656]
NH
NN
++
669
NN
N
670
R1 = Ph 64% (E-isomer)
R1 = Bu 59% (Z-isomer)H
R1
I
H
PhBF4
−
R1
t-BuOK, t-BuOH, DMF, rt
NH
NN
+
K2CO3, DMF, H2O
rt, 6 h
+
671
NN
N
672
R1 = Me, Bn, 4-ClC6H4; R2 = Me, Ph, OEt
NHR1
I
R2OC
PhOTs−
NHR1
67−94%
R2OC
556 Science of Synthesis 13.13 1,2,3-Triazoles
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FOR PERSONAL USE ONLY
b13.13.3.3.1.1.8 Method 8:
Alkylation
1H-Benzotriazole reacts with dimethyl sulfate,[657,658] diazomethane,[657] and iodometh-ane[658] to give mixtures of 1- and 2-methylbenzotriazole. The 1-methyl isomer is alwaysthe main product, except in the reaction with diazomethane where the 1-methyl/2-meth-yl ratio is 5:17.[657] Methylation of 4-nitrobenzotriazole and 5-methylbenzotriazole with di-azomethane leads to the formation of the 2-methyl derivatives.[585] Methylation of 5,6- and4,7-dichlorobenzotriazole with dimethyl sulfate gives the 1-methyl isomer as the mainproduct.[585]
The alkylation of 1H-benzotriazole is frequently carried out with alkyl halides in thepresence of a base; the 1-alkyl isomer 673 is generally the main product and, in somecases, 1,3-dialkyl-1H-benzotriazolium salts 675 are also formed (Scheme 239). Sodium hy-dride[659] and sodium alkoxides[660,661] are frequently used as the base but higher yields maybe obtained using sodium hydroxide in dimethylformamide.[662] Alkylations with alkyl ha-lides using phase-transfer catalysis with 18-crown-6,[663] polyethylene glycols or their dial-kyl ethers,[664] or quaternary ammonium salts[665–667] also give excellent yields. Many otherreaction conditions have also been used, namely aqueous sodium hydroxide,[668] triethyl-amine in toluene,[669] potassium carbonate in tetrahydrofuran,[670] potassium fluoride andalumina in acetonitrile,[661] or just by refluxing the benzotriazole and the alkyl halide inbenzene or toluene in the absence of any added base.[644,671] 1H-Benzotriazole can also bealkylated with alkyl halides in the absence of solvent, either in basic media under solvent-free phase-transfer catalysis conditions or in the absence of base by conventional or mi-crowave heating.[672]
Scheme 239 Alkylation of 1H-Benzotriazole with Alkyl Halides[659–662]
NH
NN
R1X, base
NN
N
673
X = halo
R1N
NR1N
674
NN
N
675
R1
+ +
R1
X−+
The alkylation of 1H-benzotriazole with ethyl bromoacetate, in the presence of sodiumhydride, gives different ratios of the 1-alkyl/2-alkylbenzotriazole depending on the sol-vent used: 85:15 in acetonitrile and 95:5 in toluene.[659] Mixtures of the two isomers arealso obtained by alkylation of the sodium salt of 1H-benzotriazole with other Æ-halo-genated esters or ketones.[644,671] However, in refluxing benzene or toluene, and in the ab-sence of any added base, 1H-benzotriazole reacts with these Æ-halogenated carbonyl com-pounds to yield only the 1-alkyl isomer in good yield.[644,671]
Addition of bromocyclopentane and bromocycloheptane to the anion of benzotria-zole (generated with sodium ethoxide in ethanol) yields the expected mixtures of 1- and2-cycloalkylbenzotriazoles. However, under the same conditions, bromocyclohexanegives only cyclohexene and benzotriazole, cyclohexyl tosylate affords only the 2-cyclo-hexyl-2H-benzotriazole 674 (R1 = Cy), while with tricyclohexyl phosphate the 1-cyclohex-yl-1H-benzotriazole is formed with the complete absence of the N2 isomer.[673]
A high-yielding route to produce selectively 1-ethyl-1H-benzotriazole involves thecarbonylation of 1H-benzotriazole with ethyl chloroformate (see Section 13.13.3.3.1.1.2)followed by alkylation or the resulting compound with triethyloxonium tetrafluoro-borate and then methanolysis (Scheme 240).[634] This gives pure 1-ethyl-1H-benzotriazolein 89% overall yield from 1H-benzotriazole. Another method for the selective synthesis of
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 557
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b1-alkyl-1H-benzotriazoles involves the reaction of 1-(trimethylsilyl)-1H-benzotriazole withalkyl halides.[629]
Scheme 240 A Selective Route to 1-Ethyl-1H-benzotriazole[634]
NH
NN
EtOCOCl
aq NaOH
NN
N +
CO2Et
95%
Et3O+ BF4−
CH2Cl2
NN
N
CO2Et
Et
BF4−
NN
N
94%
Et
MeOH
The reaction of 1H-benzotriazole with dibromoalkanes may give the two monosubstitut-ed derivatives or the three possible disubstituted isomers, depending on the molar ratioof the dibromoalkane to 1H-benzotriazole.[661,668] 1H-Benzotriazole reacts with 1 equiva-lent of bis(bromomethyl)benzene (1,2-, 1,3-, or 1,4-), 4,4¢-bis(bromomethyl)biphenyl and4¢,4¢¢-bis(bromomethyl)-1,3-terphenyl,[674] and 2,6-bis(bromomethyl)pyridine[675] to yield,in each case, only the bis(benzotriazol-1-yl) isomer. Addition of another equivalent ofthe bis(bromomethyl) derivative affords, in each case, only one dicationic benzotriazo-lophane (see schemes in Section 13.13.5.2.2). 1H-Benzotriazole also reacts with dichloro-methane and chloroform, in the presence of a phase-transfer catalyst, to yield mixtures ofall possible isomers of di- and tri(benzotriazol-1-yl and -2-yl)methane.[676,677]
1H-Benzotriazole reacts with diarylmethanols, in the presence of a catalytic amountof 4-toluenesulfonic acid and azeotropic removal of water, to give mixtures of the corre-sponding 1- and 2-diarylmethylbenzotriazole derivatives (Scheme 241).[669,678]
Scheme 241 Alkylation of 1H-Benzotriazole with Diarylmethanols[669,678]
NH
NN TsOH, benzene
reflux
NN
N
− H2O
66−90%
+ HO
Ar2
Ar1
Ar1Ar2
+N
NN
Ar1
Ar2
Ar1 = Ar2 = Ph, 4-Me2NC6H4, 4-MeOC6H4, 4-ClC6H4, 4-Tol
1H-Benzotriazole reacts with 2-(chloromethyl)oxirane (epichlorohydrin) in benzene toyield the two compounds resulting from oxirane ring opening.[679] Using 2 equivalents ofbenzotriazole (and triethylamine) or sodium benzotriazolide the reaction gives a complexmixture of products resulting from the oxirane ring opening and simultaneous substitu-tion of chlorine by a benzotriazolyl group (Scheme 242).[680]
558 Science of Synthesis 13.13 1,2,3-Triazoles
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FOR PERSONAL USE ONLY
bScheme 242 Alkylation of 1H-Benzotriazole with 2-(Chloromethyl)oxirane[680]
NH
NN
Et3N, toluene
reflux, 7 h
NN
N
+
Bt1 =
O
Cl
NN
N; Bt2 =
OH
Cl +O
Bt2
+
Bt2
OH
Bt1 + +Bt1OH
Bt1 Bt2OH
Bt2 Bt2
1H-Benzotriazole gives conjugate addition reactions with Æ,�-unsaturated carbonyl com-pounds to yield only 1-alkyl derivatives (reactions carried out without solvent and in thepresence of a few drops of pyridine or benzyltrimethylammonium hydroxide solu-tion).[452] Under similar conditions, and in striking contrast, 4,5,6,7-tetrahalogenated ben-zotriazoles afford only the 2-alkyl derivatives.[16,585] This difference is due mainly to thesteric effect of the 4,7-substituents, which direct this type of addition to the 2-position.This was confirmed by using 4,7-dichloro-1H-benzotriazole and 5,6-dichloro-1H-benzotri-azole, which give only 2- and 1-substituted derivatives, respectively.[585] Heating a mixtureof 1H-benzotriazole and N,2-dimethylpropenamide at 150 8C for six days gives only the N1Michael addition product in 45% yield.[681] 1H-Benzotriazole reacts with acrylamide in ba-sic medium (pyridine–sodium methoxide) to afford only the N1 Michael addition productin 96% yield.[682] However, it was shown by NMR analysis that the crude product of thisreaction is a 35:65 mixture of the N1 and N2 addition products, but after 24 hours onlythe signals of the N1 isomer are observed.[682] This means that the Michael addition yieldsa kinetic mixture which slowly equilibrates to the most stable isomer (the thermodynam-ic product). In an aqueous micellar medium, mixtures of N1 and N2 addition products areobtained from the reaction of benzotriazole with 1,3-diphenylprop-2-en-1-one (chalcone)(Scheme 243), acrylonitrile, and diethyl maleate.[667]
Scheme 243 Reaction of 1H-Benzotriazole with 1,3-Diphenylprop-2-en-1-one[667]
NH
NN
NaOH, H2O, CTAB
rt, 1 d+ Ph
NN
N
Ph
+N
NN Ph
CTAB = cetyltrimethylammonium bromide
79%Ph
O
Ph
O
Ph
O
1H-Benzotriazole reacts with aliphatic aldehydes to yield isolable crystalline 1-hydroxy-alkyl benzotriazole derivatives (Scheme 244).[683] In solution these condensation productsdissociate into their components and equilibrate between the 1- and 2-positions of thebenzotriazole ring.[8] The reaction with aromatic aldehydes or ketones does not affordthe corresponding condensation products.
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 559
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 244 Hydroxymethylation of 1H-Benzotriazole[683]
NH
NN
+O
HR1N
NN
OHH
R1
1H-Benzotriazole reacts with an aldehyde or ketone and an amine to yield the condensa-tion products 676 generally in very high yields (Scheme 245).[684] The aminomethylationof 1H-benzotriazole by the Mannich reaction[453,685] is an example of this very general re-action: both aliphatic and aromatic aldehydes can be used, ketones (particularly cyclicones), ammonia, and primary and secondary amines (aliphatic, aromatic, and heteroaro-matic) all give the expected products.[8]
Scheme 245 Aminomethylation of 1H-Benzotriazole[684]
NH
NN
+O
R2R1N
NN
NR3R4
R2R1
+R3
HN
R4
676
1-Chloro- and 1-bromo-1H-benzotriazoles 677 (X = Cl, Br) undergo electrophilic additionto alkenes to afford 1- and 2-(2-haloalkyl)benzotriazoles, with trans configuration, ingood yields.[686,687] 1-Bromo-1H-benzotriazole is much more reactive than the chloro deriv-ative. For example, the addition of 677 (X = Br) to cyclohexene (giving products 678 and679) is essentially instantaneous in dichloromethane at room temperature comparedwith a reaction time of approximately 4 hours for 677 (X = Cl), despite the low solubilityof 677 (X = Br) (Scheme 246). N,4,5,6,7-Pentachlorobenzotriazole, although extremely in-soluble in organic solvents, also undergoes rapid addition to alkenes.[687] 1-Chloro-1H-ben-zotriazole also gives addition products with enamines and enol ethers.[642]
Scheme 246 Addition of 1-Halo-1H-benzotriazoles to Alkenes[686,687]
NX
NN
+CH2Cl2, rt
NN
N
678677
NN
N+
679
X = Cl, Br
X
X
The reaction of 1H-benzotriazol-1-ol derivatives with alkyl halides in the presence of abase affords mainly the 1-alkoxy derivatives 680, but the N-alkyl derivatives 681 can alsobe formed (Scheme 247). For example, methylation of 1H-benzotriazol-1-ol with iodo-methane, in methanol/sodium methoxide, affords a mixture of the O- and N-methyl deriv-atives.[609,615,688] However, using the same conditions, 4-nitro-1H-benzotriazol-1-ol and 6-ni-tro-1H-benzotriazol-1-ol give only the 1-methoxy compounds.[615,689] Reaction of 1H-benzo-triazol-1-ol with 1-acetoxy-4-iodobutane in acetonitrile, with potassium carbonate asbase, gives only the O-alkyl derivative in 95% yield.[670] A range of 1-alkoxy-4,5-dichloro-1H-benzotriazole derivatives is prepared by reaction of the sodium salt of 4,5-dichloro-1H-benzotriazol-1-ol with the appropriate alkyl halides.[690] Several 1-alkoxy-4-nitro-
560 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b1H-benzotriazole derivatives are prepared by alkylation of the 1-hydroxy derivative withalkyl halides under phase-transfer conditions.[691]
Scheme 247 Alkylation of 1H-Benzotriazol-1-ols with Alkyl Halides[688–691]
NN
NR2X, base
680
R1
OH
NN
N
R1
OR2
+
681
NN
R2
N
R1
O−+
Alkylation of 1H-Benzotriazole with Alkyl Halides; General Procedure:[662]
To a flask provided with a CaCl2 guard tube and magnetic stirrer was introduced finelyground NaOH (40 mmol), DMF (8–10 mL), 1H-benzotriazole (10 mmol), and the alkyl ha-lide (10 mmol). After stirring for 15–60 min, the mixture was poured into H2O (50–70 mL)to give a solid or oily product. Solids were collected by filtration, washed with H2O(25 mL), and dried, while the oily products were extracted with CHCl3 (3 � 10 mL), washedwith H2O (5 � 10 mL), dried (MgSO4), and the solvent evaporated under reduced pressure.1-Alkyl- and 2-alkylbenzotriazole isomers were separated by column chromatography(hexane/CHCl3 2:1).
13.13.3.3.1.1.9 Method 9:Halogenation
Benzotriazole is rapidly converted into crystalline 1-chloro-1H-1,2,3-benzotriazole (682,X = Cl) by treatment with sodium hypochlorite in aqueous acetic acid (Scheme 248).[692]
Similar reaction with sodium hypoiodite in aqueous sodium hydroxide gives 1-iodo-1H-benzotriazole in 43% yield.[687] Alternatively 1-iodo-1H-benzotriazole is obtained in94% yield by treatment of 1-chloro-1H-benzotriazole in dichloromethane with 1 equiva-lent of iodine.[687] Similarly, 1-bromo-1H-benzotriazole is prepared in 80% yield by the ad-dition of 1-chloro-1H-benzotriazole to a solution of bromine in dichloromethane.[687] Addi-tion of sodium hypochlorite to a solution of 4,5,6,7-tetrachloro-1H-benzotriazole in gla-cial acetic acid, at room temperature, rapidly affords N,4,5,6,7-pentachloro-1H-benzotri-azole (because of the extreme insolubility of this compound, the position of the fifth chlo-rine at N1 or N2 was not assigned unambiguously).[687]
Scheme 248 Synthesis of 1-Chloro- and 1-Iodo-1H-benzotriazole[687,692]
NH
NN AcOH, H2O, rt
+ NaOXX = Cl 100%
X = I 43%NX
NN
682
1H-Benzotriazole is chlorinated to 4,5,6,7-tetrachloro-1H-benzotriazole (683, X = Cl) in87% yield by refluxing with aqua regia (a mixture of concentrated hydrochloric acid andconcentrated nitric acid) for three hours (Scheme 249).[16] Under similar conditions, 2-methyl-2H-benzotriazole gives 4,5,6,7-tetrachloro-2-methyl-2H-benzotriazole in 50%yield[16] but chlorination of 1-methyl-1H-benzotriazole with aqua regia requires threedays to give 4,5,6,7-tetrachloro-1-methyl-1H-benzotriazole in 57% yield.[585] Refluxing 4-ni-tro-1H-benzotriazole with aqua regia for three days affords 4,5,6,7-tetrachloro-1H-benzo-triazole (62%), and 2,5-dimethyl-2H-benzotriazole gives 4,5,6,7-tetrachloro-2-methyl-2H-benzotriazole (yield not reported); in these systems the substituents on the benzenicring are replaced by chlorine.[585]
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 561
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 249 Synthesis of 4,5,6,7-Tetrachloro- and4,5,6,7-Tetrabromo-1H-benzotriazole[16,585]
NH
NN
A: X = Cl 87%
B: X = Br 54%NH
NN
683
A: HCl, HNO3, reflux, 3 h
B: Br2, HNO3, reflux, 30 h
X
X
X
X
Reaction of 1H-benzotriazole with bromine in concentrated nitric acid under reflux af-fords 4,5,6,7-tetrabromo-1H-benzotriazole in 54% yield (Scheme 249).[585] 1-Methyl- and 2-methyl-1H-benzotriazoles are brominated in the same way affording, respectively,4,5,6,7-tetrabromo-1-methyl-1H-benzotriazole (48% yield) and 4,5,6,7-tetrabromo-2-meth-yl-2H-benzotriazole (67% yield).[585]
1-Chloro-1H-benzotriazole (682, X = Cl); Typical Procedure:[692]
CAUTION: 1-Chloro-1H-benzotriazole reacts violently with DMSO.
2 M NaOCl (50 mL, 0.1 mol) was added dropwise at rt to a stirred soln of 1H-benzotriazole(10 g, 0.08 mol) in aq AcOH (1:1). After dilution with H2O the resulting solid was collectedand recrystallized once (CH2Cl2/petroleum ether) to give pure (682, X = Cl) as colorlessneedles; yield: 13 g (~100%); mp 104–108 8C.
4,5,6,7-Tetrachloro-1H-benzotriazole (683, X = Cl); Typical Procedure:[16]
A soln of 1H-benzotriazole (4.76 g, 0.040 mol) in a mixture of concd HCl (525 mL) andconcd HNO3 (175 mL) was refluxed for 3 h, cooled, and diluted to precipitate the product;yield: 9.0 g, (87%). Recrystallization (MeNO2) gave a white crystalline solid; mp 256–260 8C.
13.13.3.3.1.1.10 Method 10:Sulfonylation
1H-Benzotriazole reacts with trifluoromethanesulfonic anhydride, in dry dichlorometh-ane and dry pyridine at –78 8C, to afford 1-(trifluoromethylsulfanyl)-1H-benzotriazole in87% yield.[642]
5,6-Dimethyl-1H-benzotriazole reacts with benzenesulfonyl chloride, in the presenceof 10% aqueous sodium hydroxide solution, to yield the 1-phenylsulfonyl derivative in72% yield;[587] naphthotriazoles also give only the 1-phenylsulfonyl derivatives.[582]
1H-Benzotriazol-4-amine reacts with an equimolar amount of 4-toluenesulfonyl chlo-ride in pyridine at room temperature to give 4-(tosylamino)-1H-benzotriazole (684, Ar1 = 4-Tol) (Scheme 250).[699] Under similar experimental conditions, 5-methyl-1H-benzotriazol-4-amine gives the 1-tosyl-1H-benzotriazole derivative 685 as the only isolated product. Withan excess of arenesulfonyl chloride both starting benzotriazol-4-amines afford the bis-sul-fonylated derivatives 686.[699] The reaction of benzotriazol-5-amines with arenesulfonylchlorides has also been reported.[639] 1-Mesyl- and 1-(phenylsulfonyl)-1H-benzotriazole areprepared in good yields from the reaction of the corresponding sulfonyl chlorides and 1-(trimethylsilyl)-1H-benzotriazole[630] or 1-(tributylstannyl)-1H-benzotriazole.[693]
562 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 250 Sulfonylation of Benzotriazol-4-amines[699]
NH
NN
R1 = H, Me; Ar1 = Ph, 4-Tol
TsCl (1 equiv)
py, rt
NH2
R1
NH
NN
NHTs
684
NN
N
NH2
685Ts
R1 = H
R1 = Me
Ar1SO2Cl (4 equiv)
py, rt
NN
N
NHSO2Ar1
R1
SO2Ar1
686
13.13.3.3.1.1.11 Method 11:N-Amination
1H-Benzotriazol-1-amines are valuable precursors to didehydrobenzenes under notablymild conditions, using either lead(IV) acetate[694] or N-bromosuccinimide.[695] Treatmentof 1H-benzotriazole with hydroxylamine-O-sulfonic acid in hot (70–75 8C) aqueous potas-sium hydroxide solution gives a mixture of 1H-benzotriazol-1-amine (687) and 2H-benzo-triazol-2-amine in an approximately 3:1 ratio (Scheme 251).[694] The formation of the 2-amino isomer is avoided by changing the reaction conditions (temperature and solvent).The 1-amino isomer is obtained selectively in 62% yield when the reaction is carried out indioxane containing 5% water and the reaction mixture is maintained below 50 8C. Betteryields (69%) of the 1-isomer, uncontaminated by the 2-isomer, are obtained in dimethyl-formamide containing 5% water.[696] In ethanol the conversion is nearly quantitative, but a2:1 mixture of the two isomers is formed, the 2-amino derivative being the main prod-uct.[696]
Scheme 251 N-Amination of 1H-Benzotriazole[694,696]
NH
NN
H2NOSO3H, aq KOH, DMF
<50 oC, 1 h
NN
N
NH2
NN
N+
687
NH2
N-Amination of 1H-naphtho[2,3-d][1,2,3]triazole and 1H-naphtho[1,2-d][1,2,3]triazole inaqueous potassium hydroxide with hydroxylamine-O-sulfonic acid gives mainly the 1-amino derivatives (27 and 18% yields, respectively).[697] N-Amination of benzo[1,2-d:4,5-d¢]-bistriazole (688) under similar conditions gives a mixture of five products: the two mono-amino derivatives and the three possible diamino derivatives (Scheme 252).[596] The com-bined yields of diamino and monoamino products are 45 and 48%, respectively. N-Amina-
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 563
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
btion of a 1,2,3-triazolo[4,5-d][1,2,3]triazole with O-(mesitylsulfonyl)hydroxylamine affordsthe 1-amino and 2-amino derivatives in 22 and 46% yield, respectively.[698] N-Amination of4-cyanoazuleno[1,2-d]-1,2,3-triazole with 1-(aminooxy)-2,4-dinitrobenzene gives a 3:2 mix-ture of two isomeric N-amino derivatives in 54% yield.[569]
Scheme 252 N-Amination of Benzo[1,2-d:4,5-d¢]bistriazole[596]
NN
NH
1. 10% KOH, 60 oC
2. H2NOSO3H
66−68 oC, 2 h
NN
HN
688
NN
NNN
HN
NH2
NN
NNN
N
NH2
NN
NNN
NH
+
+
H2N
NN
NNN
N
NH2
+
NN
NNN
N
+
NH2
H2N
H2N NH2
1H-Benzotriazol-1-amine (687):[696]
Hydroxylamine-O-sulfonic acid (94.9 g, 0.84 mol) was added portionwise to a stirred solnof 1H-benzotriazole (50.0 g, 0.42 mol) and KOH (117.6 g, 2.1 mol) in DMF (250 mL) and H2O(12 mL) such that the temperature of the mixture remained below 50 8C (ca. 1.0 g •min–1).After the addition was complete, the mixture was cooled to rt and stirring continued for afurther 1 h. The resulting precipitate was removed by vacuum filtration and washed thor-oughly with Et2O. The filtrate was evaporated to dryness using a rotary evaporator at-tached to a rotary pump. The temperature of the water bath was kept below 50 8C; abovethis, rearrangement to the corresponding 2-amino isomer became significant. The resi-due was dissolved in a minimum of 2 M HCl and the resulting soln kept at –2 8C overnightduring which time 1H-benzotriazol-1-amine hydrochloride crystallized and was removedby filtration. The solid was dried under vacuum and showed mp 131–134 8C and was >95%pure according to 1H NMR data. The free amine was obtained by direct basification of thesolid salt using aq 2 M NaOH followed by extraction with Et2O (3 � 100 mL). The combinedextracts were dried and evaporated to leave 687 as a colorless solid; yield: 38.8 g (69%); mp84 8C.
13.13.3.3.1.1.12 Method 12:Nitration
Nitration of 1H-benzotriazole with a mixture of concentrated nitric and sulfuric acids, atroom temperature, gives 4-nitro-1H-benzotriazole in 50% yield while 5-methyl-1H-benzo-triazole gives the 4-nitro derivative 689 (R1 = Me) in 90% yield under similar experimentalconditions (Scheme 253).[699] Nitration of 5-chloro-1H-benzotriazole (at 60 8C) affords de-rivative 689 (R1 = Cl) in 83% yield.[700] Nitration of 1H-benzotriazole-5-carboxylic acid at90 8C gives derivative 690 (R1 = CO2H) while 5-nitro-1H-benzotriazole at 115 8C affords amixture of 690 (R1 = NO2, 30%) and 691 (67%).[700]
564 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 253 Nitration of 1H-Benzotriazoles[699,700]
NN
NH
A: HNO3, H2SO4, rt, overnight
B: HNO3, H2SO4, 0−60 oC, 2 h
689R1
A: R1 = H 50%
A: R1 = Me 90%
B: R1 = Cl 83%
NN
NH
R1
NO2
A: HNO3, H2SO4, 0−90 oC, 2.5 h
B: HNO3, H2SO4, 0−115 oC, 12.5 h
690
A: R1 = CO2H 48% (690 only)
B: R1 = NO2 97%; (690/691) 30:67
NN
NH
R1
NO2
691
NN
NH
O2N
O2N
+
Nitration of 1-methyl-1H-benzotriazole affords 1-methyl-7-nitro-1H-benzotriazole[701]
while 2-methyl-2H-benzotriazole gives 2-methyl-5-nitro-2H-benzotriazole.[585] Nitration of1-(1,2,3-triazolyl)-1H-benzotriazole derivatives with potassium nitrate in concentratedsulfuric acid at 60 8C affords the corresponding 5-nitro derivatives in high yields (ca.80%). If the 5-position is occupied, nitration occurs at the 4-position.[322] 1-Phenyl- and 2-phenylbenzotriazoles give the corresponding 4-nitrophenyl derivatives by nitration withpotassium nitrate in concentrated sulfuric acid at 60 8C.[702,703] Nitration of 1-(2,4,6-trini-trophenyl)-1H-benzotriazole with a mixture of concentrated nitric and sulfuric acids, atreflux for 2 hours, gives the 5,7-dinitro derivative in 73% yield.[586] Nitration of 2-(2-hy-droxy-5-methylphenyl)-2H-benzotriazole with a mixture of concentrated nitric and aceticacids, at 70 8C for 10 minutes, gives the 2-(2-hydroxy-5-methyl-3-nitrophenyl) derivative in84% yield.[704] Nitration of 1,5-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistriazole with amixture of nitric acid and sulfuric acid gives the 4-nitro derivative in 21% yield.[595]
5-Methyl-4-nitro-1H-benzotriazole (689, R1 = Me); Typical Procedure:[699]
To 5-methyl-1H-benzotriazole (5 g, 37.5 mmol) in concd H2SO4 (20 mL) was added a mix-ture of HNO3 (70%, 5 mL) and concd H2SO4 (5 mL) at below 20 8C, and the resulting mixturewas allowed to stand overnight. The soln was poured onto ice, and the resulting precipi-tate was collected by filtration, washed with H2O, and recrystallized (EtOH) to give micro-crystals; yield: 6.0 g (90%); mp 254–255 8C.
13.13.3.3.1.1.13 Method 13:Azo Coupling
N-Unsubstituted, 1- and 2-substituted activated benzotriazoles (with a hydroxy or aminogroup) all react with arenediazonium salts to yield (arylazo)benzotriazoles.[631,701,705] Arange of benzo[1,2-d:3,4-d¢]bistriazoles 695 are prepared by oxidation of the 4-(arylazo)-benzotriazol-5-amines 694 (see Section 13.13.4.1.2.1.1) obtained from the reaction of 2-aryl-2H-benzotriazol-5-amines 692 with diazonium salt 693 (Scheme 254).[706]
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 565
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 254 Azo Coupling to 2-Aryl-2H-benzotriazol-5-amines[706]
NNAr1
N
Ar2N2 Cl−
692
R1
R1 = H, Me, Et, OMe, Cl, Br, CO2H, SO3H; Ar1 = Ph, aryl, naphthyl
H2N
+
693N
NAr1
N
694
R1
H2N
NAr2N
695
CuSO4, NH4OH
Ar2 =
SO3H
HO3S
NO2
N
NAr1N
R1
N
Ar2NN
Both 1H-benzotriazol-5-ol and 5-hydroxy-1H-benzotriazole-4-carboxylic acid afford thesame azo dye 696 when reacted with diazonium salts (Scheme 255).[631] The complemen-tary synthetic route to (arylazo)benzotriazoles, i.e. diazotization of benzotriazol-5-aminefollowed by reaction with an activated aromatic compound can also be used successful-ly.[707]
Scheme 255 Azo Coupling with Activated Benzotriazoles[631]
NN
NH
696
HO
NN
NH
HO
NNAr1
85%
− CO2
93%
NN
NH
HO
CO2H
Ar1 = 4-ClC6H4
Ar1N2 Cl−+
693
Ar1N2 Cl−+
693
4-(4-Chlorophenylazo)-1H-benzotriazol-5-ol (696); Typical Procedure:[631]
4-Chloroaniline (6.38 g, 0.05 mol) was dissolved in 2.5 M HCl (100 mL) and diazotized bythe addition of 5 M NaNO2 (10 mL) at 10 8C. This soln was filtered and diluted to 200 mLto make a 0.25 M soln. Part of this soln (8 mL, 2 mmol) was added with stirring to a solnof 1H-benzotriazol-5-ol (0.286 g, 2.12 mmol) dissolved in a mixture of H2O (40 mL), 1 MNaOH (4 mL) and 1 M Na2CO3 (2 mL). A deep orange soln was formed immediately. After15 min stirring, the soln was acidified by the addition of 5 M HCl (1 mL). The reddish-or-ange precipitate formed was collected by filtration, washed, and dried at 100 8C; yield:0.47 g (85%); mp 247–249 8C.
566 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.3.3.2 Of Carbon Functionalities
13.13.3.3.2.1 Method 1:Decarboxylation
When refluxed in water, 5-hydroxy-1H-benzotriazole-4-carboxylic acid decarboxylates toafford 1H-benzotriazol-5-ol in 76% yield (Scheme 256).[631] Its isomer, 5-hydroxy-1H-benzo-triazole-6-carboxylic acid does not decarboxylate under the same conditions.[631]
Scheme 256 Decarboxylation of Benzotriazoles[631]
H2O
reflux, 20 h
76%
NN
NH
HO
CO2H
NN
NH
HO NN
NH
HO
HO2C
H2O
reflux
13.13.3.3.2.2 Method 2:Deacylation
1-Acetyl-5-methyl-1H-benzotriazole and 1-acetyl-6-methyl-1H-benzotriazole are deacety-lated in boiling acetic acid/water (1:1) for eight to nine hours.[583] 1-Acetyl-6-(acetylamino)-5-methyl-1H-1,2,3-benzotriazole is selectively hydrolyzed to 6-(acetylamino)-5-methyl-1H-1,2,3-benzotriazole which then is hydrolyzed to 5-methyl-1H-benzotriazol-6-amine.[708]
1-Substituted benzotriazol-5-amines are obtained in 85% yield by deacylation of the corre-sponding 5-[(trifluoroacetyl)amino]-1H-benzotriazoles in methanol/potassium carbon-ate.[639] 1-Acetyl-5,6-dimethyl-1H-benzotriazole (697) is slowly deacetylated when dis-solved in ethanol/water (3:1) at room temperature (Scheme 257).[587] Compound 698 ishydrolyzed in 6 M hydrochloric acid to the propanoic acid derivative 699.[709]
Scheme 257 Deacetylation of 1-Acetyl-1H-benzotriazoles[587,709]
EtOH, H2O, rtNN
NAc
697
NN
NH
HCl, H2O, rt, 17 hNN
N
AcO
Ac
698
EtO2C90%
NN
NH
HO
699
HO2C
1,7-Diacetylbenzobistriazole 700, dissolved in ethanol/water (1:1), is deacetylated in al-most quantitative yield by acid treatment (Scheme 258).[596]
Scheme 258 Deacetylation of 1,7-Diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole[596]
NN
NAc
700
96%N
N
HN
688
NN
NAc
H2SO4, H2O, EtOH
reflux, 1 h
NH
NN
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 567
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b1,5-Dihydrobenzo[1,2-d:4,5-d¢]bistriazole (688); Typical Procedure:[596]
A mixture of 1,7-diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole (700; 0.73 g, 3 mmol),50% aq EtOH (100 mL), and concd H2SO4 (1 mL) was refluxed for 1 h, then the reflux con-denser was removed and most of the EtOH was allowed to evaporate. The resultant mix-ture was chilled and filtered to remove the product, which was washed with H2O anddried at 100 8C to give pure 688; yield: 0.46 g (96%); explosion temperature 370 8C whenheated at 20 8C •min–1.
13.13.3.3.3 Of Heteroatoms
13.13.3.3.3.1 Method 1:Deoxygenation
2H-Benzotriazole 1-oxides of type 701 are readily deoxygenated to 2H-benzotriazoles 702or 703 by reduction with zinc dust in alkaline ethanolic solutions,[710] zinc powder andsulfuric acid,[711] hydrazine hydrate in a high-boiling ether,[712] or by using baker�s yeastin sodium hydroxide solution[713] (Scheme 259). If the reduction with zinc is carried outwith heating, the 5-chloro-2H-benzotriazole 1-oxides 701 (R1 = Cl) are simultaneously de-oxygenated and dechlorinated (see Section 13.13.3.3.3.2).[710]
Scheme 259 Deoxygenation of 2-Aryl-2H-benzotriazole 1-Oxides[710,713]
NN
N
701
68−88%
Zn, NaOH, EtOH
rt, 1 h
R1
O− HO R2
R3
NN
N
702
R1
HO But
R3
NN
N
703
R1
HO R2
R3
86−90%
baker's yeast
NaOH
85 oC, 24−30 h
R1 = H, Cl; R2 = H, t-Bu, CH2t-Bu; R3 = Me, t-Bu, CH2t-Bu
+
2-Alkyl-2H-benzotriazole 704 is deoxygenated to 705 by reduction with tin(II) chloride(Scheme 260).[714]
Scheme 260 Deoxygenation of 2-Alkyl-2H-benzotriazole 1-Oxides[714]
NN
N
704
O−
72%OHC
SnCl2, HCl
NN
N
705
OHC+
Refluxing 1-nonyl-1H-benzotriazole 3-oxide (706) in neat acetic anhydride gives the deox-ygenated 1-nonyl-1H-benzotriazole (707; yield not reported) (Scheme 261).[715]
568 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 261 Deoxygenation of 1-Alkyl-1H-benzotriazole 3-Oxides[715]
NN
N
706
+
O−
Ac2O, reflux, 48 h
( )8
NN
N
707
( )8
Polymer-supported 1H-benzotriazol-1-ol 708 is readily converted into the correspondingNH derivative 709 by reductive cleavage of the 1-hydroxy moiety with either phosphorustrichloride or samarium(II) iodide (Scheme 262).[622]
Scheme 262 Reductive Cleavage of the 1-Hydroxy Moiety in a Polymer-Supported1H-Benzotriazol-1-ol[622]
NN
N
708
OH
PCl3, CHCl3, reflux, 20 h
or SmI2, THF, reflux, overnight NN
NH
709
13.13.3.3.3.2 Method 2:Dehalogenation
A simultaneous deoxygenation and dehalogenation, to give products 711, is observedduring the reduction of 5-chloro-2H-benzotriazole 1-oxides 710 with zinc dust in alkalineethanolic solution and heating on a steam bath for five hours (Scheme 263).[710]
Scheme 263 Dehalogenation of 5-Chloro-2H-benzotriazole 1-Oxides[710]
NN
N
710
Zn, NaOH, EtOH, H2O
100 oC, 5 h
Cl
+
O HO But
R1
−
NN
N
711
HO But
R1
R1 = Me 73%
R1 = t-Bu 80%
13.13.3.3.4 Addition Reactions
13.13.3.3.4.1 Method 1:Conversion into N-Oxides or Epoxides
1-Alkyl-1H-benzotriazoles react with dimethyldioxirane to give the corresponding 1-alkyl-1H-benzotriazole 3-oxides 712. In contrast, under similar conditions, 2-alkyl-2H-benzotri-azoles 713 are converted into the corresponding trans-4,5,6,7-diepoxy-4,5,6,7-tetrahydro-2H-benzotriazoles 714 (Scheme 264).[715]
13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 569
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 264 Oxidation of Benzotriazoles with Dimethyldioxirane[715]
NN
N
712
35−92%
CH2Cl2, rt, 24−36 h
(2−3 equiv)O
ON
NN
O−+
R1 = Me, Et, Pr, (CH2)5Me, (CH2)8Me, Bn, CH2CH2Ph, CHPhMe, CH2CO2Et, CH2OPh, CH2C CH, CH2CN
R1 R1
NN
N
713
CH2Cl2, rt, 3 d
(4 equiv)O
O
Ar1 = Ph 50%
Ar1 = 4-O2NC6H4 77%Ar1
NN
N
714
Ar1
O
O
2-Methyl-2H-benzotriazole is converted into its 1-oxide derivative, in very low yield, by ox-idation with 3-chloroperoxybenzoic acid (Scheme 265).[615] Most of the starting benzotria-zole is recovered unchanged.
Scheme 265 Oxidation of Benzotriazoles with 3-Chloroperoxybenzoic Acid[615]
NNMe
N0.8%
MCPBA (4 equiv)
CH2Cl2, 0 oC to rt, 12 d NNMe
N
O−
+
13.13.4 Product Subclass 4:2-Substituted Benzotriazoles
13.13.4.1 Synthesis by Ring-Closure Reactions
13.13.4.1.1 By Formation of Two N-N Bonds
13.13.4.1.1.1 Fragments N-C-C-N and N
13.13.4.1.1.1.1 Method 1:From Benzene-1,2-diamine and Nitrobenzenes
Benzene-1,2-diamine reacts with nitrobenzenes to yield 2-aryl-2H-benzotriazoles and 2-aminoazobenzenes (Scheme 266).[716] The latter compounds can be converted into 2-aryl-2H-benzotriazoles (see Scheme 267).
Scheme 266 2-Aryl-2H-benzotriazoles from Benzene-1,2-diamine and Nitrobenzenes[716]
NH2
NH2
+ Ar1NO2
NNAr1
N
NH2
NNAr1
+
Ar1 = Ph, 3-Tol
570 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b13.13.4.1.2 By Formation of One N-N Bond
13.13.4.1.2.1 Fragment N-N-C-C-N
13.13.4.1.2.1.1 Method 1:Cyclization of 2-Aminoazobenzenes
2-Aminoazobenzenes are converted into 2-aryl-2H-benzotriazoles by oxidation with cop-per sulfate in ammonia or pyridine solution (Scheme 267). Using ammoniacal copper sul-fate, 2,4-diaminoazobenzene (715, R1 = 4-NH2; R2 = H) is converted quantitatively into 2-phenyl-2H-benzotriazole-5-amine,[717] and 2,2¢-diaminoazobenzene (715, R1 = H; R2 = 2-NH2) is oxidized to 2-(2-aminophenyl)-2H-benzotriazole (716; R1 = H, R2 = 2-NH2) with cop-per sulfate in pyridine in 65% yield.[643]
Scheme 267 Oxidative Cyclization of 2-Aminoazobenzenes[643,717]
NN
N
NH2
NN
R1
715
CuSO4, H2O
NH3 or py
rt to reflux, 2 hR1
R2
716
R2
Similarly, 1-(2-nitrophenylazo)-2-naphthylamine 717 is converted into the naphthotria-zole 718 by oxidative cyclization with copper sulfate in pyridine (Scheme 268).[643] Thesame naphthotriazole is obtained in 70% yield by refluxing the azo compound in thionylchloride.[643]
Scheme 268 Oxidative Cyclization of 1-(2-Nitrophenylazo)-2-naphthylamine[643]
NN
N
NH2
NN
717
A: CuSO4, py, reflux, 4 h
B: SOCl2, benzene, reflux, 18 h
718
O2N
A: 83%
B: 70%
O2N
2-(Arylazo)anilines 719 and 1-(arylazo)-2-naphthylamines 721 are converted into the cor-responding 2H-benzotriazoles 720 and 2H-naphthotriazoles 722, respectively, by reflux-ing in dimethylformamide, with a current of bubbling air, in the presence of copper(II)acetate (Scheme 269).[718] This procedure[718,719] and the one using copper sulfate as oxi-dant,[547,720,721] can also be applied to the synthesis of heterocycle-fused 1,2,3-triazoles.
13.13.4 2-Substituted Benzotriazoles 571
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 269 Air Oxidation of 2-(2-Thienylazo)aniline and 1-(2-Thienylazo)-2-naphthylamine Derivatives[718]
NN
N
NH2
NN
719
Cu(OAc)2, air
DMF, reflux, 4 h
720
61−69%
S
S
R2
R1
R1 = Me, OMe; R2 = CN, CO2Et
R1
R2
NN
N
NH2
NN
721
Cu(OAc)2, air
DMF, reflux, 4 h
722
71−74%
S
S
R1
R1
R1 = CN, CO2Et
A range of benzo[1,2-d:3,4-d¢]bistriazoles is prepared by oxidation of 4-(arylazo)benzotri-azol-5-amines (see Scheme 254 in Section 13.13.3.3.1.1.13).[706]
2-(2-Aminophenyl)-2H-benzotriazole (716, R1 = H; R2 = 2-NH2); Typical Procedure:[643]
2,2¢-Diaminoazobenzene (4.4 g, 0.02 mol) was dissolved in pyridine (50 mL) and treatedwith anhyd CuSO4 (12.8 g, 0.08 mol) added in portions with stirring. After 30 min at rt,the mixture was refluxed for 2 h, cooled, and poured into cold H2O (200–250 mL) with stir-ring. The dark solid which separated was collected by filtration and washed with H2O.Three recrystallizations (2 � EtOH and 1 � hexane), with concomitant treatment withactivated carbon, yielded well-defined, yellow crystals; yield: 65%; mp 97–98 8C.
13.13.4.1.2.1.2 Method 2:Cyclization of 2-Azidoazobenzenes
The synthesis of 2H-benzotriazoles by thermal extrusion of nitrogen from 2-azidoazoben-zenes has been known since the 19th century.[722,723] This is a very convenient methodsince a range of 2-azidoazobenzenes can be prepared from simple precursors (Scheme270).[724,725] The kinetics of the thermal decomposition of 2-azidoazobenzenes 723 to 2-aryl-2H-benzotriazoles 724 has been investigated.[726] The reaction of 723 with boron tri-chloride or trifluoride in benzene at room temperature also gives benzotriazoles 724 inhigh yields (90–94%).[727]
572 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 270 Synthesis of 2-Azidoazobenzenes and Their Conversion into2-Aryl-2H-benzotriazoles[724,725]
NNAr1
N
N3
NNAr1
723
heat
724
− N2
NH2
N3
N2
N3
+ Ar1NO
+ Ar1X
NaNO2, H+
+
− H2O
X = NR1R2, OH
The benzotriazolo[2,1-a]benzotriazole 727 is prepared in good yield by the thermal orphotochemical decomposition of 2,2¢-diazidoazobenzene (725). This transformation re-quires the elimination of 2 equivalents of nitrogen and this can be performed at 175 8C(Scheme 271). However, since the nitrogen is liberated in two distinct stages, 1 equivalentat approximately 60 8C and the second equivalent at approximately 170 8C, it is possible toconvert 725 into 2-(2-azidophenyl)-2H-benzotriazole (726) in good yield.[643,728] Benzotria-zole 726 is also formed when a benzene solution of 725 is exposed to sunlight for threedays. Similarly, 726 is converted into 727 when exposed to sunlight for ten days.[643]
Scheme 271 Thermolysis of 2,2¢-Diazidoazobenzene[643,728]
NN
NN3
NN
725
acetone or benzene
reflux, 2 h
726
N3
− N2
70%N3
Decalin
175 oC, 2−3 hDecalin
175−185 oC, 2−3 h
− N2
95%
− 2N2
93%
N
N
N
N
+ −
727
2,4-Bis(arylazo)-1-azido- and 1-(arylazo)-2-azidonaphthalene derivatives 728 and 730 areconverted into 2H-naphtho[1,2-d][1,2,3]triazoles 729 by thermal decomposition (Scheme272).[729]
13.13.4 2-Substituted Benzotriazoles 573
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 272 Thermolysis of (Arylazo)azidonaphthalenes[729]
NNAr1
N
N3
NNAr1
R1
R1
heat
N
N3R1
heat
728
730
729NAr1
− N2
R1 = N2Ar1 78−81%
− N2
R1 = H 60−85%
1-(2-Azidophenyl)-3-methyl-3-phenyltriazene (731) is converted into 2-[methyl(phenyl)-amino]-2H-benzotriazole (732) when refluxed in m-xylene (Scheme 273).[725]
Scheme 273 Thermolysis of a (2-Azidophenyl)triazene Derivative[725]
NN
N
N3
NN
m-xylene, reflux, 1 h
− N2
63%
731 732
N
N
Ph
MePh
Me
2-Azidoazobenzenes 734 are intermediates in the conversion of 2-nitro-, 2-chloro-, and 2-bromoazobenzenes 733 into 2-aryl-2H-benzotriazoles 735 (Scheme 274). This transforma-tion is accelerated by the addition of a suitable metal catalyst (e.g., CuBr).[730]
Scheme 274 Synthesis of 2-Aryl-2H-benzotriazoles from 2-Nitro-, or 2-Haloazobenzenesand Sodium Azide[730]
NNAr1
N
N3
NNAr1
734
735
− N2
X = NO2, Cl, Br
R1
R1
X
NNAr1
733
R1
NaN3, DMSO
or DMF
125 oC, 4−10 h
2-(2-Azidophenyl)-2H-benzotriazole (726); Typical Procedure:[643]
A soln of 725 (5 g, 18.9 mmol) in acetone or benzene (CAUTION: carcinogen) was refluxedfor 2 h. N2 was evolved, and the orange color was discharged. The solvent was removed bydistillation, and the crystalline residue was recrystallized (petroleum ether or aq acetone)to afford light yellow needles; yield: 70%; mp 78–79 8C.
574 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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b13.13.4.1.2.1.3 Method 3:
Cyclization of 2-Nitroazobenzenes
2-Nitroazobenzenes 736 give reductive cyclization reactions to afford 2-aryl-2H-benzotri-azole 1-oxides 737 or 2-aryl-2H-benzotriazoles 738, depending on the reducing agent andthe reaction conditions (Scheme 275). For example, reduction of azo compounds 736 withglucose[710] or with hydroxylamine[731] in ethanolic sodium hydroxide solution, at reflux,affords 2H-benzotriazole 1-oxides 737 in good yields. 2-Nitroazobenzenes react with thio-urea S,S-dioxide in ethanolic sodium hydroxide to give, depending on the reaction condi-tions, either the corresponding 2-aryl-2H-benzotriazoles 738 or their 1-oxides 737.[732] Sev-eral other reducing agents can be used for the conversion of 2-nitroazobenzenes into 2-aryl-2H-benzotriazoles or their 1-oxides, namely sodium sulfide, sodium hydrosulfide,[733]
ammonium sulfide,[734] sodium dithionite,[735] hydrazine hydrate,[711,712] zinc dust with so-dium hydroxide,[710] molybdenum-promoted Raney nickel,[736] hydrogen in the presenceof a catalyst,[737,738] and carbon monoxide in an alkaline medium in the presence of a cop-per–amine complex catalyst.[739]
Scheme 275 Reductive Cyclization of 2-Nitroazobenzenes[710]
NNAr1
N
738
R1
NO2
NNAr1
736
R1 reduction
NNAr1
N
737
R1
O−+
reduction
2-Nitroazobenzenes 739 cyclize selectively to give 2-aryl-2H-benzotriazole 1-oxides 740by reduction with baker�s yeast (Saccharomyces cerevisiae) in sodium hydroxide solution(Scheme 276). Using twice the amount of baker�s yeast, a larger amount of sodium hy-droxide, and a longer reaction time, gives 2-aryl-2H-benzotriazoles 741 as the sole prod-uct in good yields.[713]
13.13.4 2-Substituted Benzotriazoles 575
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 276 Reductive Cyclization of 2-Nitroazobenzenes Using Baker�s Yeast[713]
NO2
NN
739
baker's yeast
NaOH, H2O
85 oC, 3.5−4 h
NN
N
740
+
R1
R2
R3
R1
OH
R3
R2
NN
N
741
R1
HO
R3
R2
baker's yeast
NaOH, H2O
85 oC, 24−30 h86−90%
baker's yeast
NaOH, H2O
85 oC, 36−40 h
84−87%
80−87%
R1 = H, Cl; R2 = H, t-Bu, CMe2Et; R3 = Me, t-Bu, CMe2Et
HO
O−
13.13.4.1.2.1.4 Method 4:Cyclization of 1-Substituted 2-(2-Nitroaryl)hydrazines
Under reductive conditions, 1-aryl-2-(2-nitroaryl)hydrazines 743 cyclize to 2-aryl-2H-ben-zotriazoles 744 (Scheme 277).[740] Frequently benzotriazoles 744 are prepared directlyfrom the reaction of 1-halo-2-nitrobenzene derivative 742 (X = Cl, Br), or a 1,2-dinitroben-zene derivative 743 (X = NO2), and an excess of an arylhydrazine.[609,645] Under acidic con-ditions, hydrazines 743 are dehydrated to 2-aryl-2H-benzotriazole 1-oxides 745 (Scheme277).[741] Most 1-aryl-2-(2,4,6-trinitrophenyl)hydrazines 743 [R1 = 4,6-(NO2)2; Ar1 = Ph, 4-Tol,C6F5] are readily cyclized by refluxing in anhydrous ethanolic hydrogen chloride.[742] How-ever, cyclization of 1,2-bis(2,4,6-trinitrophenyl)hydrazine to 4,6-dinitro-2-(2,4,6-trinitro-phenyl)-2H-benzotriazole 1-oxide requires more vigorous conditions. Cyclization pro-ceeds smoothly and nearly quantitatively by gentle heating a suspension of that hydra-zine derivative in concentrated sulfuric acid for 30–60 minutes.[742]
Scheme 277 Cyclization of 1-Aryl-2-(2-nitroaryl)hydrazines[609,445,741]
NNAr1
N
744
R1
X
NO2
742
R1Ar1NHNH2
NNAr1
N
745
R1
O−+
HN
NO2
743
R1 NHAr1
KI, AcOH, heat
or Ar1NHNH2, heat
H+
− H2O
X = Cl, Br, NO2
576 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
b2-Methyl-6-nitro-2H-benzotriazole 1-oxide (747) is prepared by acid-catalyzed dehydrationof 1-methyl-2-(2,4-dinitrophenyl)hydrazine (746) or by addition of iodomethane to a solu-tion of 2,4-dinitrophenylhydrazine (Scheme 278).[743]
Scheme 278 Acid-Catalyzed Dehydration of 1-Methyl-2-(2,4-dinitrophenyl)hydrazine[743]
HN
NO2
746
NNMe
N
747
O−+
HCl, MeOH
rt, 7 h
O2N
O2N
NHMe
MeΙ, DMSO
rt, 42 h
HN
NO2O2N
NH2
86%
60%
The 2-nitrophenylhydrazine derivative 748 gives the 2-alkyl-2H-benzotriazole 1-oxide 749when treated with pyridine (Scheme 279).[714]
Scheme 279 Base-Catalyzed Conversion of a 2-NitrophenylhydrazineDerivative into a 2-Alkyl-2H-benzotriazole 1-Oxide[714]
HN
NO2
748
NN
N
749
O−+
pyN+
Br−
OHC
13.13.4.1.2.1.5 Method 5:Cyclization of Vicinal Diazides
2,3-Diazidonaphtho-1,4-quinone (750) reacts with triphenylphosphine to form almostquantitatively the phosphorane 751 (Scheme 280). This compound undergoes an aza-Wit-tig reaction with aldehydes (e.g., to give 753) and is readily hydrolyzed to the triazol-2-amine 752, which is a stable and high-melting compound.[744]
13.13.4 2-Substituted Benzotriazoles 577
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 280 Synthesis of Naphthotriazol-2-amine Derivatives from Vicinal Diazides[744]
750
Ph3P, MeOH
rt, 3 h
O
O
N3
N3
751
O
O
NN
NN
PPh3 752
O
O
NN
NNH2
753
O
O
NN
NN
1 M HCl
reflux, 4 h
PhCHO, CH2Cl2rt, overnight
43%
36%
− N2
96%
Ph
13.13.4.2 Synthesis by Ring Transformation
13.13.4.2.1 Method 1:Isomerization of 4-(Arylazo)-2,1,3-benzoxadiazoles
Addition of a diazonium salt to 5-(dimethylamino)-2,1,3-benzoxadiazole 1-oxide (754)gives the 4-arylazo derivative 755, which isomerizes to the 2-aryl-2H-benzotriazole 756(Scheme 281).[745]
Scheme 281 2-Aryl-2H-benzotriazoles from 4-(Arylazo)-2,1,3-benzoxadiazoles[745]
NO
N
754
O−+
Ar1N2
Me2N
NO
N
755
O−+
Me2N
NNAr1
NNAr1
N
756
NO2
NMe2
Ar1 = 2,4-(O2N)2C6H3
+
13.13.4.2.2 Method 2:Transformation of 1,3,3-Trialkyl-2-(2,4-dinitrophenyl)diaziridines
1-(2,4-Dinitrophenyl)diaziridines bearing an NH group 757 (R1 = H), upon heating in tolu-ene for ca. 3 hours, rearrange to the corresponding 2,4-dinitrophenylhydrazones. Howev-er, heating 1,3,3-trialkyl-2-(2,4-dinitrophenyl)diaziridines or 1,3-dialkyl-2-(2,4-dinitro-phenyl)diaziridines 757 (R3 = H) does not give hydrazones but affords instead 2-alkyl-6-ni-tro-2H-benzotriazole 1-oxides 759 (via intermediates 758) in almost quantitative yields(Scheme 282).[743]
578 Science of Synthesis 13.13 1,2,3-Triazoles
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FOR PERSONAL USE ONLY
bScheme 282 Transformation of 1,3,3-Dialkyl-2-(2,4-dinitrophenyl)diaziridines[743]
NNR1
N
759 97−100%
O−+
R1 = Me, iPr, Cy; R2,R3 = (CH2)5; R2 = Me, Et; R3 = H, Me
O2N
758
N
NNR1
O
O2N
toluene, reflux
3−14 h
NO2
N
O2N
NR2
R3
R1
− R2COR3
757
13.13.4.2.3 Method 3:Transformation of 1-(2-Nitrophenyl)-1H-tetrazoles
5-Aryl-1-(2-nitrophenyl)-1H-tetrazoles[746,747] and 1-aryl-5-(2-nitrophenyl)-1H-tetrazoles[748]
decompose when heated to give nitrogen, carbon dioxide, and 2-aryl-2H-benzotriazoles;the former react much faster than the latter. For example, decomposition of 1-(2-nitro-phenyl)-5-phenyl-1H-tetrazole (760) in refluxing nitrobenzene is complete after one hourwhile decomposition of 5-(2-nitrophenyl)-1-phenyl-1H-tetrazole (763) requires 19 hours(Scheme 283).[748] It has been shown that the thermal decomposition of these tetrazolesto 2-aryl-2H-benzotriazoles (e.g., 762) proceeds via 2-nitrophenyl(phenyl)carbodiimides(e.g., 761; Ph may be replaced by a substituted-phenyl ring). A sequence of electrocyclicring closing and opening reactions is proposed as the mechanism of the conversion ofcarbodiimides 761 to 2-aryl-2H-benzotriazoles.[746,747] There are several other precursors(both cyclic and acyclic) of diarylcarbodiimides with an ortho nitro group and, conse-quently, they can be used in the synthesis of 2-aryl-2H-benzotriazoles.[746,747]
Scheme 283 Transformation of 1(5)-(2-Nitrophenyl-5(1)-phenyltetrazoles into2-Phenyl-2H-benzotriazole[748]
NNPh
N
761
NO2
N
PhNO2, reflux
1 h
NO2
N
− N2
70%
760
N
NN
Ph
NO2
763
NN
NN
Ph
PhNO2, reflux
19 h
− N2
60%
− CO2
762
• NPh
The carbodiimides 765 are suggested as probable intermediates in the reaction of thephosphoramidate 764 with aryl isocyanates to yield the 2-aryl-2,4-dihydroimidazo[4,5-d][1,2,3]triazoles 766 (Scheme 284).[749]
13.13.4 2-Substituted Benzotriazoles 579
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 284 Synthesis of 2-Aryl-2,4-dihydroimidazo[4,5-d][1,2,3]triazoles viaCarbodiimides[749]
764
Ar1NCO
MeCN, 60 oCEtN
N
N
NO2
P(OEt)3
765
EtN
N
N
NO2
NNAr1
NN
N
Et
766 57−79%
• NAr1
13.13.4.3 Synthesis by Substituent Modification
Since substituent modification reactions in 1H- and 2H-benzotriazoles are, in many cases,very similar, the synthesis of new 2H-benzotriazoles by substituent modification is cov-ered in Section 13.13.3.3.
13.13.5 Product Subclass 5:1,2,3-Triazolium Salts
13.13.5.1 Synthesis by Ring-Closure Reactions
13.13.5.1.1 By Formation of One N-N and One N-C Bond
13.13.5.1.1.1 Fragments C-N-N and C-N
13.13.5.1.1.1.1 Method 1:From Diarylnitrilimines and Alkyl Isocyanides
Diarylnitrilimines 768 (generated in situ from 767 and triethylamine) react with alkyl iso-cyanides to form the triazolium salts 769 (Scheme 285).[444,750] Depending on the reactionconditions, other heterocyclic compounds are obtained, namely 1,2,4-triazolium salts,pyrazole derivatives, and quinoxaline derivatives. Experiments with tert-butyl isocyanideand phenyl isocyanide failed to give the respective triazolium salts 769.
Scheme 285 Reaction of Diarylnitrilimines with Alkyl Isocyanides[444,750]
767
Et3N
MeCN, rtAr1
Cl
N
NHAr2
NAr1 NAr2+ −
N
NNAr2
Ar1
R1+
ClO4−
768
769 57−73%
1. R1NC, MeCN, rt, 24 h
2. HClO4, H2O
R1 = Me, iPr, Cy; Ar1 = Ph, 4-Tol; Ar2 = Ph, 4-Tol
580 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bSynthesis of 2H-Triazol-1-ium Salts 769; General Procedure:[444]
CAUTION: Perchlorate salts are potential explosives.
Et3N (2 mmol) was added at rt to a soln of the N-arylbenzohydrazonoyl chloride 767(2 mmol) and the alkyl isocyanide (2 mmol) in dry MeCN (50 mL); the mixture was allowedto stand for 24 h. Removal of the solvent gave a crystalline residue which was washedwith Et2O and dissolved in the minimum amount of H2O (some insoluble material was fil-tered off ). Then 10% aq HClO4 was added to cause precipitation of crude 769 as a greenish-white solid. Chromatography (acidic alumina, acetone), followed by addition of Et2O tothe concentrated eluate, afforded colorless plates.
13.13.5.1.2 By Formation of One N-C Bond
13.13.5.1.2.1 Fragment N-N-N-C-C
13.13.5.1.2.1.1 Method 1:Cyclization of Æ-Imino Hydrazones
The oxidation of substituted Æ-imino hydrazones 770 with N-bromosuccinimide affords1,2-disubstituted 2H-triazol-1-ium salts 771 (Scheme 286).[751]
Scheme 286 Oxidative Ring Closure of Substituted Æ-Imino Hydrazones[751]
N
NN
R2
+
771
R1 NPh
R2 NNH
R3
NBS
Ph
R1
R3
770
R1 = alkyl, aryl; R2 = alkyl, CN; R3 = H, halo, alkyl
13.13.5.1.2.1.2 Method 2:Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives
Cyclization of ethyl (1-methyl-3-phenyltriaz-2-enyl)acetate 772 (Ar1 = Ph; X = OEt) withthionyl chloride/pyridine gives the mesoionic compound 773 (Ar1 = Ph) together with asmall amount of the sulfide 774 (Scheme 287).[362] Under similar reaction conditions, cy-clization of amide 772 (Ar1 = Ph; X = NH2) gives only sulfide 774. Similar results are ob-tained when Ar1 = 4-tolyl. Treatment of acetonitrile derivatives 775 with dry hydrogenchloride affords 4-amino-3-aryl-1-methyl-3H-1,2,3-triazol-1-ium chlorides 776. Cyclizationof 775 with acetyl chloride gives the acetamido derivatives 777. The yields from all thesetransformations are low.
Scheme 287 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives[362]
NAr1
NN
−O
+
773
Me
Ar1 = Ph, 4-Tol; X = OEt, NH2
X
Ar1N
N
NMeO
SOCl2, py NAr1
NN
−O
+
774
Me
S
2
+
772
13.13.5 1,2,3-Triazolium Salts 581
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bNAr1
NN
H2N
+
776
Me
Ar1 = Ph, 4-Tol
HCl
Cl− NC NMe
NAr1N
775
AcCl NAr1
NN
AcHN
+
777
Me
Cl−
This type of chemistry has been applied to the synthesis of the mesoionic 1,3-diaryl-1,2,3-triazoles 778 (Scheme 288).[752]
Scheme 288 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives[752]
R1 = CO2Me, NHAc, NHCOEt
Ar1N2
NAr1
NN
−O
+
778 20−55%
OH
O
HN
R1
+HO
ON
R1
NAr1N
Ac2O, py, rt
R1
13.13.5.2 Synthesis by Introduction of Substituents
13.13.5.2.1 Method 1:Alkylation of N-Alkyl-1,2,3-triazoles
Alkylation of 1-alkyl-1H-1,2,3-triazoles 779 gives 1,3-disubstituted 3H-1,2,3-triazol-1-iumsalts 780[455] while alkylation of 2-substituted 2H-1,2,3-triazoles 781 affords 1,2-disubsti-tuted 2H-1,2,3-triazol-1-ium salts 782 (Scheme 289).[450] 2-Substituted 2H-triazoles aremuch more difficult to alkylate than the isomeric 1-substituted 1H-triazoles; this differ-ence in reactivity agrees with the fact that 1-substituted triazoles are much more basicthan the isomeric 2-substituted compounds.[450] While 1-substituted 1,2,3-triazoles reactreadily with methyl 4-toluenesulfonate,[448,449] producing 1,3-disubstituted 1,2,3-triazo-lium 4-toluenesulfonates in high yields, 2-substituted 1,2,3-triazoles, when treated withmethyl 4-toluenesulfonate, iodomethane, or dimethyl sulfate do not react, or they givethe triazolium salts in low yield only.[450] 2,4-Diphenyl-2H-1,2,3-triazole is, however, con-verted into the triazolium salt, in 80% yield, by methylation with dimethyl sulfate.[444] M-ethyl fluorosulfonate is a successful methylating reagent for 2-substituted 1,2,3-triazoles(Scheme 289).[450] The reaction is carried out in the absence of a solvent and the requiredtemperature is dependent on the substituents R1 and R2 in triazole 781. For example, 2-methyl-2H-1,2,3-triazole reacts with methyl fluorosulfonate at 0 8C, 2-phenyl-2H-1,2,3-tri-azole reacts at room temperature, and the reaction with 4,5-dibromo-2-methyl-2H-1,2,3-triazole only occurs at 60 8C.[450]
582 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 289 Alkylation of 1- and 2-Substituted 1,2,3-Triazoles[450,455]
NR2
NN
+
780
R1
I−N
NN
779
R1
+ R2I
acetone, Et2O
rt, 5−8 d
R1 = Me; R2 = Bn 83%
R1 = Bn; R2 = Me 74%
N
NNR2
+
FSO3−
N
NNR2
781
0 oC, rt, or 60 oC
R1 = H; R2 = Me 79%
R1 = H; R2 = Ph 99%
R1 = Br; R2 = Me 99%
R1
R1 FS
OMe
O O+
R1
R1
Me
782
1-Phenyl-1H-1,2,3-triazole adds fairly rapidly to vinylsulfonyl chloride, in the absence of abase, to yield quantitatively the sulfonate 783 (Scheme 290).[198]
Scheme 290 Addition of 1-Phenyl-1H-1,2,3-triazole to Vinylsulfonyl Chloride[198]
N
NN
Ph
benzene
reflux, 6 h N
NN
Ph
SO2Cl
−
+
H2O N
NN
Ph
SO3−
+
783 99%
SO2Cl
1-Ethyl-1H-1,2,3-triazole reacts with tetracyanoethene oxide, at 0 8C, to yield 3-ethyl-3H-1,2,3-triazol-1-ium-1-dicyanomethanide (784) in 73% yield (Scheme 291).[753]
Scheme 291 Reaction of 1-Ethyl-1H-1,2,3-triazole with Tetracyanoethene Oxide[753]
N
NN
Et
EtOAc
0 oC, 2−5 min
73%
784
ONC CN
CNNC
+N
NN
Et
NC
CN−
++ O
CN
CN
13.13.5.2.2 Method 2:Alkylation of N-Alkylbenzotriazoles
As discussed in Section 13.13.3.3.1.1.8, during the alkylation of benzotriazole with alkylhalides, in some cases,[672] the 1,3-dialkylbenzotriazolium salts are also formed (Scheme239). 1-Substituted 3-methyl-3H-benzotriazol-1-ium iodides 785 are prepared in low togood yields by the reaction of 1-substituted 1H-benzotriazoles with iodomethane (Scheme292).[754]
13.13.5 1,2,3-Triazolium Salts 583
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 292 Methylation of 1-Substituted 1H-Benzotriazoles[754]
785
NN
N
R1
MeI, toluene, sealed tube
80 oC, 16−72 h
R1 = CH2SPh 65%
R1 = CH2SOPh 82%
R1 = CH2SO2Ph 35%
NN
N
R1
Me
I−
+
Alkylation of 1-[(dialkylamino)methyl]-1H-benzotriazoles 786 leads to the formation of(1H-benzotriazol-1-ylmethyl)ammonium salts 787 (Scheme 293).[755] This reaction is limit-ed to iodomethane, iodoethane, and 1-(chloromethyl)-1H-benzotriazole. Methyl 4-tolu-enesulfonate can also be used but reacts only with 1-(pyrrolidin-1-ylmethyl)-1H-benzotri-azole [786, R1,R2 = (CH2)4]. In some cases, the 1,3-dialkylbenzotriazolium salts 790 are ob-tained. Indeed, when 1-(pyrrolidin-1-ylmethyl)-1H-benzotriazole [786, R1,R2 = (CH2)4] isheated with benzyl bromide in a sealed tube at 60–80 8C, 1,3-dibenzyl-3H-benzotriazol-1-ium bromide (790, R3 = Bn; X = Br) is obtained in 65% yield.[755] The explanation for the for-mation of salts 790 depends on the fact that compounds 786, in solution, are in equilibri-um with the ion pair 788, which reacts with the alkylating agent to form successively 1-alkyl-1H-benzotriazole 789 and then 790.
Scheme 293 Alkylation of 1-[(Dialkylamino)methyl]-1H-benzotriazoles[755]
786
NN
NR3X
40−60%X−
+NR1R2
NN
N
N
787
R1,R2 = (CH2)4
NN
N
−
NH2C
R1
R2
R3X
788
+
NN
N
R3
R3X
NN
N
R3
R3
X−
+
789 790 R3 = Bn; X = Br 65%
R1
R3
R2
Ethyl 1H-benzotriazole-1-carboxylate reacts with triethyloxonium tetrafluoroborate toyield the corresponding 3-(ethoxycarbonyl)-1-ethyl-3H-benzotriazol-1-ium salt (seeScheme 240).[634]
Alkylation of benzotriazole with bis(bromomethyl)benzenes (1,2-, 1,3- or 1,4-) in twosteps affords the benzotriazolophanes 791 (Scheme 294).[674] The symmetrical benzotri-azolophanes 792, 793, and 794 are prepared in a similar manner.[674,675]
584 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
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bScheme 294 Synthesis of Symmetrical Benzotriazolophanes[674]
NH
NN
2Br−
+
791
Br
BrNaOH, MeCN, rt, 2 d
1,2-xylenyl 65%
1,3-xylenyl 60%
1,4-xylenyl 71%
NN
N
NN
N
NN
N
Br
BrMeCN, reflux, 5 d
1,2-xylenyl 42%
1,3-xylenyl 40%
1,4-xylenyl 55%
+
N
NN
2Br−
792
+NN
N
NN
N
+
N
N
+NN
N
+NN
N2Br−
793
+NN
N
+NN
N2Br−
794
The unsymmetrical benzotriazolophanes 796 and 797 are obtained by alkylation of theprecyclophane 795 with the corresponding bis(bromomethyl)benzene derivatives(Scheme 295).[675]
13.13.5 1,2,3-Triazolium Salts 585
for references see p 587
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bScheme 295 Synthesis of Unsymmetrical Benzotriazolophanes[675]
N
+NN
N
+NN
N2Br−
796
OMe
N
NN
N
NN
N
795
BrBr
OMe
MeCN, reflux, 5 d
59%
N
+NN
N
+NN
N2Br−
797
NO2
N
NN
N
NN
N
795
52%
OHBrBr
NO2
MeCN, reflux, 5 d
OH
1-Ethyl-1H-benzotriazole reacts with tetracyanoethene oxide, at room temperature, toyield 3-ethyl-3H-benzotriazol-1-ium-1-dicyanomethanide 798 (Scheme 296).[753]
Scheme 296 Reaction of 1-Ethyl-1H-benzotriazole with Tetracyanoethene Oxide[753]
Et
Et2O
rt, 24 h
798 21%
ONC CN
CNNC
+
−
+
+ O
CN
CN
NN
N
EtN
NN
NCCN
586 Science of Synthesis 13.13 1,2,3-Triazoles
A. C. Tom�, Section 13.13, Science of Synthesis, � 2004 Georg Thieme Verlag KG
FOR PERSONAL USE ONLY
bReferences
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