Synthesis of pyrazoles from 2-azidoacrylates and hydrazonyl chlorides
Transcript of Synthesis of pyrazoles from 2-azidoacrylates and hydrazonyl chlorides
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Tetrahedron Letters 52 (2011) 4161–4163
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Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Synthesis of pyrazoles from 2-azidoacrylates and hydrazonyl chlorides
Yao Li, Deng Hong, Ping Lu ⇑, Yanguang Wang ⇑Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o a b s t r a c t
Article history:Received 24 April 2011Revised 24 May 2011Accepted 31 May 2011Available online 12 June 2011
Keywords:2-AzidoacrylatesHydrazonyl chloridesPyrazolesCycloaddition
0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.05.147
⇑ Corresponding authors. Tel./fax: +86 571 8795151E-mail addresses: [email protected] (P. Lu), orgwy
A regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles is established between 2-azidoacrylatesand hydrazonyl chlorides in the presence of triethylamine. The yields are moderate (43–73%) and a pos-sible mechanism for this transformation is postulated.
� 2011 Elsevier Ltd. All rights reserved.
1. Introduction adding triethylamine to a solution of ethyl 2-azido-3-phenylacry-0
As an important type of nitrogen-containing heterocycle, pyra-zole has been employed as a key structural motif, which widely ex-ists in nature and behaves with excellent biological activity inpharmaceuticals, such as celebrex,1 viagra2 and rimonabant.3 Inaddition, 1,3,4,5-tetrasubstituted pyrazoles exhibited intenseluminescence in solid states which might be used for optoelec-tronic devices,4 such as organic light emitting diodes, organic light-ening, and so on. Thus, lots of synthetic routes5 leading topyrazoles have been established. As a typical example amongestablished methods, 1,3-dipolar cycloaddition between hydrazo-nyl chlorides and alkynes6 or alkyne alternatives7 presented its un-ique convenience and effectiveness. In these cases, alkynealternatives are normally alkenes bearing a good leaving group.8
With respect to the interesting chemistry of 2-azidoacrylates,9
we have efficiently constructed indoles,10a isoquinolines,10b andtriazolines,10c respectively. Meanwhile, we realized that hydrazo-nyl chlorides11 could generate active nitrilimine in situ and partic-ipate in 1,3-dipolar cycloaddition with an alkyne alternative.Combining these two key features, we tested the reaction between2-azidoacrylates and hydrazonyl chlorides in the presence of base.Fortunately, a series of 1,3,4,5-tetrasubstituted pyrazoles are ob-tained with high regioselectivity. Crystal analysis of 3c further con-firmed pyrazole structure with multi-substituents (Fig. 1).
2. Results and discussion
zAs we mentioned above, hydrazonyl chlorides could be trans-ferred into nitrilimines in the presence of base.12 Our initial test is
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[email protected] (Y. Wang).
late (1a) and N -phenylbenzohydrazonoyl chloride (2a) in tetrahy-drofuran (Table 1, entry 1). No main product was detectedalthough both starting materials disappeared based on TLC track-ing. Similar observation was seen when toluene was used as thesolvent (Table 1, entry 2). By changing the solvent to N,N-dimethyl-foramide (Table 1, entry 3), 1,3,4,5-tetrasubstituted pyrazole (3a)was isolated in 20% yield. To our delight, the yields could be signif-icantly improved by applying methylene chloride or acetonitrile asthe solvent (Table 1, entries 4 and 5). Alternating triethylamine toCs2CO3 or K2CO3, yields were decreased apparently (Table 1, entries6 and 7). Pyridine did not work for this transformation (Table 1,
Figure 1. X-ray crystal structure of 3c.
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PhCl
NN
PhEt3N
H
Ph
NN
Ph
Ph
N COOEt
N2
Ph
NNPh
NCOOEt
HPh
N N
Ph
NNPh
COOEt
Ph
-Et3N HCl
Et3N
-Et3N HN3
1a2a AB
3a
Scheme 1. Possible mechanism for this reaction.
Table 1Screening for the reaction conditionsa
NHNPh
Cl
NNPh Ph
COOEtPh
+ Ph1a 2a 3a
Et3N
CH3CN
PhCOOEt
N3rt,12 h
Entry Solvent Reaction temperature (�C) Base Yieldb (%)
1 THF 25 Et3N 02 PhMe 25 Et3N Trace3 DMF 25 Et3N 204 CH2Cl2 25 Et3N 695 CH3CN 25 Et3N 71
6c CH3CN 25 Cs2CO3 647d CH3CN 25 K2CO3 588 CH3CN 25 Pyridine 0
9c CH3CN 50 Et3N 5210e CH3CN 80 Et3N 4711f CH3CN 25 Et3N 5212g CH3CN 25 Et3N 7213h CH3CN 25 Et3N 67
a Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), base (1.75 mmol), solvent(8 mL), 12 h.
b Isolated yields referred to 1a.c Reaction was performed for 8 h.d Reaction was performed for 10 h.e Reaction was performed for 6 h.f Compound 1a (0.5 mmol), 2a (1 mmol), base (1.5 mmol).g Compound 1a (0.5 mmol), 2a (1.5 mmol), base (2.0 mmol).h Compound 1a (0.5 mmol), 2a (1.25 mmol), base (2.0 mmol).
4162 Y. Li et al. / Tetrahedron Letters 52 (2011) 4161–4163
entry 8). By raising the reaction temperature to 50 or 80 �C, short-ening the reaction time accordingly as indicated in the notes of Ta-ble 1, yields were influenced (Table 1, entries 9 and 10). Besidesthese variations, the suitable ratio of starting materials to base(1a:2a:Et3N) was found to be 1:2.5:3.5 (Table 1, entries 11–13) con-sidering both yields and benign to environment.
With the optimized reaction conditions in hand, we subse-quently examined the scope of this transformation. A number ofsubstituted hydrazonyl chlorides (2a–h) (Table 2, entries 1–8)were tested and found to tolerate the reaction. No significant sub-stituent effect was observed for component 2. Compounds 3a–hwere prepared in yields between 56% and 73% accordingly. Simi-
Table 2Scope of the reactiona
NHNR3
Cl
NNR2 R3
COOEtR1
+ R2
1 2 3
Et3N, CH3CNR1COOEt
N3 25oC, 12h
Entry 1 (R1) 2 (R2/R3) 3 Yieldb (%)
1 1a (C6H5) 2a (C6H5/C6H5) 3a 712 1a 2b (4-MeC6H4/C6H5) 3b 633 1a 2c (4-MeOC6H4/C6H5) 3c 564 1a 2d (4-BrC6H4/C6H5) 3d 735 1a 2e (2-ClC6H4/C6H5) 3e 696 1a 2f (C6H5/4-MeC6H4) 3f 627 1a 2g (C6H5/2-ClC6H4) 3g 668 1a 2h (C6H5/4-ClC6H4) 3h 619 1b (4-MeOC6H4) 2a 3i 66
10 1c (4-MeC6H4) 2a 3j 6211 1d (4-ClC6H4) 2a 3k 7012 1e (3-NO2C6H4) 2a 3l 6713 1f (4-PhC6H4) 2a 3m 7214 1g (2-naphthyl) 2a 3n 6215 1a 2i (i-Pr/C6H5) 3o 43
a Reaction conditions: 1 (0.5 mmol), 2 (1.25 mmol), Et3N (1.75 mmol), CH3CN(8 mL).
b Isolated yields referred to 1.
larly, either electron donating or electron withdrawing on aryl partof 2-azido-3-aryllacrylate (1a–g) (Table 2, entries 1, 9–14) did notaffect reactions and afforded the desired products (3a, 3i–n)smoothly. When R2 in substrate 2 was the alkyl group (Table 2, en-try 15), the desired product 3o was obtained in lower yield.
Based on the investigations of reaction condition and substratediversity, a possible mechanism for this reaction is described inScheme 1. At the beginning, nitrilimines A, generated in situ from2a by treatment with triethylamine, reacted with 1a to form inter-mediate B via [3+2] cycloaddition reaction with high regioselectiv-ity. Aromatization of the resulting heterocycle B by kicking offhydrogen azide assisted by triethylamine constructed the finalproduct 3a.
In conclusion, we have developed an efficient method to con-struct tetrasubstituted pyrazoles from 2-azidoacrylates and hyd-razonyl chlorides in moderate to good yields.13 Reactions arecarried under mild condition and with high regioselectivity. A rea-sonable mechanism, including [3+2] cycloaddition was postulated.
Acknowledgment
Ping Lu and Yanguang Wang thank the National Nature ScienceFoundation of China (Nos. 21032005 and 20972137) for financialsupport.
Supplementary data
Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.05.147.
References and notes
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