Sulfonyl-1,2,3-Triazoles : Convenient Synthones for Heterocyclic Compounds
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Sulfonyl-1,2,3-Triazoles : Convenient Sulfonyl-1,2,3-Triazoles : Convenient Synthones for Heterocyclic CompoundsSynthones for Heterocyclic Compounds
Michaël RaymondMichaël RaymondLiterature Meeting PresentationLiterature Meeting Presentation
Université de MontréalUniversité de MontréalOctober 16October 16thth, 2013, 2013
Zibinsky, M. and Fokin, V. V. Angew. Chem. Int. Ed. 2013, 52, 1507-1510.
NN
N
R1
SO2R4R3N
R2
RhII, -N2
-R5SO2H
NN
R1
R3
R2O R2
RhII, -N2
NO
R1
SO2R5
R2
R1 = Ar; R2, R4 = Ar, alkyl R1 = Ar; R4 = Me, R2, R3 = Ar
Valery V. Fokin
2
1. Associate Professor at The Scripps Research Institute – La Jolla, California
2. B. Sc. Calvin College, Geneva, in 1993
3. M. Sc. University of Nizhny Novgorod, Russia
4. Ph. D. University of Southern California in 1998
5. Post-Doc with K. Barry Sharpless from 1999-2001 at The Scripps Research Institute – La Jolla, California
6. Author with K. Barry Sharpless and M. G. Finn of the ‘’Click Chemistry’’
7. Author of more than 60 publications in the past 10 years
Research Interests
3
2. Studies on the Copper-Catalysed Azide-Alkyne Cycloaddition (CuAAC) and the Ruthenium-Catalysed Azide-Alkyne Cycloadditon (RuAAC), or ‘’Click Reaction’’.
1. Discovery of new catalytic transformations and applying them to the studies of macromolecular and biological phenomena.
3. Catalytic transformations of 1,2,3-triazoles which proceeds via transition metal aza-vinyl carbene species.
4. Studies of dendrimers and dendritic probes for cellular and organismal imaging and targeted drug delivery.
5. Discovery of novel polymeric materials.
1,2,3-Triazoles
(a) Shafran, E. A.; Bakulev, V. A.; Rozin, Y. A. and Shafran, Y. M. Chem. Heterocycl. Comp. 2008, 44, 1040. (b) Xu, W. L.; Li, Y. Z.; Zhang, Q. S. and Zhu, H. S. J. Synth. Org. Chem. 2005, 3, 442.
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NN
N
R1
R2
R3
1. Robust heterocyclic aromatic molecules.
2. Stable to thermal decomposition.
3. Stable to oxidative and reductive conditions.
4. Building blocks for many pharmaceutical drugs such as tazobactam.
N
S
O
O O
CO2H
H
NN
N
1,2,3-Triazoles Synthesis
(a) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry (Ed.: Padwa, A.) Wiley, New-York, 1984, pp 1-176. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V. and Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. (c) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovstev, V. V.; Noodleman, L.; Sharpless, K. B. and Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
5
1. Huisgen 1,3-dipolar cycloaddition of alkynes to azides is a basic synthetic route to triazoles but elevated temperatures and mixtures of regioisomers obtained limit its application.
PhON3 Ph
neat
high temperature, 18h
NN
N
PhO
Ph NN
N
PhO
Ph
2. Copper Catalyzed Azide-Alkyne Cycloaddition (CuAAC), known as ‘Click’ reaction, first developed by Sharpless served to reinvigorated research interest in triazoles synthesis and helped to acquired regioselectivity and expand the scope of the substitutions around the triazole ring system.
R1 N3 R2
CuSO4.5H2O (0.25-2 mol%)Sodium ascorbate (5-10 mol%)
H2O/tBuOH (1:1), RT, 6-12h84-98%
R1N
NN
R2
R1 = Ph, CO2H
R2 = alkyl, CH2OBn
Click Mechanism
6Rostovtsev, V. V.; Green, L. G.; Fokin, V. V. and Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599. (b) Worrell, B. T. and Fokin, V. V. Science, 2013, 340, 457-460.
LnCu +
R1 CuLn
NN
NR2
NN
N R2
R1 CuLn
NN
N R2
R1
R1 H
NN
NR2
CuLnR1
NN
N
CuLn
R2
R1
H+
1,2,3-Triazoles Ring Opening
(a) Dimroth, O. Ann. 1909, 364, 183. (b) Gilchrist, T. L. and Gymer, G. E. Adv. Heterocycl. Chem. 1974, 16, 33. (c) Raushel, J. and Fokin, V. V. Org. Lett. 2010, 12, 4952-4955. (d) Harmon, R. E.; Stanley, F. J.; Gepta, S. and Johnson, J. J. Org. Chem. 1970, 35, 3444-3448.
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1. Electron withdrawing groups on N1 such as cyano, nitro or sulfonyl are known to favor opening of stable 1,2,3-triazoles to its diazoimine tautomers.
R1N
NN
EWG
R2R1
N EWG
R2
N
NIf R2 = NH2
Dimroth Rearrangement
R1NH
NN
NHEWG
3. Sulfonylazides give access to an easily opened 1,2,3-triazole ring system.
Me
SN3
O O
H PhCuTC (10 mol%)
Toluene (0.2M)RT, 15h
98%
N NN
PhS
OO
Me
CuTC =
S COO- Cu+
2. Diazoketones are more stable than diazoimines.
R2
O
Stable
Versus R1N
NN
R3
R2
N
R1
N
R2
N
N
R1
N
R3
More stable
Metal Carbenoids from Vinyl Diazoimines
(a) Regitz, M. Angew. Chem. Int. Ed. 1967, 79, 786. (b) Chuprakov, S.; Hwang, F. W. and Gevorgyan, V. Angew. Chem. Int. Ed. 2007, 46, 4757-4759. (c) Fu, G. C. In Modern Rhodium Catalsed Organic Reactions; Evans, D. A., Ed.; VCH; Weinheim, Germany, 2005, pp. 79. (d) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V. and Fokin, V. V. J. Am. Chem Soc. 2008, 130, 14972-14974.
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2. 1-Sulfonyl triazoles : precursors to metal carbenoids which are synthetic equivalents of α-diazoaldehydes.
R1
MLn
N
H
SO2R2 R1
N2
N
H
SO2R2
LnM LnMVersus
R1
N2
O
H
R1
MLn
O
H
1. Equilibrium of 2-pyridyl diazo compounds bearing an electron withdrawing group from their cyclic triazole form allows transformations characteristic of diazoketones.
N NN
CO2Me
R
N
CO2Me
R
N2
Rh2(OAc)4 (1 mol%)Et3SiH (2 equiv.)
CH2Cl2, RTN
R
SiEt3
If R = H, no reactionIf R = Cl, 88%
CO2Me
3. Fokin’s utilization of sulfonyl triazoles in synthesis : Transannulation with nitriles
R1N
NN
SO2R2
n-C7H15O
O
Rh
Rn
4
Rh2(oct)4
Rh-cat.
R1
Rh
NSO2R2
N R3
R1N
N
SO2R2
Rh-cat.:R3
CHCl3, uw15min., 140oC
Mechanism of Transannulation of 1,2,3-Triazoles with Nitriles
Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V. and Fokin, V. V. J. Am. Chem Soc. 2008, 130, 14972-14974. 9
1. Rh-carbene catalyzed ring opening and azavinyl carbene formation
R1N
NN
SO2R2
Rh
R1N
NN
SO2R2
Rh
R1
Rh
NSO2R2
N2
2. Path A
3. Path B : 3+2 cycloaddtion
R1
Rh
NSO2R2
R3
N
R1N SO2R2
R1N
N
SO2R2
R3
R1N
N
SO2R2
R3
N
R3
Rh RhR1
NN
SO2R2
R3
Rh- Rh
R1
Rh
NSO2R2
N
R3
R1N
N
SO2R2
R3
R1N
N
SO2R2
R3
Rh- Rh
R1N
NN
SO2R2
n-C7H15O
O
Rh
Rn
4
Rh2(oct)4
Rh-cat.
R1
Rh
NSO2R2
N R3
R1N
N
SO2R2
Rh-cat.:R3
CHCl3, uw15min., 140oC
Applications of Metal Vinyl Carbenoids
(a) Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L. and Fokin, V. V. J. Am. Chem. Soc. 2009, 131, 18034-18035. (b) Miura, T.; Yamauchi, M. and Murakami, M. Chem. Commun. 2009, 1470-1471. (c) Chuprakov,, S.; Malik, J. A.; Zibinsky, M. and Fokin, V. V. J. Am. Chem. Soc. 2011, 133, 10352-10355.
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1. Cyclopropanation of olefins.
R1N
NN
MsR2
1. Rh2(S-nttl)4 (0.5 mol%)
1,2-DCE, 65 oC
2. K2CO3, H2OMeOH, RT
O
R2
R1H N
O
OO
O
Rh
Rn
4
Rh2 (S)-nttl 4
2. Nickel(0)-catalyzed alkyne insertions.
R1N
NN
SO2R2
R3
R4
Ni(cod)2 (10 mol%)P(n-Bu)Ad2 (20 mol%)
AlPh3 (5 mol%)
Toluene, 100 oC, 12h R1
N
R4/3
R3/4
SO2R2
3. Asymmetric C-H insertions.
PhN
NN
Ms
R3HR2
R1
1. Rh2(S-nttl)4 (0.5 mol%)CHCl3, rt
2. LiAlH4 (1.2 equiv.), 0 oC
63-95%, 91-94%eePh
R1 R3R2
NH
Ms
1,3-Dipolar Cycloadditions Versus Intramolecular Cyclization : This Work
De Angelis, A.; Taylor, M. T. and Fox, J. M. J. Am. Chem. Soc. 2009, 131,1101-1105. 11
1. Reactivity expected with a rhodium catalyst : 1,3-dipolar cycloaddition.
2. New Reactivity : Intramolecular Cyclization to form 3-sulfonyl-4-oxazolines and 1,2,5-trisubstituted imidazoles.
R2O
R1N2
OR4
R3
M
-N2
R2O
R1O
R4R3
R6
R5
O
R3
R4
R1R2
O
R5/6
R5/6
ON SO2R5
R1
Rh-
R2
+RhII (1 mol%)
CHCl3, R2CHO
RT, 3-12h
R1N
NN
SO2R5R1
NO
SO2R5
R2
NN SO2Me
R1
Rh-
R3
+NNN
R1SO2Me R3N
R2
2) DBU (1.5 equiv), 120 oC, 1 min
1) RhII (1 mol%)
CHCl3, 120 oC, 5-10 min R2
NN
R1
R3
R2
Optimization of the Reaction for the Synthesis of 3-Sulfonyl-4-Oxazolines
12
ON SO2R5
PhRh-
Ph
+
RhII (1 mol%)
CHCl3, PhCHOPhN
NN
SO2R5
PhN
O
SO2R5
Ph
NO
OO
O
Rh
Rn
4
Rh2 (S)-nttl 4
N O
O
Rh
Rn
4
Rh2 (S)-ptad 4
O
O
O
O
Rh
Rn
4
Rh2(piv)4
n-C7H15O
O
Rh
Rn
4
Rh2(oct)4
Entry R5 Catalyst Temp. Time Yield ee (oC) (h) (%) (%)
1 Me Rh2(oct)4 100 0.15 61 -
2 Me Rh2(piv)4 100 0.15 83 -
3 Me Rh2(piv)4 RT 12 82 -
4 Me Rh2((S)-nttl)4 RT 12 75 88
5 Me Rh2((S)-nttl)4 40 9 80 73
6 Me Rh2((S)-ptad)4 RT 12 70 45
7 C6H4Me Rh2((S)-nttl)4 RT 48 ‹50 -
8 C6H4Me Rh2((S)-ptad)4 RT 12 82 55
Entry R5 Catalyst Temp. Time Yield ee (oC) (h) (%) (%)
1 Me Rh2(oct)4 100 0.15 61 -
2 Me Rh2(piv)4 100 0.15 83 -
3 Me Rh2(piv)4 RT 12 82 -
4 Me Rh2((S)-nttl)4 RT 12 75 88
5 Me Rh2((S)-nttl)4 40 9 80 73
6 Me Rh2((S)-ptad)4 RT 12 70 45
7 C6H4Me Rh2((S)-nttl)4 RT 48 ‹50 -
8 C6H4Me Rh2((S)-ptad)4 RT 12 82 55
Entry R5 Catalyst Temp. Time Yield ee (oC) (h) (%) (%)
1 Me Rh2(oct)4 100 0.15 61 -
2 Me Rh2(piv)4 100 0.15 83 -
3 Me Rh2(piv)4 RT 12 82 -
4 Me Rh2((S)-nttl)4 RT 12 75 88
5 Me Rh2((S)-nttl)4 40 9 80 73
6 Me Rh2((S)-ptad)4 RT 12 70 45
7 C6H4Me Rh2((S)-nttl)4 RT 48 ‹50 -
8 C6H4Me Rh2((S)-ptad)4 RT 12 82 55
Reaction Scope for 3-Sulfonyl-4-Oxazolines with Respect to R2
13
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
NN
NPh
Ms
O R2Rh2 (S)-nttl 4
(1 mol%)
CHCl3, RT, 3-12h N
OPh
Ms
R2
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
O2N
NO2
OMe
75%, 88% ee 75%, 86% ee 95%, 85% ee 98%, 80% ee
N
OPh
MsN
OPh
Ms
N
OPh
MsN
OPh
Ms
N
OPh
Ms
95%, 90% ee 90%, 90% ee 88%, 90% ee 90%, 92% d.r.
78%, 80% ee
CO2MeO
CN
N
OPh
MsN
OPh
MsN
OPh
Ms
89%, 89% ee 98%, 80% ee 96%, 95% ee
OTBS
N
OPh
Ms Br
95%, 80% ee
N
OPh
Ms
74%, 96% ee
7
Reaction Scope for 3-Sulfonyl-4-Oxazolines with Respect to R1
14
O
Rh2 (S)-nttl 4 (1 mol%)
CHCl3, RT, 3-12hCF3
R1N
NN
SO2Me
R1N
O
SO2R5
CF3
Entry R1 Yield Ee (%) (%)
1 Ph 85 92
2 4-CF3C6H4 86 92
3 4-MeC6H4 97 94
4 4-MeOC6H4 93 885 3-thiophenyl 91 80
6 n-C5H11 Trace -
Mechanism for 3-Sulfonyl-4-Oxazolines Synthesis
15
R1
Rh
N
RhII
R1N
O
R2
SO2R5SO2R5
Rh-
O R2
OR1 R2
N
SO2R5
R1N
OR2
SO2R5 R1N
NN
SO2R5
N2
RhII (1 mol%)
CHCl3, R2CHOR1N
NN
SO2R5
PhN
O
SO2R5
R2
Prolonged reaction times reduce enantioselectivity
R1N
OR2
SO2R5
R1N
OR2
SO2R5
R1N
OR2
SO2R5
Mechanism for 1,2,5-Trisubstituted Imidazoles Synthesis
16
R1
Rh
N
RhII
R1N
N
R3
SO2Me SO2MeRh-
R1N
NR3
R1N
NN
SO2Me
R3NR2
R2
R1N
N
S
R2
O
Me
O
R3H
R2
N2
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
Reaction Scope for 1,2,5-Trisubstituted Imidazoles
17
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
NN
NN
NN
Br
NN
Br
F3C
NN
Br
S
NN
Br
71%78% 85% 65%
NN
Br Br
MeO MeO90% 89%
NN
NN
NN
CN OMe F
Br Br Br
73% 66% 65% 72%
NO2
NN
F3C
80%
NN
MeO
54%
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
NN
NN
NN
Br
NN
Br
F3C
NN
Br
S
NN
Br
71%78% 85% 65%
NN
Br Br
MeO MeO90% 89%
NN
NN
NN
CN OMe F
Br Br Br
73% 66% 65% 72%
NO2
NN
F3C
80%
NN
MeO
54%
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
NN
NN
NN
Br
NN
Br
F3C
NN
Br
S
NN
Br
71%78% 85% 65%
NN
Br Br
MeO MeO90% 89%
NN
NN
NN
CN OMe F
Br Br Br
73% 66% 65% 72%
NO2
NN
F3C
80%
NN
MeO
54%
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
NN
NN
NN
Br
NN
Br
F3C
NN
Br
S
NN
Br
71%78% 85% 65%
NN
Br Br
MeO MeO90% 89%
NN
NN
NN
CN OMe F
Br Br Br
73% 66% 65% 72%
NO2
NN
F3C
80%
NN
MeO
54%
2) DBU (1.5 equiv), 120 oC, 1 minN
NN
R1Ms R3N
R2 NN
R1
R3
R2Rh2(piv)4 (1 mol%)
CHCl3, 120 oC, 5-10 min
1)
NN
NN
NN
Br
NN
Br
F3C
NN
Br
S
NN
Br
71%78% 85% 65%
NN
Br Br
MeO MeO90% 89%
NN
NN
NN
CN OMe F
Br Br Br
73% 66% 65% 72%
NO2
NN
F3C
80%
NN
MeO
54%
Conclusions
18
1. Development of a new asymmetric intramolecular cyclization to form 3 sulfonyl-4-oxazolines using a rhodium catalyzed ring opening of sulfonyl-1,2,3-triazoles giving high yields and ee.
2. Development of a new asymmetric intramolecular cyclization to form 1,2,5-sulfonyl imidazoles using a rhodium catalyzed ring opening of sulfonyl-1,2,3-triazoles giving high yields.
ON SO2R5
R1
Rh-
R2
+RhII (1 mol%)
CHCl3, R2CHO
75-98% yield80-96%ee
R1N
NN
SO2R5R1
NO
SO2R5
R2
(14 examples)
NN SO2R5
R1
Rh-
R3
+NNN
R1SO2Me R3N
R2
2) DBU (1.5 equiv), 120 oC, 1 min
1) RhII (1 mol%)
CHCl3, 120 oC, 5-10 min R2
NN
R1
R3
R2
(12 examples)54-94% yield