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.

4

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.

7

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.

8

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.

10

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