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LCMT. Patrick Metzner group. Annie-Claude Gaumont group. Vincent Reboul. Synthesis and reactivity of enantiopur cyclic sulfenamides. Easy access to 1,4-benzothiazepines and 1,3-benzothiazines. Cédric Spitz. 09/11/2010.

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Patrick metzner group

LCMT

Patrick Metzner group

Annie-Claude Gaumont group

Vincent Reboul


Patrick metzner group

Synthesis and reactivity of enantiopur cyclic sulfenamides. Easy access to 1,4-benzothiazepines and 1,3-benzothiazines

Cédric Spitz

09/11/2010

Supervisors : M. Patrick Metzner, Directeur de recherche au CNRS, (LCMT-ENSICAEN)

M. Vincent Reboul, Maître de conférences, Université de Caen, (LCMT-ENSICAEN)

Laboratoire de Chimie Moléculaire et Thioorganique, UMR CNRS 6507, ENSICAEN-Université de Caen

6 Boulevard du Maréchal Juin, 14050 Caen, France.


Patrick metzner group

  • Lone pairs of the sulfur atom adjacent to nitrogen ( effect)

S-N : Supernucleophile?

Introduction

Introduction

Sulfenamide

Sulfinamide

Sulfonamide

  • Electronegativity difference : S electrophile and N nucleophile

Sulfenamides reviews : (1) Craine, L.; Raban M. Chem. Rev. 1989, 89, 689-712. (2) Davis, F. A. Int. J. Sulfur Chem. 1973, 8, 71-81.

 Effect : Buncel E.; Um I.-H. Tetrahedron, 2004, 60, 7801-7825.


Patrick metzner group

Goerdeler, H.; Holst, A. Angew. Chem.1959, 71, 775-788.

Kuniyasu, H.; Hiraike, H.; Morita, M.; Tanaka, A.; Sugoh, K.; Kurosawa, H. J. Org. Chem.1999, 64, 7305‑7308.

Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem.2005, 117, 804-807.

Matsuo, J.-I.; Iida, D.; Yamanaka, H.; Mukaiyama, T. Tetrahedron2003, 59, 6739-6750.

Sulfenamides reactivity

Introduction

Caserio, M. C.; Kim, J. K. J. Am. Chem. Soc.1982, 104, 3231-3233.

Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett.2004, 45, 1469-1471.

Reviews on sulfenamide reactivity : (1) N. E. Heimer, L. Field J. Org. Chem., 1970, 3102-3022.

(2) L. Craine, M. Raban Chem. Rev. 1989, 89, 689-712.


Patrick metzner group

  • Action mecanism of « proton pump inhibitors »

Omeprazole (racemic) : Mopral-Losec/Astra-Zeneca

Esomeprazole (S) : Inexium/Astra-Zeneca (2001)

Global sales in 2006 :

6700 billions $ !

Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc.2004, 126, 7800-7811.

Sulfenamides applications

Introduction

  • Vulcanization

S8


Patrick metzner group

Use of sulfenamides

Introduction

- Aims: Synthesis of 1,4-benzothiazepines

Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett. 2004,45,1469-1471.

Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem.2006, 71, 2609-2616.


Patrick metzner group

Atheroma2

(accumulation and swelling in artery walls )

Hyperlipidemia3

(abnormally elevated levels of lipids in the blood)

Obesity3

Diabetes4

Cirrhosis of the liver

(2) Brieaddy, L. E. WO Patent 016055, 1993.

(3) (a) Brieaddy, L. E. WO Patent 005188, 1996. (b) Sasahara, T.; Mohri, M. WO Patent 020421, 2004. (c) Starke, I.; Alenfalk, S.; Nordberg, M. P.; Dahlstrom, M. U. J.; Bostrom, S. J. Lemurell, M. A.; Wallberg, A. C. WO Patent 076430, 2004. (d) Sasahara, T.; Mohri, M.; Kasahara, K.I. WO Patent 082874, 2005. (e) Frick, W.; Glombik, H.; Heuer, H.; Schaefer, H.-L.; Theis, S. WO Patent 009655, 2007.

(4) Nagase, T.; Sato, Y.; Eiki, J. WO Patent 053548, 2002.

Use of sulfenamides

Introduction

- Access to 1,4-benzothiazepines

-1,1-dioxydes

Heart attack1

(1) (a) Kaneko, N. WO Patent 105793, 2005. (b) Kaneko, N.; Oosawa, T.; Sakai, T.; Oota, H. WO Patent 012148, 1992. (c) Marks, A. R.; Lehnart, S. E. WO Patent 021439, 2008. (d) Marks, A. R.; Landry, D. W.; Deng, S.; Cheng, Z. Z. WO Patent 101496, 2006.


Patrick metzner group

Summary

I/ Synthesis of cyclicsulfenamides

II/ Synthesis of 2,3-disubstituted1,4-benzothiazepines

III/ Synthesis of 1,3-benzothiazines

IV/ Synthesis of 2-substituted1,4-benzothiazepines


Patrick metzner group

Summary

I/ Synthesis of cyclicsulfenamides

II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines

III/ Synthesi of 1,3-benzothiazines

IV/ Synthesis of 2-substituted 1,4-benzothiazepines


Patrick metzner group

 Synthesis of sulfoxides

Blum, S. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150-155.

Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem.2006, 71, 2609-2616.

Synthesis of precursors

Chapitre 1

 Synthesis of imines

Kanazawa, A. M.; Denis, J.-N.; Greene A. E. J. Org. Chem.1994,59, 1238-1240.


Patrick metzner group

and cyclization

Sulfenamides

Rdt (%)

96

97

99

98

98

98

99

Quantitative cyclization of sulfenamides

95

Synthesis of cyclic sulfenamides

Chapitre 1

 Addition of sulfoxides to imines

Alkyl imines :

Total asymetric induction

Aryl imines :

d.r. ≈ 80/20

N. Le Fur

a Déterminé par RMN 1H sur le brut réactionnel

Le Fur, N.; Mojovic, L.; Plé, N.; Turck, A.; Reboul, V.; Metzner, P. J. Org. Chem.2006, 71, 2609-2616.


Patrick metzner group

X-Ray Structure

Chapitre 1

Jean-François Lohier


Patrick metzner group

Conclusion

Chapitre 1

Synthesis of 8 benzisothiazolines with good yields (from 36 to 62%) over 3 steps from Ellman’s thiosulfinate

  • total asymetric induction for alkyl imines

  • d.r. = 80/20 for aryl imines

  • R2 = EWG(Ts, Boc, SES)

 Reactivity of cyclic sulfenamides?


Patrick metzner group

Summary

I/ Synthesis of cyclicsulfenamides

II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines

III/ Synthesis of 1,3-benzothiazines

IV/ Synthesis of 2-substituted1,4-benzothiazepines


Patrick metzner group

 Application to the synthesis of 1,4-benzothiazepines

  • 1st step :nucleophilic attack of nitrogen of sulfenamideto alkyne

Reactivity of sulfenamides

Chapitre 2

 Bibliography

Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett.2004, 45, 1469-1471.


Patrick metzner group

Reactivity of sulfenamides

Chapitre 2

 Nitrogen nucleophilic despite EWG?

 Deprotection of sulfenamide


Patrick metzner group

Catalyst (mol%)

Solventa

T

(°C)

Time (h)

(R)-19a

(Yield)

-

CH3CN ou DMF

60 ou 100

14

0

DPPP (20)

CH2Cl2

20

14

12

DPPP (100)

CH3CN ou toluene

60

14

16

PMe3 (100)

CH2Cl2

40

14

35

PPh3 (100)

CH2Cl2

40

14

70

PPh3 (25)

CH2Cl2

40

14

12

PPh3 (25)

CH3CN

60

4

14

DABCO (20)

CH3CN

60

14

21

a All reactions were carried out at 0.1 M concentration using 2 equivalents of DMAD.

Phosphines or amines catalysis

Chapitre 2

 Use of sulfur electrophilie


Patrick metzner group

 Use of sulfur electrophilie

  • optimized

  • conditions

Catalyst (mol%)

Solvent

Concentration

T (°C)

Time (h)

19a(Yield)

CsF (10)

CH3CN

0,1

20

24

0

CsF (200)

CH3CN

0,1

20

4

60

CsF (200)

CH3CN

0,1

60

0,5

73

TBAF (200)

CH3CN

0,1

60

0,5

37

CsF (200)

CH3CN

0,02

60

0,5

88

CsF (25)

CH3CN

0,02

60

0,5

81

CsF (10)a

CH3CN

0,02

60

2

86

A slow addition of DMAD over 30 min.

Fluoride catalysis

Chapitre 2

  • bibliography

Gorgues, A.; Stéphan, D.; Cousseau, J. J. Chem. Soc., Chem. Commun.1989, 1493-1494.


Patrick metzner group

Fluoride catalysis

Chapitre 2

Chapitre 2

Scope of the reaction

  • a slow addition of DMAD over 30 min


Patrick metzner group

X-Ray Structure

Chapitre 2

 2 conformations

i-Pr in « pseudo-equatorial »position

i-Pr in « pseudo-axial »position

Jean-François Lohier


Patrick metzner group

Scope with other alkynes

Chapitre 2

  • a All reactions were carried out with 10 % of CsF in acetonitrile at 60°C (C = 0,02 M) and slow addition of acetylene (1,1 eq.) over 30 min.


Patrick metzner group

X-Ray Structure

Chapitre 2

Jean-François Lohier


Patrick metzner group

 2nd mechanism

Mechanistic study

Chapitre 2

 1stmechanism


Patrick metzner group

supposition

Literature :

Sheppard, W. A. J. Am. Chem. Soc.1962, 84, 3058-3063.

Sandrinelli, F.; Perrio, S.; Beslin, P. Org. Lett.1999, 1, 1177-1180.

Mechanistic study

Chapitre 2

2nd mechanism?

  • - reversible

  • formation of a sulfenyl fluoride intermediate


Patrick metzner group

Conclusion

Chapitre 2

 One step synthesis of nine 1,4-benzothiazepines from benzisothiazolines with good yields (from 35 to 86%)

  • 1st use of fluorideas nucleophilic catalyst

  • formation of a sulfenyl fluoride intermediate

  • limitations : -need of 2 EWG on the alkyne

  • - no reaction withdi‑t‑butylsulfonylacetylene

Spitz, C.; Lohier, J.-F.; Sopkova-de Oliveira Santos, J.; Reboul, V.; Metzner, P. J. Org. Chem.2009, 74, 3636-3639.


Patrick metzner group

Summary

I/ Synthesis of cyclicsulfenamides

II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines

III/ Synthesis of 1,3-benzothiazines

IV/ Synthesis of 2-substituted1,4-benzothiazepines


Patrick metzner group

  • very fast reaction

  • unexpected formation of 1,3-benzothiazine

1,3-benzothiazines

Chapitre 3

 Application of the previous method with terminal alkyne


Patrick metzner group

R1

R2

E/Za

Yield (%)

  • R2 = ester : diastereoisomer Z

i-Pr

CO2Me

86

13/87

Ph

CO2Me

73

13/87

-R2 = tosyle : diastereoisomer E

Cy

CO2Me

84

14/86

3-Br-C6H4

CO2Me

57

17/83

i-Pr

CO2Et

85

13/87

- total diastereoselectivity for

R1 = aryl and R2 = Ts

i-Pr

Ts

96

92/8

Ph

Ts

92

>98/2

Cy

Ts

93

92/8

  • R2 = EWG needed

  • (no reaction with phenylacetylene)

3-Br-C6H4

Ts

74

>98/2

i-Pr

Ph

0

-

a Determined by 1H NMR of crude

1,3-benzothiazines

Chapitre 3

 Scope of the reaction with other sulfenamides and terminal alkynes


Patrick metzner group

X-Ray Structure

Chapitre 3

Jean-François Lohier


Patrick metzner group

 Boc

  • formation of an open molecule

  • possible to close it deprotecting the amine moiety

Scope with others EWG on nitrogen of sulfenamide

Chapitre 3

 SES

  • no deprotection of SES with 0.1 eq. of CsF in MeCN

  • deprotection with 2 eq. of CsF in DMF


Patrick metzner group

 Proposed mechanism

  • Key step : deprotonation

  • of alkyne by CsF

Mechanistic study

Chapitre 3

 Deprotonation of methylpropiolate with n-BuLi then addition of sulfenamide

- Formation of 1,3-benzothiazine


Patrick metzner group

Use of CsF as base

Chapitre 3

 CsF as catalyst for nucleophilic addition of alkynes to carbonyl compounds?

  • expected formation of alcohol by addition to cyclohexanone

  • deprotonation confirmed

- domino reactions with aliphatic aldehydes

1 work carried out by Damien Deschamps


Patrick metzner group

Conclusion

Chapitre 3

 One step synthesis of ten 1,3-benzothiazines from benzisothiazolines with good to excellent yields (from 57 to 96%) and moderate to excellent diastereoisomeric excess (from 66 to 96%)

  • catalytic use of fluorideas base

  • limitations : -no reaction with phenylacetylene

  •  EWG sur l’alcyne

  • - promising first results with carbonyl compounds

Spitz, C.; Lohier, J.-F.; Reboul, V.; Metzner, P. Org. Lett.2009, 11, 2776-2779.


Patrick metzner group

Summary

I/ Synthesis of cyclicsulfenamides

II/ Synthesis of 2,3-disubstituted 1,4-benzothiazepines

III/ Synthesis of 1,3-benzothiazines

IV/ Synthesis of 2-substituted 1,4-benzothiazepines


Patrick metzner group

 Promote catalyst

nucleophilie (1,4 addition)

instead of its basicity

1,4-benzothiazepine vs 1,3-benzothiazine

Chapitre 4

 With terminal alkynes,how could we favour formation of

1,4-benzothiazepine?


Patrick metzner group

Catalyst

(Equiv.)

Solvent

(C = 0,1 mol.L-1)

T (°C)

Time (h)

Conversion

A/B/Ca

Yield A (%)

DPPP (0,1)

PPh3 (0,2)

DABCO (0,2)

DMAP (0,2)

Pyridine (0,2)

MeCN

MeCN

MeCN

MeCN

MeCN

80

ta

ta

ta

ta

2

0,5

1

0,5

24

100

100

100

100

78

15/65/20

0/84/16

18/71/11

17/72/11

22/58/20

-

-

-

-

-

Pyridine (0,2)

MeCN

60

24

90

55/37/8

-

Pyridine (0,2)

DME

60

70

79

100/0/0

-

Pyridine (1)

DME

60

24

100

100/0/0

80

Pyridine (0,5)

DMEb

60

72

24

100/0/0

-

Pyridine (0,5)

DME

60

40

93

100/0/0

69

1,4-benzothiazepine vs 1,3-benzothiazine

Chapitre 4

 Optimization of conditions to promote benzothiazepine

a Determined by 1H NMR of crude

b C = 0,02 mol.L-1


Patrick metzner group

- only benzothiazepine formation

 scope with tosylacetyleneusing optimized conditions :

- need to reoptimize conditions

Scope with others sulfenamides

Chapitre 4

  • best conditions to promote 1,4-benzothiazepine :

  • 0.5 equiv. of pyridine in DME at 60°C


Patrick metzner group

 Application of these new optimized conditions to other sulfenamides

- only formation of benzothiazepine

 Use of pyridine with DMAD?

With tosylacetylene

Chapitre 4

 best conditions : sequentialaddition


Patrick metzner group

 proposed pathway : 2 steps, totally different from previous work

1st step : -sulfanylation of an aldehyde with sulfenamide

2nd step : intramolecular reductive amination

2,3-dihydro-1,4-benzothiazepines

Chapitre 4

 Aim:Synthesis of 1,4-benzothiazepines of type A, monosubstituted on C-2 by an alkyl group and structurally close to biologically active compounds of type B

Diabetes

Nagase, T.; Sato, Y.; Eiki, J. WO Patent 053548, 2002.


Patrick metzner group

1st step : -sulfanylation

Chapitre 4

 Reaction with isovaleraldehyde catalyzed by amine

a Determined by 1H NMR of crude

  • best conditions : 0.3 equiv. of diethylamine at rt in acetonitrile

  • - no diastereoselectivity


Patrick metzner group

1st step : -sulfanylation

Chapitre 4

 Scope with other sulfenamides

a Determined by 1H NMR of crude

b 0,6 eq. of diethylamine

c 2 eq. of diethylamine


Patrick metzner group

1st step : -sulfanylation

Chapitre 4

 Scope with other carbonyl compounds

a Determined by 1H NMR of crude

  • propionaldehyde : low yields

  • phenylacetaldehyde and acetophenone : no reaction


Patrick metzner group

 intramolecular Mitsunobu reaction from alcohol

  • 1,4-benzothiazepine obtainedbut with a low yield and a 70/30 diastereoisomeric ratio

  • but major product : sulfenamide!!!

2nd step : cyclization

Chapitre 4

 reductive amination : no cyclization, formation of alcohol


Patrick metzner group

  • acid conditions : small amount of deprotection

  • – cyclic major product

 Optimization of acid conditions and scope

R1

R2

Rdt (%)

i-Pr

Boc

84

i-Pr

Ts

94

Ph

Ts

83

Cy

Ts

75

m-BrC6H4

Ts

80

2nd step : cyclization

Chapitre 4

 Deprotection of nitrogen to enhance its nucleophilie


Patrick metzner group

« One-pot »synthesis

Chapitre 4

 no purification of intermediate

  • low global yields

  • need to use 0.5 equiv. of TsOH.H2O for 2nd step


Patrick metzner group

Conclusion

Chapitre 4

 One step synthesis of eight 1,4-benzothiazepines from benzisothiazolines with moderate to good yields (from 51 to 82%)

  • with a terminal alkyne, it is possible to promote formation of 1,4-benzothiazepines instead of 1,3-benzothiazines using different reaction conditions


Patrick metzner group

Conclusion

Chapitre 4

Synthesis of nine 1,4-benzothiazepines over 2 steps with low to good global yields (from 25 to 72%)

  • 1st step : -sulfanylation of aldehyde with sulfenamide in presence of a catalytic amount of amine

  • 2nd step : p-toluenesulfonic acid-catalyzed cyclization


Patrick metzner group

1,4-benzothiazepines

Diethylamine

organo-catalysis

+ acid catalyzed

cyclization

Pyridine

organo-catalysis

Catalytic fluoride

as base

2,3-dihydro-1,4-benzothiazepines

Diethylamine organo-catalysis

+Reduction

+Mitsunobu

1,3-benzothiazines

General conclusion

Conclusion

Nucleophilic fluoride

catalysis

1,4-benzothiazepines


Patrick metzner group

 Next steps : reduction of double bond, oxidation of sulfur and deprotection of nitrogen

Sato, A.; Yorimitsu, H.; Oshima, K. Synlett2009, 28-31.

Perspectives

Perspectives

 How could we insert an aryl group in position 2?

Solution? Initiate the reaction by a metal insertion in sulfur-nitrogen bond

Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-A. Tetrahedron Lett.2004, 45, 1469-1471.


Patrick metzner group

 New method of synthesis of sulfenamides or sulfinic acids in mild conditions?

Perspectives

Perspectives

 Formation of sulfenamide from disulfure


Patrick metzner group

  • Fonction protectrice des sites actifs d’enzymes

Protéine Tyrosine Phosphatase 1B

Sivaramakrishnan, S.; Keerthi, K.; Gates, K. S. J. Am. Chem. Soc.2005, 127, 10830-10831.

Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc.2007, 129, 8872–8881.

Introduction

Application des sulfenamides

  • Pro-drogue

Hemenway, J. N.; Nti-Addae, K.; Guarino, V. R.; Stella, V. J. Biorg. Med. Chem. Lett. 2007, 6629-6632.


Patrick metzner group

 Addition du sulfoxyde lithié au thiosulfinate

Synthesis des sulfoxydes

 Synthesis du thiosulfinate

Blum, S. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2003, 68, 150-155.


Patrick metzner group

 N-Carbamoylimines

 N-SESimine

Imine aliphatique Boc non isolable

Weinreb, S. M.; Chase, C. E.; Wipf, P.; Venkatraman, S. Organic Syntheses 2004, 70-71.

Synthesis des imines

 N-Tosylimines


Patrick metzner group

- di-t-butylsulfonylacétylène

(a) Riera, A.; Cabré, F.; Moyano, A.; Pericàs, M. A.; Santamaría, J. Tetrahedron Lett.1990, 31, 2169-2172.

(b) Riera, A.; Martí, M.; Moyano, A.; Pericàs, M. A.; Santamaría, J. Tetrahedron Lett.1990, 31, 2173-2176.

1,4-benzothiazépines disubstituées en 2 et 3

 Généralisation de la méthode à d’autres alcynes

  • Synthesis des alcynes :

  • dicyanoacétylène

(a) Hopf, H.; Witulski, B. In Modern Acetylene Chemistry

(b) Stang, P. J.; Diederich, F., Ed.; VCH: Weinheim, 1995, 60.


Patrick metzner group

Application à un autre alcyne

Chapitre 4

 Optimisation des conditions avec le tosylacétylène

a Déterminé par RMN 1H du brut réactionnel

  • Meilleures conditions :

  • d’abord 0,25 éq. de pyridine dans le DME à 80°C pdt 30 min

  • puis à nouveau 0,25 éq. de pyridine dans le DME à 80°C pdt 30 min


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