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Patrick Metzner group

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

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  1. LCMT Patrick Metzner group Annie-Claude Gaumont group Vincent Reboul

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10.  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.

  11. 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.

  12. X-Ray Structure Chapitre 1 Jean-François Lohier

  13. 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?

  14. 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

  15.  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.

  16. Reactivity of sulfenamides Chapitre 2  Nitrogen nucleophilic despite EWG?  Deprotection of sulfenamide

  17. 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

  18.  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.

  19. Fluoride catalysis Chapitre 2 Chapitre 2 Scope of the reaction • a slow addition of DMAD over 30 min

  20. X-Ray Structure Chapitre 2  2 conformations i-Pr in « pseudo-equatorial »position i-Pr in « pseudo-axial »position Jean-François Lohier

  21. 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.

  22. X-Ray Structure Chapitre 2 Jean-François Lohier

  23.  2nd mechanism Mechanistic study Chapitre 2  1stmechanism

  24. 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

  25. 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.

  26. 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

  27. very fast reaction • unexpected formation of 1,3-benzothiazine 1,3-benzothiazines Chapitre 3  Application of the previous method with terminal alkyne

  28. 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

  29. X-Ray Structure Chapitre 3 Jean-François Lohier

  30.  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

  31.  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

  32. 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

  33. 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.

  34. 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

  35.  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?

  36. 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

  37. - 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

  38.  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

  39.  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.

  40. 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

  41. 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

  42. 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

  43.  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

  44. 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

  45. « One-pot »synthesis Chapitre 4  no purification of intermediate • low global yields • need to use 0.5 equiv. of TsOH.H2O for 2nd step

  46. 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

  47. 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

  48. 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

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