Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones from Ellman’s N-tert-Butylsulfinyl Ketimines and Methyl Phenyl Sulfone

Abstract

A practical and straightforward approach for the highly stereoselective synthesis of γ,δ-unsaturated β-amino sulfones by nucleophilic (phenylsulfonyl)methylation of N-tert-butylsulfinyl ketimines with methyl phenyl sulfone was achieved. With lithium bis(trimethylsilyl)amide as the base, the corresponding sulfone-­stabilized carbanion derived from methyl phenyl sulfone can be transferred to (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines in very good yields and with high diastereoselectivities. Electron-withdrawing or electron-donating substituents on the aryl rings of (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines did not exert a significant effect on the outcome of the diastereoselective nucleophilic (phenylsulfonyl) methylation.

Key words

amines - ketimines - nucleophilic addition - β-amino sulfones

• References and Notes

• 1a Xue C.-B, Chen X.-T, He X, Roderick J, Corbett RL, Ghavimi B, Liu R.-Q, Covington MB, Qian M, Ribadeneira MD, Vaddi K, Trzaskos JM, Newton RC, Duan JJ.-W, Decicco CP. Bioorg. Med. Chem. Lett. 2004; 14: 4453
• 1b Gauthier JY, Black WC, Courchesne I, Cromlish W, Desmarais S, Houle R, Lamontagne S, Li C, Masse F, McKay DJ, Ouellet M, Robichaud J, Truchon J.-F, Truong V.-L, Wanga Q, Percival MD. Bioorg. Med. Chem. Lett. 2007; 17: 4929
• 1c Paikt S, White EH. Tetrahedron Lett. 1996; 37: 4663
• 2a Tamamura H, Koh Y, Ueda S, Sasaki Y, Yamasaki T, Aoki M, Maeda K, Watai Y, Arikuni H, Otaka A, Mitsuya H, Fujii N. J. Med. Chem. 2003; 46: 1764
• 2b Nakatani S, Hidaka K, Ami E, Nakahara K, Sato A, Nguyen J.-T, Hamada Y, Hori Y, Ohnishi N, Nagai A, Kimura T, Hayashi Y, Kiso Y. J. Med. Chem. 2008; 51: 2992
• 2c Munroe JE, Shepherd TA, Jungheim LN, Hornhadc WJ, Hatch SD, Muesing MA, Wiskerchen M, Su KS, Campanale KM. Bioorg. Med. Chem. Lett. 1995; 5: 2897
• 3 Raja SN, Surber BW, Du J, Cross JL. J. Labelled Compd. Radiopharm. 2009; 52: 98
• 4a Wang Q, Tran HuuDau M.-E, Sasaki NA, Potier P. Tetrahedron 2001; 57: 6455
• 4b Pauly R, Sasaki A, Portier P. Tetrahedron Lett. 1994; 35: 237
• 5 de Blas J, Carretero JC, Dominguez E. Tetrahedron Lett. 1994; 35: 4603
• 6 Ermolenko L, Sasaki NA, Potier P. J. Chem. Soc., Perkin Trans. 1 2000; 2465
• 7a Alonso DA, Costa A, Mancheno B, Najera C. Tetrahedron 1997; 53: 4791
• 7b Giovannini R, Petrini M. Synlett 1997; 90
• 8 Simpkins NS. Sulfones in Organic Synthesis . Baldwin JE, Magnus PD. Pergamon Press; Oxford: 1993
• 9a Rao AV. R, Gurjar MK, Pal S. Tetrahedron Lett. 1995; 36: 2505
• 9b Mirilashvili S, Chasid-Rubinstein N, Albeck A. Eur. J. Org. Chem. 2010; 4671
• 9c Jakobsche CE, Peris G, Miller SJ. Angew. Chem. Int. Ed. 2008; 47: 6707
• 10a Ma D, Zou B, Zhu W, Xu H. Tetrahedron Lett. 2002; 43: 8511
• 10b Aionso DA, Costa A, Manchéno B, Nájera C. Tetrahedron 1997; 53: 4791
• 10c Das I, Pathak T. J. Org. Chem. 2005; 70: 8047
• 11 Zhang H, Li Y, Xu W, Zheng WR, Zhou P, Sun ZH. Org. Biomol. Chem. 2011; 9: 6503
• 12 Shiau TP, Houchin A, Nair S, Xu P, Low E, Najafi R, Jain R. Bioorg. Med. Chem. Lett. 2009; 19: 1110
• 13a Liu J, Hu JB. Chem.–Eur. J. 2010; 16: 11443
• 13b Ni CF, Zhang LJ, Hu JB. J. Org. Chem. 2008; 73: 5699
• 14a Esquivias J, Arrays RG, Carretero JC. J. Org. Chem. 2005; 70: 7451
• 14b McMahon JP, Ellman JA. Org. Lett. 2005; 7: 5393
• 15a Li Y, Hu J. Angew. Chem. Int. Ed. 2005; 44: 5882; Angew. Chem. 2005, 117, 6032
• 15b Li Y, Hu J. Angew. Chem. Int. Ed. 2007; 46: 2489 ; Angew. Chem. 2007, 119: 2541
• 15c Li Y, Ni C, Liu J, Zhang L, Zheng J, Zhu L, Hu J. Org. Lett. 2006; 8: 1693
• 15d Liu J, Li Y, Hu J. J. Org. Chem. 2007; 72: 3119
• 15e Liu J, Zhang L, Hu J. Org. Lett. 2008; 10: 5377
• 16a Ho T.-L. Hard and Soft Acids and Bases Principle in Organic Chemistry. Academic Press; New York: 1977
• 16b Hard and Soft Acids and Bases . Pearson RG. Dowden, Hutchinson & Ross; Stroudsburg: 1973
• 17 Fleming I. Frontier Orbitals and Organic Chemical Reactions. Wiley; London: 1976
• 18a Prakash GK. S, Krishnamurti R, Olah GA. J. Am. Chem. Soc. 1989; 111: 393
• 18b Krishnamurti R, Bellew DR, Prakash GK. S. J. Org. Chem. 1991; 56: 984
• 19 Sosnovskikh VY, Usachev BI, Sevenard DV, Röschenthaler G.-V. J. Org. Chem. 2003; 68: 7747
• 20 Maruoka K, Shimada I, Akakura M, Yamamoto H. Synlett 1994; 847
• 21 General Procedure for the Synthesis of Compounds 3 LiHMDS (1.3 equiv, 1.3 mL, 1.0 mol/L) was added to a mixture of the (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines 2 (1 mmol) and methyl phenyl sulfone (1, 1.2 equiv, 1.2 mmol) in CH₂Cl₂ (5 mL) at –65 °C. Reaction mixtures were stirred over 4 h. Then a half-saturated NH₄Cl/H₂O solution (2 mL) was added at lower temperature, and the quenched reaction mixture was extracted three times with EtOAc. The combined organic layers were dried over anhyd MgSO₄. Evaporation of the solvent afforded the crude product, which was subject to flash chromatography to give the corresponding γ,δ-unsaturated β-amino sulfones 3.Spectral Data of the Product 3a White solid; mp 157.5–158.1 °C; [α]²⁵ 128.4 (c 0.61, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.77–7.76 (d, J = 8 Hz, 2 H), 7.75–6.80 (m, 10 H), 6.82–6.80 (d, J = 8 Hz, 1 H), 6.29–6.27 (d, J = 8 Hz, 1 H), 6.23 (s, 1 H), 4.39–4.35 (d, J = 14 Hz, 1 H), 4.13–4.09 (d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 1.41 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.3, 140.7, 134.8, 134.2, 134.0, 133.3, 133.0, 131.4, 129.4, 129.1, 128.1, 128.0, 127.7, 127.2, 126.5, 113.7, 64.6, 63.3, 56.6, 55.2, 23.1. ESI-HRMS: m/z calcd for C₂₇H₂₉Cl₂NO₄S₂Na [M + Na]⁺: 588.08073; found: 588.07789. Other spectral data can be found in the Supporting Information.
• 22 The crystal structure of 3d has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 884490.