Synthesis of Sulfoximines through Selective Sulfur Alkylation of Sulfinamides Generated In Situ from β-Sulfoximine Esters

Abstract

Over the past decade, the incidence of sulfoximine functional groups in pharmaceuticals and agrochemicals has increased significantly. This increase has led to a range of useful strategies for installing a S(VI) functionality into complex organic molecules. Conventional synthetic methods for forming α-substituted sulfonimidoyl motifs rely on late-stage modifications at sulfur and involve multistep routes. We report the development of an efficient and general method for the synthesis of various α-arylated sulfoximines through a selective S-alkylation. This strategy uses economical and readily available β-sulfoximine esters as precursors of sulfinamides and has been demonstrated by the preparation of 31 sulfoximines in good yields (up to 87%).

Key words

sulfoximines - S-alkylation - sulfinamides - sulfoximine esters

• References and Notes

• 1 Campos KR, Coleman PJ, Alvarez JC, Dreher SD, Garbaccio RM, Terrett NK, Tillyer RD, Truppo MD, Parmee ER. Science 2019; 363: eaat0805
• 2a Lücking U. Angew. Chem. Int. Ed. 2013; 52: 9399
• 2b Frings M, Bolm C, Blum A, Gnamm C. Eur. J. Med. Chem. 2017; 126: 225
• 2c Sirvent JA, Lücking U. ChemMedChem 2017; 12: 487
• 3a Walker DP, Zawistoski MP, McGlynn MA, Li J.-C, Kung DW, Bonnette PC, Baumann A, Buckbinder L, Houser JA, Boer J, Mistry A, Han S, Xing L, Guzman-Perez A. Bioorg. Med. Chem. Lett. 2009; 19: 3253
• 3b Ouvry G, Bihl F, Bouix-Peter C, Christin O, Defoin-Platel C, Deret S, Feret C, Froude D, Hacini-Rachinel F, Harris CS, Hervouet C, Lafitte G, Luzy A.-P, Musicki B, Orfila D, Parnet V, Pascau C, Pascau J, Pierre R, Raffin C, Rossio P, Spiesse D, Taquet N, Thoreau E, Vatinel R, Vial E, Hennequin LF. Bioorg. Med. Chem. Lett. 2018; 28: 1269
• 3c Loso MR, Benko Z, Buysse A, Johnson TC, Nugent BM, Rogers RB, Sparks TC, Wang NX, Watson GB, Zhu Y. Bioorg. Med. Chem. 2016; 24: 378
• 3d Liu Y, Xia Q, Fang L. Bioorg. Med. Chem. 2018; 26: 3992
• 3e Mäder P, Kattner L. J. Med. Chem. 2020; 63: 14243
• 3f Lücking U, Kosemund D, Böhnke N, Lienau P, Siemeister G, Denner K, Bohlmann R, Briem H, Terebesi I, Bömer U, Schäfer M, Ince S, Mumberg D, Scholz A, Izumi R, Hwang S, von Nussbaum F. J. Med. Chem. 2021; 64: 11651
• 3g Kang D, Fang Z, Huang B, Lu X, Zhang H, Xu H, Huo Z, Zhou Z, Yu Z, Meng Q, Wu G, Ding X, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X. J. Med. Chem. 2017; 60: 4424
• 4 Foote KM, Nissink JW. M, McGuire T, Turner P, Guichard S, Yates JW. T, Lau A, Blades K, Heathcote D, Odedra R, Wilkinson G, Wilson Z, Wood CM, Jewsbury PJ. J. Med. Chem. 2018; 61: 9889
• 5 Lücking U. Org. Chem. Front. 2019; 6: 1319
• 6a Bizet V, Hendriks CM. M, Bolm C. Chem. Soc. Rev. 2015; 44: 3378
• 6b Okamura H, Bolm C. Org. Lett. 2004; 6: 1305
• 6c Zenzola M, Doran R, Degennaro L, Luisi R, Bull JA. Angew. Chem. Int. Ed. 2016; 55: 7203
• 6d Andresini M, Tota A, Degennaro L, Bull JA. Chem. Eur. J. 2021; 27: 17293
• 7 Gao B, Li S, Wu P, Moses JE, Sharpless KB. Angew. Chem. Int. Ed. 2018; 57: 1939
• 8a Davies TQ, Tilby MJ, Ren J, Parker NA, Skolc D, Hall A, Duarte F, Willis MC. J. Am. Chem. Soc. 2020; 142: 15445
• 8b Zhang Z.-X, Davies TQ, Willis MC. J. Am. Chem. Soc. 2019; 141: 13022
• 9a Aota Y, Kano T, Maruoka K. Angew. Chem. Int. Ed. 2019; 58: 17661
• 9b Aota Y, Kano T, Maruoka K. J. Am. Chem. Soc. 2019; 141: 19263
• 10 Shultz ZP, Scattolin T, Wojtas L, Lopchuk JM. Nat. Synth. 2022; 1: 170
• 11a Mendonça Matos P, Lewis W, Argent SP, Moore JC, Stockman RA. Org. Lett. 2020; 22: 2776
• 11b Mendonça Matos P, Lewis W, Moore JC, Stockman RA. Org. Lett. 2018; 20: 3674
• 11c Aota Y, Maeda Y, Kano T, Maruoka K. Chem. Eur. J. 2019; 25: 15755
• 11d Moragas T, Liffey RM, Regentová D, Ward J.-PS, Dutton J, Lewis W, Churcher I, Walton L, Souto JA, Stockman RA. Angew. Chem. Int. Ed. 2016; 55: 10047
• 11e Yu H, Li Z, Bolm C. Angew. Chem. Int. Ed. 2018; 57: 324
• 11f Briggs EL, Tota A, Colella M, Degennaro L, Luisi R, Bull JA. Angew. Chem. Int. Ed. 2019; 58: 14303
• 12 Pilathottathil F, Unnikrishnan S, Kaliyamoorthy A. J. Org. Chem. 2022; 87: 14980
• 13 Yu X, Zhang Y, Liu Y, Li Y, Wang Q. J. Agric. Food Chem. 2019; 67: 4224
• 14 Zhang Y, Chen S, Liu Y, Wang Q. Org. Process Res. Dev. 2020; 24: 216
• 15 Sulfoximines 3; General Procedure The appropriate benzylic bromide 2 (0.12mmol) was added to a solution of TBAB (5 mol%) and β-sulfoximine ester 1 (0.1 mmol) in toluene (1 mL) at 25 °C, and the mixture was stirred at 25 °C for about 8 h until the starting material disappeared (TLC). The solution was then directly purified by column chromatography [silica gel, PE–EtOAc (10:1 to 4:1)]. N-[Benzyl(oxido)phenyl-λ⁴-sulfanylidene]-2,2-dimethylpropanamide (3a) White solid; yield: 0.026 g (0.082 mmol, 82%); mp 105–107 °C; TLC: R_f = 0.4 (PE–EtOAc, 4:1; UV). ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J = 7.8 Hz, 3 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 2 H), 6.95 (d, J = 7.5 Hz, 2 H), 4.92 (d, J = 13.6 Hz, 1 H), 4.67 (d, J = 13.6 Hz, 1 H), 1.25 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 188.8, 135.9, 133.8, 131.3, 129.1, 129.1, 128.6, 128.5, 127.8, 61.9, 41.7, 27.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₂₁NNaO₂S: 338.1185; found: 338.1187.