One-Pot Efficient Synthesis of Sulfonimidamides from Sulfonyl Chloride

Abstract

Sulfonimidamides, featuring a hexavalent sulfur structure, are a class of key compounds with broad application prospects in the fields of pharmaceuticals and agrochemicals. However, their applications have been limited due to the lack of economically effective synthetic methods. Utilizing the cost-effective and readily accessible sulfonyl chloride as the initial reagent, this method involves the sequential formation of intermediates, including sulfinamide and sulfonimidoyl chloride, culminating in the synthesis of the sulfonylimidamide compounds. This approach yields sulfonimidamides in moderate to good yields, thereby offering a viable synthetic route for the expanded application of these important compounds.

Key words

one-pot strategy - sulfonimidamide - sulfonyl chloride - sulfinamide - sulfonimidoyl chloride

Publikationsverlauf

Eingereicht: 13. Januar 2025

Angenommen nach Revision: 06. März 2025

Accepted Manuscript online:
06. März 2025

Artikel online veröffentlicht:
11. April 2025

• References and Notes

• 1 Bentley R. J. Ind. Microbiol. Biotechnol. 2009; 36: 775
• 2a Natarajan A, Guo Y, Harbinski F, Fan Y.-H, Chen H, Luus L, Diercks J, Aktas H, Chorev M, Halperin JA. J. Med. Chem. 2004; 47: 4979
• 2b Chinthakindi PK, Naicker T, Thota N, Govender T, Kruger HG, Arvidsson PI. Angew. Chem. Int. Ed. 2017; 56: 4100
• 3 Sehgelmeble F, Janson J, Ray C, Rosqvist S, Gustavsson S, Nilsson LI, Minidis A, Holenz J, Rotticci D, Lundkvist J, Arvidsson PI. ChemMedChem 2012; 7: 396
• 4 Borhade SR, Svensson R, Brandt P, Artursson P, Arvidsson PI, Sandström A. ChemMedChem 2015; 10: 455
• 5a Verhaegen Y, Liu L, Nguyen TT, Loy TV, Schols D, Voet AR. D, Dehaen W, De Jonghe S. Bioorg. Chem. 2024; 145: 107181
• 5b Lücking U. Org. Chem. Front. 2019; 6: 1319
• 5c Nandi GC, Arvidsson PI. Adv. Synth. Catal. 2018; 360: 2976
• 6 Frings M, Bolm C, Blum A, Gnamm C. Eur. J. Med. Chem. 2017; 126: 225
• 7 Agarwal S, Sasane S, Shah HA, Pethani JP, Deshmukh P, Vyas V, Iyer P, Bhavsar H, Viswanathan K, Bandyopadhyay D, Giri P, Mahapatra J, Chatterjee A, Jain MR, Sharma R. ACS Med. Chem. Lett. 2020; 11: 414
• 8 Steinkamp A.-D, Schmitt L, Chen X, Fietkau K, Heise R, Baron JM, Bolm C. Skin Pharmacol. Physiol. 2016; 29: 281
• 9 Thota N, Makam P, Rajbongshi KK, Nagiah S, Abdul NS, Chuturgoon AA, Kaushik A, Lamichhane G, Somboro AM, Kruger HG, Govender T, Naicker T, Arvidsson PI. ACS Med. Chem. Lett. 2019; 10: 1457
• 10 Luisi R, Bull JA. Molecules 2023; 28: 1120
• 11a Yang G.-f, Yuan Y, Tian Y, Zhang S.-q, Cui X, Xia B, Li G.-x, Tang Z. J. Am. Chem. Soc. 2023; 145: 5439
• 11b Toth JE, Grindey GB, Ehlhardt WJ, Ray JE, Boder GB, Bewley JR, Klingerman KK, Gates SB, Rinzel SM, Schultz RM, Weir LC, Worzalla JF. J. Med. Chem. 1997; 40: 1018
• 11c Liang C, Robert-Peillard F, Fruit C, Müller P, Dodd RH, Dauban P. Angew. Chem. Int. Ed. 2006; 45: 4641
• 12 Chen Y, Gibson J. RSC Adv. 2015; 5: 4171
• 13a Liang D.-D, Lional N, Scheepmaker B, Subramaniam M, Li G, Miloserdov FM, Zuilhof H. Org. Lett. 2023; 25: 5666
• 13b Li S, Wu P, Moses JE, Sharpless KB. Angew. Chem. Int. Ed. 2017; 56: 2903
• 13c Gao B, Li S, Wu P, Moses JE, Sharpless KB. Angew. Chem. Int. Ed. 2018; 57: 1939
• 13d Huang H.-s, Yuan Y, Wang W, Zhang S.-q, Nie X.-k, Yang W.-t, Cui X, Tang Z, Li G.-x. Angew. Chem. Int. Ed. 2024; e202415873
• 13e Greed S, Briggs EL, Idiris FI. M, White AJ. P, Lücking U, Bull JA. Chem. Eur. J. 2020; 26: 12533
• 13f Teng S, Shultz ZP, Shan C, Wojtas L, Lopchuk JM. Nat. Chem. 2024; 16: 183
• 14a Pan S, Mulks FF, Wu P, Rissanen K, Bolm C. Angew. Chem. Int. Ed. 2024; 63: e202316702
• 14b Terhorst S, Jansen T, Langletz T, Bolm C. Org. Lett. 2022; 24: 4109
• 14c Wu P, Ling L, Hu Y, Pan S, Bolm C. ACS Sustainable Chem. Eng. 2024; 12: 15875
• 14d Wu P, Demaerel J, Kong D, Ma D, Bolm C. Org. Lett. 2022; 24: 6988
• 15 Izzo F, Schäfer M, Stockman R, Lücking U. Chem. Eur. J. 2017; 23: 15189
• 16 Briggs EL, Tota A, Colella M, Degennaro L, Luisi R, Bull JA. Angew. Chem. Int. Ed. 2019; 58: 14303
• 17a Zasukha SV, Timoshenko VM, Tolmachev AA, Pivnytska VO, Gavrylenko O, Zhersh S, Shermolovich Y, Grygorenko OO. Chem. Eur. J. 2019; 25: 6928
• 17b Wen J, Cheng H, Dong S, Bolm C. Chem. Eur. J. 2016; 22: 5547
• 17c Wright M, Martínez-Lamenca C, Leenaerts JE, Brennan PE, Trabanco AA, Oehlrich D. J. Org. Chem. 2018; 83: 9510
• 18a Li L, Zhang S.-q, Chen Y, Cui X, Zhao G, Tang Z, Li G.-x. ACS Catal. 2022; 12: 15334
• 18b Andrews JA, Kalepu J, Palmer CF, Poole DL, Christensen KE, Willis MC. J. Am. Chem. Soc. 2023; 145: 21623
• 18c Lo PK. T, Willis MC. J. Am. Chem. Soc. 2021; 143: 15576
• 18d Davies TQ, Hall A, Willis MC. Angew. Chem. Int. Ed. 2017; 56: 14937
• 19 Harmata M, Zheng P, Huang C, Gomes MG, Ying W, Ranyanil K.-O, Balan G, Calkins NL. J. Org. Chem. 2007; 72: 683
• 20a Jabczun M, Nosek V, Míšek J. Org. Biomol. Chem. 2023; 21: 2950
• 20b Funes Maldonado M, Sehgelmeble F, Bjarnemark F, Svensson M, Åhman J, Arvidsson PI. Tetrahedron 2012; 68: 7456
• 20c Richards-Taylor CS, Martínez-Lamenca C, Leenaerts JE, Trabanco AA, Oehlrich D. J. Org. Chem. 2017; 82: 9898
• 21 Yuan Y, Han Y, Zhang Z.-k, Sun S, Wu K, Yang J, Zhang J. Angew. Chem. Int. Ed. 2024; 63: e202409541
• 22 Miah AH, Champigny AC, Graves RH, Hodgson ST, Percy JM, Procopiou PA. Bioorg. Med. Chem. 2017; 25: 5327
• 23 Cho GY, Bolm C. Org. Lett. 2005; 7: 1351
• 24 Bohnen C, Bolm C. Org. Lett. 2015; 17: 3011
• 25 Li D, Williams NH. J. Phys. Org. Chem. 2016; 29: 709
• 26 Yue H.-Q, Li Q.-W, Shi D.-W, Yang R.-J, Han L.-L, Yang B. Eur. J. Org. Chem. 2023; 26: e202300812
• 27 Carbamoyl Transfer Reaction; General Procedure A mixture of 1a (19.0 mg, 0.1 mmol, 1.0 equiv) and triphenylphosphine (PPh₃, 26.2 mg, 0.1 mmol, 1.0 equiv) in DCM (1.0 mL) was stirred at 0 ℃. Then TEA (10.1 mg, 0.1 mmol, 1.0 equiv) and amine (2.0 equiv) were added dropwise to the flask at 0 °C. The reaction mixture was stirred for 5 min before the addition of trichloroisocyanuric acid (TCCA; 23.2 mg, 0.1 mmol, 1.0 equiv) at 0 °C. The resultant mixture was stirred for 30 min. To the mixture was added morpholine (17.4 mg, 0.2 mmol, 2.0 equiv) or amine (0.2 mmol, 2.0 equiv). The resultant mixture was stirred at 0 °C for 10 h. Upon completion, the reaction was quenched with saturated sodium chloride solution (NaCl, 5.0 mL), followed by extraction with DCM three times. The combined organic phases were dried with anhydrous MgSO₄ and concentrated under reduced pressure. Purification of the residue by flash chromatography (petroleum ether/EtOAc = 20:1 to 10:1) gave the product. 4-(N-(tert-Butyl)-4-methylphenylsulfonimidoyl)morpholine (5a) Yellow oil (83% yield); R_f = 0.51 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 8.2 Hz, 2 H), 7.27 (d, J = 8.0 Hz, 2 H), 3.70 (d, J = 4.7 Hz, 4 H), 2.92 (t, J = 4.7 Hz, 2 H), 2.42 (s, 3 H), 1.42 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 142.0, 134.0, 129.0, 127.5, 66.6, 54.9, 47.5, 33.0, 21.3. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₅H₂₄N₂O₂S: 297.1631; found: 297.1637. 4-(N-(tert-Butyl)-4-fluorophenylsulfonimidoyl)morpholine (5b) Colorless oil (71% yield); R_f = 0.42 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (dd, J = 8.7, 5.3 Hz, 2 H), 7.16 (t, J = 8.4 Hz, 2 H), 3.71 (t, J = 4.6 Hz, 4 H), 2.92 (t, J = 4.8 Hz, 4 H), 1.42 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.56 (d, J = 260.2 Hz), 133.0 (d, J = 3.0 Hz), 130.0 (d, J = 9.1 Hz), 115.5 (d, J = 22.2 Hz), 66.5, 55.1, 47.5, 33.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –107.90. HRMS (ESI): m/z [M+Na]⁺ calcd. for C₁₄H₂₁FN₂O₂S: 323.1200; found: 323.1200. 4-(N-(tert-Butyl)-4-chlorophenylsulfonimidoyl)morpholine (5c) Colorless oil (82% yield); R_f = 0.45 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.73(d, J = 8.6 Hz, 2 H), 7.46 (d, J = 8.6 Hz,2 H), 3.71 (t, J = 4.7 Hz, 4 H), 2.92 (t, J = 4.6 Hz, 2 H), 1.42 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 137.9, 135.5, 128.9, 128.6, 66.5, 55.1, 47.5, 33.0. HRMS (ESI): m/z [M+Na]⁺ calcd. for C₁₄H₂₁ClN₂O₂S: 339.0904; found: 339.0909. 4-(N-(tert-Butyl)-4-bromophenylsulfonimidoyl)morpholine (5d) Colorless oil (78% yield); R_f = 0.42 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.69–7.61 (m, 4 H), 3.71 (t, J = 4.7 Hz, 4 H), 2.93 (t, J = 4.6 Hz, 4 H), 1.41 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 136.0, 132.1, 131.6, 129.0, 128.5, 126.4, 66.5, 62.8, 55.2, 47.5, 33.0, 30.1. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₄H₂₁BrN₂O₂S: 361.0580; found: 361.0582. 4-(N-(tert-Butyl)-4-iodophenylsulfonimidoyl)morpholine (5e) Colorless oil (63% yield); R_f = 0.45 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 3.71 (t, J = 4.7 Hz, 4 H), 2.93 (t, J = 4.6 Hz, 4 H), 1.41 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 137.6, 136.7, 129.0, 99.9, 66.5, 55.2, 47.5, 32.9. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₄H₂₁IN₂O₂S: 409.0441; found: 409.0449. 4-(N-(tert-Butyl)-3-bromophenylsulfonimidoyl)morpholine (5f) Colorless oil (51% yield); R_f = 0.42 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 1.9 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.9 Hz, 1 H), 7.37 (t, J = 7.9 Hz, 1 H), 3.72 (t, J = 4.7 Hz, 4 H), 2.95 (t, J = 4.7 Hz, 4 H), 1.43 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 138.9, 134.6, 130.3, 129.9, 125.9, 122.6, 66.5, 55.2, 47.5, 33.0. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₄H₂₁BrN₂O₂S: 361.0580; found: 361.0583. 4-(N-(tert-Butyl)-3-Chloro-2-fluorophenylsulfonimidoyl)morpholine (5g) Colorless oil (67% yield); R_f = 0.56 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 7.9 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.18 (d, J = 7.9 Hz, 1 H), 3.72 (t, J = 4.7 Hz, 4 H), 3.13 (t, J = 4.7 Hz, 4 H), 1.40 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.3 (d, J = 258.5 Hz), 134.0, 130.1, 124.0 (d, J = 5.05 Hz), 123.2, 123.0, 66.5, 55.6, 46.9, 32.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –107.80. HRMS (ESI): m/z [M+Na]⁺ calcd. for C₁₄H₂₀ClFN₂O₂S: 357.0810; found: 357.0814. 4-(N-(tert-Butyl)-2-fluorophenylsulfonimidoyl)morpholine (5h) Colorless oil (56% yield); R_f = 0.56 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.93 (m, 1 H), 7.52 (t, J = 6.3 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1 H), 7.17 (dd, J = 10.4, 8.2 Hz, 1 H), 3.73 (t, J = 4.7 Hz, 4 H), 3.13 (q, J = 5.1 Hz, 4 H), 1.41 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.8 (d, J = 255.5 Hz), 133.8 (d, J = 8.0 Hz), 132.0, 123.9 (d, J = 4.0 Hz), 117.3 (d, J = 23.2 Hz), 66.7, 55.5, 46.9, 32.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.17. HRMS (ESI): m/z [M+Na]⁺ calcd. for C₁₄H₂₁FN₂O₂S: 323.1200; found: 323.1201. 4-(N-(tert-Butyl)-3-methylphenylsulfonimidoyl)morpholine (5i) Yellow oil (74% yield); R_f = 0.55 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (s, 2 H), 7.36–7.28 (m, 2 H), 3.70 (t, J = 4.7 Hz, 4 H), 2.92 (t, J = 4.8 Hz, 4 H), 2.43 (s, 3 H), 1.43 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 138.5, 136.6, 132.3, 128.3, 127.6, 124.6, 66.5, 54.9, 47.5, 33.0, 21.4. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₅H₂₄N₂O₂S: 297.1631; found: 297.1628. 4-(N-(tert-Butyl)-2-methylphenylsulfonimidoyl)morpholine (5j) Colorless oil (57% yield); R_f = 0.54 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.91–7.89 (m, 1 H), 7.39–7.36 (m, 1 H), 7.28 (t, J = 8.0 Hz, 2 H), 3.71 (t, J = 4.7 Hz, 4 H), 3.13–3.11 (m, 4 H), 2.73 (s, 3 H), 1.39 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 137.7, 133.0, 131.4, 129.5, 127.5, 125.7, 66.7, 55.2, 47.5, 46.5, 33.0, 21.6. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₅H₂₄N₂O₂S: 297.1631; found: 297.1625. 4-(N-(tert-Butyl)-4-trifluoromethyl-phenylsulfonimidoyl)morpholine (5k) Colorless oil (45% yield); R_f = 0.55 (PE/EA = 10:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 8.1 Hz, 2 H), 7.76 (d, J = 7.9 Hz, 2 H), 3.72 (t, J = 4.7 Hz, 4 H), 2.95 (t, J = 4.5 Hz, 4 H), 1.44 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 140.5, 133.4, 127.9, 127.4, 125.6 (q, J = 4.0 Hz), 124.8, 122.1, 66.4, 55.3, 47.5, 33.0, 30.1. ¹⁹F NMR (376 MHz, CDCl₃): δ = –362.12. HRMS (ESI): m/z [M+H]⁺ calcd. for C₁₄H₂₁F₃N₂O₂S: 351.1349; found: 351.1351.