A Facile and Mild Alkylation Protocol of NH-Diphenyl Sulfondiimines

Abstract

As a promising pharmacophore, sulfondiimines have drawn increasing attention in recent years, but their uptake in medicinal chemistry is jeopardized by the scarcity of related transformations. Herein, we report a facile and mild N-alkylation protocol of NH-diphenyl sulfondiimines with alkyl halides to prepare a myriad of N-alkylated diphenyl sulfondiimines. Owing to air atmosphere, room temperature, as well as mild reaction conditions, this protocol has exhibited great potential in organic synthesis and medicinal chemistry by the late-stage functionalization of natural products.

Key words

sulfondiimines - alkylation - mild - alkyl bromides - functional group tolerance

Publication History

Received: 20 June 2022

Accepted after revision: 18 September 2022

Accepted Manuscript online:
18 September 2022

Article published online:
14 October 2022

• References and Notes

• 1 Passia MT, Schobel JH, Bolm C. Chem. Soc. Rev. 2022; 51: 4890
• 2 Cogliano JA, Braude GL. J. Org. Chem. 1964; 29: 1397
• 3a Ried W, Jacobi MA. Chem. Ber. 1988; 121: 383
• 3b Haake M, Holz H. Phosphorus, Sulfur Silicon Relat. Elem. 1999; 153: 407
• 3c Diederich WE, Haake M. J. Org. Chem. 2003; 68: 3817
• 3d Bohmann RA, Unoh Y, Miura M, Bolm C. Chem. Eur. J. 2016; 22: 6783
• 3e Bohmann RA, Schöbel JH, Unoh Y, Miura M, Bolm C. Adv. Synth. Catal. 2019; 361: 2000
• 4a Lücking U. Angew. Chem. Int. Ed. 2013; 52: 9399
• 4b Chinthakindi PK, Naicker T, Thota N, Govender T, Kruger HG, Arvidsson PI. Angew. Chem. Int. Ed. 2017; 56: 4100
• 4c Frings M, Bolm C, Blum A, Gnamm C. Eur. J. Med. Chem. 2017; 126: 225
• 5 Siemeister G, Lücking U, Wengner AM, Lienau P, Steinke W, Schatz C, Mumberg D, Ziegelbauer K. Mol. Cancer Ther. 2012; 11: 2265
• 6 Lücking U. Org. Chem. Front. 2019; 6: 1319
• 7a Haake M, Georg G, Fode H, Eichenauer B, Ahrens KH, Szelenyi I. Pharm. Ztg. 1983; 128: 1529
• 7b Gnamm C, Oost T. US20150239875A1, 2015
• 8 Appel R, Ross B. Chem. Ber. 1969; 102: 1020
• 9 Hendriks CM. M, Bohmann RA, Bohlem M, Bolm C. Adv. Synth. Catal. 2014; 356: 1847
• 10 Wang Y, Meng T, Su S, Han L, Zhu N, Jia T. Adv. Synth. Catal. 2022; 364: 2040
• 11 Prat D, Wells A, Hayler J, Sneddon H, McElroy CR, Abou-Shehada S, Dunn PJ. Green Chem. 2016; 18: 288
• 12 General Procedure for Alkylation To an oven-dried microwave vial equipped with a stir bar were added 1a (185.2 mg, 0.5 mmol) and Cs₂CO₃ (243.8 mg, 0.75 mmol). Acetone (0.5 mL) and benzyl bromide (2a, 79.0 μL, 0.75 mmol) were added via syringe, and the vial was sealed with a septum. The reaction was stirred for 6 h at room temperature under an air atmosphere. Upon completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluted with EtOAc–hexane = 1:4) to give the pure product 3aa. R _f = 0.3 (EtOAc–hexane = 1:4); mp 128.3–128.9 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.98–7.95 (m, 4 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.51–7.47 (m, 2 H), 7.43–7.38 (m, 4 H), 7.29–7.26 (m, 4 H), 7.23–7.19 (m, 1 H), 7.03 (d, J = 8.0 Hz, 2 H), 3.95 (s, 2 H), 2.28 (s, 3 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 142.1, 140.9, 140.5, 138.4, 132.9, 129.3, 129.0, 128.5, 128.1, 127.4, 126.9, 126.6, 47.0, 21.4 ppm. IR (thin film): 1495, 1403, 1292, 1149, 1071, 1038, 1061, 848, 749, 720 cm^–1. HRMS: m/z calcd for C₂₆H₂₅O₂N₂S₂ ⁺: 461.1352; found: 461.1347 [M + H]⁺.