Synthesis of Sulfonimidamides from Sulfenamides via an Alkoxy‐amino‐λ⁶‐sulfanenitrile Intermediate

Abstract

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry,a nd provide attractive bioisosteres for sulfonamides.However,there remain few operationally simple methods for their preparation. Here,t he synthesis of NH-sulfonimidamides is achieved directly from sulfenamides,themselves readily formed in one step from amines and disulfides.Ahighly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source,and in the presence of 1equivalent of acetic acid. Awide range of functional groups are tolerated under the developed reaction conditions,w hich also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel SNsulfanenitrile species as intermediates.Several alkoxy-amino-l 6 -sulfanenitriles are prepared with different alcohols,a nd shown to be alkylating agents to arange of nucleophiles. Scheme 1. Potential bioisosteres for sulfones and sulfonamides, examples of bioactive sulfonimidamides, and current strategies for the synthesis of sulfonimidamides.

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides

“…Considerable advances have been made in recent years in the synthesis of sulfoximines and sulfonimidamides by the Bolm and Bull groups, as well as others, which have simplified the imination of thioethers, 10 sulfoxides, 11 and sulfenamides. 12 Sulfonimidates 13 and sulfinamides 14 are also established as useful intermediates toward these targets. However, these methods share the fundamental limitation of ultimately needing thiol starting materials, which can be unpleasant to use due to their odor, oxidize to form disulfides in air, and are not widely commercially available.…”

Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

“…We envisioned that an analogous β-hydroxy ethyl activation/elimination strategy could be implemented to generate vinyl sulfonimidamides by combining it with our sulfenamide oxidation/imidation method. 33 Accordingly, phenyl piperidine (15a) was treated with THP-protected β-hydroxy ethyl disulfide (16) and silver nitrate to generate the corresponding sulfenamide (Scheme 5). The inclusion of Et3N, in modified Yield conditions, gave improved results by reducing the acidity of the reaction.…”

“…32 We have developed the synthesis of sulfonimidamides from sulfenamides by NH and O transfer. 33 It is notable that by using this NH transfer methodology, the reaction of phenylvinylsulfoxide was effective in generating phenyl vinyl sulfoximine, though in moderate yield (54%). 30 However, the corresponding method from the sulfide was ineffective (14% yield for phenylvinyl sulfide), 31a compounded by difficulties in the synthesis and acid instability of terminal vinyl sulfides.…”

Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

“…Analytical data in agreement with those reported in the literature. 33 Imino(4-methoxyphenyl)(methyl)-l 6 -sulfanone (2b). The title compound was prepared according to General Procedure A employing diacetoxyiodobenzene (10.4 g, 32.4 ((tert-Butyldiphenylsilyl)imino)(4-methoxyphenyl)(methyl)-l 6 -sulfanone (3b).…”