Preparation of Sulfilimines by Sulfur-Alkylation of N-Acyl Sulfenamides with Alkyl Halides

Abstract

Sulfur alkylation of N-acyl sulfenamides with alkyl halides provides sulfilimines in 47% to 98% yields. A broad scope was established with a variety of aryl and alkyl sulfenamides, including for different N-acyl groups. Alkyl halides with different steric and electronic properties were effective inputs, including methyl, primary, secondary, benzyl, and propargyl halides. A proofof-concept asymmetric phase-transfer alkylation was also demonstrated. A sulfilimine product was readily converted to an N-acyl and to a free sulfoximine, which represent important motifs in medicinal chemistry.

Synthesis of N‐Acylsulfenamides from (Hetero)Aryl Iodides and Boronic Acids by One‐Pot Sulfur‐Arylation and Dealkylation

“…To demonstrate the utility of our new approach for the discovery and development of high oxidation state sulfur containing drugs, we carried out diverse sulfur‐functionalization reactions on the apixaban‐derived sulfenamide 3 r (Scheme 2A). The S ‐methyl sulfilimine 5 was obtained in 91 % yield by S ‐alkylation, [3a] and a medicinally relevant S ‐cyclopropyl substituent was directly incorporated into sulfilimine 6 in 76 % yield using Chan–Lam conditions [4b] . The sulfur ylide 7 was generated in 84 % yield by coupling ethyl cyano diazoacetate in the presence of Rh 2 (OAc) 4 [2] .…”

1,2-Difunctionalization of Aryne with Sulfenamide and Organohalide: Mild and Metal-Free Access to S-(o-Halo)aryl Sulfilimine

“…Considering the importance of sulfilimines, many protocols have been developed for their preparation. The most common reports include the imination of sulfide or arylation/alkylation of sulfenamide. ,− It is worth mentioning that in 2023 there was a sudden surge in sulfilimine preparation via S-functionalization of sulfenamide. ,− Very recently, the groups of Tan and Wu have independently prepared sulfilimine via the reaction of sulfenamide and aryne. Nevertheless, our focus extends beyond just the preparation of sulfilimine; it involves the incorporation of an extra reactive handle (halogen) into it via a one-pot method.…”

Sulfur-Arylation of Sulfenamides via Ullmann-Type Coupling with (Hetero)aryl Iodides

“…Our group and others have recently developed sulfur–carbon bond formation reactions utilizing readily accessible sulfenamide starting inputs for the convergent and efficient synthesis of sulfilimines (the aza-analogues of sulfoxides) as intermediates to sulfoximines and sulfondiimines (Scheme B). − Our initial report detailed the catalytic enantioselective S -alkylation of N -acyl sulfenamides with diazo coupling partners, and we and others have since reported additional methods for sulfenamide S -alkylation . Our group and others have also focused on the development of methods for the S -arylation of sulfenamides.…”

“…The sulfilimine products 3 are versatile intermediates to high oxidation state sulfur­(VI) functionalities. We and many others have previously reported a variety of transformations of N -acyl sulfilimines, including their conversion to sulfoximines and sulfondiimines. ,− Here we chose to investigate the conversion of highly sterically hindered, and consequently potentially challenging, sulfilimine 3aa to sulfoximines (Scheme ). Sulfur-oxidation was successfully carried out to provide the N -protected sulfoximine 9 in high yield.…”