Multistep Continuous Flow Synthesis of Isolable NH2‐Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide. Issue 59 (23rd August 2022)

• Record Type: Journal Article
• Authors: Andresini, Michael; Carret, Sébastien; Degennaro, Leonardo; Ciriaco, Fulvio; Poisson, Jean‐François; Luisi, Renzo
• Is Part Of: Chemistry. Volume 28:Issue 59(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-23
• Subjects: flow chemistry -- organolithiums -- sulfinamidines -- sustainable chemistry -- synthetic methodologies; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202202066
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The growing interest in novel sulfur pharmacophores led to recent advances in the synthesis of some S(IV) and S(VI) motifs. However, preparation and isolation of uncommon primary sulfinamidines, the aza‐analogues of sulfinamides, is highly desirable. Here we report a multistep continuous flow synthesis of poorly explored NH2 ‐sulfinamidines by nucleophilic attack of organometallic reagents to in situ prepared N ‐(trimethylsilyl)‐ N ‐trityl‐λ 4 ‐sulfanediimine (Tr−N=S=N−TMS). The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen‐lithium exchange of aryl bromides and iodides with n ‐butyllithium. Moreover, the synthetic potential of the methodology was assessed by exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas. Abstract : Primary sulfinamidines, the aza‐analogues of sulfinamides, are neglected S(IV) compounds. We report here the first synthesis of isolable NH2 ‐sulfinamidines through a multistep continuous flow approach via addition of organometallics to a transient sulfurdiimide. The transformation is highly chemoselective and compatible with a variety of in situ generated organolithiums. Further manipulation of the products gives access to unexplored S(IV) aza‐analogues of pharmaceutically relevant targets.