Multistep Continuous Flow Synthesis of Isolable NH2‐Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide

• Michael Andresini^a
• Sebastien Carret^b
• Leonardo Degennaro^a
• Fulvio Ciriaco^a
• Jean-François Poisson^b
• Renzo Luisi^a

• ^aUniversity of Bari: Universita degli Studi di Bari Aldo Moro, Pharmacy - Drug Sciences, Via E. Orabona,4, 70125 Bari, ITALY
• ^bUniversite Grenoble Alpes, Chemistry, rue de la chimie, 38000 Grenoble, FRANCE

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 NH 2 -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 exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas.

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