Modular Sulfondiimine Synthesis Using a Stable Sulfinylamine Reagent

Abstract

Sulfondiiminesthe double aza-analogues of sulfoneshold significant potential as leads in discovery chemistry, yet their application in this arena has been held back by the scarcity of appropriate synthetic routes. Existing methods employ sulfides as substrates, and rely on consecutive imination reactions using the hazardous reagent O-mesitylenesulfonyl hydroxylamine.Here we report a method for sulfondiimine synthesis that does not begin with a sulfide or a thiol, and instead employs two Grignard reagents and a bespoke sulfinylamine (RNSO) reagent as starting materials. Lewis acid-mediated assembly of these three components provides efficient access to a series of sulfilimine intermediates. A novel rhodium-catalyzed imination of these electron-rich sulfilimines then delivers a varied range of sulfondiimines featuring orthogonal N-functionalization. Conditions for the selective manipulation of both Natoms of the sulfondiimines are reported, allowing access to a broad range of mono-and difunctionalized products. The oxidation of the sulfilimine intermediates is also described, and provides a complementary route to sulfoximines.

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

“…More recently we described a second sulfinylamine reagent, this time featuring a tert -alkyl substituent ( t -Oct-NSO), and used this reagent to prepare sulfilimines, en route to sulfondiimines. 22 As with the TrNSO chemistry, this route to sulfondiimines again required a S(IV) to S(VI) oxidation using an external oxidant ( Scheme 1 , eq 2). Neither of these sulfinylamine reagents allowed the direct synthesis of sulfoximines from an electrophilic S(VI)-intermediate.…”

How do we address neglected sulfur pharmacophores in drug discovery?

“…Despite sulfondiimine 10 showing promising results, its synthesis on scale was challenging due to the requirement to use hazardous reagents. Recently, sulfondiimines have been prepared from organometallic reagents [21]. Use of the latter, resulted in a more straightforward preparation of a diverse range of sulfondiimines.…”

Rediscovering Sulfinylamines as Reagents for Organic Synthesis

“…We considered that sulfinylamines could be used to prepare sulfondiimines, the diaza analogues of sulfones, through a sulfilimine intermediate by a deoxygenative transformation. [29] This was achieved by the consecutive addition of trimethylsilyl triflate (TMSOTf) and a carbon‐centred organometallic reagent to N ‐sulfinyl‐ tert ‐octylamine ( t ‐OctNSO 11 ) at −78 °C to give O ‐silylated intermediate 12 (Scheme 6 ). Subsequent addition of a second organometallic reagent at −30 °C gave t ‐octyl‐protected sulfilimines 13 by substitution of the −OTMS group.…”