A Silyl Sulfinylamine Reagent Enables the Modular Synthesis of Sulfonimidamides via Primary Sulfinamides

Abstract

A new N -silyl sulfinylamine reagent allows the rapid preparation of a broad range of (hetero)aryl, alkenyl, and alkyl primary sulfinamides, using Grignard, organolithium, or organozinc reagents to introduce the carbon fragment. Treatment of these primary sulfinamides with an amine in the presence of a hypervalent iodine reagent leads directly to NH-sulfonimidamides. This two-step sequence is straightforward to perform and provides a modular approach to sulfonimidamides, allowing ready variation of both reaction components, including primary and secondary amines.

Sulfondiimidamides as new functional groups for synthetic and medicinal chemistry

“…Unsymmetrical (bis-silyl)sulfurdiimide 8 can be prepared as before, but using tri-isopropylsilyl sulfinylamine 7 as the substrate. 42 The forward sequence then mirrors our earlier route, with organometallic addition (8 / 9), N-nosylation (9 / 10), S-fluorination (10 / 11), and then amine addition leading to sulfondiimidamide 12. Importantly, from silyl-protected sulfondiimidamide 12, the imidic N-H can be liberated by treatment with fluoride (TBAF), which is formally basic, in contrast to the acidic conditions needed to remove the t-octyl group, providing 6c in 97% yield.…”

Modular Two-Step Route to Sulfondiimidamides

“…To avoid the issues associated with these intermediates, and to achieve a shorter overall sequence, we planned to generate and exploit a reactive sulfur­(VI)-intermediate in situ. Taking inspiration from a recent synthesis of sulfonimidamides, we proposed an I­(III)-mediated oxidative amination of suitably protected primary sulfinamidines as the key step in our new route (Figure d). Related I­(III) chemistry has been described using tertiary sulfenamides and tertiary sulfinamides as substrates, leading to sulfonimidamides and sulfonimidates as products, depending on the reaction conditions employed.…”

“…To avoid steps associated with protecting group manipulations, we proposed installing the terminal N-substituents early in the reaction sequence and using the resultant N-functionalized sulfinamidines in the key I­(III)-transformation. Finally, in order to achieve maximum functional group tolerance, we would exclude the t -octyl-decorated sulfurdiimide reagent in favor of an unsymmetrical bis (silyl)­sulfurdiimide ( 1b ). , Together, these innovations should provide a shorter route that is amenable to greater diversification than the earlier chemistry. The concise nature of this proposed route is clear if we consider the preparation of functionalized sulfondiimidamide 8 , in which the imidic CN-substituent has been selected as a representative terminal functional group.…”

“…Reaction conditions for the key oxidative amination were based on a related transformation to access sulfonimidamides . The optimized reaction conditions involved treating sulfinamidine 10a with a slight excess of amine and using 1.5 equiv of commercial PhI­(OAc) 2 in the presence of NEt 3 , with toluene as the solvent.…”

The advent of electrophilic hydroxylamine-derived reagents for the direct preparation of unprotected amines

“…Similarly, a novel N-silyl analogue was used to synthesise primary sulfinamides. 177 O-Aryl reagent R13 by contrast exhibits a weaker N-O bond and thus differs in reactivity (Scheme 14B). 30 The mechanistic experiments conducted by the group of Willis indicate that, upon attack of the first equivalent of an organometallic carbon nucleophile and loss of a phenolate, a sulfinyl nitrene species is formed.…”