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 N-atoms 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.
Highlights
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
The mono- and diaza analogues of these groups sulfoximines, sulfondiimines and sulfonimidamides are less prevalent; they too are emerging as useful functionalities in discovery chemistry (Figure 1a,b).[2]
Sulfondiimines are the least represented member of this class, their attributes have been recognized, with the result that they too are starting to feature in medicinal chemistry programs
Summary
Communication of methods for sulfoximine preparation, with most routes usually starting from the corresponding sulfides or sulfoxides. A range of aryl Grignard reagents can be employed as the first organometallic reagent, followed by the addition of alkyl or aryl Grignard reagents, to provide sulfondiimines in respectable yields for this four-component two-stage assembly (4a−4h) These products are the first examples of orthogonally N-functionalized sulfondiimines prepared. Dialkyl-substituted sulfondiimines were the most challenging class of products to obtain, and the low yields achieved reflect the instability of the sulfilimine intermediates, which were not purified and undergo a degree of decomposition during the imination step. The yields given for the individual examples are based on the initial Grignard reagent as the limiting substrate Using this method a broad range of aryl−alkyl (5a−c) and aryl−aryl (5d−5j) substituted sulfoximines were obtained in high yields (Table 3).
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