α-Triphenylmethylamines, a sub-class of α-tertiary amines, are structural components of rhodamine spirolactams employed as chemosensors for ions and neutral molecules, and as photoactivatable molecules used in subcellular super-resolution imaging. The strategy of choice for the preparation of α-tertiary amines is the addition of carbon nucleophiles to ketimines. Accordingly, an efficient approach for the synthesis of α-triphenylmethylamines would be the direct 1,2-addition of phenyl rings to benzophenone imines, as their parent ketones are either commercially available or quickly accessed from numerous synthetic routes. The remarkably low reactivity of such bis-aromatic ketimines, however, renders this task daunting and may, in part, be the reason for the dearth of synthetic methods available. A few examples of such transformations have appeared in general studies on imines, such as racemic 1,2-additions of Grignard reagents to activated benzophenone imines, or asymmetric rhodium- and palladium-catalyzed cross-coupling reactions. To the best of our knowledge, there are no asymmetric organocatalytic methodologies for the preparation of these valuable motifs. We developed a chiral Brønsted acid-catalyzed formal Betti reaction – a Mannich-type reaction between imines and phenols – to afford enantioenriched α-triphenylmethylamines. Key to success of this transformation is the in situ generation of the reactive benzophenone iminium species from Nα-hydroxymethylamides (Scheme 1). Various phenols reacted smoothly in a 1,2-addition, enabling the synthesis of a variety of chiral α-triphenylmethylamines. Developed protocol affords products in up to 98% isolated yield, and up to &gt;99:1 e.r. Reaction mechanism and the origin of stereoselectivity is discussed.

Chiral Brønsted acid-catalyzed formal Betti reaction enables enantioenriched α-triphenylmethylamines from diaryl ketimines and phenols

ACS Spring Meeting 2021

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