The advent of bioorthogonal bond-forming reactions has heralded momentous advances in chemical biology The Staudinger ligation, which is the focus of this work, along with native chemical ligation and the growing number of so-called "click" reactions, share commonality in that their development was the result of an understanding of the underlying reaction mechanisms governing such systems and innovative exploitation of those mechanisms to effect highly selective transformations in complex settings. Despite compelling evidence detailing the mechanism of the Staudinger ligation, based primarily on the accepted mechanism of the classical reduction reaction, a detailed description of the mechanism governing the "traceless" ligation of an aryl azide 1 and phosphino phenyl ester 2 has yet to emerge. We present key empirical evidence supporting a difference between the two with respect to product-distributions obtained under identical conditions from the ligation of triarylphosphines and organic azides. When 1 & 2 (20:1 equiv) were combined in solution, the reaction followed a pseudo-consecutive first-order kinetic model with the ratio of products obtained strongly dependent on the initial conditions. Compounds 1 & 2 initially react in the cold to afford a mixture of s-cis (3c) & s-trans (3t) phosphazides, which either undergo subsequent elimination of N2 to form the corresponding iminophosphorane 4 under "anhydrous" conditions or to afford the desired anilide 5 under "wet" conditions. However, unlike alkyl azide-derivatives, 4 could not be hydrolyzed to 5. We propose that the traceless Staudinger ligation between 1 and 2 affords 5 via a mechanism in which acyl-transfer occurs to the g-nitrogen of 3 with concomitant expulsion of N2. The role of H2O in the ligation is attributed to a favorable interaction with 3, which inhibits formation of 4.

Evidence supporting a revised mechanism for the traceless Staudinger ligation of phosphino phenyl esters and aryl azides

249th National Meeting (2015)

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