Well-Defined Palladium(II)-NHC Precatalysts for Cross-Coupling Reactions of Amides and Esters by Selective N-C/O-C Cleavage.

Transition-metal-catalyzed cross-coupling reactions represent a most powerful tool for the rapid construction of C-C and C-X bonds available to synthetic chemists. Recently, tremendous progress has been made in the burgeoning area of cross-coupling reactions of amides and esters enabled by regio- and chemoselective acyl C-X (X = N, O) cleavage using well-defined Pd(II)-NHC complexes. The use of N-heterocyclic carbenes as ligands in palladium-catalyzed cross-couplings permits reactions of amides and esters that were previously impossible using palladium or could be achieved only under harsh conditions. These reactions provide an attractive method to synthetic chemists to manipulate the traditionally inert amide and ester bonds with the broad cross-coupling generality inherent to palladium catalysis. Research in the area of cross-coupling of stable acyl electrophiles can be broadly categorized by the type of electrophile undergoing the cross-coupling. Recent studies have shown that cross-coupling of amides by transition-metal catalysis represents one of the most straightforward and wide-ranging ways of manipulating the classically inert amide bonds into generic acyl-metal intermediates that can be systematically exploited in cross-coupling reactions as a new paradigm in organic synthesis. The key to achieving high chemoselectivity of the process is control of amidic resonance (nN to πC═O * conjugation, rotation of ca. 15-20 kcal/mol in planar amides), enabling oxidative addition of the N-C amide bond to a metal in a rational and predictable manner. This mode of catalysis has been extended to C(acyl)-O cross-coupling reactions of aryl esters, where selective C-O bond cleavage is accomplished through a rational match of aryl ester electrophiles and nucleophilic metal catalysts. These two types of transition-metal-catalyzed cross-coupling reactions represent an attractive concept in synthetic chemistry because of the ubiquity of esters and amides as precursors in organic synthesis. Furthermore, the high stability of amides and esters provides unprecedented opportunities for orthogonal cross-coupling strategies in the presence of other electrophiles. In this Account, we highlight advances that have taken place in the past few years in the field of cross-coupling of amides and esters, focusing on both (1) the stereoelectronic properties of well-defined Pd(II)-NHC complexes that have been critical to realize this challenging cross-coupling manifold and (2) the role of the isomerization barrier of the acyl electrophiles undergoing the cross-coupling. In a broader sense, the chemistry described here provides a practical approach to functionalize common amide and ester functional groups in organic synthesis and establishes straightforward access to acyl-metal intermediates that enable nonconventional cross-coupling strategies.