New Methods for Palladium-catalyzed Decarboxylative Benzylation, Arylation and Dearomatization Reactions

Abstract

Development of novel synthetic methods for the efficient generation of new carbon-carbon bonds is a valuable endeavor in organic synthesis. In this regard, palladium-catalyzed decarboxylative cross-coupling has significant potential as a waste-free reaction manifold with increased functional group tolerance due to the avoidance of preformed organometallics and basic reagents. Since the initial reports by Saegusa and Tsuji on decarboxylative allylation (DcA) of β-ketoesters in 1980, this concept remained relatively unexplored until the independent reports from Tunge and Stoltz in 2004. Since then, couplings of a broad array of nucleophiles, as well as asymmetric variants of the DcA reactions, have been heavily developed. However, due to the inherently low reactivity of benzyl electrophiles, catalytic decarboxylative benzylation reactions are comparatively less developed. Presented herein are the developments of new methods for the catalytic decarboxylative benzylic cross-coupling reactions with weakly-stabilized nucleophiles. In particular, the benzyl alkyne cross-coupling, which was initially limited to extended aryl systems, was further developed to allow couplings of primary benzyl electrophiles without extended π-conjugation. Our efforts were then directed toward developing a highly stereospecific decarboxylative coupling of acetylides and ketone enolates with secondary benzyl electrophiles that possess a 1,1-diarylmethane structure. The coupling of secondary benzyl electrophiles with acetylides proceeded with high stereospecificity to provide enantioenriched 1,1-diarylethynyl methanes, and we are unaware of any other method for the direct synthesis of such motifs. However, racemization was observed in the decarboxylative coupling of enantioenriched benzylic β-ketoesters. In the search for a new method to couple secondary benzyl electrophiles with ketone enolates, we serendipitously discovered the unprecedented catalytic decarboxylative dearomatization and arylation reactions of ketone enolates. Two sets of protocols involving simple variation of ligands were then developed for the selective decarboxylative dearomatization or arylation of enolates. These methods provided alicyclic and mono-α-arylated ketones in a highly regioselective manner and the expected benzylation of ketone enolates was never observed. Additionally, initial results have also shown that the palladium-catalyzed decarboxylative dearomatization of benzyl carbonates is highly stereospecific.