The development of palladium catalyzed regioselective rearrangements and cross-couplings

Abstract

Palladium catalysts were used to control selectivity in two different classes of reaction. The first reaction, developed in the Cook lab, aims to tackle the limited methods available towards the asymmetric synthesis of all-carbon quaternary stereocenters, which are a common motif in natural products and high-value pharmaceuticals. We developed an auto-tandem, branched-selective rearrangement of substituted N-alloc-N-allyl ynamides that proceeds through two separate and distinct catalytic cycles using the same catalytic entity. This reaction provides ready access to complex quaternary nitrile products with vinylogous stereocenters in excellent diastereoselectivity (>20:1 d.r.), including contiguous all-carbon quaternary centers. The stereochemical outcome is determined via a Pd(0)-catalyzed dipolar ketenimine aza-Claisen rearrangement and computational studies exemplify the key role ligand geometry plays. The second reaction, developed in the Neufeldt lab, aims to disrupt the inherent reactivity trends of 2,4-dihalogenated pyrimidines. 2,4-Disubstituted pyrimidines appear frequently in bioactive small molecules; however, strategies to elaborate the pyrimidine core through divergent synthesis (e.g., to prepare a library) are limited because 2,4-dihalopyrimidines tend to react only at C4 in both cross-couplings and nucleophilic aromatic substitutions. Substrate-controlled approaches can enable C2-selective functionalization, but a catalyst-controlled strategy to invert the conventional selectivity of cross-coupling would be more step-economical and general. Here we report that Pd(II) precatalysts supported by bulky N-heterocyclic carbene ligands uniquely effect C2-selective cross-coupling of 2,4-dichloropyrimidines with thiols and amines. The unusual selectivity is proposed to arise from a novel isohypsic mechanism in which there is no oxidative addition step, enabling a new mode of Pd catalyzed cross-coupling. Additionally, we demonstrated the synthesis of a novel thermally stable Pd(0) complex, Pd(Ph 2-COD) 2 with the potential for future applications in cross-coupling reactions.