Buchwald–Hartwig Amination (BHA), which establishes C−N bonds between aryl halides and amines via Pd (0)-catalyst, has widely used as an indispensable technique in numerous basic and applied chemistry, such as syntheses of natural products, ligands, and heterocyclic molecules. The synthetic utility of Buchwald Hartwig Amination has emerged primarily due to the shortcomings of other aromatic C-N bond formation synthetic approaches due to functional group intolerance. Using BHA, a large pool of structurally and functionally diverse products can be synthesized in a single step which otherwise requires a multi-step complex synthetic method.<br/><br/>Recent advancements in Pyridine-Enhanced Pre-catalyst Preparation Stabilization and Initiation (PEPPSI) Palladium-catalyst has significantly simplified the synthetic utility of BHA that allows the reactions to take place under an ambient condition offering high overall yield. Using Pd-PEPPSI-IPr catalyst, we successfully synthesized a series of N-protected amino esters by coupling a variety of heterocyclic haloesters and N-protected piperazine derivatives. In particular, we found interesting reaction outcomes while carrying out BHA with a variety of differentially pre-disposed heterocyclic and aryl halo-esters under similar reaction conditions. Based on the result, we proposed a possible mechanism to account for the observed reaction outcome. Following the successful synthesis of N-protected amino esters, we further tested the compatibility of the molecules for solid-phase peptidomimetic synthesis following saponification and validated the purity of the products using HPLC.

Synthesis of a library of N-protected amino esters using PEPPSI-IPr via Buchwald Hartwig reaction

ACS Fall 2021

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