Lanigan, RM; (2014) B(OCH2CF3)3-mediated amidation reactions. Doctoral thesis , UCL (University College London).

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Abstract

This thesis describes the further development of a borate ester, B(OCH2CF3)3, as a reagent for amidation with a focus on carboxylic acids, including N-protected amino acids, and on the amidation of unprotected amino acids. In addition, a novel methodology for the determination of enantiomeric ratio in chiral amines is reported. The B(OCH2CF3)3-mediated direct amidation of carboxylic acids furnishes the amide product in generally excellent yield (A). A formylation method using DMF as the formyl donor was also developed (B). The B(OCH2CF3)3-mediated amidation method allows the amidation of α-chiral acids (for example, N-protected amino acids) in good yield with excellent retention of enantiopurity (C). Importantly, a solid-phase work-up procedure was developed which enables the purification of all of these amide products without the need for column chromatography or aqueous work-up. The application of B(OCH2CF3)3 to the amidation of unprotected amino acids is described (D). This covers an optimisation study and an investigation into the scope of the reaction. As a result of this study a new method for the determination of enantiomeric purity of chiral amines was developed. Using an aldehyde derived from lactic acid the enantiopurity of chiral amines can be determined by NMR, circumventing the need for chiral HPLC. Additionally, a mechanistic study of the direct amidation reaction is discussed. A reaction intermediate as well as a tentative mechanism are proposed based on the results of this mechanistic study and preliminary experimental evidence.

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