Reductive elimination to form new C-C bonds is a cornerstone of transition-metal catalysis; however, limited compatibility with nitrogen-containing heterocycles has restricted the utility of these methods in the preparation of functionalized pyridines and pyrimidines. An alternative, metal-free strategy to trigger heteroaromatic coupling from a pentacoordinate phosphorous atom has been uncovered which overcomes current shortcomings of metal catalysis and provides a fundamentally new way to construct therapeutic candidates. As part of our ongoing efforts to rationalize the mechanism and selectivity in C-C bond formation from P(V) intermediates, we studied the theory and mechanism underlying the challenging coupling of trifluoromethyl and pyridyl groups that proceed via P(V) intermediates and lead to the synthesis of different functionalized pyridines of pharmaceutical relevance.<br/>In this work, we describe mechanistic studies on CF3-Py ligand couplings at P(V) intermediates. CF3 ligands of phosphoranes undergo coupling selectively, leading to C-CF3 functionalization even in complex molecules with many potentially interfering functional groups. We report the results of computational studies carried out in collaboration with experiment, which lead to new insights into the reaction mechanism and provide a stereoelectronic model for the excellent levels of selectivity. The role of ligand apicophilicity and orbital symmetry upon controlling reactivity and selectivity in ligand coupling will also be discussed. Quantum mechanical calculations, including DFT (ωB97X-D) and coupled cluster theory (DLPNO-CCSD(T)) calculations, are used to study the mechanism and the energy profile of this reaction.

Mechanism, selectivity, and orbital symmetry of CF3-Py ligand couplings at pentacoordinate phosphorous

2019 Fall National Meeting

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