ABSTRACT
N-heterocycles are essential building blocks and scaffolds in medicinal chemistry. A Pd-catalyzed, Ru-photoredox-mediated C-H arylation is applied herein, for converting a series of functionality-inclusive (6-phenylpyridin-2-yl)pyrimidines to single arylated derivatives, using phenyldiazonium tetrafluoroborate as aryl source. This green chemistry-compliant transformation is induced by LED light. The drug-like modular substrates are constructed via combination of Biginelli multi-component condensation and Suzuki C-C cross-coupling, in order to strategically install, adjacent to the Ph-ring intended to undergo C-H arylation, a (6-pyridin-2-yl)pyrimidine that plays the role of a chelating directing moiety for the C-H arylation catalyst. The scope has been demonstrated on a series of 26 substrates, comprising diverse Ph-ring substituents and substitution patterns, as well as with 13 different aryl donors. Substrates in which the Ph-ring (arylation acceptor) was replaced by an electron-rich heteroaryl counterpart (2-/3-thiophene or -benzofuran) have also been examined and found to undergo arylation regioselectively. End-product conformations afford interesting motifs for occupying 3D chemical space, as implied by single-crystal X-ray diffraction, which has allowed the elucidation of six structures of aryl derivatives and one of an unprecedented pyrimidine-pyridine-benzofuran carbopalladated complex, believed to be a C-H activation derivative.
ABSTRACT
Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Until now, the most potent aldose reductase inhibitors have been carboxylic acid derivatives, which poorly permeate biological membranes. In this work, continuing our previous works, we promote the bioisosteric replacement of the carboxylic acid moiety to make equally potent yet more druggable inhibitors.
