N-Directed Pd-Catalyzed Photoredox-Mediated C-H Arylation for Accessing Phenyl-Extended Analogues of Biginelli/Suzuki-Derived Ethyl 4-Methyl-2,6-diphenylpyrimidine-5-carboxylates

The availability and application of direct, functional group-compatible C-H activation methods for late-stage modification of small-molecule bioactives and other valuable materials remains an ongoing challenge in organic synthesis. In the current study, we demonstrate that a LED-activated, photoredox-mediated, Pd(OAc)(2)-catalyzed C-H arylation, employing a phenyldiazonium aryl source and either tris(2,2 '-bipyridine)ruthenium(II) or (2,2 '-bipyridine)bis[3,5-di-fluoro-2-[5-(trifluoromethyl)-2-pyridinyl-kN][phenyl-kC]iridium(III) as photoredox initiator, may successfully produce unprecedented mono- and bis-phenyl derivatives of functionality-rich 2,6-diphenylpyrimidine substrates at room temperature. The series of 19 substrates employed herein, which share the biologically-relevant 4-methyl-2,6-diphenylpyrimidine-5-carboxylate scaffold, were generated via a synthetic route involving (3-component) Biginelli condensation, oxidative dehydrogenation of the obtained 3,4-dihydropyrimidin-2(1H)-one to 2-hydroxypyrimidine, O-sulfonylation, and Suzuki-Miyaura C-C cross-coupling. Submission of these substrates to pyrimidine-N-atom-directed C-H arylation conditions led to regioselective phenylation at the ortho site(s) of the pyrimidine-C2-connected phenyl ring, revealing substituent-dependent electronic and steric effects. A focused library of 18 mono- and 10 bis-phenyl derivatives was generated. Its members exhibit interesting 3D and peripheral substitution features that render them promising for evaluation in drug discovery efforts.

Automated summary

This study demonstrates the successful synthesis of mono- and bis-phenyl derivatives of functionality-rich 2,6-diphenylpyrimidine substrates using a LED-activated, photoredox-mediated method. The phenylation at the ortho site(s) of the pyrimidine-C2-connected phenyl ring was found to be influenced by substituent-dependent electronic and steric effects. The generated library of derivatives shows promising features for evaluation in drug discovery efforts.