期刊
CATALYSTS
卷 11, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/catal11091071
关键词
C-H arylation; photoredox catalysis; LED; Suzuki-Miyaura C-C cross-coupling; Biginelli reaction; pyrimidine-based compound library
资金
- University of Cyprus
- COST organization [CA15106]
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.
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.
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