Abstract
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.
Highlights
The Biginelli 3-component condensation belongs to a set of multi-component, atomeconomic chemical transformations, frequently employed by medicinal chemists for singlestage generation of N-based heterocyclic scaffolds from readily available building blocks [1,2]
Direct C–H arylation has proven to be a valuable tool for the late-stage installation of aryl–aryl bonds in medicinally-relevant scaffolds, creating products that may correspond to unchartered areas of 3D chemical space
We have demonstrated a productive combination of a multicomponent reaction (Biginelli) with a LED-activated photoredoxmediated C–H arylation approach
Summary
The Biginelli 3-component condensation belongs to a set of multi-component, atomeconomic chemical transformations, frequently employed by medicinal chemists for singlestage generation of N-based heterocyclic scaffolds from readily available building blocks [1,2]. Previous efforts have led to the discovery of Biginelli products exhibiting a diverse range of biological activities, including anti-inflammatory, anti-viral, anti-cancer, anti-mitotic, anti-microbial, anti-tubercular, anti-fungal, anti-diabetic, anti-oxidant, anti-hypertensive, adrenoreceptor antagonistic, and calcium channel blocking [8,9]. Another biologically significant N-based scaffold, the 2-hydroxypyrimidine (2-HP, Scheme 1), can be readily obtained by oxidative dehydrogenation of 3,4-DHPMs and ensuing aromatization [10,11,12,13,14]. 2-hydroxypyrimidines may serve as synthetic precursors to nucleo of 26 bases, vitamins, synthetic/unnatural amino-acids, natural products, and pharmaceuticals [15,16,17,18,19]
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