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Article

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

Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Aglandjia, 2109 Nicosia, Cyprus
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Author to whom correspondence should be addressed.
Academic Editor: Sabine Berteina-Raboin
Catalysts 2021, 11(9), 1071; https://doi.org/10.3390/catal11091071
Received: 1 August 2021 / Revised: 29 August 2021 / Accepted: 1 September 2021 / Published: 3 September 2021
(This article belongs to the Special Issue Catalyzed Mizoroki–Heck Reaction or C–H Activation II)
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. View Full-Text
Keywords: C–H arylation; photoredox catalysis; LED; Suzuki-Miyaura C–C cross-coupling; Biginelli reaction; pyrimidine-based compound library C–H arylation; photoredox catalysis; LED; Suzuki-Miyaura C–C cross-coupling; Biginelli reaction; pyrimidine-based compound library
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MDPI and ACS Style

Georgiades, S.N.; Nicolaou, P.G.; Panagiotou, N. 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. Catalysts 2021, 11, 1071. https://doi.org/10.3390/catal11091071

AMA Style

Georgiades SN, Nicolaou PG, Panagiotou N. 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. Catalysts. 2021; 11(9):1071. https://doi.org/10.3390/catal11091071

Chicago/Turabian Style

Georgiades, Savvas N., Persefoni G. Nicolaou, and Nikos Panagiotou. 2021. "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" Catalysts 11, no. 9: 1071. https://doi.org/10.3390/catal11091071

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