<i>N</i>-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, photoredo...
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MDPI AG
2021-09-01
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| Online Access: | https://www.mdpi.com/2073-4344/11/9/1071 |
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| author | Savvas N. Georgiades Persefoni G. Nicolaou Nikos Panagiotou |
| author_facet | Savvas N. Georgiades Persefoni G. Nicolaou Nikos Panagiotou |
| author_sort | Savvas N. Georgiades |
| collection | DOAJ |
| description | 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)<sub>2</sub>-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(1<i>H</i>)-one to 2-hydroxypyrimidine, <i>O</i>-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 <i>ortho</i> 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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| spelling | doaj.art-1a5332a3bfb24e0eb39e90ec89bca71c2023-11-22T12:20:58ZengMDPI AGCatalysts2073-43442021-09-01119107110.3390/catal11091071<i>N</i>-Directed Pd-Catalyzed Photoredox-Mediated C–H Arylation for Accessing Phenyl-Extended Analogues of Biginelli/Suzuki-Derived Ethyl 4-Methyl-2,6-diphenylpyrimidine-5-carboxylatesSavvas N. Georgiades0Persefoni G. Nicolaou1Nikos Panagiotou2Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Aglandjia, 2109 Nicosia, CyprusDepartment of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Aglandjia, 2109 Nicosia, CyprusDepartment of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Aglandjia, 2109 Nicosia, CyprusThe 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)<sub>2</sub>-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(1<i>H</i>)-one to 2-hydroxypyrimidine, <i>O</i>-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 <i>ortho</i> 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.https://www.mdpi.com/2073-4344/11/9/1071C–H arylationphotoredox catalysisLEDSuzuki-Miyaura C–C cross-couplingBiginelli reactionpyrimidine-based compound library |
| spellingShingle | Savvas N. Georgiades Persefoni G. Nicolaou Nikos Panagiotou <i>N</i>-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 C–H arylation photoredox catalysis LED Suzuki-Miyaura C–C cross-coupling Biginelli reaction pyrimidine-based compound library |
| title | <i>N</i>-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 |
| title_full | <i>N</i>-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 |
| title_fullStr | <i>N</i>-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 |
| title_full_unstemmed | <i>N</i>-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 |
| title_short | <i>N</i>-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 |
| title_sort | i n i 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 |
| topic | C–H arylation photoredox catalysis LED Suzuki-Miyaura C–C cross-coupling Biginelli reaction pyrimidine-based compound library |
| url | https://www.mdpi.com/2073-4344/11/9/1071 |
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