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

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.

LED-induced Ru-photoredox Pd-catalyzed C–H arylation of (6-phenylpyridin-2-yl)pyrimidines and heteroaryl counterparts

“…Chelation is believed to be key in this initial activation event, based on the superiority of this system relative to a phenylpyrimidine counterpart. 12 The Ru(II)/ (III)-photoredox cycle, triggered by light, is well-established in the literature 7h and in our described system photoactivation is brought about by a commercial LED light. Single-electron transfer from the photoexcited Ru(II)*-species to the diazonium salt results in dissociation of the latter to generate an aryl radical.…”

“…, 2-, 3- or 4-monosubstitution, 3,5-disubstitution) on the arylation-receiving phenyl ring performed comparably ( Scheme 3 ), indicating that electronic effects of pre-existing substituent(s) do not significantly impact this arylation, unlike the case of a pyrimidine-directed arylation in our previous study, where the substrates' electronic features proved significant. 12 This difference could be indicative of a strong influence of the chelating (6-pyridin-2-yl)pyrimidine directing moiety employed herein on the arylation mechanism, especially on facilitating the initial C–H palladation step. The current C–H arylation occurs independently of pre-existing substituent effects, thus broadening the synthetic scope with regard to substrate diversity.…”

“…Introduction of the triate was achieved with triuoromethane-sulfonic anhydride in DCM, in the presence of excess TEA. 12,18 Triate derivatives 9 and 10 were submitted to treatment with NaHCO 3 in MeOH, under reux, to achieve conversion to the corresponding methyl ethers, 11 (70%) and 12 (76%), respectively, by means of addition-elimination. Each of the desired methyl ethers was accompanied by a percentage (<30%) of the triate methanolysis productpyrimidin-2-ol 7 or 8.…”

“…Ethyl-4-(6-bromopyridin-2-yl)-2-methoxy-6methylpyrimidine-5-carboxylate (12). Compound 10 (0.19 g, 0.4 mmol, 1.0 equiv.)…”

“…Having identified an emerging need to address the issue of C–H arylation in structurally complex substrates of medicinal relevance, while taking into account chemical functionality tolerance and applicability considerations, we have recently investigated a 2,6-diphenylpyrimidine series of polysubstituted substrates under mild (r.t., light-induced) C–H phenylation conditions ( Scheme 1C ). 12 These involved Pd( ii )-catalysis combined with Ru( ii )- or Ir( iii )-photoactivation to generate phenyl radicals from a readily accessible phenyldiazonium precursor. This methodology, which afforded C–H phenylation on challenging substrates regioselectively, was inspired from pre-existing work by Sanford and co-workers 7 f , h and was adapted/extended by our team, for application on the system at hand.…”