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. 2020 Apr 22;142(16):7683-7689.
doi: 10.1021/jacs.0c02805. Epub 2020 Apr 10.

Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source

Stavros K Kariofillis  1 , Benjamin J Shields  1 , Makeda A Tekle-Smith  1 , Michael J Zacuto  2 , Abigail G Doyle  1
Affiliations

Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source

Stavros K Kariofillis et al. J Am Chem Soc. .

Abstract

Methylation of organohalides represents a valuable transformation, but typically requires harsh reaction conditions or reagents. We report a radical approach for the methylation of (hetero)aryl chlorides using nickel/photoredox catalysis wherein trimethyl orthoformate, a common laboratory solvent, serves as a methyl source. This method permits methylation of (hetero)aryl chlorides and acyl chlorides at an early and late stage with broad functional group compatibility. Mechanistic investigations indicate that trimethyl orthoformate serves as a source of methyl radical via β-scission from a tertiary radical generated upon chlorine-mediated hydrogen atom transfer.

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Figures

Figure 1.
Figure 1.
A Examples of aryl methylation that have resulted in enhanced bioactivity. B Established radical-based methylation strategies in cross-coupling. C This work.
Figure 2.
Figure 2.
A Computed reaction coordinate (CBS-QB3). B Initial result. a [Ir[dF(CF3)ppy]2(dtbbpy)]PF6 (1 mol%), Ni(cod)2 (10 mol%), dtbbpy (15 mol%), K3PO4 (2 equiv), (MeO)3CH:PhH (1:1) (0.05 M).
Figure 3.
Figure 3.
Methylation of (hetero)aryl chlorides (0.5 mmol scale). a GC yield. b Yield after hydrogenolysis of reaction mixture (5 mol% Pd/C, H2 (balloon), MeOH (0.05 M), 10 h). c Isolated with 10% homocoupled product; d 19F NMR yield. e 0.2 mmol scale reaction. f1H NMR yield. g0.25 mmol scale reaction (48 h) in trimethyl orthoformate:benzene (1:1).
Figure 4.
Figure 4.
A Proposed catalytic cycle. B Reaction progress by ReactIR (normalized single wavelength kinetics at 762 cm−1). C Investigation of hydrodealkoxylation pathway. D Alternative mechanistic possibility for methylation. E Methyl radical trapping experiment in the absence of Ni. a Optimized Ni/photoredox methylation conditions in Figure 3.
Figure 5.
Figure 5.
A Alkylation with trialkyl orthoformates. B Alkylation with acetals. Reaction conditions indicated in Figure 3 with the following modifications: a Reaction performed in triethyl orthoformate. b Reaction performed 1:1 with orthoformate or acetal in benzene. c Reaction performed with 12 equiv acetal in benzene.
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