A methylation platform of unconventional inert aryl electrophiles: trimethylboroxine as a universal methylating reagent†

Methylation is one of the most fundamental conversions in medicinal and material chemistry. Extension of substrate types from aromatic halides to other unconventional aromatic electrophiles is a highly important yet challenging task in catalytic methylation. Disclosed herein is a series of transition metal-catalyzed methylations of unconventional inert aryl electrophiles using trimethylboroxine (TMB) as the methylating reagent. This transformation features a broad substrate type, including nitroarenes, benzoic amides, benzoic esters, aryl cyanides, phenol ethers, aryl pivalates and aryl fluorides. Another important merit of this work is that these widespread “inert” functionalities are capable of serving as directing or activating groups for selective functionalization of aromatic rings before methylation, which greatly expands the connotation of methylation chemistry.

Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. The solvents were purified and dried using Innovative Technology
General procedure: The amide substrates were prepared by a modified procedure according to the report. 9 The corresponding benzoyl chloride (5 mmol, 1.0 equiv) was added to a mixture of aniline (0.51 g, 5.

Phenyl 2-naphthoate (4b)
According to the general procedure for ester synthesis, 4b was obtained as a white solid. 1

Phenyl 4-methoxylbenzoate (4f)
According to the general procedure for ester synthesis, 4f was obtained as a white solid. 1

Phenyl 4-fluorobenzoate (4g)
According to the general procedure for ester synthesis, 4g was obtained as a white solid. 1

Phenyl 4-(trifluoromethyl)benzoate (4h)
According to the general procedure for ester synthesis, 4h was obtained as a white solid. 1

Methyl phenyl terephthalate (4q)
According to the general procedure for ester synthesis, 4q was obtained as a white solid. 1

Phenyl benzo[b]thiophene-2-carboxylate (4r)
According to the general procedure for ester synthesis, 4r was obtained as a white solid. 1
Diphenylacetylene (35.6 mg, 0.2 mmol) was subjected as internal standard after the completion of reaction. The yield of 2f was determined by GC analysis using calibration curves based on data from the authentic sample of 2f and diphenylacetylene (84% yield).
From ester: According to the general methylation procedure of ester, 2r was obtained as a white solid starting from 4r (21 mg, 70% yield).