Selective Monomethylation of Anilines by a Copper-Promoted Cross-Coupling Reaction

Although selective monoarylation of anilines can be easily achieved, aniline monomethylation represents a challenging task that has been barely investigated despite the prevalence of the methylamino moiety in drug candidates. The lack of really efficient processes for this transformation prompted us to undertake, as part of our own R&D projects, the development of a method for the selective monomethylation of anilines and other heterocyclic amines.

Monomethylation represents a challenging task that has been barely investigated despite the enormous number of compounds containing the methylamino moiety among drug candidates. As an example, a search in the Integrity database showed 1340 biologically active compounds with the dimethylaminoaryl moiety and 250 compounds with the methylaminoaryl moiety. These numbers do not include methyl or dimethylaminoheteroaryl moieties.

It is clear that a fast, efficient, selective reaction for the preparation of this type of compounds would be a welcomed addition for many chemists. The classical approaches call for the use of a base and an alkylating agent, reductive amination with formaldehyde, or full reduction of a carbamate with LAH (two steps route). These methods have been widely described in the literature, but the two first lack from selectivity (mono and dimethylated compounds are usually obtained) or require a carefully controlled addition of reagents. The carbamate method is the only one really selective, but involves two steps and a strong reducing agent.

We centered our efforts in a very interesting and underdeveloped reaction called Chan–Lam. This reaction is similar to the Buchwald–Hartwig coupling in providing amines through C–N coupling but, in this case, the partners are an amine and a boronic acid. We envisioned that the coupling of a suitable methyl boron compound with anilines could be effective. After a comprehensive screening of catalysts, methyl sources, bases, and solvents, we found that Cu(OAc)2 can promote the cross-coupling reaction of aromatic amines with MeB(OH)2. Applying DoE techniques, we fine-tuned the reaction conditions to achieve optimal yields and reaction times.

With an optimized procedure in hand, we focused on the scope and limitations of the reaction, to find that it could be run under mild reaction conditions and good functional group tolerance. Carbonyl, nitrile, halide, thioether, and other groups can be present in the molecule, with yields ranging from 70% to 80%.

This work has been submitted for publication in Organic Letters, and further extension of this new reaction is currently under investigation in our labs.