ORGANIC
LETTERS
2009
Vol. 11, No. 8
1677-1680
Selective Monomethylation of Anilines
by Cu(OAc)2-Promoted Cross-Coupling
with MeB(OH)2
Israel Gonza´lez, Jesu´s Mosquera, Ce´sar Guerrero, Ramo´n Rodr´ıguez, and
Jacobo Cruces*
GalChimia, S.L. R&D Department, Cebreiro s/n 15823 O Pino, A Corun˜a, Spain
Received January 19, 2009
ABSTRACT
N-Methylanilines are readily synthesized in high yields through the copper(II)-promoted coupling of anilines and methylboronic acid. This
method represents a new approach for the selective monomethylation of anilines, and it is the first reported example of a Chan-Lam coupling
involving the use of methylboronic acid. An incubation period of the substrate with the copper reagent is needed before addition of the
methylboronic acid.
Anilines are important compounds found throughout the
pharmaceutical and agrochemical industries.1 In the last few
years, C-N bond forming reactions have become one of the
most explored reactions, especially regarding N-arylation.2
Although selective monoarylation of anilines can be easily
achieved, aniline monoalkylation (particularly N-methylation)
represents a challenging task which has been barely inves-
tigated despite the prevalence of the methylamino moiety in
drug candidates.3 Classical approaches call for the use of a
base and an alkylating agent, or reductive amination with
formaldehyde. Although both methods are widely described
in the literature, they lack from selectivity (mono and
dimethylated compounds are usually obtained) and require
a carefully controlled addition of reagents. Besides that, there
are problems associated with the toxicity of the methylating
reagents and functional group tolerance for reductive ami-
nations.
Two alternative methods have been developed to overcome
these problems. The first is the functionalization based on
the use of a temporary protecting group (e.g., carbamate,
benzyl) that allows the introduction of the methyl moiety,
followed by removal of the protecting group. The second
method for the monomethylation of a primary aniline is the
full reduction of a carbamate with LAH or other reducing
agent. Both methods involve the use of a protecting group
or the use of a powerful reducing reagent, so several steps
are introduced or harsh reaction conditions must be used.
(1) (a) Negwer, M. Organic-Chemical Drugs and their Synonyms: (An
International SurVey), 7th ed.; Akademie Verlag GmbH: Berlin, 1994. (b)
Montgomery, J. H. Agrochemicals Desk Reference: EnVironmental Data;
Lewis Publishers: Chelsea, MI, 1993.
Copper-promoted carbon-nitrogen bond forming cross-
coupling reactions of NH-containing substrates with aryl-
boronic acids have emerged as a powerful synthetic method
(2) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2047–2067. (b)
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860. (c) Guram, A. S.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901–7902. (d) Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805–818. (e) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413–2416. (f) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144–1157. (g) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793–
796.
(4) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941–2944. (c) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett
2000, 674–676. (d) Lam, P. Y. S.; Deudon, S.; Kristin, M. A.; Li, R.; He,
M.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 22, 7600–7601.
(3) 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.
10.1021/ol802882k CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society