Rapid and efficient access to secondary arylmethylamines

Abstract

Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki-Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes.

Figure 1

Examples of Bioactive Molecules Containing the Aminomethyl Moiety.

Figure 2

X-ray Structures of Ammoniomethyltrifluoroborates1h and 1j.

Scheme 1

Possible Disconnections to Access the Aminomethylarene Moiety.

Scheme 2

Scope of Amino and Ammoniomethyltrifluoroborates.

Scheme 3

Synthesis and X-ray Stucture of the Palladium Biphenyl tri-tert-Butylphosphine Precatalyst 2.^[17]

Scheme 4

Attempts of Cross-Coupling 1k and 5-Bromoquinoline.

Scheme 5

Rapid Synthesis of Indoline Derivative7a from Trifluoroborate 1r in Two Metal-Catalyzed Reactions.