Abstract
The regioselective and general synthesis of aminopyrimidines by Buchwald-Hartwig amination or SNAr reactions from arylpyrimidine 1 is reported. Thus, treatment of 1 (conveniently prepared by Suzuki cross-coupling) with amines under Buchwald-Hartwig conditions leads cleanly to C-4-aminated products while exclusion of catalyst leads to mixtures of C-4 and C-2 aminopyrimidines. Compound 1, obtained by crystallization from a Suzuki reaction when used for SNAr amination, gave an impressive 99:1 ratio of C-4/C-2 products. In contrast, pure 1, obtained by careful column chromatography, was less reactive and afforded a 7:3 ratio of C-4/C-2 amination products. These different phenomena were rationalized by the presence of an impurity of the organopalladium species A (2%) in crystallized 1, which catalyzed this reaction. The structure of compound A was established by X-ray crystal structure analysis. Comprehensive ligand screening showed that the simple and inexpensive phosphines Ph3P and dppb (1 mol%) were more effective compared to t-Bu3P, X- and Josi-Phos ligands.
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