Palladium-catalyzed Cross-coupling of Phenylboronic Acid with Heterocyclic Aromatic Halides

Abstract

me coupling reaction of bromo-and iodopyridines with phenylboronic acid (2) by Pd(Ph P) provides a convenient route to 3 4 phenylpyridines, even when electrondonating orwithdrawing substituents are present.The method is also successful for the preparation of other phenylated N-containing heterocycles 5 as phenylquinolines and -pyrimidines.In the course of our biological studies of 2-amino-5-phenylpyridine (a)), a asupectedly carcinogenic pyrolysis product of phenylalanine.' we were also interested in the 3-methyl derivative and its pu-2 tative N -oxygenated metabolites.2 we synthesized 2-amino-5-phenylpyridine (a) and several of its N -oxygenated derivatives1 via a modificafion of the Cedogen arylation of aromtic arnine~.~According t o this method, aminopyridines were diazotized with pentyl nitrite in refluxing benzene.The resulting diazonium compounds coupled with the solvent to give the desired phenylpyridines.Although this procedure was also svitable for the syntheses of the 3-methyl analogues,3 the successfvl palladium-catalyzed cross-coupling of phenylboronic acid (5) with haloarenes, developed by Miyaura er prompted us to investigate this procedure for the synthesis of phenylated N-containing heterocycles, especially because Miller and Dugar were able to prepare mononitrobiphenyls with this m e t h ~d .~ Since 2-nitro-5-bromopyridines are more easily available, the Miyaura method allows to avoid cumber$ome syntheses of 2-nitro-5-aminopyridines, which are the necessary precvrsors for Z-nitr0-5-~henylpyridines in the Cadogan reaction.I First, we examined the coupling reaction of phenylboronie acid (&) with a number of halopyridines I. Treatment of 1 with 2 (I.I mol eq) in the presence of Pd(Ph P) (3 and aqueous sodium car- -3 4bonate (2 mol eq) in benzene at reflux temperatwe gave phenylpyridines 3 in moderate to excellent yields.The results are listed in Table I.