Efficient synthesis of an androgen receptor modulator

An efficient synthesis of the androgen receptor modulator (R)-4a having an 8H-[1,4]oxazino[2,3-f]quinolin-8-one skeleton is described. Synthesis of this ring system, not readily accessible by classical Knorr cyclization methodology, was accomplished by an ortho-metallation strategy. Thus, lithiation of a pivaloyl-protected 7-amino-3,4-dihydro-1,4-benzoxazine using n-butyllithium allowed the introduction of a trifluoroacetyl group regioselectively at the 8-position. Subsequent Wittig reaction and acid catalyzed cyclization afforded the desired 8H-[1,4]oxazino[2,3-f]quinolin-8-one (R)-4a in very good overall yield from the corresponding benzoxazine.