Nucleophilic additions to deactivated 2-fluoropyridine derivatives

ORGN 737

Martin Pettersson,, Subas M. Sakya, Christopher W. am Ende, and Longfei Xie. CNS Chemistry, PGRD, Pfizer Inc, Eastern Point Road, Groton, CT 06340

During the course of a recent drug discovery program, we required an efficient synthesis of 2-benzyloxy pyridine derivatives. The initial route relied on an alkylation of a 2-hydroxy pyridine intermediate, which proceeded in good overall yield but gave a mixture of products resulting from O- and N-alkylation. To avoid the need for separation of regioisomers, an alternative strategy was examined that involved nucleophilic addition to various 2-fluoropyridine derivatives.  We found that additions of a variety of primary and secondary alcohols proceed in excellent yield under mild conditions (KOt-Bu, THF, 50 ˚C, 2-6 h) even when strongly electron donating groups are present on the 2-fluoropyridyl template. This approach would be well suited for rapid expansion of chemical space using parallel medicinal chemistry.