Highly Regioselective Nitration Reactions Provide a Versatile Method of Functionalizing Benzocycloheptapyridine Tricyclic Ring Systems: Application toward Preparation of Nanomolar Inhibitors of Farnesyl Protein Transferase.

A comprehensive study of nitration reaction of azatricyclic systems has been carried out. Whereas classical nitrations using KNO3−H2SO4 at low temperatures gave nitrated products mainly at the 9-position, use of tetrabutylammonium nitrate−trifluoroacetic anhydride (TBAN−TFAA) resulted in exclusive nitration of the 3-position in the case carbamates 1, and 4−6 and the tricyclic ketone 7. These 3-nitro tricyclic derivatives have been valuable intermediates for the preparation of the very potent farnesyl protein transferase inhibitors such as the tricyclic pyridyl acetamide 32 and other new analogues.