One-pot methodology for the synthesis of polysubstituted pyridines and terpyridines

Abstract

Polysubstituted pyridines are prepared by a one-pot three-component cyclocondensation process, developed by modification and improvement of the traditional Bohlmann-Rahtz reaction. The synthesis combines a 1,3-dicarbonyl compound, ammonia, and an alkynone without the use of an additional acid catalyst. This three-component heteroannulation reaction proceeds by tandem Michael addition-heterocyclization with total control of regiochemistry and the resulting library of pyridines is isolated in good yield. Modified Bohlmann-Rahtz procedures were applied to the synthesis of a range of terpyridines, by a two- and three-component condensation of 2,6-propynoylpyridine derivatives and a range of enamines, or 1,3-dicarbonyl compounds and ammonia, proceeding in moderate to good yield using a range of conditions. The synthesis of fluorescent cyanopyridines with desirable photophysical properties from p- aminocrotononitrile and a variety of heterocyclic alkynones was established by one-pot Bohlmann-Rahtz reaction in excellent yields. These cyanopyridines can be generated in good yield, rapidly, using microwave irradiation. Primary thioamides are prepared in excellent yield from the corresponding nitriles by treatment with ammonium sulfide in methanol, at room temperature for electron deficient aromatic nitriles or under microwave irradiation at 80 C or 130 C in 15-30 minutes for other aromatic and aliphatic nitriles without the need for chromatographic purification