Ann De Blieck

Synthesis of a variety of 2-alkyl-2-azabicyclo[3.1.1]heptane-1-carbonitriles via a dynamic addition-intramolecular substitution sequence

An improved two-step synthetic approach towards 3-(2-chloroethyl) cyclobutanone is described and used in the synthesis of a class of 2-alkyl-2-azabicyclo[3.1.1]heptane-1-carbonitriles. The key step consists of a reversible addition of hydrogen cyanide onto the in situ generated imines, followed by an intramolecular nucleophilic substitution, thereby leading to the bicyclic skeleton in moderate to good yields (47-92%). These bicyclic compounds are stable, and the incorporated cyano group can be easily reduced to the corresponding aminomethyl group in high yields (93-99%), using lithium aluminum hydride.