Synthesis of nornicotine‐2,4,5,6‐d4 and its N′‐nitroso derivative

Nornicotine‐2,4,5,6‐d4 and its N′‐nitroso derivative were synthesized from pyridine‐d5. Initially, pyridine‐d5 was brominated in fuming D2SO4 to give 3‐bromopyridine‐d4. Treatment of this material with n‐butyllithium and dry ice followed by acidification gave nicotinic acid‐2,4,5,6‐d4. Conversion of this substance to the acid chloride hydrochloride (via thionyl chloride) followed by treatment with absolute ethanol gave ethyl nicotinate‐2,4,5,6‐d4. The ester was condensed with N‐trimethylsilyl‐2‐pyrrolidinone in the presence of n‐butyllithium and diisopropylamine to give, after hydrolysis and decarboxylation, myosmine‐2,4,5,6‐d4. Reduction of this material with sodium borohydride gave nornicotine‐2,4,5,6‐d4. Conversion to the N′nitroso derivative was achieved by treatment with nitrous acid.