Facile construction of small and normal-sized, or more precisely, four to seven-membered aza-heterocyclic ring systems is always a challenging yet rewarding task for the synthetic organic chemists. Fortunately, activated aziridines and azetidines provide a direct and convenient access to this coveted molecular architectures through several elegant ring-expansion approaches. This chapter presents some of the illustrative and contemporary examples to demonstrate the synthetic diversity and efficiency of the ring-expansion strategies of activated aziridines and azetidines towards a vast array of small to normal-sized aza-heterocyclic moieties.
A simple synthetic route to access
racemic 3,3-disubstituted propylamines
in excellent yields (up to 95%) via Lewis acid catalyzed SN2-type ring opening of activated azetidines with electron-rich arenes
and heteroarenes under mild conditions has been accomplished. The
methodology is efficiently used for the racemic synthesis of an antimuscarinic
drug, tolterodine, in four steps in 47% overall yield.
Two efficient, modular, step- and pot-economic strategies to access various 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indoles and 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[1,7-a]indoles are disclosed that advance via S2-type regioselective ring opening of enantiopure aziridines with 2-(2-bromophenyl)-1H-indoles at their C3 and indolyl N centers, respectively, followed by Cu-mediated C-N cyclization which furnishes the products in excellent yields with outstanding enantiomeric excesses (up to >99%).
A simple
and efficient one-pot three-component synthetic route
to highly substituted and functionalizable piperazines in high yields
with excellent stereoselectivity (de, ee >99%) is reported. The
SN2-type ring-opening of N-activated aziridines
by anilines followed by Pd-catalyzed annulation with propargyl carbonates
gives rise to the final piperazine products.
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