A practical route to epibatidine

Organocatalyzed Intramolecular Michael Addition of Morita–Baylis–Hillman Adducts of β‐Arylnitroethylenes: An Entry to 3‐Aryl‐4‐nitrocyclohexanones

“…The reduction of the nitro group of 8 to an amine followed by reflux in chloroform provided the endo isomer of epibatidine ( endo ‐ 3 ). The formation of the endo isomer of epibatidine further supports the trans selectivity of the developed intramolecular Michael addition reaction 11n,11o. The conversion of the endo isomer to epibatidine ( exo isomer) has already been reported 11n…”

Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation

“…It was eventually found that microwave irradiation not only accelerated the reaction considerably, but also shifted the equilibrium in favour of the desired exo isomer (21) relative to previously reported conditions which gave a 1 : 1 mixture of exo (21) and endo (24) isomers. 78 The amine product was then captured onto a sulfonic acid ion exchange resin (Amberlyst A-15) and washed to remove any non-basic impurities. Finally, treatment of the resin with ammonia in methanol afforded a 3 : 1 mixture of easily separable exo (21) and endo (24) isomers (Scheme 33).…”

[3 + 2] Cycloaddition of Nonstabilized Azomethine Ylides. 7. Stereoselective Synthesis of Epibatidine and Analogues,

“…[13][14][15][16][17][18] Similarly, another well exploited methodology for the synthesis of 1 has employed intramolecular nucleophilic ring closure of 1,4-aminocyclohexane derivatives 7, originally developed for the construction of 7-azanorbornane system, 19 and employs multiple steps even to reach the crucial trans-1,4-aminocyclohexanol derivatives. [20][21][22][23][24][25][26][27] More recently, 28 the elaboration of tropinone skeleton (6) into 1 via Favorskii rearrangement by Bai et al, although elegant, suffers from the poor yield. Moreover, these strategies lack easy adaptability for the synthesis of epibatidine analogues.…”