Quinolizidine, alkylative cyclization

Alternatively, the enamine portion may be located in the Aralkyl chain. For instance, piperidines bearing a 7-chloro substituent yielded quinolizidines 263 through a conjugate addition of the nitrogen atom to acetylenic sulfones followed by an intramolecular alkylation (Scheme 55) <2000JOC4543>. Other cyclizations that are summarized below used as starting materials piperidine derivatives obtained by similar conjugate additions to vinyl sulfones (see Section 12.01.9.3.6). 

The synthesis of isosophoramine (26) employs as crucial stages the partial hydrogenation of iV-alkyl salts of ) -acyl (or cyano) pyridines, and acid-catalysed cyclization of the resulting l-alkyl-3-acyl (or cyano)-2-piperideines. Alkylation of nicotinonitrile with 6-bromohexan-2-one ethylene ketal afforded the salt (27), which on palladium-catalysed hydrogenation yielded the piperideine (28). Anhydrous acid-catalysed (TsOH) cyclization of (28) gave the three quinolizidine stereoisomers (29)—(31), which were separated and analysed by n.m.r. spectroscopy and equilibration studies in acid (TsOH-CgH ) and alkaline (KOBu -Bu OH)... 

Metallation and alkylation of fV-formamidine derivatives of tetrahydroisoquinolines (173), followed by reductive regeneration of the amino group and intramolecular cyclization, affords benzo[fl]quinolizidines (174) (Scheme 28) <81TL515>. 

In a related procedure, thermal cyclization of 7V-(phenylethyl)glutaric acid monoamide (306) affords benzo[a]quinolizidines (307). An isomer of (306), in the presence of methyl iodide, gave compounds (308) through two successive alkylations <82H(17)263>. Related emetine precursors (309) were similarly obtained (Scheme 68) <90JCS(P1)1469>. 

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