Piperidines, addition conjugated esters

There ate many examples of piperidine carboxylic acids, prepared by a variety of methods. Reduction of azide 7.278 led to an amine, and subsequent internal Michael addition to the conjugated ester gave methyl 2-(2-piperidino)ethanoate, 7.27P.138... 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

For both 1 and 2, the synthesis started with the alkenyl amide 3. Salen-mediated conjugate addition proceeded with remarkable induction, to give S in 92% as a mixture of diastereomers. Reduction and cyclization followed by deprotonation and kinetic quench delivered the enantiomerically-enriched cis dialkyl piperidine 6. Homologation of the two sidechains then gave the alkenyl boronic ester 8. 

Bicyclic azepine 33 was formed by the conjugate addition of a piperidine to a tethered a,P-unsaturated ester 32 which was formed by the Morita-Baylis-Hillman reaction of the corresponding aldehyde 31 <07JOC5608>. 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

---