Isophorone conjugate addition

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. 

Bicyckmnneiation. The first step of a new method for this reaction involves conjugate addition of a cyclic dienolate to a nitro olefin followed by an intramolecular displacement with loss of the nitro group. An example is the reaction of the a -enolale of isophorone (1) with 1-nitropropene. When refluxed with HMPT the initial adduct (2), which can be isolated, is converted into the tricyclooctanones 3 uml 4 iu 63 yield.4... 

This cuprate also underwent the conjugate addition with acyclic enones, for example, 2-hexene-4-one, to give 5-methyl-3-tridecanone in 47% yield. We have not attempted further optimization. Reaction of this calcium cuprate with a sterically hindered enone, for example, isophorone, produced <3% of the desired compound in 24h. The isolated yield, however, increased to 84% when the additives BF3 etherate and chlorotrimethylsilane [12] were used. In the aryl case, / -tolylcalcium cuprate also underwent this transformation with 2-cyclohexenone to give 3-(p-methylphenyl)cyclohexanone in reasonable yield (Table 9.3). 

Conjugate Addition. Reagent (1) in THE adds in 1,2-fashion to Q , -unsaturated ketones, whereas in THF/HMPA, 1,4-addition is observed as result of kinetic control (eq 4) The hindered Q , -unsaturated ketone isophorone gave smooth 1,2-addition in THE (89%), while in THF/HMPA, 1,2- and 1,4-addition occurred (1 1) in low conversion. 1,2-Addition of (1) to acrolein afforded a building block for bongkrekic acid. 1,4-Addition of (1) to j" -(dienyl)Fe(CO)3 substituted alkylidene malonates is highly stereoselective. ... 

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