One of the syntheses starts by the Knoevenagel condensation of cyclohexanone with ethyl cyanoacetate, hydrolysis of which leads to the corresponding cyano acid. The latter loses carbon dioxide under reaction conditions to give 1-cyclohexenylacetonitrile. The out-of-conjugation shift of the olefin is a direct consequence of the mechanism of the decarboxylation reaction.
The use of the Bischler–Napieralski cyclodehydration of phenylacetamides of arylethylamines constitutes one of the standard methods for synthesis dihydroisoquinolines; the reaction interestingly works well when the benzene ring in the cyclization is replaced by cyclohexane. Thus reaction with polyphosphoric acid or POCl3 gives the hexahydroisoquinoline via the enol form of the amide.
Exposure to sodium borohydride or hydrogenation over Raney nickel leads to selective reduction of the imine bond and formation of the morphinan precursor.
There are two ways to proceed with the next stage:
(1): Treatment with strong acid leads proceeds to the morphinan. Acylation with ethyl chloroformate followed by reduction of the intermediate urethane leads to Methorphan. Cleavage of the methyl ether then leads to racemorphan.
(2): The 2° amine is N-methylated by treatment with paraform and reduction over Raney-nickel. The cyclization and O-demethylation step is performed concomitantly with polyphosphoric acid.
^Schnider, O.; Hellerbach, J. (1950). "Synthese von Morphinanen. (2. Mitteilung)". Helvetica Chimica Acta33 (6): 1437. doi:10.1002/hlca.19500330606.
^Submitted by A. C. Cope, A. A. D'Addieco, D. E. Whyte, and S. A.Glickman. Checked by T. L. Cairns and R. E. Heckert. (1951). "CYCLOHEXYLIDENECYANOACETIC ACID AND 1-CYCLOHEXENYLACETONITRILE [Δ1,α-Cyclohexaneacetic acid,α-cyano-, and 1-Cyclohexene-1-acetonitrile]". Organic Syntheses31: 25. doi:10.15227/orgsyn.031.0025.