Hofmann degradation, 2-stage

Twofold Hofmann degradation of IV without hydrogenation in the first stage, followed by ozonolysis, led to the products XI and XII hence it was inferred that the intermediate X is a mixtru-e of XIII and XIV. 

The Knorr oxazine theory of morphine structure led to the preparation of a series of bases derived from morpholine [xxxm], so called on account of its supposed relationship to morphine [49-50]. In particular it was found that N-methylnaphthalanmorpholine [xxxrv] undergoes Hofmann degradation to a methine base [xxxv] that can be degraded further to naphthalene and /3-dimethylaminoethanol. The extraordinary ease with which this last stage takes place led Knorr to believe that an ort/to-attacbment of the nitrogen side-chain to the phenanthrene residue in the morphine alkaloids was improbable, and he accordingly advanced the structure [xxxvi] [51]). 

L. fil. was determined by X-my analysis of its methiodide. It is thus a close relative of hetisine. The interesting chemical features were its pX (see Section 2B), its acetylation to an N-acetyl ketone and a basic 0-acetate, and its reaction with methyl iodide. The first stage in attempted Hofmann degradation (equation 3) gave the A-methyl ketone. Further methylation and treatment with silver... 

Warren and von Klemperer (166) as this chapter was going to press. The argument rests upon the three-stage Hofmann degradation of (—)-heliotridane to (- -)-3-methylheptane, of known absolute configuration (CXXVII) (167, 168). Thus, (— )-heliotridane, with cis hydrogens at Ci... 

It has now been demonstrated that carpaine, which was previously assumed to be a pyrrolidine derivative, is actually a piperidine alkaloid. The key to the skeleton previously suggested was provided by a nitrogen-free hydroxy acid of probable composition C14H28O3, m.p. 20-25°, isolated from carpaine by a two-stage Hofmann degradation, followed by hydrogenation and hydrolysis (111). Rapoport and Baldridge (112)... 

Isotetrandrine, a crystalline base obtained from the alcoholic extract of Stephania cepharantha, is identical with 0-methylberbamine and must therefore have the structure XXX (23, 35, 126, 127, 132). A two-stage Hofmann degradation of the methiodide of isotetrandrine yielded des-V-isotetrandrine (m.p. 220°), which did not depress the melting points of des-V-berbamine methyl ether. Final proof of the relation of these two alkaloids lies in the fact that berbamine methylated with diazomethane... 

At the same time an important paper (67) appeared in which essentially the same conclusions with regard to the structure of bebeerine were arrived at by a different route. Faltis, Kadiera, and Doblhammer (67) treated the inactive a, a -dimethylbebeerine methine, obtained by a one-stage Hofmann degradation of bebeerine dimethyl ether, with ozone and obtained a mixture of two dimethylamino dialdehydes. These were not isolated but were converted to the chloromethylate derivatives, oxidized with potassium permanganate to the acids, and boiled with dilute alkah to decompose the quaternary bases. Besides trimethylamine, a mixture of two vinyl carboxylic acids were obtained. One of these proved to be 4, 6-dicarboxy-2,3-dimethoxy-5-vinyldiphenyl ether (LIX). The other vinyl carboxylic acid, which was readily separated from LIX by virtue of its low solubility, was first decarboxylated by heating with quinoline and naturkupfer C and then oxidized with potassium permanganate in acetone. This yielded 4-carboxy-2,2 -dimethoxydiphenyl ether (LXIII), the structure of which was proved by direct comparison with the synthetic compound prepared by the Ullmann condensation of o-bromoanisole and vanillic acid. 

---