Degradation reactions Hofmann

Amine oxides 2, which can be prepared by oxidation of amines 1, react upon heating to yield an olefin 3 and a hydroxylamine 4. This reaction is called the Cope elimination reaction,and as a synthetic method is a valuable alternative to the Hofmann degradation reaction of quaternary ammonium salts. 

Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hofmann degradation reaction. 

A reaction pathway important for the structure elucidation of oncinotine and neooncinotine is the acid-catalyzed opening of the lactam ring to the amino acid, which, following esterification with methanolic HC1, is acety-lated and the basic tertiary nitrogen atom methylated with CH3I. The thus-formed quaternary ester acetate mixture of 43 and 44 (as the fluorides) is then pyrolyzed, whereby a Hofmann degradation reaction occurs to form the three compounds 45, 46, and 47, shown in Scheme 6. 

Scheme 6. Hofmann degradation reaction of quaternary ester mixture.

Evidence for the N-10—C-l 1 bond was the Hofmann degradation reaction summarized in Scheme 34. Methylation of aphelandrine (179) afforded a monoquaternized product [dimethylation at N-6], which under mild basic conditions yielded the Hofmann base 186, and under strong basic conditions (retro-Michael reaction) followed by benzoylation yielded the 1,3-di-aminopropane derivative 187. The latter was identified by synthesis. A combination of the arguments given above and further results not described here led to proposal of the structure of 179. The relative and absolute configurations of aphelandrine were determined in connection with the structure elucidation of O-methylorantine (190) (see below). 

The structure elucidation of the main alkaloid 194 was based primarily on the products of a Hofmann degradation reaction resulting in the base 198 (see Scheme 36). The observation was made that homaline, which contains no formal C=C double bonds apart from the two benzene rings, can be transformed (H2/Pd-C) to an open-chained spermine derivative. This derivative can be converted to 199 by methylation (H2CO/H2/Pd-C). The structure of homaline as 194 follows from these properties. Compound 199 was also obtained by hydrogenation of the Hofmann base 198. A structural alternative to 194 could be excluded on the basis of spectroscopic arguments. Similar investigations led to the formulas 195,196, and 197 for the three minor alkaloids. 

Subsequent chlorination of the amide takes place ia a two-phase reaction mixture (a dispersion of diamide ia hydrochloric acid) through which a chlorine stream is passed. The temperature of this step must be maintained below 10°C to retard the formation of the product resulting from the Hofmann degradation of amides. Reaction of the A/,A/-dichloroamide with diethylamine [109-89-7] ia the presence of base yields /n j -l,4-cyclohexane-bis-l,3-diethylurea (35), which is transformed to the urea hydrochloride and pyroly2ed to yield the diisocyanate (36). 

Pyrimidine-5-carboxamide, 4-amino-purine synthesis from, 5, 582 Pyrimidine-5-carboxamide, 4-amino- N- pheny synthesis, 3, 122 Pyrimidinecarboxamides Curtius degradation, 3, 82 dehydration, 3, 82 Hofmann degradation, 3, 82 hydrolysis, 3, 81 reactions, 3, 81 synthesis, 3, 127 Pyrimidinecarboxamides, thio-synthesis, 3, 128... 

Radical copolymerization is used in the manufacturing of random copolymers of acrylamide with vinyl monomers. Anionic copolymers are obtained by copolymerization of acrylamide with acrylic, methacrylic, maleic, fu-maric, styrenesulfonic, 2-acrylamide-2-methylpro-panesulfonic acids and its salts, etc., as well as by hydrolysis and sulfomethylation of polyacrylamide Cationic copolymers are obtained by copolymerization of acrylamide with jV-dialkylaminoalkyl acrylates and methacrylates, l,2-dimethyl-5-vinylpyridinum sulfate, etc. or by postreactions of polyacrylamide (the Mannich reaction and Hofmann degradation). Nonionic copolymers are obtained by copolymerization of acrylamide with acrylates, methacrylates, styrene derivatives, acrylonitrile, etc. Copolymerization methods are the same as the polymerization of acrylamide. 

Our recent studies on effective bromination and oxidation using benzyltrimethylammonium tribromide (BTMA Br3), stable solid, are described. Those involve electrophilic bromination of aromatic compounds such as phenols, aromatic amines, aromatic ethers, acetanilides, arenes, and thiophene, a-bromination of arenes and acetophenones, and also bromo-addition to alkenes by the use of BTMA Br3. Furthermore, oxidation of alcohols, ethers, 1,4-benzenediols, hindered phenols, primary amines, hydrazo compounds, sulfides, and thiols, haloform reaction of methylketones, N-bromination of amides, Hofmann degradation of amides, and preparation of acylureas and carbamates by the use of BTMA Br3 are also presented. 

The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

Fig. 32. Reaction scheme of the Hofmann degradation of amides with BTMA Br3 BTMA Bfj, rt or 70 C...

The rigidity of the hexacyclic cage structure of koumine (18) renders some of its chemical behavior quite unusual, for instance, the resistance to Hofmann degradation shown by /Va-acetyldihydrokoumine methyl hydroxide (27). However, owing to the presence of a /J-aromatic imino system in 18, reductive cleavage by sodium-alcohol to yield dihydrokouminol (39) proceeds smoothly. This reaction has been considered to occur through a radical-anion mechanism as indicated in Scheme 12 (27). 

The Hofmann degradation is the most well-known C—N bond cleavage reaction, and its value to structural elucidation of alkaloids has been demonstrated (76). Hofmann degradation of tetrahydroberberine methohy-droxide (1) led to two products base A (2), the C-14—N bond cleavage product, and base B (3), the C-6—N bond cleavage product (Scheme 2) (17,18). The former was the major product when 1 was heated under reduced pressure, but the latter, the thermodynamically controlled product, predominated when the reaction was carried out at atmospheric pressure or in an alkaline medium because base A recyclized back to the starting quaternary base through the transannular reaction. In fact, 2 was heated in aqueous alcohol to afford 1. The mechanism of this recyclization reaction was discussed by Kirby et al. (19). 

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