Hofmann degradation, amines from

We have meet NO2 and CN before, but a primary amine can also be made from an amide by the Hofmann degradation (see Norman p.446-7 or Tedder, vol.2, p.281-2). 

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

Fig. 2.1.9. Mass chromatograms (m/z 58) of alkylbenzyldimethylammonium chlorides as their corresponding alkyldimethylamines and the internal standard (undecyldimethyl-amine) (a) prior to debenzylation and (b) after Hofmann degradation with potassium tert-butoxide and El mass spectra detected in river water. Reproduced with permission from Ref. [141]. 2001 by American Chemical Society.

Phenylcyclopentylamine has also been prepared from 1-phenylcyclopentanecarboxylic acid by means of the Hofmann degradation of the intermediate amide4 6 and from the intermediate carboxylic acid chloride by the Curtius reaction.6 In the method described, using the mixed carboxylic-carbonic anhydride,7 improved yields of the amine are obtained. 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

Arylfurazancarboxamides on treatment with alkaline hypochlorite undergo Hofmann degradation to the amines likewise carbamates result from Curtius rearrangement of furazanylacyl azides in the presence of alcohols. 

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

The amine group in primary amines can be replaced by halogen by warming the benzoyl derivative with phosphorus pentachloride or phosphorus pentabromide. Oftentimes, the separation of the halide from the benzonitrile, which is also formed, is troublesome. The process has been applied mostly to high-moIecuIar-weight amines obtained by the Hofmann degradation of acid amides or by reduction of nitriles." Diamines lead to dihalogen derivatives." If N-benzoyl piperidines are treated, substituted pentamethylene halides are formed. An example is the synthesis of pentamethylene bromide by the action of phosphorus pentabromide on N-benzoyl piperidine (72%). ... 

The main interest in steroidal tertiary amino-derivatives has centred on their quaternisation and Hofmann degradation. As part of an extensive study of amines of many types, McKenna found that equatorial amines react more rapidly than their axial epimers with methyl iodide [32], to give quaternary salts, although the situation was reversed at C( ) [33]. Steric hindrance from the C xs) position made the... 

The amines are best prepared by the Hofmann degradation of the homologous amides, which may be obtained from the acyl chloride and ammonia ... 

As a method of synthesis of amines, the Hofmann degradation of amides has the special feature of yielding a product containing one less carbon than the starting material. As we can see, reaction involves migration of a group from carbonyl... 

Ethylene derivatives from oximes via amines Hofmann degradation of quaternary ammonium salts... 

A review of the synthesis of morphinans includes discussion of the possible mechanism of formation of isomorphinans/ The amine (91 R = H) has been used as the key intermediate in the total synthesis not only of 3,14-dihydroxymorphinans and 9a-hydroxy-3-methoxyhasubanans but also of the first 3,14-dihydroxyisomorphinans, e.g. (94), (Scheme 7). Treatment of the morphinan thiocarboxamide (90 R = CSNHPh) with acid, instead of giving a 14-mercaptomorphinan derivative, caused isomerization first to the hasubanan (95) (presumably via an aziridinium intermediate) and then to the thiazinohasubanan (96) (cf. Scheme 8). Mechanisms for these transformations have been discussed in the light of deuterium incorporations observed when H2S04 or HCl was used. The last compound was converted, via an 8-mercapto-compound, into the hasubanan (97 R = H). The structure of this was confirmed by synthesis from (91 R = H) of the product obtained from its Hofmann degradation. 

Amines can also be converted into olefins by thermal treatment (100-200°) of their quaternary hydroxides (Hofmann degradation).82 Of the possible olefins the main product is that containing the smallest number of alkyl substituents i.e., the proton is removed from the / -carbon atom carrying the smallest number of alkyl groups 83... 

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