BRAUN Amine Degradation

BOYLAND - SIMS o-Hydroxyamlme synthesis 46 von BRAUN Amine degradation 47 von Braun 324 Braverman 266... 

The tertiary amines 303 and the acid chlorides 304 (X = Cl) initially formed acylammonium salts 305, which underwent a von Braun type degradation by an attack of the nucleophilic chloride ion at the allyl system to give allyl chlorides 306/307 and carboxylic acid amide functions. 

Subsequent reduction of the prochiral ketone with diborane in THF and chlorination of the resulting secondary alcohol 9 provided a reactive benzylic chloride that underwent subsequent nucleophilic displacement with 4-trifluoromethylphenoxide to give 10. Von Braun degradation of the V,V-dimethyl amine in 10, via the V-cyano intermediate 11, gave racemic fluoxetine (4). 

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-... 

Some ideas exist on circumventing the problem. Amine hydrochlorides at higher temperatures are in equilibrium with HCl and the amine. Provided the amide chloride is thermally stable (no von Braun degradation, no selfcondensation), which is true for a lot of aromatic amide chlorides or formamide chlorides, the amine hydrochloride can be reacted at elevated temperatures (150-170 C) for strongly basic aliphatic amines, whereas weakly basic aromatic amides react under more gentle conditions. In another approach, instead of the amine the A(,A(-dialkylsilylamine is used, hence trimethylsilyl chloride is formed as a byproduct, which can be removed by distillation. 

A dimerisation reaction of N-methylanabasine (17) has been reported and a modification of the useful dealkylation reaction for tertiary amines has been used in a partial degradation (17) -> (18). The harsh conditions necessary for the von Braun reaction of heterocyclic benzamides with phosphorous penta-bromide has generally precluded its application to structural determination. It has now been found that carbonyl bromide is a useful reagent for this reaction... 

The compound was quite obviously an amine due to its basic character. Von Braun degradation (NMe - NCN) and Hofmann degradation (sequential methylation -elimination) implied a cyclic tertiary amine. Further exhaustive Hofmann degradation led to an unusual net elimination of both trimethylamine and ethylene. (This reaction was driven by aromatization of the C-ring after elimination of the Q5-C16-N17 ethylamine bridge). 

Daphniphylline/ —On oxidation with sodium metaperiodiate followed by reduction with sodium borohydride and acetylation, daphniphylline (1) was converted into daphnialcohol acetate (91)." Treatment of (91) with excess cyanogen bromide afforded the cyanamide (92). On heating (92) with 6-M methanolic HCl, an amine (94) containing a new heterocyclic skeleton was obtained, possibly via the intermediate (93). Compound (94) was transformed into the original cyanamide (92) by von Braun degradation and acetylation. The secondary amine (95) proposed as a biogene tic intermediate" could not be obtained. 

The von Braun degradation of tertiary cyclic amines by cyanogen bromide1149,1150 is less important as a preparative reaction than the treatment of benzoyl amines with PX5, but it plays a role in the determination of the structure of alkaloids (see, e.g.9 Bartlett et al.1151). 

The classical example of this type of reaction is the v. Braun method of degradation, by which a secondary amine can be transformed into a primary amine, and finally into ammonia, via the imidoyl chloride intermediates. This reaction has been used for the structure elucidation of alkaloids. Although degradative studies are not conducted to any extent today due to the convenience of spectral methods, the v. Braun elimination is still used in organic synthesis to prepare nitriles as well as alkyl halides. 

The reaction of carboxylic acid amides with phosphorus pentachloride, to yield compounds I and II, was investigated extensively by Wallach and his students in 1876-1882, and later by v. Braun, who utilized this reaction to degrade secondary amines to ammonia. The highly reactive imidoyl chlorides have been used, especially by v. Braun, as synthetic tools to produce a variety of compounds which could not easily be synthesized by other procedures. However, imidoyl chlorides never made the headlines in synthetic organic chemistry, most likely because of the inherent difficulty involved in handling these highly reactive compounds. 

Different from the von Braun degradation reaction (amide to nitrile), the von Braun reaction refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide. 

Methoxycarbonylmercury compounds undergo acid-catalyzed decomposition in the presence of assistors of a soft nature, e.g., RSH, I , and Br (55). In the von Braun degradation (56) tertiary amines are ruptured on exposure to cyanogen bromide to yield bromocyanamides, in accordance with Saville s rule. 

---