Von Braun degradation

Prior and Wiegrebe (52,53) examined the von Braun degradation of 7,8-secoberbines. It proceeded analogously to the reaction with chloroformates... 

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). 

Demethylation at the nitrogen in position 6 could be realized by new modifications of the von Braun degradation. The 6-nor-6-cyano derivatives 46, obtained in the usual way by the action of cyanogen bromide on the parent compounds, could be reduced directly with zinc in acetic acid in good yield (46) to the 6-nor compounds (47). An alternative procedure was published independently by a Japanese group (47), using a two-step process via a urea-type compound 48. 

Biogenetically, daphnilactone-B (36) is regarded as a plausible intermediate between daphniphylline-type and yuzurimine-type alkaloids. Thus, daphnilactone-B (36) was converted to a daphniphylline-type compound (38, mp 166-168° C22H3302N) via a bromocyanamide [39, mp (dec) 210°] and a debromocyanamide (40, mp 208-212°), as shown in Scheme V. The structure of this daphniphylline-type compound 38 was confirmed by its mass, IR, and NMR spectra coupled with von Braun degradation of 38 leading to the formation of a new... 

Von Braun degradation of 55 with BrCN in benzene followed by NBH reduction in dimethyl sulfoxide (DMSO) afforded a cyanamide... 

The zero-bond in a bicyclic system with certain structural features can be cleaved by the von Braun degradation. In this case a nitrogen atom must be in a bridgehead position. For example, ring cleavage of the dihydroindole derivative, VIII/118, gives benzazocines VIII/119 and VIII/120 in good yields [70] [71], Scheme VIII/22. 

C. The Quaternary Salts and Their Reactions with Nucleophilic Reagents The Hofmann and von Braun Degradations... 

The von Braun degradation (85, 67) was reinvestigated and fully worked out by Boit (86). The reaction of strychnine with cyanogen bromide in hot benzene leads to the formation of two products, the amorphous bromocyanamide-I (LXXX) and the crystalline bromo-cyanamide-II (LXXXI). Dihydrostrychnine, on the other hand, gives only one product (LXXXII), which is identical with the product of catalytic hydrogenation (platinum in ethyl acetate) of bromocyan-amide-II. The corresponding brucine compounds behave analogously. 

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. 

The reaction product (CXLVII) of matrine and cyanogen bromide primarily undergoes the von Braun degradation. The halogen can be... 

Norlatifoline had been previously synthesized 97) from conessine via 3 -hydroxyconan-5-ene by cyanogen bromide degradation or, alternatively, from 3a,5a-cycloconan-6-one by von Braun degradation and re-formation of the 3 3-hydroxy-5,6-unsaturated steroid system. 

Monoterpene Bases.—Yohimbine-Corynantheine (and Related Oxindoles)-Pier aline Group. It is well known that 3,4-dehydroyohimbane (35a) is reduced by zinc-acetic acid to a mixture of yohimbane (35c) and i/ -yohimbane (35d) however, when 10-methoxy-3,4-dehydroyohimbane (35b) was similarly treated, a 2,3,4,7-tetrahydro-derivative (17 % yield) was formed as well as the corresponding 10-methoxy-yohimbanes. It was shown that this did not arise by further reduction of either of the methoxy-yohimbanes and no explanation is yet available for this interesting difference. Reserpine, a 6-methoxyindole, underwent C(3)-N(4) bond fission on reaction with zinc-acetic acid, as did indoles with no ring A methoxy-group. Cleavage of the C(3)-N(4) bond with the formation of N(4)-cyano-C(3)-alkoxy- or hydroxy-seco-derivatives was observed when yohimbine, i/ -yohimbine, and methyl reserpate were subjected to von Braun degradation conditions in alcohol or aqueous solution. 

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). 

The reactions of sandwicine and several of its derivatives, and notably their behaviour in the von Braun degradation, have been... 

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. 

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