Von Braun cyanogen bromide reaction

H. A. Hageman, "The Von Braun Cyanogen Bromide Reaction," in R. Adams and co-workers, eds.. Organic Reactions, Vol. 7, John Wiley Sons,... 

The reaction of phenyl chloroformate with tertiary aliphatic and alicyclic amines to give the corresponding N-carboxylates (pathway a) is an efficient general procedure for cleavage of tertiary amines, and provides a convenient alternative to the weil-known von Braun cyanogen bromide cleavage. The choice of phenyl chloroformate over alkyl esters in this reaction probably results in suppression of the undesired competitive reaction pathway b. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

K. H. Pausacker, Current Trends Heterocyclic Chem., Proc. Symp., Canberra, 1957 p. 8. Academic Press, New York, 1958. von Braun reaction (cyanogen bromide reaction of amines, including heterocycles) ... 

Treatment of quinoline with cyanogen bromide, the von Braun reaction (17), in methanol with sodium bicarbonate produces a high yield of l-cyano-2-methoxy-l,2-dihydroquinoline [880-95-5] (5) (18). Compound (5) is quantitatively converted to 3-bromoquinoline [5332-24-1], through the intermediate (6) [66438-70-8]. These conversions are accompHshed by sequential treatment with bromine in methanol, sodium carbonate, or concentrated hydrochloric acid in methanol. Similar conditions provide high yields of 3-bromomethylquinoHnes. 

Deall lation. Chloroformates such as vinyl chloroformates (40) are used to dealkylate tertiary amines. Chloroformates are superior to the typical Von Braun reagent, cyanogen bromide, because of increased selectivity producing cleaner products. Other chloroformates such as aHyl, methyl, phenyl, and trichloroethyl have also been used in dealkylation reactions. Although the dealkylation reaction using chloroformates is mostiy carried out on tertiary amines, dealkylation of oxygen or sulfur centers, ie, ethers or thioethers, can also be achieved. a-Chloroethyl chloroformate [50893-53-3] (ACE-Cl) (41,42) is superior to all previously used chloroformates for the dealkylation reaction. ACE-Cl has the advantage that the conditions requked for ACE... 

The von Braun reaction (Scheme 6) is another basic reaction for C—N bond cleavage 32). Tetrahydroberberine (26) was heated under reflux with cyanogen bromide in benzene to afford the bromocyanide (28) and the unsaturated cyanide (29) through C-6—N and C-14—N bond cleavage, respectively. The C-8—N bond cleavage product was not obtained because of the steric hindrance of the methoxyl group at C-9 in SN2-type reactions 33). The... 

Alternatively, as shown in Scheme 2, the von Braun reaction of 16 using cyanogen bromide produced the N-cyanopiperidine 17. Acidic hydrolysis of 17 in refluxing glacial acetic acid containing concentrated HCI then provided desloratadine (2) in 93% yield. 

Treatment of quinoline with cyanogen bromide, the von Braun reaction, in methanol with sodium bicarbonate produces a high yield of l-cyano-2-methoxy-1,2-dihy droquinoline (3). 

The von Braun Reaction with Dihydroatisine.—Indian researchers37 have reported a study of the von Braun reaction of dihydroatisine (29) and a mass spectral analysis of the resulting product, the N-nitrile (93). Reduction of atisinium chloride (94) with sodium borohydride gave dihydroatisine (29). The reaction of the latter with cyanogen bromide in anhydrous ether at room temperature for 24 hours gave (93) [m.pt 265 °C] in a yield of 86%. Acid hydrolysis of (93) with 10% HC1 afforded compound (95). 

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. 

Generation of benzomorphan secondary amines, for conversion to appropriate N-substituted derivatives, usually requires N-demethylation of the corresponding tertiary amine. This may be effected by the von Braun reaction with cyanogen bromide or by the use of alkyl-, halogenated alkyl-, and arylchloroformates or diethylazodicarboxylate. Methods for N-demethylation in the series have been summarized by Rice.(62) Removal of an N-benzyl substituent affords an alternative path to norbenzomorphans and is exemplified by Michne and co-workers(63) and Kametani and Aoyama.(s4)... 

The von Braun reaction involves the cleavage of tertiary amines by cyanogen bromide to give an alkyl bromide and a disubstituted cyanamide, and can be applied to many tertiary amines.Usually, the R group that cleaves is the one that gives the most reactive halide (e.g., benzyl or allyl). For simple alkyl groups, the smallest... 

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

During investigations of the reaction between cyanogen bromide and cyclic bases von Braun [17] discovered that thebaine reacts with this compound to give a substance subsequently identified as cyanonorthe-benine [xv] [18]. This cannot be prepared from thebenine, nor can it be hydrolysed to northebonine. On catalytic reduction it absorbs eight... 

Further studies of the von Braun reaction with 8-isoLSD and the dihydroderivatives of LSD and 8-isoLSD showed that the reaction was completely or almost completely inhibited in those isomers that possessed an axial substituent at C-8 in a 1,3-diaxial relationship with respect to the lone electrons on the basic nitrogen atom otherwise the reaction with cyanogen bromide proceeded smoothly. 

The synthesis of buprenorphine has a certain similarity to that of etorphine. After the Diels-Alder reaction of thebaine with methyl vinyl ketone, the double bond is hydrogenated. Then follows a Grignard reaction with t-butyhnagnesium chloride. For modification of the tertiary amine, this is demethylated with cyanogen bromide (von Braun reaction) and treated with cyclopropanecarbonyl chloride. Following reduction with lithium aluminium hydride, the aromatic methoxy-group is finally replaced by nucleophihc substitution under forcing conditions. 

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. 

Contrary to an earlier report O-acetyldemissidine (275) reacted smoothly with cyanogen bromide in refluxing chloroform to yield bromocyanamide 276. In agreement with the postulated mechanism of the von Braun degradation, reaction of CN with the nitrogen lone pair of electrons at the j face of... 

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