Cyanogen bromide, reactions with tertiary amines

Cyanoethylation, 5, 2 Cyanogen bromide, reactions with tertiary amines, 7, 4... 

The effect of cyanogen bromide on acyclic tertiary amines is to remove the smallest w-alkyl group (up to w-hexyl) as alkyl bromide in reaction (a). This reaction usually leads to the alkyl bromide that most readily exchanges its bromine thus, when R is allyl or benzyl it readily appears as the bromide RBr, but when R is phenyl this is not so. The quaternary ammonium bromide is obtained as by-product, by reaction of the RBr with the tertiary amine used,... 

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... 

VOll Braun reaction. Reaction of tertiary amines with cyanogen bromide to form disubsti-tuted cyanamides and an alkyl halide. 

The reaction has found use in the degradation of alkaloids . Unlike the Hofinann exhaustive methylation procedure which may be repeated until the nitrogen of the natural product is freed as tertiary amine, the cyanogen bromide reaction is only practicable with tertiary amines. With secondary amines, cyanogen bromide yields disubstituted cyanamides direcdy and these react further with the amine hydrobromide formed at the same time to give guanidines (equation 53) . 

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)... 

Indirect routes232 can be employed to synthesize JV,JV-bis(TMS)-carbodiimide (458) (a) by applying silver imidazole to 7V,jV-bis(TMS)-thiourea (457) (equation 213), (b) by reaction of Me3SiCl with silver cyanamide (459) (equation 214), (c) by reaction of Me3SiCl with hydrogen cyanamide (460) in the presence of a tertiary amine (equation 215) and (d) from cyanogen bromide (461) and hexamethyldisilazane (405) (equation 216). 

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. 

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. 

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