Cyanoborohydride reaction with ammonia

The reductive amination of hexane-2,5-dione and heptane-2,6-dione with ammonia and primary amines RNH2 (R = PhCH2, Ph2CH, PhMeCH, Ph, 4-MeOC6H4, 2-ClC6H4 and 2,6-Me2CgH3) under the influence of sodium cyanoborohydride or sodium triacetoxyboro-hydride has been studied. The reactions yield respectively pyrrolidines and piperidines as mixtures of cis- and fraws-isomers no cyclic products were obtained when 2-chloroaniline of 2,6-dimethylaniline were employed (equation 57)168. 

Consequently, by choosing proper conditions, especially the ratios of the carbonyl compound to the amino compound, very good yields of the desired amines can be obtained [322, 953]. In catalytic hydrogenations alkylation of amines was also achieved by alcohols under the conditions when they may be dehydrogenated to the carbonyl compounds [803]. The reaction of aldehydes and ketones with ammonia and amines in the presence of hydrogen is carried out on catalysts platinum oxide [957], nickel [803, 958] or Raney nickel [956, 959,960]. Yields range from low (23-35%) to very high (93%). An alternative route is the use of complex borohydrides sodium borohydride [954], lithium cyanoborohydride [955] and sodium cyanoborohydride [103] in aqueous-alcoholic solutions of pH 5-8. 

This synthetic procedure, using the hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems to be quite general for ketone compounds related to 3,4-methylenedioxyphenylacetone. Not only were most of the MD-group of compounds discussed here made in this manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P) itself appears to be equally effective. The reaction of butylamine hydrochloride in methanol, with phenyl-2-propanone and sodium cyanoborohydride at pH of 6, after distillation at 70-75 °C at 0.3 mm/ Hg, producedN-butylamphetamine hydrochloride (23.4 g from 16.3 g P-2-P). And, in the same manner with ethylamine hydrochloride there was produced N-ethyl-amphetamine (22.4 g from 22.1 g P-2-P) and with methy lamine hydrochloride there was produced N-methylamphetamine hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple ammonia (as ammonium acetate) gives consistently poor yields in these reactions. 

Aldehyde groups can be converted into terminal amines by a reductive amination process with ammonia or a diamine compound. The reaction proceeds by initial formation of a Schiff base interaction—a dehydration step yielding an imine derivative. Reduction of the Schiff base with sodium cyanoborohydride or sodium bor-ohydride produces the primary amine (in the case of ammonia) or a secondary amine derivative terminating in a primary amine (for a diamine compound) (Fig. 88). 

The reaction of a ketone with ammonia, followed by catalytic reduction or reduction by sodium cyanoborohydride, produces a 1° amine. 

Thus reaction of cyclohexanone, n-propylamine, and sodium cyanoborohydride in methanol at pH 6-8 at 25° for 24 hr. gives n-propyleyelohexylamine in 85 % yield. The reaction is general for ammonia and primary and secondary amines aromatic amines are somewhat sluggish. All aldehydes and relatively unhindered ketones can be reduc-tively aminated. Yields are improved by use of 3A molecular sieves to absorb the water generated in the reaction. Note that reductive amination of substituted pyruvic acids with ammonia leads to oi-amino acids. Thus alanine can be obtained from pyruvic acid in 50 % yield. A pH of 7 is optimum for. synthesis of a-amino acids. 

Reductive amination (Section 21.10) Reaction of ammonia or an amine with an aldehyde or a ketone in the presence of a reducing agent is an effective method for the preparation of primary, secondary, or tertiary amines. The reducing agent may be either hydrogen in the presence of a metal catalyst or sodium cyanoborohydride. R, R, and R" may be either alkyl or aryl. 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

In the first step, the ketone and ammonia arc in equilibrium with their imine, which, at pH 6, is partly protonated as an iminium ion. The iminium ion is rapidly reduced by the cyanoborohydride to give the amine. Reactions like this, using ammonia in a reductive amination, are often carried out with ammonium chloride or acetate as convenient sources of ammonia. At pH 6, ammonia will be mostly protonated anyway. 

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