Ketones, reaction with cyanoborohydride

Derivatives of hydrazine, especially the hydrazide compounds formed from carboxylate groups, can react specifically with aldehyde or ketone functional groups in target molecules. Reaction with either group creates a hydrazone linkage (Reaction 44)—a type of Schiff base. This bond is relatively stable if it is formed with a ketone, but somewhat labile if the reaction is with an aldehyde group. However, the reaction rate of hydrazine derivatives with aldehydes typically is faster than the rate with ketones. Hydrazone formation with aldehydes, however, results in much more stable bonds than the easily reversible Schiff base interaction of an amine with an aldehyde. To further stabilize the bond between a hydrazide and an aldehyde, the hydrazone may be reacted with sodium cyanoborohydride to reduce the double bond and form a secure covalent linkage. 

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. 

The first reported synthesis of MDMA was from safrole by converting it to its bromo derivative followed by reaction with meth-ylamine (Biniecki et al., 1960). Bailey et al. describe the synthesis of MDMA from 3,4-methylenedioxyphenylacetone using a Leuckart reaction with N-methylformamide and hydrolysis of the N-formyl derivative (Bailey et al., 1975). A third synthesis for MDMA described in the literature starts with peperonal which is reacted with nitroethane, ammonium acetate, and acetic acid to form a nitrostyrene derivative that is reduced to the ketone and then reacted with methylamine to form MDMA (Rabjohns, 1963). Using the method of Borch et al., MDMA can be synthesized by the reductive amination of the appropriate ketone in the presence of sodium cyanoborohydride (Borch et al., 1971). The MDMA syntheses used in clandestine laboratories are analogous. 

In an alternative approach, Nakayama and Schultz [25] have successfully achieved the enantiofacial reduction of prochiral ketones. By utilizing the phosphonate hapten 15 catalytic antibodies were elicited which catalyze a highly stereospecific reduction of ketone 16 with sodium cyanoborohydride as a cofactor (Scheme 4). The most active antibody, A5, was found to have a pH optimum at acidic pH, consequently the reductions were performed in aqueous buffer at pH 5.0. The reaction was followed for multiple turnovers (>25) without any decrease in activity or stereoselectivity highlighting the utility of this catalytic system. 

Redox catalysis with antibodies was first described for the reduction of resazu-rin using sulfite [43] and for heme-based peroxidase activity [44]. Concerning reactions relevant to preparative synthesis, Schultz and coworkers have described an elegant regio- and enantio-selective reduction of ketone 25 a with cyanoborohydride giving enantioselectively keto-alcohol 26 using an antibody... 

Aldehydes and ketones are unaffected by sodium cyanoborohydride in neutral solution, but they are readily reduced to the corresponding alcohol at pH = 3-4 by way of the protonated carbonyl group. By previous exchange of the hydrogens of the borohydride for deuterium or tritium, by reaction with D2O or tritiated water, an efficient and economical route is available for deuteride or tritiide reduction of aldehydes and ketones. 

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. 

In the presence of excess monoalkylamine, carbonyl compounds in aqueous solution are in equilibrium with the corresponding imine. In most cases these imines cannot be isolated but they are reduced at a less negative potential than the carbonyl compound. Selective reduction of such equilibrium mixtures is a useful route to alkylamines from ketones in yields of 70-90%. The process fails with hindered ketones such as camphor and with bulky amines such as fert.-butyl amine. Overall the reaction has advantages of lower costs and simpler work-up compared to the use of cyanoborohydride reducing agents. In the electrochemical reaction, protonation of carbanion intermediates occurs from the more hindered side and where two isomeric products are fomied, the least hindered amine predominates [193]. 

Reduction of chiral ketoximes results in formation of a new stereogenic center. Although mixtures of stereoisomers are generally obtained, kineticaUy controlled reduction of cyclic oximes (e.g. 86, equation 59 and 87, equation 60) with sodium cyanoborohydride can proceed with high diastereoselectivity Stereoselectivity in these reactions closely resembles that of reduction of ketones with complex hydrides featuring attack from the least hindered side. 

Reductive amination (or alkylation) may be used to conjugate an aldehyde- or ketone-containing molecule with an amine-containing molecule. The reduction reaction is best facilitated by the use of a reducing agent such as sodium cyanoborohydride,... 

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

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). 

Another reducing agent that can be used in this reaction is sodium cyanoborohy-dride, a derivative of sodium borohydride with one of the hydrogens replaced by a cyano group. Sodium cyanoborohydride is less nucleophilic than sodium borohydride and does not react with aldehydes or ketones under these conditions. However, it does react with the protonated form of the imine. which is considerably more electrophilic ... 

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. 

This transient intermediate decarboxylates under reaction conditions to afford the bis(enone) 154. Hydrogenation over platinum proceeds to give the saturated ketone (155). Treatment of 155 with benzylamine in the presence of cyanoborohydride leads to the product from reductive amination (156). Acylation with hydrocinnamoyl chloride affords the amide 157. ... 

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. 

Treatment of cyclopropyl ketones with an acidic methanol mixture of an amine and sodium cyanoborohydride afforded the corresponding 1-amino-1-cyclopropylalkanes in moderate yields.The same reaction has been achieved with a similar compound by using dimethylammonium formate in dimethylformamide. ... 

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