Sodium cyanoborohydride carbonyl compounds

Reductive amination of carbonyl compounds. Sodium cyanoborohydride has been the reductant of choice for this reaction, even though it is highly toxic (4, 448-449). Borane-pyridine is recommended as a nontoxic substitute. The reactions are conducted in acetic acid, in which this borane is fairly stable, and a co-solvent such as CH2CI2 or THE... 

A variation of the classical reductive amination procedure uses sodium cyanoboro hydride (NaBH3CN) instead of hydrogen as the reducing agent and is better suited to amine syntheses m which only a few grams of material are needed All that is required IS to add sodium cyanoborohydride to an alcohol solution of the carbonyl compound and an amine... 

Another route to the formation of a hydrazide on a surface is to use an aldehyde-containing particle (such as HEMA/acrolein copolymers) and subsequently modify the aldehydes to form hydrazone linkages with bis-hydrazide compounds, which then can be stabilized by reduction with sodium cyanoborohydride (Chapter 2, Section 5). The resulting derivative contains terminal hydrazides for immobilization of carbonyl ligands (see Figure 14.18). 

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

Reduction of conjugated carbonyl compounds using stoichiometric amounts of the ammonium salt shows little advantage over the sodium salt in acidic methanol [11] with both reagents producing allylic alcohols (58-88% for acyclic compounds and 15-64% for cyclic compounds) by selective 1,2-reduction of the conjugated systems. Aldehydes, ketones and conjugated enones are also reduced by tetra-n-butylammonium cyanoborohydride in HMPA [11, 12], whereas haloalkanes and alkanesulphonic esters are cleaved reductively under similar conditions [13]. 

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. 

Asymmetric reduction of a,/ -unsaturated carbonyl compounds using chiral complexes (Section 5.4.1, p. 521) could feasibly lead to optically active allylic alcohols. Other reducing agents which have some merit of regioselectivity, but not stereoselectivity, are sodium cyanoborohydride,244 and sodium boro-hydride in the presence of lanthanide salts.245... 

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). 

This can be done in two steps, provided the intermediate is stable, but, because the instability of many imines makes them hard to isolate, the most convenient way of doing it is to form and reduce the imine in a single reaction. The selective reduction of iminium ions (but not carbonyl compounds) by sodium cyanoborohydride makes this possible. When NaCNBH3 is added to a typical imine-formation reaction it reacts with the products but not with the starting carbonyl compound. Here is an example of an amine synthesis using reductive amination. 

Ammonia reacts with formaldehyde to give hexamethylenetetramine (3.13) and with acetaldehyde to give a trimer (3.14). Other more steric-ally hindered imines remain as the monoadduct and do not add a. second molecule of amine. These imines are readily reduced by, for example, sodium cyanoborohydride to form amines or they may be hydrolysed to regenerate the carbonyl compound. 

Sodium triacetoxyborohydride Na[BH(OAc)3] ° and hydrogenation (H2, Pd/C) are used as alternatives to sodium cyanoborohydride for the reductive amination of carbonyl compounds. Also, Zn[BH4]2 is a particularly effective agent for the reductive amination of a,p-unsaturated aldehydes and ketones. ... 

The reaction of a 1° or 2° amine with an aldehyde or ketone in the presence of sodium cyanoborohydride (NaBHsCN) to give a 2° or 3° amine is called reductive alkylation (of the amine) or reductive amination (of the aldehyde or ketone) and is a valuable method for alkylating amines. The starting amine is mostly protonated and hence nonnucleophilic under mildly acidic conditions, but it is in equilibrium with a small amount of unprotonated amine that can act as a nucleophile toward the carbonyl compound. NaBH3CN is an acid-stable source of H that reacts only with iminium ions, not carbonyl compounds or imines. Slightly acidic conditions are required to generate the iminium ion. The iminium ion can also be reduced by catalytic hydrogenation (Chapter 6). 

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