Imines sodium cyanoborohydride

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

The reactivity of these tricyclic compounds has been investigated in detail. Reaction of these with sodium cyanoborohydride in acetic acid reduces the imine double bonds to give the tetrahydro-derivatives, for example, 37 gives 39. Reaction of 37 with sodium methoxide results in the ring-opened sulfonate salt 40 re-acidification of this salt gives the corresponding sulfonic acid which cyclizes back to the tricycle 37. Further heating of the sulfonic acid... 

Hydrogen will not reduce ketones or imines using CATHy or related catalysts. Inorganic hydrogen donors that have been used include dithionite and di-hydrogenphosphite salts, metal hydrides such as sodium borohydride, and sodium cyanoborohydride. Recently, amines have been shown to function as hydrogen donors with some catalysts. The enzymic cofactor NADH can be used stoichiometrically, and the potential exists to use this catalytically [56]. 

Schkeryantz and Pearson (59) reported a total synthesis of ( )-crinane (298) using an intramolecular azide-alkene cycloaddition (Scheme 9.59). The allylic acetate 294 was first subjected to an Ireland-Claisen rearrangement followed by reduction to give alcohol 295, which was then converted into the azide 296 using Mitsunobu conditions. Intramolecular cycloaddition of the azide 296 in refluxing toluene followed by extrusion of nitrogen gave the imine 297 in quantitative yield. On reduction with sodium cyanoborohydride and subsequent reaction with... 

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). 

Direct conversion of 14 to (+)-himbacine is achieved in a one-pot procedure by removing the BOC group with trifluoroacetic acid and reaction of the resulting free amine with aqueous formaldehyde and sodium cyanoborohydride. This reductive elimination furnishes the imine which is in situ reduced to the tertiary amine. Another common method for /V-methylation is the reaction with a base like sodium hydride and methyl iodide. But this method is not suitable for molecules with C-H acidic protons. 

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). 

The authors were unable to carry out any transformation of staphinine and staphimine to staphisine and staphidine, respectively, because of the instability of these alkaloids toward various mild reducing agents (e.g., sodium borohydride, sodium cyanoborohydride). Staphimine and staphinine occur in extremely small amounts in the seeds of D. staphisagria. It has been suggested that the imine-containing alkaloids may be biogenetic precursors of staphisine and staphidine. 

In our selected example, Lehn and coworkers [80] reported the synthesis of a dynamic 12-member, template-directed imine library 1, obtained from the reversible condensation of three aldehydes (monomer set M, Figure 7.11), with four primary amines (monomer set M2, Figure 7.11) in buffered aqueous conditions, followed by irreversible reduction to amines 2 with sodium cyanoborohydride. The library was prepared in the presence of a large excess of M2, to prevent further condensation of an aldehyde onto the secondary amine product. A template-driven imine library 1 was prepared in the presence of the metalloenzyme carbonic anhydrase II (CAII). After the template-assisted, reversible dynamic reaction was complete, the reducing agent was added and the amine library 2 was produced (Figure 7.11). Without any... 

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 ... 

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. 

Catalytic hydrogenation reduces the imine (as the protonated iminium ion) but not the ketone from which it is formed. This chemoselectivity (reduction of iminium ions but not ketones) is also displayed by sodium cyanoborohydride and we can add NaCNBH3 to complete our table of reactivity, if we insert imines at the left-hand end. 

An obvious means by which to increase the affinity of a molecule for DNA is to link the molecule to a short segment of nucleic acid. Such a plan has been pursued by Paoletti and co-workers (129,130). To prepare the tetrathymidylate-ellipticine conjugate 348, these workers synthesized the appropriate ox-azolopyridocarbazole carboxylic acid, as described previously (i.e., 267), and coupled it to the appropriate tetradeoxynucleotide. A second method of linking ellipticine to a nucleic acid involves condensation of the aldehyde moiety of 3 -apurinic octathymidylate with 9-aminoellipticine, followed by reduction of the imine with sodium cyanoborohydride (130). This reaction is depicted in a different context in Scheme 66 (see Section VIII). 

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. 

Na(BH3CN] (sodium cyanoborohydride) Alcohols, water, DMSO 0 to RT ketone —> alcohol aldehyde —> alcohol alkyl halide —> alkane imine —> amine... 

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