Sodium cyanoborohydride, reduction imines

Some primary amines, when heated with a catalytic amount of a strong base, are converted into secondary amines this reaction has been studied furtherand an alternative mechanism proposed. A formaldehyde-sodium cyanoborohydride reductive alkylation system provides an efficient method for the per-methylation of amines the success of the method is based on the ability of the borohydride reagent selectively to reduce imines. A correlation has been made between geometric and steric parameters in the quaternization of hindered amines. 

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). 

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). 

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... 

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). 

The absolute configuration of the structurally unique fungal metabolite mycosporins was determined in the laboratory of J.D. White by means of enantioselective total synthesis." In the endgame of the synthetic effort, the Staudinger reaction was used to elaborate the side chain. The cyclic vinyl azide was first converted to a stable vinyl iminophosphorane, which was subsequently reacted with benzyl glyoxylate to afford the corresponding Schiff base. Reduction of the imine was achieved with sodium cyanoborohydride. 

An important PEG attachment chemistry for reaction with amino groups involves PEG aldehydes. In this chemistry, PEG aldehyde reacts with amino group on the target protein to form a reversible Schiff base linkage. The imine intermediate is then reduced with a suitable reductant such as sodium cyanoborohydride (Eigure 24.3). The most notable feature of this reaction is that, when conducted at low pH, the reaction is specific for the amino terminus of the protein [42,43]. The reason for this selectivity is that, relative to other nucleophilic residues in the molecule, the amino terminus has a lower pKa. Therefore, this reaction scheme can be used to reduce the side reactions that form multipegylated products in other amine selective chemistries. 

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