Amines from imines reductive amination

A useful way of making amines is by reduction of imines (or iminium ions). This overall process, from carbonyl compound to amine, is called reductive amination. This is, in fact, one of the few successful ways, and the best way, of making secondary amineLs. This should be your first choice in amine synthesis. 

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. 

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. 

In the second step of the synthesis, amine plus formaldehyde gives an imine, present as its protonated iminium form, which gets reduced. Formaldehyde is so reactive that it reacts again with the secondary amine to give an iminium ion again, this is reduced to the amine. 

Living things make amino acids using imines 

You wifi again meet the hignly electrophilic Iminium ions produced by re ctiwi of fofrmaldetiyde with amines in Chapter 27, where we introduce you tothe Manrtic reaction. 

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Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

Since imines derived from alkyl-alkyl ketones are relatively unstable, reductive amination may be more practical compared to imine reduction. Compared to the reductive amination, which employs three equivalents of the ketone substrate, the in situ imine generation/one-pot reduction protocol has the significant advantage that it does not require an excess of the carbonyl compound. 

It can be seen that the de does not reach zero, as the benzylic chiral center induces diastereoselective imine reduction, depending upon the system thermodynamics (that is catalyst, solvent, and temperature). Since the epimerization is first order with respect to the (IS, 4R) isomer but zero order with respect to the mixture of isomers, the process is unaffected by concentration and was conveniently run at the same high concentration as that of the mother liquors from the resolution process. A critical part of the process was the separation of the catalyst from the product, and its removal after the amine epimerization was preferred as this provided the greatest potential for its recycle. Removal of the catalyst was achieved by forming an insoluble ammonio complex formed by bubbling gaseous... 

Reduction ofimines using formates Ammonium formates and formic acid have been employed as reducing agents in the synthesis of secondary amines from imines. By simple mixing of the reagents and microwave irradiation without solvent, the amines were produced in good yields within 2.5-10 min (Scheme 4.28)51. 

Mechanistic details involved in imine and carbonyP - reductions are undoubtedly similar, although thorough investigations of the former are lacking. Certainly, hydride transfer to the electrophilic carbon, with or without prior activation by protonation or complexation is essential for both types of ir-systems (Scheme 1). Whether or not alcohol solvents participate in imine reductions by borohydride (in the absence of added acid) to furnish the amine proton (as is the case with carbonyls) is not known and must await detailed kinetic study and analysis of the initial intermediates formed before hydrolysis. Direct, in situ, reductive amination with NaBHsCN has been attributed to initial, reversible formation (via an intermediate hydroxyamine, (1) of an iminium ion (2) from carbonyls and amines followed by rapid attack by hydride (Scheme 2). However, the inermess of an imine (partial structure 3) to the usual reductive... 

Since these adducts undergo reductive desulfurization with Raney Ni, the optically active aryl methyl sulfoxide is a versatile reagent for the synthesis of optically active amines from imines. 

Primary amine formation is equally well promoted in alkaline medium, e.g., aqueous ethanolic NaOH solution, that selectively poisons the catalyst for hydrogenolysis reactions. However, saturated NH3/alcohol solutions best afford almost quantitative yields of primary amines from catalytic reduction of nitriles. Ammonia adds to imine 1 to give a 1,1-diamine, which is hydrogenolyzed to the primary amine. In the presence of NHj, finely divided Ni can be used, platinized finely divided Ni for the hydrogenation of hindered nitriles, and rhodium-on-alumina for sensitive compounds. Mild reduction of 3-indoleacetonitrile to tryptamine [equation (c)] is effected at RT over 5% rhodium-on-alumina in 10% ethanolic NH3 with little side reaction , and branched chain amino sugars are conveniently prepared using this selective hydrogenation [equation (d)] . 

Transfer hydrogenation of ketones is quite general with regard to the molecular complexity of substrates and tolerates many functional groups. Recently, enatioselective transfer hydrogenation has been successfully applied to imine reduction [39]. From a synthetic perspective the principal virtue of this approach is the ease of generation of alcohols and amines in excellent yields with high enantiomeric excess. 

Aldehydes and ketones serve as useful precursors to amino acids when they are converted to a Schiff base (from aldehydes) or an imine (from ketones). Reduction of the imino C=N moiety, usually in situ, generates the amine. When 1.83 (m = 1, 2) was treated with ammonia, for example, the resulting iminium salt (1,84) was hydrogenated to give either 8-aminooctanoic acid (7.[Pg.18]

In parallel work, the synthetic enzyme has been gradually refined through further optimization. In a later paper [139], human carbonic anhydrase 11 was combined with a sulfonamide derived from pyridine/IrCp to create a catalyst for the ATH of imines. The X-ray structure of a derivative was used to improve the catalytic performance, ultimately achieving 68 % e.e. A ribonuclease has also been used as the basis of an artificial amine reductase. In this case, the incorporation of a Cp lr complex gave an efficient and selective artificial enzyme for imine reduction [140]. 

Prim, and sec. amines from oximes Reductive rearrangement s. 72, 411 Cyclic imines from alicyclic nitro compounds... 

Besides the alkylation reactions in polyamine synthesis, the reductive am-ination approach found broad entry in solid phase chemistry in the backbone amide hnker (BAL) strategy [202] (Scheme 2). Thereby, amino acids are bound to a linker via imine reduction bearing a secondary amine, which can be further acylated to obtain peptides with a variety of C-terminal function-ahties. Besides the effective synthesis of C-modified peptides, this also opens access to amide formation in peptides if C- and N-terminal residues are de-protected, commonly leading to cychc peptides [ 177]. Cleavage from the resin... 

On the contrary, the intermediate aldehyde from the reductive ring-opening can be intercepted with an amine prior to the allylation [37]. The allylation takes then place on the formed imine and results in the introduction of an amino group. Thus, treatment of iodofuranose 3 with zinc, benzylamine, and allyl bromide succeeded in giving a 6 1 mixture of the amino dienes 38 and 39 in an 81% yield (Scheme 3.13). 

Reductive amination is a well-known methodology in organic synthesis as is evident from the literature reviews. There are a large number of reports available in the literature that deal with the asymmetric imine reduction, but there are few reports available on asymmetric reductive amination. The asymmetric version of this brilliant methodology was introduced in 1999 when Blaser et al. reported on the first asymmetric reductive amination for the synthesis of metolachlor. ... 

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