Nitrogen compounds reductive amination

Excellent procedures are available for the preparation of primary, secondary, and tertiary amines by the reduction of a variety of nitrogen compounds. Primary amines can be obtained by hydrogenation or by lithium aluminum hydride reduction of nitro compounds, azides, oximes, imines, nitriles, or unsubstituted amides [all possible with H2 over a metal catalyst (Pt or Ni) or with LiAlH4] ... 

We might first think of removing the structural heteroatom—the ring nitrogen. With reductive amination in mind we might consider imines from 52 or amides from 53. But these compounds have four different carbonyl groups and obviously problems of selectivity arise. 

This section focuses on inhibitors that are transformed by P450 enzymes into metabolic intermediate (MI) products that coordinate so tightly to the heme iron atom that they can be displaced only under unique experimental conditions. The two major classes of these inhibitors are compounds with a dioxymethylene function and nitrogen compounds, usually amines that are converted in situ to nitroso metabolites. A related mechanism is also partially responsible for the inhibition of P450 by 1,1-disubstituted hydrazines and acyl hydrazines. The anaerobic reductive coordination of halocarbons to the heme iron atom is discussed in Section 3.4 because the reaction is linked to destruction of the heme. 

Carbon-nitrogen bond formation, by reductive amination, 59, 1 Carbon-phosphorus bond formation, 36, 2 Carbonyl compounds, addition of... 

Metal-Nitrogen Compounds The cobalt catalyzed reaction of primary and secondary amines with carbon monoxide leads to the formation of formamide derivatives. Dimethylamine, for example, gives iV,i T-dimethvlformamide in 60% yield (90, 91). Very likely cobalt-nitrogen compounds are intermediates which undergo a CO insertion and then reduction. The following mechanism has been suggested for the reaction (90). 

The methyleneamino(hydroxy) or i >[CH2-N(OH)] link 2, which may be also called an N-hydroxy reduced amide bond, was introduced by Grundke et aL in 1987.W Compound 13 can be obtained in good yield by reduction of the homologous (nitrono) peptide 12 (Scheme 2). Alternatively, Urban et aI.15 have prepared the (IV-hydroxy reduced amide) peptide 15, a potent HIV protease inhibitor, by direct oxidation of the amine nitrogen in the homologous reduced peptide 14, obtained by classical reductive amination (Scheme 3). 

To use reductive amination in synthesis, you must be able to determine what aldehyde or ketone and nitrogen compound are needed to prepare a given amine—that is, you must work backwards in the retrosynthetic direction. Keep in mind the following two points ... 

What carbonyl and nitrogen compounds are needed to make each compound by reductive amination When more than one set of starting materials is possible, give all possible methods. 

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