Mechanism reductive amination

Pyrazines have been prepared by heating 1,2-dicarbonyl compounds with a-amino acids. Thus Rizzi (308) observed that under the conditions of the Strecker degradation, equimolar amounts of DL-valine (44) and butane-2,3-dione in refluxing bis(2-methoxyethyl) ether, diglyme, gave isobutyraldehyde, tetra-methylpyrazine (9%), and a mixture of cis- and trans-2-isopropyl-4,5-dimethyl-3-oxazoline (4%). He proposed a reductive amination mechanism in which butane-23-dione was converted to 2-aminobutan-3-one which underwent self-condensation to the pyrazine. Tetramethylpyrazine was also prepared when the same reactants were heated in dimethylformamide at 123° for 5 hours (and other pyrazines prepared similarly) (308a). 

DCHA is normally obtained in low yields as a coproduct of aniline hydrogenation. The proposed mechanism of secondary amine formation in either reductive amination of cyclohexanone or arene hydrogenation iHurninates specific steps (Fig. 1) on which catalyst, solvents, and additives moderating catalyst supports all have effects. 

Active Figure 24.4 MECHANISM Mechanism of reductive amination of a ketone to yield an amine. Details of the imine-forming step were shown in Figure 19.8 on page 711. Sign in afwww.thomsonedu.com to see a simulation based on this figure and to take a short quiz. 

One problem with reductive amination as a method of amine synthesis is that by-products are sometimes obtained. For example, reductive amination of benzaldehyde with methylamine leads to a mixture of iV-methylbenzylamine and i -methyldibenzylarnine. How do you suppose the tertiary amine byproduct is formed Propose a mechanism. 

The reaction has broad applications and a large number of secondary and especially tertiary amines was prepared in isolated yields ranging from 60% to 84% [1136]. Although the mechanism of this reaction is not clear it is likely that the key step is reduction of the acid by borane, generated in situ from sodium borohydride and the acid, to an aldehyde which reacts with the amine as described in the section on reductive amination (p. 134-136). 

Another type of reductive amination is shown in Figure 13-18. This reaction illustrates the formation of an amine from a ketone through the formation of an intermediate oxime. Figure 13-19 shows the conversion of a nitrile to an amine. (The nitrile can be formed by the action of cyanide ion, CN", on a halide via an Sf 2 mechanism.)... 

Data given in Table 2. indicated that upon increasing the reaction temperature in the reductive amination of acetone the selectivity towards DIPA especially on tin modified catalysts significantly increased, whereas selectivitiss towards other prodocts decreased in different extent. Such an increase in the selectivity of formation of DIPA upon increasing the reaction temperature can not be explained by thermodynamics LlA], and it has not been observed n conventional skeletal nickel catalysts [2, 14 ]. Therefore, it is suggested that the enhanced selectivity towards OIPA obtained at 19D-20G°C can be attributed to the high A10(0H) content of the catalyst l2]. However, the mechanism of the formation of the secondary amine requires further elucidation. 

Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 °C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. 

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358... 

Mechanism 19-6 Diazotization of an Amine 910 19-17 Reactions of Arenediazonium Salts 911 Summary Reactions of Amines 915 19-18 Synthesis of Amines by Reductive Amination 918 19-19 Synthesis of Amines by Acylation-Reduction 920... 

Based on the above activation mechanism we wondered whether it would be possible to develop a biomimetic, organocatalytic reductive amination or transfer hydrogenation of ketimines. We reasoned that the activation of the imine by catalytic protonation through the Brpnsted acid should enable the hydrogen transfer from a suitable NADH mimic to yield the corresponding amine (Fig. 2). Hence, initial experiments focused on the examination of various Brpnsted acids in combination with different hydride sources (Rueping et al. 2005a). 

Lithium aluminium hydride reduces amides to amines. Mechanism of LiAlH4 reduction of amides is given in Scheme 6.11. 

The first step in the biological degradation of lysine is reductive amination with a-ketoglutarate to give saccharopine. Nicotinamide adenine dinucleotide phosphate (NADPH), a relative of NADH, is the reducing agent. Show the mechanism. 

The molecule is a chiral analogue of pyridoxamine and transamination occurs chemically by a mechanism similar to the biological one described in the chapter (pp. 1384-6). The zinc holds the molecule in a fixed conformation during reaction. The key step is the protonation of the enamine as that produces the new chiral centre. If the chain is across the top of the ring, protonation occurs preferentially from underneath. Hydrolysis gives the new amino acid (Phe) and the pyridoxal analogue, which can be recycled by reductive amination via the oxime. 

Show the mechanism of reductive amination of cyclohexanone and dimethylamine with NaBHaCN. 

Enantiospecific reduction of C=N bonds is of interest for the synthesis of a-amino acids and derivatives such as amines. While nonenzymatic reductive amination has been known since 192711, only recently have enzymatic procedures to L-amino acids became established. The reduction can be achieved by different enzymes following different mechanisms, e.g. by pyridoxalphosphate (PLP)-dependent transaminases (E.C. 2.6.1, discussed in Chapter 12.7) or by amino acid dehydrogenases (E.C. 1.4.1) using NADH or NADPH as the cofactor. The synthetic usefulness of the transaminase reaction is diminished by the location of the equilibrium (Keq often is close... 

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