Reductive amination

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Reductive amination (also known as reductive alkylation) is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is considered the most important way to make amines, and a majority of amines made in the pharmaceutical industry are made this way.[1]

Reaction process

In this organic reaction, the amine first reacts with the carbonyl group to form a hemiaminal species, which subsequently loses one molecule of water in a reversible manner by alkylimino-de-oxo-bisubstitution, to form the imine. The equilibrium between aldehyde/ketone and imine can be shifted toward imine formation by removal of the formed water through physical or chemical means. This intermediate imine can then be isolated and reduced with a suitable reducing agent (e.g., sodium borohydride). This is indirect reductive amination.

However, it is also possible to carry out the same reaction simultaneously, with the imine formation and reduction occurring concurrently. This is known as direct reductive amination, and is carried out with reducing agents that are more reactive toward protonated imines than ketones, and that are stable under moderately acidic conditions. These include sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OCOCH3)3).[2] This reaction has in recent years been performed in an aqueous environment casting doubt on the necessity of forming the imine.[3] This is because the loss of the water molecule is thermodynamically disfavoured by the presence of a large amount of water in its environment, as seen in the work of Turner et al.[4] Therefore, this suggests that in some cases the reaction proceeds via direct reduction of the hemiaminal species.[5]

Variations and related reactions

This reaction is related to the Eschweiler–Clarke reaction, in which amines are methylated to tertiary amines, the Leuckart–Wallach reaction,[6] or by other amine alkylation methods such as the Mannich reaction and Petasis reaction.

A classic named reaction is the Mignonac reaction (1921)[7] involving reaction of a ketone with ammonia over a nickel catalyst for example in a synthesis of 1-phenylethylamine starting from acetophenone:[8]

In industry, tertiary amines such as triethylamine and diisopropylethylamine are formed directly from ketones with a gaseous mixture of ammonia and hydrogen and a suitable catalyst.

Biochemistry

A step in the biosynthesis of many α-amino acids is the reductive amination of an α-ketoacid, usually by a transaminase enzyme. The process is catalyzed by pyridoxamine phosphate, which is converted into pyridoxal phosphate after the reaction. The initial step entails formation of an imine, but the hydride equivalents are supplied by a reduced pyridine to give an aldimine, which hydrolyzes to the amine.[9] The sequence from keto-acid to amino acid can be summarized as follows:

HO2CC(O)R → HO2CC(=NCH2–X)R → HO2CCH(N=CH–X)R → HO2CCH(NH2)R.

See also

References

  1. ↑ Stuart Warren and Paul Wyatt (2008). Organic synthesis : the disconnection approach (2nd ed. ed.). Oxford: Wiley-Blackwell. p. 54. ISBN 978-0-470-71236-8. 
  2. ↑ Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents, Organic Reactions, 1, 59, 2002 (Review)
  3. ↑ Shinya Sato, Takeshi Sakamoto, Etsuko Miyazawa and Yasuo Kikugawa, One-Pot Reductive Amination of Aldehydes and Ketones with α-Picoline Borane in Methanol, in Water, and in Neat Conditions, Tetrahedron, 7899–7906, 60, 2004, doi:10.1016/j.tet.2004.06.045
  4. ↑ Colin J. Dunsmore, Reuben Carr, Toni Fleming and Nicholas J. Turner, A Chemo-Enzymatic Route to Enantiomerically Pure Cyclic Tertiary Amines, J Am Chem Soc, 2224–2225, 128(7), 2006
  5. ↑ V. A. Tarasevich and N. G. Kozloz, Reductive Amination of Oxygen-Containing Organic Compounds, Russian Chemical Reviews, 68(1), 55–72, 1999
  6. ↑ George, Frederick; & Saunders, Bernard (1960). Practical Organic Chemistry, 4th Ed.. London: Longman. p. 223. ISBN 9780582444072. 
  7. ↑ Nouvelle méthodegénérale de préparation des amines à partir des aldéhydes ou des cétones. M. Georges Mignonac, Compt. rend., 172, 223 (1921).
  8. ↑ John C. Robinson, Jr. and H. R. Snyder (1955), "α-Phenylethylamine", Org. Synth. ; Coll. Vol. 3: 717 
  9. ↑ Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6.

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