Reductive amination
Reaction type Coupling reaction
Identifiers
RSC ontology ID RXNO:0000335

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 a common method to make amines and is widely used in green chemistry since it can be done catalytically in one-pot under mild conditions. In biochemistry, dehydrogenase enzymes use reductive amination to produce the amino acid, glutamate. Additionally, there is ongoing research on alternative synthesis mechanisms which various metal catalysts which require more mild reaction conditions, allowing the reaction to be less energy taxing. Investigation into biocatalysts, such as EnelRED, have allowed for the reduction of chiral amines which is an important factor in pharmaceutical synthesis.[1]

Reaction process

Direct Reductive Amination

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 method is sometimes called indirect reductive amination.

Indirect Reductive Amination

In a separate approach, imine formation and reduction can occur sequentially in one pot. This approach, known as direct reductive amination (Borch reaction), employs reducing agents that only react slowly (or not at all) with the ketone/aldehyde precursors. These hydride reagents also must tolerate moderately acidic conditions. Typical reagents that meet these criteria include sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OCOCH3)3).[2] These reactions are generally conducted at pH ~ 5, typically using a weak acid (e.g., acetic acid) as a catalyst. Under these conditions, the reaction of the carbonyl and amine results in formation of a small amount of the iminium ion (R1R2C=N+R3R4), which is reduced much more readily than the carbonyl starting material. As a result, the selective reduction of the iminium takes place to give the amine (rather than direct reduction of the carbonyl to form the alcohol).[3]

The intermediates of a reductive amination reaction.


Intramolecular reductive amination can also occur to afford a cyclic amine product if the amine and the carbonyl are on the same molecule of the starting material.

There are many considerations to be made when designing a reductive amination reaction.[4]

  1. Chemoselectivity issues may arise since the carbonyl group is also reducible.
  2. The reaction between the carbonyl and amine are in equilibrium, with favouring for the carbonyl side unless water is removed from the system.
  3. Reducible intermediates may appear in the reaction which can affect chemoselectivity.
  4. The amine substrate, imine intermediate or amine product might deactivate the catalyst.
  5. Acyclic imines have E/Z isomers. This makes it difficult to create enantiopure chiral compounds through stereoselective reductions.

To solve the last issue, asymmetric reductive amination reactions can be used to synthesize an enantiopure product of chiral amines.[4] In asymmetric reductive amination, a carbonyl that can be converted from achiral to chiral is used.[5] The carbonyl undergoes condensation with an amine in the presence of H2 and a chiral catalyst to form the imine intermediate which is then reduced to form the amine.[5] However, this method is still limiting to synthesize primary amines which are non-selective and prone to overalkylation.[5]

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]

Reductive amination acetophenone ammonia

Nowadays, one-pot reductive amination fulfil by acid-metal catalysts that act as a hydride transfer. Much research study on this kind of reaction show high efficiency.[9]

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.

In green chemistry

Reductive amination is commonly used over other methods such as SN2 type reactions with halides to produce an amine since it can be done in mild conditions and has high selectivity for nitrogen-containing compounds.[10][11] Reductive amination can occur sequentially in one-pot reactions, which eliminates the need for intermediate purifications and reduces waste.[10] Some multistep synthetic pathways have been reduced to one step through one-pot reductive amination.[10] This makes it a highly appealing method to produce amines in green chemistry.

Biochemistry

In biochemistry, dehydrogenase enzymes can catalyze the reductive amination of α-keto acids and ammonia to yield α-amino acids. Reductive amination is predominantly used for the synthesis of the amino acid glutamate starting from α-ketoglutarate, while biochemistry largely relies on transamination to introduce nitrogen in the other amino acids.[12]

In the critically acclaimed drama Breaking Bad, main character Walter White uses the reductive amination reaction to produce his high purity methamphetamine, relying on phenyl-2-propanone and methylamine.

See also

References

  1. ↑ Thorpe, Thomas W.; Marshall, James R.; Harawa, Vanessa; Ruscoe, Rebecca E.; Cuetos, Anibal; Finnigan, James D.; Angelastro, Antonio; Heath, Rachel S.; Parmeggiani, Fabio; Charnock, Simon J.; Howard, Roger M.; Kumar, Rajesh; Daniels, David S. B.; Grogan, Gideon; Turner, Nicholas J. (April 2022). "Multifunctional biocatalyst for conjugate reduction and reductive amination". Nature. 604 (7904): 86–91. Bibcode:2022Natur.604...86T. doi:10.1038/s41586-022-04458-x. hdl:11311/1232494. ISSN 1476-4687. PMID 35388195. S2CID 248001189.
  2. ↑ Baxter, Ellen W.; Reitz, Allen B. (2004). "Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents". In Overman, Larry E. (ed.). Organic Reactions. pp. 1–714. doi:10.1002/0471264180.or059.01. ISBN 978-0-471-17655-8.
  3. ↑ Vollhardt, K. Peter C. (2018). Organic chemistry : structure and function. Neil Eric Schore (8th ed.). New York. pp. 1036–1037. ISBN 978-1-319-07945-1. OCLC 1007924903.{{cite book}}: CS1 maint: location missing publisher (link)
  4. 1 2 Wang, Chao; Xiao, Jianliang (2013), Li, Wei; Zhang, Xumu (eds.), "Asymmetric Reductive Amination", Stereoselective Formation of Amines, Berlin, Heidelberg: Springer Berlin Heidelberg, vol. 343, pp. 261–282, doi:10.1007/128_2013_484, ISBN 978-3-642-53928-2, PMID 24158548, retrieved 6 November 2023
  5. 1 2 3 Reshi, Noor U Din; Saptal, Vitthal B.; Beller, Matthias; Bera, Jitendra K. (19 November 2021). "Recent Progress in Transition-Metal-Catalyzed Asymmetric Reductive Amination". ACS Catalysis. 11 (22): 13809–13837. doi:10.1021/acscatal.1c04208. ISSN 2155-5435. S2CID 240250685.
  6. ↑ George, Frederick & Saunders, Bernard (1960). Practical Organic Chemistry, 4th Ed. London: Longman. p. 223. ISBN 9780582444072.
  7. ↑ Mignonac, Georges (1921). "Nouvelle méthode générale de préparation des amines à partir des aldéhydes ou des cétones" [New general method for preparation of amines from aldehydes or ketones]. Comptes rendus (in French). 172: 223.
  8. ↑ Robinson, John C.; Snyder, H. R. (1955). "α-Phenylethylamine". Organic Syntheses. doi:10.1002/0471264180.os023.27.; Collective Volume, vol. 3, p. 717
  9. ↑ Kalbasi, Roozbeh Javad; Mazaheri, Omid (2015). "Synthesis and characterization of hierarchical ZSM-5 zeolite containing Ni nanoparticles for one-pot reductive amination of aldehydes with nitroarenes". Catalysis Communications. 69: 86–91. doi:10.1016/j.catcom.2015.05.016.
  10. 1 2 3 Van Praet, Sofie; Preegel, Gert; Rammal, Fatima; Sels, Bert F. (12 May 2022). "One-Pot Consecutive Reductive Amination Synthesis of Pharmaceuticals: From Biobased Glycolaldehyde to Hydroxychloroquine". ACS Sustainable Chemistry & Engineering. 10 (20): 6503–6508. doi:10.1021/acssuschemeng.2c00570. ISSN 2168-0485. S2CID 248767494.
  11. ↑ He, Jian; Chen, Lulu; Liu, Shima; Song, Ke; Yang, Song; Riisager, Anders (2020). "Sustainable access to renewable N-containing chemicals from reductive amination of biomass-derived platform compounds". Green Chemistry. 22 (20): 6714–6747. doi:10.1039/d0gc01869d. ISSN 1463-9262. S2CID 225001665.
  12. ↑ Metzler, D. E. "Biochemistry—The Chemical Reactions of Living Cells, Vol. 2" 2nd Ed. Academic Press: San Diego, 2003.
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