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Reductive Amination

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General Overview

Reductive amination / reductive alkylation is a methodology for the synthesis of substituted amines from aldehydes or ketones and less substituted amines. Reductive amination is often proposed as a greener way of constructing amines since it avoids having to use reactive and potentially genotoxic reagents like alkyl halides and sulphonates used in traditional SN2 –type reactions of amines with alkylating reagents (and also avoids issues such as over-alkylation).

The reductive amination reaction proceeds via the immediacy of an imine or imminium species, which can be pre-formed/ isolated, but is normally formed and reduced in situ through the judicious choice of a selective reducing agent. As well as aldehydes and ketones, surrogates for these molecules can be used – lactones, hydrates, bisulphite complexes provided an equilibrium exists to provide a sufficient standing concentration of the free carbonyl compound. Dehydrative conditions are sometimes used to increase the rate of imine formation – typically azeotropic drying, or addition of chemical reagents like Ti(iPrO)4, Ti(OEt)4, Al(iPrO)3, orthoformates, activated molecular sieves etc.

Occasionally, carboxylic acids are added as electrophiles in reductive amination reactions. This normally requires a very large excess of both the acid and reducing agent, and probably proceeds via in situ generation of the aldehyde.

Reducing agents used are normally based on boranes – BH3-amine complexes or borohydride reagents like NaBH4, NaHB(OAc)3, NaH3BCN. Alternatively, traditional hydrogenation using supported metal catalysts and hydrogen gas. Occasionally with hydride reagents acids are added as catalysts. These protonate the imine and increase the rate of reduction.

The use of chiral amines to give chiral imines can lead to new chiral products on reduction, and the use of homogeneous metal catalysts/H2 can also give chiral amines from imines/enamines in the presence of chiral ligands. A number of enzymes catalyse reductive amination processes – amino acid dehydrogenases and imine reductases, and these are used for the preparation of chiral amine products. Transaminase enzymes also produce chiral amines, but not via a reductive pathway.

The synthesis of amines from alcohols – ‘borrowing hydrogen’ methodology has been covered in the “alkylation at sp3 carbon” guide.

Green Criteria for Reductive Amination

  1. Large molar excesses of reagents should be avoided if possible.
  2. Ideally reduction with H2/metal catalyst is the preferred reductant
  3. H2 pressure should be minimised
  4. Reagents with lower mass intensity should be used if possible
  5. NaBH4 is preferred over STAB and Cyanoborohydride
  6. If STAB/Cyanoborohydride are used, stoichiometry should be optimised to reduce any excess of the reductant
  7. Reaction conditions should be optimised to avoid loss of aldehyde/ketone to side reactions such as reduction/aldol condensations
  8. The use of dehydrating agents should be avoided if possible
  9. Azeotropic drying is preferred
  10. If primary or secondary amines are the targets, the reaction should be optimised to avoid over-alkylation.
  11. See also:

    Green Chem. 2013, 15, 1542-1549 Development of GSK’s reagent guides – embedding sustainability into reagent selection

General Literature Reviews on Reductive Amination

Reductive Amination Review

Russian Chemical Reviews, 2015, 84(3) 288-309 New potential of the reductive alkylation of amines

Adv. Synth. Catal. 2011, 353, 804 Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction

J. Am. Chem. Soc., 1933, 55. 4571–4587 The Action of Formaldehyde on Amines and Amino Acids Eschweiler-Clarke reductive alkylation of amines

Organic Reactions, 2001, 59, 1. Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

Tetrahedron  Asymmetry, 1998, 9(5), 715-740.  Recent applications of α-phenylethylamine (α-PEA) in the preparation of enantiopure compounds. Part 1: Incorporation in chiral catalysts. Part 2: α-PEA and derivatives as resolving agents

Chem. Soc. Rev., 1998, 27, 395-404 Sodium borohydride in carboxylic acid media: a phenomenal reduction system

ChemCatChem., 2010, 2, 1346-1371 Highlights of Transition Metal-Catalyzed Asymmetric Hydrogenation of Imines

Synth. Commun., 2013, 43, 2127-2133 Synthesis of Primary Amines by One-Pot Reductive Amination of Aldehydes

Org. Process Res. Dev., 2001, 5, 283–293 Case Studies in Process Screening and Optimization Utilizing a New Automated Reactor−Analysis System