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 S_N2 –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

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

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

www.organic-chemistry.org/synthesis/C1N/amines/reductiveamination.shtm