Borane Pyridine Mediated Reductive Amination

Borane pyridine (BAP) is a tempered reducing agent compared to its parent compound, sodium borohydride (NaBH4). It is commercially available, inexpensive, and non-toxic, extensively used in many reduction reactions, notably reductive amination. BAP serves as an alternative reagent for reductive amination, alongside sodium cyanoborohydride (NaBH3(CN)) and sodium triacetoxyborohydride (NaBH(OAc)3). Three seminal articles posted explored three distinctive reaction conditions, employing BAP as a reductant to facilitate reductive amination. These investigations underscored BAP’s versatility across a spectrum of solvents, encompassing both protic and aprotic, as well as polar and nonpolar environments except for highly acidic media. It performs efficaciously with pairs of aldehydes/secondary amines and ketones/primary amines. Additionally, it tolerates numerous functional groups, including esters, alkenes, halides (excluding iodide), nitriles, and some heterocycles.

Despite its advantageous diminished reduction potential, enhancing selectivity for imines over aldehydes and ketones, BAP’s efficacy is constrained in the reduction of sterically demanding and electron-deficient substrates.

MeOH (0.25 M)
4 Å MS (5 X wtH2O)
BH3•py (0.87 eq.)
20 °C, > 1 h

DiMare
J Org Chem
1995, 60, 5995

• Reactions in MeOH were much faster than in DCM, THF, CHCl3, Et2O, and DMF, but all can be used.
• The recommended 4 Å MS to theoretical H2O ratio is 5:1. A lower amount of MS usually resulted in a poorer yield, especially for ketones.
• The ratio of amines to aldehydes/ketones is 1:1.
• A higher concentration facilitates imine intermediate formation.
• Cyclohexanone is as reactive as benzaldehyde and alkyl hexanal.
• Acyclic ketones are less active than cyclohexanone but more active than acetophenone.
• In situ NMR showed only trace amounts of alcohol formed during the reaction. Acid workup presumably promoted alcohol formation (6 N HCl).
• EtOAc, MeCN, and cyclohexene are stable under the reaction conditions.

EtOH (0.54 M)
BH3•py (1.0 eq.)
20 °C, > 4 h


Moormann
Synth Commun 1993, 23, 789

• Nitrile side product could be produced when using NaBH3(CN), especially under acidic conditions.
• BAP was compatible with alkene, ester, alcohol, halide (exclude iodide), methoxy, and tertiary amine.
• Furan/thiophene aldehyde could react with piperidine.
• Pyridine aldehyde was reduced to alcohol due to pyridine’s electron-withdrawing effect, resulting low yields.
• Aliphatic aldehydes proceed well.
• BAP is compatible with both protic and aprotic solvents, including toluene and DCM.

PE/AcOH (7:2)
BH3•py (1.0 eq.)
20 °C, 2-16

Pleter
JCS Perkin Trans. 1984, 717

• Less polar solvents favor reductive amination and suppress carbonyl reduction.
• In AcOH/DCM (2:7), reductive amination is favored at a higher temperature.
• An AcOH/PE (2:7) biphasic system gave a higher yield because the reductant/imine and ketone/aldehyde are in different phases.
• Works better with hindered/less reactive ketones than NaBH3(CN).
• Weakly basic anilines react with aldehydes but not ketones.
• Prefer equatorial attack by BAP, as other hydride reagents on the intermediate imine give cis-products as the major.
• Primary or more basic amines are readily protonated in acidic conditions to prevent condensation reactions with their partners, which are usually reduced to give alcohol.
• Aromatic amines usually react faster than aliphatic amines under acidic conditions.
• Aldehydes usually overreact with primary amines to form dialkylated compounds. Excess amines can prevent this side reaction.
• Separation: Aniline derivatives—silica column; aliphatic amine—distillation; secondary amine salt—precipitation.

References: 

  1. Bomann, M. D.; Guch, I. C.; DiMare, M., A mild, pyridine-borane-based reductive amination protocol. J. Org. Chem. 1995, 60, 5995-5996.
  2. Moormann, A. E., Reductive Amination of Piperidines with Aldehydes Using Borane-Pyridine. Synth. Commun. 1993, 23, 789-795.
  3. Pelter, A.; Rosser, R. M.; Mills, S., Reductive aminations of ketones and aldehydes using borane–pyridine. J. Chem. Soc., Perkin Trans. 1 1984, 717-720.