What Is Borch Reductive Amination Reaction?
Richard F. Borch developed the Borch reductive amination process which stands as a core organic chemistry reaction that turns aldehydes or ketones into secondary or tertiary amines within a single reaction vessel. The reaction creates an imine intermediate by combining a carbonyl compound with an amine which subsequently reduces to produce the corresponding amine. The Borch reductive amination technique stands out from conventional methods because it uses sodium cyanoborohydride (NaBH3CN) to effect selective reductions under mild acidic conditions.
- Reagents: NaBH3CN; acetic acid or ammonium acetate buffer; polar aprotic solvents (e.g., methanol, THF) or aqueous mixtures.
- Reactants: Aldehydes or ketones; amines.
- Products: Secondary amines, tertiary amines.
- Reaction type: Reductive amination.
- Related reactions: Eschweiler-Clarke reaction, Staudinger reaction, Leuckart reaction.
- Experimental tips:
a) pH Control: Maintain pH 4~6 using a buffer (e.g., 1~2 equiv. of ammonium acetate). Excess acid decomposes NaBH3CN, while higher pH deprotonates the imine, hindering reduction.
b) Stoichiometry: Use 1.1~1.5 equiv. of amine and 1~2 equiv. of NaBH3CN relative to the carbonyl compound.
c) NaBH(OAc)3 and 2-picoline-borane are also often used as reducing agents in this reaction. The former is less toxic, and the latter can also be used in water and is often used as an improved method. - Methanol is often used as solvent for NaBH3CN, and DCE or DCM is often used as solvent for NaBH(OAc)3. When the solubility of the raw material is poor, a small amount of DMF can be added to promote dissolution.
Fig 1. Borch reductive amination reaction and its mechanism. [1]
Mechanism of Borch Reductive Amination
- Imine Formation: A primary or secondary amine reacts with the carbonyl group of an aldehyde or ketone to form an imine known as a Schiff base. The reaction step benefits from acid catalysis with acetic acid or ammonium acetate buffer which protonates the carbonyl oxygen to increase its electrophilicity for subsequent nucleophilic attack by the amine.
- Reduction: NaBH3CN selectively reduces the imine intermediate to the corresponding amine. NaBH3CN is preferred over stronger reductants (e.g., NaBH4) due to its stability in weakly acidic media and its ability to avoid over-reduction of other functional groups (e.g., esters, nitriles). The cyanide ligand stabilizes the borohydride, slowing its decomposition and enabling selective hydride transfer to the protonated imine.
Application Examples of Borch Reductive Amination
- Example 1: In the total synthesis strategy for (-)-balanol, the intermediate diol (14) was oxidatively cleaved to form the dialdehyde, which was immediately subjected to Borch reductive amination in the presence of benzylamine. The cyclic carbamate (15) was mildly hydrolyzed to give the N-benzyl derivative (3). [2]
- Example 2: Borch reductive amination can be used as a general synthetic route to fold all-cis-azatetraquinolane ring systems. Taking the reductive amination of cis,syn,cis-triquinanedione (1) with aniline (3a) as an example, azatetraquinane (4a) was obtained in a syrupy oily form with a yield of 75% in the presence of NaBH3CN and methanol solvent. [3]
Fig 2. Synthetic examples via Borch reductive amination reaction.
Related Aniline Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 270-271.
- Sullivan, Bradford, et al. Tetrahedron Letters, 2008, 49(35), 5211-5213.
- Mehta, Goverdhan, et al. The Journal of Organic Chemistry, 1995, 60(14), 4638-4640.
