Reductive Amination

by James

Description: Aldehydes and ketones can be converted into amines, through formation of an imine and treatment with a reducing agent. This is called “reductive amination”.
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Notes: This works for both primary and secondary amines. A common reducing agent for this is sodium cyanoborohydride (NaCNBH3) although sodium borohydride (NaBH4) and sodium tri-acetoxy borohydride [NaBH(OAc)3] may also be used.

Examples:

Notes: Example 1 shows a “normal” reductive amination of a ketone and a primary alcohol. Slightly acidic conditions (although not shown) help to promote the reaction. Example 2 shows a secondary amine. Example 3 shows the use of NaBH(OAc)3 , which for our purposes behaves exactly similar to NaCNBH3. The fourth example shows an intramolecular reaction. Note that “pH 4.5” here just signifies that we are using slightly acidic conditions.

Mechanism: Protonation of the carbonyl oxygen by acid (Step 1, arrows A and B) makes the carbonyl carbon a better electrophile, which is then attacked by amine in an addition reaction (Step 2, arrows C and D). Transfer of a proton from the nitrogen to the oxygen (Step 3, arrows E and F) results in an oxonium ion, which is then expelled as H2O in an elimination reaction (Step 4, arrows G and H). This forms an iminium ion, which is then reduced by sodium cyanoborohydride (Step 5, arrows I and J) to give the new amine.

Notes: Note that the first 4 steps just show formation of the imine. H2SO4 is just used as an example of an acid; others can certainly be used, however.   The proton transfer step can be shown in an alternative manner involving two consecutive steps. Sodium cyanoborohydride (NaCNBH3) is favored as a reducing agent because it will react more quickly with the iminium ion (in step 5) than it will with free aldehyde. Therefore one can do this reaction without worrying that the aldehyde will be reduced first.

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