What is the correct way to get reduced amines? Here is a more versatile method for making amines that does not result in excessive alkylation. This method is quite simple and transparent even for beginners in chemistry. Just a few simple reactions. However, you will need a number of reagents that are difficult to find commercially. This method, for example, can be used to carry out reductive amination of amino acids.
Start
Starting with an aldehyde or ketone, form an imine (analogous to nitrogen aldehyde or ketone). Reduce the imine with a reducing agent such as sodium cyanoborohydride (NaBH3CN), sodium borohydride (NaBH4) or sodium acetoxyborohydride (NaBH(Oac)3). It turns out a new amine. There is no need to isolate the imine intermediate (which can be somewhat unstable anyway). The reduction can be done in situ (i.e. in the same reaction flask),then give the iming sufficient time to form.
This process is called reductive amination. The name "reductive amination" is also encountered. Here is a specific example: hydro-methylbenzylamine.
Let's say you have a primary amine like benzylamine and you want to make hydro-methylbenzylamine. How will you do it? Direct treatment of benzylamine with an alkene agent (eg, methyl iodide) will result in significant formation of the unwanted tertiary amine (i.e., dealkylation).
Yes, you can try to separate the secondary amine that is formed from the tertiary amine, but we are not going to settle for the 10-30% concentration that this method gives. Separating mixtures is fine on paper, but it can be a real pain in practice. Is there any other way to do this? Try reductive amination. This is a much more controlled way of forming nitrogen-carbon bonds.
After the imine is formed, it must be reduced to the amine. The familiar reducing agent sodium borohydride (NaBH4) can be used for this process. It may be recalled that NaBH4 is used to reduce aldehydes and ketones. There are two other commonly used reductive amination reducing agents: sodium cyanoborohydride (NaBH3CN) and sodium acetoxyborohydride (NaBH(Oac)3). For our purposes, they can be considered the same. In practice, NaBH3CN is slightly better than NaBH4.
Application
Reductive amination is veryversatile and can be used to establish a wide variety of different alkyl groups on amines. The best part is that the bands just go once.
Ketones also work
How about ketones? They work too! Use a ketone, which will take us to the branched alkyl substituents on the amine. For example, using acetone in the next reductive amination gives an isopropyl group. Further, everything is simple.
Sequential amination is another useful feature of the reductive amination reaction. The special feature is that two (or three, if one starts with ammonia) processes can be used in sequence. For example, see the synthesis of a tertiary amine. It is important to note that the sequence of reactions is not critical here. We could do the first reductive amination with benzaldehyde first and acetone second and still get the same product.
Intramolecular reductive amination
Finally, there is an intramolecular case that always gives students a headache. If the molecule contains both amine and carbonyl groups, it can give a cyclic amine. When pulling out the ringing product, it is highly recommended to count and number your corners. Many students make mistakes when redrawing, which is worth the time spent.
Working backwards: planning for reductive amination
This may take some time, but reductive amination is an extremely powerful way to make amines. It's very helpful to be able to think backwards from the amine product to what the raw materials look like.
In general, reductive amination is a very powerful and useful protocol for the formation of amines. Every student can understand it. If you want to replicate these reactions at home, the easiest way for a beginner is to do reductive amination of glutamic acid.
