Last updated: May 11th, 2020 |
OK – so making amines through direct alkylation is generally not a great way to go. You could even say it’s crappy.
So what’s the “right” way to do it?
Glad you asked.
Today we’re going to discuss a far more versatile way to make amines that doesn’t result in over-alkylation. It’s called reductive amination.
Table of Contents
- How Do We Make This Amine?
- Reductive Amination To The Rescue
- Applying Reductive Amination
- Ketones Also Work
- Sequential Reductive Aminations
- Intramolecular Reductive Aminations
- Working Backwards: Planning A Reductive Amination
- Test Yourself!
- (Advanced) References and Further Reading
Say you have a primary amine such as benzylamine and would like to make N-methylbenzylamine. How do you do it?
Direct treatment of benzylamine with an alkylating agent (e.g. methyl iodide, CH3I ) will result in significant formation of the undesired tertiary amine (i.e. di-alkylation).
Yes, you could try and separate out the secondary amine that’s formed from the tertiary amine, but we’re not going to settle for 10-30% yields here. Separating mixtures is fine on paper, but (trust me on this) it can be a real a pain in practice. Is there another way to do it?
Enter reductive amination!
While alkylation can happen multiple times on an amine, imines only form once on a given amine. Once the imine is formed, the C=N bond can be reduced, giving us a new alkyl group attached to nitrogen.
This is a much more controlled manner of forming nitrogen-carbon bonds.
Here’s the mechanism for imine formation, in case you’ve forgotten. [click to see image]
After the imine is formed, it must be reduced to the amine. It’s possible to use the familiar reducing agent sodium borohydride (NaBH4) for this process. You may recall that NaBH4 is used for the reduction of aldehydes and ketones.
There are two other commonly used reductants for reductive amination: sodium cyanoborohydride (NaBH3CN) and sodium tri-acetoxyborohydride (NaBH(OAc)3 ). For our purposes, they can be considered to be the same. In practice, NaBH3CN is a little bit better than NaBH4.
[For a discussion as to why NaBH3CN tends to be a better choice than NaBH4, see this footnote. In the schemes below, we’ll use NaBH3CN, but NaBH4 and NaBH(OAc)3 can be considered to work just as well. ]
Reductive amination is extremely versatile and can be used to install a large variety of different alkyl groups on an amine. The nice part is that the groups just go on once.
The table below shows examples of how methyl, ethyl, propyl, butyl, and benzyl groups can be installed on an amine, by employing an appropriate aldehyde . (Note that reductive amination doesn’t work for installing a phenyl group. Why not?)
What about ketones? They work too! Employing a ketone will result in a branched alkyl substituent on the amine. For example, using acetone in the following reductive amination gives an isopropyl group.
Another useful feature of reductive amination reactions is that two (or three if one starts with ammonia) reductive aminations can be employed in sequence. For example, look at the synthesis of the tertiary amine below.
Importantly, the sequence of reactions isn’t crucial here. We could have done the first reductive amination with benzaldehyde first, and acetone second, and still obtained the same product.
Finally, there’s the intramolecular case, which always seems to give students a headache. If a molecule contains both an amine and a carbonyl, then it can cyclize to give a cyclic amine.
When drawing out the product of ring formation, I strongly advise counting and numbering your carbons. I’ve seen so many students make mistakes when redrawing that it’s well worth the time to double check that you haven’t left anything out.
It might take some time to appreciate, but reductive amination is an extremely powerful way of making amines.
It’s very helpful to be able to think backwards from an amine product to what the starting materials look like.
Look at the following tertiary amine. It is connected to three carbons, which we can label a, b, and c. Each of these N–C bonds could potentially be formed through reductive amination, since they have C-H bonds.
That means that there are three possible ways of making this amine through reductive amination, all of them acceptable!
In short, reductive amination is a very powerful and useful protocol for the formation of amines.
What about installing a phenyl group (see above)? For formation of bonds between nitrogen and sp2-hybridized carbons (e.g. alkenes or phenyl groups) or between nitrogen and sp-hybridized carbons (e.g. alkynes), reductive amination won’t work.
Think about it. Note that the carbon attached to the nitrogen doesn’t have a C-H bond. Therefore we can’t work backwards to the reduction of a C=N bond with a hydride source.
One must resort to alternative techniques. Buchwald-Hartwig cross coupling is one of them.
NaBH4 can be a perfectly acceptable reducing agent for reductive amination.
There’s one slight problem with this reagent, however. What if the NaBH4 ends up reducing the aldehyde or ketone before it has a chance to react with the imine? That would lead to lower yields. [In practice, this can be reduced somewhat by giving the imine sufficient time to form, and then adding in NaBH4.
An even better approach involves the use of the slightly weaker reducing agent sodium cyanoborohydride (NaBH3CN).
Why use a weaker reducing agent?
Recall that formation of an imine is best done under mildly acidic conditions (pH 4 or 5). [At mildly acidic pH, the carbonyl oxygen is protonated, speeding up the rate of addition to the carbonyl carbon; if the solution is too acidic, however, the amine nucleophile will be converted into its (non-nucleophilic) conjugate acid, an ammonium salt, and no reaction will occur.]
Once the imine forms at pH 4-5, some of it will be converted into its conjugate acid, an iminium salt.
The advantage of using NaBH3CN is that it isn’t a strong enough reducing agent to reduce aldehydes or ketones, but it is a strong enough nucleophile to reduce iminium ions. Therefore more of the starting aldehyde/ketone will be converted into the amine. [This is particularly important when working with very precious samples of aldehyde].
- Cyanohydridoborate anion as a selective reducing agent
Richard F. Borch, Mark D. Bernstein, and H. Dupont Durst
Journal of the American Chemical Society 1971, 93 (12), 2897-2904
The first report on the use of NaBH3CN as a reducing agent for reductive amination.
- An improved method for reductive alkylation of amines using titanium(IV) isopropoxide and sodium cyanoborohydride
Ronald J. Mattson, Kahnie M. Pham, David J. Leuck, and Kenneth A. Cowen
The Journal of Organic Chemistry 1990, 55 (8), 2552-2554
Ti(OiPr)4 can be used as a Lewis acid to activate the ketone/aldehyde towards addition by the amine and the resulting imine can then be reduced in situ by NaBH3CN, which is a reductive amination.
- Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures
Ahmed F. Abdel-Magid, Kenneth G. Carson, Bruce D. Harris, Cynthia A. Maryanoff, and Rekha D. Shah
The Journal of Organic Chemistry 1996, 61 (11), 3849-3862
NaBH(OAc)3 can also be used as a reducing agent in reductive amination procedures as an alternative to NaBH3CN, if one is concerned about cyanide ion concentrations in the product or waste stream.
- Development of a Scaleable Route for the Production of cis-N-Benzyl-3-methylamino-4-methylpiperidine
David H. Brown Ripin, Stefan Abele, Weiling Cai, Todd Blumenkopf, Jeffrey M. Casavant, Jonathan L. Doty, Mark Flanagan, Christian Koecher, Klaus W. Laue, Keith McCarthy, Cliff Meltz, Mike Munchhoff, Kees Pouwer, Bharat Shah, Jianmin Sun, John Teixeira, Ton Vries, David A. Whipple, and Glenn Wilcox
Organic Process Research & Development 2003, 7 (1), 115-120
OPRD is a great source of reliable procedures, since reactions being scaled up need to be robust, high-yielding, not require exotic solvents or superstoichiometric amounts of overly expensive reagents, and have simple purification procedures (avoiding chromatography where possible).
- One-Pot Reductive Amination of Conjugated Aldehydes and Ketones with Silica Gel and Zinc Borohydride
Brindaban C. Ranu, Adinath Majee, and Arunkanti Sarkar
The Journal of Organic Chemistry 1998, 63 (2), 370-373
Zn(BH4)2 can also be used as a reducing agent in reductive amination.
- Single Stereodifferentiation Associated with Carbon Atom Insertion during the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols
Leo A. Paquette, James C. Lanter, and Jeffrey N. Johnston
The Journal of Organic Chemistry 1997 62 (6), 1702-1712
Prof. Leo Paquette demonstrates that stereodifferentiation is possible in pinacol-type rearrangements.
John C. Robinson, Jr. and H. R. Snyder
Synth. 1943, 23, 68
A reductive amination using NH3 as the amine.
- The 25th Anniversary of the Buchwald–Hartwig Amination: Development, Applications, and Outlook
Paola A. Forero-Cortés and Alexander M. Haydl
Organic Process Research & Development 2019, 23 (8), 1478-1483
A short review on the Buchwald-Hartwig amination, covering its development, applications, and future prospects. OPRD (along with Organic Syntheses) is a great place to look for reliable and robust reactions, as that is what is most valued in process chemistry, when developing reactions on a large scale.