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Amines

By James Ashenhurst

Reductive Amination

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

  1. How Do We Make This  Amine?
  2. Reductive Amination To The Rescue
  3. Applying Reductive Amination
  4. Ketones Also Work
  5. Sequential Reductive Aminations
  6. Intramolecular Reductive Aminations
  7. Working Backwards: Planning A Reductive Amination
  8. Notes
  9. Test Yourself!
  10. (Advanced) References and Further Reading

1. How Do We Make This Amine, If Direct Alkylation Doesn’t Work?

Say you have a primary amine such as benzylamine and would like to make N-methylbenzylamine. How do you do it?

synthesis of n methylbenzylamine from benzylamine how to do it quiz

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?

direct alkylation of primary amines with ch3I is not a reliable method for mono alkylation

2. Reductive Amination To The Rescue

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.

 

what is reductive amination - shows formation of imine from amine and then reduction to give n methyl amine

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)).  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. ]

3. Applying Reductive Amination

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?)

examples of reductive amination in synsethis of n methyl, n ethyl and more

4. Ketones Also Work

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.
reductive amination on ketones with nabh3dcn as the reductant

5. Sequential Reductive Aminations

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.

redudtive amination with nabh3cn example

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.

6. Intramolecular Reductive Aminations

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.

intramolecular reductive amination using amine as nucleophile.

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.

7. Working Backwards: Planning A Reductive Amination

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.

three different ways of making tertiary amines through reductive amination

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.


Notes

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.

cant make aniline c-n bonds through reductive amination must use buchwald hartwig

One must resort to alternative techniques. Buchwald-Hartwig cross coupling is one of them.

 

Why sodium cyanoborohydride?

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.

advantage of using nabh3 cn can be added to reaction mixture directly

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].


Test Yourself!

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(Advanced) References and Further Reading

  1. 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
    DOI:
    1021/ja00741a013
    The first report on the use of NaBH3CN as a reducing agent for reductive amination.
  2. 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
    DOI:1021/jo00295a060
    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.
  3. 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
    DOI:
    1021/jo960057x
    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.
  4. 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
    DOI:1021/op025599x
    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).
  5. 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
    DOI: 1021/jo971117h
    Zn(BH4)2 can also be used as a reducing agent in reductive amination.
  6. 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
    DOI:
    1021/jo962019j
    Prof. Leo Paquette demonstrates that stereodifferentiation is possible in pinacol-type rearrangements.
  7. α-PHENYLETHYLAMINE
    John C. Robinson, Jr. and H. R. Snyder
    Synth. 1943, 23, 68
    DOI: 10.15227/orgsyn.023.0068
    A reductive amination using NH3 as the amine.
  8. 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
    DOI: 10.1021/acs.oprd.9b00161
    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.

Comments

Comment section

20 thoughts on “Reductive Amination

  1. We are interested in reductive amination of secondary fatty amines to dialkylmethylamines with formaldehyde under hydrogen partial pressure, rather than solid reducing agents.

    Also of interest is direct conversion of primary fatty nitriles to dimethylalkylamines with DMA. This seems to be less well-described in the available literature.

    At industrial scale, conversions and yields above 95% are important.

    Enjoyed your post!

  2. I have a question.
    How can be explained difffent reactivity of imine (iminium ion) between (protonated) carbonyl with NaBH3CN?

    1. The electrophile is the carbon, correct? And the more partial positive charge there is on that carbon, the better an electrophile it is, correct? Now draw the resonance form for the imine where you move the pair of electrons in the C-N pi bond to the nitrogen. Next, draw the conjugate acid (iminium) and do the same. Which resonance form do you think will be more stable between the two? Therein lies your answer.
      Bottom line, protonation of the nitrogen results in a greater contribution from the resonance form where there is a positive charge on the carbon, and it’s more electrophilic.

  3. I learnt that usually, excess amine must be used while carrying out reductive amination. Is this to increase the yield of the imine?
    If yes, then would using excess of aldehyde/ketone also work?

    1. Hey Britney – you want to use excess to make sure that the amine has a chance to react with all of the aldehyde/ketone first, before adding your hydride source. Once the hydride source is added any aldehyde/ketone that remains will be reduced to an alcohol rendering it useless for the process.

  4. Doesn’t the section “Sequential Reductive Aminations” contradicts with the statement that “While alkylation can happen multiple times on an amine, imines only form once on a given amine”?

    1. Ah. Yes, I see the source of your question. Maybe I should have written, “in the same reaction vessel”.

      During the course of an alkylation reaction, an amine can be alkylated, and then that product can be alkylated again. So when you go to try an isolate the product, you may find that multiple alkylations have occurred.

      In reductive amination, imines will only form once in the same reaction vessel, and once they’re reduced, that’s the end of the reaction. Only one new C-N bond will have formed.
      Now, once you’ve isolated and purified the product, if it’s a primary or secondary amine there’s nothing stopping you from doing a *second* reductive amination with a different aldehyde.

      Does that make sense?

  5. Hi, nice post. I wanted to comment on a common misconception you have here though. From above:

    “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.]”

    The pka of a protonated amine is 9-12, whereas the pka for a protonated carbonyl is -6 or thereabout. Hence in a mildly acidic solution the carbonyl won’t be appreciably protonated at all in comparison to the amine. The first step of this mechanism is amine addition to the carbonyl. The mild acidity serves to rapidly protonate the oxygen after addition of the amine and facilitate proton transfer for the removal of water. At least that’s how I understand it. It’s been awhile since phys org. Most texts get this wrong as well.

    I love your cite, awesome resource for teachers and students!

    Cheers,

    EBB

    1. Thanks for this, I’m adding it to my correction queue! Although I may be mistaken, I see pKa’s of protonated carbonyls at about -2 or so. Still, that’s about 15 orders of magnitude to traverse, so you’re correct on this point.

  6. I think this makes more sense as well, the acid “serves to rapidly protonate the oxygen after addition..” instead of protonating the carbonyl ahead of time. But, why does the mechanism appear this way in so many texts? Surely, the authors know the drastic pKa differences of a carbonyl oxygen and an amine (which is a base!). I wonder if in certain solvents the carbonyl actually is preferentially protonated? I use dichloromethane as the solvent for this reaction and it works twice as fast with a little acetic acid present. In any case, reaction mechanisms tend to be just good guesses with lots of contradictions if examined too closely.

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