Tuesday, May 15, 2007

The Mannich Reaction revisited

The Mannich Reaction (Carl Ulrich Franz Mannich, 1877-1947) is yet another one of those reactions that look brilliant on paper. However, I have on many occasions heard chemists attempting the reaction moan a fair bit to say the least. The major problem seems to be that the reaction is sluggish requiring heating/reflux to get anywhere and that the reagents (and desired product) start polymerising. You can find Mannich's original paper here: Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, p. 647. There is a detailed entry in Wikipedia on the reaction for those not familiar with it. A good alternative to the classic Mannich conditions is to use Eschenmoser's salt which I've seen used successfully in a number of total syntheses. Anyway, recently a PhD student in my lab was bitching about his Mannich Reaction. He left the lab, did some reading and came back with this nice JOC Note by A. Erkkila and P. M. Pihko, DOI: 10.1021/jo052529q. When he started using this stuff all his problems were solved. Fortunately, he sorted all this out right before I had to do my first Mannich Reaction. It also worked as a charm for me so I warmly recommend this simple, and efficient Mannich protocol.

Now Erkkila and Pihko are quite concerned about reaction times because they are thinking of industry applications. However, for the average chemist that does a lot of work overnight (whilst at home in bed) it isn't essential that it's done in 1 hour. We found that if you do these reactions overnight no heating is required and the products are of very high purity. Very clean reactions indeed. Here's four examples from the paper:

As it turns out the chemistry works really well for most systems using catalyst 1. However, some aldehydes require catalyst 2 to give a good result, eg. entries 3 and 4. The only compounds tested in this paper that failed completely were aldehydes that exist predominantly in a hemiacetal form, eg. 5-hydroxy-valeraldehyde. So there you have it. Maybe something you should consider giving a go next time it's alpha-methylenation time. D!

8 comments:

Petr said...

did they try only aldehydes? no esters? i am particularly interested in gamma-butyrolactone.

Daniel Sejer said...

They only look at aldehydes in this paper. I have a feeling it wouldn't work for esters because they show an example with a keto-aldehyde that only alpha-methylenates the aldehyde. D!

milkshake said...

I am quite amazed you that you don't get dimeric products (of Michael addition of starting aldehyde to the formed alpha-subst. acrolein

Daniel Sejer said...

I agree Milkshake. It's a pretty good system that these guys have developed. D!

Matthew Daniels said...

It's not really a traditional Mannich reaction, due to the elimination of pyrollidine at the end of the catalytic cycle. I worked on Mannich-type reactions for my masters thesis, maybe someday I'll get a paper from it and post here.

I can't access the paper, but did they try just proline as a catalyst?

What I think might be the most interesting part of this (and the reasons aldehydes are prefered as substrates) is that the amine could attack both the formaldehyde and the starting aldehyde, making both iminium and enamine species, leading to super-reactivity that goes away when the catalyst regenerates, minimizing side products. Amine attack on the aldehyde product would lead to a pretty strong Michael donor, though.

kiwi said...

i imagine esters won't work, it no doubt goes via the imine. and i'm sympathetic to the horrible experiences of people with this chemistry - i'm currently trying to cook up an alpha-methylene ester, and both the Baylis-Hillman reaction and the Hoffmann elimination are in my bad books at the moment.

Daniel Sejer said...

Matthew, I never answered your question about proline. They did in fact test proline (and some derivatives) as well as some imidazolidinone derivatites. The best result by far was obtained with Pro-beta-Ala. D!

ProCyan said...

Thanks for those ref!

I'm trying to immobilize a dye, 1,2-dihydroxyanthraquinone onto aminopropyl-silica gel + formaldehyde. 50 % ethanol (in water). Low loading so far. Are primary amines less reactive? best pH? the amine silica "local" pH is quite alkaline (by local i meant internal pore volume)