[tmartin]

Well, it has been a long time since I've been around (Since December, I think).  I've noticed azmanam must be a little busy so I figure I'll post an interesting problem I've come across in my literature readings.  What is the reactive intermediate X that is formed from the reaction of this amine with an aldehyde, and what is the product upon addition of a nucleophile?

Bonus question:  What potential side reaction could occur arising from X?

[Oxy]

[nj_bartel]

Kinda seems like that proposed side product would be the main product.

[tmartin]

Sorry for the slow response,  I was at some seminars this morning and not able to check up on this.  Formation of the imine will occur as oxy notes, however, the structure for X is not correct.  Also, the final and side products are not what the authors note.  However, oxy is on the correct path to reaching X by further reaction of his intermediate X.  Starting with Oxy's scheme and following nj_bartel's insight would most likely lead to intermediate X...hopefully that doesn't give too much away. 

[nj_bartel]

Is the side reaction polymerization of [X] to a polyester?

[tmartin]

The potential side reaction is not polymerization.  It may be helpful to think about some prevalent reactive intermediates that could be formed from this type of system... what is your proposed X?  I should also be careful with discussing the side product, so as to not lead you down a dead end, thinking of it as more of a potential pitfall of this reaction the authors sought to avoid may provide some insights once you obtain X.

[Oxy]

Kinda seems like that proposed side product would be the main product.

It cannot be the main product because it's disfavoured according to Baldwin's rule (5-endo-trig).
Does the iminium salt lost carbon dioxide and form 1,3-dipolar intermediate? It can add to the aldehyde, but nothing to do with the nucleophile

[tmartin]

Oxy: That's correct, X is the azomethine ylide.  And there was concern of reaction with the aldehyde, if I recall correctly...but it did not really become a problem (I left my cheat sheet at work).  Thoughts on the identity of the product(s)? 

[Ulfsaar]

i guess that is the reaction which is developed by Seebach,right?

[Ulfsaar]

maybe i have seen the reaction in a book ,like . organic synthesis workbook??i don't know ... but i find the reaction could use amino acids to synthesis many other nature products,this is a good idea

[tmartin]

Ulfsaar,  Your X needs to go one step further, and you are missing a charge (unless I cannot see the minus) on your azomethine ylide.  As far as I can tell, this is work based upon the Strecker degradation all the way back in 1862, with contributions along the way by Rizzi and Grigg.  Currently the authors only report using proline in this fashion, however I do agree that they would want to extend it to many other natural and unnatural amino acids.

Oxy, A little bit more on the side product, they were able to avoid formation of the cycloadduct by slow addition of the aldehyde over 18h. (Hint at the answer here I suppose  )

[mirro]

I do a guess at the products.

[tmartin]

Mirro, your products are correct.  The authors speculate that the azomethine ylide is formed after addition of the carboxylate to the imine, but that's kind of splitting hairs there.

Any thoughts on regioselectivity?  I'll leave that as more of an open ended discussion.  Tomorrow I'll post the references/etc from work.

[tmartin]

Sorry for the delay.  The paper was published recently in JACS asap. I believe this should be the correct DOI:
10.1021/ja910719x.  Seidel and coworkers report "a three-component
decarboxylative alpha-functionalization of amino acids that involves a
new reaction pathway for azomethine ylides."  I lifted their proposed mechanism from the paper and have included it below.