Sciencemadness Discussion Board

aza-michael addition question

feynmann - 15-5-2009 at 14:26




I want to ask about aza michael addition
Is the above reaction likely to proceed that way and what are the possible side products??
I know that beta -aryloylacrylic acids are good michael acceptors and aza-michael additon can proceed using different amines at room temp or they say in general below 60 degree (I don't know why really the temp should be below 60 degree celsius???

I read about reversibility of michael addition at temp above 60 but need rational if u can plz

I will provide general references for that later

UnintentionalChaos - 15-5-2009 at 15:19

I don't think you're going to have very good control over which end of the double bond the amine adds to.

I've only worked with phospha-michaels before, but those are perfectly capable of happening up to 200C. Some of the very activated double bonds reacted cleanly and went to completion at room temperature, while less activated and more hindered acceptors needed a lot of heat to get started.

[Edited on 5-15-09 by UnintentionalChaos]

feynmann - 15-5-2009 at 15:22

the strange thing is that beta benzoyl acrylic acid exhibits addition on that position mainly (alpha to the carboxylic acids) and they have used it to make amino acids

The thing I want to know :is this reaction likely to proceed readily???

Nicodem - 19-5-2009 at 00:20

Quote: Originally posted by feynmann  

Is the above reaction likely to proceed that way and what are the possible side products??

Yes, such a reaction should be regioselective provided the media is basic (which it has to be anyway in order for the nucleophile to be free of protonation). The carboxylate group ( -COO(-) ) has very poor electron withdrawing properties so that the Michael addition, if it happens, it happens with complete regioselectivity.
Quote:
I know that beta -aryloylacrylic acids are good michael acceptors and aza-michael additon can proceed using different amines at room temp or they say in general below 60 degree (I don't know why really the temp should be below 60 degree celsius???

I read about reversibility of michael addition at temp above 60 but need rational if u can plz

I will provide general references for that later

We are still waiting for the reference.

feynmann - 19-5-2009 at 06:46

thanks nicodem for replying
I want to know some information
1-I think that the cpd is basic enough and would add to that michael acceptor ........what about the steric hindrance ...??? Is it high to cause no addition (btw the above reaction is not in the literature but I think about carrying it out)
2-I want to isolate the product from the reaction mixture without using column ..........can I use the difference in the properties of the starting materials and the product to separate the product ???

Sorry for not posting the ref ........I think in this patent p5 they point out to the reversibility
http://rapidshare.com/files/234792257/patent_show_dirct_addi...

Nicodem - 22-5-2009 at 02:21

1. The nucleophile is a zwitterion and the electrophile is an acid, so unless you add some triethylamine there will either be no reaction or the reaction will be very slow. The nucleophile is not particularly stericaly hindered.

2. Your product is an amino acid and therefore using a column would not be particularly useful since you would have to use a very polar eluent and the product would trail itself all over the column. You separate the product as you do with amino acids.

PS: You will most likely need a protecting group on that phenolic function or else you will only obtain the product of the intramolecular Michael addition.

feynmann - 22-5-2009 at 05:13

thanks nicodem for concern but regarding the intramolecular michael addition :do u have any literature proof of a cpd with that bulkiness (dibromo and carbonyl ) which can add up to a double bond .................I really think that it will be very difficult................:o

Nicodem - 22-5-2009 at 05:49

Just about all 1-(ortho-hydroxybenzoyl)alkenes readily cyclisize to the corresponding 4-oxochromanes at mild conditions (such as NaHCO3 or AcONa as base and >50°C). beta(ortho-Hydroxybenzoyl)acrylic acids are no exceptions and they cyclisize to 4-oxochroman-2-carboxylic acids. SciFinder and Beilstein give several hits, for example, see: Bioorganic & Medicinal Chemistry Letters, 15 (2005) 2745-2748; Arzneimittel Forschung, 44 (1994) 344-348; US2005054630; EP625522; and several papers in Chinese. Obviously, an intramolecular 1,4-conjugate addition of such a nucleophile like the phenoxide to give a six-membered ring, is more favourable than a intermolecular addition of a secondary amine. Neither the bromo or the carbonyl substituents ortho to the phenolic group represent no steric hindrance, because both are totally out of the reaction trajectory in the transition state.

feynmann - 22-5-2009 at 07:43

it is really a precious information
what if the oh is in the para position ???? do u think the intra molecular addition will take place preferentially
Another problem is that if I protected the OH group with MEI or something ...what will be the suitable agent to deprotect it without affecting the amide bond???? BBr3 is difficult to obtain in our country :(

[Edited on 22-5-2009 by feynmann]