[faust]

Hello,

I have to synthetise
ethyl 4-(N-(3-methoxy-3-oxopropyl)-4-methylphenylsulfonamido)but-2-enoate

(just look the picture).

I'm an undergraduated student, so I need some help for this synthesis.

I think a good idee is to start from beta alanine.

I tryed to protect the beta alanine with TBSCl, but I doesn't work, I think the amine also react with TBSCl.

Than, I tryed to protect with a methyl ester. It works with a yield of 100% without purification!. And you can see the others steps of my synthesis on the picture. But I think it's a pretty long synthesis for a not really complicated molecule...

I could also use the ethyl bromo crotonate insteed of bromo allyl or ally carbonate so that I can avoid the ozonolyse and Wittig. But I don't really know how to selectivly unproted the methyl ester and not the ethyl ester.

So If you have any ideas with less steps (and so less purifications!) or any publications you're really welcome!

Thank you

[HP]

If you have  ethyl bromo crotonate as reagent you could easily convert it to ethyl amino crotonate with NaNH2 or indirectly by Staudinger Reaction with ethyl azide crotonate and P(Ph)3. Then this amino derivate in direct Michael addition(i do similar syntheses with beta alanine and acrylic acid at heat 90C for 24h under N2 atm) with  unprotected acrylic acid in small excess  which should be much reactive in this addition than the amino crotonate itself. Another syn path i am thinking is Michael addition of beta-alanine to ethyl buta-2,3-dienoate but i dont have much knowledge how this reaction works with allenes and which C-athom of the allene will the H-athom from the amine will go.
So i suggest:
NH2-CH2-CHCHCOOEt + CH2CHCOOH= your desired product
or:
HOOC-CH2CH2NH2 + CH2-C-CHCOOEt = i dont know  
Whish success!

[faust]

Ho yes thank you so much!

Do you have any reference? (Publication) with experimental section?

First :

Aceton + NaNH2 in exces + ethyl bromocrotonate --> Amino ethyl crotonate + NaBr (precipitate)

Work up : Wash with saturated NaHCO3 and extraction with ether.

Second :
Reaction with acrylic acid (here I need a reference)

Then : reaction with Et3N + TsCl

[faust]

Oh I have another idea...

If I start from the beta alanine, then I put a tosylate on the amine AND on the acid.
After what, I do the amine alkylation in one pot.

Then I wash with water, and the sulfonic anhydride on the acid liberate the free acid.

[HP]

Faus i dont have reference with acrylic acid and amines Michael addition but believe me it works Theres many references on using different catalists for these reactions and may be interesting for you can be this:
"LiClO4 Accelerated Michael addition of amines to ?,?-unsaturated olefins under solvent-free conditions" N. Azizi, M. R. Saidi, Tetrahedron, 2004, 60, 383-387.
Insted of acrylic acid you may use acrylonitrile CH2CHCN which has low boiling point than acrylic acid and easier removed the excess from the reaction mixture but then you should think how best to hydrolize the nitrile group of obtain derivate to carboxylic group without hydrolize the other ethyl ester group so may be better first suggested from me reaction directly with acrylic acid...
For the first step in synthesis of  ethyl amino crotonate with NaNH2 be careful with this reagent and think if theres other efficient reactions for obtainig desired amine.
Think also about possible routes from crotonate amine with 3-bromo propanic acid for N-alkylation or with NHMgX salt(from amine + MeMgI Grignard- first should react quantitly the amine with methyl grignard before possible side reaction with the ester group if use excess Grignard reagent) with the 3-bromo propanic acid.
Regards

[HP]

Yah your second idea for direct alkylation of beta-alanine with ethyl bromocrotonate seems easiest way. But i have some doubts about how the reaction of TosCl with the carboxylic group will work to form mixed anhydride as i understand your idea. Also beta alanine exist as zwiterionic molecule and it could be problematic. I am thinking if you work with the amonium salt of b-alanine which may be alkylated with your esterbromide/N(Et)3 and could easily hydrolyze to free carboxylic acid without hydrolyze the ethylester group.
And one question: what your compound is used for or its still a secret

[faust]

I'm sorry but I don't really understand your last sentence :

"Also beta alanine exist as zwiterionic molecule and it could be problematic. I am thinking if you work with the amonium salt of b-alanine which may be alkylated with your esterbromide/N(Et)3 and could easily hydrolyze to free carboxylic acid without hydrolyze the ethylester group"

How can I be assured that when I use Et3N and R-Br; it will only alkyle my N and no O alkylation from the carboxyle?

For the moment, I can easyly do : Beta alanine --> methyl ester beta alanine .HCl --> methyl ester beta alanine NH-Ts --> Methyl ester beta alanine N-Ts-ethylcrotonate. But I can't selectivly remove the acid protection.

I have some article that show how to N-allylate an amino acid, but the acid is a methyl ester, and the N have a Ts.

In fact I have to find out how to : Beta alanine --> Beta alanine NH-R (without anyprotection on the acid fonction, or in one pot reaction and also a mono alkylation) then I can add a Ts on my amine, and anyway if the acid fonction is tosylated, It can be unprotection with water

My final molecule is for a test of the Kolbe reaction

[HP]

Faust you are right for the O-alkylation if not use COO-ester protected b-alanine but then you will again have two ester protected COO groups in molecule. This is specific problem and in your synthesis you have one methyl and one ethyl ester prot groups which i dont know how selectively to remove the Me-protection without cause and ethyl. May be if use easy hydrolizable tert-butyl protection of COO-group of b-alanine you could selectively deprotect it to some extend without causing COOEt group which is much stable i think. Anyway i think the Michael synthesys i suggest you lead directly to desired product...Hope was in help you not in complication as always  

[faust]

Michael Synthesis is a really good Idea! But my 4-aminocrotonate seems to be unstable... because on scifinder there are only 3 references with this molecule... And Acros sell the 3-aminocrotonate very cheap, but not the 4 one...

[faust]

What do you think about this article?
http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/2001/44/i13/pdf/jm010087e.pdf

First : N-addition on alanine of (2 nitrobenzyl chlorhyde) for me it will be the bromo crotonate.

1eq of alanine + 1eq of Et3N + 1eq of RCl in CH3CN

purif : evaporation of the solvant then addition of water + addition of citric acid until pH 7 --> recristallisation during one night a 4°C.

Secondly : 1eq of the previous molecule + 1eq of TsCl + 1eq of KHCO3 or Et3N or NaHCO3 in aceton 100/water 25

purification : evaporation of the solvant + addition of water than extraction with ethyl acetate, evap of ethyl acetate and finally recristallisation in MeOH or EtOH.
 

[HP]

Indeed, Faust found the right way before the hour hand points midnight  
Seriously not in Goethe tone this is the most direct synthetic way i tought for too but didnt search articles this topic
So try this syntheses and if obtainmore 60% yeld share us for your success.
Good luck!

[faust]

Well! I'have taken a deep looking in "bioorganic journal" and I finally found what I want I think.

What to you think about this :

1- Schotten Baumann reaction : in aqueous NaOH 2N : beta alanine 1eq + TsCl 1eq
extraction with ethyl acetate.

2- Addition of 2 NaH forming : -OOC----N(^-)-Ts + 1eq of Bromo crotonate give the final product in 2 steps.

[HP]

Well the first  Schotten Baumann procedure i agree and sure it will work perfectly.
The second one is little problematic for me. First why adding 2 moles NaH: if one mole is for the COOH group of alanine i think in the first synthesis the end product should be COO:Na salt if the media have excess NaOH? Could you explain us the role of NaH in the amino-tosylate group- does it for forming
 -:OOC-CH2CH2-N(Tos):-Na+ salt which easily to react with your bromo crotonate If so it;s OK i think. But do you think the Tosylate could be cleavage by the strong NaH to Tos:-Na+?Anyway the lab experiments will show best so go go go  

[faust]

after Shotten Bauman, I have to acidify and extract HOOC----NH-Ts

So today, I have tryed : MeOOC----NH2 -->(Et3N 2.2eq + 1.4eq TsCl) in CH2Cl2 --> MeOOC----NHTs

And After extraction with ethyl acetate and wash with water, all I have is cristals and it's Ts-OH... really strange because my reaction was totaly dry... and CH2Cl2 freshly distilated

[HP]

Hi
Strange result but that's chemistry friend   I think TosOH may be obtained only by moisture hydrolyze of TosCl at reaction mixture or if stored TosCl opened. Also are you sure your extraction procedure is effective for extraction of your product- it may be well soluble in CH2Cl2 too but i dont know... Did you analyze the residue after evaporation CH2Cl2? Also if your product is water soluble may be not bad to extract first with water after that saturate with some salt and then some extraction withwith proper organic. As you said if you do your synthesis with MeOOC--NH2 and ethyl bromo crotonate then its impossible selectively to deprotect MeOOC-group.
Here another idea for synthesis path:
NC-CH2CH2-Br(3-bromo propanenitrile, commercially available ) which to convert to NCCH2CH2-NH2 then reaction first with bromo ethyl crotonate-->
If dont use base like Pyr then HBr + R-CN--> aldimine salt R-C=NH(Br) which + H2O/acid or base  hydrolyze to COOH and last TosCl procedure to sub NH bond which is much basic than NH2 but i dont know how TosCl with the zwiterionic structureR-NH2+-R-COO:-    You had some doubts for Tos-esterification COOH group but you should know this possible ester is less stable than TosNH and easily removeable i think.