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Natural Science Forum / Chemistry / Organic Synthesis / October 2005N-alkylation of beta amino acid
Helo, I'm an undergraduated student, and I have to synthetise this simple molecule: (E)-ethyl 4-(N-(3-methoxy-3-oxopropyl)-4-methylphenylsulfonamido)but-2-enoate In other words beta alanine with one Tosylate and an ethyl crotonate on the amine. Even if this molecule seems to be simple, I can't find out easy way for its synthesis. First I tryed to protect my acid fonction with TBSCl, but I failed, I think the amine reacted with the silicium... Than, I looked into scifinder, and I protected my acid group by forming methyl ester hydrochloride of my beta alanine. b-Alanine + SOCl2 + MeOH --> MeO-betaAlanine.HCl 100%, No further purification is needed. Than I add Et3N and TsCl --> purification on column. So Now I have to ways : First option : reaction with Cs2CO3 and ethyl bromo crotonate. But at the end, I will have 2 esters and I only want to unprotect the methyl one... I don't know how to do this. Second option : I can allylate with the allyl bromide and than, in one pot : ozonolyse + Wittig with Ph3P=COOEt So, If you have any other ideas(hydroamination?), or publications, you're very welcome. Thank you for your further help, Kev The best would be if you could start with 2 esters that you can deprotect independently of each other. It turns out that it is quite easy to make beta alanine tert-butyl ester from beta alanine, isobutylene and conc. H2SO4 (1.05 eq.) if you have a tank with isobutylene and closable heavy-wall flask that can withstand 50psi. tBu ester is cleavable by acids, like TFA (neat or 1:1 diluted with dichloromethane) or anhydrous 4M HCl in dioxane. Ethyl ester will survive these conditions if you do it carefuly and keep the moisture out. Another good protecting group is allyl - one can make allyl ester by refluxing beta alanine with allyl alcohol and benzene and TsOH.H2O (or camphorsulfonic acid). Allyl esters are selectively cleaved by Pd(0), such as trace of Pd(PPh3)4 in presence of allyl acceptor: diethylamine, N.N-dimethylbarbituric acid, dimedone, Meldrum's acid or PhSiH3 will all work fine although Et2NH (20-30% in THF or CH2CL2) would be probably be easiest to get rid of. You can selectively deprotect methyl esters using potasium trimethylsilanolate (usually in THF i think). There is also another method using potassium iodide in pyridine, the name of which eludes me at the moment. To deprotect methyl esters TMTOH (tri methyl tin hydroxyde) works very well. I use it very often. But the issue is that TMTOH could work in good way with the ethyl ester. In my oppinion you have to choose another protecting group, one that show a marked diferential reactivity. I work with esters (an his remotion) and I usually use p-methoxybenzyl esters (put in with Cs2CO3 p-methoxy benzyl chloride, and removed with TFA/Anisol CH2Cl2), Benzyl ester could work very well but insted of carry over the cleavage with hydrogenolysis maybe you have to use AlCl3, tri chloroethyl esters, benzhydryl esters and so on......you coul find a lot of option that could work. I suggest pMB. A thing that you could try with the liberation of the amine from his hydrochloride is to suspend the hydrochloride in dry Et2O and bubble NH3 gas into the suspension at 0?C, then let without stirring for two hours and filtrate the NH4Cl, you obtain the amine in quantitative yields and avoid the flsh chromatography. To carry out the alkylation maybe (if you have the building block) you could try a reductive amination. Best wishes. |
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