[Babcock_Hall]

We are trying to make a diester of dibromosuccinic acid from the free acid.  We would prefer to make something that will deprotect easily in the presence of a vinyl sulfone, but at this point I would settle for just about any ester.  The two problems we envision are low solubility in some common organic solvents and the possible replacement of bromine by a nucleophile.  When we tried DCC/catalytic DMAP coupling in acetonitrile, the crude yield was very low, possibly because the acid did not want to go into solution.  When we tried DCC/catalytic DMAP in DMF, I was unable to interpret the NMR.  So far our literature searching has not been very successful, but we did turn up a protocol of an acid-catalyzed esterification of a di-acid that used cation-exchange resin as the catalyst, which I thought was promising.

If we try acid-catalyzed esterification, the only way that I can think to avoid a substitution entirely is to use HBr (not HCl) as the catalyst.  However, cation-exchange resin and para-toluenesulfonic acid are not very nucleophilic to the best of my knowledge.  If we try DCC-promoted coupling again, it occurred to me that we could try dissolving the acid in an excess of the alcohol that we wish to use, then add DCC and catalytic DMAP.  Once the reaction is done, we could add ether or DCM to precipitate out the dicyclohexylurea.  Does anyone have any advice for us?

[rolnor]

Have you tried the standard way to dissolve the acid in large eccess alcohol an add some sulphuric acid?

[wildfyr]

You should also try DMSO for DDC/DMAP too. And have you heated up any of these reactions? You can easily push DMF/DMSO all the way up to 120C. Refluxing AcCN is worth trying too. You might have to try with more exotic solvents like diphenyl ether, anisole, or HMPA(heaven forbid). Getting DCU out of a reaction is a total pain though, so may I suggest trying the acid catalyzed route?

You can run acid catalyzed esterification best with catalytic sulfuric acid, not HBr. Sulfate is a terrible nucleophile and won't attack. This reaction might even work heterogenously in pure methanol/ethanol/t-butanol whatever you want.  You will need to drive water out of the reaction. The simplest way to do this I've seen is to reflux the reaction and put an addition funnel with molecular sieves above it, and a condenser above that.

Make sure your solvents and reagents are rigorously dry. I once again bring up sieves and their efficacy at drying virtually all solvents (including alcohols!) by citing this great paper https://pdfs.semanticscholar.org/ec7d/d3c01b54535f93d48187980c11e0f789f47f.pdf

[wildfyr]

great minds think alike Rolnor, you posted while I was typing

[Babcock_Hall]

Thank you; those all sound like reasonable suggestions.  We have not tried acid-catalyzed reactions yet.  Do you see any advantage in Dowex 50 as the acid catalyst over sulfuric?  The only potential one I see is that Dowex resin is easy to remove.  My only reservation about molecular sieves concerns how to activate them.  I am not sure that I have an oven that goes to 300 °C, but I will look into it.

[wildfyr]

I have often had perfectly good success using sieves baked in our normal glassware oven at 80°C for a week or so. I just put a bunch in at a time and use as needed. Get as hot as you reasonably can for a few days, they don't need to be 100% activated. You could even put some in a rbf in an oil bath at 100°C+ with a good vacuum pump on overnight and that would likely work fine.

Well the advantage of sulfuric over Dowex is your solubility problem. If dibromosuccinic acid isnt soluble in the alcohol, then this is a heterogenous reaction, and you aren't gonna get your suspended powder to interact much with the Dowex. I personally consider the drop or so of sulfuric acid you use to catalyze the reaction pretty easy to remove (bicarb wash).

[wildfyr]

Also, did you check scifinder? someone else must have esterified this thing before

[rolnor]

I am also thinking maby you can make the acid bromide with oxalylbromide?

[wildfyr]

PBr3 will work in that pathway if you dont have oxalyl bromide. Either way just quench the reaction with the alcohol of the desired ester

[Babcock_Hall]

Also, did you check scifinder? someone else must have esterified this thing before

IIRC we found one procedure in a patent that suggested that the esterification could proceed at room temperature.  I will double-check on this, but I am somewhat skeptical.

I had forgotten the oil-bath idea for activating sieves...

[Babcock_Hall]

We rechecked SciFinger and found a reference from the patent literature.  It describes what appears to be the formation of the dimethylester of dibromosuccinicate with catalytic sulfuric acid in water as the solvent.  The conditions are room temperature and two hours.  This does not sound reasonable to me.  Given these conditions, I have to wonder whether or not this was meant as a hydrolysis step of the diester to the free acid, although why one would want to do that is open to question.

Reference
Process for the preparation of dimethyl acetylenedicarboxylate, By Chen, Xueping, From Faming Zhuanli Shenqing, 103664600, 26 Mar 2014

[clarkstill]

Do you need to start with the dibromo compound? Could you instead form the diester of fumaric acid then brominate it? I'm sure you could hit it pretty hard then, using Fischer esterification conditions without worrying about any possible elimination reactions etc.

[Babcock_Hall]

We had the dibromo free acid on hand already, and I was trying to cut down on the number of steps (this is an undergraduate independent study project).  However, we had thought a little about esters derived from fumaric and maleic acids.  These esters could be dibrominated, or there are other routes to the vinyl sulfone (though less attractive ones at first glance) that do not proceed via dibromosuccinate esters.  Di-tert-butylfumarate is beyond our price point, but diethylfumarate is not.

[wildfyr]

Dissolving fumaric acid in dry tert-butanol with sulfuric acid catalyst doesn't seem like such a bad step. Probably just cook it overnight, bicarb wash, then a dead easy distillation (tert-butanol BP=82°C). I can't believe Oakwood is selling it for $1800/5gram! If it doesn't want to esterify easily then you could use the acid chloride pathway of fumaric acid+SOCl2 then quench that with tert-butanol. Distill off tert-butyl chloride and tertbutanol and wash with water.

After that its just stirring with bromine and voila your final product! This really might be easier than fighting the solubility battle of that other compound.

[Babcock_Hall]

Just a quick and incomplete update.  One attempt to make di-tert-butyl-dibromosuccinic acid seems to have failed.  We tried 1.6 moles of DMAP per mole of di-acid (having seen a couple of protocols which suggested near stoichiometric amounts).  It is unclear what happened to the starting acid.  It might have eliminated in some way (when attempting to make a vinylsulfone from this compound, we saw evidence of a decarboxylation).

We tried to prepare the dimethylester of fumaric acid using acid-catalyzed conditions.  This reaction went with low yield, but I will take what I can get.  My student found an old thesis in which there are conditions for adding bromine to the ester, which is what Clark suggested IIUC.