[wildfyr]

Thanks for the update. Not to be a hater, but I'll be a shiny nickel that your student had something a little wet in there or the evolved water wasn't being removed well, but the materials are cheap so if you need a bunch the scale up is no sweat even at low yield. Don't forget to do the bromination workup cold or the whole reaction with NBS, or that hard earned ester will hydrolyze from the HBr.

[Babcock_Hall]

We found a paper by Neises and Steglich that converted 0.20 moles of monoethyl fumarate into the corresponding tert-butylester.  The reference is Organic Synthesis 1985 63, p. 183 DOI:10.15227/orgsyn.063.0183.  The question I have concerns the amount and mass of DMAP (MW 122.17), which is given as 2.00 grams, 0.16 moles.  There is a tenfold discrepancy:  either it should be 20 grams or it should be 0.016 moles.  It occurs to me that a tert-butylester might require a high mole ratio of DMAP to monoethyl fumarate because of an undesirable side reaction (the isomerization of the acylurea).  If the value of 0.16 moles is correct, then the ratio of DMAP to acid is 0.80.  I have seen one protocol for the production of tert-butyl aminoacid esters that used 0.50 equivalents of DMAP.  Does anyone have an opinion as to what the authors intended?

[wildfyr]

I think the grams is correct. DMAP is typically catalytic in this reaction and it called for 0.22 mols of DCC. On the other hand, I have trouble thinking of a way in which excess DMAP will screw things up. Perhaps this reaction could be run both ways in an NMR tube to get an idea? No aqueous workup needed. The conversion should be trackable by loss of the C=C-H next to the carboxylic acid and conversion to ester by ¹H.

I looked at OrgSyns site a bit and they are extremely fastidious about this sort of thing, perhaps an email to them might help clear this up if they have some other documentation associated with the reaction. The way Orgsyn works is that a reaction is submitted to them, then repeated in an editor's lab, so there might be some extra stuff they can refer to.

No luck on improving the Fischer esterification route? I've just always had such terrible luck with Steglich, and getting DCU out of this kind of moderately polar molecule one of my personal nightmares. Even the excellent suggestion of recrystallization in MeCN doesn't always work.

[Babcock_Hall]

Madhup K. Dhaon, Richard K. Olsen,* and K. Ramasamy J. Org. Chem. 1982, 47, 1962-1965 report using 0.5 equivalents of DMAP in making the tert-buytesters of amino acids.  BTW they discuss the issue of racemization, but that is not presently an issue for us.

[rolnor]

Dimethylfumarate is comersially available?

[Babcock_Hall]

Yes, it is, thank you.  I had seen diethyl fumarate, but I missed dimethyl fumarate.

My student found the Ph.D. thesis of Victor Francis Hoffman from the University of Iowa in 1981 that gives information on the addition of bromine to fumaric esters, acid, and salts.  He provides stereochemical information for a variety of reaction conditions.  We are just starting to look this over for useful information.

[Babcock_Hall]

My student determined that a solid that was thought to be waste produced in one reaction was actually the dimethylester of dibromosuccinic acid.  We plan to add sodium phenulsulfinate to this to make the sulfone.  That just leaves deprotection.  I found one procedure in which TMSBr was used to deprotect a methyl ester.  We will explore other ideas as we go forward.

[wildfyr]

Oy. Which version of the reaction was producing good product that was being thrown away?

[Babcock_Hall]

It was a Fischer-type esterification with sulfuric acid as the catalyst.  Nothing had been thrown away, to the best of my knowledge.  However, the solid was not initially analyzed, and the supposition was that it was solid sodium sulfate generated in the workup of the reaction.  IIRC the procedure calls for the addition of a solution of sodium carbonate.

[kriggy]

haha yeah, always analyze everything I guess (learned the hard way).
I wonder though, how much of H2SO4 did you use and what was the scale ? Seems odd to confuse sodium sulfate and product. Just the amount of solid should say something aboout it (how much of H2SO4 would you need to get reasonable amounts of sulfate?

[Babcock_Hall]

There were 0.22 mL sulfuric acid and 3 grams of starting material, which was the di-acid.  Undergraduate students need a certain number of experience in a lab before they get to the point of realizing when an explanation is untenable IMO.

[wildfyr]

Babcock, you must have the patience of a saint. It was hard enough for me to teach 1st year grad students who had a lot more time and skin in the game. So many little points of technique to correct, let alone the analysis side which becomes second nature after a few years.