[Babcock_Hall]

We are trying to displace the bromine from diethylbromoethylphosphonate with ethylglycine.  Ethylglycine is sold as a hydrochloride salt, and we use 2.5 equivalents of TEA and ethanol as the solvent.  One reaction used DMAP and about two days of reflux, and the second reaction used about 18 hours of reflux and catalytic DMAP  The original synthesis is from Bigge et al, J. Med Chem., 1992,35, 1371-1384, and it used methylglycine hydrochloride.  We performed it some years ago, but our records are incomplete with respect to a P-31 NMR of the crude product.  Our two P-31 spectra looked similar.  The major peak is around 30.5 and has about the expected chemical shift of the product.  A second peak appears around 17.8 ppm and a third at 9.5.  The identities of these compounds are not known.  However, a second alkylation of nitrogen is possible, and bromide could also remove an ethyl group to produce ethyl bromide and a mono ester at phosphorus.

The area percent of the product peak is just under 60% of the total.  I am OK with this if our purification gives us a clean product.  However, we previously prepared the iodoethyl version of our starting phosphonate, and we are considering whether or not to try another alkylation.  Any thoughts as to whether this change will provide an improvement?

[discodermolide]

The iodoethyl may make the deesterification at P worse.
If anything use the chloromethyl and perhaps sodium ethnocide as a base.

[Babcock_Hall]

Do you mean sodium ethoxide?  Thank you.

[discodermolide]

Yes, that damm spell checker, sodium ethoxide

[phth]

You could use an inert solvent like hex spiked with x amount of EtOH, 18-crown-6 and KOEt.  Hexanes should bring the nucleophiles+electrophiles together nicely

[Babcock_Hall]

Just a quick update.  Tentatively, I would say that the major side product is the diethylester of vinylphosphonate, but I have not done all of the NMR legwork yet.  Somewhat surprisingly, we are having a difficult time visualizing the material in the fractions using TLC and phosphomolybdate dip.  However, we have found that ashing a small portion, followed by a total phosphate assay can be used to locate the fractions containing phosphorus.

A previous synthesis of a similar compound used the glycine methylester and purified using methanol in chloroform over silica.  The workers noted some transesterification.  Given the presence of heat, I am more inclined to think that transesterification happened during the synthesis, as opposed to the chromatography.  Is there any reason to think otherwise?