For some time I am struggling with a tricky synthesis problem in my pHD. I think I came closer now, but I still need a link in the chain to make my idea work. The principle goal here is access a free phosphonic acid as a pure substance. The challenge here is, that the substance itself does not tolerate acid too well. Therefore, the direct reaction of the dichloride is not favorable. Additionally the intended compound is very polar, therefore when you have polar reagents around like salts to neutralize the acid, they really cant be separated off. Therefore I want to go by a detour to create a symmetric diester, bring this into the organic phase during workup and than perform a clean and efficient de protection step. The best case would be, that all byproducts that are formed during the deprotection are of volatile nature.

enter image description here

  1. At first tried the obvious choice, the benzyl protective group.

But here I had the problem, that when I used stoichiometric amounts of phenylalcohol, the reaction performed quite slowly and inefficiently. I had in the past big problems to remove an excess of the alcohol due to the high boiling point of 220 °C, leaving with a mixture of monoester, diester and phenylalcohol

  1. The Cyanoethylgroup

that is used from the phosphoramidite approach could be attached just one time in my specific case. During the coupling with cyanoethanol I observed, that the pyridine that was present during the reaction seamed to already cleave off the monoester, but resulting in an unwanted side product, not the intended free phosphonic acid.

I am wondering if there is a viable alternative for a temporary protection group that may be removed by oxidation, reduction, irradiation or heating that is suitable for double protection? Most strategies explained in the Green are mostly for single protection. I was thinking about allylalcohol as an alternative to benzyl, but there are no real examples for this in the literature.

  • $\begingroup$ So the only problem with the diethyl phosphonate is that it's too difficult to hydrolyze? Have you considered something like cleavage with trimethylsilyl iodide? The ethyl iodide byproduct would be volatile, and the bis-TMS phosphonate would be very readily cleaved to the acid, even with just MeOH, forming volatile TMSOMe. $\endgroup$ Commented Jul 10 at 12:21
  • $\begingroup$ Oh now I see the previous step of your synthesis, and you suspect TMS+ would degrade your substrate. $\endgroup$ Commented Jul 10 at 12:26
  • $\begingroup$ Yeah,.TMS+ will likely kill the product. Cyanoethyl delivers after a long reaction time a mixture of a monster side product and diester, but it seems like they can't be separated. Could there be the possibility to quench the dichloride with water in acetonitrile and than just Schick freeze the mixture to avoid acid deterioration by HCl? $\endgroup$
    – raptorlane
    Commented Jul 10 at 19:50
  • $\begingroup$ Maybe? No clue, would have to try it out. That said, if you're already going to the dichloride, you might be able to do some kind of TMSCl elimination with a weak enough TMS+ source, like AcOTMS, and leave the rest of your substrate untouched. $\endgroup$ Commented Jul 10 at 23:02
  • $\begingroup$ Can you use something like 1,3-Dichlorotetramethyldisiloxane to protect the phosphonic acid as a cyclic bis-silyl ester which would cleave to F-? $\endgroup$
    – Waylander
    Commented Jul 11 at 13:22


Your Answer

By clicking “Post Your Answer”, you agree to our terms of service and acknowledge you have read our privacy policy.