Ideas on disappearing furan in TFA?

23 Mar
Published by jcbradley

We have a problem in synthesizing our anti-malarials that could use some feedback from some organic chemists:

Ever since we isolated our Ugi products, we've been trying to cyclize them to the diketopiperazines. As described by Hulme, we are trying to effect an intramolecular transamidation catalyzed by trifluoroacetic acid (TFA). Instead of dichloroethane we are generally using CDCl3 so that we can monitor the reaction by NMR.

The first step of removing the boc group seems to proceed very smoothly, with the appearance of t-butyl trifluoroacetate at 1.61 ppm within a few minutes or hours, depending on the concentration of TFA. Here is a H NMR from Khalid's EXP070, 13 min after addition of 50% TFA in CDCl3 showing complete deprotection:

After 2 days at room temperature, a clean conversion to another set of peaks is completed. Whatever is going on, this is not to the desired diketopiperazine. For one thing the furan methyl group is gone.

There also appears to be one missing methylene and the furan protons have disappeared as well. A pair of mysterious doublets appear at 8.4 and 5.6 ppm.

Alicia observes a very similar course for her reaction (EXP065). Upon washing with water, nothing remains in the organic phase. This suggests that all the components are trifluoroacetate salts, most likely still in one piece.

Does anybody have any idea what is going on?

(If you look at the NMR spectra on the wiki with JSpecView, use IE; Firefox is still unstable)


Furans are susceptible to strong acid-catalyzed hydrolysis to ring-opened products.  The loss of furan-associated methyl and aromatic peaks is consistent with this.  The doubling of the original CH peak and lack of additional methyls from the ring opened furan to a probable diketone species suggests that this fragment of the molecule somehow detached from the amide, giving the doublet coupling between the CH and NH peaks (NH at ~8.5 ppm).  Additionally, if the t-butyl signal ascribed to t-butyl trifluoroacetate integrates to 9 (it appears to but I can't tell) theres the possibility that the tert butyl cation formed during the reaction attached to some other portion of your molecule before it was scavenged.  Since your furan is very electron-rich with the 2 alkyl substituents strong acids will be a difficult process to optimize.  I would suggest the following: 1.  Trying weaker acids such as formic acid for longer reaction times.  2.  Trying thermolysis conditions (silica gel and microwave heating, quinoline solvent, heat to 200°C or more, etc.)  3.  Adding cation scavengers (thioanisole, phenol, etc.) to reaction mixtures to prevent t-butyl migration.  Note I took some of this information from Greene's Protective Groups in Organic Synthesis, 4th edition.  I personally am working on t-butyl esters but some of the conditions also remove Boc groups and have been applied to furan-containing molecules.  Good luck!