Missing Methyl Mystery Mechanism

I think I have a plausible mechanism for the missing methyl problem we've been trying to solve recently.

After basification, the amine component drags everything except for the methylfufuryl group into the organic phase. For example, Khalid is showing that the Ugi product A generates free amine B pretty clearly by MS and NMR. (EXP097). (Other examples: EXP065 EXP067 EXP070 EXP091)

Since the methyl group disappears along with the furan ring and methylene, my best guess is that C forms intractable products that get lost in the baseline during H NMR monitoring.

Also, it turns out that the mysterious doublets formed during the monitoring of these reactions corresponds to the coupling between the benzylic H and the amide H in B. I would not have expected to see coupling under the rapid exchange conditions of 50% TFA in CDCl3. (see methanol-d4 exchange discussion in EXP091 for assignment support)

If this mechanism is correct, I would expect it to take place for 5-methylfurfurylamine (EXP073), its acetate(EXP081) and its boc-gly amide (EXP092). None of those experiments generated the methyl loss scenario. Maybe the rate is just faster for these Ugi products for some reason.

Any advice from furan experts out there?





Chemical Blogspace Tags

InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
5-methylfurfurylamine

InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)
boc-glycine

InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2
benzyl isonitrile

InChI=1/C2HF3O2/c3-2(4,5)1(6)7/h(H,6,7)/f/h6H
trifluoroacetic acid

InChI=1/C5H7F3O2/c1-3(2)10-4(9)5(6,7)8/h3H,1-2H3
t-butyl trifluoroacetate