To isolate the product after a prolonged treatment of 99C with 50% trifluoroacetic acid in CDCl3 in order to confirm the Missing Methyl Mystery Mechanism also discussed as the Disappearing Methyls puzzle in the UsefulChem blog


To a solution of ugi product 99C (88.6 mg, 0.2 mmol) in CDCl3 (500uL), trifluoroacetic acid (500uL) was added in an NMR tube. The reaction was monitored by NMR. After a complete conversion the solution was poured into a centrifuge tube and neutralized with 10% NaOH solution, extracted from with dichloromethane, dried with anhy. MgSO4. The product was subjected to NMR analysis after .


Ugi Product (99C from Exp099)
t = 06min
t = 13min
t = 19min
t = 25min
t = 54min (C NMR)
t = 1h 13min
t = 5h 44min
t = 10h 13min
t = 25h 24min
t = 30h 04min
t = 3days
t = 6days
t = 7days
t = 9days
t = 10days
t = 1month
t = 38days

Kinetics Spreadsheet


Over a period of 30 hours, the furfuryl group clearly remains stable in the acidic environment, which is unlike what has been observed with the methyl furfuryl analog of the statring material, as in Exp098, Exp091, Exp070, EXP065, EXP067, EXP091 all of which undergo loss of the entire methyl furfuryl group under similar conditions. This suggests that the methyl group on the 5th postion of the furan rings somehow is involved in loss of the entire methyl furfuryl group upon a prolonged exposure to 50%TFA.
It took one month for the boc-deprotected ammonioum trifluoroacetate salt to undergo a 60% conversion to the secondary amide after a furfuryl cleavage. Moreover the conversion does not follow first order kinetics, unlike the 1,6-methyl furfuryl cleavage. This indicates that a mechanism different than the 1,6-methyl furfuryl cleavage operates during the furfuryl cleavage.
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A closer look at 8.5 ppm region in the 6 days H NMR (and later), a new peak peak has started to form, this is a doublet (as in the the 7th day spectrum) which indicates that the molecule has started to cleave again..this is very slow compared to the earlier experiences. (give estimate of rate compared to methylfurfuryl derivative)...This may suggest that a methyl group (maybe a broader generalization; an electron donating group) accelarates the rate of the furfuryl cleavage. Therefore if the hypothesis holds, then a tert-butyl group, a methoxy, NR2, etc substituents on the 5th position of the furan ring should accelerate this cleavage while electron withdrawing groups like -CF3, CN or NO2 should slow it even further.




11:34 Obtained H NMR of a solution of the Ugi product (99C) (88.6 mg) in CDCl3 (500 uL)
11:38 Added TFA (500 uL) to the NMR tube containing 99C in CDCl3, this is 101A
11:44 Obtained H NMR of 101A (t = 06min)
11:51 Obtained H NMR of 101A (t = 13min)
11:57 Obtained H NMR of 101A (t = 19min)
12:03 Obtained H NMR of 101A (t = 25min)
12:32 Obtained C NMR of 101A (t = 54min)
12:51 Obtained H NMR of 101A (t = 1h 13min)
12:53 The solution in the NMR tube has remained clear; this is unlike the previous observations with other ugi products under similar conditions where the solution in the NMR tube turns deep red to brown with in the first 10 mins.
17:22 Obtained H NMR of 101A (t = 5h 44min)
21:51 Obtained H NMR of 101A (t = 10h 13min)


13:02 Obtained H NMR of 101A (t = 25h 24min); the color of the solution turned deep brown.
17:42 Obtained H NMR of 101A (t = 30h 04min)


13:35 Obtained H NMR of 101A (t = 3days)


15:28 Obtained H NMR of 101A (6days)


12:28 Obtained H NMR of 101A (7days)


15:29 Obtained H NMR of 101A (9days)


19:19 Obtained H NMR of 101A (10days)


The capped NMR tube containing 101A was left in a fume hood.
15:52 Obtained H NMR of 101A (1 month)


15:59 Obtained H NMR of 101A (38days)


099C-Ugiproduct: InChI=1/C24H33N3O5/c1-23(2,3)26-21(29)20(17-11-8-7-9-12-17)27(16-18-13-10-14-31-18)19(28)15-25-22(30)32-24(4,5)6/h7-14,20H,15-16H2,1-6H3,(H,25,30)(H,26,29)