To isolate the product after a prolonged treatment of the Ugi product 64C with 50% trifluoroacetic acid in CDCl3 inorder to answer the Disappearing Methyls puzzle and to isolate the free amine


The Ugi product 64C (51.7 mg ,0.092 mmol) was dissolved in 500uL CDCl3 in an NMR tube. Then 500 uL of trifluoroacetic acid was added to the above solution in the NMR tube (50% solution in CDCl3) The reaction was monitored by NMR. After a complete conversion the solution was poured into a centrifuge tube and neutralized using 10% NaOH solution. The organic component was extracted from the solution using dichloromethane and dried with anhy. MgSO4. The product was subjected to NMR analysis. Yield - 18% (6mg)


H NMR in CDCl3
H NMR in CDCl3 / CD3OD
64C Overlay
64C 13C-NMR
64C -DEPT spectrum
64C [DEPT] all protonated carbon along a single scale
98A (Ugi Product + TFA-500uL + CDCl3-500uL)
t = 03min
t = 07min
t = 12min
t = 24min
t = 27min
t = 40min
t = 42min
t = 53min
t = 55min
t = 01h 00min
t = 02h 01min
t = 17h 53min
t = 45h 11min
t = 66h 05min
t = 68h 58min
HOMODEC of 98A (Irradiated peak-8.4ppm, peak affected 5.6ppm)
98B (98A + CD3OD-400uL)
t = 06min
t =10min
t = 14min
H NMR (200scans) - minimal peaks relative to residual chloroform and TMS
H NMR (800scans)


From the NMRs it is evident that during the first 12 min of the reaction there is a clear deprotection of the BOC group from the molecule, however over a period of 68 hours, the doublets at 8.4 and 5.6 ppm develop which represent two protons coupled to each other (HOMODEC) on an adjacent N and C atoms. The peaks can be explained on the basis that the molecule is undergoing a cleavage, resulting in the loss of methyl furfuryl group of the ugi product. This is a trend which has been observed consistently Exp091, Exp070, EXP067, EXP065., also summarized in the UsefulChem blog. with ugi products containing 5-methyl furfuryl substitutent on the tertiary amide up exposure to 50% TFA in CDCl3..

When 10% NaOH was added the reaction mixture was not sufficiently basified (see log-pH 7 reported) as a result of which most of the free amine remained in a salt form in the aqueous layer when extracted with dichloromethane.


A cleavage of the methyl furfuryl group from the ugi product up on a prolonged exposure to 50% TFA in CDCl3 has been observed yet again by NMR monitoring. The product was not isolated due to experimental error.



18:10 Weighed the ugi product (64B) (51.7 mg, 0.1 mmol) in an NMR tube and dissolved it in CDCl3 (500 uL)
18:59 Obtained H NMR of the ugi product 86B in CDCl.
19:15 Added TFA (500uL) to the NMR tube, this is 98A
19:18 Obtained H NMR of 98A. (t = 03min)
19:22 Obtained H NMR of 98A (t = 07min)
19:27 Obtained H NMR of 98A (t = 12min)
19:39 Obtained H NMR of 98A (t = 24min)
19:42 Obtained H NMR of 98A (t = 27min)
19:55 Obtained H NMR of 98A (t = 40min)
19:57 Obtained H NMR of 98A (t = 42min)
20:08 Obtained H NMR of 98A (t = 53min)
20:10 Obtained H NMR of 98A (t = 55min)
20:15 Obtained H NMR of 98A (t = 01h 00min)
21:16 Obtained H NMR of 98A (t = 02h 01min)


13:08 Obtained H NMR of 98A (t = 17h 53min)


16:26 Obtained H NMR of 98A (t = 45h 11min)


13:20 Obtained H NMR of 98A (t = 66h 05min)
16:13 Obtained H NMR of 98A (t = 68h 58min)
16:19 Obtained HMODEC of 98A by irradiating the peak at 8.4 ppm
16:30 Added methanol-d4 (400uL) to obtain 98B
16:36 Obtained H NMR of 98B (t = 06min)
16:40 Obtained H NMR of 98B (t = 10min)
16:44 Obtained H NMR of 98B (t = 14min)


17:40 Poured the contents of the NMR tube into a centrifuge tube, added 10% NaOH (1mL), which was sufficient enough to get the pH up to 7 (that won't be enough to generate the free base), a deep purple colored precipitate settled down in thecentrifuge tube.
17:55 Centrifuged the heterogenous solution, carefully pipetted out the clear supernatant, saved the bottom purple viscous component 98C for further workup if required.
18:20 To the clear supernatant, dichloromethane (3 mL) was added and the bottom organic layer was separated using a separatory funnel. To the top aqueous layer dichloromethane (3mL) was once again added, and the layers were separated.
18:45 To the combined bottom layers anhydrous MgSO4 (~1g) was added.
18:55 A dry dichloromethane solution was obtained by filtering the MgSO4 slurry through a sintered glass funnel.
19:00 The dry and clear organic layer was set on a high vac for solvent evaporation to give 98D (6mg)


12:52 Dissolved 98D (~ 6mg) in 700mg of CDCl3 and obtained a H NMR (Varian 300MHz, with 200scans)
14:20 Obtained another H NMR of 98D with 800 scans.


12:30 The residue from centrifugation (98C) was poured out into a clean vial and the solvent was set for evaporation under a gentle stream of Nitrogen gas.


64C InChI=1/C27H39N3O7/c1-17-10-12-19(36-17)16-30(22(31)15-28-25(33)37-27(5,6)7)23(24(32)29-26(2,3)4)18-11-13-20(34-8)21(14-18)35-9/h10-14,23H,15-16H2,1-9H3,(H,28,33)(H,29,32)