Researcher: Khalid Mirza

Supervisor: Prof. Jean-Claude Bradley

Furfuryl Cleavage



To isolate the product after a prolonged treatment of 62E with 50% trifluoroacetic acid in CDCl3 inorder to solve the Disappearing Methyls puzzle.


Dissolved 50 mg (0.1 mmol) of the Ugi product 62E from Exp062 in 500 uL CDCl3. 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. Qantitative conversion; yield: 100%?


H NMR (62E)

t = 03 min [ Spectrum distorted]
t = 08 min
t = 14 min
t = 20 min
t = 25 min
t = 2 h 27 min
t = 18 h 37 min
t = 24 h 45 min
t = 45 h 29 min
t = 47 h 09 min
91B (methylene chloride extract of basified aqueous layer)
H NMR (before CD3OD addition)
91C (91B + CD3OD-200 uL)
FAB MS of 91C
High Res (matrix- 3-nitrobenzyl alcohol; calibrant- PEG)
Low Res (matrix 3-nitrobenzylalcohol)
91D (33mg) (Evaporated after MeOH addition)

Kinetics of the 1,6-elimination of methyl furfuryl group.

Fig - UCExp091-i First Order Kinetics for the acid catalyzed 1,6-methyl furfuryl elimination


Methylene chloride extraction of the basified aqueous layer yields material that is consistent with the following: a t-butyl group at 1.28 ppm, a methylene group at 3.40 ppm, methylenedioxy at 5.93 ppm and 3 aromatic H's at 6.85 and 6.74 ppm. It follows then that the glycine, piperonal and t-butyl isocyanide components of the Ugi product are still connected together and to an amine. The benzylic H is plausibly at 5.35 ppm, leaving only the broad peak at 8.26 ppm in the low field region. Because it is broad, this could be an amide N-H and tested by adding methanol-d4 to observe exchange.
The simplest hypothesis is that C-N cleavage between the furan methylene and amide occurs during prolonged exposure to TFA. A mechanism can be drawn with the protonated amide as a leaving group and the formation of an oxonium species on the furan ring. If the furan component then reacts to yield an abundance of intractable products, these could be burried in the baseline as a series of very small peaks. The upfield region of 91B does support this.
This would also explain the presence of 2 doublets in the monitoring spectra. The doublet at 5.48 would correspond to the benzylic H coupling with the newly formed adjacent amide N-H at 8.43.
This hypothesis has been confirmed from the MS of 91C which does show peaks corresponding to the [M+H] m/z 108 and [M+D] m/z 109 ions.

The 1,6-elimination of methyl furfuryl group has been determined to follow first order kinetics with a rate constant k = 1.2x10-3 min-1
This reaction is very similar 1,6-elimination observed in Exp070, where the rate constant was determined to be k = 0.9x10-3 min-1


A cleavage of the methyl furfuryl group from the ugi product up on a prolonged exposure to 50% TFA has been confirmed.



15:00 Dissolved 50 mg of 62E in CDCl3 (500 uL) in an NMR tube.
15:17 Obtained H NMR of 62E
15:20 Added TFA (500 uL) to the NMR tube.
15:23 Obtained H NMR (t = 03 min)
15:28 Obtained H NMR (t = 08 min)
15:34 Obtained H NMR (t = 14 min)
15:40 Obtained H NMR (t = 20 min)
15:45 Obtained H NMR (t = 25 min)
16:35 Obtained H NMR (t = 1 h 15 min)
17:47 Obtained H NMR (t = 2 h 27 min)


10:03 Obtained H NMR (t = 18 h 37 min)
16:05 Obtained H NMR (t = 24 h 45 min)


12:49 Obtained H NMR (t = 45 h 29 min)
14:29 Obtained H NMR (t = 47 h 09 min)
14:35 Poured the contents of the NMR tube into centrifuge tube, (pH 1) added 4 mL of 10% NaOH solution to it, mixed the contents thouroughly by squirting back and forth with a pasteur pipette, when the pH of the solution was raised to ~ 8. A precipitate had formed by now. did the precipitate go into the methylene chloride ?- No
15:00 Added dichloromethane (3 mL) to the solution and extracted the non ionic organic components into DCM layer, the bottom layer which was removed with a pasteur piptte. The extraction process was repeated a couple of times more (2 x 3 mL ) for the top layer with fresh dichloromethane. The off white / yellow precipitate always remained dangling in the top aqueous layer.
16:00 To the combined organic (bottom) layers anhydrous MgSO4 (1 gm) was added to dry any traces of water.
17:00 The combined organic layers with MgSO4 was centrifuged. The supernatant was carefully decanted in to another centrifuge tube. To the residual MgSO4 in the centrfuge tube dichloromethane (2 x 3 mL) was added, mixed by squirting and centrifuged.
18:30 The obtained supernatant solutions were combined again and set on a high vac to evaporate the solvent.


10:40 Obtained 91B (41 mg)
15:36 Obtained H NMR of 91B


15:45 Obtained H NMR of 91B
15:48 Added methanol-d4 (200 uL) to obtain 91C
15:50 Obtained H NMR of 91C


16:00 Obtained the FAB MS back after analyses. Both low and high resolution spectra were obtained. It was informed that 3-nitrobenzyl alcohol was used as a matrix for both the spectra and PEG was used as a calibrant for obtaining a high resolution mass spectrum.


12:15 The sample (91C) in CDCl3/CD3OD was poured out into a preweighed vial from the NMR tube. The NMR tube was rinsed with methanol (2 mL). The vail was exposed to a gentle stream of Nitrogen gas so as to rid the sample off the solvents.
21:30 After evaporation 91D (33mg) was obtained; obviously this mass indicates that there has to be some impurity that has swollen the mass. A quantitative conversion to the amine would give no more than 0.1mmol of the product, i.e, 30.7mg


Ugi product 62E InChI=1/C26H35N3O7/c1-16-8-10-18(35-16)14-29(21(30)13-27-24(32)36-26(5,6)7)22(23(31) 28-25(2,3)4)17-9-11-19-20(12-17)34-15-33-19/h8-12,22H,13-15H2,1-7H3,(H,27,32)(H,28,31)
91DInChI=1/C15H21N3O4/c1-15(2,3)18-14(20)13(17-12(19)7-16) 9-4-5-10-11(6-9)22-8-21-10/h4-6,13H,7-8,16H2,1-3H3,(H,17,19)(H,18,20)