To perform a 4-component Ugi reaction with 3,4-dimethoxybenzaldehyde, 5-methylfurfurylamine, 2-morpholine ethyl isocyanide and Boc-Gly-OH in deuterated methanol (CD3OD).


One molar methanol-D4 solutions of 3,4-dimethoxybenzaldehyde (166mg, 1mmol) and 5-methylfurfurylamine (111uL, 1mmol) are prepared in separate 1 dram vials. 800uL of the solutions are used to obtain initial H NMR spectra. Then 400uL of each solution is transfered to a clean nmr tube and shaken vigorously for a few seconds, the reaction is monitored by proton NMR. After 2h, the solution is added to 400uL of 1M solutions of 2-morpholinoethyl isocyanide (105uL, 1mmol) and Boc-Gly-OH(175mg, 1mmol) in CD3OD. The whole process is carried out in an NMR tube with NMR monitoring.


(*Spectra obtained on a Varian Inova 300MHz instrument, unless specified otherwise)
HMR CH2 - 3.68 ppm (t) 4H, J=4.74Hz; CH2 - 3.60 ppm(tt) 2H, J big=6.35Hz, J small=1.95Hz; CH2 - 2.65 ppm (tt) 2H,J big=6.35Hz, J small=2.2Hz; CH2 - 2.51ppm (distorted t) 4H,J=4.64Hz with peak integrations of 2:1:1:2; Solvent peaks at 4.78 ppm (s) and 3.30 ppm (quintet).

46A - (MFA+Veratraldehyde)
t = 04min 20% based on 9.76 to 8.26 ppm conversion.
t = 13min 39% based on 9.76 to 8.26 ppm conversion.
t = 18min 48% based on 9.76 to 8.26 ppm conversion.
t = 50min 72% based on 9.76 to 8.26 ppm conversion.
t = 82min 81% based on 9.76 to 8.26 ppm conversion.
t = 87min 82% based on 9.76 to 8.26 ppm conversion.
t = 105min 85% based on 9.76 to 8.26 ppm conversion.
Figure 1.
Excel Data Sheet
46B - (46A +Boc-Gly-OH + 2Morpholinoethyl isocyanide)
t = 02min
t = 15min
t = 21min
t = 44min
t= 73min
t = 114min
t = 169min
t = 226min
t = 300min
t = 17h 56min
t = 20h 27min
t = 24h 00min
t = 44h 31min
t = 48h 00min C13-NMR
t = 48h 05min
t = 50h 50min
t = 52h 51min
t = 68h 29min
t = 73h 15min (800 Scans)
t = 74h 47min (1200 Scans)
t = 89h 35min (2000 Scans with 20s relaxation; overnight run)
t = 93h 39min
t = 93h 44min
t= 96h 21min

Figure 2.
Excel Data Sheet


Overlay1: Imine Formation (An Overlay of proton NMRs of Veratraldehyde, methylfurfurylamine and imine after t=105min)
Overlay2: Ugi monitor (Veratraldehyde, t=105min (imine), Boc-Gly-OH, 2- Morpholinoethylisocyanide, 5-Methyl furfurylamine, t=02min, (all mixed)).
Overlay3: Ugi monitor (Veratraldehyde, t=105min (imine), Boc-Gly-OH, 2-morpholinoethylisocyanide, 5-Methyl furfurylamine, t=300min(all mixed)).
Overlay4: Ugi monitor (t=105min (Imine), Ugi t=02min, t=300min, t=24h 00min, t=48h 05min, t= 50h 50min)


  1. From the slope in Figure 1 using all the available data, a rate constant of 1.06 x 10-1 /M*min is calculated for imine formation. Thus, veratraldehyde and 5-methylfurfurylamine react about 10 times faster in CD3OD compared to CDCl3 (Exp045). In CD3OD, it just takes about 105 min for 85% conversion to imine while it took about 1044min for a similar conversion in CDCl3.
  2. From Overlay 4, there is a significant shift in many of the peaks immediately after addition of the acid and isocyanide, although this is made more difficult to ascertain in some cases because of the peak broadening and left to right upward sloping of all peaks, including the TMS peak. It would seem that there is considerably more noise in the spectra after addition of these two components, especially obvious in the TMS region, presumably due to dilution. However, taking a spectrum (46B-89h35min) after overnight acquisition did not further resolve the peaks.
  3. Although peak overlap makes it difficult to quantify the changes in concentration for most of the components, the clear separation of the imine and aldehyde singlets downfield afford an opportunity to track these closely by measuring the ratio of their integration to the total integration of the spectrum. Figure 2 shows the changes in absolute concentration of aldehyde and imine after the addition of the isonitrile and the acid. Within a few minutes there is a substantial increase of the aldehyde peak, not just relative to the imine but also in absolute concentration. Within the first 2 hours the combined imine and aldehyde concentration decreases from 250 mM to about 160 mM and then remains constant over several days, although there is a gradual conversion of the aldehyde back to the imine over this extended period. The appearance of peaks at 6.88 and 6.81 ppm (see Overlay 4) within the first 2 hours and the disappearance of the isonitrile methylene group as a shoulder around 3.6 ppm is consistent with the formation of the Ugi product only during this time period. However, the lack of any splitting structure in the 6.88 and 6.81 ppm peaks is troubling for their assignments as the aromatic protons in the Ugi product.


If the Ugi product forms, it does so within the first 2 hours after adding the acid and isonitrile and does not account for the major process involving the isonitrile. The rapid reversion of the imine to the aldehyde upon addition of the acid and isonitrile suggests that there may be benefit in removing water from the system during the imine formation stage.



01.06:28 - Added Veratraldehyde (3,4-dimethoxybenzaldehyde) to methanol-d4 and obtained an HMR .
Added 5-methylfurfurylamine to methanol-d4 and obtained an HMR.
Added Boc-Gly-OH to methanol-d4 and obtained HMR.
Added 2-morpholinoethyl isocyanide to methanol-d4 and obtained an HMR
02. 13:15 - Added 400uL of veratraldehyde and 400uL of 5-methyl furfurylamine to a clean NMR tube shaken it vigorously for about 30 sec to obtain 46A.
03. 13:19 - Obtained HMR (t = 04min)
04. 13:28 - Obtained HMR (t = 13min)
05. 13:33 - Obtained HMR (t = 18min)
06. 14:05 - Obtained HMR (t = 50min)
07. 14:37 - Obtained HMR (t = 82min)
08. 14:42 - Obtained HMR (t = 87min)
09. 15:00 - Obtained HMR (t = 105min)
10. 15:09 - Poured the imine solution from the NMR tube into a 1dram vial and to it, added 400uL each of Boc-Gly-OH and 2-morpholino ethyl isocyanide. The reaction mixture was shaken vigourously for about 30s, the imine nmr tube was rinsed with this mixture; 46B.
11. 15:11 - Obtained HMR (t = 2min)
12. 15:24 - Obtained HMR (t = 15min)
13. 15:30 - Obtained HMR (t = 21min)
14. 15:53 - Obtained HMR (t = 44min)
15. 16:22 - Obtained HMR (t = 73min)
16. 17:03 - Obtained HMR (t = 114min)
17. 17:58 - Obtained HMR (t = 169min)
18. 18:55 - Obtained HMR (t = 226min)
19. 20:09 - Obtained HMR (t = 300min)


20. 09:05 - Obtained HMR (t = 17h 56min)
21. 11:36 - Obtained HMR (t = 20h 27min)
22. 15:09 - Obtained HMR (t = 24h 00min)


23. 11:40 - Obtained HMR (t = 44h 31min)
24. 15:09 - Obtained CMR (t = 48h 00min)
25. 15:14 - Obtained HMR (t = 48h 05min)
25. 17:59 - Obtained HMR (t = 50h 50min)
25.20:00 - Obtained HMR (t = 52h 51min)


26. 11:38 - Obtained HMR (t = 68h 29min)
27. 16:24 - Obtained HMR (t = 73h 15min) (800 Scans)
28. 17:56 - Obtained HMR (t = 74h 47min) (1200 Scans)


29. 08:44 - Obtained HMR (t = 89h 35min), 2000 Scans, 20s relaxation time, overnight run)
30. 12:48 - Obtained HMR (t = 93h 39min)
31. 12:53 - Obtained HMR (t = 93h 44min)
32. 15:31 - Obtained HMR (t = 96h 21min)

Henk Wensink, Fernando Benito-Lopez, Dorothee C. Hermes, Willem Verboom, Han J. G. E. Gardeniers, David N. Reinhoudt and Albert van den Berg, Measuring reaction kinetics in a lab-on-a-chip by microcoil NMR Lab Chip, 2005, 5, 280 - 284


2-morpholin ethyl isocyanideInChI=1/C7H12N2O/c1-8-2-3-9-4-6-10-7-5-9/h2-7H2
Veratradehyde InChI=1/C9H10O3/c1-11-8-4-3-7(6-10)5-9(8)12-2/h3-6H,1-2H3
Boc-Gly-OH InChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)