To synthesize a Ugi adduct with 3,4-dimethoxybenzaldehyde, 5-methylfurfurylamine, Benzylisocyanide and Boc-Gly-OH in deuterated methanol (CD3OD).


Step 1: Imine synthesis
One molar methanol-D4 solutions of 3,4-dimethoxybenzaldehyde (166mg, 1mmol) and 5-methylfurfurylamine (numbers.JPG) (166uL,1.5mmol ) 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 imine syntheis is monitored by proton NMR. for approximately 2hours.
Step 2: Addition of Benzyl isocyanide
The preformed Imine solution is transferred to a 1 dram vial and 400uL of 1M Benzylisocyanide (120uL, 0.99mmol) solution is added to it. Using a micropipette 800uL of the imine and the isocyanide solution is transferred to a clean NMR tube for further analysis.
Step 3: Addition of Boc-Gly-OH
After a period of time 400uL Boc-Gly-OH(175mg, 1mmol) solution in CD3OD is added to the reaction.
The whole process is carried out in an NMR tube with NMR monitoring.


(*Spectra obtained on a Varian Inova 300MHz instrument, unless specified otherwise, all spectra referenced with respect to CD3OD, H NMR at 3.31 ppm quintet and C NMR at 49.15ppm septet).
5-Methyl furfurylamine
H NMR Tentative assignments
Benzyl isocyanide
H NMR Signature triplet at 4.68ppm. J = 2.2Hz
54A (Veratraldehyde + 5-Methyl furfurylamine)
t = 04min
t = 10min
t = 12min
t = 16min
t = 32min C NMR
t = 39min
t = 93min
t = 117min C NMR
t = 122min
t = 125min
t = 258min C NMR
t = 300min
t = 374min C NMR
t = 415min
t = 456min
54B (54A + Benzyl Isonitrile)
t = 06min
t = 10min
t = 13min
t = 65min C NMR
t = 72min
t = 77min
t = 169min C NMR
t = 183min
t = 15h 15min C NMR
t = 15h 31min
t = 17h 12min
t = 17h 20min
54C (54B + Boc-Glycine)
t = 03min
t = 07min
t = 11min
t = 14min
t = 19min
t = 22min
t = 25min
t = 28min
t = 33min
t = 35min
t = 39min
t = 44min
t = 52min
t = 56min
t = 61min
t = 163min C NMR
t = 173min
t = 241min
t = 300min
t = 353min C NMR
t = 360min
t = 20h 35min C NMR (solid in NMR tube)
t = 22h 10min (solid in NMR tube)
H NMR of 54D
Melting point 172-174C.
H NMR of 54E in acetone-d6.
H NMR 54F after centrifuging the solid particles out.

Spectral Overlays

Overlay1: H NMR of Veratraldehyde, 5-methylfurfurylamine and 54A[10min, 16min, 39min, 93min, 125min, 300min, 456min].
Overlay1modified H NMR of Veratraldehyde, 5-methylfurfurylamine and 54A [04min and 456min only]
Overlay2 : H NMR of 5-Methylfurfuryl amine, Veratraldehyde, 54A-456min, Benzyl isocyanide, 54B-06min, 54B-17h20min.
Overlay3 : H NMR of 5-Methylfurfuryl amine, Veratraldehyde, 54A-456min, Benzyl isocyanide, 54B-17h20min, Boc-Gly-OH, 54C-03min, 54C-360min, 54C-22h10min.

Reaction Profiles

EXP054ImineProfile: Veratraldehyde, 5-methylfurfurylamine and 11 monitoring spectra of imine formation (Zip File) as described here.
Figure 1a, 1b: Imine Kinetics

Figure 2: 54C Kinetics
Excel Sheet Incorporating 54C data


  1. The imine formation in this case is 100% relative to the aldehyde. The imine formation reaction profile in Fig 1 shows that monitoring of the methylene conversion from the amine to imine parallels exactly the conversion of the aldehyde peak to imine. There is clearly 50% extra amine left over after all the aldehyde is reacted. Integration of the residual methanol peak at 3.1 ppm and comparing with various solutions in the past few experiments reveals a ratio of about 10:1 per hydrogen for a 1M solution. As shown in the imine profile Excel file, the aldehyde ratio is about 9, consistent with a 1 M solution, while the amine is almost twice that, suggesting that the error occurred during preparation of the amine stock solution. The values for all ranges used in the calculation of the reaction profile is located in the ini file in the zip folder.
  2. Tentative Imine assignments. Aromatic protons & coupling constants: 6.92d [J=8.3Hz], 7.19dd [Jsmall=1.95Hz, Jbig=8.3Hz], 7.43d [J=1.95Hz] (As described here). The imine proton at 8.24ppm looks like an incompletely formed triplet, hence it is defined as multiplet to avoid ambiguity, it may well be called a distorted singlet.
  3. The imine does not react with benzyl isocyanide over 15 h in the absence of the carboxylic acid component.
  4. After the addition of the boc-gly, the reaction profile over the next 6 hours is shown In Fig 2. The consumption of benzylisocyanide parallels the loss of the imine, consistent with the progression of the Ugi reaction. Both the amine and aldehyde show a slight increase in concentration, peaking after about 30 min then slowly decreasing. The hydrolysis of the imine upon addition of boc-gly has been observed previously (Exp052, Exp048). The concentration of boc-gly cannot be tracked unambiguously via H NMR because of peak overlap.


1.Although each reactant was successfully tracked except boc-glycine, the Ugi product itself could not be assigned the peaks with certainty. (Assignments in Exp064) But now that we know where the peaks are can we track the concentration of the Ugi product over time in this experiment?
2.The isocyanide does not react in the absence of the carboxylic acid in this Ugi reaction..



07:35 - Made up numbers1M.JPG1.5M solution of 5-Methyl furfurylamine in methanol-d4, and also 1M solution of veratraldehyde in methanol-d4.
08:10 - Made up 1M solution of Boc-Gly-OH in methanol-d4.
09:20 - Obtained H NMR and C NMR of Veratraldehyde and 5-Methyl furfurylamine
10:46 - Added 400uL of veratraldehyde and 5-Methylfurfurylamine in a clean nmr tube and mixed it well for about 45sec to obtain 54A
10:50 - Obtained H NMR (t = 04min)
10:56 - Obtained H NMR (t = 10min)
10:58 - Obtained H NMR (t = 12min)
11:02 - Obtained H NMR (t = 16min)
11:18 - Obtained C NMR (t = 32min)
11:25 - Obtained H NMR (t = 39min)
12:19 - Obtained H NMR (t = 93min)
12:43 - Obtained C NMR (t = 117min)
12:48 - Obtained H NMR (t = 122min)
12:51 - Obtained H NMR (t = 125min)
15:04 - Obtained C NMR (t = 258min)
15:46 - Obtained H NMR (t = 300min)
17:00 - Obtained C NMR (t = 374min)
17:39 - Obtained H NMR (t = 415min)
18:22 - Obtained H NMR (t = 456 min)
18:34 - Added 400uL of 1M Benzylisocyanide to the NMR tube containing the already reacted aldehyde and amine, to obtain 54B
18:40 - Obtained H NMR (t = 06min)
18:44 - Obtained H NMR (t = 10min)
18:47 - Obtained H NMR (t = 13min)
19:39 - Obtained C NMR (t = 65min)
19:46 - Obtained H NMR (t = 72min)
19:51 - Obtained H NMR (t = 77min)
21:23 - Obtained C NMR (t = 169min)
21:37 - Obtained H NMR (t = 183min)


09:49 - Obtained C NMR (t = 15h 15min)
10:05 - Obtained H NMR (t = 15h 31min)
11:46 - Obtained C NMR (t = 17h 12min)
11:54 - Obtained H NMR (t = 17h 20min)
14:42 - Added 400uL of 1M Boc-Gly-OH (1mmol, in CD3OD) to the nmr tube already containg the imine and isonitrile, to obtain 54C.
14:45 - Obtained H NMR (t = 03min)
14:49 - Obtained H NMR (t = 07min)
14:53 - Obtained H NMR (t = 11min)
14:56 - Obtained H NMR (t = 14min)
15:01 - Obtained H NMR (t = 19min)
15:04 - Obtained H NMR (t = 22min)
15:07 - Obtained H NMR (t = 25min)
15:10 - Obtained H NMR (t = 28min)
15:15 - Obtained H NMR (t = 33min)
15:17 - Obtained H NMR (t = 35min)
15:21 - Obtained H NMR (t = 39min)
15:26 - Obtained H NMR (t = 44min)
15:30 - Obtained H NMR (t = 48min)
15:34 - Obtained H NMR (t = 52min)
15:38 - Obtained H NMR (t = 56min)
15:43 - Obtained H NMR (t = 61min)
17:25 - Obtained C NMR (t = 163min)
17:35 - Obtained H NMR (t = 173min)
18:43 - Obtained H NMR (t = 241min)
19:42 - Obtained H NMR (t = 300min)
20:35 - Obtained C NMR (t = 353min)
20:42 - Obtained H NMR (t = 360min)


11:17 - Obtained C NMR (t = 20h 35min) Overnight.
11:50 - Almost 25-30% of the solution in the NMR tube had already turned solid.
12:52 - Obtained H NMR (t = 22h 10min) Amost 60-70% solid in the nmr tube.
13:10 - The entire reaction mixture solified. Unable to gain lock on the NMR instrument...Further NMR monitoring of 54C is not possible.[Solid in the NMR tube]
14:20 - The NMR tube was put in a sonicator for 15min assuming methanol (solvent) would dissolve the solid, but it did not.
14:40 - Added 500uL of methanol-d4 to the NMR tube, tried dissolving the solid by shaking the nmr tube vigourously, but it did not work. The nmr tube is again subjected to the sonicator.The solid started showing some signs of atleast partially being soluble in methanol-d4.
15:20 - Removed from the NMR tube and transferred the heterogenous solution in a preweighed (28.8882gm) 2ml roundbottom flask. A total of 2ml of methanol-d4 was used to clean the nmr tube (500uL, above).The contents of the nmr tube had an unmistakable benzyl isocyanide stench.
16:00 - The round bottom flask with the contents was set of a rotvap at 55C to evaporate methanol-d4, the solid seemed like gaining solubility. It was immediately removed from rotovap.
16:30 - The round bottom flask was set on a high vac to evaporate methanol-d4 in which the solid is partially soluble at room temperature.


09:15 - The round bottom flask (weighs 29.0873g) was removed from high vac and approximately 200mg of a yellow solid 54D was recovered.


22:15 - Obtained H NMR of 54D in CDCl3. The solid was readily soluble in CDCl3 and sparingly soluble in methanol-d4.


20:30 - Recrystallized 54D from 7ml of ethanol. [Dissolved 200mg of 54D in 7ml of ethanol in a 15ml beaker, placed the beaker in a warm waterbath, dissolved the solid,added ~7drops of hexanes, chilled the clear solution in a dry ice bath for 10min, removed from the dry ice bath, let it warm to room temperature when some solid started forming in the ethanol solution.]
20:50 - Weighed a clean sintered glass funnel (34.40153 g), filtered the solution, air dried the funnel reweighed it (34.42646g). Scraped the solid out.
21:50 - Obtained ~25mg of 54E. Yield - 11% (limiting reagent concentration - 0.4mmol, 0.25M)


16:33 : A sharp melting point of 172-174C was determined for 54E.
18:43 - Obtained H NMR of 54E. A few solid black particles settled at the bottom of the nmr tube, these must have come in from the sintered glass funnel (possibly graphite).


17:20 : Decanted the nmr contents of the nmr tube in to a clean centrifuge tube, rinsed the nmr tube with acetone-d6, placed the centrifuge tube in warm water bath,dissolved forming crystals, centrifuged the solid black particles out, removed the supernatent in to a clean NMR tube and obtained another proton nmr spectrum 54F.


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