To synthesize a Ugi adduct with 3,4-dihydroxybenzaldehyde, 5-methylfurfurylamine, tert-butylisocyanide and Boc-Gly-OH in methanol.


1.0 M 3,4-dihydroxybenzaldehyde (138mg, 1mmol), Boc-Gly-OH (175mg, 1mmol), tert-butylisocyanide ( 113uL, 1mmol) and 1.1 M 5-methylfurfurylamine (122uL, 1.1mmol) solutions were made in methanol and CDCl3 (Note: 3,4-dihydroxybenzaldehyde has a limited solubility in CDCl3, less than 0.5M, so acetone-D6 will be used to obtain an HMR of the starting materials and reaction points) using 1 mL volumetric glassware, and placed into 1 dram vials. The Acetone-D6 solutions were used to obtain initial HMR spectra of the starting materials. The methanol solutions of 3,4-dihydroxybenzaldehyde and 5-methylfurfurylamine were added together into a separate vial, shaken vigorously for 30 seconds, and allowed to sit overnight (without stirring) to form the imine. 400 uL of the solution was transferred into a clean, dry round bottom flask and placed under vacuum to remove the solvent, then redissolved in acetone-D6 to check the formation of the imine. The imine solution and the 1M Boc-Gly-OH solution were added to a clean, stoppered 25mL Erlenmeyer flask and swirled for 30 seconds. The solution was allowed to sit (without stirring) for 2 hours. 400 uL of the reaction mixture were placed in a separate round bottom flask, placed under vacuum to remove the solvent, then redissolved in 1 mL acetone-D6 to obtain a HMR spectra of the mixture. The 1M tert-butylisocyanide solution was added to the reaction mixture, and the mixture was monitored by NMR.


(*Spectra obtained on a Varian Inova 300MHz instrument, unless specified otherwise)
HMR (Acetone-D6)
HMR (Acetone-D6)
HMR (Acetone-D6)
t=66h 47min
t=136h 17min
t=2h 58min

Spectral Overlays

Reaction Profiles


1.) The imine solution was left in the NMR tube for approximately 69 hours in acetone D-6 between HMRs, which could explain when the t=136h 17min time point looks drastically different than the t=66h 47min point. It is possibly that the acetone affected the imine equilibrium, and possibly reacted with the aldehyde, which could explain the multiple other peaks in the spectra. Possible reactions it could have undergone are competition between the ketone and aldehyde for the imine, or any left over aldehyde could have undergone aldol condensation, shifting the imine equilibrium back to the aldehyde and causing it to be consumed. The imine can also react with acetone-d6 via aldol chemistry. It will be noted that leaving an imine solution in acetone for too long causes degradation of start materials and imine. NMR spectra of primary amines will no longer be obtained using acetone-D6.




17:30 - Made up solutions of 1M 3,4-dihydroxybenzaldehyde in methanol and acetone-D6, and 1.1 M solutions of 5-methylfurfurylamine in methanol and CDCl3.
22:30 - Obtained HMR spectra of 3,4-DHB and 5-MFA.
22:50 - Mixed the methanol solutions of 3,4-DHB and 5-MFA. Shook vigorously for 30 seconds. (61A)


14:15 - Removed 400uL of 61A, placed in a 10mL round bottom flask, and placed under vacuum to remove solvent.
16:41 - Removed flask from vacuum, added 1mL acetone-D6 to dissolve contents (contents were a dark red-orange oil).
16:45 - Placed 800uL of 61A in an NMR tube.
17:37 - Obtained spectra of 61A (t=66h 47min)


15:08 - Obtained spectra of 61A (t=136h 17min, has been in NMR tube of Acetone-D6 for 69 hours, 30 min)
15:14 - Obtained spectra of Boc-Gly-OH in acetone-D6.
15:17 - Obtained spectra of 5-methylfurfuylamine in acetone-D6.
15:35 - Mixed the imine solution and the Boc-Gly-OH solution in a 25mL stoppered Erlenmeyer flask, swirled for 30 sec. (61B)
17:45 - Removed 400uL 61B, placed in a round bottom flask, placed under vacuum to removed solvent (contents were a brown oil).
18:33 - Removed 61B from vacuum, dissolved in 1mL acetone-D6, placed 800uL of the solution into an NMR tube and obtained spectra of 61B.


t-butyl isocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
3,4-dihydroxybenzaldehyde InChI=1/C7H6O3/c8-4-5-1-2-6(9)7(10)3-5/h1-4,9-10H