To obtain a high yield Ugi product link from piperonal, tert-butylamine, Boc-Gly-OH, and tert-butyl isocyanide in order to go on to the cyclization step.


Made solutions of piperonal(75mg, 0.5mmol in 1 ml MeOH-d4, 0.5M) and tertbutylamine(57.8uL, 0.55 mmol in 1 ml MeOH-d4, 0.55M ) for HMR identification. Next, made up piperonal(301.9mg, 2mmol in 2 ml MeOH, 1M-) and tertbutylamine(231uL, 2.2mmol in 2 ml MeOH, 1.099M-) solutions using 10% extra amine for imine formation. Aldehyde and amine solutions were mixed in the presence of 65 activated 3A sieves (452mg). The solution was stirred by hand for two minutes and left over night. Stirring by stir bar not yet used in this step.


Characterization of starting materials

Piperonal HMR
Tertbutylamine HMR

Imine Formation - Part 1

20min HMR (this is after evaporation of a sample - any t-butylamine would have evaporated)
24hour HMR(this is after evaporation of a sample - any t-butylamine would have evaporated)

Addition of Acid - Part 2

05mins HMR(this is after evaporation of a sample - any t-butylamine would have evaporated)
20mins after five mins of spining HMR(this is after evaporation of a sample - any t-butylamine would have evaporated)


The 2mmol amount of water that formed probably exceeded the amount of water that the molecular sieves can adsorb reversing the imine reaction when the acid is added. Verify that with a reference to the capacity of 3A sieves for water. The fact that the reaction mixture was not stirred for most part is still a factor.


Because the reversal of the aldehyde (peak 9.8ppm) is still extensive as the percent difference in the imine from parts 1 and 2 compared to the aldehyde is 28%. This experiment will be terminated and followed no further. When successful completion of the imine is accomplished without reverting back to the aldehyde, a Ugi product will be attempted.



19:30] Made up 0.5M sample of piperonal(from different bottle) and 0.5M tertbutylamine (same bottle used in previous experiments) in MeOH-d4 to take HMR of starting materials of imine reaction. Also prepared 2mL, 1M solutions of piperonal and 1.1M tertbutylamine in methanol.
19:45] Mixed piperonal and amine methanol solutions in the presence of 65x activated 3A molecular sieves(452mg).
19:50] Took a 0.5mL sample of the imine solution for NMR. Used an in house vacuum to take off the methanol. This is about 5-10 times more than you need for HMR - also use high vac to dry the samples so there is no delay
20:45] Took HMR of piperonal starting material
20:55] Took HMR of tertbutylamine starting material
21:05] Took HMR of Imine solution in MeOH-d4. This will be designated part1_20minutes as there was an approximately 20 min lapse between taking the sample, having all of the methanol vacuumed off and taking the HMR.


16:40] Started stirring imine solution on stir plate.
17:50] Stopped stirring imine solution. Took sample approx. 0.5mL for NMR. Vacuumed off methanol. Added MeOH-d4. This is after 24hrs of reacting.
18:35] Attempted to get HMR spectrum but side peaks were prevalent in spectra. Did not save NMR but saved sample. Aldehyde was reduced to the baseline and imine peak at 8.4 was present.
19:10] Prepared sample of Boc-Gly-OH for HMR identification in MeOH-d4 and 1M solution for the reaction.
19:20] Added the acid solution to the imine mixture.
19:20] Took sample 0.5mL of imine acid solution to see if aldehyde had reformed. Vacuumed off methanol and added methanol-d4.
19:21] Put imine acid solution on spin.
19:26] Stopped spin and took another sample to see if aldehyde had reformed.


tert-butylamine InChI=1/C4H11N/c1-4(2,3)5/h5H2,1-3H3
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)
imine: InChI=1/C12H15NO2/c1-12(2,3)13-7-9-4-5-10-11(6-9)15-8-14-10/h4-7H,8H2,1-3H3/b13-7-