To accomplish the Ugi Synthesis and cyclization to a diketopiperazine using 3,4-dihydroxybenzaldehyde, 5-methylfurfurylamine, Boc-Gly-OH, and benzylisocyanide using the protocol described here, with the modification that THF will be used instead of 1,2-dichloroethane in the cyclization step. The target diketopiperazine is not predicted to be active but is a close analog of the product that we wish to make once the catechol aldehyde is obtained.


To a 50ml Erlenmeyer flask added methanol (25 mL), 3,4-dihydroxybenzaldehyde (80.38mg, 0.58mmol) , 5-methylfurfurylamine (65µl, 0.58mmol) by micro pipette, benzylisocyanide (70µl, 0.58mmol) by 500 µl GC syringe and Boc-Gly-OH (101.98mg, 0.58mmol). After stirring at room temperature for 20 hours, the solvent was evaporated. A 10% solution of TFA in THF (30 mL) was added and stirred under nitrogen for 20 hours. Performed Flash column chromatography.


Characterization of 20A

TLC1: 20

Characterization of 20B

TLC2: 20B

Characterization of 20C

NMR of 20C. TLC of TFAvac vs Ugi

Characterization of 20C Fractions 1 & 2

HMR Frac1 HMR Frac2 HMRFrac2 w/D2O
TLC of Fraction components compared to 20C


Based on the HMR of 20B, there is a small peak at 9.7 suggesting there is still some aldehyde present, a cluster of peaks in the 4.4-4.6 region may suggest some benzylisocyanide is still present as well. The sharp peak at 3.8 may suggest that there is also some acid but it may be misleading as the CH2 group between the N and carboxyl group may lead that peak anywhere. The NH on the amine can be anywhere on the spectrum so it can not be determined readily.
At quick analysis, the NMR of Fraction2 seems reasonable in that the peaks that we expect for the methylfurfurylamine are there. There are some peaks that I can't identify just yet but there is also some aldehyde present which is expected by the ghost-like second spot on the TLCs which will be uploaded. Also it is disturbing that the D2O does not exchange with most of the peaks present.


It is difficult to make a conclusion for this experiment at this time because the peak splitting we see in the HMR of Frac1 in the 5.8 region is not consistant with previous NMR of methylfurfurylamine. There seems to be coupling with some thing but we can not determine what without clear C13 or COSY.



1. 21:30] Started stirring methanol solution with the four starting components, color of solution is yellowish Video


2. 17:30] Stopped stirring and change of color of solution to reddish (Sample 20A) Video
3. Performed TLC of 20A after 20 hours vs 3 of the four starting components. The amine and the benzylisocyanide were done in 1:1 methylene chloride hexanes while the aldehyde was done in 7:1 methylene chloride methanol PIC
4. 19:30] Put on rotovap with heating bath going from room temp to 60C over 40mins


5. 16:30] Put on High Vacuum with average pressure 1.5mmHg for 3.5 hours (20B). Flask had a slightly wet, thick, slow moving globule that probably contains methanol while the edges were dry. Weight=356.39mg


6. TLC of 20B vs Ugi and starting materials. Amine and Benzylisocyanide were done in 1:1 methylene chloride hexanes while Aldehyde was done in 7:1 methylene chloride methanol. PIC
7. 21:00] Added to round bottom flask with 20B 20ml and then 10mL THF and transferred to another round bottom flask then added 3mL TFA to original round bottom flask to take out any remaining 20B and transferred to 30mL THF. Pipetted another 0.3mL TFA to make a 10% solution. Round bottom flask with TFA solution is under nitrogen while stirring.Video


8. 18:30] Stopped stirring solution
9. 19:30] Added TFA solution to separatory funnel with 85mL dichloromethane and extracted with 5x100mL distilled water and 1x50mL. All aqueous layers were combined and showed a neon yellow color. The dark brown color of the organic layer diminished over time. (Have not added Magnesium sulfate yet and may have to substitute with sodium sulfate)


10. Did a TLC of organic layer and aqueous layer against 20B and the aldehyde.


11. Added MgSO4 to organic layer and filtered off.
12. Put organic layer on rotovap and then high vacuum. A thin film usually forms as the solvent evaporates off however this was avoided but tilting the round bottom flask as the vacuum begins. This however does cause spattering. Wt of 20C is 192.3mg
13. Took NMR of 20C. TLC of TFAvac vs Ugi


14. Started a flash chromatography. Collected 50 fractions then left with solvent over night. Silica in the column did break however due to too much pressure and too quick of a release.


15. Complete Fraction1 was vacuumed to obtain about 30mg. Complete Fraction2 was vacuumed to obtain about 97mg.


16. Took HMR of Fractions1 & 2. HMR Frac1 HMR Frac2 HMRFrac2 w/D2O TLC of Fraction components compared to 20C


Benzylisocyanide InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2
3,4-dihydroxybenzaldehyde InChI=1/C7H6O3/c8-4-5-1-2-6(9)7(10)3-5/h1-4,9-10H
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)
5-methylfurfurylamine InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
ugi018: InChI=1/C29H35N3O6/c1-19-10-11-21(14-19)18-32(25(35)17-31-28(37)38-29(2,3)4)26(22-12-13-23(33)24(34)15-22)27(36)30-16-20-8-6-5-7-9-20/h5-13,15,26,33-34H,14,16-18H2,1-4H3,(H,30,36)(H,31,37)
DKP018 InChI=1/C17H18N2O4/c1-10-2-3-11(6-10)9-19-15(22)8-18-17(23)16(19)12-4-5-13(20)14(21)7-12/h2-5,7,16,20-21H,6,8-9H2,1H3,(H,18,23)