Exp60.JPG

Objective

To synthesize a 2,5diketopiperazine from 3,4-dimethoxybenzaldehyde, 5-methylfurfurylamine, Benzylisocyanide and Boc-Gly-OH in methanol using Ugi 4CR and post cyclization by UDC (Ugi/De-BOC/Cyclization) strategy.

Procedure

This is similar to Exp054, except on a different scale.
A one molar methanol solution of 3,4-dimethoxybenzaldehyde (Veratradlehyde) (332mg, 2mmol/2ml*) is mixed with 1.1M methanolic solution of 5-methylfurfurylamine(5-MFA) (244uL, 2.2mmol/2ml*, 10% excess ) in a 25ml erlenmyer flask with a stopper and left undisturbed overnight for the imine to form. The next day, a 2M Boc-Gly-OH(350mg, 2mmol/2ml) solution in methanol and 1M Benzylisocyanide (240uL, 2mmol/2ml) solution in methanol is added to the preformed imine solution. A Ugi adduct is formed within a few minutes.
(*3,4-dimethoxybenzaldehyde and 5-MFA are made up with 1ml CD3OD and remaining CH3OH for NMR analysis)

Results

Veratradehyde
H NMR
5-Methyl furfurylamine
H NMR Tentative assignments methyl shows fine coupling with one of the furan protons.
Benzyl isocyanide (HNMR from Exp054)
H NMR Signature triplet at 4.68ppm. J = 2.2Hz
Boc-Gly-OH (H NMR from Exp054)
H NMR

60A (Veratraldehyde +5-MFA)
HNMR - 17h 50min
HNMR - t = 195min (in CDCl3 after drying)

60B (60A +Benzylisocyanide + Boc-Glycine)
HNMR - (nothing much discernible- unable to achieve a good lock signal, only about 25% deuterated solvent) Benzylisocyanide at 7.2 ppm (triplet)
60C- [C30H37N3O7, Mol. Wt.: 551.63]
H NMR (300MHz)
H NMR (500MHz)
C-13 NMR
60D
HNMR
60E
HNMR (A few milligrams of 60E only) - store in a 1 dram vial and measure it

Discussion

  1. NMR of 60C represents the structure assigned for the Ugi adduct in the scheme. Tentative Assignments you need to add some methanol-d4 to remove any amide H's - then make sure that all integrations and peak multiplicity make sense
  2. After treatment with TFA, an NMR of 60E suggests that almost all the product was washed away in the water layer (during extraction) indicating that a 2,4-diketopiperazine was hardly formed if any and cyclization under the conditions used may be difficult or unlikely.

Conclusion

  • The Ugi product was obtained in 25.4% isolated yield.
  • Cyclization of the ugi product could not be accomplished.
  • A different cycliation method with Methanol / AcCl may also be tried as an alternative.

Log

2007-02-17

19:10 - Made up 1M solution of 3,4-dimethoxybenzaldehyde (Veratraldehyde) and 5-MFA in 1ml methanol-d4 and remaining CH3OH and obtained HNMR.
21:20 : Mixed Veratraldehyde and 5-Methylfurfurylamine solutions together.

2007-02-18

15:10: Obtained H NMR of 60A.
15:20 : Added 1M solutions of benzyl isocyanide (240uL, 2mmol/2ml) and Boc-Glycine (350mg, 2mmol/2ml) to 60A.
15:33 : Unable to obtain a clean HNMR because the spectrum was overwhelmed by methanol (non deuterated). Monitoring this way requires putting a sample (50 ul maybe) on the high vac for 5 mins then taking up in a deuterated solvent, preferably CDCl3.
16:10 : Solid has appeared in the reaction mixture.
16:15 : There is complete solidification in the erlenmyer flask.
16:40 : The product looks like a solid cake, although with benzylisocyanide stench.
18:40 : Removed a small amount of the wet solid in clean round bottom flask, dried under high vac for ~15min dissolved the product (~ 60mg) in CDCl3 and obtained a HNMR.(t = 195min)
19:18 : Added 5ml of methanol, warmed the solution up on a steam bath when all the solid dissolved and the solution turned clear.

2007-02-19

10:30 : The overnight recrystallization has agian yielded a solid product. The procuct now looks lighter in color.
10:37 : Added 5ml more methanol and warmed it on steam bath to dissolve the solid to a clear solution.
11:20 : The solid formed again was filtered under house vac and washed with methanol.
12:45 : Approximately 280mg of a highly electrostatic 60C was obtained
17:45: Dissolved 178mg of 60C in 9ml of 1,2-Dichloroethane, added 1ml Trifluroacetic acid and started stirring the solution at room temperature. (60D)
21:05 : Stopped stirring.

2007-02-23

18:40 : Dissolved the deep brown solution of 60D in 10ml Dichloromethane, transferred to to 50ml separatory funnel, added 10ml disstilled water, separated the dark brown organic layer from the aqueous layer, washed the organic layer with 10ml of distilled water again. Poured the organic layer in an erlenmeyer flask. Transferred the collected aqueous layers to the separatory funnel, added 5ml Dichloromethane, after the layers separated, added the organic to the previously collected organic layers. The aqueous layer (60F) is about 15ml.
19:00 : Dried the combined organic layers with 4g MgSO4 (anhy.)
20:30 : Rotovaped the solvents from dried organic layers. (Trap of the rotovap was furnished with KOH pellets)
20:45 : The residue, after evaporation was set on high vac.

2007-02-24

13:00 : Removed from the high vac and obtained a few milligrams of 60E.

2007-03-12

20:20 : Added 15ml of saturated sodium bicarbonate solution until the pH turned neutral.

Tags

Benzylisocyanide InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2
VeratradehydeInChI=1/C9H10O3/c1-11-8-4-3-7(6-10)5-9(8)12-2/h3-6H,1-2H3
Boc-Gly-OHInChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)
5-methylfurfurylamineInChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
ugi054:InChI=1/C30H37N3O7/c1-20-12-14-23(39-20)19-33(26(34)18-32-29(36)40-30(2,3)4)27(22-13-15-24(37-5)25(16-22)38-6)28(35)31-17-21-10-8-7-9-11-21/h7-16,27H,17-19H2,1-6H3,(H,31,35)(H,32,36)