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Objective

To produce a diketopiperazine by Ugi synthesis using piperonal, 5-methylfurfurylamine, N-tert-butoxycarbonyl L-methionine, and benzylisocyanide using the protocol described here. This compound is not an anti-malarial target. The target 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. This is a practice of the Ugi reaction.

Procedure

Methanol (20 mL), piperonal (73.71mg, 0.49 mmol), N-tert-butoxycarbonyl L-methionine (124.96 mg, 0.50 mmol), 5-methylfurfurylamine (55µL, 0.49 mmol), and benzylisocyanide (60µL, 0.49mmol) were added to a 50 mL Erlenmeyer flask. The flask was stoppered and the mixture was stirred for 22 hr, then evaporated on a rotovap. 1,2-dichloroethane (9mL) and trifluoroacetic acid (1mL) was added to the product and the solution was refluxed for 27 min. The crude product was taken up in methylene chloride (10 mL) and then separated by washing with 5% HCl. The organic layer was dried over anhydrous MgSO4 and evaporated again. A dark, reddish oil was obtained. In order to recover any lost product, a backwash was also done on the water layer obtained during separation and the filtered magnesium sulfate.

Results

TLCs of 17A (before TFA)

1. TLCs were performed in 3:2 methylene chloride/hexanes. The starting materials, including the benzylisocyanide, were spotted on the left in methanol solutions of similar concentrations, with 17A spotted on the right of the plate. Picture of iodine stain under UV light. Left to right: piperonal, amine, amino acid, and benzylisocyanide.
2. TLCs were also performed in 3:1 methylene chloride/hexanes. The starting materials, including the benzylisocyanide, were spotted on the left in methanol solutions of similar concentrations, with 17A spotted on the right of the plate. Picture of iodine stain under UV light. Left to right: piperonal, amine, amino acid, and benzylisocyanide.
3. TLCs were performed in 3:1 methylene chloride/hexanes and then stained in potassium permanganate. One TLC was done with just the piperonal. Another TLC plate was done with piperonal (left) and 17A (right). Pictures of stained TLC of piperonal against 17A when wet and with dry stains of piperonal (left) and piperonal against 17A (right).
4. TLCs were performed in 3:1 methylene chloride/hexanes and then stained in anisaldehyde. One TLC was done with just the piperonal. Another TLC plate was done with piperonal (left) and 17A (right). Pictures of stained TLC of piperonal against 17A and with dry stains of piperonal (left) and piperonal against 17A (right).
NMR results before TFA.
Full HMR 1.3-2.6 region 3.1-3.8 region 3.5-4.6 region 5.7-6.3 region 6.7-7.8 region

TLCs of 17D (after TFA and rotovap)

5. TLCs were performed in 1:1 methylene chloride/hexanes. The starting materials, including the benzylisocyanide, were spotted on the left in methanol solutions of similar concentrations, with 17A spotted in the center of the plate. 17D was spotted on right side of each plate. Picture under UV light.(dead link) Left to right: piperonal, amine, amino acid, and benzylisocyanide.

Discussion

From the TLC info on 17A (crude product before TFA), the fastest moving spot might be unreacted piperonal. A stain should be done to check that (e.g. permanganate or anisaldehyde).

Due to some steps being irreproducible including the reflux which has an indeterminable amount of water present (because of refluxing in open air) and the impurities found in the NMR of Boc-Met-OH, this experiment is being terminated and the acid will be changed to Boc-Gly-OH.

Conclusion

No conclusion can be drawn.

Log

2006-07-06

1. 17:20) Mixed chemicals and started stirring at room temperature (Video).

2006-07-07

2. 15:10) Stirring was stopped to produce sample 17A.
3. TLC of sample 17A was performed in 3:2 methylene chloride/hexanes. Rf = 0.654
4. TLC of piperonal was performed in 3:2 methylene chloride/hexanes.
5. TLC of 5-methylfurfurylamine was performed in 3:2 methylene chloride/hexanes.
6. TLC of n-tert-butoxycarbonyl L-methionine was performed in 3:2 methylene chloride/hexanes. No movement.
7. 17:15) Methanol was evaporated from the solution by rotovap on heating setting 4 for 1 hour.

2006-07-10

8. TLCs of piperonal, 5-methylfurfurylamine, n-tert-butoxycarbonyl L-methionine, and benzylisocyanide (all in methanol solutions of similar concentration) were run against 17A in 3:2 methylene chloride/hexanes.
9. TLCs of piperonal, 5-methylfurfurylamine, n-tert-butoxycarbonyl L-methionine, and benzylisocyanide (all in methanol solutions of similar concentration) were run against 17A in 3:1 methylene chloride/hexanes.
10. 16:30) High vac for 2 hr with an average pressure, by manometer, of 1.5 mmHg. Product 17B had a mass of 0.2537g.

2006-07-12

11. Ran TLC of piperonal in methanol against 17A in 3:1 methylene chloride/hexanes. Stained in potassium permanganate solution.
12. Ran TLC of piperonal in methanol in 3:1 methylene chloride/hexanes. Stained in potassium permanganate solution.
13. Ran TLC of piperonal in methanol against 17A in 3:1 methylene chloride/hexanes. Stained in anisaldehyde solution.
14. Ran TLC of piperonal in methanol in 3:1 methylene chloride/hexanes. Stained in anisaldehyde solution.

2006-07-13

15. Added 1 mL TFA and 9 mL 1,2-dichloroethane to 17B to get 17C.
16. 12:15) Started heating 17C on low heat and stir setting of 4.
17. 12:23) Reflux observed to start 17C (Video).
18. 12:45) 22min reflux on heat. Turned heat off, did not take r.b.f. off of hotplate. Reflux continued for another five minutes on cool down.
19. 13:08) Rotovaped for 3 min to get 17D, water bath 110C.
20. Ran TLC of each starting material (including benzylisocyanide) against 17A and 17D. Solvent system used was 1:1 methylene chloride/hexanes.

2006-07-17

21. Add 10 mL methylene chloride to 17D.
22. Separated the organic layer in a separatory funnel by washing with 5% HCl (10.5 mL x 4) to get 17E. Some globs of organic layer was floating on top of water layer, more methylene chloride is needed next time to achieve better separation.
23. Saturated 17E with anhydrous magnesium sulfate and filtered solution by gravity into a round bottom flask (mass of RBF is 32.63782g).
24. 15:40) High vac at 1 mmHg to get 17F (mass of product is 5.48mg). Removed from high vac at 18:35.

2006-07-18

25. Ran TLC of 17F (dissolved in CDCl3) against both 5-methylfurfurylamine and 17D. Solvent system was 1:1 methylene chloride to hexanes. 17F had no movement.
26. Ran TLC of 17F (dissolved in CDCl3) against both 5-methylfurfurylamine and 17D. Solvent system was pure methylene chloride. 17F had no movement.
27. Washed the filtered magnesium sulfate from yesterday with methylene chloride and filtered solution by vacuum.
28. Added more methylene chloride and separated the organic layer by washing with distilled water (40 mL x 4). After each separation, the pH of water layer was taken until the solution became neutral.
29. Saturated the organic layer with anhydrous magnesium sulfate and filtered by vacum.
30. 17:08) Rotovap in a round bottom flask at 59C. Removed from rotovap at 17:11. Mass of round bottom flask is 65.2714g.
31. 17:30) High vacuum solution at 1.5 mmHg and left overnight to get 17G.

Tags

Benzylisocyanide InChI=1/C8H7N/c1-9-7-8-5-3-2-4-6-8/h2-6H,7H2
Piperonal InChI=1/C8H6O3/c9-4-6-1-2-7-8(3-6)11-5-10-7/h1-4H,5H2
Boc-Methionine InChI=1/C10H19NO4S/c1-10(2,3)15-9(14)11-7(8(12)13)5-6-16-4/h7H,5-6H2,1-4H3,(H,11,14)(H,12,13)
5-methylfurfurylamine InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
ugi017 InChI=1/C30H35N3O6/c1-20-10-12-23(39-20)18-33(27(35)17-31-26(34)15-30(2,3)4)28(22-11-13-24-25(14-22)38-19-37-24)29(36)32-16-21-8-6-5-7-9-21/h5-14,28H,15-19H2,1-4H3,(H,31,34)(H,32,36)
DKP017 InChI=1/C17H16N2O5/c1-10-2-4-12(24-10)8-19-15(20)7-18-17(21)16(19)11-3-5-13-14(6-11)23-9-22-13/h2-6,16H,7-9H2,1H3,(H,18,21)