EXP+018

==

=Objective= 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.

=Procedure= To a 50ml Erlenmeyer flask added methanol (20ml), [|3,4-dihydroxybenzaldehyde] (67.65mg, 0.49mmol), [|5-methylfurfurylamine] (50µl, 0.44mmol) by GC syringe, [|benzylisocyanide] (50µl, 0.41mmol) by GC syringe, and [|Boc-Gly-OH] (87.84mg, 0.50mmol). After vacuuming off methanol, 10%TFA in THF was added and refluxed under nitrogen for 30minutes. An extraction with methylene chloride and water is performed. Vacuum off excess solvent after drying. Perform chromatography for purification if NMR and TLCs warrant.

=Results=

Characterization of 18B
[|Viedo of setup] with common yellow color. [|TLC of starting materials vs the Ugi] reaction were done when stirring started in 1:1 methylene chloride hexanes. The order is: amine, acid, aldehyde, benzylisocyanide [|Video after 17 hours] was taken and unusual red color solution. [|Second TLC of starting materials vs Ugi] in 3:1 methylene chloride hexanes. The order is: acid, amine, benzylisocyanide, aldehyde. NMR of 18C was taken. JPG is a screen shot from MestRe-C. [|HMR screen shot]

Characterization of 18C
[|Video] of reflux with 10% TFA in THF [|TLC of product after THF] but before extraction was against starting materials vs 18B, & 18C.

Characterization of 18D
[|HMR] [|9-10 region] [|6.4-7.6 region] [|4.9-5.7 region] [|3.7-4.6 region] [|0.8-2.6 region]

=Discussion= The HMR of 18D has many broad peaks and there is a problem with phasing however the amine 5.8-6 region, 2.3-2.5 region and benzene ring 7-8 region are there so continuing to the chromatography step is warranted. Unfortunately due to the chromatotron plate breaking apart during the addition of the solvent the experiment was aborted. Looking at this [|review article], the cyclization step can be done at room temperature which could reduce the number of side reactions.

=Conclusion= Experiment inconclusive and should be repeated. =Log=

2006-07-20
1.**17:05]** Added aldehyde and acid with methanol to Erlenmeyer flask 2.**17:20]** Last two components added and stirring started. Sample taken for TLC. **[|Video]** 3.Performed TLC of starting components with beginning Ugi mixture(18A) in 1:1 methylene chloride hexanes **[|Picture]**

2006-07-21
4. **13:35**] Stopped stirring **[|Video]** 5. **13:50**] Performed TLC in 3:1 methylene chloride hexanes of starting materials vs ugi (18B) **[|Picture]** 6. Weighed round bottom flask 7. **15:20**] Put on rotovap with bath at around 70C 8. **16:00**] Took off rotovap

2006-07-24
9. **14:30**] Put 18B on high vacuum for an 1.5hours with an average pressure of 1mmHg (18C) weight = 237.7mg 10. Took HMR of 18C

2006-07-26
11. Added 27mL of THF to r.b.f. with 3mL of TFA for reflux 12. **12:07**] Put heat on. Set hot plate to low but high temperature accumulates due to malfunction. 13. **12:14**] Reflux observed **[|Video]** 14. **12:46**] Round bottom flask taken off of heat 15. **20:00**] Extracted with 50mL methylene chloride added to THF solution and 5 x 100mL washings of Distilled water. Water is neon yellow and some of the bottom layer stuck to the separatory funnel as well as was lost in the water layer. pH 6.5 to neutral. 16. Had taken a small sample before extraction for TLC. Amine, acid and benzylisocyanide were done in 1:1 methylene chloride hexanes. Aldehyde was done in 2%methanol in methylenechloride. **[|Pic]**

2006-07-27
17. Took the washings of water and added it together. Added 50mL methylenechloride and separated without shaking. Took the methylene chloride and washed with 100mL of distilled water. pH was 6.5 to neutral. 18. Combined organic layers were put on rotovap in water bath temp = 50C 19. **18:40**] Put remaining methylene chloride on high vacuum 20. **20:40**] Took off of vacuum and average pressure was 1.5mmHg.

2006-07-31
21. Added 25mL of dichlormethane to sample to dissolve. 22. Dried with anhydrous magnesium sulfate and filtered off 23. Rotovaped at low temperature about 50C

2006-08-01
24. 12:30] Put sample on high vacuum for 1hr 15 mins with average pressure of 0.8mmHg to get **18D** (157mg) 25. Took [|NMR of vacuumed sample].

2006-08-03
26. Attempted to do chromatotron but the plate fell apart due to channeling that formed from a high flow rate from previous use. =Tags= [|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)]

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