Exp100.JPG

Objective

To synthesize a Ugi adduct from Benzaldehyde, tert-butylamine, tert-butyl isocyanide and Boc-Gly-OH in methanol using Ugi 4CR.

Procedure

A solution of benzaldehyde (106 uL, 1 mmol) and tert-butylamine (115.6 uL, 1.1 mmol, 10% excess) was made in methanol-d4 in a 2 mL volumetric flask. The imine formation was monitored by HNMR.
A solution of Boc-Gly-OH(175 mg, 1 mmol), and tert-butyl isocyanide (113 uL, 1 mmol) was made up in 2 ml volutmeric flask in methanol-d4. This solution was added to the preformed Imine solution. The reaction was monitored by analysing 800uL of the reaction mixture by NMR. At the end the reaction a crystalline Ugi product was obtained which was filtered and washed with methanol.

Results

tert-butylamine
H NMR (methyls at 1.15 ppm and amine at 1.20 )
C NMR
Benzaldehyde
H NMR
C NMR
tert-butyl isocyanide
H NMR
C NMR
Boc-Gly-OH
H NMR
C NMR

100A
t = 48min
t = 1h 10min
t = 1h 11min
t = 1h 13min
t = 1h 16min
t = 4h 01min
t = 4h 03min
t = 4h 13min
t = 7h 27min
100B
t = 16h 51min
t = 45h 52min
100C
HNMR

Discussion

Proton NMR 100C, indicates that the there still remain some unreacted starting materials and /or impurities in the product. Imine formation was almost complete after 7.5h, however, there appears to be an imine hydrolysis (reversal) upon acid addition. This has definitely had a negative impact on the course of the Ugi reaction. As a result in the HNMR of 100C, several t-butyl peaks between 1.2ppm-1.6ppm can be attributed to a)the t-butyl groups from unreacted amine, imine, Ugi product, and b) the t-butyl groups from unreacted acid, boc-glycine, and the the Ugi product. It does appear like there are a cluster or five peaks which does appear reasonable.
does the imine revert after addition of the acid? by how much?

Conclusion

The experiment failed to produce a good quality ugi product and thus will have to be repeated. Imine was reversal prominent in this reaction...Imine reveral had also been previously noted when t-butyl amine was used.(Exp051, Exp069, Exp076, Exp077 (James Giammarco's work)

Log

2007-05-16

13:03 Made-up a solution of benzaldehyde (106uL) and tert-butylamine (115.5uL) in CD3OD (2mL) in a volumetric flask. This is 100A. Tried to obtained monitor immediately on the 300MHz NMR, but unable to shim properly, signals were not clear and sharp enough. Therefore switched over to the 500MHz instrument.
13:51 Obtained H NMR of 99A (t = 48min)
14:13 Obtained H NMR of 99A (t = 1h 10min)
14:14 Obtained H NMR of 99A (t = 1h 11min)
14:16 Obtained H NMR of 99A (t = 1h 13min)
14:19 Obtained H NMR of 99A (t = 1h 16min)
17:04 Obtained H NMR of 99A (t = 4h 01min)
17:07 Obtained H NMR of 99A (t = 4h 04min)
17:16 Obtained H NMR of 99A (t = 4h 13min)
20:30 Obtained H NMR of 99A (t = 7h 27min)
20:45 Made-up a solution of Boc-Glycine (175mg) and tert-butylisocyanide (113uL) in CD3OD (2mL) in a volumetric flask
20:47 Transferred 99A from the NMR tube into a centrifuge tube.
20:50 Added the Boc-Glycine-tert-butylisocyanide solution to 99A in centrifuge tube, obtained 100B.

2007-05-17

13:41 Obtained H NMR of 100B (t = 16h 51min)

2007-05-18

18:42 Obtained H NMR of 100B (t = 45h 52min); almost of the reaction mixture from the centrifuge tipped over and got lost accidentally.

2007-05-21

10:30 White crysatalline solid had appeared in the bottom of the centrifuge tube.
21:30 The centrifuge tube was left in a dessicator connected to a high vac, this was done to evaporate the solvent and recover the solid (only) since some of the reaction mixture had already been lost accidentally, it was felt appropriate to just obtain the solid crystals, without taking into account the yield aspect for this reaction. so you evaporated without removing the supernatant and washing with methanol?

2007-05-25

16:45 Washed the colorless solid collected after a complete evaporation of the solvent with methanol (how much?); 100C (5.5 mg) was obtained..a H NMR was obtained.



Tags

benzaldehyde InChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
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)
tert-butyl isocyanide InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
100Ugiproduct InChI=1/C23H37N3O4/c1-21(2,3)25-19(28)18(16-13-11-10-12-14-16)26(22(4,5)6)17(27)15-24-20(29)30-23(7,8)9/h10-14,18H,15H2,1-9H3,(H,24,29)(H,25,28)