ugi_exp52.JPG

Objective:


To form a Ugi product using piperonal, 5-methylfurfurylamine, Boc-Gly-OH, and t-butyl isocyanide.

Procedure:


To four separate vials was added piperonal (0.150 g, 1 mmol), 5-methylfurfurylamine (111 uL, 1 mmol), Boc-Gly-OH (0.175 g, 1 mmol), and t-butyl isocyanide (113 uL, 1 mmol) and diluted to mark to approximately 1 mL with methanol. To four separate vials was added piperonal (0.150 g, 1 mmol), 5-methylfurfurylamine (111 uL, 1 mmol), Boc-Gly-OH (0.175 g, 1 mmol), and t-butyl isocyanide (113 uL, 1 mmol) and diluted to mark to approximately 1 mL with CDCl3. This was used to take the spectra of the starting materials. In a separate 5 dram vial were added piperonal and 5-methylfurfurylamine solutions and allowed to sit for approximately 3 hours. A 400uL sample was taken and placed under high vacuum to eliminate solvent. 1mL CDCl3 was added and NMR spectra was taken to confirm the formation of the imine. The Boc-Gly-OH solution was then added to the vial and shaken for approximately 30 seconds. Solution was allowed to sit for approximately 30 mins. A 400 uL sample was taken placed under high vacuum to eliminate solvent. 1mL of CDCl3 was added and an NMR spectra was taken of the reaction. The t-butyl isocyanide solution was then added to the solution and then monitored by NMR.

Results

Starting Materials

Piperonal
CMR, HNMR

5-MFA
CMR, HNMR

Boc-Gly-OH
CMR, HNMR

t-butyl isocyanide
CMR, HNMR

Imine Formation

52A
HNMR

Addition of Boc-Gly-OH

52B T=68 mins
CMR, HMR

Addition of Isocyanide

52C
T=70 min
HNMR, CMR

52D
T=24 hrs
HNMR, CMR

Mass Spec Analysis

52E
Matrix spectra

Characterization of 52F (crystals)

163.7mg, m.p. 174C
HMR Proton Assignments HMR-added methanol d4
CMR
Picture

Discussion

1. The addition of the Boc-Gly-OH only leads to minimal reversion to the aldehyde (8.3%). This is surprising as in previous experiments the imine completely reverted to aldehyde after 20 mins in James' experiment (exp046) and 96 hrs in Khalid's experiment (exp048).
2. The triplet peak (in the CMR at 54.4ppm (19.8Hz) of t-butyl isocyanide disappears 70 minutes after t-butyl isocyanide is added (52C)to the reaction flask, indicating the possibitlity of the Ugi product forming.
3. Proton Assignments
Singlets at 1.2 and 1.4- t-butyl protons of t-butyl isocyanide and Boc-Gly-OH
Singlet at 2.2ppm- methyl group of 5-methylfurfurylamine
Singlets at 4.2ppm and 4.4ppm- methylene groups of Boc-Gly-OH and 5-methylfurfurylamine.
Broad singlet peak at 5.6 ppm- one NH group
Multiplet at 5.8ppm- one NH group, chiral proton, and furan protons.
Doublet at 6.0ppm- Methylene group of piperonal
Multiplet at 6.8ppm- Aromatic protons
The HNMR of 52F shows peaks with integration congruent to that of the expected Ugi product.

By adding a few drops of methanol d4 to the NMR tube of 52F, ambiguity is eliminated with the multiplet at 5.8ppm and at 5.6 ppm. The deuterium of the methanol exchanges with the protons of the amide groups, making them invisible to the NMR. With those signals suppressed, the integration of the multiplet changes from 4 to 3 proton units and the broad singlet at 5.6ppm disappears.

4. FAB Mass spec analysis of 52E is inconclusive because an expected peak of 400 [M-101]+, corresponding to the loss of the BOC group despite the expected [M+H]+ peak at 502 and [M+Na]+ peak at 524.

5. It is difficult to estimate a pre-isolation yield based on knowing where the peaks are for the Ugi product in the NMR because of the presence of starting materials.

Conclusion


Based on the H NMR evidence, it is concluded that the Ugi product did form in this experiment. One of the important factors for completion of this reaction is the kinetics of the reaction once the carboxylic acid is added. In other experiments, Khalid and James both showed (exp046 and exp048) that the aldehyde and imine interconvert during the course of the reaction, although it is unclear why this occurs. It may be important to conduct a kinetics study with this particular aldehyde and imine for at minimum 24hrs (Khalid and James used different aldehyde/amine combinations) to determine why interconversion did not occur for this experiment.

Log

2007-01-24
12:36 Prepared 1M solutions of 5-methylfurfurylamine and piperonal.

2007-01-25
8:18 Took NMR spectra of starting materials. Mixed solutions together. (pale yellow)
13:52 Removed 400uL sample (52A) from reaction vial. Took NMR spectra of imine.
14:00 Prepared 1M Boc-Gly-OH solution. Took NMR spectra.
14:20 Added Boc-Gly-OH solution to reaction vial. Solution turned more yellow.
15:08 Removed 400uL(52B) sample from reaction vial. Took NMR spectra.
17:19 Prepared 1M solution of t-butyl isocyanide. Added to reaction flask.
18:29 Removed 400uL(52C) sample from reaction vial. Took NMR spectra.

2007-01-26
10:08 Removed 400uL sample (52D) from reaction vial. Noticed white crystals at the bottom of the reaction vial.Took NMR spectra of solution.

2007-01-30
11:35 Submitted sample of solution (52E) for MS Analysis.

2007-02-08
15:00 Removed crystals (0.1637g, 0.32 mmol)) from vial and rinsed them in methanol. Evaporated off solvent using high vacuum and added 12 drops of acetone d6 and approx. 500ul of chloroform. Some crystals appeared to dissolve while some needle-like structures were still seen at the bottom of the flask. Took NMR spectra (52F).

2007-02-12
17:00 Took Dept Spectra of 52F.

2007-02-16
11:39 Added 3 drops of deuterated methanol to 52F. Took HNMR spectra

Tags

PiperonalInChI=1/C8H6O3/c9-4-6-1-2-7-8(3-6)11-5-10-7/h1-4H,5H2
5-methylfurfurylamineInChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
t-butyl isocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
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)
imine: InChI=1/C14H13NO3/c1-10-2-4-12(18-10)8-15-7-11-3-5-13-14(6-11)17-9-16-13/h2-7H,8-9H2,1H3/b15-7-
ugi052:InChI=1/C26H35N3O7/c1-16-8-10-18(35-16)14-29(21(30)13-27-24(32)36-26(5,6)7)22(23(31)28-25(2,3)4)17-9-11-19-20(12-17)34-15-33-19/h8-12,22H,13-15H2,1-7H3,(H,27,32)(H,28,31)/i1-12,2-12,3-12,4-12,5-12,6-12,7-12,8-12,9-12,10-12,11-12,12-12,13-12,14-12,15-12,16-12,17-12,18-12,19-12,20-12,21-12,22-12,23-12,24-12,25-12,26-12,27-14,28-14,29-14,30-16,31-16,32-16,33-16,34-16,35-16,36-16