Exp086-4.JPG

Objective

To synthesize the Ugi product from benzaldehyde, 5-methylfurfurylamine, tert-butyl isocyanide and Boc-Gly-OH in methanol via a 4CR ugi reaction

Procedure

A solution of benzaldehyde (212 uL, 2 mmol) and 5-methylfurfurylamine(5-MFA) (244 uL, 2.2 mmol, 10% excess) was made in methanol in a 4mL volumetric flask. The reaction mixture was allowed to sit for about 6 hours without stirring to form the imine.
A solution of Boc-Gly-OH(350 mg, 2 mmol), and tert-butyl isocyanide (226 uL, 2 mmol) was made up in 4 ml volutmeric flask in methanol. This solution was added to the preformed Imine solution. The reaction mixture was allowed to sit undisturbed overnight, when a crystalline Ugi product was obtained which was filtered and washed with cold methanol. The crystalline product was saved in a vial.
Characterization of UCExp086B : C25H35N3O5 tert-butyl (2-{[2-(tert-butyla​mino)-2-oxo-1-phenylethyl][(5-​methylfuran-2-yl)methyl]amino}​-2-oxoethyl)carbamate:1H NMR (external image delta.gif ppm, CDCl3) 1.32 (s, 9H),1.44 (s, 9H), 2.13 (s, 3H), 4.15-4.22 (m, 2H), 4.35-4.55 (m, 2H), 5.4-6.0 (m, 5H), 7.2-7.4 (m, 5H, phenyl); 13C NMR (external image delta.gif ppm, CDCl3) 13.3, 28.2, 28.4, 42.4, 42.7, 51.4, 62.9, 79.3, 106.1, 108.6, 128.2, 128.4, 129.6, 134.7, 147.6, 151.5, 155.5, 168.3, 170.0; HRMS (FAB,m-nitrobenzyl alcohol): m/z calcd for C25H36N3O5(M+H) 458.2649 Da, found 458.2648 Da; yield 38%

Results

Benzaldehyde
H NMR
C NMR
5-methylfurfurylamine
H NMR
C NMR
tert-butyl isocyanide
H NMR
C NMR
Boc-Gly-OH
H NMR
C NMR
86A
H NMR (t = 5 h 44 min) [no deuterated solvent, unlocked]

86B (C25H35N3O5, Mol. Wt.: 457.56)
H NMR -500 MHz
H NMR -300 MHz
C NMR
DEPT
All protonated carbons
Overlay of C NMR and All protonated carbons
FAB

X - Ray studies
86B-Crystal
86B-Crystal analysis cif file
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Discussion

  1. From the 5 h 44 min H NMR of 86A, in undeuterated methanol, it is estimated that all (9.79 ppm) of the aldehyde has been consumed, it also appears that all the amine (CH2-4.49 ppm) has also been consumed which is surprising becuase a 10% excess of amine was added to begin with. Therefore it is expected that there should be 10% unreacted amine present in the solution which is not seen in the NMR. This may be because a) either an inaccurate measurement was done when the amine was actually added. b) The NMR is unable to detect it..due to the inhomogenous magnetic field since no deuterated solvent was used.
  2. The reaction was monitored without using deuterated methanol, which obscured 3.1-3.4 ppm and 4.6-5.0 ppm ranges in the H NMR spectra. Fortunately it does not appear that any information has been lost because of the solvent peaks, although using CD3OD would have given sharper peaks with a decent looking spectrum.
  3. 86B assignments (these assignments are similar to that of the ugi product of Exp064 - 64C. What about the N-H protons?

Conclusion

A synthesis of the ugi product was successfully accomplished.

Log

2007-04-02

16:20 Made up a solution of benzaldehyde and 5-methylfurfurylamine in methanol (4 mL)
22:04 Obtained H NMR of 86A (t = 5 h 44 min)
22:15 Made up a solution of Boc-glycine and t-butyl isocyanide in 4 mL methanol (2 mmol each)
22:20 Added t-butylisocyanide and boc-glycine solution in methanol to 86A.

2007-04-03

10:40 Crystals have started to form in the reaction mixture.
12:30 Filtered the crystals using a buchner funnel and washed them with ice cold methanol.
12:40 Obtained white crystals of 86B (348.8 mg). The yield so far is 38%.

2007-12-07

17:20 Sent 62E for Crystallography studies

2007-12-21

18:13 Received the cif file after crystal studies, which were performed by Dr. Matthias Zeller


Tags

86BInChI=1/C25H35N3O5/c1-17-13-14-19(32-17)16-28(20(29)15-26-23(31)33-25(5,6)7) 21(18-11-9-8-10-12-18)22(30)27-24(2,3)4/h8-14,21H,15-16H2,1-7H3,(H,26,31)(H,27,30)
benzaldehydeInChI=1/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H
5-methylfurfurylamine InChI=1/C6H9NO/c1-5-2-3-6(4-7)8-5/h2-3H,4,7H2,1H3
tert-butyl isocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
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)