176scheme.PNG

Objective

To synthesize a Ugi adduct from furfurylamine, phenanthrene-9-carboxaldehyde, phenyl acetic acid and n-butyl isocyanide in methanol using Ugi 4CR following Explan005. The target compound was ranked 29 in the DEXP014-V1B file from D-EXP014. The purpose of this experiment is to synthesize an anti-malarial compound based on the inhibition of falcipain-2, as described in this summary post. This experiment is a repeat of Exp170.

Procedure

To a one dram screw-cap vial was added methanol (1 mL), furfurylamine (44.2uL, 0.5 mmol) phenanthrene-9-carboxaldehyde (103.1 mg, 0.5 mmol), phenylacetic acid (68.08 mg, 0.5 mmol) then n-butyl isocyanide (52.28 uL, 0.5 mmol). After each addition, a homogeneous solution was obtained following vortexing for at least 15 s. The vial was capped and left at room temperature for 22 h. At this point a precipitate was observed. Methanol (1 mL) was then added followed by 20 s of vortexing and 5 min of centrifugation. The supernatant was discarded and the washing procedure was repeated twice. The resulting solid was left to dry under vacuum and yielded 156.5 mg (0.31 mmol, 62% yield) of
176C: N-butyl-2-[2-furylmethyl-(2-phenylacetyl)amino]-2-(9-phenanthryl)​acetamide; C33H32N2O3; White solid; 1H NMR (external image delta.gif ppm, CDCl3) 0.89 (t, 3H, J=7.3Hz), 1.22-1.39 (m, 2H), 1.4-1.5 (m, 2H), 3.18-3.31 (m, 1H), 3.32-3.44 (m, 1H), 3.93-4.02 (m, 2H), 4.54 (d, 1H, J=17.5Hz), 4.67 (d, 1H, J=17.5Hz), 4.90 (d, 1H, J=2.9Hz), 5.58-5.68 (m, 1H), 5.95 (t, 1H, J= 5.8Hz),6.76-6.83 (m, 1H), 6.95 (s, 1H), 7.17-7.37 (m, 5H), 7.44-7.52 (m, 1H), 7.56-7.63 (m, 2H), 7.64-7.72 (m, 1H), 7.77-7.87 (m, 2H), 7.89 (s, 1H), 8.63 (d, 2H, J=8.3Hz) ; HRMS (FAB,m-nitrobenzyl alcohol): m/z calcd for C33H33N3O2 (M+H); 505.2491 found 505.2450; yield 62%

ID/ Lib Rank
Solvent
Aldehyde
Amine
Carboxylic Acid
Isocyanide
Ppt Yes/No
176/29
Methanol
Phenanthrene-9-
carboxaldehyde
furfurylamine
phenyl acetic acid
n-butyl isocyanide
YES
Quantity
1000uL
0.5 mmol, 103.1 mg
0.5mmol, 44.2uL
(density=1.022g/ml)
0.5mmol, 68.08 mg
0.5mmol, 52.28 ul
(density=0.795g/ml)

Density information: Ugi Chemicals


Results

Furfurylamine
H NMR
C NMR
Phenanthrene-9-Carboxaldehyde
HNMR
phenyl acetic acid
HNMR
1-Butylisocyanide
HNMR
CNMR

(176A)
(176B)
Exp176A.JPG
Exp176B.JPG

Characterization of 176C

weight, IR, mp, appearance
H NMR
HNMR
C NMR
Nominal Mass FAB MS
High Resolution FAB MS


Discussion

All results are recorded Master Table and Workflow Tables.
Describe your strongest evidence for the formation of the Ugi product

Conclusion

A solid product was formed after 22 hours. After characterizing report the yield.

Log

2008-2-26

16:38- Started to weigh out the phenanthrene-9-carboxaldehyde
16:42- Started to weigh out the phenylacetic acid.
16:45- Charged a vial with 1 ml of methanol.
16:47- Added the furfurylamine to the vial and vortexed for 15 seconds. A clear solution was obtained.
16:49- Added the phenanthrene-9-carboxaldehyde to the vial and vortexed for 5 minutes. No clear solution was obtained.
16:55- Added the phenylacetic acid and vortexed for 3 minutes. A clear solution was obtained.
16:59- Added the n-butylisocyanide and vortexed for 15 seconds. A clear solution was obtained.
17:05- Took a photo of the vial (176A).

2008-2-27

15:30- Took a photo of the vial (176B).

2008-2-29

14:28- There was very little liquid on top of the solid product in the vial. Added 1 mL of methanol to the vial and vortexed for 20 seconds. The solid was still caked on the bottom of the vial. Tapped the vial to loosen the solid and vortexed for 20 seconds longer. Then placed in the centrifuge for five minutes.
14:48- Poured off the clear liquid and then added 1 mL of methanol to the vial. Vortexed for 20 seconds and placed on the centrifuge for 5 minutes longer.
14:56- Poured off the clear liquid and added 1 mL of methanol to the vial. Vortexed for 20 seconds and placed in the centrifuge for 5 minutes.
15:08- Poured off the clear liquid and placed the vial on high vac to dry.
21:15- Removed from the high vac and put on the house vac line.

2008-3-6

20:19- The dry, solid product (176C) weighs 0.1565 grams; 62% yield.


Tags

furfurylamine InChI=1/C5H7NO/c6-4-5-2-1-3-7-5/h1-3H,4,6H2 InChIKey: DDRPCXLAQZKBJP-UHFFFAOYAX
phenanthrene-9-carboxaldehyde InChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H InChIKey: QECIGCMPORCORE-UHFFFAOYAE
phenyl acetic acid InChI=1/C8H8O2/c9-8(10)6-7-4-2-1-3-5-7/h1-5H,6H2,(H,9,10) InChIKey: WLJVXDMOQOGPHL-UHFFFAOYAR
n-butyl isocyanide InChI=1/C5H9N/c1-3-4-5-6-2/h3-5H2,1H3 InChIKey: FSBLVBBRXSCOKU-UHFFFAOYAR
Ugi Product Exp176 InChI=1/C33H32N2O3/c1-2-3-19-34-33(37)32(30-22-25-14-7-8-16-27(25 ​)28-17-9-10-18-29(28)30)35(23-26-15-11-20-38-26)31(36)21-24-12-5-​ 4-6-13-24/h4-18,20,22,32H,2-3,19,21,23H2,1H3,(H,34,37) InChIKey: RGGYLRDGJAJICY-UHFFFAOYAH