175.gif

Objective

To synthesize a Ugi adduct from benzylamine, phenanthrene-9-carboxaldehyde, 4-chlorophenyl acetic acid and n-butyl isocyanide in methanol using Ugi 4CR following Explan005. The target compound was ranked 18 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 is a repeat of Exp159.


Procedure

To a one dram vial, charged with methanol (1mL) and benzylamine, phenanthrene-9-carboxaldehyde, 4-chlorophenyl acetic acid and n-butyl isocyanide (0.5mmol each) was added in that order. After each addition, the resulting solution was vortexed for at least 15 seconds and confirmed that a homogeneous solution had been obtained. The vial was capped tight and left at room temperature for 1 day.

175D 2-[benzyl-[2-(4-chlorophenyl)acetyl]amino]-N-butyl-2-(9-phenanthr​yl)acetamide: C35H33ClN2O2; White solid; 1H NMR (external image delta.gif ppm, 500MHz, CDCl3); 0.86 (t, 3H, J=7.3Hz), 1.04-1.32 (m, 2H), 1.33-1.47 (m, 2H), 3.04-3.27 (m, 1H), 3.29-3.46 (m, 1H), 3.51 (d, 1H, J=16.1Hz), 3.60 (d, 1H, J=16.1Hz), 4.73 (d, 1H, J=17.5Hz), 4.75 (d, 1H, J=17.5Hz), 6.14 (t, 1H, J=5.8Hz), 6.61 (s, 1H), 6.62 (s, 1H), 6.70-6.79 (m, 2H), 6.80-6.87 (m, 1H), 6.97 (d, 2H, J=8.3Hz), 7.14 (s, 1H), 7.16 (d, 2H, J=8.3Hz), 7.48-7.72 (m, 4H), 7.78 (d, 1H, J= 7.8Hz), 7.87 (s, 1H), 8.10 (d, 1H, J=7.8Hz), 8.55 (d, 1H, J=8.3Hz), 8.62 (d, 1H, J=7.8Hz)


ID/ Lib Rank
Solvent
Aldehyde
Amine
Carboxylic Acid
Isocyanide
Ppt Yes/No
175/18
Methanol
Phenanthrene-9-
carboxaldehyde
benzylamine
4-chlorophenyl acetic acid
n-butyl isocyanide
YES
Quantity
1000uL
0.5 mmol, 103.12 mg
0.5mmol, 54.6uL
(density=0.981g/ml)
0.5mmol, 85.30 mg
0.5mmol, 52.28 ul
(density=0.795g/ml)

Density information: Ugi Chemicals

Results

Phenanthrene-9-Carboxaldehyde
HNMR
benzylamine
HNMR
4-chlorophenyl acetic acid
HNMR
1-Butylisocyanide
HNMR
CNMR

175A
Soon after mixing

175B

175C

Exp175A.JPG
175B.JPG
Exp175C.JPG

Characterization of 175D

weight, CMR, m,p, missing
HNMR
HNMR
Labile H Exchange how did you prepare?
Nominal Mass FAB MS
High Resolution FAB MS
Overlay of 175D and starting materials

Discussion

From the proton NMR peaks which may correspond to a Ugi product are seen,( Link to GoogleDoc with a list of all isolated Ugi product peaks - you also need to add D2O to figure out which is amide) The FAB-MS supports the idea of a Ugi product. However, a CNMR and a crystal structure is needed to confirm the structure of the product.


All results are recorded Master Table and Workflow Tables.

Conclusion

A solid product formed after 45 minutes of mixing and moving the vial. Only a small volume of liquid is visible on top of the solid.

Log

2008-2-26

15:29- Started to weigh out the phenanthrene-9-carboxaldehyde.
15:33- Started to weigh out the 4-chlorophenyl acetic acid.
15:39- Charged a vial with 1 mL of methanol.
15:41- Added the benzylamine to the vial and vortexed for 15 seconds. A clear solution was obtained.
15:44- Added the phenanthrene-9-carboxaldehyde to the vial and vortexed for 5 minutes until a clear solution was obtained.
15:53- Added the 4-chlorophenyl acetic acid to the vial and vortexed for 15 seconds. A clear solution was obtained.
15:57- Added the n-butyl isocyanide to the vial and vortexed for 15 seconds. A clear solution was obtained.
15:03- Took a photo (175A) of the vial and left it to sit for 24 hours at room temperature.
15:48- Took a photo (175B) of the vial. A solid formed after the vial was moved. (you got all that solid in less than one hour?) Yes! :)

2008-2-27

15:30- Took a photo (175C).

2008-2-29

14:28- There was not 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

20:09- The dry, solid product weighs 0.1977 grams. (175D)


Tags

benzylamine InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 InChIKey: WGQKYBSKWIADBV-UHFFFAOYAL
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
4-chlorophenyl acetic acid InChI=1/C8H7ClO2/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4H,5H2,(H,10,11)
n-butyl isocyanide InChI=1/C5H9N/c1-3-4-5-6-2/h3-5H2,1H3 InChIKey: FSBLVBBRXSCOKU-UHFFFAOYAR
Ugi Product InChI=1/C35H33ClN2O2/c1-2-3-21-37-35(40)34(32-23-27-13-7-8-14-29( ​27)30-15-9-10-16-31(30)32)38(24-26-11-5-4-6-12-26)33(39)22-25-17-​ 19-28(36)20-18-25/h4-20,23,34H,2-3,21-22,24H2,1H3,(H,37,40) InChIKey: NCOSMKWGNCJPCR-UHFFFAOYAK