Exp150-i.JPG

Objective

To synthesize a Ugi adduct from Phenanthrene-9-carboxaldehyde, benzylamine, Tert-butylisocyanide and Crotonic acid in methanol using Ugi 4CR following Explan005. This is a repeat of Exp143c.The target compound was ranked 155 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.
[The experiment is repeated because the Phenanthrene-9-carboxaldehyde which was used in the previous experiment (Exp143) was acquired as a liquid. The aldehyde used here was obtained from Sigma Aldrich as a solid- Mpt-100C.]

Procedure

To a one dram vial, charged with methanol (1 ml), benzylamine, phenanthrene-9-carboxaldehyde, crotonic acid and tert-butyl isonitrile (0.5mmol each) was added in that order. After each addition, the resulting solution was vortexed for 15 seconds (or more) and confirmed that a homogeneous solution had been obtained. The vial was capped tight and left at room temperature. After crystallization, the solution was decanted and the crystals were washed with methanol (3x 500uL) and dried under vacuum to obtain 150D in 58.5% yield.

Characterization of 150D: White powder; H-NMR (external image delta.gif ppm ppm, CDCl3) 1.39 (s, 9H), 1.77 (d, 3H J=6.3Hz), 4.79 (d, 1H, J=17.9 Hz), 4.88 (d, 1H, J=17.9 Hz), 5.67 (s, 1H), 6.18 (d, 1H, J=15.0 Hz), 6.33-6.81 (m, 4H), 6.88-7.23 (m 2H ), 7.36-7.74 (m, 4H), 7.80 (d,1H J=7.3 Hz), 7.90 (s 1H), 8.09 (d 1H J 12.2 Hz), 8.51 (t 2H J=12.8Hz); 13C NMR (external image delta.gif ppm, CDCl3) 18.1, 28.6, 49.0, 50.6, 51.7, 57.6, 94.6, 122.2, 122.4, 122.9, 124.2, 125.8, 126.6, 126.68, 127.1, 127.2, 128.7, 129.3, 130.1, 130.2, 130.4, 130.7, 30.9, 137.3, 143.4, 168.0, 169.9 ; IR (KBr, 1/cm): v = 3323, 3058, 2969, 1677, 1655, 1594, 1526, 1421, 722, 695; HRMS m/z calcd for C31H32N2O2 : 465.2542 [M+H] found 465.2448; C31H32N2O2Na 487.23614 [M+Na] found 487.23761; yield 59%
ID/ Lib Rank
Solvent
Aldehyde
Amine
Carboxylic Acid
Isocyanide
Ppt Yes/No
148C/155
Methanol
Phenanthrene-9-
carboxaldehyde
benzylamine
Crotonic acid
tert-butylisocyanide
Yes
Mol Formula-C31H32N2O2
Quantity
1000uL
0.5mmol, 103.1mg
0.5mmol, 54.61ul
(density=0.981g/ml)
0.5mmol, 43.0mg
0.5mmol, 56.5uL
(density=0.735g/ml)
135.8mg
Mol wt-464.60 g/mol
Yield: 58.5%

Results

Phenanthrene-9-Carboxaldehyde (solid from Sigma-Aldrich)
HNMR
benzylamine
HNMR
Crotonic Acid
HNMR
tert-Butyl isocyanide
HNMR

Characterization of 150D

HNMR
CNMR
MS (FAB)
HRMS
IR

X- Ray studies
150D-Crystal Structure
150D-Crystal analysis
To view the above file:
1.Right click, save to desktop
2. Download MERCURY or enCIFer from CCDC (free) install the program and view the file)
6 min after mixing
all components (150A)
15 h after mixing
all components (150B)
17h After mixing
all components (150C)
Exp150A.JPG
Exp150A-2.JPG
Exp150A-3.JPG

Discussion

Until about 15h after mixing all the components, the solution remained clear....however once the solution was disturbed, crystal induction took place. This indicates that the solution had become saturated with the ugi product.
All results are recorded in the Master Table of all Ugi synthesis attempts

Conclusion

The Ugi product was obtained in 59% yield.

Log

2007-11-27

19:30- Charged a vial with 1ml of methanol and began to weigh out the crotonic acid and phenanthrene-9-carboxaldehyde.
19:40- Added 54.61 ul of benzylamine into the vial and vortexted for 15 seconds. A clear solution was achieved.
19:44- Added 103.1 mg of phenanthrene-9-carboxaldehyde to the vial and vortexed for one minute. The solution was light yellow and somewhat cloudy, and the sediment settled to the bottom of the vial. Therefore the solution was vortexed for another three minutes. The solid now went in to the solution, however a few oil like droplets were observed at the bottom of the vial. The solution homogenized upon standing.
20:10- Weighed out and added 43.0 mg of crotonic acid into the vial and vortexed for 30 seconds. The solution became clear.
20:25- Added 56.5 ul of tert-butyl isocyanide to the vial and vortexed for 30 seconds. The solution became cloudy with a few small flakes on the bottom of the vial. It was vortexed for a total of five more minutes before a clear yellow solution was obtained.
20:31 Obtained a picture of the vial (150A) remember to always label results so you can discuss them
20:35- The vial was left to sit at room temperature for a day.

2007-11-28

11:23 Moved the vial to another location and obtained a picture of 150B, still a clear solution..
12:18 Crystallization has started in.
13:29 Obtained another picture (150C)

2007-12-05

19:00 Decanted the clear solution from 150C in to another vial and washed the crystals with methanol (3x500uL), each time vortexing (how long?) the solution and just decanting the supernatant..(did not centrifuge because the crystals separated out from the supernatant easily)
19:30 Evaporated the methanol under high vac for half an hour.
20:20 Obtained 135.8mg of 150D.

2007-12-06

19:30 Obtained HNMR of 150D. (62.3mg / 623uL CDCl3)

2007-12-07

17:20 Sent 150D for Crystallography studies.

2007-12-08

12:30 Obtained IR of 150D. Pulverized 150D (~20mg ) with KBr (~200mg) (spectrograde ) using a tiny mortar-pestle, pressed the powder (mix) in to a pellet. Obtained an IR spectrum on a Perkin Elmer FTIR -Model: Spectrum One.
13:00 Submitted ~5mg of the sample (150D) for MS (FAB) analysis.

2007-12-14

14:09 Results from X -ray studies have come.

Tags

Phenanthrene-9-carboxaldehydeInChI=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
tert-butylisocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3 InChIKey: FAGLEPBREOXSAC-UHFFFAOYAL
Crotonic Acid: InChI=1/C4H6O2/c1-2-3-4(5)6/h2-3H,1H3,(H,5,6)/f/h5H InChIKey: LDHQCZJRKDOVOX-UHFFFAOYAC
benzylamine InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 InChIKey: WGQKYBSKWIADBV-UHFFFAOYAL
Ugi Product : InChI=1/C31H32N2O2/c1-5-13-28(34)33(21-22-14-7-6-8-15-22)29(30(35​)32-31(2,3)4)27-20-23-16-9-10-17-24(23)25-18-11-12-19-26(25)27/h5​-20,29H,21H2,1-4H3,(H,32,35)/b13-5 InChIKey: PBZQTKRWYXTXIS-WLRTZDKTBU