external image File?id=dfs2qbbj_216f5db7nc7_b



Objective


To synthesize the precursor diamide to be used subsequently in the pictet spengler reaction affording praziquantel

Procedure

To a solution of formaldehyde/water in methanol, aminoacetaldehyde dimethylacetal was added. The reaction was monitored by HNMR to confirm a complete conversion to the corresponding imine. Subsequently cyclohexanecarboxylic acid and 2-phenylethyl isocyanide was added. The reaction was left undisturbed over night. The final Ugi product obtained as crystals was filtered out next day. The product was analyzed by NMR, MS and IR.



Results

1-cyclohexanoic acid
HNMR
formaldehyde (37% solution in water)
HNMR- in CDCl3
HNMR - Neat (DMSO-d6- Coaxial insert)
aminoacetaldehyde dimethylacetal
HNMR
2-phenylethyl isocyanide
HNMR (contaminated with acetone?)
UCExp258-1B
SAMS -spreadsheet-UCEXp258
Total volume of the solution -172.8uL
Concentration per component - 1.15M

Discussion

Mechanism of the Ugi reaction
[From the NMR of the crude reaction mixture does it look like the starting materials were consumed? Any evidence for the formation of the Ugi product? JCB]
Unreacted isocyanide CH2 (tt) is seen at 2.98ppm, indicating that the reaction is not complete yet.
[True some unreacted isocyanide but the peaks looks very small - can you estimate %conversion? JCB]
It is not possible to figure if any Ugi product is formed, because of severe peak overlaps with reactants. There are two types if methoxys seen at 3.96 ppm and 4.01ppm, one of them could possibly be from the imine and other one could be either from the Ugi product or from the unreacted amine. Based on the SAMS calculation, at least 0.55M (0.095mmol) of 2-phenyl ethyl isocyanide is remaining. In other words it shows that 60% of the isocyanide has been used-up. It could have been used up either in a Ugi reaction or a 3-component
Passerini reaction. If a Ugi reaction did happen the reaction is slow.

[The presence of methanol might be shifting the peaks and making it hard to identify some of the starting materials - if you wash with dilute base you will get rid of the unreacted cyclohexane carboxylic acid and see if any acid got incorporated. You could then wash with dilute acid to get rid of unreacted amine - this will work but will also probably hydrolyze the acetal. JCB] -

Conclusion

After two days of reaction time, it is not clear if a Ugi product is formed. Owing to the small scale on which this reaction was carried out (total volume <175uL), and the minuscule amount of precipitate obtained, further work-up seems impractical.
Experiment aborted.

Log

2010-05-15
12:00 noon- Make-up a 2M methanolic solution of formaldehyde (37% wt in water) by dissolving 1.621g in a methanol in a10mL volumetric flask. Obtained HNMRs of formaldehyde solution in water (both in CDCl3 and neat (DMSO-D6 coaxial insert)), aminoacetaldehydedimethylacetal, cyclohexanecarboxylic acid and 1-phenylethylisocyanide.
15:00- In a clean half dram vialpipetted out the 2M formaldehyde solution (100uL, 0.2mmol).
15:03- Pipette-out aminoacetaldehyde dimethylacetal (21.8uL 0.2mmol, 21.0mg) in to half dram vial. The solution warmed-up a little. Vortexed the vial for 30s.

15:06 Then pipette out cyclohexanecarboxylic acid (24.8uL, 0.2mmol, 25.6mg), vortexed 30s
15:09- Soon after pipette-out 2-phenylethyl isocyanide (26.2mg, 0.2mmol, ~26.2uL) in to the vial and vortexed again. The solution was clear after completing the additions
2010-05-17
15:30 After two days, some form of turbidity has appeared in the vial.

16:00 Cerntrifuged the vial and obtained the supernatant (UCExp258-1B). ...there was hardly any ppt found in the vial. Therefore it is not possible to characterize the ppt.

Reference:
1. Kim, J.,H.; Lee, Y., S.; Kim, C., S.; Heterocycles, 48; 11; 1998; 2279- 2285; 1998 (doi:10.3987/COM-98-8293)
Characterization data for the diamide product: "mp-128-130C, IR (KBr) 3350,2970,1670,1560,1465,1140,1090 cm-1; 1H NMR (CDCl3) 1.60-1.80 (10H, m, cyclohexyl protons),. 2.48 (1H, m, CHCONH), 3.22 (2H, t, J=6.0Hz, PhCH2), 3.65 (2H, t, J=6.0 Hz, CH2NH), 3.80 (6H, s, OCH3), 4.40 (2H, s,. COCH2N), 4.93 (1H, m, CH2CH(OCH3)2), 7.60 (5H, m, phenyl protons); Anal. Cacld for C21H32N2O4 : C,66.99; H,8.57; N, 7.44. Found C, 66.93; H, 8.58; N, 7.49."