Objective

To synthesize 12 Ugi products using phenanthrene-9-carboxaldehyde and phenylacetic acid in THF.

UCExp240-7A :Mp 182-184C; C34H34N2O3; 1H NMR (external image delta.gif ppm, CDCl3) 0.9 (t, 3H, J=7.3Hz), 1.24-1.38 (m, 2H), 1.42-1.50 (m, 2H), 1.73 (s, 3H), 3.22-3.33 (m,1H), 3.36-3.46 (m, 1H), 3.92-4.07 (m, 2H), 4.51 (d, 1H, J=17.5Hz), 4.63 (d, 1H, J=17.5Hz), 4.88 (m, 1H), 5.18 (m, 1H), 5.3 (bt, 1H, J=5.3Hz), 6.96 (s, 1H), 7.22-7.39 (m, 5H), 7.47-7.54 (m, 1H), 7.57-7.63 (m, 2H), 7.65-7.71 (m,1H), 7.8-7.92 (m, 3H), 8.64 (d, 2H, J=7.8Hz); HRMS (CI): m/z calcd for C35H36NO3 [M+H]+ 519.264768 Da, found 519.262438 Da; yield 36%

Results

Pictures
Immediately after mixing
UCExp240-i, UCExp240-ii
2.5h after mixing
UCExp240-iii, UCExp240-iv [nice! JCB]
11.5h after mixing
UCExp240-v
24h after mixing
UCExp240-vi, UCExp240-vii
41.5h after mixing
UCExp240-viii, UCExp240-ix
48h after mixing
UCExp240-xi, UCExp240xii

Characterization Data
UCExp240-2A

UCExp240-7A

UCExp240-9A
HNMR
CI MS
Nominal
HRMS
IR
m.p 231-233 C

HNMR
CI MS
Nominal
HRMS
IR
m.p 182-184 C

HNMR
CI MS
Nominal
HRMS
IR
m.p 237-239 C


Spreadsheet



Discussion

  • After 24h of starting the reaction, three reactions formed solid ppts. Interestingly each of them had a different isocyanide component. Six isocyanides were used in this experiment, reactions involving cyclohexyl isocyanide and n-butylisocyanide with 5-methylfurfurylamine and t-butylisocyanide with furfurylamine formed ppts from THF within 24h.
  • The starting materials for UCExp240-2A were phenanthrene-9-carboxaldehyde, furfurylamine. phenylacetic acid and t-butylisocyanide. A similar reaction is known to form a ppt from methanol when carried out with n-butylisocyanide (

UCExp176, the product was not characterized).
  • After 48h of starting the reaction, seven out of twelve reactions had precipitated out some product...Since the reactions were carried out on 0.1mmol scale, isolation of the products after washing with THF was difficult because of relatively high solubility in the solvent...Therefore the seven reactions which formed ppts have to be carried out on a larger scale to enable isolation and complete characterization, including C-NMR.
  • HNMRs of UCExp240-2A yielded inconclusive results because of possible contamination, which appears between 0.6-2.2ppm.HNMRs of UCExp240-7A and UCExp240-9A seem consistent with a Ugi product. Complete characterization will carried out when these reaction are carried out on a 1mmol scale.
  • Mass Spec confirms that UCExp240-2A, UCExp240-7A and UCExp240-9A are the desired Ugi products.
  • It appears that, it takes longer for Ugi reactions to form precipitates when the reaction is carried out in THF (compared to methanol).

Conclusion

After 24h of starting the reactions three formed solid Ugi products, however another four precipiated out in the next 24h.

Log

2009-07-28
16:00 Made-up a 1.5M solution of phenanthrene-9-carboxaldehyde in THF by dissolving 309.5mg (1.5mmol) of the aldehyde in 746uL of the solvent; this was done assuming there volumes are additive; volume of phenanthrene-9-carboxaldehyde was calculated using its predicted density obtained from Chemspider
16:30 Made-up a 5M solution of phenylacetic acid in THF by dissolving 680.7mg (5mmol) in 319.3uL of the solvent; again this was done assuming there volumes are additive; volume of phenylacetic acid was calculated using its predicted density obtained from Chemspider.
17:00 Labeled 12 vials half dram screw cap vials 240-1 to 240-12.
17:10 Started pipetting out the aldehyde (1.5M solution in THF, 67uL, 0.1mmol) in to the vials.
17:25 Added furfurylamine (8.8uL, 0.1mmol) in to vials labeled 240-1 to 240-6.
17:30 Added 5-methylfufurylamine (11.1, 0.1mmol) in to vials labeled 240-7 to 240-12.
17:40 Pipetted out phenylacetic acid (5M solution in THF, 20uL, 0.1mmol) in to the vials.
17:50 Transfered isocyanide (0.1mmol see spreadsheet for volumes) to the reaction from the spreadsheet, in to the vials.
18:05 Vortexed the vials for 10s each.
18:15 Obtained pictures for the reaction vials UCExp240-i and UCExp240-ii, labeled 'Immediately after the addition of all chemical' in the Results section.
20:45 Some solid ppt has appeared in vials 240-2 and 240-9; obtained pictures of the vials UCExp240-iii, UCExp240-iv - labeled '2.5h after mixing'.
2009-07-29
11:30 Vial 240-7 had developed some ppt in it, therefore another picture of the vials was taken, UCExp240-v- labeled 11.5h after mixing
11:40 Vortexed vials containing solutions for 20s each.
17:50 No further change has been noticed in other vials. Obtained a picture of the vials. UCExp240-vi, UCExp240-vii-labeled 24h after mixing.
17:52 Transferred 100uL THF to each vial, vortexed them for ~20s each, to break the solid at the bottom of the vials, .the solid ppt in sample vial 240-7 almost dissolved entirely in THF with just a grain size particle remaining at the bottom of the vial, therefore instead of centrifuging the sample it was set for evaporation with gentle flow of N2 gas.
The remaining two vials (240-2 and 240-9) were centrifuged and the supernatant was separated by decanting. This was the first wash.
18:05 Residue in vials 240-2 and 240-9 was washed with THF (100uL) a further two times. Each time after vortexing the solution was centrifuged and decanted to remove the supernatant. After the last wash a small amount of a pale colored residue obtained was set in a desiccator connected to a high vac-pump.
18:25 The mother liquors obtained after decanting the supernatant from each sample, was collected separately and are named 204-2B, 240-7B and 240-9B.
18:30 To the residue in sample vial 240-7 after evaporation of THF, methanol (100uL) was added, vortexed and centrifuged. The supernatant was removed from the vial by decanting. The residue was washed with methanol (100uL) a further two more times. Each time after vortexing the solution was centrifuged and decanted to remove the supernatant. After the last wash a small amount of a white residue wasobtained. It was set in a desiccator connected to a high vac-pump to dry.
21:45 Removed from the vacuum dessicator and obtained UC240-2A - 12mg (from vial 240-2), UC240-7A - 18.5mg (from vial 240-7), and UC240.9A -23.5mg (from vial 240-9).
22:10 Obtained melting points of UC240-2A, UC240-7A and UC240-9A (only one run per sample)
22:30 Obtained IR spectra of UC240-2A, UC240-7A and UC240-9A on a Perkin-Elmer Spectrum One FTIR Spectrometer in its ATR mode
22:45 Obtained HNMR of UC240-2A, UC240-7A and UC240-9A on a 500MHz varian Inova.
2009-07-30
11:20 Vials 240-1, 240-8 and 240-12 have developed some solid in them, therefore obtained a picture of the vials, UCExp240-viii, UCExp240-ix
13:00 Added THF (100uL) in to vials 240-1, 240-8 and 240-12, vortexed for 1min each and centrifuged them. Almost all the solid dissolved in vial 240-8..substantial amount of solid also dissolved in vials 240-1 and 240-12. Obtained a picture of vials after centrifuging.
13:45 Since there was hardly any solid in 240-8, the solvent in it was set for evaporation under a gentle flow of N2.
14:30 Stopped evaporation, obtained some solid...
14:40 To the solid in the vial, 240-8 methanol (100uL) was added and vortexed for approximately one minute, again all the solid dissolved in the solvent...isolation of the product from this vial is now aborted and will be carried out when the reaction is performed on a larger scale, possibly 1mmol.
18:00 Vial 240-6 has now developed some solid in it. Obtained a picture of the vials, including 240-6, UCExp240-xi, UCExp240xii
18:30 Mass spec results for 240-2A, 240-7A and 240-9A have been received and are available under results.