CombiUgiExp116-vii.JPG

Objective

To synthesize four different Ugi adducts following the EXPLAN005 . The compounds will contribute toward a library for enoyl reductase inhibitors.

Procedure

Four ugi reactions are carried out in four preweighed, 1.5 ml eppendorf tubes labeled EP1, EP2, EP3 and EP4.
In EP1 methanol (500uL), benzylamine (0.5mmol, 54.6uL), benzaldehyde (0.5mmol, 50.8uL), formic acid (0.53mmol, 20uL) and p-toluenesulfonylmethyl isocyanide (0.5mmol, 97.6 mg) was added in that order. In EP2, methanol (500uL), benzylamine (0.5mmol, 54.6uL), 3-hydroxybenzaldehyde (0.5mmol, 61.0mg), formic acid (0.53mmol, 20uL) and p-toluenesulfonylmethyl isocyanide (0.5mmol, 97.6mg) was added in that order. In EP3, methanol (500uL), 5-methylfurfurylamine (0.5mmol, 55.7uL), o-tolualdehyde (0.5mmol, 57.8 uL), formic acid (0.53mmol, 20uL) and p-toluenesulfonylmethyl isocyanide (0.5mmol, 97.6mg) was added in that order. In EP4, methanol (500uL), methylamine (2.0M solution in methanol, 0.5mmol, 250uL), 2,4-dimethylbenzaldehyde (0.5mmol, 69.7uL), formic acid (0.53mmol, 20uL) and p-toluenesulfonylmethyl isocyanide (0.5mmol, 97.6mg) was added in that order.
After each addition the solution was vortexed for 15 s and made sure a homogeneous solution was obtained. The eppendorf tubes were left at room temperature.

Discussion

EP2- 3-hydroxybenzaldehyde and benzylamine reacted immediately and formed a white precipitate. This maybe because the phenol may have reacted with the amine (acid-base reaction) forming an ammonium phenolate. However after the addition of formic acid the precipitate started to dissolve. Therefore the isocyanide was added.
The solubility of p-toluenesulfonylmethyl isocyanide is apparently less than 1M in methanol. A slighly lower concentration might work.
After 42 hours, no solid has formed in the eppendorf tubes. The experiment failed to produce any solid ugi products.

Conclusion

Experiment aborted.

Log

2007-08-02

19:45 Weighed the eppendorf tubes- [EP1= 0.8715g, EP2= 0.8780g, EP3= 0.8675g, EP4= 0.8670g]
20:20: Added methanol (500uL) to each of the eppendorfs.
20:40 Weighed out p-toluenesulfonylmethyl isocyanide (97.6mg x 4)
21:10 Weighed out 3-hydroxybenzaldehyde (61.0mg).
21:30 Started adding the amines into each of the eppendorf tubes, EP1-benzylamine, EP2-benzylamine, EP3- 5-methylfurfurylamine, EP4-methylamine, vortexed each for 15-20s after the addition.
21:35 Added the aldehydes into the tubes, EP1-benzaldehyde, EP2- 3-hydroxybenzaldehyde, EP3- o-tolualdehyde, EP4- 2,4-dimethylbenzaldehyde, vortexed each for 15-20s after the additions - Solution in EP2 precipitated out..
21:45 Completed addition of formic acid to each eppendorf tube. Vortexed for 15-20s.
21:55 Completed addition of isocyanide to each eppendorf tube. Vortexed for 15-20s. p-toluenesulfonylmethyl isocyanide had limited solubility in methanol, even after vortexing multiple times, some of it still remained undissolved.
22:00 Left the tubes in the hood...

2007-08-03

20:00 Solutions in the eppendorf tubes remain clear..a solid product has not formed.

2007-08-04

16:21 Solutions in the eppendorf tubes remain clear..a solid product has not formed.