27ab.JPG

Objective

To obtain a simple Ugi adduct in methanol.

Procedure

To a 100 ml round bottom flask added methanol (20 ml), formaldehyde 37% w/w, (100 µl, 3.3 mmol), tert -butylamine (105µl, 1.0 mmol ) 2-morpholin ethyl isocyanide (105µl, 1.0mmol ) and Boc-Gly-OH (0.175 mg, 1.0mmol). The mixture is stirred, evaporated. The product is subjected to deprotection and cyclization, using 10% TFA in 1, 2-dichloroethane.

Results

Characterization of 27A

1. A TLC of the starting materials could not be obtained because the components are so volatile that as soon as they were spotted on the plate they disappeared and a run in methylene chloride / hexanes (1:1) showed nothing except the isocyanide. (Boc-Gly-OH being UV inactive).
2. A HNMR of 27A was obtained in CDCl3 (500MHz Varian Inova)
3 A C13-NMR of 27A was also obtained. (300MHz Varian Inova)
4. A TLC was run in methylene chloride against the isocyanide and the amine (not visible because of its volatile nature), under UV lamp , stained with ninhydrin.
5. A C-13 NMR of 10% TFA in 1,2-DCE was obtained (note the strong C-F coupling gives quartets)

Characterization of 27B

6. A C-13 NMR of 27B (after 16hr 21mins) was obtained.

Characterization of 27C

7. A HNMR of 27C was obtained
8. A C-13 of 27C was not obtainable because of the small amount of the sample.
9. A H-NMR and C13-NMR of formaldehyde.

Discussion

1.The C13-NMR of 27A is showing peaks consistent with that for the isonitrile (C NMR spectrum), except that it is missing the 38.4 ppm (corrected from off scale 77.0 CHCl3 ref) peak. Thus the peak near 155 ppm may not correspond to an isonitrile.
2. Peaks corresponding to Boc-Gly-OH [(a) Carbamate carbonyl - 156.1 ppm (b) - Carboxyl carbonyl - 174.0 ppm (c) tertiary carbon - 80.4 ppm (d) - CH2 - 42.2 ppm] do not show up on the CMR of 27A, indicating a disappearance of the starting material.
3. Usually the carbonyl peak of an aldehyde would appear beyond 190 ppm; this is significantly absent in the C-13 NMR of 27A, indicating the absence of any formaldehyde, which is expected since it is volatile.
4. Assigning tert- butyl amine peaks might be tricky because we also encounter another tert-butyl group coming from Boc-Gly-OH; therefore presence of any unreacted tert-butyl amine in 27A cannot be ruled out, although it is unlikely because of its low boiling point (44-46C)
5.The C-13 NMR of 27A suggests that there may be some amide linkages established during the course of reaction (peaks between175 and 168).
6.The NMRs of formaldehyde (formalin- a 37% w/w solution in water) clearly shows that in solution it mostly exits in its polymeric (paraformaldehyde or triaoxane) forms, also it might contain some amount of methanol. Therefore formaldehyde, after all might not have been the best choice as an aliphatic aldehyde.
7. Since the first step of the Ugi reaction is supposed to be the imine formation, presence of water in the reaction might in fact have a negative impact on its (imine) formation, which might be detrimental on the overall Ugi reaction itself.
8. Larger R- groups on both the aliphatic aldehyde and the primary amine counterpart, and a quick water removal from the reaction might in fact facilitate an imine formation.

Conclusion

No diketopiperazine product was obtained. Although the CMR of the crude product from the first step was consistent with the Ugi product, this was not established by purification and further characterization.

Log

2006/09/06

1. 16:40] Added all the chemicals to a 100ml round bottom flask and started stirring. A very pale yellow colored solution is obtained to begin with.

2006-09-10

2. 16:40] Evaporated the solvent, dried on a high vac and obtained 27A (441.9 mg). 27A will be subjected to deprotection and cycliztion using 10% TFA in 1, 2-dichloroethane.

2006-09-19

Deprotection and Cyclization (UDC- Ugi Deprotection Cyclization strategy):
3. 16:30] Made a solution of 10% TFA in 1,2-dichloroethane (by mixing 4.5ml of DCE in 0.5ml of TFA and 1ml of CDCl3 with traces of TMS in a vial)

2006-09-20

4. 19:50] Obtained 27B by adding 2ml of the above 10% TFA in DCE solution to 353.7mg of 27A; transferred the reaction mixture to an NMR tube.

2006-09-20

5. 20:07] A C13 NMR of 27B-T1 was obtained after a 15 min run

2006-09-21

6.12:20] A C13 NMR of 27B-T2 was obtained after a 16hr 21 min run, as an average over the course of the entire experiment.
7.12:30] Added 50 ml of water, extracted with 25ml of methylene chloride, washed the DCM layer with another 50ml of water, separated the DCM layer, dried it over anhydrous MgSO4, evaporated under a gentle flow of Nitrogen, set on high vac for 1h and obtained (14.1mg) of 27C.

Tags


Formaldehyde InChI=1/CH2O/c1-2/h1H2
2-morpholin ethyl isocyanideInChI=1/C7H12N2O/c1-8-2-3-9-4-6-10-7-5-9/h2-7H2
Boc-Gly-OHInChI=1/C7H13NO4/c1-7(2,3)12-6(11)8-4-5(9)10/h4H2,1-3H3,(H,8,11)(H,9,10)
tert -butylamineInChI=1/C4H11N/c1-4(2,3)5/h5H2,1-3H3
ugi027:InChI=1/C19H36N4O5/c1-18(2,3)23(16(25)13-21-17(26)28-19(4,5)6)14-15(24)20-7-8-22-9-11-27-12-10-22/h7-14H2,1-6H3,(H,20,24)(H,21,26)
DKP027 InChI=1/C8H14N2O2/c1-8(2,3)10-5-6(11)9-4-7(10)12/h4-5H2,1-3H3,(H,9,11)