Exp067-3.JPG

Objective

To cyclize the Ugi product obtained in Exp064 (64C-2) by an acid catalyzed transamidation reaction.

Procedure

Dissolved 55mg (0.1mmol) of the Ugi product 64C-2 from Exp064 in 900uL CDCl3, obtained an HNMR. Then 100uL of trifluoroacetic acid was added to the above solution in the NMR tube (10% solution in CDCl3). The reaction was continuously monitored by NMR spectroscopy.

Results

Reactants in CDCl3
Ugi Product 64C-2 in CDCl3
TFA in CDCl3 (100uL / 900uL - 10% ; densities of CDCl3 and TFA are similar)

67A (64C-2 + TFA) -all files are mislabeled as exp064C instead of exp067A
t = 02min
t = 04min
t = 06min
t = 08min
t = 10min
t = 12min
t = 15min
t = 20min
t = 23min
t = 35min
t = 52min
t = 1h 02min
t = 1h 11min
t = 1h 17min
t = 2h 10min
t = 2h 56min
t = 3h 00min
t = 3h 24min
t = 4h 00min
t = 4h 12min
t = 5h 00min
t = 5h 27min
C NMR - 67A
DEPT -67A
t = 19h 50min
t = 21h 05min
t = 40h 12min
t = 73h11mim
t = 74h 27min (after 1h heating at 67C)

HNMR of 67B-1 (very small amount of TFA remaining, replenished 800uL CDCl3)
HNMR of 67B-2

Boc- deprotection kinetics

Spectral Overlay : Overlay of 67A and B

Discussion


firstorderkineticsforboc-deprotection-67C.JPG
Figure - Exp067-i
  1. The loss of the boc group proceeds smoothly at a rate of 1.22x10-2 min -1 It can be followed by monitoring the disappearance of the 1.42 ppm peak (Fig Exp067-i).
  2. The compound does not cyclize under the given conditions. There is a furfuryl cleavage that occurs, possibly as a result of an elimination similar to 1,6-Hoffman elimination reaction. The coupling constant of the doublets at 8.27 ppm and 5.54 ppm is 7.3Hz. Peak at 8.27ppm corresponds to the hydrogen on N and the double at 5.54ppm is the chiral proton
  3. From Exp068 it is evident that there is a removal of t-butyl group from the Ugi product by the addition of TFA (10%) This occurs in about 5h. This is also explained in this reference.
  4. After 74h 27min, from the HNMR it still is not clear if a 2,5 diketopiperazine is formed or not, this may be due to the mere fact that the peaks of the cyclized product may be overlapping with the uncyclized salt and other side products..
  5. It does not appear valuable to continue this experiment any further because of the evaporation of the solvent during heating, and any further addition of TFA may render it unreproducible. Therefore this experiment will be aborted and yet another attempt at cyclization will be Exp070.
  6. The coupling constant of the doublets at 8.27 ppm and 5.54 ppm is 7.3Hz

Conclusion

A salt of TFA was produced. Heating evaporated TFA and CDCl3, hence this was experiment aborted. The Ugi product undergoes a methyl fufuryl loss after an initial boc deprotection.
Kinetics of N-boc deprotection was determined successfully.
Kinetics for the 5-methyl furfuryl cleavage has also been determined successfully.

Log


2007-03-10

15:20 : Weighed 55mg of 64C-2 in an NMR tube, added 900uL CDCl3 to the NMR tube
15:30 : To another clean NMR tube added 900uL CDCl3 and 100uL TFA, obtained HNMR
16:01 : Obtained HNMR of 64C-2 in CDCl3
16:09 : Added 100uL TFA to the NMR tube containg 64C-2 in 900uL CDCl3. This is 67A
16:11 : Obtained HNMR of 67A (t = 02min)
16:13 : Obtained HNMR of 67A (t = 04min)
16:15 : Obtained HNMR of 67A (t = 06min)
16:17 : Obtained HNMR of 67A (t = 08min)
16:19 : Obtained HNMR of 67A (t = 10min)
16:21 : Obtained HNMR of 67A (t = 12min)
16:24 : Obtained HNMR of 67A (t = 15min)
16:29 : Obtained HNMR of 67A (t = 20min)
16:32 : Obtained HNMR of 67A (t = 23min)
16:44 : Obtained HNMR of 67A (t = 35min)
17:01 : Obtained HNMR of 67A (t = 52min)
17:11 : Obtained HNMR of 67A (t = 1h 02min)
17:20 : Obtained HNMR of 67A (t = 1h 11min)
17:26 : Obtained HNMR of 67A (t = 1h 17min)
18:19 : Obtained HNMR of 67A (t = 2h 10min)
19:05 : Obtained HNMR of 67A (t = 2h 56min)
19:09 : Obtained HNMR of 67A (t = 3h 00min)
19:33 : Obtained HNMR of 67A (t = 3h 24min)
20:09 : Obtained HNMR of 67A (t = 4h 00min)
20:21 : Obtained HNMR of 67A (t = 4h 12min)
21:09 : Obtained HNMR of 67A (t = 5h 00min)
21:46 : Obtained HNMR of 67A (t = 5h 27min)

2007-03-11

(Daylight saving time-1h ahead)
12:50 : Obtained CNMR of 67A; Overnight run.
12:59 : Obtained HNMR of 67A ( 19h 50min)
14:14 : Obtained HNMR of 67A (21h 05min)

2007-03-12

13:21 : Obtained HNMR of 67A (40h 12min)

2007-03-13

18:20 : Obtained HNMR of 67A (73h 11min)
18:25 : Placed the NMR tube (uncapped) in a water bath preheated to 67C.
19:25 : Removed the NMR tube from the water bath.
19:36 : Obtained HNMR of 67A. (t = 74h 27min, 1h at 67C)
20:00 : Placed the NMR tube back in the water bath, this time refluxing it at 72C. (Reflux setup, with dryice)
20:35 : Almost all the solvent had evaporated from the NMR tube.
20:47 : Added 800uL of CDCl3 and obtained a HNMR of the changed 67A, called 67B.

2007-03-15


09:38 : Obtained HNMR of 67B

References

1.Removal of t-butoxycarbonyl protecting groups with trifluoroacetic acid. (Lundt, Johansen, Volund, Markussen) Int J Pept Protein Res. 1978 Nov;12(5):258-68

Tags

ugi054:InChI=1/C30H37N3O7/c1-20-12-14-23(39-20)19-33(26(34)18-32-29(36)40-30(2,3)4)27(22-13-15-24(37-5)25(16-22)38-6)28(35)31-17-21-10-8-7-9-11-21/h7-16,27H,17-19H2,1-6H3,(H,31,35)(H,32,36)