Objective

To synthesize 4 Ugi products following the EXPLAN005 . The compound will contribute towards a library for falcipain-2 inhibitors. These compounds were ranked 1,3,6, and 8 in the DEXP014-V2B file from D-EXP014.

Procedure

As described in Explan005
Four Ugi reactions were carried out in vials labeled Exp147-1, Exp 147-2, Exp 147-3, and Exp 147-4. To the first dram vial (147-1) was added methanol (250 ul), 4,7-dimethoxy, 1-naphthaldehyde (0.25mmol, 54.1mg), methylamine(in 2M methanolic solution, yielding 125 ul for 0.25mmol), 2,3-dihydroxybenzoic acid(0.25mmol, 38.5mg), and tosylmethyl isocyanide (0.25mmol, 38.8mg), in that order. To the second vial (147-2) was added methanol (250 ul), phenanthrene-9-carboxaldehyde (0.25mmol, 51.6mg), methylamine(in 2M methanolic solution, yielding 125 ul for 0.25mmol), 2,4,6 trihydroxybenzoic acid (0.25mmol, 47.0mg), and tosylmethyl isocyanide (0.25mmol, 38.8mg), in that order. To the third vial (147-3) was added methanol (250 ul), 2-naphthaldehyde(0.25 mmol, 39.0 mg), methylamine(in 2M methanolic solution, yielding 125 ul for 0.25mmol),1-pyrenebutyric acid (0.25 mmol, 72.1), and t-butyl isocyanide (0.25 mmol, 28.3 ul), in that order. To the fourth vial (147-4) was added methanol (250 ul), 3,5 dimethoxy benzaldehyde (0.25 mmol, 41.5 mg), methylamine(in 2M methanolic solution, yielding 125 ul for 0.25mmol), 2,4,6 trihydroxybenzoic acid (0.25mmol, 47.0mg), and tosylmethyl isocyanide (0.25mmol, 38.8mg), in that oder. After each addition, the solution was vortexed for 15 or 30 seconds and made sure a homogeneous solution was obtained. The formation or absence of precipitate was noted. The dram vials were left at room temperature.
Comp ID/ Lib Rank
Aldehyde
Amine
Carboxylic Acid
Isocyanide
Ppt Yes/No
147-1/1
4,7-dimethoxy, 1-naphthaldehyde (0.25 mmol, 54.1 mg)
Methylamine (0.25mmol, 12.2 uL)
[Methylamine in form of 2M methanolic solution, 0.25 mmol equivalent to 125 ul]
2,3 dihydroxybenzoic acid (0.25mmol, 38.5 mg)
Tosylmethyl isocyanide (0.25mmol, 38.8 mg)
No
147-2/3
Phenanthrene-9-carboxaldehyde(0.25mmol, 51.6mg)
Methylamine (0.25mmol, 12.2 uL)
[Methylamine in form of 2M methanolic solution, 0.25 mmol equivalent to 125 ul]
2,4,6 trihydroxybenzoic acid (0.25 mmol, 47.0 mg)
Tosylmethyl isocyanide (0.25mmol, 38.8mg)
not enough proof


147-3/6
2-naphthaldehyde(0.25mmol, 39.0mg)
Methylamine (0.25mmol, 12.2 uL)
[Methylamine in form of 2M methanolic solution, 0.25 mmol equivalent to 125 ul]
1-pyrenebutyric acid (0.25mmol, 72.1 mg)
t-butyl isocyanide (0.25mmol, 28.3uL)
No
147-4/8
3,5 dimethoxy benzaldehyde (0.25 mmol, 41.5 mg)
Methylamine (0.25mmol, 12.2 uL)
[Methylamine in form of 2M methanolic solution, 0.25 mmol equivalent to 125 ul]
2,4,6 trihydroxybenzoic acid (0.25 mmol, 47.0 mg)
Tosylmethyl isocyanide (0.25mmol, 38.8mg)
not enough proof


Results

All results are recorded in the master table of all ugi synthesis attempts
Link to NMRs of starting materials
Exp 147-2 (10.2mg in 800uL CdCl3)
HNMR (post in JCAMP format)

Exp 147-4 (21.2mg in 800uL CdCl3)
HNMR (post in JCAMP format)

Photo of 147-1-A taken at 17:03 immediately after adding all components:
vial_before.jpg


Photo of 147-1-B taken at 13:00 the following day,approximately 20 hours following addition of all components:
vial_after.jpg

Photo of 147-2-A, 147-3-A, and 147-4-A taken at 12:18 immediately after addition of all components:

co.jpg


Photo of 147-2-B, 147-3-B, and 147-4-B taken at 15:00, 6 days following the addition of components:
co1.jpg


Discussion

For Exp 147-2, the peak near 4 indicates an aldehyde functionality, indicating unreacted aldehyde. The peak between 2 and 3 ppm indicates an acid or amine functionality, indicating that there may be unreacted acid or amine in the sample. It appears the same problem of unreacted material is in Exp147-4. For Exp 147-4, the multiplet near 4 ppm indicates an aldehyde functionality. This means there may be a significant amount of unreacted aldehyde in the sample. The peak between 2 and 3 ppm indicates an acid or amine functionality, indicating that there may be unreacted acid or amine in the sample. The problem with Exp 147-2 is that the solid precipitate was having trouble separating from the methanol, indicating the presence of starting materials. So, it is difficult to say now whether this indeed formed precipitate in the first place. For Exp 147-4, the solid sample was able to separate from methanol, but had dissolution problems with the CdCl3. An accurate HNMR is unlikely if there are dissolution problems in the NMR tube.

Conclusion

The recommendation is for samples 147-2 and 147-4 to be re-prepared in another experiment and subsequently analyzed by HNMR.

Log


Exp 147-1

2007-11-19

16:44: Weighed out 2,3-dihydroxybenzoic acid, tosylmethyl isocyanide, and 4,7-dimethoxy,1-naphthaldehyde on weighing paper
16:50: Added methanol (250uL) into the dram vial, followed by 30 seconds vortexing.
16:52: Added aldehyde into the dram vials, followed by 15 seconds vortexing.
16:54: Added amine into the dram vials, followed by 30 seconds vortexing.
16:57: Added acid into the dram vials followed by 15 seconds vortexing
17:02: Added isocyanide into dram vials followed by 15 seconds vortexing
17:03: Took photo of 147-1-A
17:03: Vials were kept in hood overnight

2007-11-20

11:10: Vial were looked at and determined to have no precipitate
13:00: Took photo of 147-1-B
there are no pics after 11/20 for vial 1 -why?


Exp 147-2

2007-11-20

11:43: Weighed out phenanthrene-9-carboxaldehyde, 2,4,6 trihydroxbenzoic acid, and tosylmethyl isocyanide on weighing paper
11:45: Added methanol (250uL) into the dram vials, followed by 30 seconds vortexing.
11:47: Added aldehyde into the dram vials, followed by 15 seconds vortexing.
11:48: Added amine into the dram vials, followed by 30 seconds vortexing.
11:49: Added acid into the dram vials followed by 15 seconds vortexing
11:51: Added isocyanide into dram vials followed by 15 seconds vortexing
11:52: Vials were kept in hood overnight
12:18: Took photo of 147-2-A


2007-11-26

15:00: Vial was looked at and determined to have precipitate
15:00: Took photo of 147-2-B

Exp 147-3

2007-11-20

11:54: Weighed out 2-naphthaldehyde and t-pyrenebutyric acid on weighing paper
11:55: Added methanol (250uL) into the dram vials, followed by 30 seconds vortexing.
11:57: Added aldehyde into the dram vials, followed by 15 seconds vortexing.
11:59: Added amine into the dram vials, followed by 30 seconds vortexing.
12:00: Added acid into the dram vials followed by 15 seconds vortexing
12:02: Added isocyanide into dram vials followed by 15 seconds vortexing
12:03: Vials were kept in hood overnight
12:18: Took photo of 147-3-A


2007-11-26

15:00: Vial was looked at and determined to have no precipitate
15:00: Took photo of 147-3-B

Exp 147-4

2007-11-20

12:06: Weighed out 3,5 dimethoxy benzaldehyde, 2,4,6 trihydroxybenzoic acid, and tosylmethyl isocyanide on weighing paper
12:08: Added methanol (250uL) into the dram vials, followed by 30 seconds vortexing.
12:10: Added aldehyde into the dram vials, followed by 15 seconds vortexing.
12:12: Added amine into the dram vials, followed by 30 seconds vortexing.
12:14: Added acid into the dram vials followed by 15 seconds vortexing
12:16: Added isocyanide into dram vials followed by 15 seconds vortexing
12:18: Took photo of 147-4-A
12:18: Vials were kept in hood overnight


2007-11-26

15:00: Vial was looked at and determined to have precipitate
15:00: Took photo of 147-4-B

2007-12-07

14:25: Added methanol (500uL) to vials 147-2 and 147-4 (does this mean that the samples were dry? It would have been key to take a pic here to prove that no solvent evaporated since the last pic)
14:30: Centrifuged vials for 5 minutes (you centrifuged without decanting the supernatant?) next time follow the protocol of washing twice with methanol with vortexing
14:45: Placed vials (with methanol?) in dessicator (under high vac?) to dry overnight and remove undissolved materials

2007-12-08

15:10: Weighed vials with samples
15:30: Added 4 portions of CdCl3(200uL) to each vial
15:40: Placed contents of each vial into NMR tubes (sample + 800uL CdCl3)
15:50: Re-weighed empty vials to determine weight of product
16:10: Received HNMR of each sample


It is really hard to see precipitate or absence of precipitate from these pics - take pics again so that the solvent line and presence of ppt is much clearer (see for example **//http://usefulchem.wikispaces.com/Exp148//** )
And if there is a precipitate centrifuge, wash and get a weight and NMR + MS


Tags

phenanthrene-9-carboxaldehyde InChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13%2811%2915-8-4-3-7-14%2812%2915/h1-10H
4,7-dimethoxy, 1-naphthaldehyde InChI=1/C13H12O3/c1-15-10-4-5-11-12(7-10)9(8-14)3-6-13(11)16-2/h3-8H,1-2H3
methylamine InChI=1/CH5N/c1-2/h2H2,1H3
tosylmethyl isocynaide InChI=1/C9H9NO2S/c1-8-3-5-9(6-4-8)13(11,12)7-10-2/h3-6H,7H2,1H3
2,3 dihydroxybenzoic acid InChI=1/C7H6O4/c8-5-3-1-2-4(6(5)9)7(10)11/h1-3,8-9H,(H,10,11)/f/h10H
2-naphthaldehyde InChI=1/C11H8O/c12-8-9-5-6-10-3-1-2-4-11(10)7-9/h1-8H
1-pyrenebutyric acid InChI=1/C20H16O2/c21-18(22)6-2-3-13-7-8-16-10-9-14-4-1-5-15-11-12-17(13)20(16)19(14)15/h1,4-5,7-12H,2-3,6H2,(H,21,22)/f/h21H
t-butyl isocyanide InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
2,4,6 trihydroxybenzoic acid InChI=1/C7H6O5/c8-3-1-4(9)6(7(11)12)5(10)2-3/h1-2,8-10H,(H,11,12)/f/h11H
3,5 dimethoxybenzaldehyde InChI=1/C9H10O3/c1-11-8-3-7(6-10)4-9(5-8)12-2/h3-6H,1-2H3