4 October 2016
Reagent |
Quant. |
Mol. wt. |
mmoles |
Equiv. |
1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one |
70 mg |
210.54 |
0.333 |
1 |
Benzylamine (Phenylmethylamine, 1-Phenylmethanamine) |
35.63 mg, .036 mL |
107.16 |
0.333 |
1 |
TiCl4 (1M in Chloroform) |
0.167 mL x2 |
189.68 |
0.167 |
0.5 |
NaBH3CN |
62.685 mg |
62.84 |
.998 |
3 |
Crude product |
0.10 g (theoretical) 0.020 g (actual) |
301.70 |
0.333 0.066 |
1 (theoretical) 0.2 (actual) |
Procedure
-
Combine benzylamine and starting material in 10 mL chloroform (under argon in dried flask).
-
Add titanium(IV) tetrachloride via syringe.
-
Stir rxn mixture for 18 hours. (10/4/16) Turned a cloudy pale orange color.
-
Dissolve sodium cyanoborohydride in 3 mL MeOH, and add to mixture. Stir for 15 minutes.
-
Bring rxn mixture to pH 13 with 2M KOH.
-
Extract with EtOAc (3 x 20 mL).
-
Wash with water (2 x 20 mL) and brine (2 x 20 mL).
-
Dry with magnesium sulfate.
-
Evaporate to give a yellow oil (10/6/16).
20 September 2016
Reference
Holsinger, L.J., Compounds that Inhibit Protease Cathepsins and HCV Replication. U.S. Patent 2008080785, April 30, 2009.
Data Table
Substance | Quant. | Mol. wt. | mmoles | Equiv. |
methyl 6-chloropyrazine-2-carboxylate | 0.58 g | 172.57 | 3.36 | 1 |
dimethoxy ethane | 10 mL | 90.12 | ||
trimethylsilyltrifluoro-methane | 0.70 g | 142.2 | 4.92 | 1.5 |
caesium fluoride | 0.051 | 151.9 | 3.36 | 1 |
THF | 4.0 mL | 72.11 | ||
acetic acid | 2.0 mL | 60.05 | ||
tertbutylammoniun fluoride | 0.90 g | 261.46 | 3.4 | 1 |
ethyl acetate | 50 mL | 88.11 | ||
1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one |
0.71 g (theoretical) 0.07 g (actual) |
209.98 |
3.36 (theoretical) 0.33 (actual) |
1 (theoretical) 0.1 (actual) |
- Dissolved starting material in dimethoxy ethane (10 mL).
- Added trimethylsilyltrifluoro-methane (0.70 mL) and caesium fluoride (0.051 g).
- Stirred at room temperature overnight. Solution turned a dark yellow, then brown color.
- Concentrated mixture under reduced pressure, resulting in a dark brown oil. Step 3 brown oil.jpg
- Dissolved resulting residue in THF (4.0 mL) and acetic acid (2.0 mL)
- Added tertbutylammonium fluoride (0.867 g)
- Allowed reaction to stir overnight.
- Diluted reaction with ethyl acetate (50 mL)
- Washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions).
- Washed with brine (100 mL)
- Dried over anhydrous magnesium sulfate, then filtered.
- Removed solvent under reduced pressure.
- Triturated with a 1:1 dichloromethane/hexanes solution (50 mL), causing a dark brown semi-solid to precipitate from solution. Results were not consistent with literature precedent.
- Removed solvent under reduced pressure, concentrating product back into a dark brown oil. Dark brown oil re-rotovap.jpg
- Crude product (dark brown oil) was tested via TLC.
Left = SM, Center = cospot, Right = productTLC Crude Product 3.jpg
1:1 EtOAc:Hexanes solvent system; silica gel plate; UV visualization
Rf(bottom) = 0.25, Rf(middle) = 0.42, Rf(top) = 0.50 - Purified solution using Biotage Isolera. Fractions 2, 3, 6 and 7 were shown to most likely contain the purified product. Step 3 Biotage Screen.JPG
- Fractions were analyzed using TLC, GCMS, and NMR. Analysis of the results showed that fractions 6 and 7 contained the most pure sample of product 3, 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one.
- Fractions 6 and 7 were combined and solvents removed in vacuo in preparation for step 4.
Conclusions and Next Steps
From our TLC, GCMS, and NMR data, we have concluded that we produced some of our desired product, 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one. TLC of the crude product indicated an incomplete reaction as some UV-visualizable spots characteristic of the starting material were present in the product. However, after submitting the crude product to the Biotage Isolera, it appeared that we acheived some separation upon TLC and GCMS analysis. Although Fraction 2 appeared to contain some impurity in the TLC, fractions 3, 6, and 7 appeared to be fairly pure (with 6 and 7 containing the same product). We combined fractions 6 and 7, then submitted the 3 samples to GCMS. We found the combined fractions 6 and 7 appeared to be out desired product as we observed the M+ of m/z 209.98, which is characteristic of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one. However, upon analysis by NMR, we found that our product also likely contained the more reduced version of the product, 2-(6-chloropyrazin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol. This is evidenced by by the m/z 279.9, 281.9 in GCMS, as well as the peaks at 8.07 and 5.73 ppm in the 1HNMR.
2-(6-chloropyrazin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Image courtesy of Chase Smith via Github)
In any repeat trials, shortening the reaction, running it at 0 deg. C, and/or reducing the amount of trimethylsilyltrifluoro-methane to 1 equivalent, may help to increase the yield of our desired product (advice courtesy of Chase Smith via Github).
Because we produced primarily the desired product, we continued on with step 4 in which we will perform a reductive amination in an attempt to produce N-benzyl-1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-amine. However, for future trials, it may be more effective to perform another separation using Biotage Isolera in order to achieve a more pure product.
8 September 2016
References
- Nikishkin et al. New J Chem. 2013. 37, 394.
-
Scanio, M. J. C.; Shi, L.; Bunnelle, W. H.; Anderson, D. J.; Helfrich, R. J.; Malysz, J.; Thorin-Hagene, K. K.; Handel, C. E. V.; Marsh, K. C.; Lee, C.-H.; Gopalakrishnan, M. J. Med. Chem. Journal of Medicinal Chemistry 2011, 54(21), 7678–7692.
Substance |
Quant. |
Mol. wt. |
mmol |
Equiv. |
2-(6-chloropyrazin-2(1H)-ylidene)malononitrile |
0.92 g |
178.58 |
5.15 |
1 |
MeOH |
54.2 mL |
32.04 |
||
Li2CO3 |
0.571 g |
73.891 |
7.72 |
1.5 |
magnesium monoperoxyphthalate hexahydrate (80% tech) |
1.911 g |
494.64 |
3.86 |
0.75 |
H2O |
21 mL |
|||
CHCl3 |
21 mL |
|||
Methyl 6-chloropyrazine-2-carboxylate |
0.89 g (theoretical) 0.60 g (actual) |
172.57 |
5.15 (theoretical) 3.48 (actual) |
1 |
-
Dissolved 2-(6-chloropyrazin-2(1I)-ylidene) malnonitrile (0.92 g, 5.15 mmol) in MeOH (54.2 mL).
-
Added Li2CO3 (0.571 g, 7.72 mmol) to this solution.
-
Stirred mixture for 30 min.
-
Added magnesium monoperoxyphthalate hexahydrate (1.911 g, 3.86 mmol) in small portions at 0 deg. C.
-
Allowed mixture to stir overnight in ice bath.
-
The solution was dry filtrated in vacuo, resulting in a dark yellow residue. (9/13/2016)
Step 2 yellow residue.jpg -
Residue was partitioned between H2O (21 mL) and CHCl3 (21 mL).
-
Dried organic phase over MgSO4, and filtered through a short plug of silica.
-
Removed all volatiles in vacuo.
-
Product was a pale yellow oil that crystallized upon standing (0.60 g, 3.48 mmol, 67% yield).
Product 2.jpg
This procedure was repeated on 9/15/16 with the second batch of starting material, with amounts adjusted for 0.75 grams of starting material. 0.29 g (39.9 % yield) of product was collected.
6 September 2016
References
-
Nikishkin et al. New J Chem. 2013, 37, 394.
-
P. J. J. Colbon, A. C. Foster and M. E. Giles, J. Heterocycl. Chem., 2008, 45, 1451–1456.
Data Table
Substance |
Quant. |
Mol. wt. |
mmoles |
Equiv. |
2,6-dichloropyrazine |
1.00 g |
148.98 |
6.71 |
1 |
malononitrile |
0.887 g |
66.06 |
13.42 |
2 |
NaH (in mineral oil suspension, 60% by mass) |
0.27 g (pure) 0.45 g (in oil) |
23.99771 |
||
THF |
109 mL |
72.1 |
||
HCl (1 M) |
15 mL |
36.46094 |
||
2-(6-chloropyrazin-2(1H)-ylidene)malononitrile |
1.20 g (theoretical yield) 1.14 g (95% yield according to precedent) 0.95 g (79% actual yield) |
178.58 |
6.71 (theoretical) 5.32 (actual) |
1 (theoretical) 0.79 (actual) |
Procedure
-
Malononitrile (0.887 g, 13.42 mmol, 2 equiv.), a brown crystalline solid, was dissolved in dry THF (84 mL) and placed in a system under argon.
-
NaH in mineral oil suspension (0.45 g, 60% NaH by mass) was added to the mixture in small portions, and the mixture was stirred for 30 minutes.
-
2,6-dichloropyrazine (1.00 g, 6.71 mmol, 1 equiv.) was dissolved in dry THF (25 mL). A small amount of a white solid impurity remained undissolved. The solution was added dropwise to the existing mixture under argon.
-
The resulting mixture was bright yellow. It was allowed to reflux overnight for 24 hours.
Reflux conditionsReflux conditions -
HCl (1M, 20 mL) was used to acidify the solution. The solution turned a deep red color. (9/8/2016)
Product 1 before rotovap .jpg -
The organic phase was separated and volatiles removed in vacuo.
-
The residue was partitioned between H2O (150 mL) and Et2O (150 mL) to wash away inorganic salts and excess malononitrile.
-
Et2O was removed under vacuum.
-
Product was a dark red crystalline solid (0.95 g, 5.32 mmol, 79% yield).
Product 1.jpg
- SM visualized by UV, not visualized by KMnO4 or ninhydrin
- Product not visualized by UV, KMnO4, or ninhydrin
- SM spots travelled too far up plate
Solvent system attempt #2: 1:2 EtOAc:Hex
- Same results as solvent system attempt #1
Attempted to redissolve product in methanol --> dissolved much more successfully
Solvent system attempt #4: 1:4 EtOAc:Hex
- SM visualized by UV, not visualized by KMnO4 or ninhydrin
- Product not visualized by any methods
- Shows up as yellow-orange spot near bottom of plate (at starting point)
Solvent system attempt #5: 10% methanol in EtOAc
- SM and product visualized by UV
- Potentially trace amounts of SM in product
10% methanol in EtOAc solvent system, silica gel plate, UV visualization
Left = SM, Center = cospot, Right = product
Rf(SM) = 0.763, Rf(Prod)= 0.289