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26th October 2016 @ 21:18

Repeat of Fourth step in synthesis, first attempt: synthesis of 3-(4-(difluoromethoxy)phenyl)-5-(phenylethynyl)-[1,2,4]triazolo[4,3-a]pyrazine, in attempt of final step in the synthesis of the "internal alkyne".

Reaction Scheme:



This reaction was run in the microwave for two hours at 110 C under standard conditions. The reagents were as follows:

10% Pd/C (89 mg, 0.084 mmol, 0.01 eq), XPhos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 40 mg, 0.084 mmol, 0.01 eq), and K2CO(1.76 g, 12.7 mmol, 1.5 eq) all dissolved in DMSO. Product from Third step in synthesis, second attempt: Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine was added (2.5 g, 8.4 mmol, 1 eq, dissolved in DMSO) along with phenyl acetylene (1.4 mL, 12.7 mmol, 1.5 eq). This reaction was stirred in the microwave under the previously indicated conditions. 

After the reaction mixture was removed from the microwave, a few drops of the crude reaction mixture were worked up with ~1 mL each of water and EtOAc, yielding the following TLC:

TLC (glass/silica, 1:1 EtOAc/hexanes, UV):

IMG_0115.JPG

(picture taken two days after initial run, but immediately after the run the spot that appeared in the product lane was brighter blue, the same color as in the TLC from Fourth step in synthesis, first attempt: synthesis of 3-(4-(difluoromethoxy)phenyl)-5-(phenylethynyl)-[1,2,4]triazolo[4,3-a]pyrazine.)

The Pd/C in the rest of the reaction mixture was filtered through Celite and the mixture worked up with EtOAc. TLC of this mixture showed a bright blue spot on top of the starting material spot. Further analysis of this mixture will be carried out in the near future. 

Attached Files
16th October 2016 @ 01:56

Reaction scheme drawn from "Efficient Copper-Free Sonogashira Coupling of Aryl Chlorides with Palladium on Charcoal" (Komáromi et al.), as the first attempt in the final step of synthesis of the "internal alkyne". 

Reaction scheme:

A dry 10 mL round-bottomed flask was charged with 10 % Pd/C ( 5 mg, 0.005 mmol), XPhos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2.4 mg, 0.005 mmol) and K2CO3 (97 mg, 0.75 mmol). The rb flask was purged with argon and DMSO was added (1 mL). Product from Third step in synthesis, second attempt: Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine was added (148 mg, 0.5 mmol) along with phenylacetylene (76.6 mg, 0.75 mmol). The reaction mixture was stirred while in a 110 C oil bath for 2 hours. 

Filtration of the Pd/C through Celite was attempted, but unsuccessful. The reaction mixture was extracted with EtOAc and the resulting organic layers were collected and the solvent removed under reduced pressure. TLC of the crude mixture indicates the presence of a bright blue, potential product spot. Discussion with other groups working to synthesize the same alkyne intermediate has shown that this bright blue TLC spot is consistent in this step of the process.

(TLC on silica/glass, 1:1 EtOAc:hexanes, UV light)

IMG_0075.JPG

This reaction will be scaled up and re-attemped in the future.

 

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Attached Files
15th October 2016 @ 21:32

Repeat of Third step in synthesis, first attempt: Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine in preparation for synthesis of "internal alkyl".


Reaction Scheme:

Product from Second step in synthesis, fourth attempt: Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine (3.5 g, 11.72 mmol, 1 eq) was dissolved in CH2Cl2. PhI(OAc)2 (3.8 g, 11.72 mmol, 1 eq) was added and the resulting solution was stirred at room temperature for 

The reaction was stopped upon confirmation of completion via TLC and the organic layer washed with 10% NaHCO3 solution. The inorganic layer was extracted with CH2Cl2 (3 x 120 mL). The combined organic layers were dried over MgSO4, filtered and the solvent removed by rotary evaporation before the crude product was dried in vacuo (3.53 g, 101.4% crude yield). 

This product was purified via column chromatography using a solvent gradient, starting with equal parts hexanes and EtOAc and increasing concentration of EtOAc. The product fractions (confirmed with TLC) were combined and the solvent removed under reduced pressure, and yielding a red-brown solid (2.71 g, 79% yield).

TLC (silica/glass, 50% EtOAc/hexanes, UV) showed a product spot at Rf=0.214. 

Crude product:

1H NMR (500 MHz, CDCl3):

1H NMR confirms presence of product with comparison of peaks to those in the pure product NMR in the previous synthesis 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (JU 19-1).

 

Rxn3Impure.pdf


Puified product:

1H NMR (500 MHz, CDCl3):

4th3rdproton.pdf

13C NMR (500 MHz, CDCl3):

4th3rdCNMR.pdf
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Attached Files
15th October 2016 @ 21:18

Repeat of Second step in synthesis, third attempt: Synthesis of 5-chloro-3-(4-(difluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyrazineSecond step in synthesis, second attempt: Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazineSecond step in synthesis, first attempt: Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine in preparation for synthesis of the "internal alkyne". 

Reaction Scheme:

 

Product from First step in synthesis, fourth attempt: Synthesis of 2-chloro-6-hydrazinylpyrazine (1.9 g, 13.14 mmol) was dissolved in EtOH (100% solution, 50 mL). 4-(difluoromethoxy)benzaldehyde (1.73 mL, 13.14 mmol) was added and the mixture was stirred at room temperature for ~30 min. The solvent was removed under reduced pressue, yielding a light yellow/brown solid (3.82 g, 97.6 crude yield).

Data:

The reaction was monitored by TLC (silica/glass, 50% EtOAc/hexanes, UV light) and after 20 min TLC showed a single product spot with Rf=0.67.

NMR:

1H NMR (500 MHz, CDCl3):

4th2ndproton.pdf

13C NMR (500 MHz, CDCl3):

4th2ndCNMR.pdf


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15th October 2016 @ 21:06

Repeat of Second step in synthesis, first attempt: Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazineSecond step in synthesis, second attempt: Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine in preparation for synthesis of "internal alkyne".

 Reaction Scheme:

Product from First step in synthesis, third attempt: Synthesis of 2-chloro-6-hydrazinylpyrazine(3.16 g crude (2.43 g ideal), 16.8 mmol ideal, 1 eq) was dissolved in 100% EtOH. 4-(difluoromethoxy)benzaldehyde (2.2 mL, 16.8 mmol) was added and the mixture was stirred at room temperature for ~30 min. TLC after 20 min in good agreement with completed reaction TLC from Synthesis of 2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazinyl)pyrazine (JU 18-1), so reaction said to be complete (shown in Data below). The solvent was removed under reduced pressue, yielding a light yellow/brown solid. Most of the product was spilled, and 0.321 g were recovered. NMR was not performed on this product because another line of reactions was begun due to the spill.


Data:

TLC (silica/glass, 50% EtOAc/hexanes, UV light) after 20 min: After workup, single product spot, Rf= 0.72.

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