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30th January 2018 @ 18:34

Masses and measurements:

SnAr product - 0.05g, 0.116mmol

NaOtBu - 0.0156g, 0.162mmol

Morpholine - 0.02mL, 0.139mmol

Pd2(dba)2 - 0.53mg, 0.583μmol

John Phos- 1.158mg, 5.22μmol

Toluene - 2mL


Procedure:


(SnAr product) 3-(4-bromophenethoxy)-[1,2,4]triazolo[4,3,a]pyrazine (0.05g, 0.116mmol) was dissolved in toluene (2mL) in a RBF and the base, NaOtBu, (0.0516g, 0.162mmol) was added. The ligand, John Phos (1.158mg, 5.22μmol) and the amine, morpholine (0.02mL, 0.139mmol) were added to the reaction mixture. Lastly, the palladium source, Pd2(dba)(0.53mg, 0.58μmol) was added to the RBF and the mixture was left to stir and heat to 80°C until TLC analysis showed any sign of reaction. 

TLC step 5 3 cropped 1.jpg
               
TLC step 5 3 cropped 2.jpg
                       
TLC step 5 3 cropped 3.jpg

 TLC after 1 day                     TLC after 1 week                          TLC with 100% DCM                   

The reaction mixture was seperated using 2M HCl givng an orange layer and a pale yellow layer. TLC analysis was done using the organic top layer. After 1 day TLC analysis (98% DCM, 2% methanol) still showed presence of the starting material. After 1 week TLC analysis confirmed less starting material and possibly a new product. Next the whole top organic layer wasextracted and rotary evapoaretd leaving a dark green crude product. The crude product was run on a flash column (2% methanol, 98% DCM) and TLC analysis (2% methanol, 98% DCM) confirmed the presence of a possible product in test tube 16-25. These test tubes were collected and rotary evapoarted, however H NMR analysis confirmed no presence of the desired final product. 

                             

TLC step 5 2.jpg
                       

                    TLC analysis Test tubes 21-35                

 

 
Attached Files
2nd January 2018 @ 15:20

Reaction scheme snar.jpg

Masses and measurements:

3-(4-bromophenyl)-5-chloro-[1,2,4]triazolo[4,3,a]pyrazine- 0.5627g

3,4-diflurophenylethan-1-ol - 0.370g

NaH - 0.0876g

THF - 15mL

Procedure:

3-(4-bromophenyl)-5-chloro-[1,2,4]triazolo[4,3,a]pyrazine (0.5627g, 1.82mmol) was placed in a RBF and under inert gas, THF (15mL). Still under an inert atmosphere, the 3,4-difluorophenylethan-1-ol (0.370g, 2.34mmol) and the reaction mixture was put under ice, the NaH (0.0876g, 2.19mmol) was added and left to react until TLC analysis confirmed the completion of the reaction. Before the NaH was added the reaction mixture was an orange solution and after addition of the NaH , the reaction mixture turned to a dark brown opaque mixture.

Step 4 reaction mixture.jpg

The reaction was left to react until TLC analysis (1:1 ethyl acetate & petroleum ether) confirmed complete of reaction.

TLC after 3 hours.jpg
                                  
TLC after 20 hours.jpg

Once reaction was complete 2M HCl (20mL) was added to quench reaction and the mixture was seperated and extracted using ethyl acetate (3 x 30mL). Upon seperation, the organic layer was orange and the inorganic layer was a pale yellow colour. The organic layers were kept, dried with MgSO4, filtered under vacuo and rotary evaporated to give a dark brown solid crude material (0.95g).

Filtrate.jpg
                                   
Crude product.jpg

The crude material was run on a flash column (100% ethyl acetate solvent) and TLC analysis confirmed that test tubes 13-30 contained the final product. Test tubes 13-30 were collected in a RBF and rotary evaporated to give a dark green/brown solid product of 3-(4-bromophenethoxy)-[1,2,4]triazolo[4,3,a]pyrazine(0.1318g, 16.79%).

Start of flash column.jpg
                         
Progress of flash column.jpg
                   
End of flash column.jpg

 

 

Attached Files
2nd January 2018 @ 14:46

Step 3.jpg

Masses and measurements:

3,4-difluorophenyl acetic acid - 0.9934g

LiAlH4 - 0.2386g

THF - 6.3mL

Procedure:

The 3,4-difluorophenyl acetic acid (0.9934g, 5.78mmol) was added to a RBF and was dissolved in THF (6.3mL). The reaction mixture was further stirred whilst the LiAlH4 (0.2386g, 6.29mmol) was added and the reaction mixture was stirred under reflux for 2-3 hours or until TLC analysis (1:1 ethyl acetate & petroleum ether) confirmed the completion of the reaction. Around 20mins after all reagents were added, the mixture turned a deep red and soon after turned to a pale yellow solution.

reaction of alcohol.jpg
                                          
alcohol synthesis.jpg

Once the reaction was complete, the reaction mixture was left to cooland quenched with 25% NaOH (10mL) and the product was seperated and extracted using 2M HCl (20mL) and ethyl acetate (20mL). Seperation of the reaction mixture gave 2 colourless solution layers. The aqueous layers were re-extracted using diethyl ether (20mL) - it was learnt in the research we underook that the alcohol product is very volatile so diethyl ether was used as it has a lower volatilty to match that of the final product. The organic layers were collected, dried using MgSO4 and filtered under vacuo. The filtrate was rotary evporated with a small amount of solvent present still. The product given was a pale yellow oily solution (0.729g, 79.85%).

Attached Files