Author Archives: Aron Schwartz

Ring Closing at 35˚C (HASJK-2-11)

3/28/2017

Reference: http://malaria.ourexperiment.org/triazolopyrazine_se/14086/Synthesis_of_5chloro34difluoromethoxyphenyl124triazolo43apyrazine_AEW_2056.html

Scheme

Smiles: ClC1=C(C)N=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

 (Scheme is not showing up in ELN. See attachment)

3/28/17-Ring Closing Take #2

The reaction is going be run with more PhI(OAc)2

Reagent

mass (g)

mols

Molecular Weight (g/mol)

Volume (mL)

Density (g/mL)

Product Dimethyl Benzaldehyde Rxn

0.2

0.00064

312.70

   

CH2Cl2

8.48

0.101

84.930

~7.0

1.325

PhI(OAc)2

0.4123

0.00128

322.10

   

Product Dimethyl PhI(OAc)2 Rxn

   

310.060

   
Reaction began at 9:15am. The solid reagent was yellow. The reagent dissolved easily into  DMC and the solution turned a translucent yellow. When PhI(OAc)2 was added there was no change to the solution.

3/30/2017

  1. Reaction was stopped at 8:30 on 3/30/17. The solution was translucent yellow and had viscosity similar to water.

  2. Added saturate aqueous solution of sodium hydrogen carbonate (10 mL)

  3. White solid formed in the aqueous layer.

  4. Drained organic layer

  5. Washed aqueous layers with 10 mL DCM twice times.

  6. Combined the organic layers, washed with 10 mL of saturated aqueous sodium hydrogen carbonate two times,

       7. Organic layer was then dried in sodium sulfate.

4/1/17

     9. Sodium sulfate was gravity filtered. The organic layer was yellow

    10. Organic layer was then rotovapped to afford a yellow oil that quickly became crystalline.

 

Open= Opened Ring

Phi = PhI(OAc)2

Co= co Spot

Closed= Closed ring product.

Silica gel plate

50/50 hexane to ethanol


Room Temperature Ring Closing (HASJK-2-10)

Reaction was run on 2/17/2017.

Reference

Scheme

Smiles: ClC1=C(C)N=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21

 (Scheme is not showing up in ELN. See attachment)

Table of Reagents (Ring-closing)

         

Reagent

mass (g)

mols

Molecular Weight (g/mol)

Volume (mL)

Density (g/mL)

Product Dimethyl Benzaldehyde Rxn

0.2

0.00064

312.70

   

CH2Cl2

8.48

0.101

84.930

~6.4

1.325

PhI(OAc)2

0.2237

0.00069

322.10

   

Product Dimethyl PhI(OAc)2 Rxn

   

310.060

   

The product from the last step (0.2g, .64 mmol), (E)-2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazineyl)-3,5- monomethylpyrazine, was combined with CH2Cl2 (6.4 ml) while stirring in a round bottom flask at room temperature.  PhI(OAc)2 (.221g, .32mmol, 0.5eqv) was then added under argon gas. Solution was left to stir overnight. At the beginning of stirring, the solution was a pale yellow color. Began stirring at 9:15am.

2/21/17- Ring Closing of the MonoMethyl work up

Stirring was turned off after 119 hours. Reaction progress was checked to assess completion. Silica gel plate. 50/50 etoac/hexane, UV active. See TLC

Silica Gel Plate

S=starting material

Phi= Phi(OAc)2

Closed=closed ring product

Co= CoSpot

Active under UV light. 



Addition of 4-(difluoromethoxy) benzaldehyde (HASJK-2-9)

Reaction run on 1/26/17



4-(difluoromethoxy) benzaldehyde (1.5mL) was added to the 2-chloro-6-hydrazineyl-3,5-dimethylpyrazine (0.8g) produced in the last reaction. Ethanol (20mL) was also added with vigorous stirring. The product will be left to stir under an argon atmosphere overnight and TLC will be used to monitor the completeness of the reaction.


Table of Reagents (Addition of DifluoromethoxyBenzaldehyde)

     

Reagent

mass (g)

mols

Molecular Weight (g/mol)

Volume (mL)

Density (g/mL)

Product Monomethyl after Hydrazine Rxn

0.4000

0.0025

158.59

   

Difluoromethoxy benzaldehyde

1.9530

0.0075

172.1300

1.0

1.3020

Ethanol

11.08

0.3427

46.0690

15.0

0.7893

Product Dimethyl Benzaldehyde Rxn

0.2000

0.00064

312.70

   
   

Percent Yield

 

Actual Yield: 1

0.2

26%

*When I first weighed this product after the reaction the yield was 127%. The mass must have come from the solvent.

     

 

 

 

 
Attachments Below: 
1. Silica gel plate, 50/50 etoac/hexane, UV active.
2. NMR attached
 

Step Four: Synthesis of (E)-2-chloro-6-(2-(4-(difluoromethoxy)benzylidene)hydrazineyl)-3,5-dimethylpyrazine

Reaction run on 12/8/16

CC1=NC(C)=C(N=C1Cl)N/N=C/C2=CC=C(OC(F)F)C=C2

Procedure:

4-(difluoromethoxy) benzaldehyde (1.5mL) was added to the 2-chloro-6-hydrazineyl-3,5-dimethylpyrazine (0.8g) produced in the last reaction. Ethanol (20mL) was also added with vigorous stirring. The product will be left to stir under an argon atmosphere overnight and TLC will be used to monitor the completeness of the reaction.



Third Step: Synthesis of 2-chloro-6-hydrazineyl-3,5-dimethylpyrazine (HASJK-3-3)

Reaction taken place on 12/5

CC1=NC(C)=C(N=C1Cl)NN

Procedure:

2,6 dichloro-3,5 dimethylpyrazine (0.6g), ethanol (6mL) and hydrazine (0.15 mL) were combined in a round bottom flask and stirred under argon atmosphere. It was then heated in an 80oC oil bath overnight. After, the solvent will be removed under vacuum. Yellow/gold crystals (0.8g) resulted NMR shown below.

 


Second Step: Synthesis of 2,6-dichloro-3,5-dimethylpyrazine Column Chromatography (HASJK-3-2)

Columned on 11/28/16

The product was columned by the Biotage. The fractions 5-7 (high spots) were combined. The product was a white crystal. Fractions 19-30 were also combined (low spot). NMR was run on the high spot. Initial look suggests that the chlorinated dimethyl product was synthesized with traces of starting material. Ran NMR/GCMS on both high and low spots, shown below.

 

Silica gel plates. 50/50 EtoAc/Hexane. Active under UV light.


Second Step: Synthesis of 2,6-dichloro-3,5-dimethylpyrazine (HASJK-3-1)

Date of Reaction: 11/23

CC1=NC(C)=C(N=C1Cl)Cl

 

Procedure:

Excess phosphoryl chloride (5.0mL, 0.0535 mol) was added to the oxidized dimethyl product (1.2g, 0.008 mol). The mixture was stirred and refluxed for 1.5 hours at 70oC. The reaction mixture was then alkalized using 20% NaOH. An extraction was carried out with CHCl3 (3 x 20 mL). Next steps will be to run a column chromatography on that product and then to get NMR data.

 

Table of Reagents (Rxn2) DiMethyl

 
 
 
 
 

Reagent

mass (g)

mols

Molecular Weight (g/mol)

Volume (mL)

Density (g/mL)

Product RxN1

1.200

0.008

158.590

 
 

Phosphoryl Chloride

3.481

0.023

153.333

2.122

1.640

Product RxN2 Dimethyl

1.347

0.008

178.040

 
 
 
 
 
 

*Used 5 mL of POCl3

 

Attached are TLCs 

First Step Synthesis of 2-chloro-3,5-dimethylpyrazine 1-oxide. (HASJK-3-0)

CC1=NC(C)=C(Cl)[N+]([O-])=C1

ImageIMG_9860.JPG

SM/P 

2-chloro-3,5-dimethylpyrazine 

sulfuric acid, conc. 

potassium persulfate 

2-chloro-3,5-dimethylpyrazine 1-oxide 

mw 

142.59 

  

270.31 

158.59 

Equiv 

1.00 

  

1.07 

1.00 

mmol 

14.00 

  

15.00 

14.00 

mg 

2000 

  

4000 

2220 

mL 

  

14.00 

  

  

11/8/2016.  To a 1-neck 14/20 50 mL RB were added 14 mL of concentrated H2SO4, which was cooled to approximately 0 C with ice bath.  The pyrazine was then added, followed by potassium persulfate.  The resulting suspension was allowed to stir with warming to room temperature overnight. 

11/9/16.  The resulting clear solution was poured into a separatory funnel with distilled water and ice and extracted 3 x ~ 90 mL CHCl3.  The combined organic layer was washed with saturated aqueous NaHCO3, water, and brine and dried over MgSO4

11/13/16.  The resulting clear, colorless solution was concentrated with rotary evaporation to afford 2.5 g of a clear, colorless liquid from which a colorless solid formed upon cooling. 

11/14/16.  The Round bottom flask was placed under high vacuum for approximately 1-1.5 hours to afford 1.9 g of a colorless crystalline solid after removal of high vacuum volatiles.  

Crude yield 1900/2200 x 100 = 86%