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09-06-2016, First step in synthesis of the hetero-oxadiazole, reaction of 2-6 dichloropyrazine with malononitrile, following procedure from Nikishkin et al (2013)
09-11-2016, Work up of the second attempt at step 1
09-23-2016. Step 1 redo, on 5 gram scale
09-24-2016. Work up of 09-23-2016
09-29-2016, work up and purification of [4]
09/28/2016 Step 4, on a larger scale this time. Conversion of methyl 6-chloropyrazine-2-carboxylate [3] to methyl 6-hydrazineylpyrazine-2-carboxylate [4] using hydrazine according to AEW 85-5
10/07/2016 GC mass spec characterization of rxn from [4]->[5]
10/18/16: Trial work up of reaction of 6-chloropyrazinecarbonitrile and hydrazine
10/4/16: Trial of Step 4:Product [4] to Product [5]
10/6/16: Trial Synthesis of 6-hydrazinelypyrazine-2-carbonitrile and from 6- hydrazinelypyrazine-2-carboximidhydrazide from chloropyrazinecarbonitrile
9/12/16 Step 2 in synthesis. Going from [2]->[3]
9/13/16: Work-up of product [3] and TLC plates
9/15/16: Second Synthesis of Methyl 6-chloropyrazine-2-carboxylate [product 3]
9/18/16-9/20/16: Trial Synthesis of Methyl 6-hydrazineylpyrazine-2-carboxylate (Product 4)
9/22/16: Inconclusive Trial Synthesis of Methyl 6-hydrazineylpyrazine-2-carboxylate (Product 4)
9/25/16-9/27/16: Synthesis of Product 3, methyl 6-chloropyrazine-2-carboxylate
9/27/2016 Late Night
9/29/2016 HNMR of product 4, and HNMR of product 4 after D2O exchange 01/10/2016
9/8/16-Continued Synthesis of 2-(6-chloropyrazin-2(1H)-ylidene)malononitrile
CNMR so far
HNMR so far, of all relevant compounds
The Synthetic scheme of Hetero-oxadiazole Synthesis
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22nd September 2016 @ 19:31

 

Reaction Scheme

0.843 g of product 3 from fractions 2 and 3 (from 9/15/16) was dissolved in 2 mL EtOH, and .05 mL hydrazine hydrate was added. This step is an attempt to turn product 3 into Methyl 6-hydrazineylpyrazine-2-carboxylate (Product 4), based off an experiment in Alice Williamson’s notebook (AW 85-5)

http://malaria.ourexperiment.org/triazolopyrazine_se/11581/Synthesis_of_2Chloro6hydrazinylpyrazine_AEW_855.html).

The solution was foggy with a slight yellow tint. The solution was stirred at reflux for 7 hours.

TLC was used evaluate the hydrazine reaction after the reflux period (See TLC_1st hydrazine). Lane 1: product 3, Lane 2: co spot, Lane 3: hydrazine reaction product. Eluent: ethanol. Product 3 rf is .56. In lane 3 there was one product that moved up the plate with an rf of .39, and one product stayed where it was initially spotted. We expected to have multiple products from this reaction.  There was also starting material (product 3) still present. Therefore, more hydrazine hydrate (1 mL) was added and the reaction was stirred at reflux to try to use up all the starting material. The solution turned a brighter yellow color. After 2 hours the reaction was taken off the heat and evaluated by TLC again (See TLC after excess hydrazine). Lane 1: product 3, Lane 2: Co-spot, Lane 3: Reaction after excess hydrazine. The eluent was 2 equivalents of EtOAc to 1 equivalent of Hexane. Rf product 3: .67. Rf of co-spots: .64 and .28. The spot with rf of .28 did not appear in lane 1 or lane 3.The product of the hydrazine reaction did not move up the plate (lane 3), but it does show that all of product 3 was consumed.

 

Fractions 4-10 from 9/15/16 of product 3 were pooled and passed through a plug of silica using vacuum filtration to rid product 3 of a polar impurity. The TLC plate after this step showed no impurity (See TLC after silica). The eluent was chloroform. Product 3 rf: .42. Impurity rf: 0.08. The volatiles were removed by rotary evaporation, and the resulting yellow oil was left to crystallize. After a day, the resulting yellow crystal product weighed .054g. 

Attached Files
tlc_1sthydrazine.png
TLC after silica plug
TLC after excess hydrazine
Reaction Scheme