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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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20th October 2016 @ 20:06

Scheme3.png

The solution from 10/6/16 contained a red liquid and an orange precipitate. Vacuum filtration was used to separate the mixture; it was poured into a Buchner funnel, and washed with ethanol. The precipitate was a flaky orange solid. The weight of the solid was 0.165 grams. From TLC, (TLC plate called orangesolid) it looked like the solid was ones single polar molecule. The eluent was 100% ethyl acetate. Lane 1 was spotted with the starting material, 6-chloropyrazinecarbonitrile, lane 2 was a co-spot, and lane 3 was spotted with the orange solid in methanol. The rf for the starting material was .70, but the orange solid did not move at all on the plate. However, the TLC does show that the starting material was completely used in the reaction, which is promising. When we tried to evaluate the product with NMR, it was not clean (see NMR trace: Foks) There was a DMSO peak at 2.48 ppm, and a large water peak at 3.33 ppm. We believe some of the upfield peaks are ethanol. There were 4 peaks in the aromatic range that all integrate to about ~1. This would make sense if the reaction did make a mixture of products (see scheme 3).

TLC was conducted for the filtrate (TLC plate: filtrate). The eluent was 2:1 ethyl acetate to hexanes. Lane 1: 6-chloropyrazinecarbonitrile, Lane 2: co-spot, Lane 3: filtrate solution. It showed us that there was a mixture of products in the filtrate, but that again, all the starting material was used up in the reaction. We hoped that once we worked-up the reaction, we could isolate a single product.

The work-up of the reaction that we based this scheme on from Folks et. al. included a continuous extraction with ether for 48 hours. Instead, we extracted the filtrate with ether three times with 20 mL. The ether solution was a dull, opaque, yellow-orange color. The volatiles were removed under pressure to leave a red oil (see picture: red_oil). Although we hoped to see one product through TLC, we saw a smudge again. We tried a variety of eluents to try to resolve the products in the oil, but none were successful. The TLC plate attached, called “after_ether,” shows 6-chloropyrazinecarbonitrile in lane 1, a co-spot in lane 2, and a red oil in lane 3. The eluent was 100% ethyl acetate.

Although we could not isolate a single product from this reaction, it would be interesting to see if we carried through the next step (2.2) in scheme 2, if the mixture of products would become product 3.2.

Foks, H. et. al. (1974) Pyrazine derivatives. III. Synthesis and tuberculostatic activity of 6-(N-methylamino)-pyrazine-2-carboxylic acid derivatives Polish journal of pharmacology and pharmacy. 26(5). 537-543.

Attached Files
red_oil.png
Scheme3.png
TLC_filtrate.png
TLC_orangesolid.png
TLC_after_ether.png
Scheme2.png
NMR_Foks.pdf