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27th February 2014 @ 22:42

Modified procedure using 2-MeTHF as solvent and Chloramine-T as oxidant.

According to literature procedure DOI: 10.1002/anie.201001999

Github Tag: Issue #

Procedure:

AEW 95-2 (100 mg, 0.39 mmol, 1 equiv.), Chloramine-T (132 mg, 0.47 mmol, 1.2 equiv.) and 2-methyltetrahydrofuran (1.1 mL) were combined in a flask and the reaction mixture was heated to 60 ˚C for 1.5 hours. TLC showed SM.

Data:

AEW 125-1 (50% EtOAc in Hexane) UV.jpg

Hazard and Risk Assessment:

InChi:

InChI=1S/C12H8ClN5/c13-11-7-15-8-12(17-11)18-16-6-10-3-1-9(5-14)2-4-10/h1-4,6-8H,(H,17,18)/b16-6-

to 

InChI=1S/C12H6ClN5/c13-10-6-15-7-11-16-17-12(18(10)11)9-3-1-8(5-14)2-4-9/h1-4,6-7H


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27th February 2014 @ 22:10

Attempted New Synthetic Route to Series 4 Amides

To a well stirred solution of 6-chloropyrazine-2-carboxylic acid (200 mg, 1.26 mmol) in ethanol (1.8 mL) was added hydrazine hydrate (61 microL, 1.26 mmol) and the resulting mixture was heated at 80 ºC for 2 hours. TLC was inconclusive, so worked up reaction by evaporating volatiles and drying in vacuo. NMR in CDCl3 showed no product (solubility issues) NMR in DMSO showed starting material. Reaction will be attempted again but with longer reaction time.

Data:


Hazard and Risk Assessment:

InChi:

InChI=1S/C5H3ClN2O2/c6-4-2-7-1-3(8-4)5(9)10/h1-2H,(H,9,10)

to

InChI=1S/C5H6N4O2/c6-9-4-2-7-1-3(8-4)5(10)11/h1-2H,6H2,(H,8,9)(H,10,11)

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27th February 2014 @ 20:48

A three necked round bottomed flask was fitted with a reflux condenser and two stoppers. The hydrazone product (EO 11-1), 0.1547 g was added to the flask. Potassium carbonate (0.2209 g) was also added and the flask was flushed woth nitroge. Toluene (1.238 ml) and product from EO 9-1 (0.25 g) wewre added, followed by Pd(dppf)CL2.CH2Cl2 (0.0040 g). The flask was flushed again with nitrogen amd the reaction mixture was heated to 100oc for 2.5 houirs. The reaction misture was then cooled to room temperature at which point water (0.572 ml) was added to solubulise the inorganic by products. The mixture was stirred at room temperature for 15 minutes and then filtered through a filter funne. The resulting wetcake was rinsed with tolune (3 x 0.286 ml). ir drying afforeded the coupled product

27th February 2014 @ 06:39

scheme

Pyrazine carboxylic acid (15.16 g, 122 mmol) was placed in methanol (130 mL, excess), and H2SO4 (~1 mL, catalytic) added. The solution was refluxed for ~24 h, until very little starting product was observed by TLC. The methanol was removed under vacuum, giving crude TM 2-2 as pale brown chunks. Yield: 16.9 g, 122 mmol, 100 % (but likely still containing some carboxylic acid)

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27th February 2014 @ 06:33

scheme

Resynthesis of Synthesis of methyl 4-oxy-2-pyrazine carboxylate (TM 4-1). 16.9 g (122 mmol) of crude TM 2-2 suspended in DCE (160 mL), and mCPBA (144 mmol, 1.5 eq, 29.3 g at 85% purity) added. Solution refluxed for ~72 h (far too long, but it was the weekend). A lump of dark brown polymer-looking gunk was present after the reaction was completed.

The reaction mixture was diluted with DCM (~400 mL), solids filtered out and discarded, and the filtrate dried over anhydrous potassium carbonate. The resulting yellow solution was concentrated under vacuum to give a yellow solid, which was suspended in petroleum ether, filtered, and washed with more pet. ether. After drying under vacuum, yield was 32.7 g: once again, there appeared to be lots of m-chlorobenzoic acid present.

NMR:

Crude product, 1H, CDCl3, 200 MHz:

TM 4-2 crude 1H CDCl3 200 MHz aromatic.pdf

TM 4-2 crude 1H CDCl3 200 MHz whole.pdf

Reference spectrum for m-chlorobenzoic acid (remaining from the m-CPBA oxidation):

TM 2-2 workup CHLOROBENZOIC ACID 1H CDCl3 200 MHz.pdf

It can be seen that that crude mixture contains the N-oxide and the benzoic acid in a ~1:1.7 molar ratio, with around 85% conversion of the pyrazine to the pyrazine N-oxide. The crude mixture was carried on to the next stage, with the intention of completing the synthesis then separationg the final product by column chromatography.

 

HIRAC: see TM 4-1.

HIRAC.pdf
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