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17th February 2014 @ 03:50

A repeat of Synthesis of methyl 6-chloro-2-pyrazinecarboxylate (IT 3-1), using the product from Synthesis of methyl 4-oxy-2-pyrazine carboxylate (TM 4-1). Final product was an intractable brown oil: See Resynthesis of methyl 6-chloro-2-pyrazinecarboxylate (TM 5-2) for a successful synthesis.

 

TM 5-1

PROCESS:

23.8 g of the product of TM 4-1 (Synthesis of methyl 4-oxy-2-pyrazine carboxylate (TM 4-1)), determined by NMR to consist of a 1:1.3 mixture of the oxide to m-chlorobenzoic acid (67 mmol N-oxide, 1 eq), was dissolved in thionyl chloride (80 mL) and refluxed for ~24 h. The product was obtained as a dark orange liquid, from which thionyl chloride was removed under vacuum (care needed, thionyl chloride then quenched by slow addition to ice water). Crude TM 5-1, along with m-chlorobenzoyl chloride remaining from TM 4-1, obtained as a brown oil. The crude product was washed with saturated sodium bicarbonate solution until neutral, then extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulphate, then concentrated under vacuum to give a brown oil.

Crude NMR (1H, CDCl3, 200 MHz):

TM 5-1 200 MHz CDCl3.pdf

TM 5-1 crudeliq.zip

The crude was purified by chromatography, eluted by petroleum ether. (?).

1st fraction, as a clear liquid (1H, CDCl3, 200 MHz):

5-1 frac 1st 200 MHz CDCl3.pdf

TM 5-1 frac 1st.zip

Second fraction, as a darker liquid (1H, CDCl3, 200 MHz):

5-1 frac 9-27 CDCl3 200 MHz.pdf

TM 5-1 frac 9-27.zip

The first fraction appears to be m-chlorobenzoyl chloride or m-chlorobenzoic anhydride. The literature appears not to contain a spectrum of the anhydride, and I could not find a good spectrum of acid chloride. Here is one: http://sdbs.db.aist.go.jp/sdbs/cgi-bin/cre_frame_disp.cgi?spectrum_type=hnmr&sdbsno=4282
It does seem surprising that an acid chloride (or even anhydride) could survive the aqueous bicarbonate washes used in workup.

 

The second fraction contains some m-chlorobenzoic impurities, but is largely the desired chloropyrazine.

HIRAC:

HIRAC.pdf

Linked Posts
Attached Files
scheme.png
HIRAC.pdf
TM 5-1 200 MHz CDCl3.pdf
5-1 frac 1st 200 MHz CDCl3.pdf
5-1 frac 9-27 CDCl3 200 MHz.pdf
TM 5-1 frac 9-27.zip
TM 5-1 crudeliq.zip
TM 5-1 frac 1st.zip
Comments
Re: Synthesis of methyl 6-chloro-2-pyrazinecarboxylate (TM 5-1) by Alice Williamson
17th February 2014 @ 04:12
HIRAC seen and approved - also discussed the use of a blast shield for the duration of reaction.