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7th March 2014 @ 01:55

This reaction is a model reaction for the ether linkage in the ether linked triazolopyrazine series. See blog post here (based on reaction from ref 4).

Literature reference: 10.1021/jo901707x

Reaction Scheme



Procedure

Started 12pm


Phenethyl alcohol (0.1 mL, 100 mg, 0.8 mmol, 1 equiv) was added to 1.6 mL toluene along with 2,6-dichloropyrazine (139 mg, 0.93 mmol, ~1.1 equiv), potassium hydroxide (170 mg, 3 mmol, 3.7 equiv) and 18-crown-6 (10 mg, 0.04 mmol, 0.05 equiv). The mixture was heated at reflux for 3.5 h (bath tempertaure 110oC). Examination of the reaction by TLC under UV light showed residual starting material.

TLC JU 4-1 EtOAc:Hex 30:70 3.5h.png

The reaction was stirred for a further hour. Examination by TLC under UV light showed the reaction was complete.

TLC JU 4-1 EtOAc:Hex 30:70 4.5h.png

The sample was cooled to room temperature and diluted with 4 mL of water. The mixture was extracted with EtOAc (4 x 3 mL). The combined organic layer was washed with water (~ 4 mL) until the aqueous layer became neutral followed by brine (3 mL) and dried over Na2SO4. This was filtered and dried under reduced pressure and in vacuo to yield a pale yellow oil (170 mg, 90% crude yield). 1H NMR analysis of the crude product showed one peak for the two pyrazine protons which integrated for one proton. Absence of starting material means that the product formed may be the dimer (shown below). Crude yield of the dimer is 66%.

JU 4-1 crude CDCl3 200 MHz.pdf
JU 4-1 crude.zip

The crude product was purified by flash column chromatography over silica using 10/90 EtOAC/Pet Benzine. The pure product was a pale yellow oil (x g, x yield) and was analysed by 1H NMR.

1H NMR, CDCl3, 200 MHz

The sample contains residual EtOAc but is otherwise pure. 

JU 4-1 pure CDCl3 200 MHz.pdf
JU 4-1 pure.zip

 

HIRAC

HIRAC JU 4-1.pdf

InChI strings

InChI=1S/C4H2Cl2N2/c5-3-1-7-2-4(6)8-3/h1-2H

and

InChI=1S/C8H10O/c9-7-6-8-4-2-1-3-5-8/h1-5,9H,6-7H2

to

InChI=1S/C12H11ClN2O/c13-11-8-14-9-12(15-11)16-7-6-10-4-2-1-3-5-10/h1-5,8-9H,6-7H2

SMILES

ClC1=CN=CC(Cl)=N1

and

OCCC1=CC=CC=C1

to

InChI=1S/C12H11ClN2O/c13-11-8-14-9-12(15-11)16-7-6-10-4-2-1-3-5-10/h1-5,8-9H,6-7H2

Attached Files
Reaction Scheme JU 4-1.png
HIRAC JU 4-1.pdf
TLC JU 4-1 EtOAc:Hex 30:70 4.5h.png
TLC JU 4-1 EtOAc:Hex 30:70 3.5h.png
JU 4-1 dimer.png
JU 4-1 crude CDCl3 200 MHz.pdf
JU 4-1 crude.zip
JU 4-1 pure CDCl3 200 MHz.pdf
JU 4-1 pure.zip
Comments
Re: Synthesis of 2-chloro-6-phenethoxypyrazine by Matthew Todd
7th March 2014 @ 03:22
HIRAC approved. As always, correct to treat product as toxic.