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5th February 2014 @ 06:02

T3P was used as a coupling reagent to clearnly form amide TM 1-2, in 83 % yield after purification by column chromatography.

Scheme TM-1-2

 

A simple and effective amide coupling reaction will be very useful when making multiple amide-substituted triazolopyrazines. T3P appears to be easy to use, relatively benign, and so is trialled here. 

Procedure

Carboxylic acid (500 mg, 3.15 mmol, 1 eq), aniline (440 mg, 0.370 mL, 1.1 eq), and pyridine (0.86 mL, 3 eq) were dissolved in ethyl acetate (1.7 mL) and cooled over ice with stirring. T3P (50% wt in ethyl acetate, 3.8 mL, 2.2 eq) was added dropwise, and the reaction mixture left to stir overnight.

 

TLC1.jpg

After 20 hours, the reaction was judged complete by TLC in DCM (although the pyridine large obscured the product, the starting reagents were absent). The reaction mixture was cooled in ice while hydrochloric acid (0.5M, 3 ml) was added dropwise, after which the reaction was left to stir for one hour.

At this point, the procedure being followed claimed that product would precipitate out of solution. However, no precipitate was formed. The reaction mixture was then worked up and washed with saturated sodium bicarbonate, and the organic layer rotavapped to give the crude product as a dark brown crust. Yield: 0.875 g, 102%.

1H NMR of crude product (200 MHz, CDCl3):

TM 1-2 200MHz crude.pdf

The crude product was purified through column chromatography, with a 1:6 ethyl acetate:petroleum ether mixture as eluent. The TM 1-2 containing fractions were combined, and the solvent removed under vacuum. Pure TM 1-2 was obtained as hard brown flakes; after drying under vacuum, overall yield was 0.710 g (83 %).

product.jpg

1H spectrum of final product (200 MHz, CDCl3):

TM 1-2 pure CDCl3 200 MHz.pdf

Raw NMR files:

TM 1-2 PURE.zip

InChI:

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

InChI=1S/C6H6ClN/c7-5-2-1-3-6(8)4-5/h1-4H,8H2

to

InChI=1S/C11H7Cl2N3O/c12-7-2-1-3-8(4-7)15-11(17)9-5-14-6-10(13)16-9/h1-6H,(H,15,17)

 HIRAC

HIRAC 02.05 amide.pdf

 

Context

An earlier attempt at this amide coupling with thionyl chloride was not very succesful (details to come). T3P has been suggested by Sabin as a coupling reagent, and so is used here. The reaction conditions have been taken from this paper

Linked Posts
Attached Files
scheme 1-2.png
HIRAC 02.05 amide.pdf
TM 1-2 200MHz crude.pdf
TLC1.jpg
product.jpg
TM 1-2 pure CDCl3 200 MHz.pdf
TM 1-2 PURE.zip
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