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30th September 2014 @ 02:13

See Repeat synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (TM 37-14) for method.

scheme

hydrazinylpyrazine (from Preparation of 2-hydrazinylpyrazine (TM 62-1): 1.5 g, 13.6 mmol) was dissolved in toluene (15 mL), triethyl orthoformate (3.4 ml, 20.4 mmol, 1.5 eq) and TsOH (235 mg, 1.36 mmol, 10 mol %) added, and the reaction mixture refluxed (bath temp 110 oC) for 24 h. Solvents removed under reduced pressure, around half the the reaction mixture was lost by knocking over the flask, and the remainder was purified by FCC (EtOAc, hexanes) to give 345 mg (2.9 mmol, 22 %, see above) of pure TM 65 as a yellow powder.

 

 

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29th September 2014 @ 05:06

Trialling an aromatic Finkelstein reaction, to give an iodo TP hopefully more suitable for Pd-catalysed carbonylative couplings. Conditions taken from 10.1021/ol048987n.

scheme

 

5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (from Repeat synthesis of 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (TM 37-14): 155 mg, 1 mmol), sodium iodide (3.0 g, 20 mmol, 20 eq), and TFA (0.38 mL, 5 mmol, 5 eq) were stirred in butanone (20 mL) at –45 °C (dry ice in 60:40 ethylene glycol:ethanol bath) for 5 h. The product was added to saturacted NaHCO3 solution (10 mL), extracted with DCM (3 x 25 mL), and the organic layers washed with water (5 mL) and brine (5 mL) before being concentrated under reduced pressure to give 260 mg of crude product as a tacky brown solid.

Attached Files
29th September 2014 @ 02:33

scheme

See Resynthesis of 2-chloro-6-hydrazinylpyrazine (TM 34-3) for method.

2-chloropyrazine (3 g, 26.2 mmol) was dissolved in EtOH (15 mL), and hydrazine hydrate (2.6 mL, 52 mmol, 2 eq) added. The mixture was refluxed for ?? h.

 

HIRAC:

62-1 hirac.pdf
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25th September 2014 @ 07:20

Reaction performed in parallel to TM 60-1.

scheme

A 21 mL sample vial was oven dried, then allowed to cool under vacuum (using a teflon vial adapter fitted with a septum). A stirbar, 3 Å powdered molecular sieves (stored in an oven, then microwave activated; 150 mg), potassium carbonate (also stored in oven; 207 mg, 1.5 mmol), palladium acetate (5 mg, 2 mol %), and dcpp • 2HBF4 (25 mg, 4 mol %) were added to the vial, which was then evacuated for several minutes (avoiding disturbance of the finely powdered solid contents). Two nested balloons attached to a short section of tubing fitted with a stopcock were flushed three times with carbon monoxide, then filled (around 150 mL), and attached to a three-way valve connected to the vial and vacuum. The vial was evacuated and refilled with CO three time, then DMF (dried over 4 Å sieves, degassed by freeze-thawing, then stored over 4 Å sieves under argon; 1 mL), 3-chloropyridine (114 mg, 1 mmol, 0.95 uL), and ethanol (0.3 mL, ~5 mmol, 5 eq)) added by syringe.

The reaction mixture was heated to 110 °C for 5 hours, then diluted with EtOAc (~ 15 mL), filtered through a plug of celite, rinsed with more EtOAc (~25 mL), then concentrated on celite before purification by automatic column chromatography (silica, hexanes:EtOAc) to give one fraction.

Pure TM 61-1 was obtained as a white solid (80 mg, 53 %).

NMR:

1H (CDCl3, 500 MHz)

Ethyl picolinate 1H CDCl3 500 MHz.pdf

13C (CDCl3, 500 MHz)

Ethyl picolinate 13C CDCl3 500 MHz.pdf

carbonylative screening Ethyl pyridinyl.zip
Attached Files
25th September 2014 @ 06:34

Attempting to use similar conditions to DOI:10.1021/jo800907e for test carbonylative palladium coupling. Reaction completed successfully (first successful carbonylation), in 62 % yield.

scheme

 

A 21 mL sample vial was oven dried, then allowed to cool under vacuum (using a teflon vial adapter fitted with a septum). A stirbar, 3 Å powdered molecular sieves (stored in an oven, then microwave activated; 150 mg), potassium carbonate (also stored in oven; 207 mg, 1.5 mmol), palladium acetate (5 mg, 2 mol %), and dcpp • 2HBF4 (25 mg, 4 mol %) were added to the vial, which was then evacuated for several minutes (avoiding disturbance of the finely powdered solid contents). Two nested balloons attached to a short section of tubing fitted with a stopcock were flushed three times with carbon monoxide, then filled (around 150 mL), and attached to a three-way valve connected to the vial and vacuum. The vial was evacuated and refilled with CO three time, then DMF (dried over 4 Å sieves, degassed by freeze-thawing, then stored over 4 Å sieves under argon; 1 mL), 3-chloropyridine (114 mg, 1 mmol, 0.95 uL), and methanol (0.2 mL, ~5 mmol, 5 eq)) added by syringe.

The reaction mixture was heated to 110 °C for 5 hours, then diluted with EtOAc (~ 15 mL), filtered through a plug of celite, rinsed with more EtOAc (~25 mL), then concentrated on celite before purification by automatic column chromatography (silica, hexanes:EtOAc) to give one fraction.

Pure TM 60-1 was obtained as a grassy-smelling yellow oil (85 mg, 62 %).

NMR:

1H (CDCl3, 500 MHz)

methyl picolinate 1H CDCl3 500 MHz.pdf

13C (CDCl3, 500 MHz)

methyl picolinate 13C CDCl3 500 MHz.pdf

carbonylative screening Methyl pyridinyl real.zip

Success!

 

Attached Files