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23rd March 2012 @ 00:35
JRC 8-1 lead to a crude yield of only 15% (m/m), and JRC 8-2 gave a crude yield of 28% (m/m). The column purification step of JRC 8-1 lead did not give good separation, and the column purification step of JRC 8-2, while yet to be analysed by 1H-NMR, does not look promising. This synthesis aims to synthesise the desired compound with greater yield than JRC 8-1 and JRC 8-2.

This procedure is adapted from Dhanoa (2011, p. 4) and is summarised below.

2095.png

Part I

Sub-conclusion: Reaction did not lead to desired product, but instead to methyl 3-formamidothiophene-2-carboxylate (pictured below) in 60% yield.

Reaction start time: 10:30 am, 23/03/2012
Methyl-3-aminothiophene-2-carboxylate (0.300 g, 2.110 mmol, 1 equiv.) and ammonium acetate (0.226 g, 2.932 mmol, 1.4 equiv.) were dissolved in formic acid (1 mL, 26 mmol, 12 equiv.) and left stirring at a gentle reflux for 7 hr. Following this the reaction was cooled to rt and a pale brown granular solid appeared in the reaction vessel (no appreciable quantity of liquid visible in the vessel after it was cooled to rt), which was tipped onto ice, filtered and washed with water to yield a very light brown powder (0.575 g). TLC at this point (+6.5 hr) shows a mixture of the ester starting material, and new product.

TLC at +6.5 hr in 10% ethyl acetate/hexane, visualised with UV/vanillin
JRC9-1(23rd 5pm).png


This powder was recrystallised from 50% acetone/water (approx. 4 mL), which was not a good solvent system since both a brown impurity (suspected to be starting material) and the fluffy white crystals (suspected to be product) crashed out at the same time. Product was recrystallised from hot ethanol/water, where a single drop of water was added for each approx. 10 drops of ethanol. This successfully dissolved the suspected product and left the brown material undissolved. The hot liquid was pipetted out and the ethanol/water removed under reduced pressure to yield fluffy, white crystals (237 mg, 1.27 mmol, 60%).

1H-NMR did not show the desired product and, instead, showed the following as a product:

JRC9-1halfwaystructure.png

methyl 3-formamidothiophene-2-carboxylate

1H-NMR:
1.zip
JRC9-1.pdf


The solvent (formic acid) had evaporated from the reaction earlier, so it was reasoned that perhaps more formic acid and ammonium acetate would drive the reaction to completion.

Part II:

Sub-conclusion: The desired product was, again, not synthesised and the half-cyclised heterocycle, methyl 3-formamidothiophene-2-carboxylate, was synthesised in 76% yield.

The remains of the previous reaction (236 mg, 1.27 mmol, 1 equiv.) and ammonium acetate (300 mg, 3.89 mmol, 3.8 equiv.) were dissolved in formic acid (1.5 mL, 39 mmol, 39 equiv.) and stirred at reflux for 4 hr. The reaction mixture was cooled (solvent did not evaporate and remained a liquid) and as this liquid was poured over ice a light brown solid crashed out of solution. This solid was filtered and washed with ice water. The resultant brown powder was dried and evaluated by 1H-NMR, indicating the presence of starting material (179 mg, 0.96 mmol, 76%).

1H-NMR:
2.zip
JRC9-1(Excess).pdf


In a last ditch effort to drive this reaction to the intended product, it was reasoned that harsher conditions might be a possible method of driving this reaction to formation of the intended product.

Part III

Reaction start time: 4pm, 13/04/2012
The remains of the previous reaction (179 mg, 0.96 mmol, 1 equiv.) and ammonium formate (363 mg, 5.75 mmol, 6 equiv.) were dissolved in formic acid (1.5 mL, 39 mmol, 39 equiv.) and heated to 140 °C for 66 hr. The reaction mixture was cooled and water (5 mL) was added before this solution was poured onto ice water. Too much of the product dissolved in the water (probably too much ice water) so the water was removed under reduced pressure to yield X (304 mg, x mmol, x %)

Risk Assessment: Paper copy signed
JRC 9-1 RA.pdf


Linked posts:
Synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one (JRC 8-1)
Re-synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one (JRC 8-2)

References:

Dhanoa, D.J. (Del Mar, CA, US.). Deuterium-enriched pyrimidine compounds and derivatives and pharmaceutical use. United States Patent Application Publication 20110028496 A1, 2011; SciFinder Scholar AN 2011:149048 (accessed 19/03/2012).
Linked Posts
Attached Files
JRC 9-1.png
JRC 9-1.png
JRC 9-1 RA.pdf
JRC9-1(23rd 5pm).png
JRC9-1halfwaystructure.png
1.zip
JRC9-1.pdf
2.zip
JRC9-1(Excess).pdf