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19th April 2012 @ 03:19
This experiment, from Mitchell et al. (2005), combines procedural elements from both JRC 9-1 and JRC 8-1. The intended reaction is summarised below:

2252.png


Conclusion: The desired product was formed over two steps in 31% yield.

Part I:

Reaction start time: 12pm 18/04/2012
Methyl-3-aminothiophene-2-carboxylate (235 mg, 1.16 mmol, 1 equiv.) and ammonium acetate (173 mg, 2.24 mmol, ~1.9 equiv.) were dissolved in formic acid (1.0 mL, 26.5 mmol, ~22.8 equiv.). The mixture was refluxed for 3 hr, before being cooled to ambient temperature. The cooled mixture was filtered, washed with water and dried under reduced pressure to afford a light brown, fluffy powder. Due to problems in arriving at the intended final product in JRC 8-1, 8-2 and 9-1, this brown powder was used immediately in the following reaction.

Part II
Reaction start time: 5pm 18/04/2012
JRC 9-2 (Part I) was assumed to be methyl-3-formamidothiophene-2-carboxylate, based on both the results from JRC 9-1 and the procedure outlined by Mitchell et al (2005). Methyl-3-formamidothiophene-2-carboxylate (268 mg, 1.44 mmol, 1 equiv.) and ammonium formate (259 mg, 4.11 mmol, 2.9 equiv.) were dissolved in formamide (0.778 mL, 19.57 mmol, 13.6 equiv.) and the resultant slurry was heated to 140 %degC and refluxed for 19.5 hr. The reaction mixture was cooled and the resultant brown sludge was filtered, washed with water and dried to yield the desired product (50.6 mg, 0.37 mmol, 25%*).

*yield from intermediate weight, which is incorrect. total yield over all steps is 31%.

1H-NMR:
1.zip
JRC9-2-1H.pdf


13C-NMR

Low Res. Mass Spec.: 153 m/z+

Risk Assessment: As for:
Synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one using formic acid (JRC 9-1) and;
Synthesis of Thieno[3,2-d]pyrimidine-4(3H)-one (JRC 8-1)

References:
Mitchell, I.S.; Spencer, K.L.; Stengel, P.; Han, Y.; Kallan, N.C.; Munson, M.; Vigers, G.P.A.; Blake, J.; Piscopio, A.; Josey, J.; Miller, S.; Xiao, D.; Xu, R.; Rao, C.; Wang, B.; Bernacki, A.L (Array Biopharma, CO, US.). AKT Protein Kinase Inhibitors for use in treatment of hyperproliferative diseases. World Intellectual Property Organisation 2005051304 A2, 2005; SciFinder Scholar AN 2005:490266 (accessed 24/04/2012).
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Attached Files
JRC9-2.png
1.zip
JRC9-2-1H.pdf