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16th January 2013 @ 02:57

This experiment is an upscale of previous reactions in the JRC 40-x series.

Experiment start time: 2PM, 16/01/2013

Two sealed tubes are charged with 4-chloro-6-bromothieno[3,2-d]pyrimidine (tube A: 354.7 mg, x mmol, 1 eq) (tube B: 289.6 mg, x mmol, x eq). To each sealed tube was added 4.7 mL aqueous 28% ammonium hydroxide solution (5 mL, x mmol, x eq). The sealed tubes were heated to 120 &deg C with stirring for 6 hr. The solutions were allowed to cool to rt. TLC analysis suggested that the reactions were incomplete. Solutions were heated to 120 oC for a further 5 hr before they were allowed to cool to rt. Solutions were combined and  extracted with EtOAc (100 mL), washed with water (2 x 50 mL), brine (40 mL) and dried over MgSO4 and then concentrated under reduced pressure to yield the title compound (by TLC) as a (Seemingly) fluorescent green powder (YIELD UNKNOWN: ADMIN TO UPDATE).

9th January 2013 @ 02:43


Conclusion:
Desired product synthesised in 81% yield.

Start: 1:43 PM

4-chlorothieno[3,2-d]pyrimidine (96 mg, 0.562 mmol, 1 eq) was dissolved in MeOH (3 mL) and stirred at rt. To the stirring solution was added thiomorpholine (0.12 mL, 1.19 mmol, 2.1 eq) in a dropwise manner. The solution was stirred at rt for 20 hr. TLC at this time showed the formation of a new product, and some residual starting material.

To the solution was added ethyl acetate (50 mL), and water (40 mL). The organic layer was separated, washed with water (2 x 30 mL), brine (30 mL), dried over MgSO4 and concentrated in vacuo to yield a pale orange solid. 1H-NMR spectroscopy indicates that this is the title compound.

58-1.pdf

This solid was recrystallised from 10% DCM/petrol to yield the title compound as pale yellow crystals (109 mg, 0.46 mmol, 81%).

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8th January 2013 @ 02:40

This experiment is a simple repeat of the JRC 27-x series. The product from this reaction is valuable in the generation of analogues of the thienopyrimidine series hit compound.

Conclusion: Desired product synthesised (107 mg).

Experment start time: 1:30pm, 8/1/13

4-chlorothieno[3,2-d]pyrimidine (485.0 mg, 2.84 mmol, 1 eq) was dried and dissolved in anhydrous THF (12 mL), forming a yellow solution. The solution was stirred for 5 min at -78 °C before n-BuLi (2.5 M in hexanes, 1.2 mL, 3 mmol, 1.05 eq.) was added dropwise. Solution turned brown and was stirred at -78 °C for a further 1 hr. Bromine (0.2 mL, 3.88 mmol, 1.4 eq) was added in three short bursts. The solution turned orange after the second burst, and retained its colouration on the third. The solution was allowed to warm to rt and was stirred at rt for 2 h. To the solution was added water (5 mL, dropwise) and chloroform (200 mL). The entire biphasic solution was washed with sodium thiosulfate solution until no further decolouration took place. The organic layer was separated, washed with water (2 x 50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo to yield an orange solid.

Crude NMR suggests presence of some starting material. Product purified by flash chromatography. Two products eluted, with some overlap:

 

F1 (0-5% EtOAc/petrol): 104.7 mg. This turned out to be the title compound

27-5f1.pdf

F2 (5-10% EtOAc/petrol): 101.7 mg. This turned out to be starting material.

27-5F2.pdf
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7th January 2013 @ 04:14

This experiment aims to synthesis one half of an analogue within the thienopyrimidine series. The logic of this analogue is to explore the effects of an aryl group at the 4-position of the core bicyclic ring structure.

Conclusion: Desired product synthesised (by HNMR) to give 192 mg pure product.

Experiment start time:3:14 pm, 7/1/13

4-chlorothieno[3,2-d]pyrimidine (178.2 mg, 1.04 mmol, 1 eq) was dissolved in methanol (6 mL). To the stirring solution was added 4-chloro-N-methylaniline (0.24 mL, 1.98 mmol, 1.9 eq) dropwise. The solution did not change colour, nor result in an apparent evolution of warmth. The solution was stirred at rt for 18 hr. TLC at this time showed appearance of a new starting material on the baseline alongside some side products, however, significant starting materials remained. To drive the reaction to completion DIPEA (0.18 mL, 1.03 mmol, 0.9 eq.) and DMAP (24 mg, 20 mol %) were added. No apparent evolution of warmth.

TLC following workup (10% EtOAc/petrol):

JRC57-1(finish).JPG

 

Crude product NMR:

57-1CRUDE.pdf



Crude product was purified via column chromatography, using the following solvent system

F1: 0% EtOAc/hexane (long streak):
F2: 20% EtOAc/hexane -> 50% EtOAc/hexane: 192 mg

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6th January 2013 @ 22:43

In this experiment, an ester is cleaved to give a carboxylic acid, which is then decarboxylated using oxalic acid to give the free amine. This amine is then used in later experiments to generate a thienopyridine bicyclic ring structure.

Experiment start time: 10 am, 7/1/13 Methyl-3-aminothiophene-2-carboxylate (458.2, 2.91 mmol, 1 eq) and 2.5 M sodium hydroxide solution (4 mL, 10 mmol, 5 eq) were heated at reflux for 2 hr. The solution was cooled to 0 °C on an ice bath and acidified with conc. HCl solution, before the resultant solid was filtered, and washed with a little chilled water. The solid was dissolved in acetone and dried over MgSO4, filtered and concentrated in atmospheric conditions (no heat!). The solid and oxalic acid (440.5 mg, 3.2 mmol, 1.1 eq [rel. to SM]) in propanol (1 mL) were heated to 40 °C with stirring. Solution went darker quite quickly. The solution was allowed to cool to rt before diethyl ether (40 mL) was added. A solid formed, which was filtered and washed with a little chilled diethyl ether. The solid was collected and suspended in water, before the pH was adjusted to pH ~ 8-9 by the addition of NH4OH solution. This aqueous solution was extracted with DCM (4 x 40 mL), dried over MgSO4 and concentrated in vacuo to yield an orange oil (10 mg).

The filtrate was collected and concentrated in vacuo to yield a purple solid which, by 1H-NMR is indeed a new, albeit unknown product.

JRC56-2.pdf

Suggestion: Next time, isolate the intermediate and fuly characterise so I can properly troubleshoot the reaction. This is a lit. prep., so it should work.

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