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31st August 2012 @ 01:26
Though initial 1H-NMR experiments for JRC 37-1 failed due to precipitation of product in the NMR tube, there is little reason to doubt that this reaction has proceeded: The reaction is well known. This experiment aims to scale up this synthesis.

Desired product synthesised in 47% yield

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Experiment start time: 11:00 am, 31/08/2012
Methyl-3-aminothiophene-2-carboxylate (1.560 g, 9.92 mmol, 1 equiv.) was dissolved in pyridine (20 mL) and acetonitrile (25 mL) and stirred at 0 °C under nitrogen for 10 min before trifluoroacetic anhydride (1.50 mL, 10.61 mmol, 1.06 equiv.) was added dropwise. Cloudy, white gas evolved upon addition. The solution was left stirring at 0 °C for 2 hr before being allowed to warm to rt. The solution was concentrated in vacuo to yield an orange liquid, and then left under nitrogen over the weekend. This orange liquid was concentrated in vacuo once more before being extracted with diethyl ether (50 mL) and water (20 mL). The organic layer was washed with water (2 x 30 mL) and brine (30 mL) before being dried over anhydrous magnesium sulfate. The residue was concentrated in vacuo to yield an orange solid (2.133 g), which was recrystallised from DCM/pet. ether. Crystals collected on the bottom of the flask. Sonification lead to all product crashing out of solution (2.130 g). Recrystallisation again from 50% EtOH/H2O lead to recovery of off-yellow crystals (1.1905 g 4.702 mmol, 47%).

mp = 74.9-75.3
lit = 76-77
28th August 2012 @ 22:14
JRC 34-1 synthesised the desired product in what appears to be only a very small amoubt (by NMR). This experiment uses trifluoroacetic anhydrde to affect the same reaction. The literature precedent carries out the reaction at 0 °C. TLC will be used to monitor the reaction and if it has not gone to completition at 2hr, as per the literature, the reaction will be heated to reflux. This experiment is based upon a procedure described by Zhang et al.

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Experiment start time: 11:00 am, 29/08/2012
Methyl-3-aminothiophene-2-carboxylate (314 mg, 2.00 mmol, 1 equiv.) was dissolved in pyridine (5 mL) and acetonitrile (5 mL) and stirred at 0 °C under nitrogen for 10 min before trifluoroacetic anhydride (0.30 mL, 2.12 mmol, 1.06 equiv.) was added dropwise. Cloudy, white gas evolved upon addition. Reaction was stirred at 0 °C for 3 hr before being quenched by the addition of water (5 mL). The solvent was removed in vacuo to yield a white, odourous solid. This solid was extracted with ethyl acetate (50 mL) and washed with water (2 x 30 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The residue was concentrated in vacuo to yield an orange solid (381.8 mg), which was subsequently used in JRC 40-1 without further purification.

Risk Assessment: Paper copy signed
JRC37-1.pdf


Reference:
Zhang, M.; Tamiya, J.; Nguyen, L.; Rowbottom, M. W.; Dyck, B.; Vickers, T. D.; Grey, J.; Schwarz, D. A.; Heise, C. E.; Haelewyn, J.; Mistry, M. S.; Goodfellow, V. S., Thienopyrimidinone bis-aminopyrrolidine ureas as potent melanin-concentrating hormone receptor-1 (MCH-R1) antagonists. Bioorganic & Medicinal Chemistry Letters 2007, 17 (9), 2535-2539.
Attached Files
28th August 2012 @ 03:47
Suzuki reactions performed thus far have failed to synthesise the desired products. 2-Bromothiophene is utilised in these two reactions to detect whether the thienopyrimidine ring is responsible for the problematic results. So too is the meta-boronic acid pinacol ester utilised to determine if the para-boronic acid pinacol ester is causing the problematic results.

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Part A: META
Reaction start time: 11:30 am, 28/08/2012
2-Bromothiophene (0.1 mL, 1.03 mmol, 5.8 equiv.) was dissolved in 1,4-dioxane (4 mL) and water (2 mL). The solution was degassed with nitrogen gas for 1 hr before cesium fluoride (455 mg, 3.00 mmol, 17 equiv.), sodium bicarbonate (168 mg, 2.00 mmol, 11 equiv.), 3-sulfamoylphenylboronic acid pinacol ester (50 mg, 0.18 mmol, 1 equiv.) and tetrakis(triphenylphosphine)palladium (20 mg, 0.13 mmol, 56 mol %) were added to the stirring solution. The solution was stirred under argon at reflux for 5 hr. At this time it had been discovered that the solvent had boiled off. Unknown if the argon atmosphere had remained in the reaction vessel. 1,4-dioxane (4 mL) and water (2 mL) were re-added and the solution was again stirred at reflux, under nitrogen, for a further 16 hr. TLC at this point indicates a new product at rf=1. This is by comparison to the para reaction below. This one didn't stain well, though.

Workup lead to an orange solid (46.2 mg). Purified on a column using standard conditions. Three fractions collected.

F1: 2mg
F2: 18 mg
F3: 18 mg

TLC (10% MeOH/DCM): Visualised with UV/vanillin
meta36-1.JPG


Part B: PARA
Reaction start time: 11:30 am, 28/08/2012
2-Bromothiophene (0.1 mL, 1.03 mmol, 5.8 equiv.) was dissolved in 1,4-dioxane (4 mL) and water (2 mL). The solution was degassed with nitrogen gas for 1 hr before cesium fluoride (455 mg, 3.00 mmol, 17 equiv.), sodium bicarbonate (168 mg, 2.00 mmol, 11 equiv.), 4-sulfamoylphenylboronic acid pinacol ester (50 mg, 0.18 mmol, 1 equiv.) and tetrakis(triphenylphosphine)palladium (20 mg, 0.13 mmol, 56 mol %) were added to the stirring solution. The solution was stirred under argon at reflux for 4 hr, before the atmosphere inlet was replaced with nitrogen. In this atmosphere the solution was stirred for 21 hr. TLC at this point indicates a new product formed at rf=1 (indicated by stain colour). There's a new spot on baseline, probably a salt.

TLC (10% MeOH/DCM): Visualised with UV/vanillin
para36-1.JPG


Workup lead to an orange solid (71.6 mg). Purified on a column using standard conditions. Three fractions eluted.

F1 (hex): neg.
F2 (EtOAc): 10 mg
F3 (10% MeOH/DCM): 24 mg

Risk Assessment:
JRC 36-1.pdf
Attached Files
25th August 2012 @ 04:56
The desired product from this reaction is useful since the reactive carbon on the pyrimidine ring, in the thienopyrimidine core, is masked by a trifluoro methyl group. Once the thienopyrimidine ring is assembled, it will be treated with BuLi to determine the effect this has on the reactivity. This is the first step towards the synthesis of this altered thienopyrimdine.

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Experiment start time: 4:40 pm, 25/08/2012
Methyl-3-aminothiophene-2-carboxylate (314 mg, 1.99 mmol, 1 equiv.) was dissolved in trifluoroacetic acid (2.0 mL, 26.1 mmol, 13 equiv.) and heated to reflux with stirring for 24 hr. The solution was cooled to rt before being extracted with ethyl acetate (30 mL). The organic layer was washed with water (2 x 20 mL) and brine (20 mL) before being dried over anhydrous magnesium sulfate. The residue was concentrated in vacuo to yield...
Attached Files
23rd August 2012 @ 02:36
This is a repeat of JRC 7-2.

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Conclusion: Five fractions were collected, each exhibiting similar 1H-NMR spectra and mass spectra, but with subtle differences (especially in the NMR spectra). These differences are so subtle, and the spectra so complicated, that conclusions are difficult to be drawn from this experiment. The NMR spectra also exhibit marked differences from the last time this experiment was performed (JRC 7-2), indicating that this experiment suffers from a lack of repeatability.

Experiment start time: 12:00pm, 23/08/2012
Titanium tetrachloride (0.34 mL, 3.13 mmol, 1 equiv.) was added to dry dichloromethane (5 mL) and stirred at -5 °C. To the stirring solution was added dry JRC 4-2 (0.60 mL, 3.13 mol, 1 equiv.) in dried DCM (10 mL) dropwise over 5 min. The resultant brown solution was stirred at -5 °C for a further 10 min before triethylamine dried over mol. sieves (0.96 mL, 6.86 mmol, 3 equiv.) was added dropwise. The solution became black upon the addition of the first drop. Intense fuming resulted alongside the formation of a white solid on the needle tip. The reaction was left stirring at this temperature for 3 hr. The solution gradually became brown. The solution was diluted with water (5 mL) before being made neutral (pH 7). The solution was extracted with chloroform (30 mL) being the resultant solids were filtered. The aqueous layer of the filtrate was extracted again with chloroform (30 mL) before the combined organic layers were washed with water (20 mL) and brine (20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, before the residue was concentrated in vacuo. This residue was purified over flash silica using my standard solvent system. Five fractions were collected.

F1: 24.5 mg
1H-NMR:
F2: 37.4 mg
1H-NMR:
F3: 7 mg
1H-NMR:
F4: 87.9 mg
1H-NMR:
F5: 147.0 mg
1H-NMR:

total mass recovery = 303.8 mg