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Synthesis of Boronic Acid Pinacol Ester - MNR103-1 was repeated at a scale of 0.7067. 3-bromobenzenesulfonamide (1.06 g, 4.488 mmol), bis(pinacolato)diboron (1.710 g, 6.735 mmol), potassium acetate (1.762 g, 17.96 mmol) was dissolved in 1,4-dioxan (22.5 mL) and degassed with argon for ten minutes. Pd(dppf)2.CH2Cl2  (184 mg, 0.226 mmol) was added and the reaction heated to reflux under argon for 22 hours, then cooled and filtered through a plug of celite, followed by washings with methanol (20 ml) and dichloromethane (20 ml). The combined organic layers were concentrated in vacuo and purified using dry column vacuum chromatography (1-10% methanol in dichloromethane, 10 fractions) to give three products:
C1, a tan solid (380 mg)
NMR indicated only one set of aromatic peaks consistent with the desired product and some excess pinacol.
C2, a dark oily solid (1.773 g)
NMR indicated only one set of aromatic peaks consistent with the desired product and a large amount of excess pinacol.
C3, a tan solid (49 mg)
NMR indicated only one set of aromatic peaks consistent with the desired product and a small amount of excess pinacol.
C1 was triturated with XX
1) used instead of Pd(dppf)2Cl2 due to availability of dichloromethane complex;
As per US2006199817 (page 53). p-toluenesulfonamide (4 g, 2.32 mmol) and iron (0.81 g, 250 mesh, 14.72 mmol, 6.35 equivalents) were stirred and to the mixture was slowly added bromine (12 mL). The reaction was stirred in air for 1 hour and then slowly poured into sodium thiosulfate (1M, 200 mL) with vigorous stirring. The aqueous layer was extracted with dichloromethane (200 mL * 2) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow-white solid (7.41g). 1H NMR (B1) indicated 2 parts of the desired product, contaminated with 1 part starting material and no undesired regioisomers or multiply-brominated species (less than 0.2%). TLC indicated co-elution of starting material with product (dichloromethane, Rf ca. 0.3). Therefore, the reaction was repeated exactly as previously described and left stirring overnight.
After 16 hours, 1H NMR from a mini-workup (D1) indicated completion, and the reaction was diluted with dichloromethane (150 mL) and quenched by the addition of aqueous sodium thiosulfate (1M, 300 mL) with stirring. The organic layer was separated and the aqueous layer extracted with a further portion of dichloromethane (150 mL). The combined organic layers were dried over magnesium sulfate and filtered through a short plug of silica, which was then flushed with methanol/dichloromethane (1:9 v/v, 50 mL). The combined organic fractions were concentrated in vacuo to give a XX
1) The iron sticks to the magnetic stirrer. This is fine.
2) There is a slight exotherm upon addition but temperature is effectively controlled by boil-off of bromine.
3) The reaction flask was rinsed out with a little DCM until colourless; no trace of metallic iron remained.
Reaction was unsuccessful
CT 3 (32 mg, 0.14 mmol, 1 equiv.), CT 2-1 (50 mg, 0.17 mmol, 1.2 equiv.), Pd(dppf)Cl2 (21 mg, 0.03 mmol, 0.2 equiv.) and K2CO3 (1 M, 0.28 mL, 0.28 mmol, 2 equiv.) were dissolved in isopropanol (2.8 mL) and degassed with argon for 10 minutes. The mixture was heated in a microwave reactor at 85°C for 35 minutes, then diluted with MeOH (50 mL) and filtered through Celite. The solvent was removed under reduced pressure to yield a black solid.
TLC of crude product CT 8 (after filtration) against starting material CT 3 in 95:4.5:0.5 DCM/MeOH/NH3. Disappearance of CT 3 starting material, with appearance of one major product, and some other compounds.
Not sure what the new spot was - there was no apparent reaction by 1H NMR, and the boronic ester CT 2 is not visualised under UV.
1H NMR of crude product. Signals from boronic ester are visible, but no extra peaks corresponding to the thienopyrimidine. Appeared that no reaction occurred, with the thienopyrimidine likely removed from the crude product by filtration with Celite.
Repeat of CT 7-1 due to product decomposition during purification.
CT 6-2 (511 mg, 1.66 mmol), potassium acetate (652 mg, 6.64 mmol, 4 equiv.) and bis(pinacolato)diboron (631 mg, 2.49 mmol, 1.5 equiv.) were dissolved in anhydrous 1,4-dioxane (9 mL). Argon was bubbled through the suspension for 10 minutes before [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2) (62 mg, 0.082 mmol, 0.05 equiv.) was added and the suspension heated with reflux and stirring overnight.
TLC of crude product (C) after mini work-up in EtOAc/water with the starting material CT 6-2 (SM) in 50% EtOAc/petrol. Stained with anisaldehyde. SM was not visualised in the product, with appearance of a new spot.
TLC during column purification
Appears that some starting material was present in the crude product (fractions 22-25)
1H NMR of crude. Consistent with desired structure, with extra alkyl shifts, likely due to excess bis(pinacolato)diboron.
1H NMR of fraction 1 from the first column. Appears to be recovered excess bis(pinacolato)diboron
Reaction successful with 83% yield, product used in CT 7-2
N,N-dimethylethylenediamine (0.23 mL, 2.1 mmol, 1.05 equiv.) and N,N-diisopropylethylamine (0.36 mL, 2.1 mmol, 1.05 equiv.) were dissolved in THF (4 mL) and cooled to 0°C. 3-bromobenzenesulfonyl chloride (0.29 mL, 2.0 mmol, 1.0 equiv.) was added dropwise with stirring at 0°C. The reaction mixture was allowed to warm to room temperature and was stirred under argon for 5 hours.
The reaction mixture was diluted with ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (2x15 mL) and brine (10 mL), dried with MgSO4 and the solvent removed under reduced pressure to yield a pale yellow oil (511 mg, 1.66 mmol, 83%)
TLC of produt (C) after mini work-up in EtOAc/water and starting material 3-bromobenzenesulfonyl chloride (SM). Solvent system 50% EtOAc/hexane
1H NMR of product after work-up. Consistent with desired product, and some residual EtOAc. Product was dried further before use in the next reaction