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14th January 2014 @ 04:30

Reaction successful with 77% yield, product waiting for next reaction. 

Repeat of Synthesis of N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (AEW 69-1) on twice the scale

Reaction scheme

Procedure

CT 1-1 (500 mg, 2 mmol, 1 equiv.) potassium acetate (785 mg, 8 mmol, 4 equiv.) and bis(pinacolato)diboron (762 mg, 3 mmol, 1.5 equiv.) were dissolved in anhydrous 1,4-dioxane (10 mL). Argon was bubbled through the suspension for 10 minutes before [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol, 0.05 equiv.) was added and the suspension was heated with reflux and stirring overnight. The mixture was cooled to room temperature, filtered through Celite and washed with ethyl acetate and methanol to yield a black mixture. 

The crude product was purified by flash column chromatography over silica (EtOAc/Hexane 30-50%) to yield the product as a white powder (414 mg, 70%). 

Note: KOAc not completely dissolved before heating, still some clumps (moisture?). Will check if dissolved after heating. 

Start time: 4:50 pm 15/1/14. Finish time: 9:30 am 16/1/14

Overnight, some of the reaction mixture leaked out at the junction between flask and condenser. May be possible that air/oxygen entered and affected reaction efficiency. 

Data

-TLC 

 Crude mixture: 70% EtOAc/Hexane, stained with vanillin and heated as product is not visible under UV

(S = starting material CT 1-1, P = crude product after mini work-up in EtOAc/water.)

Silica column: 50% EtOAc/Hexane, stained with vanillin and heated. No product visualised in fractions 1-6. Fractions 7-8, and 9-16 were combined separately and checked by 1H NMR

 

-NMR

1H NMR of crude after Celite and EtOAc/MeOH wash. Consistent with desired product, with additional alkyl peaks, possibly from the boron starting material. Still some residual MeOH, but crude product will be purified further by column chromatography. 

CT 2-1 crude proton.pdf

Fractions 7-8 (major fraction, white powder): 1H NMR is consistent with desired product and suitable for use in the next reaction

CT 2-1 Fr 7-8 (major) proton.pdf

Fractions 9-16 (less material, mix of white and yellow compounds when dried): Appears to be a mix of the desired product and other compounds, possibly the boron starting material. These fractions were kept separate to the major fractions 7-8, and will require further purification if needed in the future. 

CT 2-1 Fr 9-16 proton.pdf

HIRAC

CT 2-1 HIRAC.pdf

InchI strings

InChI=1S/C7H8BrNO2S/c1-9-12(10,11)7-4-2-3-6(8)5-7/h2-5,9H,1H3

and

InChI=1S/C12H24B2O4/c1-9(2)10(3,4)16-13(15-9)14-17-11(5,6)12(7,8)18-14/h1-8H3

to

InChI=1S/C13H20BNO4S/c1-12(2)13(3,4)19-14(18-12)10-7-6-8-11(9-10)20(16,17)15-5/h6-9,15H,1-5H3

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13th January 2014 @ 01:11

Reaction successful, product used in CT 2-1

Repeat of Synthesis of 3-bromo-N-methylbenzenesulfonamide (AEW 68-1) on twice the scale.

Reaction scheme

Procedure

A solution of 3-bromobenzenesulfonyl chloride (0.29 mL, 2 mmol) in THF (3 mL) was cooled to 0°C. Methylamine (24% aq soln, 1.4 mL, 10 mmol) was added dropwise at 0°C and the mixture stirred o/n whilst reaching room temperature. 

Water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (2x10 mL) and washed with brine (10 mL). The brine was extracted with more ethyl acetate (5 mL). The extract was dried over MgSO4 and the solvent removed by rotary evaporation to yield a pale yellow powder (598 mg, 2.4 mmol).

Note:

Yield is over 100%, there was slightly more starting material added than written (>0.3 mL).
32 mg used for 1H/13C NMR recovered and kept as reference. Accidentally got some marker ink (from NMR tube) into the sample, so currently a blue colour.

Data

TLC

1:1 hexane/ethyl acetate

S = starting material 3-bromobenzenesulfonyl chloride, P = reaction mixture after mini work-up in water/ethyl acetate

NMR

Sample (pale yellow oil) has residual EtOAc, but otherwise proton NMR is consistent with desired product. It will be ready for the next reaction and another NMR spectrum after further drying. 

CT 1-1 proton (EtOAc).pdf

The sample was recombined, washed with DCM and dried to yield a pale yellow powder. Proton NMR:

CT 1-1 solid proton.pdf

Carbon NMR:

CT 1-1 (solid) carbon.pdf

Other: Old methylamine used, with solid ppt in the bottle

Hazard and risk assessment

CT 1-1 HIRAC.pdf

InChI strings: 

InChI=1S/C6H4BrClO2S/c7-5-2-1-3-6(4-5)11(8,9)10/h1-4H 

to

InChI=1S/C7H8BrNO2S/c1-9-12(10,11)7-4-2-3-6(8)5-7/h2-5,9H,1H3

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