All Notebooks | Help | Support | About
28th January 2014 @ 22:35

Reaction successful with yield of 39 mg/43%

Repeat of AT 6-4 with the original time of 6 hours to compare yield/purity with shorter times. 

Reaction scheme

Procedure

AEW 99-1 (0.100 g, 0.4 mmol), isopropanol (3 mL) and ammonia (6 mL) were added to a sealed tube, stirred and heated at 120 °C for 6 hours. The solvent was removed under vacuum. The crude product was purified by flash column chromatography over silica (96:3.5:0.5 to 95:4.5:0.5 DCM/MeOH/NH3) to yield the product as a yellow solid (39 mg, 1.7 mmol, 42% ).

Start time: 9:50 am

Note: lower MeOH % than previous attempts (3.5% vs 4.5%) as products always eluted with overlap. However, still some overlap between fractions (see TLC data). 

Data

-TLC

TLC of crude (P), co-spotted with product from CT 3-1 (R). Solvent 95:4.5:0.5 DCM/MeOH/NH3. Appears to have 2 major products, confirmed by 1H NMR below.

TLC of column fractions. Still some overlap between the two major fractions (fraction 12) despite lower MeOH.

Some fractions co-spotted with CT 3-1 as a reference (R) to check whether it is the desired product.  Fractions 13-18 were combined and dried. Fractions 8-11 were also combined for potential further analysis. 

-NMR

1H NMR of crude product. Two products, appear to be the same as CT 3-2 (desired product and possibly the -OH product) and no starting material. 

CT 3-3 crude proton.pdf

1H NMR of second fraction. Consistent with desired product, though small trace of other impurities. 

CT 3-3 fraction 2.pdf

HIRAC

CT 3-1 HIRAC.pdf

InChI strings

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
23rd January 2014 @ 11:46

Yield of 45%, though solvent (mainly IPA, NH3) leaked through seal. 

Repeat of CT 3-1 with a shorter time to see if there is a difference in yield/mixture of products. 4 hours was sufficient for all starting material to disappear, but a mix of products was obtained in CT 3-1. 

Reaction scheme

Procedure

AEW 99-1 (0.100 g, 0.4 mmol), isopropanol (3 mL) and ammonia (6 mL) were added to a sealed tube, stirred and heated at 120 °C for 2 hours. The reaction mixture was cooled to rt and the solvent removed under vacuum. The crude product was purified by flash column chromatography over silica (95:4.5:0.5 DCM:MeOH:NH3) to yield the product as a yellow solid (41 mg, 0.18 mmol, 45%).

Note: Over half of the solvent had evaporated after 2 hours. Seal was not in great condition before the reaction (but worked for the last reaction), and seemed to be cracked upon inspection afterwards. 

Data

-NMR

1H NMR of crude product. Two products, the major product consistent with the desired product (CT 3-1. The other product could be the -OH substituted product (also replacing -Cl), as the reaction was concentrated in water due to a faulty seal. 

CT 3-2 crude proton.pdf

1H NMR of 3rd fraction. Chemical shifts correspond with the other major product (not the desired product), thought to possibly be the -OH substituted product (~18 mg). The fraction appears to be quite pure, so will further characterise the product to determine structure. 

CT 3-2 fraction 3 proton.pdf

1H NMR of 4th fraction. Chemical shifts correspond to the desired product (see previous CT 3-1) though with a small impurity. The fractions may require further drying, although the impurity is not a water signal. 

CT 3-2 fraction 4 proton.pdf

-TLC

Crude TLC showed two spots, consistent with two products in the 1H spectrum. 

After column chromatography

The 'smear' in tubes 9-11 appears to be 2 spots, as separated in 12-13.

4 fractions collected, co-spotted with pure product from CT 3-1

 

HIRAC

CT 3-1 HIRAC.pdf

InChI strings

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
23rd January 2014 @ 04:53

Reaction successful with 75% yield

Repeat of Synthesis of N,N-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (AEW 91-1) on twice the scale

Reaction scheme

Procedure

CT 4-1 (528 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 heated with reflux and stirring overnight. 

The crude reaction mixture was purified by flash column chromatography over silica (20-30% EtOAc/petroleum) to yield CT 5-1 as a white powder (467 mg, 1.5 mmol, 75%).

Data

-TLC

Crude reaction mixture after mini work-up in ethyl acetate/water. Solvent 50% EtOAc/hexane, stained with anisaldehyde. Major spot appears to be desired product upon comparison with AEW 91-1.

After column purification: 20-30% EtOAc/hexane, desired product eluted quickly and with other spots. Still need to check purity by 1H NMR, but lower polarity and a slower gradient required for future columns. Fractions 3-6 were combined (impure product, may require further purification), and fractions 7-16 (clean fraction). 

 -NMR

1H NMR of first fraction. No previous characterisation data in last attempt in this notebook (AEW ). However, signals are similar to CT 2-1, but consistent with the additional methyl group. Protons ortho- to the N,N-dimethylsulfonamide substituent are shifted slightly upfield relative to CT 2-1 due to extra electron donation from the additional methyl group. 

Sample is not quite dry, with ethyl acetate present in the spectrum, but otherwise looks pure with no other unexpected peaks. Sample needs to be further dried before taking another spectrum.

CT 5-1 column fraction 1 proton.pdf

Sample after drying

CT 5-1 fraction 1 dry.pdf

 

1H NMR of second fraction. Similar spectrum to first fraction, however there appears to be an impurity. Not sure if fraction was impure, or if flask/NMR sample was contaminated as the TLC straight after the column showed only one spot. Need to re-purify with a less polar solvent system. 

CT 5-1 column fraction 2 proton.pdf

After a second column using lower polarity (0-20% EtOAc).

'Major' fraction (concentrated fractions)

CT 5-1 fraction 2 major.pdf

'Minor' fraction (less concentrated fractions before/after major fraction)

CT 5-1 fraction 2 minor.pdf

Did not continue with trying to purify the second fraction from the first column, as obtained expected yield from the first fraction (see AEW 91-1)

HIRAC

CT 5-1 HIRAC.pdf

InChI strings

InChI=1S/C8H10BrNO2S/c1-10(2)13(11,12)8-5-3-4-7(9)6-8/h3-6H,1-2H3

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/C14H22BNO4S/c1-13(2)14(3,4)20-15(19-13)11-8-7-9-12(10-11)21(17,18)16(5)6/h7-10H,1-6H3

Linked Posts
This post is linked by:
Attached Files
20th January 2014 @ 04:26

Reaction successful, product obtained with a yield of 33%

Repeat of Althea's procedure AT-6-4 on a shorter time scale to optimise the amination reaction, as yield/products were found to be inconsistent (AEW 100-4).

Reaction scheme

Procedure

AEW 99-1 (0.100 g, 0.4 mmol), isopropanol (3 mL) and ammonia (6 mL) were added to a sealed tube, stirred and heated at 120°C for 4 hours. The solvent was removed under vacuum.

The crude product was purified by flash column chromatograph on silica (95:4.5:0.5 DCM:MeOH:NH3) to yield the product as a yellow solid (30 mg, 33%)

Data

-TLC

TLC of crude reaction mixture in 95:45:0.5 DCM/MeOH/NH3. Not very clear separation, but solvent system used successfully to purify product (see AT-6-4)

-NMR

1H NMR of starting material AEW 99-1

AEW 99-1 SM for CT 3-1 proton.pdf

1H NMR of crude reaction mixture after drying. Starting material has disappeared, with a mix of other compounds. The major product appears to be the desired product upon comparison with AT 6-4

CT 3-1 crude proton.pdf

1H NMR of first fraction after column purification. Appears to be a mix of products, with the major peaks not corresponding to the desired product.

CT 3-1 1st fraction proton.pdf

1H NMR of second fraction after column purification. One product, consistent with desired product according.

CT 3-1 2nd fraction proton.pdf

HIRAC

CT 3-1 HIRAC.pdf

InChI

InChI=1S/C6H2BrClN2S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H

to

InChI=1S/C6H4BrN3S/c7-4-1-3-5(11-4)6(8)10-2-9-3/h1-2H,(H2,8,9,10)

Attached Files
15th January 2014 @ 03:04

Reaction successful, product used in CT 5-1

Repeat of Synthesis of 3-Bromo-N,N-dimethylbenzenesulfonamide (AEW 89-1) on twice the scale

Reaction scheme

 

Procedure

A solution of 3-bromobenzenesulfonyl chloride (0.3 mL, 2.1 mmol) in THF (3 mL) was cooled to 0°C. Dimethylamine (33% in abs. alcohol, 1.8 mL, 10 mmol) was added dropwise at 0°C and the mixture stirred o/n whilst reaching room temperature. 

The crude reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3x10 mL). The organic layers were combined, washed with brine (10 mL), dried with magnesium sulfate and the solvent removed to yield a brown oil which crystallised when taken off the vacuum (590 mg). 

Note: reaction was complete as analysed by TLC within 7 hours, however, insufficient time to work-up reaction by end of the day. Leaving the reaction mixture for longer does not seem to be a problem since it is normally run overnight.

Also seems like extra starting material was added (using syringe) as yield >100% again.

Data

-TLC

SM = 3-bromobenzenesulfonyl chloride, P = reaction mixture after mini work-up in EtOAc/water

After 7 hours: 25% EtOAc/Hexane. Disappearance of starting material. 

After overnight: 25% EtOAc/Hexane. Product does not seem to have degraded overnight. 

-NMR

1H NMR of product after work-up. Spectrum is consistent with desired product according to AEW 89-1, suitable for use in the next reaction. 

CT 4-1 proton.pdf

Hazard and risk assessment

CT 4-1 HIRAC.pdf

InchI strings

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

to

InChI=1S/C8H10BrNO2S/c1-10(2)13(11,12)8-5-3-4-7(9)6-8/h3-6H,1-2H3

Linked Posts
This post is linked by:
Attached Files