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1st May 2013 @ 03:46

Repeat of AT-9-1 for more material. Lower catalyst loading used (0.10 eq.). 

 

To a degassed solution of isopropanol (5 mL) and aqueous potassium carbonate (1 M, 0.870 mL, 2.0 equiv.) was added AT-6 (0.100 g, 0.44 mmol, 1.0 equiv.) and phenylboronic acid (0.64 g, 0.52 mmol, 1.2 equiv.) and the reaction mixture further degassed for 5 minutes. PdCl2dppf (0.028 g, 0.043 mmol, 0.2 equiv.) was added and the reaction mixture stirred at 80 C overnight. 

Reaction mixture diluted with methanol (50 mL), filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (95:4.5:0.5 dichloromethane:methanol:ammonia) to give the product as a yellow solid (0.454 g, 460%). This is obviously not right, but 1H NMR indicates that the desired product has been synthesised. Salt-like impurities??

The isolated solid was diluted with ethyl acetate (50 mL) and water (20 mL). The organic phase was extracted, dried (MgSO4) and concentrated under reduced pressure. Resultant solid (0.060 g, 61%), product. 

The aim of this experiment was to obtain more of the aryl-substituted aminoheterocycle, for displacement of the amine group with hydrazine for the corresponding hydrazyl compound. Forgot that the displacement needs to be from the chloro-compound, rather than the amino-compound...

 

HIRAC

AT-9-1.pdf

 

NMR

AT-9-2.pdf
1H NMR (500 MHz, MeOD). 
Attached Files
1st May 2013 @ 01:02
Mnr: mnr121-130

Starting material from - Nucleophilic Displacement of MNR99 with Dimethylamine to give MNR122-1

As for - Bromination of MNR100-2 to give MNR101-2

Hazard Assessment

 

Procedure

MNR122-1 (1.8 g, 10.04 mmol) was dissolved in THF (200 mL) and cooled to -78 °C.  To the stirring solution was added n-BuLi (2.5 M in hexanes, 6.03 mL, 15.06 mmol) and the stirring was continued for 30 minutes.  Bromine (1.03 mL, 20.08 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 2 hours.  Sodium thiosulfate solution (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL).  The organic layers were commbined, dried and filteres then concentrated in vacuo to yield the crude as pale yellow solid.

TLC

75% EtOAc/Hex

2013-05-02 12.26.38.jpg

 

Column - 25-80% EtOAc/Hex

 

fracs 16-46        1.481 g, 5.74 mmol, 57% as a white solid               mainly product

fracs 47-53         0.140 g as i pale brown solid -              starting material

 

fraction 28 was concentrated and dried for a quick NMR

mnr124-1_frac28_1H.pdf
mnr124-1_frac28_13C.pdf
mnr124-1_frac28.zip
Attached Files
30th April 2013 @ 07:09
Mnr: mnr121-130

Using 4-bromobenzenesulfonamide as a test system as it's a lot cheaper than 3-bromobenzenesulfonamide.

As for - Synthesis of N,N-dimethyl-3-bromobenzenesulfonamide - MNR109-1

 

 

Hazard Assessment


Procedure

To a solution of 4-bromobenzenesulfonyl chloride (5.2 g, 20.35 mmol) in EtOH  (18mL) at 0 °C (THF (10 mL) was added as not all the starting material went into the EtOH solution) was added dimethylamine (33% in EtOH, 18.2 mL).  The resulting solution was allowed to warm to room temperature and stirred overnight.  In the morning TLC showed complete consumption of starting material.  The mixture was concentrated then washed with HCl (1M) (20 mL) and extracted with CHCl3 (4 x 50 mL).  The organic fractions were combined, dried, filtered and concentrated to give the crude at a off white solid.

TLC

50% EtOAc/Hexane

2013-05-01 12.19.27.jpg

 NMR

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30th April 2013 @ 05:05
Mnr: mnr121-130

Starting material from commercially purchased 4-chloroethieno[3,2-d]pyrimidine

As for Nucleophilic Displacement of MNR99 with Morpholine to give MNR100-1

 

Hazard Assessment


Procedure

To 4-chloroethieno[3,2-d]pyrimidine (2.0 g, 11.72 mmol) was added dimethylamine in absolute alcohol (4.2 mL, 23.44 mmol) at room temperature.  The mixture gave off some white gas and was stirred.  The solid quickly went into solution then almost instantly as solid started to precipitate out of the mixture.  The mixture was not heated as planned and was left to stir for 20 minutes.  TLC after 20 minutes showed complete consumption of starting material and one new, lower running spot.  The mixture was concentrated and crude NMR showed what looked like product but with a 1:1 ratio of dimethylamine still present.

TLC


TLC 50% EtOAc/Hex 

2013-04-30 11.56.14.jpg

TLC 100% EtOAc

2013-04-30 12.07.53.jpg


Crude NMR

mnr122-1_crude_1H.pdf
mnr122-1_crude_13C.pdf
mnr122-1_crude.zip

 

The crude was dissolved in CHCl3 (25 mL) and washed with sodium hydrogen carbonate (20 mL) and then extracted with CHCl3 (25 mL x 2).  The organic layers were combined, dried, filtered and concentrated to give an off white/pale yellow solid (1.94 g, 10.82 mmol, 92%)

 

Workup NMR

mnr122-1_workup_1H.pdf
mnr122-1_workup_13C.pdf
mnr122-1_workup.zip

Conclusion

Product obtained clean and in high yeild after workup, no need for further purification.  Taken on to the next step MNR124-1

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Attached Files
23rd April 2013 @ 03:54

Scale up for more material.

 

To a degassed solution of isopropanol (10 mL) and potassium carbonate (1 M, 0.870 mL, 0.870 mmol, 2.0 equiv.) was added AT-6 (0.100 g, 0.43 mmol, 1.0 equiv.), 3-sulfamoylphenyl boronic acid pinacol ester (0.148 mg, 0.52 mmol, 1.2 equiv.) and PdCl2dppf (0.064 g, 0.087 mmol, 0.2 equiv.) and the reaction mixture heated to 90 C in a microwave reactor (200 W) and stirred for 1 h.

Reaction incomplete after 1 h. Heated to 90 C under the same conditions again. 

Reaction mixture diluted with methanol (50 mL), filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (90:9:1 dichloromethane:methanol:ammonia) to give the product as a brown solid (0.077 g, 50%).

 

NMR

AT-11-4-1H-DMSOMeOD.pdf
1H NMR in MeOD/DMSO-d6.

 

HIRAC

AT-Suzuki.pdf

 

Attached Files