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19th February 2014 @ 23:24

Reaction was unsuccessful

Synthesis of one of the final Series 3 compounds (compound 7)

Reaction scheme

Procedure

CT 3 (32 mg, 0.14 mmol, 1 equiv.), CT 2-1 (50 mg, 0.17 mmol, 1.2 equiv.), Pd(dppf)Cl(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. 

Data

-TLC

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. 

-NMR

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. 

CT 8-1 crude proton.pdf

HIRAC

CT 8-1 HIRAC.pdf

InChI strings

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

and

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

to

InChI=1S/C13H12N4O2S2/c1-15-21(18,19)9-4-2-3-8(5-9)11-6-10-12(20-11)13(14)17-7-16-10/h2-7,15H,1H3,(H2,14,16,17)

Attached Files
18th February 2014 @ 06:02

Repeat of CT 7-1 due to product decomposition during purification.

Reaction scheme

Procedure

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.

Data 

-TLC

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)

-NMR

1H NMR of crude. Consistent with desired structure, with extra alkyl shifts, likely due to excess bis(pinacolato)diboron.

CT 7-2 crude proton.pdf

1H NMR of fraction 1 from the first column. Appears to be recovered excess bis(pinacolato)diboron

CT 7-2 column 1.pdf

HIRAC

CT 7-1 HIRAC.pdf

InChI strings

InChI=1S/C10H15BrN2O2S/c1-13(2)7-6-12-16(14,15)10-5-3-4-9(11)8-10/h3-5,8,12H,6-7H2,1-2H3

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/C16H27BN2O4S/c1-15(2)16(3,4)23-17(22-15)13-8-7-9-14(12-13)24(20,21)18-10-11-19(5)6/h7-9,12,18H,10-11H2,1-6H3

Attached Files
18th February 2014 @ 03:44

Reaction successful with 83% yield, product used in CT 7-2

Repeat of CT 6-1 as CT 7-1 decomposed.

Reaction scheme

Procedure

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%)

Data

-TLC

TLC of produt (C) after mini work-up in EtOAc/water and starting material 3-bromobenzenesulfonyl chloride (SM). Solvent system 50% EtOAc/hexane

-NMR

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

CT 6-2 proton.pdf

HIRAC

CT 6-1 HIRAC.pdf

InChI strings

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

and

InChI=1S/C4H12N2/c1-6(2)4-3-5/h3-5H2,1-2H3

to

InChI=1S/C10H15BrN2O2S/c1-13(2)7-6-12-16(14,15)10-5-3-4-9(11)8-10/h3-5,8,12H,6-7H2,1-2H3

Attached Files
12th February 2014 @ 06:00

Repeat of CT 3-6 twice with the same conditions to synthesise more material, to be combined together during purification. 

Reaction scheme 

Procedure

AEW 99-1 (0.200 g, 0.80 mmol), isopropanol (4.5 mL) and ammonia (aq, 28% (w/w), 9 mL) were added to a sealed tube, stirred and heated at 120 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvent was removed under vacuum.

2 batches of CT 3 were made (total 0.400 g starting material). CT 3-6 and CT 3-7 were purified together by column chromatography over silica (99:1 DCM:MeOH to 97:3 DCM:MeOH to 96.5:3.5:0.5 DCM:MeOH:NH3).

Data

-NMR

1H NMR of crude first batch. Ratio of products consistent with CT 3-6 i.e. desired:side product ratio is slightly higher than the less concentrated, smaller scale reactions.

CT 3-7 crude proton.pdf

1H NMR of crude second batch. Similar to first batch.

CT 3-7(2) crude.pdf

1H NMR of purified product (3 batches, CT 3-6 and CT 3-7)

CT 3-7 purified.pdf

-TLC

TLC of column purification. Lower polarity system used, with addition of NH3 later in the column for more complete separation of products, as it is thought that the first eluted product may be -OH substituted. 

Appears to have clear separation between the 2 products

Fractions 23 onwards appear to be a different product which should have eluted first. Co-spotting 20 and 24 with reference product (CT 3-1) showed them both to be the desired product however. 

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)

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Attached Files
12th February 2014 @ 03:46

Reaction was successful, with the crude NMR consistent with the desired product. However, the product decomposed, most likely due to purification over silica without basic conditions, or possibly from storage at room temperature for ~3 days. 

Synthesis of boronic ester of CT 6-1 using same conditions as CT 2-1, CT 5-1 in preparation for coupling with aminothienopyrimidine CT 3 (see CT 6-1 for final analog structure)

Reaction scheme

Procedure

CT 6-1 (495 mg, 1.61 mmol), potassium acetate (632 mg, 6.44 mmol, 4 equiv.) and bis(pinacolato)diboron (613 mg, 2.42 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) (Pd(dppf)Cl2) (59 mg, 0.08 mmol, 0.05 equiv.) was added and the suspension heated with reflux and stirring overnight. The reaction mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and MeOH. The solvent was removed under reduced pressure and the residue purified by column chromatography over silica (1:0 petrol:EtOAc to 0:1 petrol:EtOAc)

Note: did not require 100% EtOAc to elute product, around 50% would have been sufficient as there was overlap with another more polar compound. However, high polarity used due to time restrictions. Should probably use NH3 in the column next time, or the crude product in the next reaction

Data

-TLC

TLC of crude reaction mixture after mini workup with EtOAc/water and staining with anisaldehyde. Left (/top) sample is CT 6-1, Right (/bottom) sample is the reaction mixture, and a co-spot in the middle. Disappearance of least mobile spot in the reaction mixture. Another spot appeared to be present in both starting material and the reaction mixture, but they were slightly different colours (hard to see in the photo, but blue-green and purple). 

TLC during column purification. First spot appears to be product (yet to be confirmed by 1H NMR), with a more polar compound eluting with the product. Tubess 20-27 were combined as fraction 1, tubes 28-32 as fraction 2 and tubes 33-36 as fraction 3. 

-NMR

1H NMR of crude product after filtration/wash. Peaks and integration consistent with desired spectrum, along with some dioxane, and possibly excess bis(pinacolato)diboron (seen in spectra for crude of other Suzuki couplings)

CT 7-1 crude proton.pdf

1H NMR of first fraction. Appears to have broken down, many more signals than the crude NMR, with very few corresponding signals between them. Possibly due to purification over silica, as it was not done in basic conditions. Also

CT 7-1-1 column.pdf

1H NMR of third fraction. Also appears to have broken down.

CT 7-1-3 column.pdf

HIRAC

CT 7-1 HIRAC.pdf

InChI strings

InChI=1S/C10H15BrN2O2S/c1-13(2)7-6-12-16(14,15)10-5-3-4-9(11)8-10/h3-5,8,12H,6-7H2,1-2H3

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/C16H27BN2O4S/c1-15(2)16(3,4)23-17(22-15)13-8-7-9-14(12-13)24(20,21)18-10-11-19(5)6/h7-9,12,18H,10-11H2,1-6H3

Attached Files