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20th February 2013 @ 23:33

Experiment start time: 6.30 pm, 20/2/2013


6-bromothieno[3,2-d]pyrimidin-4-amine (100 mg, 0.435 mmol, 1 equiv.) and phenylboronic acid pinacol ester (107 mg, 0.524 mmol, 1.2 equiv.) were combined and 5.44 mL of dimethylformamide was added. Dichloro [1,1' bis(di-tert-butylphosphino)]ferrocene palladium (II) (57 mg, 20 mol%) and sodium carbonate (1M, 0.952 mL, 0.952 mmol) were added to the mixture. Argon was then passed through the mixture whilst stirring for 2 minutes before being heated overnight at 80 °C.  After 17 hours, analysis by TLC showed the reaction was close to completion. The mixture was left to cool to rt, then diluted with ethyl acetate (50 mL) and washed with water (4 x 20 mL) and brine (2 x 20 mL). The aqueous layer was re-extracted, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The 111 mg of residue was separated by column. TLC showed good separation of the product and starting materials which could be in the mixture in  an eluent system of 86% EtOAc/ hexane. The residue was dry loaded into the column. 50%, 60%, 70%, 80%, 100% EtOAc/Hexane was used. The product appeared as a single spot by TLC starting from the eluent system 80% EtOAc/ Hexane. Fractions 86-159 contained the product and were concentrated in vacuo (RBF = 104.467 g --> 104.588 mg).  Fractions 5-10 contained supposed starting material. 48 mg of the product was placed in the refrigerator. Analysis by NMR showed the desired product was formed, however grease (from the hexane used in the column) was present. The product was put through a column to remove the grease.

Attached Files
20th February 2013 @ 01:31

Experiment start time: 11.53 am, 20/02/2013

Phenylboronic acid (1.000 g, 8.20 mmol , 1 eq) and pinacol (968 mg, 8.19 mmol , 1 eq) were dissolved in anhydrous diethyl ether (19 mL). Under nitrogen gas, the solution was left to stir at room temperature for 1hr then concentrated under reduced pressure. Crystals were visible in the mixture. The crude product was prepared to be filtered through silica to remove an impurity. Upon dissolving the product in hexane, fine fluffy white crystals were suspended in solution. These crystals were filtered off to retrieve a fine white powder. The remaining oil was analysed by NMR which verified that it was the desired product (mp = 27-31°C). 1.50 g of the oil was retrieved and 0.107 g was used in the following Suzuki coupling reaction. 

Attached Files
6th February 2013 @ 23:19

Experiment start time: 5.25 pm 6/2/2013

6-bromothieno[3,2-d]pyrimidin-4-amine (100 mg, 0.435 mmol, 1 equiv.) and 4-sulfamoylphenylboronic acid, pinacol ester (135 mg, 0.478 mmol, 1.1 equiv.) were combined with potassium acetate (171 mg, 1.739 mmol, 4 equiv.) and dissolved in 20% 1,4-dioxane/H2O (8 mL). The mixture was degassed (under argon gas) and PdCl2 (dppf) (31.81 mg, 10 mol %) was added. The resultant solution was heated at reflux (101 °C).

After 16 hours, a TLC was taken of the reaction mixture, using an ethyl acetate work up. 100% ethyl acetate was used as the eluent. The plate showed that some conversion had occured (as observed in the previous experiment) but the reaction was not complete. Since conversion was evident, the reaction was left to cool to rt. The reaction mixture was filtered to remove the catalyst (using celite), then extracted with ethyl acetate (100 mL) and washed with water (2 x 75 mL) and brine (75 mL). The mixture was dried with MgSO4 and concentrated under reduced pressure to retrieve 37 mg of crude product. The celite used to filter out the catalyst was washed with methanol to retrieve any more product which may have been trapped in the layer. The fltrate was dried in vacuo and then extracted to yield a further 9 mg of product. The aqueous layer was concentrated in vacuo then re-extracted with ethyl acetate. TLC showed that the organic layer contained the product. This was dried in vacuo to retrieve a further 7 mg of crude product. The 53 mg of crude product were dissolved in methanol. TLC showed the product was present, as well as 2 other spots. The product was dry-loaded and added to a column, starting with a solvent system of 80% EtOAc/ hexane, to 100% EtOAc, and lastly 5% methanol/ EtOAc. Fractions 123-165 were concentrated in vacuo (RBF = 60.219), as were fractions 7-42 separately (RBF = 37.620).


Fraction

Spot

NMR

Weight

%

 

1-35
(80% EtOAc/ Hexane)

0-6 none

7-41 top spot 

 

Y - odd 

 

15 mg 

 

 novel, dark red powder

36-107
(100% EtOAc/ Hexane)

42-107 no dot

 

 

 

 

108-164
(5% Methanol/ EtOAc)

108-124 no dot

125-164 faint bottom spot (product?)

 

 


10 mg 

 

 

 

orange-yellow powder

165
(7% Methanol/ EtOAc) 

165 faint bottom spot

11 mg

 
 

  orange-yellow powder 






 

 

 

 

 

The supposed product was analysed by NMR which showed that the aromatic species was present, yet the mixture was not pure and clean for testing. A further TLC using 10% MeOH/DCM showed that the product spot was now 4 small spots suggesting possible decomposition or insolubility. The product from fractions 108-165 were dissolved in MeOH/DCM and added to a small column with eluent 10% MeOH/DCM followed by 15% MeOH/ DCM. It is suspected that the unstable product may have decomposed in the column.  The possibility of adding an acid to the end product to make a more stable salt has been considered for future experiments. 

Fraction

Spot

NMR

Weight

%

 

1-50
10% MeOH/DCM

Fraction 1: long spot

 

 

 

Brown oil (colour change)

51
15% MeOH/DCM


Fractions 21-28:
bottom spot

 

4 mg

 

Light yellow sticky crystals



Attached Files
4th February 2013 @ 04:29

Experiment start time: 3.10 pm 4/2/2013



Two sealed tubes were charged with 4-chloro-6-bromothieno[3,2-d]pyrimidine (tube A: 299 mg, 1.20 mmol, 1 eq) (tube B: 300 mg, 1.20 mmol, 1 eq). To each sealed tube was added 4.7 mL aqueous 28% ammonium hydroxide solution. The sealed tubes were heated to 120 °C with stirring. After 20 hours, TLC analysis showed that the reaction had not gone to completion. However there were multiple dots for product. The rubber part of the seal used for the sealed tube deteriorated during the reaction and contaminated the mixture. 
 


The product spot was still evident however there  were many other impurities in the mixture. The disrupted mixture was brown in colour, whereas the other mixture was brown-yellow, as observed in previous reactions. 

The non-contaminated reaction mixture was extracted with ethyl acetate (100 mL) and water (2 x 100 mL) then washed with brine (100 mL). The resultant organic layer was light yellow and transparent, and was dried in vacuo to yield a fine yellow powder (153 mg).
The contaminated mixture was extracted in sections with ethyl acetate and water. The resultant layer was washed extensively with water and brine, until the brown contaminant was washed out. The resultant organic layer had the same appearance as the previous one, and was dried in vacuo to yield a fine yellow powder (~150 mg). Both samples were analysed separately by NMR, which showed that both samples contained the product as well as other impurities. The samples were then recrystallised with ethanol and hexane which upon refrigeration did not yield crystals in solution. After 16 hours, the solutions were decreased in volume in vacuo, and crystals began to form. The lower volume solutions were left to recrystalise for 2.5 hrs. Crystals formed in both solutions. The crystals were filltered out by Buchner funnel and collected (44 mg). All crystals retrieved were pure by NMR. Product was lost during the filtration. Thus, the filtrate was concentrated in vacuo to retrieve 182 mg of product which was still impure by NMR. The product was recrystallised with methanol and hexane and filtered to yield 72 mg of product which was shown to be pure by NMR analysis. 

Attached Files
29th January 2013 @ 00:29

This reaction will be carried out with two reaction vessels, each containing 1.00g of the starting material (AB2-1/JRC13-6) to allow for large-scale synthesis of the desired material. 

 

Experiment start time: 11.30am 29/01/2013

Under argon gas, 4-chlorothieno[3,2-d]pyrimidine (1.000 g, 5.861 mmol, 1 equiv.) was dissolved in dried THF (50 mL) at -78 °C for 10 min before n-butyllithium solution (2.086 M in hexane, 2.809 mL, 5.861 mmol, 1 equiv.) was added dropwise. The solution was dark yellow in colour. After 40 min with occassional stirring at  -78 °C, elemental bromine (0.304 mL, 5.920 mmol, 1.01 equiv.) was added dropwise. The reaction vessels were not the same in colour. Possible contamination from the suba-seal may explain the colour difference as the other reaction vessel was dark with a green tinge. For both mixtures, a distinct colour change occured as the solution turned a dark red. The solution was left to cool to rt. After 1 hr, the solution was quenched with water and extracted with chloroform. The mixture was washed with aqueous Na2S2O3 until it became light orange and the colour no longer faded upon further addition. The organic layer was washed with brine (100 mL) and was dried over MgSO4 before removing CHCl3 in vacuo. The crude product was retrieved and was separated by column.

Two separate columns were done simultaneously due to a large amount of product to be dry-loaded. From one column, the product formed one spot on TLC, whereas the other showed an additional shadow beneath the spot of interest. The products were kept separate and dried in vacuo. Analysis by NMR showed that the reaction had not gone to completion as a large amount of starting material was recovered. 227 mg pure product was retrieved (12.3 %). The low yield is possibly due to the contaminated suba-seal and lack of stirring. 

 

Fraction

Spot

NMR

Weight

 Observation

Column A:

1-3
(5% EtOAc/ hexane)

 

None

-

-

 

4
(5% EtOAc/ hexane)

Supposed product plus top impurity

 -

-

 

5-8

(5% EtOAc/ hexane)

Co-spot (supposed product)

 

 Y - product

 115 mg

White (with orange-yellow tinge) fluffy crystals, finer than column B crystals

9 -22
(5% EtOAc/ hexane)

Co-spot plus starting material

 Y – SM

171 mg

 

22- 30
EtOAc

Starting material

 Y – SM

184 mg

 Dark orange liquid

Column B:

1-6
(5% EtOAc/ hexane)

None

 -

-

-

7 -9
(5% EtOAc/ hexane) 

Top impurity plus cospot

 

 

 

10-17
(5% EtOAc/ hexane)

Supposed product

 Y – product

112 mg

White (with orange-yellow tinge) fluffy crystals

18-40
(5% EtOAc/ hexane, 10%, 100%)

None

 Y – SM

381 mg

 Dark orange

Attached Files