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9th July 2013 @ 23:40

Bromination of MJT 7-2, using same process as MJT 9-1 but with more (2.5) equivalents of n-BuLi to account for deprotonation on the amine hydrogen as well as deprotonation at the N-6 position to improve the yield compared to MJT 9-1. This is an effort towards synthesising aminothienopyrimidine analogues discussed in the May 2013 Open Consultation.

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Reaction proceeded to give a mixture of the desired product and one other product brominated at the other carbon of the thiene bond. It was discovered that column chromatography is able to separate these products.

The reaction was repeated in an attempt to synthesise just the desired product - see MJT 9-3.


Procedure

11AM 11-07-2013

MJT 7-2 (0.200 g, 1.21 mmol, 1.0 equiv.) was dissolved in THF (25 mL) under an atmosphere of argon and cooled to -78 °C. To the stirring solution was added n-BuLi (2.5 M in hexane, 1.2 mL, 3.0 mmol, 2.5 equiv.) and the stirring was continued for 30 minutes. Bromine (0.12 mL, 2.4 mmol, 2.0 equiv.) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 3.5 hours, it is now an orange solution. TLC shows some SM remains and two new product spots of which one is feint and one is sharp. The reaction mixture was quenched with a saturated sodium thiosulphate solution on ice (70 mL). From this the product was extracted with ethyl acetate (3 x 50 mL). The combined organic extract was washed with brine, dried with MgSO4 and concentrated to a brown sludge (0.200 g, 0.82 mmol, "68%"). NMR analysis of this crude product showed the desired product (major) was formed along with a byproduct (minor) and that some SM remained and that there is grease contaminant in this crude product.

In future the aqueous wash would be basified during extraction to ensure all SM and products are collected and don't remain in aqueous phase as a salt (see MJT 16-1 first vs second extraction NMR). This was completed on a small scale and analysis of the resulting organic layer revealed that the duplicate peaks were not caused by the presence of a salt; rather they were more likely caused by the two possible monobrominated products.

Flash column chromatography (50% ethyl acetate in hexane; 40-60 micron silica particles) was used to isolate a single spot fraction (0.060 g after concentration) which NMR showed  contained a mix of isomers of the monobrominated product. A further fraction containing a mixture of spots (0.030 g) was also isolated but NMR showed that it contained one of the monobrominated species along with a small amount of product dimer. Salt remained on the column and was washed off with 10% methanol in DCM to give 0.020 g of brown sludge which was discarded.

 

 

 

Hazard and Risk Assessment

HIRAC MJT 9-1.pdf

Data


TLC

MJT 9-2 post workup

H NMR

crude produt:

MJT 9-2 crude.pdf

single product spot from column:

MJT 9-2 pure from column.pdf

two spot mix from column:

MJT 9-2 column mix.pdf

after basic workup:

MJT 9-2 after basic workup.pdf

H NMR of SM, MJT 7-2

Linked Posts
Attached Files
MJT 9-2 amounts table
MJT 9-2 post workup
MJT 9-2 crude.pdf
MJT 9-2 crude nmr raw data
MJT 9-2 pure from column.pdf
MJT 9-2 column mix.pdf
MJT 9-2 after basic workup.pdf