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Reduction of ester with new batch of LiAlH4 in THF following failed reduction of carboxylic acid in Synthesis of 2-phenylpropane-1,3-diol (AEW 268-1)
AEW 266-2 (1.50 g, 7.72 mmol, 1.00 equiv.) was dissolved in anhydrous diethyl ether (77 mL) and cooled to 0 ˚C. LiAlH4 (1 M in THF, 4.94 mL, 4.94 mmol, 0.64 equiv.) was added dropwise and the reaction mixture stirred for ten mins at 0 ˚C and then ten mins after reaching rt. Reaction mixture refluxed for x h.
Repeat of SJD 4-1 with a different source of LiAlH4 used.
Anhydrous diethyl ether ( 10.0 mL, 192 mmol) was added to a stirred solution of LiAlH4 ( 11 mL, 1 M) at 0 oC. Anhydrous diethyl ether (5.50 mL) was added dropwise to methyl 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (17.2 mmol, 4.3 g) under argon for 5 minutes. The reaction mixture was stirred at 0 oC for 1 hour. It was then stirred at room temperature for 18 hours under reflux.
Diethyl ether (40 mL) was added to the reaction mixture, proceeded by rochelle salt (15 mL). The reaction mixture was filtered through CeliteTM. A white oil remained in the reaction flask due to not leaving the reaction to stir for long enough. The filtered reaction mixture was thus transferred back into the flask, acetone (10 mL) was added along with more diethyl ether (10 mL)
1H NMR (300 MHz) was performed on the worked up product. The data shown indicates that the reaction was succesful.
Note: Reaction started on 29/01/2016, date shown on ELN is due to draft being written beforehand
5-chloro-3-(pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyrazine (AEW 201-1) (250 mg, 1.08 mmol, 1 equiv.) was added to potassium hydroxide (212 mg, 3.78 mmol 3.5 equiv.) and 18-crown-6 (20 mg, 0.07 equiv.). 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (SJD 3-1) (264 mg, 1.19 mmol, 1.1 equiv) was dissolved in toluene (~ 4 mL) and added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes, after which it was heated to 40 oC.
1H NMR (300 MHz) data was collected on the crude product. The data look promising and can undergo the next step of the synthesis which is removal of the THP protecting group.
Methyl 2-hydroxy-2-phenylacetate (5.75g, 34.6 mmol) was dissolved in anhydrous CH2Cl2 (35.0 mL, 0.1 M). 3,4-dihydro-2H-pyran (3.24 g, 38.5 mmol, 1.1 equiv) and p-TsOH (1.21 g, 7.00 mmol, 0.2 equiv) were then added to the reaction mixture, left to stir at room temperature for 2 hours.TLC was performed in 20% EtOAc to hexane and showed that there was still some starting material present in the mixture. As a result, more p-TsOH (0.63 g, 3.6 mmol) was added and left to stir at room temperature for 3 hours.
The reaction mixture was transferred to a seperating funnel and was washed dichloromethane (35 mL) and sodium hydrogen carbonate (35 mL). The bottom organic layer was collected. The aqueous layer was further washed with dichloromethane ( 2 x 35 mL), collecting the organic layers together. The combined organic layer was washed with brine (20 mL), collecting again the bottom organic layer. This was then dried with sodium sulphate, filtered andevaporated to obtain the crude product (8.04 g), which had a dark brown appearance.
1H NMR (300 MHz) data was gathered on the product. The data suggests that the reaction was succesfully completed.
Anhydrous diethyl ether (20 mL) was added to a stirred solution of LiAlH4 (800 mg, 21.1 mmol, 0.64 equiv.) at 0 ˚C. Anhydrous diethyl ether ( 11 mL) was added dropwise to methyl 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (32.9 mmol) under argon for 5 minutes. The reaction mixture was stirred at 0 ˚C for 4 hours and then at room temperature for 10 minutes after which it was refluxed for 20 hours.
The reaction mixture was cooled to room temperature and then to 0 oC. Diethyl ether ( ~ 40 mL)was added to the reaction mixture. Rochelle salt was added (~15 g) to the mixture so that no reflux was required. The mixture was then filtered through CeliteTM twice however LiAlH4 still remained in the mixture. Thus the mixture was seperated with ethyl acetate (3 x 50 mL) collecting the top organic layer. The combined organic layers were dried over sodium sulphate, filtered and evaporate. The crude product (4.80 g) had a yellow oily appearance.
HCl (~ 25 mL) was added to the aqueous solution (pH 4) which was then seperated with ethyl acetate (3 x 15 mL). The top layer was collected, dried over sodium sulfate, filtered and evaporated.
Crude NMR of starting material performed post reaction due to NMR facilities being under maintenance. NMR data of starting material was confirmed.
1H NMR (200 MHz) was originally performed on both the neutral workup and acidic workup mixtures, however both data files were corrupted. 1H NMR (300 MHz) was thus done on just the neutral workup. The data suggests that the reaction had failed to reduce the methyl ester. It is thought that this is possibly due to the LiAlH4 no longer being reactive. TLC will be performed on the reaction mixture with the starting material to determine the next course of action.
TLC was performed in 20% EtOAc to hexane, indicating that the starting material was in the final reaction mixture, confirming that the reaction was not succesful, likely due to LiAlH4's loss of reactivity.