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8th July 2016 @ 01:53

This methylation has previously been done with Cs2CO3 in DMF (See: Synthesis of methyl 2-methoxy-2-phenylacetate (AEW 184-1) ) which has led to low yields (~ 50% ). As a result, the use of silver oxide as a replacement is investigated here to determine if it will lead to an improvement of yields and/or efficiency.

Literature reference: http://onlinelibrary.wiley.com.ezproxy1.library.usyd.edu.au/doi/10.1002/anie.201410371/abstract

with the experiment details listed in the supporting information .pdf, found on page 23, listing a 75% yield.

Experiment

Methyl iodide (14.9 mL) and silver oxide (0.64 g) was added to methyl 2-hydroxy-2-phenylacetate (0.44 g) in anhydrous dichloromethane (10.0 mL), stirred at room temperature for 24 hours, the flask covered in aluminium foil.

TLC was performed in a 8:2 hexane:EtOAc eluent, showing that some starting material remained. The reaction mixture was filtered through a pad of CeliteTM and washed in DCM to remove the silver oxide. The DCM was then evaporated and the crude product dried. The crude product had a yellow colour.  The yield was 0.56 g, % yield: 117%. This is to expected as some of the starting material would be present in the crude product as determined by TLC. As a result, the crude product will be purified tomorrow by column.

1H NMR (200 MHz) was performed in deuterated chloroform. The spectra looks promising, however it does seem that some dichloromethane remains.

Column chromatography was performed however there was not enough time to finish the column, with 105 fractions collected starting from a 10:1 hexane:EtOAc and finishing on a 6:4 hexane:EtOAc gradient and no product obtained.

Strings

InChI=1S/C9H10O3/c1-12-9(11)8(10)7-5-3-2-4-6-7/h2-6,8,10H,1H3

to

InChI=1S/C10H12O3/c1-12-9(10(11)13-2)8-6-4-3-5-7-8/h3-7,9H,1-2H3

Attached Files
5th July 2016 @ 00:54

See Synthesis of methyl 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)acetate (SJD 3-2)

 

rac-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. The reaction mixture went from a colourless liquid to a black liquid.

TLC was performed in 8:2 hexane:EtOAc. The following workup was applied:

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 and evaporated to obtain the crude product. The yield was 10.1 g, % yield = 117 %, suggesting that some dichloromethane remains as residue.

A TLC error was then seen which meant that the reaction had not actually gone to completion as previously thought. The product was columned with the Isolera machine in a 8:2 hexane:EtOAc system. however upon completion it was apparent that the separation was not fully succesful, with only 16 fractions collected. As a result TLC was performed on each fraction to determine which contained product and which contained starting material. The product fractions were combined together and the solvents evaporated, as was the combined starting material.

The runoff from the Isolera machine was also evaporated. NMR will be performed on these samples later today.

 

Strings

InChI=1S/C9H8F2O3/c1-14-9(13)8(12)5-2-3-6(10)7(11)4-5/h2-4,8,12H,1H3

to

InChI=1S/C14H16F2O4/c1-18-14(17)13(20-12-4-2-3-7-19-12)9-5-6-10(15)11(16)8-9/h5-6,8,12-13H,2-4,7H2,1H3

Attached Files
4th July 2016 @ 02:21

See:

Synthesis of Methyl-2-hydroxy-2-phenylacetate (SJD 2-1)

                

(S)-mandelic acid (1.00g, 6.57 mmol) was added to p-toluene sulfonic acid (14.9 mg, 0.086 mmol) and dissolved in MeOH (12.2 mL), with the reaction heated to reflux and stirred (24 hours, 75 oC).

TLC was performed in 8:2 hexane: ethyl acetate. The methanol was then evaporated to yield the crude product, which was a clear solution. The yield was 0.998 g, % yield = 91.4 %.

 

Strings:

InChI=1S/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11)/t7-/m0/s1

to

InChI=1S/C9H10O3/c1-12-9(11)8(10)7-5-3-2-4-6-7/h2-6,8,10H,1H3/t8-/m0/s1

Attached Files
4th July 2016 @ 02:09

See: Synthesis of Methyl-2-hydroxy-2-phenylacetate (SJD 2-1)

rac-mandelic acid (15.0 g, 0.10 mol) was added to p-toluene sulfonic acid (171 mg, 0.10 mmol) and dissolved in MeOH (150 mL), with the reaction heated to reflux (70.0 oC) and stirred overnight. TLC was performed in a 8:2 hexane: ethyl acetate ratio and showed that the reaction had gone to completion. The methanol solvent was evaporated to yield a yellow liquid. Crude product yield was 17.1 g, % yield = 103.8, suggesting that some residue methanol remained in the flask.

1H NMR was performed (200 MHz, CDCl3) which showed that the product had formed.

InChi:

InChI=1S/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11)

to 

InChI=1S/C9H10O3/c1-12-9(11)8(10)7-5-3-2-4-6-7/h2-6,8,10H,1H3

Linked Entries
Attached Files
27th January 2016 @ 03:31

Repeat of SJD 4-1 with a different source of LiAlH4 used.

See Synthesis of 2-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (SJD 4-1)

 

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

1H NMR (300 MHz) was performed on the worked up product. The data shown indicates that the reaction was succesful.

Strings:

InChI=1S/C14H18O4/c1-16-14(15)13(11-7-3-2-4-8-11)18-12-9-5-6-10-17-12/h2-4,7-8,12-13H,5-6,9-10H2,1H3

to

InChI=1S/C13H18O3/c14-10-12(11-6-2-1-3-7-11)16-13-8-4-5-9-15-13/h1-3,6-7,12-14H,4-5,8-10H2

O=C(OC)C(OC1OCCCC1)C2=CC=CC=C2

to

OCC(OC1OCCCC1)C2=CC=CC=C2

Attached Files