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20th July 2012 @ 02:49
Repeat of MNR41-5 but monitoring the reaction for longer.

MNR41-4%20scheme.png
mnr41-5%20table.PNG

To a solution of MNR42-1 (0.5 g, 1.59 mmol) in dry acetonitrile (50 mL, HPLC grade stored over 3 Å molecular sieves for 24 hours) and 3 Å molecular sieves (10 g, dried in microwave) under argon at -10 C, was added was added acetyl chloride (0.23 mL, 3.18 mmol), 2,6-lutidine (0.37 mL, 3.18 mmol, stored over 3 Å molecular sieves) and diphenylmethane (0.27 mL, 0.268 mmol). Yb(OTf)3 (0.049 g, 0.08 mmol) was added and the reaction was allowed to warm to room temperature and then heated in an oil bath to 25 °C.

The reaction was monitored by LCMS by taking samples carrying out the following procedure.

0.1 ml was removed from the reaction mixture using a disposable syringe and transferred to a vial. EtOAc (0.2 mL) and sodium hydrogen carbonate saturated solution (0.2 mL) was added and the vial capped and shaken. The layers were allowed to separate and the organic layer was carefully removed by pipette and transferred to another vial and concentrated to dryness under reduced pressure.

Acetonitrile (1.8 mL) was added and the mixture shaken, 0.02 mL was transferred to a LCMS vial and acetonitrile 0.4 mL).

Samples taken at

5 mins
10 mins
15 mins
30 mins
60 mins
90 mins
120 mins
150 mins
180 mins
210 mins
240 mins
330 mins

Plotting the relative peak area of the product against time showed the reaction was competed after 1 hour.

MNR41-6%20LCMS%20Graph.png

Unfortunately, an accurate yield cannot calculated from the LCMS trace as calculations show the yield to be 140% - more calibration is being carried out to try and solve this problem

After 5.5 hours, the mixture was filtered to remove the molecular sieves and washed with EtOAc (50 mL). The filtrate was washed with saturated sodium bicarbonate solution (75 mL). The aqueous layer was extracted with ethyl acetate (3 × 110 mL). The organic fractions were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield a yellow oil 0.851 g.

5 samples of the crude were then transferred to vials for test recrystallisations and were left to stand at room temperature (10-17 °C) over the weekend.

135 mg in MeCN (2 ml) - no crystals
101 mg in toluene (2 ml) - cloudy, slight precipitation
132 mg in Et2O (2 mL) - didn't go into solution
126 mg in EtOH (2 mL) - fine crystals - 49 mg
144 mg in IPA (2 mL) - fine crystals. - 60mg
The remainder of the crude was disolved in EtOAC (4 mL)- fine crystals but didn't look as good as the above.

Hexane (5 ml) was added to the IPA vial and no more crystals/precipitate appeared. Filtered and washed with hexane.

The IPA crystals appeared to wash better and came out of the vial cleanly, the EtOH crystals were a bit more sticky.

IPA sample contained 17% of the crude. data]4698[/data] pure product as yellow crystals.
EtOH sample contained 15% of the crude.
mnr41-6_EtOH.pdf
50:50 mixture of product and starting material. Why is there still starting material??

** Note - crystals of both starting material and product contain 0.5 H2O

Filtrates combined with other recrystallisation attempts and concentrated to give a yellow oil - 0.672 g

Column

50-80% EtOAc/Hex - lutidine elutes just above the product but can be separated at this gradient.

Fracs 21-36 0.219 g - clean product
mnr41-6_frac12-36.pdf


Total product recovered - 0.357 g, 1.00 mmol, 63%
Attached Files
MNR41-6 LCMS Graph.png
mnr41-6_30mins.pdf
mnr41-6_90mins.pdf
mnr41-6_120mins.pdf
mnr41-6_180mins.pdf
mnr41-6_10mins.pdf
mnr41-6_150mins.pdf
mnr41-6_240mins.pdf
mnr41-6_0mins.pdf
mnr41-6_60mins.pdf
mnr41-6_15mins.pdf
mnr41-6_210mins.pdf
mnr41-6_05mins.pdf
mnr41-6_IPA.pdf
mnr41-6_EtOH.pdf
mnr41-6_frac12-36.pdf
From KAB26-20 - Yb(OTf)3BINOL .jpg