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17th July 2012 @ 02:09
Synthesis of MNR40-4 - monitoring reaction progress by LCMS

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

HIRAC
HIRAC MNR41.pdf


Procedure

To a solution of MNR42-1 (1.5 g, 4.77 mmol) in dry acetonitrile (160 mL, HPLC stored over 3 Å molecular sieves for 24 hours) and 3 Å molecular sieves (30 g, dried in microwave) under argon at 0 C, was added was added acetyl chloride (0.34 mL, 4.77 mmol) and 2,6-lutidine (0.55 mL, 4.77 mmol, stored over 3 Å molecular sieves). Yb(OTf)3 (0.03 g, 0.05 mmol) was added and the reaction was stirred at ambient temperature (~15 °C).

The reaction was monitored by LCMS by taking samples every hour 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, 0.055 mL was transferred to a LCMS vial and acetonitrile 0.345 mL).

Samples taken at

830am - 0 hours (before catalyst was added)
mnr41-4_0hours.pdf
-slight signs of product!?
930am - 1 hour (after adding catalyst)
mnr41-4_1hour.pdf

1030am - 2 hours
1130am - 3 hours
1230pm - 4 hours
130pm - 5 hours
230pm - 6 hours
330pm - 7 hours
430pm - 8 hours
530pm - 9 hours
mnr41-4_9hours.pdf

630pm - 10 hours*
mnr41-4_10hours.pdf

730 pm - 11 hours
mnr41-4_11hours.pdf

830am - 24 hours
930am - 25 hours

*just before the 10 hour mark Diphenylmethane (0.3 mL, 1.79 mmol) was added as an internal standard as early LCMS results showed the need for an internal standard. It's not clear if this will work as a standard but it was late in the evening and it was thought best to add something and try and follow the reaction from this point.

After 24 hours and seeing the results of the previous LCMS runs it looked like the reaction was not progressing an further than it had after 1 hour. It was decided to take a sample for mini work-up and 1H NMR.

After 26 hours, 1 mL was taken from the reaction and was diluted with EtOAc (4 mL) and washed with sodium hydrogen carbonate saturated solution (2 mL), extracted and reextracted with EtOAc (5 mL x 3). Dried, filtered and concentrated to give the crude as a yellow oil, 0.016 g.

1,1,2,2-tetrachloroethane (6 uL, 0.056 mmol) was added to the NMR sample of the crude.

mnr41-4_26 hours.pdf
mnr41-4_26 hours zoom.pdf


1H NMR showed a ratio of 0.38:0.12:1 (SM:Prod:Standard)
0.022 mmol:0.007 mmol - SM-Prod
6.8:2.4 mg = total 9.2 mg of the crude recovered.

Unclear why the reaction was not progressing and it's unusual still to see starting material in the crude NMR as this has not been seen before. It was good to see only slight traces of aldehyde therefore minimal hydrolysis has taken place. Decided to add another equivalent of AcCl to the reaction in an attempt to drive it towards completion.

After 29 hours - Acetyl chloride (0.4 mL, 5.63 mmol, 1.2eq) was added to the mixture at ambient temperature and stirring was continued
Attached Files
MNR41-4 scheme.png
mnr41-4 table.PNG
mnr41-4_3hours.pdf
mnr41-4_6hours.pdf
mnr41-4_0hours.pdf
mnr41-4_1hour.pdf
mnr41-4_4hours.pdf
mnr41-4_9hours.pdf
mnr41-4_8hours.pdf
4nitrobenzaldehyde.pdf
mnr41-4_5hours.pdf
mnr41-4_10hours.pdf
mnr41-4_2hours.pdf
mnr41-4_11hours.pdf
mnr41-4_7hours.pdf
mnr41-4_26 hours zoom.pdf
mnr41-4_26 hours.pdf
mnr41-4_26hours.zip