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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
19th July 2012 @ 08:46
After it looked like MNR40-4 went to completion after 1 hour it was decided to monitor the reaction over the first hour. Increasing equivalents of reagents was also investigated.

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

To a solution of MNR42-1 (0.5 g, 1.59 mmol) in dry acetonitrile (47 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 stirred at ambient temperature (~15 °C).

The reaction was monitored by LCMS by taking samples every 10 minutes 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
20 mins
30 mins
40 mins
50 mins
60 mins

Plotting the relative peak area of the product against time showed the reaction progressing but after 1 hour the reaction was not completed. Monitoring stopped at this stage due to the time in the evening but this shows that we've a working assay to follow the reaction. reaction needs to be repeated over a longer time to see completion.

mnr41-5_plot.PNG
Attached Files
18th July 2012 @ 09:02
START: 18/07/12
FINISH: 20/07/12

Scheme%20KAB26-12.png
Table%20KAB26-13.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11)
Yb(OTf)3 catalysed (5 mol%) acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-12)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-2) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.

Procedure
All acetonitrile was dried over 3 Å molecular sieves (2.5-5 mm) for >24 h

Catalyst Solution Preparation
Yb(OTf)3 (41 mg, 0.063 mmol) was dissolved in acetonitrile (10 mL) to give a 6.4 mM solution.

To 3 Å MS was added acetonitrile (25 mL) and MNR42-1 (199 mg, 0.633 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath. Acetyl chloride (0.05 mL, 0.6 mmol, 1 equiv.), 2,6-lutidine (0.07 mL, 0.06 mmol, 1 equiv.) and the Yb(OTf)3/MeCN solution (5 mL, 0.05 equiv.) were added. The reaction mixture was allowed to warm to ambient temperature and stirred under argon from 19:00.
Off at 15:00, 19/07/12, 20 h. Workup identical to KAB26-12. Crude KAB26-13 (198 mg, 87%)
Column chromatography (65%, EtOAc/hexane, v/v).
Final yield (163 mg, 72%).
Summary and Conclusion

References
[1] S. W. Youn, J. Org. Chem. 2006, 71, 2521-2523. DOI: 10.1021/jo0524775. Paper
[2] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.
[3] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.

Abbreviations Used:
EtOAc = ethyl acetate
TLC = thin layer chromatography
RM = reaction mixture
MS = molecular sieves
Soln = solution


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NOTES
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Attached Files
18th July 2012 @ 04:21
START: 18/07/12
FINISH: 19/07/12

Scheme%20KAB26-12.png
Table%20KAB26-12.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-2) - SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1, InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-, InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11) - SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1, InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3, InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N.

Procedure
MNR42-1 (205 mg, 0.652 mmol, 1 equiv.) was dissolved in anhydrous acetonitrile (30 mL). The clear yellow solution was cooled in a brine ice bath before the addition of acetyl chloride (0.05 mL, 0.652 mmol, 1 equiv.) and 2,6-lutidine (0.05 mL, 0.652 mmol, 1 equiv.). Yb(OTf)3 (0.021 g, 0.034 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to ambient temperature and stirred under argon from 14:20.
At 15:20, an aliquot (1.5 mL) was extracted and diluted with EtOAc (10 mL). The mixture was washed with saturated sodium bicarbonate solution (10 mL). The organic fraction was separated and the aqueous layer further extracted with EtOAc (3 × 10 mL). The organic fractions were combined, dried over magnesium sulfate, filtered then concentrated under reduced pressure to give a yellowish semi-solid (10 mg).
At 17:30 the remainder of the reaction mixture was diluted with EtOAc (30 mL) and the mixture was triturated off the MS. The solution was washed with saturated sodium bicarbonate solution (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried (MgSO4) and concentrated under reduced pressure to give crude KAB26-12 (390 mg, 168%).
Crude KAB26-12

The crude product was purified by silica gel column chromatography (60% EtOAc/Hexane, v/v) yielding the KAB26-12 as a yellow solid (205 mg, 88%).

Summary and Conclusion
Yb(OTf)3 catalyst loading: 5 mol%.
Reaction time: 3 hours.
Temperature: Ambient.
Substrate Scale: 200 mg.
Isolated Yield: 88% (following chromatography).

References
[1] S. W. Youn, The Journal of Organic Chemistry 2006, 71, 2521-2523. DOI: 10.1021/jo0524775. Paper
[2] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.

Abbreviations Used:
EtOAc = ethyl acetate
TLC = thin layer chromatography
RM = reaction mixture
MS = molecular sieves
Soln = solution


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NOTES
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Linked Posts
Attached Files