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Pictet-Spengler route to Praziquantel
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23rd July 2012 @ 00:37
START: 23/07/12
FINISH: 23/07/12

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 103 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 51% (following chromatography).

Scheme%20KAB26-14.png
Table%20KAB26-15.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)
Yb(OTf)3 catalysed acyl-PS formation of KAB26-14 in THF
Acyl-PS to give KAB26-13 using Yb(OTf)3 (5 mol%) catalyst solution

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine - 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 (KAB26-14) - 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 THF was dried over 3 Å molecular sieves (1.5-2.5 mm) for >72 h

Catalyst Solution Preparation
Yb(OTf)3 (113 mg, 0.182 mmol) was dissolved in THF (5.1 mL) to give a 36 mM solution.

To a mixture of 3 Å molecular sieves in THF (16 mL) was dissolved MNR42-1 (103 mg, 0.328 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.7 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3/THF (0.46 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:30.
After 1.5 hours, the reaction mixture was diluted with EtOAc (20 mL). Saturated sodium bicarbonate solution was added (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure before dry loaded onto a silica gel column.
Column chromatography (60-65%, EtOAc/hexane, v/v) of the crude product yielded KAB26-15 as a yellow solid (59 mg, 51%).

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 103 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 51% (following chromatography).

References
[1] 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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Linked Posts
Attached Files
Scheme KAB26-15
Table KAB26-15