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Pictet-Spengler route to Praziquantel
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24th July 2012 @ 14:06
START: 25/07/12
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Scheme%20KAB26-18.png
Table%20KAB26-18.png

Hazard and Risk Assessment
HRA KAB26-18


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3/PyBOX catalysed asymmetric acyl-PS formation of KAB26-17

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - 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 (KAB26-18) - 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.
(S)-[1,1'-binaphthalene]-2,2'-diol ((S)-BINOL) - SMILES: OC1=[C@]([C@]2=C(C=CC=C3)C3=CC=C2O)C4=CC=CC=C4C=C1, InChI: InChI=1S/C20H14O2/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22/h1-12,21-22H, InChIKey: PPTXVXKCQZKFBN-UHFFFAOYSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.

Catalyst Solution Preparation
(S)-[1,1'-binaphthalene]-2,2'-diol (28 mg, 0.097 mmol, 3 equiv.) and Yb(OTf)3 (0.020 mg, 0.032 mmol, 1 equiv.) were dissolved in dried THF (0.5 mL) to give a chiral catalyst solution of 64 mM.

To a mixture of 4 Å molecular sieves (~1.5 g) in MeCN (16 mL) was dissolved MNR42-1 (100 mg, 0.318 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, 1.8 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3/(S)-BINOL/THF (0.25 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:00.
After 2 hours, the reaction mixture was diluted with EtOAc (15 mL). The mixture was washed with saturated sodium bicarbonate solution (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 to yield crude KAB26-18 as a yellow solid (167 mg, 143%).

Summary and Conclusion


References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2] H. Ishitani and S. Kobayashi, TetLett 1996, 37, 7357.
[3] S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi and M. Shibaski, TetLett 1998, 39, 7353.
[4] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

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NOTES
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Attached Files
HRA KAB26-18
Scheme KAB26-18
Table KAB26-18