Pictet-Spengler route to Praziquantel

 

START: 10/04/12
FINISH:

Background
Extending the reaction time. Also see synaptic leap post: here.




Hazard and Risk Assessment
As for KAB24-1 (here)

Previous Experiments
Synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-4)
Synthesis of 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-1)
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-1)
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-2)

Following Experiments
TFA catalysed synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-4)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (1, KAB23-1) - 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.
6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (2, KAB24-3) - SMILES: O=[N+]([O-])C1=CC=C(C2NCCC3=CC(OC)=C(OC)C=C32)C=C1, InChi: InChI=1S/C17H18N2O4/c1-22-15-9-12-7-8-18-17(14(12)10-16(15)23-2)11-3-5-13(6-4-11)19(20)21/h3-6,9-10,17-18H,7-8H2,1-2H3, InChIKey: GITFNMZGMQLGOX-UHFFFAOYSA-N.

Procedure
KAB23-1 (313 mg, 996 mmol) was dissolved in toluene (30 mL) before the addition of trifluoroacetic acid (0.15 mL, 2.0 mmol, 2 equiv.) at rt. The reaction mixture was reflux heated to 110 °C from 9:45.


Monitoring the Reaction Progress by TLC


TLC at 5 min: Eluted with 5%, MeOH/DCM, v/v; ninhydrin stain.
All other TLCs: Eluted with 15%, MeOH/DCM, v/v; ninhydrin stain.

Diluted with EtOAc (30 mL)
Quenched with saturated sodium bicarbonate (80 mL)
Extracted with EtOAc (2 × 50 mL)
Crude yield: 316 mg (101%).

Summary and Conclusion


References
[1] R. Gitto, M. L. Barreca, L. De Luca, G. De Sarro, G. Ferreri, S. Quartarone, E. Russo, A. Constanti, A. Chimirri, Journal of Medicinal Chemistry 2003, 46, 197.



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NOTES 10/04/12
- At 5 hours: reaction mixture contains both the suspected iminium ion and the cyclised product.

NOTES 12/04/12
- Flask weight: 47.1237 g
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