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9th April 2012 @ 23:14
START: 10/04/12
FINISH:

Background
Also see synaptic leap post: here.




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

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

Following Experiments
TFA mediated synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-3)
TFA catalysed synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-4)

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, KAB24-4) - 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 (407 mg, 1.295 mmol) was dissolved in toluene (40 mL) before the addition of trifluoroacetic acid (49.6 μL, 0.647 mmol, 0.5 equiv.) at rt. The reaciton mixture was heated to 110 °C from 9:45.
After the addition of TFA
Reaction mixture (7 h)
Reaction mixture (25 h)
Reaction mixture (32 h)
Reaction mixture (71 h)


Monitoring the Reaction Progress by TLC
TLC of reaction mixture (5 min)
TLC of reaction mixture (5 h)
TLC of reaction mixture (23 h)
TLC of reaction mixture (32 h)
TLC of reaction mixture (71 h)

TLC at 5 min: Eluted with 5%, methanol/dichloromethane, v/v; ninhydrin stain
All other TLCs: Eluted with 15%, methanol/dichloromethane, v/v; ninhydrin stain

Diluted with EtOAc (30 mL)
Quenched with saturated sodium bicarbonate (80 mL)
Extracted with EtOAc (2 × 50 mL)
Crude KAB24-4 (417 mg, 102%)

Raw H-NMR crude KAB24-4


1H-NMR of the crude product (300 MHz, CDCl3) did not show the trace amounts cyclised product as indicated by TLC.

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: The reaction mixture contained a mixture of the imine and the suspected iminium ion.

NOTES 11/04/12
- Traces of product by TLC at 23 hours. Reaction mixture still contains starting material and iminium. TLC appeared very spotty under UV. Also contained spots visible under long wave UV.
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Linked Posts
Attached Files
Scheme KAB24-4
TLC of reaction mixture (5 min)
TLC of reaction mixture (5 h)
After the addition of TFA
Reaction mixture (7 h)
Reaction mixture (25 h)
Reaction mixture (32 h)
TLC of reaction mixture (32 h)
TLC of reaction mixture (32 h)
TLC of reaction mixture (23 h)
TLC of reaction mixture (71 h)
TLC of reaction mixture (71 h)
Reaction mixture (71 h)
Raw H-NMR crude KAB24-4