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1st April 2012 @ 23:30
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Summary and Conclusion
Assay conditions worked out for the cyclisation to give racemic 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline. Isolated yield for the TFA mediated reaction was 28%, however low result may be due to incomplete conversion of starting material. Suspect red colour arises from protonation to give the intermediate iminium ion prior to cyclisation, which corroborates with the fading of the red colour over time and the appearance of the known product spot by TLC.
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START: 02/04/12
FINISH: 03/04/12

Background
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)

Following Experiments
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-3)
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, KAB24-2) - 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 (401 mg, 1.28 mmol, 1 eq) was partially dissolved in toluene (40 mL) to give a pale yellow solution. Trifluoroacetic acid (0.2 mL, 2.6 mmol, 2 eq) was added dropwise, turning the solution orange. The reaction mixture was reflux heated to 110 °C from 09:10, and the reaction progress monitored by TLC.
Before the addition of TFA
After the addition of TFA
Reaction mixture (30 min)
Reaction mixture (6 h)


Monitoring the Reaction Progress by TLC
TLC at 5 min: Eluted with 15% MeOH/DCM, v/v with a ninhydrin stain.
All other TLCs: Eluted with 5% MeOH/DCM, v/v with a ninhydrin stain.
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (5 h)
TLC of reaction mixture (6 h) - 15%

TLC of reaction mixture (6 h) - 5%


After 6.5 hours, the reaction mixture was removed from the oil bath and allowed to cool. The reaction was diluted with EtOAc (20 mL) then basified with NaOH (6 M) to pH 9-10, which resulted in the brief formation of a fine white solid, which dissolved into the organic layer. The organic fraction was isolated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB24-2 as dark yellow oil (524 mg, 131%).
Crude KAB24-2
TLC of crude KAB24-2 (5% MeOH/DCM; ninhydrin)
TLC of crude KAB24-2 (5% MeOH/DCM; KMnO4)
TLC of crude KAB24-2 (15% MeOH/DCM; ninhydrin)


The crude product was purified by silica gel column chromatography, eluting with 5% methanol/dichloromethane, v/v. The suspected product spot appeared in fractions 4-6. Fractions 5-6 were combined and concentrated under reduced pressure to give a yellow oil that solidified (partially crystallised) on standing (112 mg, 28%).
Fractions 1-10 (5% MeOH/DCM; ninhydrin)
Fractions 3-6 (5% MeOH/DCM; ninhydrin)
KAB24-2 fractions 5-6


1H-NMR of the combined fractions 5-6 confirmed the presence of the expected KAB24-2 product.
Raw H-NMR KAB24-2 f5-6


Summary and Conclusion
Assay conditions worked out for the cyclisation to give racemic 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline. Isolated yield for the TFA mediated reaction was 28%, however low result may be due to incomplete conversion of starting material. Suspect red colour arises from protonation to give the intermediate iminium ion prior to cyclisation, which corroborates with the fading of the red colour over time and the appearance of the known product spot by TLC.

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.
[2] Proton NMR Spectrum (ZI_4051247_cbi_01136), Wiley Subscription Services, Inc. (US)


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NOTES 02/04/12
- ~10 mins: Immiscible red droplets visible in the bottom of the reaction mixture.
- 15 min: starting to see formation of suspected product spot.
- Stain of 6 hr reaction mixture with KMnO4 shows more spots.

NOTES 03/02/12
- Possible to monitor reaction progress by UV-Vis absorbance? Strong colour changes over time.
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Attached Files
Scheme KAB24-2
Before the addition of TFA
After the addition of TFA
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (5 h)
Reaction mixture (30 min)
Reaction mixture (6 h)
TLC of reaction mixture (6 h) - 15%
TLC of reaction mixture (6 h) - 5%
Reaction mixture after removal from heat
After basification
Crude KAB24-2
TLC of crude KAB24-2 (5% MeOH/DCM; ninhydrin)
TLC of crude KAB24-2 (5% MeOH/DCM; KMnO4)
TLC of crude KAB24-2 (15% MeOH/DCM; ninhydrin)
Fractions 1-10 (5% MeOH/DCM; ninhydrin)
Fractions 3-6 (5% MeOH/DCM; ninhydrin)
Raw H-NMR KAB24-2 f5-6
KAB24-2 fractions 5-6