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27th March 2012 @ 08:13
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Summary and Conclusion
Unknown if the cyclisation was successful. Value for yield unreliable. Presence of 2° amine and consumption of starting material suggested formation of expected product. No confirmation by H-NMR. The crude product decomposed overnight before it was purified by chromatography.
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START: 27/03/12
FINISH: 30/03/12

Background
See synaptic leap post: here.




Hazard and Risk Assessment
Hazard and Risk Assessment KAB24-1


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)

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

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, KAB24-1) - 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
27/03/12. A suspension of KAB23-1 (610 mg, 1.94 mmol, 1 eq) in toluene (20 mL) was prepared before the slow addition of trifluoroacetic acid (6 mL, 78.4 mmol, 40 eq).
The pale yellow suspension turned clear and orange-red immediately after the addition of TFA. The reaction mixture was reflux heated to 110 °C from 18:45. After 15 minutes, the reaction turned clear yellow.
TLC indicated complete consumption of the starting material after 35 minutes (MeOH/DCM, 15%, v/v; ninhydrin stain).
TLC of reaction mixture (30 min)

The reaction mixture was promptly removed from the oil bath and allowed to cool.

28/03/12. After standing at rt for 13 hours, the reaction mixture was poured over ice then basified with NaOH (6 M), resulting in the brief formation of a white precipitate, which was presumably dissolved in the organic phase. The organic fraction was isolated and the aqueous fraction extracted with EtOAc (3 × 30 mL) then Et2O (50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB24-1 as a yellow paste, which showed signs of solidifying (~2 g wet). The crude product was put under a high vacuum for >7 hours, which solidified some of the product. The remainder was a paste.

Attempted to purify by silica gel column chromatography (5% MeOH/DCM). However collection of the first 10 fractions revealed product decomposition overnight (product had also went from a yellow solid to a brown gel). The product was taken no further. Experiment requires repeat.

Summary and Conclusion
Unknown if the cyclisation was successful. Value for yield unreliable. Presence of 2° amine and consumption of starting material suggested formation of expected product. No confirmation by H-NMR. The crude product decomposed overnight before it was purified by chromatography.


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 27/03/12
- Still working out assay conditions. Will need to monitor consumption of starting materials vs appearance of product. So far: Appearance of product - 15% MeOH/DCM, v/v.

NOTES 29/03/12
- Poorly soluble in CDCl3
- Proton NMR unclear of crude product unclear. Will need to purify by column chromatography.
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Linked Posts
Attached Files
Scheme KAB24-1
Hazard and Risk Assessment KAB24-1
Table KAB24-1
TLC of reaction mixture (30 min)