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9th May 2012 @ 06:15
START: 09/05/12
FINISH: 11/05/12

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4

Previous Experiments
Yb(OTf)3 catalysed PS reaction to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-9)
TFA catalysed synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-4)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24
AuCl3/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-1 & KAB26-2)
Preparation of the 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine starting material (KAB23-2)

Following Experiments

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-2) - 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 (KAB26-4) - 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.

All glassware was ovendried overnight prior to use.
09/05/12. KAB23-1 (0.365 g, 1.161 mmol, 1 equiv.) was dissolved in freshly distilled MeCN (60 mL) before the sequential addition of well dried 3Å powdered MS, acetyl chloride (0.08 mL, 1.2 mmol, 1 equiv.) and 2,6-lutidine (0.13 mL, 1.161 mmol, 1 equiv.). Yb(OTf)3 (60 mg, 0.097 mmol, 10 mol%) was added and the reaction mixture was left to stir at rt, under argon from 18:00.
10/05/12. TLC of the reaction mixture at 15 hours.
TLC of RM (15 h)

Product, Rf 0.23
4-nitrobenzaldehyde, Rf 0.23
Mono-acetylated dimethoxyphenethylamine, Rf 0.06
Suspected Diacetylated dimethoxyphenethylamine, Rf 0.16
Flask + Reaction Mixture: 132.974 g

Filtration through celite, eluting with EtOAc.
Crude yield: 317 mg

Sample for NMR: 5.7 mg
1,1,2,2-tetrachloroethane: 8.8 mg, 0.052 mmol
Yield from NMR: 4.6 mg
Yield from NMR: 81%

Total Crude yield: 437 mg

Crude KAB26-4 before aqueous wash

Some material insoluble in organic solvent was removed following aqueous wash (deionised water). Aqueous layer was extracted with EtOAc, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give a yellow oil.

Silica gel column chromatograhy (100% EtOAc).

Combined fractions 7-14.
NMR indicated presence of product.
TLC contained 3 spots.
Mass recovered 218 mg, 0.611 mmol.
Isolated percentage yield: 53%
TLC KAB26-4 fractions 7-14

Summary and Conclusion
Crude NMR suggested 81% conversion to the expected product. Aqueous wash and column chromatography of the remaining crude product produced a final isolated yield of 53%
Possibility of loss of product into aqueous layer, despite extraction with EtOAc. Also, the remaining product was sitting at rt, in the reaction mixture for an additional 4+ hours under non-anhydrous conditions, while waiting for the results of the internal standard H-NMR.
Suggested course of action for next reaction: Concentration of the reaction mixture after 12-15 hours (or less - subject to reaction mixture TLC) followed by immediate silica gel column chromatography (100% EtOAc). Extraction of crude concentrated product for H-NMR. Comparison of conversion as indicated by NMR with final isolated product.

[1] S. W. Youn, The Journal of Organic Chemistry 2006, 71, 2521-2523. DOI: 10.1021/jo0524775. Paper

NOTES 10/05/12
- Flask = 50.4784
- Washed with water!

Linked Posts
Attached Files
Scheme KAB26-4
Hazard and Risk Assessment KAB26-4
TLC of RM (15 h)
Crude KAB26-4 before aqueous wash
TLC KAB26-4 fractions 7-14