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17th May 2012 @ 03:49
START: 17/05/12

Altering reaction and workup conditions of experiment KAB26-5.


Hazard and Risk Assessment
As for KAB26-4
Hazard and Risk Assessment KAB26-4

Previous Experiments
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-4)
AuCl3/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-3)

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 (KAB26-6) - 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. The acetonitrile used was dried over activated 3Å (30 %(w/v)) for 72 hours prior. 2,6-Lutidine was dried over activated 3Å MS.
KAB23-1 (299 mg, 0.951 mmol, 1 equiv.) was dissolved in MeCN (45 mL) before the addition of activated 3Å powdered MS. The reaction mixture was cooled in a MeCN/liq. N2 bath to -40 &degC before the addition of Yb(OTf)3 (60 mg, 0.097 mmol, 0.1 equiv.) turning the pale yellow reaction mixture a bright yellow colour. Acetyl chloride (0.08 mL, 0.951 mmol, 1 equiv.) was added, dropwise. No change in appearance of reaction mixture. The dropwise addition of 2,6-lutidine (0.11 mL, 0.951 mmol, 1 equiv.) reduced the yellow intensity of each drop. The reaction mixture was left to stir at -40 &degC from 12:45.
TLC of the reaciton mixture after 5 minutes suggested formation of the hydrolysis products in addition to the expected product. Consequently, after 10 minutes, the reaction mixture was allowed to gradually warm to rt.
The reaction mixture was diluted with ethyl acetate (20 mL) before the addition of citric acid solution (20 mL). The organic fraction was isolated and the aqueous fraction extracted with ethyl acetate (3 × 30 mL). The organic fractions were combined then washed with saturated sodium bicarbonate solution (~40 mL). The alkaline aqueous layer was extracted with ethyl acetate (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated in vacuo to give the crude product as a yellow oil which rapidly crystallised on standing (247 mg).

H-NMR of the crude product suggested the composition consisted of the hydrolysis products (4-nitrobenzaldehyde and the monoacetylated dimethoxyphenethyamine), with minimal amounts of the starting material and the desired product. However, there was a complete absence of the diacetylated dimethoxyphenethylamine.

NMR Composition:

Summary and Conclusion

[1] S. W. Youn, The Journal of Organic Chemistry 2006, 71, 2521-2523. DOI: 10.1021/jo0524775. Paper
[2] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.

NOTES 19/05/12
I suspect the hydrolysis products were a result of the workup. Significantly diluted the citric acid solution for following experiment workups.
- Initially suspected the reaction reached completion, based on the TLC showing hydrolysis products and expected product. I now suspect the silica on the TLC (or column) is acidic enough to hydrolyse the KAB23 imine.
- Does not occur with the KAB19 imine (no NO2 EWG - must make a difference).
- This means I probably ceased the reaction too quickly.
Linked Posts
Attached Files
Scheme KAB26-6