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14th May 2012 @ 09:15
START: 14/05/12
FINISH: 15/05/12

Altering workup conditions of experiment KAB26-4 under otherwise identical conditions.

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 (KAB26-5) - 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.
14/05/12. KAB23-1 (0.299 g, 0.951 mmol, 1 equiv.) was dissolved in acetonitrile (45 mL) before the sequential addition of well dried 3Å powdered MS, acetyl chloride (0.8 mL, 0.951 mmol, 1 equiv.) and 2,6-lutidine (0.12 mL, 0.951 mmol, 1 equiv.). Yb(OTf)3 (60 mg, 0.095 mmol, 10 mol%) was added and the reaction mixture was left to stir at rt, under argon from 18:10.
TLC of reaction mixture at 10 minutes suggested formation of a significant amount of product. Possibly to completion.
15/05/12. After 15 hours the reaction mixture was diluted with ethyl acetate (20 mL) then quenched with citric acid solution (30 mL). The organic layer was isolated and the aqueous layer extracted with ethyl acetate (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give a yellow gel (X g).

At least two different solids crystallised from the oil. After 7 hours standing at room temperature, yellow, granular crystals remained.

1H-NMR Assay development:
Crude: 11.3 mg
TCE: 2.6 mg

Re-run DMSO
Crude: 32.2 mg
TCE: 14 mg
Unclear. Run on 200 MHz. Re-run of TCE sample doped with isolated KAB26-2 product on 300 MHz. Clearer separation stereogenic centre proton and TCE peak. Possible to assay reaction mixture using DMSO-d6 in lieu of CDCl3, avoiding solubility issues.

Re-run CDCl3
Crude: 39 mg
TCE: 15.1 mg
~23% yield.
1.5% 4-nitrobenzaldehyde
Presence of monoacetylated dimethoxyphenethylamine (~8%), N-acetyl acetamide (~13%).
Crude product was also contaminated with EtOAc (~8 mg), the mass of which was removed from the percentage yield calculations.

Summary and Conclusion
Low yield based on NMR of the crude product following workup of the reaction mixture (citric acid wash). Reaction also appeared to near conclusion after 10 minutes.
Suggested workup alteration - silica gel filtration following concentration of the reaction mixture.
Reduce reaction temperature to ~-10 °C. Preparation of imine/catalyst/MS mixture before slow, dropwise addition of lutidine/AcCl mixture.

[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 15/05/12
Flask 47.1280 g
- Crude product contained the very poorly insoluble unknown. Need to get MS trace of unknown.
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Attached Files
Scheme KAB26-5