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22nd May 2012 @ 00:02
START: 22/05/12
FINISH:

To Do: MS isolated products.
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Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Extending the Yb(OTf)3 catalysed acyl-Pictet-Spengler reaction time at -30 °C (KAB26-8)
Yb(OTf)3 (1 mol%) catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-7)
Optimising Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-6)
Preparation of the 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine starting material (KAB23-2)

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 (KAB26-9) - 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.

Procedure
22/05/12. Acetonitrile (160 mL) was added to a flask charged with microwave activated 3Å molecular sieves. The mixture was left to stand at room temperature for 30 minutes before the addition of KAB23-2 (1.00 g, 3.18 mmol, 1 equiv.). Acetyl chloride (0.24 mL, 3.18 mmol, 1 equiv.) and 2,6-lutidine (0.38, 3.18 mmol, 1 equiv.) were added, dropwise to the stirring reaction mixture before the addition of Yb(OTf)3 (130 mg, 7 mol%). The reaction mixture was left to stir at room temperature, under an atmosphere of nitrogen, from 11:55.
KAB23-2 dissolving in MeCN
Reaction mixture at time zero

The reaction was monitored by TLC against the expected major product (analogous to KAB26-2). All TLCs were eluted with EtOAc/hexane, 1:1, v/v, visualised under UV (254 nm) then stained with KMnO4.
TLC of RM (5 min)
TLC of RM (15 min)
TLC of RM (30 min)

After 35 minutes, the MS were removed via filtration before the solution was washed with 10% citric acid solution (50 mL) and ethyl acetate (70 mL) was added. The organic fraction was isolated and the acidic aqueous layer was further extracted with ethyl acetate (3 × 40 mL). The organic fractions were combined, then adjusted to pH 8 by the addition of saturated sodium bicarbonate solution (~100 mL). The organic fraction was isolated, and the basic aqueous fraction was extracted with ethyl acetate (3 × 70 mL). The organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, then concentrated under reduced pressure to give the crude product as a yellow oil, which partially solidified on standing (YIELD).
Transferring RM after 30 min
After addition of citric acid soln
Drying combined organic fractions over MgSO4
Crude KAB26-9
TLC of crude KAB26-9

23/05/12. Purification of the crude product by silica gel column chromatography (50-100% EtOAc/hexane).
Combined fractions 2-7: 162 mg, 34% (4-nitrobenzaldehyde)
Combined fractions 18-43: 17 mg, (lutidine)
Combined fractions 78-197: 679 mg, 60% (Product)
Combined fractions 205+: 134 mg (contained monacetylated)

Summary and Conclusion
By products were isolated by silica gel column chromatography and identified by H-NMR. 95% Mol recovery - including aldehyde hydrolysis product. Final isolated product yield of 60% following reaction termination at 30 minutes.

References
[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.

Abbreviations Used:
EtOAc = ethyl acetate
TLC = thin layer chromatography
RM = reaction mixture
MS = molecular sieves
Soln = solution


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NOTES 22/05/12
Flask: 46.2258 g
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Linked Posts
Attached Files
Scheme KAB26-9
Scheme KAB26-9
KAB23-2 dissolving in MeCN
Reaction mixture at time zero
TLC of RM (5 min)
TLC of RM (15 min)
TLC of RM (30 min)
Transferring RM after 30 min
After addition of citric acid soln
Drying combined organic fractions over MgSO4
Crude KAB26-9
TLC of crude KAB26-9