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29th May 2012 @ 08:07
START: 29/05/12
FINISH: 31/05/12

Lowering catalyst load to 1 mol%. Letting reaction run for >30 min.
Scheme%20KAB26-11.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Isolating byproducts in the Yb(OTf)3 catalysed acyl Pictet-Spengler reaction (KAB26-9)
AuCl3/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-10)
Extending the Yb(OTf)3 catalysed acyl-Pictet-Spengler reaction time at -30 &degC (KAB26-8)

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 (KAB26-11) - 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
NOTE: Reaction was performed under anhydrous conditions.
29/05/12. KAB23-2 (1.50 g, 4.77 mmol, 1 equiv.) was dissolved in acetonitrile (160 mL) over 3 Å MS. Acetyl chloride (0.34 mL, 4.8 mmol, 1 equiv.) and 2,6-lutidine (0.55 mL, 4.8 mmol, 1 equiv.) were sequentially added, dropwise, at 0 °C. Yb(OTf)3 (0.034 g, 0.048 mmol, 0.01 equiv.) was added. The mixture was allowed to warm to rt and left to stir under an argon atmosphere from 18:00.
30/05/12. After 24 hours, the molecular sieves were removed via vacuum filtration. The filtrate was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 solution (30 mL). The organic layer was isolated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried (MgSO4), and concentrated under reduced pressure to give crude KAB26-11 as a yellow oil (1.8 g, 106%).
RM at 23 h
TLC of RM (15 h)
TLC of RM (23 h)

31/05/12. The crude oil partially crystallised overnight. Methanol was added to the oil and solid mixture, which was heated until all the solid had dissolved. Dry silica was added and the mixture concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 70-100% EtOAc/hexane. The KAB26-11 product was collected in fractions 26-51, which were combined and concentrated in vacuo to yield a yellow powder (1.30 g, 77%).

Summary and Conclusion

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
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28th May 2012 @ 08:10
START: 28/05/12
FINISH:




Hazard and Risk Assessment
As for KAB26-2
HRA KAB26-X


Previous Experiments

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.

Procedure
28/05/12. A mixture of HAuCl3·3H2O (31 mg, 0.079 mmol, 1 mol%) and AgOTf (30 mg, 0.12 mmol, 2 mol%) in acetonitrile (15 mL) was vigorously stirred at room temperature from 17:10.
KAB23-2 (1.9 g, 6.1 mmol, 1 equiv.) was dissolved in acetonitrile (250 mL) before the sequential addition of acetyl chloride (0.40 mL, 6.1 mmol, 1 equiv.) and 2,6-lutidine (0.70 mL, 6.1 mmol, 1 equiv.). After the gold/silver mixture had stirred for 1 hour, the KAB23-1 mixture was added, and the reaction mixture was left to stir overnight, from 18:10.
29/05/12. After 14 hours, the reaction mixture was concentrated under reduced pressure.
F8-16 (aldehyde).
F50-68 Product (875 mg).

Summary and Conclusion
Isolated yield of KAB26-10 was 40% following silica gel column chromatography. By products of the reaction included 4-nitrobenzaldehyde and N-(3,4-dimethoxyphenethyl)acetamide.

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

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NOTES 28/05/12
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22nd May 2012 @ 00:02
START: 22/05/12
FINISH:

To Do: MS isolated products.
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Scheme%20KAB26-9.png

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 &degC (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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18th May 2012 @ 05:40
START: 18/05/12
FINISH: 22/05/12

TO DO: Write summary and conclusion - from NMR assay.




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 (KAB26-8) - 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
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.
KAB23-2: 298 mg
Yb(OTf)3: 61 mg
AcCl: 0.08 mL
2,6-lutidine: 0.11 mL
On at 14:30.
Overnight.

Crude yield: 0.560 g.

Summary and Conclusion

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.


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NOTES 21/05/12
- Flask + crude = 44.2717 g

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18th May 2012 @ 04:08
MNR14-3%20scheme.png

KAB6-1 (0.29 g, 0.73 mmol) in toluene (4 mL) was treated with methanesulfonic acid (0.05 mL, 0.73 mmol) and the reaction was stirred at room temperature for 5 hours by which time TLC had shown complete consumption of SM. The reaction was neutralised with sat. sodium hydrogen carbonate solution, the organic fraction extracted and the aqueous fraction was washed with EtOAc (10 mL x 3). The organic layers were combined, dried, filtered and concentrated to give a dark orange oil.

TLC after 5 hours in 100% EtOAc
MNR14-3 5 hours


Crude - 0.277 g

Column 30-100% EtOAc

Fracs 36-65 as MNR14-3-INT 0.028 g

MNR14-3-INT.png


Other frac - 0.182 g - messy NMR's

As expected, no fully PS cyclised product isolated. Yield of the intermediate enediamide is low, perhaps to due the delay between running the reaction and running the column or may this is just a messy reaction as it doesn't run cleanly to the desired product.
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