Notice: Undefined index: showkeys in /home/www/hosts/www.ourexperiment.org/lib/proc_blog.php on line 23
Pictet-Spengler route to Praziquantel
All Notebooks | Help | Support | About
24th July 2012 @ 14:06
START: 25/07/12
FINISH:

Scheme%20KAB26-18.png
Table%20KAB26-18.png

Hazard and Risk Assessment
HRA KAB26-18


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3/PyBOX catalysed asymmetric acyl-PS formation of KAB26-17

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - 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 (KAB26-18) - 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.
(S)-[1,1'-binaphthalene]-2,2'-diol ((S)-BINOL) - SMILES: OC1=[C@]([C@]2=C(C=CC=C3)C3=CC=C2O)C4=CC=CC=C4C=C1, InChI: InChI=1S/C20H14O2/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22/h1-12,21-22H, InChIKey: PPTXVXKCQZKFBN-UHFFFAOYSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.

Catalyst Solution Preparation
(S)-[1,1'-binaphthalene]-2,2'-diol (28 mg, 0.097 mmol, 3 equiv.) and Yb(OTf)3 (0.020 mg, 0.032 mmol, 1 equiv.) were dissolved in dried THF (0.5 mL) to give a chiral catalyst solution of 64 mM.

To a mixture of 4 Å molecular sieves (~1.5 g) in MeCN (16 mL) was dissolved MNR42-1 (100 mg, 0.318 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.8 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3/(S)-BINOL/THF (0.25 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:00.
After 2 hours, the reaction mixture was diluted with EtOAc (15 mL). The mixture was washed with saturated sodium bicarbonate solution (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure to yield crude KAB26-18 as a yellow solid (167 mg, 143%).

Summary and Conclusion


References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2] H. Ishitani and S. Kobayashi, TetLett 1996, 37, 7357.
[3] S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi and M. Shibaski, TetLett 1998, 39, 7353.
[4] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

------------------------------------------
NOTES
------------------------------------------
Attached Files
24th July 2012 @ 12:49
START: Scheduled for 25/07/12
FINISH:

Scheme%20KAB26-17.png
Table%20KAB26-17.png

Hazard and Risk Assessment
HRA KAB26-17


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 (THF solution) catalysed acyl-PS formation of KAB26-16 in MeCN

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (MNR42-1) - 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 (KAB26-17) - 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.
2,6-bis((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine ((R)-PyBOX) - SMILES: CC([C@@H]1COC(C2=CC=CC(C3=N[C@H](C(C)C)CO3)=N2)=N1)C, InChI: InChI=1S/C17H23N3O2/c1-10(2)14-8-21-16(19-14)12-6-5-7-13(18-12)17-20-15(9-22-17)11(3)4/h5-7,10-11,14-15H,8-9H2,1-4H3/t14-,15-/m0/s1, InChIKey: CSGQGLBCAHGJDR-GJZGRUSLSA-N.

Procedure
NOTE: All THF was dried over microwave activated 3 Å molecular sieves (2.0-2.5 mm) >72 h prior to use. All acetonitrile was dried over microwave 3 Å molecular sieves (2.0-2.5 mm) >24 h prior to use.[1] All glassware used was dried overnight at 115 °C.

Catalyst Solution Preparation
2,6-Bis[(4R)-(+)-isopropyl-2-oxazolin-2-yl]pyridine (39 mg, 0.129 mmol, 2 equiv.) and Yb(OTf)3 (0.040 mg, 0.064 mmol, 1 equiv.) were dissolved in dried THF (1.9 mL) to give a chiral catalyst solution of 34 mM.

To a mixture of 3 Å molecular sieves (~1.5 g) in MeCN (16 mL) was dissolved MNR42-1 (100 mg, 0.318 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.8 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). The catalyst solution (0.47 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:30.
After 2 hours, the reaction mixture was diluted with EtOAc (15 mL). The mixture was washed with saturated sodium bicarbonate solution (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure to yield crude KAB26-17 (176 mg, 155%).


Summary and Conclusion


References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.
[2] H. C. Aspinall, J. F. Bickley, N. Greeves, R. V. Kelly and P. M. Smith, Organometallics 2005, 24, 3458. DOI: 10.1021/om050197+ Paper.
[3] H. Suga, K. Inoue, S. Inoue, A. Kakehi and M. Shiro, J. Org. Chem. 2005, 70, 47. DOI: 10.1021/jo049007f Paper
[4] Rare-Earth Metal Triflates in Organic Synthesis, S. Kobayashi, M. Sugiura, H. Kitagawa and W. W.-L. Lam, Chem. Rev. 2002, 102, 2227–2302. DOI: 10.1021/cr010289i Paper.

------------------------------------------
NOTES
------------------------------------------
Linked Posts
Attached Files
23rd July 2012 @ 00:38
START: 23/07/12
FINISH: 23/07/12

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 100 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: 1:32, THF/MeCN, v/v.
Isolated yield: 97% (following chromatography).

Scheme%20KAB26-16.png
Table%20KAB26-16.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11)
Yb(OTf)3 catalysed (5 mol%) acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-12)
Acyl-PS formation of KAB26-15 using Yb(OTf)3/THF solution
Yb(OTf)3 catalysed acyl-PS formation of KAB26-14 in THF

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine - 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 (KAB26-14) - 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 THF was dried over 3 Å molecular sieves (2.5-5 mm) for >72 h

Catalyst Solution Preparation
Yb(OTf)3 (113 mg, 0.182 mmol) was dissolved in THF (5.1 mL) to give a 36 mM solution.

To a mixture of 3 Å molecular sieves in MeCN (16 mL) was dissolved MNR42-1 (100 mg, 0.318 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.8 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3/THF (0.45 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:35.
After 2 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure before dry loaded onto a silica gel column.
Column chromatography (60-65%, EtOAc/hexane, v/v) of the crude product yielded KAB26-16 as a yellow solid (110 mg, 97%).

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 100 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: 1:32, THF/MeCN, v/v.
Isolated yield: 97% (following chromatography).

References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.

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


------------------------------------------
NOTES
Product - combined fractions 22-34.
------------------------------------------
Linked Posts
Attached Files
23rd July 2012 @ 00:37
START: 23/07/12
FINISH: 23/07/12

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 103 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 51% (following chromatography).

Scheme%20KAB26-14.png
Table%20KAB26-15.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11)
Yb(OTf)3 catalysed (5 mol%) acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-12)
Yb(OTf)3 catalysed acyl-PS formation of KAB26-14 in THF
Acyl-PS to give KAB26-13 using Yb(OTf)3 (5 mol%) catalyst solution

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine - 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 (KAB26-14) - 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 THF was dried over 3 Å molecular sieves (1.5-2.5 mm) for >72 h

Catalyst Solution Preparation
Yb(OTf)3 (113 mg, 0.182 mmol) was dissolved in THF (5.1 mL) to give a 36 mM solution.

To a mixture of 3 Å molecular sieves in THF (16 mL) was dissolved MNR42-1 (103 mg, 0.328 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.7 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3/THF (0.46 mL, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:30.
After 1.5 hours, the reaction mixture was diluted with EtOAc (20 mL). Saturated sodium bicarbonate solution was added (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure before dry loaded onto a silica gel column.
Column chromatography (60-65%, EtOAc/hexane, v/v) of the crude product yielded KAB26-15 as a yellow solid (59 mg, 51%).

Summary and Conclusion
Yb(OTf)3/THF catalyst solution: 36 mM.
Substrate scale: 103 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 51% (following chromatography).

References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.

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


------------------------------------------
NOTES
------------------------------------------
Linked Posts
Attached Files
22nd July 2012 @ 23:07
START: 23/07/12
FINISH: 23/07/12

Summary and Conclusion
Substrate scale: 104 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 27% (following chromatography).

Scheme%20KAB26-14.png
Table%20KAB26-14.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB26-4


Previous Experiments
Preparation of MNR42-1
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-11)
Yb(OTf)3 catalysed (5 mol%) acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-12)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine - 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 (KAB26-14) - 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 THF was dried over 3 Å molecular sieves (1.5-2.5 mm) for >72 h
To a mixture of 3 Å molecular sieves in THF (17 mL) was dissolved MNR42-1 (104 mg, 0.331 mmol, 1 equiv.). The mixture was cooled in an acetone ice bath (-10 °C) before the addition of acetyl chloride (0.04 mL, 0.6 mmol, 1.7 equiv.) and 2,6-lutidine (0.06 mL, 0.5 mmol, 1.6 equiv.). Yb(OTf)3 (10 mg, 0.016 mmol, 0.05 equiv.) was added. The reaction mixture was allowed to warm to 25 °C and stirred under argon from 09:10.
After 1.5 hours, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (15 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure before dry loaded onto a silica gel column.
Column chromatography (60-65%, EtOAc/hexane, v/v) of the crude product yielded KAB26-14 as a yellow solid (32 mg, 27%).

Summary and Conclusion
Substrate scale: 104 mg (to 0.02 M).
Yb(OTf)3 loading: 5 mol%.
Solvent: THF.
Isolated yield: 27% (following chromatography).

References
[1] D. Bradley, G. Williams and M. Lawton, J. Org. Chem. 2010, 75, 8351. DOI: 10.1021/jo101589h Paper.

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


------------------------------------------
NOTES
------------------------------------------
Linked Posts
Attached Files