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2nd May 2012 @ 02:00
START: 02/05/12
FINISH:

To do:
Purification of KAB26-1
LRMS KAB26-2 f24-32




Hazard and Risk Assessment
HRA KAB26-X


Previous Experiments
Yb(OTf)3 catalysed PS reaction to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-9)
TFA catalysed synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-4)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24

Following Experiments

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-1) - 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.

Procedure

Gold(III) chloride and silver triflate were vigorously stirred in MeCN (5 mL) for 1 hour before the addition of a solution of KAB23-1 and AcCl in MeCN. The reaction mixtures were left to stir overnight at rt.

KAB26-1
HAuCl4·3H2O : 13 mg, 0.033 mmol, 1 mol%
AgOTf: 17 mg, 0.066 mmol, 2 mol%
KAB23-1: 1.0 g, 3.2 mmol, 1 equiv.
AcCl: 0.22 mL, 3.2 mmol, 1 equiv.
MeCN: 160 mL (0.05 M)

Catalyst activation: 14:30 - 15:30, 02/05/12
Reaction start: 15:30, 02/05/12

KAB26-1 catalyst activation


KAB26-2
HAuCl4·3H2O : 16 mg, 0.041 mmol, 1 mol%
AgOTf: 21 mg, 0.081 mmol, 2 mol%
KAB23-1: 1.3 g, 4.1 mmol, 1 equiv.
AcCl: 0.30 mL, 4.1 mmol, 1 equiv.
2,6-Lutidine: 0.5 mL, 4.1 mmol, 1 equiv.
MeCN: 200 mL (0.05 M)

Catalyst activation: 14:30 - 15:30, 02/05/12
Reaction start: 15:50, 02/05/12

Reaction mixtures. L: KAB26-1 (20 min), R: KAB26-2 (0 min)
Reaction mixtures. L: KAB26-1 (1 h), R: KAB26-2 (40 min)
TLC of reaction mixture (18 h)

TLC of reaction mixtures. KAB26-1 (1.5 h), KAB26-2 (~1 h)


After 18 hours, both reaction mixtures were concentrated under reduced pressure. KAB26-1 was concentrated to a dark reddish oil. KAB26-2 was a pale yellowish solid.

Crude mass KAB26-1: ~20 g
Crude mass KAB26-2:
NOTE: Both compounds were not dried under a high vacuum

Purification of KAB26-2 (03/05/12)
Purification by silica gel column chromatography, eluting with 25-100% EtOAc/hexane.
The solid was poorly soluble in the initial eluent system (i.e. 25% EtOAc/hexane). Addition of DCM aided dissolution, however MeOH was required to adequately dissolve the crude product. Dry silica was added to the solution, which was re-concentrated under reduced pressure, before the crude product was dry loaded onto the column.

All TLCs were eluted with 50%, EtOAc/hexane, v/v and stained with KMnO4

Combined Fractions 9-17, Rf ~0.6 (260 mg):
TLC KAB26-2 fractions 9-17
Raw H-NMR KAB26-2 f9-17
KAB26-2 concentrated f9-17

1H-NMR (200 MHz; CDCl3): δ 10.21 (s, 1H), 8.44 (d, J = 8.6 Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H).

Combined Fractions 24-32, Rf ~0.37 (46 mg):
TLC KAB26-2 fractions 24-32-17
Raw H-NMR KAB26-2 f24-32

NOTE: TLC description should read "TLC KAB26-2 fractions 24-32"
1H-NMR suggested isolated spot was N-acetyl-N-(3,4-dimethoxyphenethyl)acetamide.
1H-NMR (200 MHz; CDCl3): δ 6.87-6.74 (m, 3H), 3.89 (m, 8H), 2.84 (t, J = 7.3 Hz, 2H), 2.36 (s, 6H).

Combined Fractions 76-92, Rf 0.15 (537 mg):
TLC KAB26-2 fractions 71-79
TLC KAB26-2 fractions 79-86

1H-NMR(200 MHz; CDCl3): δ 8.17 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 6.74 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.81 (s, 3H), 3.77-3.71 (m, 1H), 3.38 (t, J = 12.5 Hz, 1H), 3.38 (t, J = 12.5 Hz, 1H), 3.09-2.93 (m, 1H), 2.23 (s, 3H).


After standing for 3 days, the KAB26-1 crude product, which was previously a dark reddish oil, crystallised. TLC of the crystals predominantly showed spots corresponding to 4-nitrobenzaldehyde and the expected product. Additional baseline spots presumably correspond to 3,4-dimethoxyphenethylamine or one of its derivatives. Attempts to dissolve the sample for TLC: Very poorly or not soluble in EtOAc. Very poorly soluble in MeOH. Soluble in DCM after vigorous shaking. 4-nitrobenzaldehyde is readily soluble in EtOAc. And the dimethoxyphenethylamine by products are typically oils.
Crude KAB26-1 after XST


Summary and Conclusion
The KAB26-2 cyclisation reaction proceeded as expected according to the literature. Isolated yield of the final KAB26-2 THIQ (36%) was reduced due to accidental loss of material during purification procedures (literature ~80%). Material isolated from the chromatography included p-nitrobenzaldehyde (42%) and N-acetyl-N-(3,4-dimethoxyphenethyl)acetamide (4%).

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

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NOTES 02/05/12
- Need to get TLC sample of acylimine before addition of the catalyst.
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Linked Posts
Attached Files
HRA KAB26-X
Scheme KAB26-X
KAB26-1 catalyst activation
Reaction mixtures. L: KAB26-1 (20 min), R: KAB26-2 (0 min)
Reaction mixtures. L: KAB26-1 (1 h), R: KAB26-2 (40 min)
TLC of reaction mixtures. KAB26-1 (1.5 h), KAB26-2 (~1 h)
Table KAB26-X
TLC KAB26-2 fractions 9-17
TLC of reaction mixture (18 h)
Raw H-NMR KAB26-2 f9-17
TLC KAB26-2 fractions 24-32-17
Raw H-NMR KAB26-2 f24-32
TLC KAB26-2 fractions 71-79
TLC KAB26-2 fractions 79-86
TLC KAB26-2 fractions 86-93
KAB26-2 concentrated f9-17
Crude KAB26-1 after XST