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30th April 2012 @ 01:33
START: 30/04/12
FINISH:

Scheme%20KAB21-9.png

Hazard and Risk Assessment
As for KAB25-2 here:
Hazard and Risk Assessment KAB25-2


Previous Experiments
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-1)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-3)
Synthesis of N-benzylidene-N-phenethylamine (KAB18-2)

Following Experiments

Chemical Information
N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-2) SMILES: O(c1ccc(cc1OC)CC/N=C/c2ccccc2)C, InChI: InChI=1S/C17H19NO2/c1-19-16-9-8-14(12-17(16)20-2)10-11-18-13-15-6-4-3-5-7-15/h3-9,12-13H,10-11H2,1-2H3/b18-13+, InChIKey: HEYKSOUNCDDROU-QGOAFFKASA-N

Procedure
(All glassware was ovendried prior to use.)
30/04/12. KAB19-2 (52 mg, 193 mmol, 1 equiv.) was dissolved in dry toluene (1.2 mL) before the addition of well dried 3Å powdered MS. Yb(OTf)3 (25 mg, 0.040 mmol, 0.2 equiv) was added under an atmosphere of nitrogen before the reaction mixture was reflux heated, under nitrogen, to 110 °C from 14:50.

Monitoring the Reaction Progress by TLC
All TLCs were eluted with 15%, MeOH/DCM, v/v and stained with ninhydrin.
TLC of reaction mixture (1 h)
TLC of reaction mixture (18 h)


Summary and Conclusion


References
[1] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.
[2] M. J. V. Eynden, K. Kunchithapatham, J. P. Stambuli, Journal of Organic Chemistry 2010, 75, 8542-8549.


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NOTES 30/04/12
- Reaction mixture went yellower after addition of Yb.
- Yellow faded after 15 min
Flask = 47.1232
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Attached Files
27th April 2012 @ 08:07
START: 27/04/12
FINISH:

Increasing reagent concentration (decreasing rxn volume).
Scheme%20KAB25-2.png

Hazard and Risk Assessment
As for KAB25-2 here:
Hazard and Risk Assessment KAB25-2


Previous Experiments
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-1)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24

Following Experiments
Yb(OTf)3 catalysed PS reaction to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-9)

Chemical Information
3,4-Dimethoxyphenethylamine (1) - SMILES: O(c1ccc(cc1OC)CCN)C, InChI: InChI=1S/C10H15NO2/c1-12-9-4-3-8(5-6-11)7-10(9)13-2/h3-4,7H,5-6,11H2,1-2H3, InChIKey: ANOUKFYBOAKOIR-UHFFFAOYSA-N.
Benzaldehyde (2)- SMILES: c1ccc(cc1)C=O, InChI: InChI=1S/C7H6O/c8-6-7-4-2-1-3-5-7/h1-6H, InChIKey: HUMNYLRZRPPJDN-UHFFFAOYSA-N.


Procedure
(All glassware was ovendried prior to use.)
26/04/12. Yb(OTf)3 (120 mg, 0.194 mmol) was added to a 3-necked flask containing well dried 3Å powdered MS under a nitrogen atmosphere. Dry toluene (5 mL) was before the sequential addition of benzaldehyde (0.10 mL, 0.97 mmol) and 3,4-dimethoxyphenethylamine (0.16 mL, 0.97 mmol). The reaction mixture was reflux heated to 110 °C from 17:10.
Reaction mixture (5 min)
Reaction mixture (20 min)
Reaction mixture (63 h)


Monitoring the Reaction Progress by TLC
All TLCs were eluted with 15%, MeOH/DCM, v/v and stained with ninhydrin. Lane 19-2 corresponds to the isolatable imine intermediate and 25-3 corresponds to the reaction mixture. Co = cospot.
TLC of reaction mixture (10 min)


Unsure of TLC at 0820 30/04/12
- 0.5 mL of reaction mixture was extracted then worked up. 2 mL sat NaHCO3. EtOAc 2 × 2 mL. MgSO4.

After 3 days, the reaction mixture was removed from heat and allowed to cool. After dilution with EtOAc (20 mL), the mixture was quenched with saturated sodium bicarbonate solution (20 mL). The organic fraction was isolated and the basic aqueous fraction was extracted with EtOAc (3 × 20 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB25-3 as thick yellow oil (291 mg, 111%).

Summary and Conclusion


References
[1] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.
[2] M. J. V. Eynden, K. Kunchithapatham, J. P. Stambuli, Journal of Organic Chemistry 2010, 75, 8542-8549.


-----------------------------------------------------------------------------
NOTES 30/04/12
- Still unable to upload files. Hence missing TLC photos.
- Flask: 47.1254
- Crude product smelled faintly like benzaldehyde
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Attached Files
26th April 2012 @ 00:05
START: 26/04/12
FINISH:

Altering conditions slightly from KAB25-1.

Scheme%20KAB25-2.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB25-2


Previous Experiments
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-1)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24

Following Experiments

Chemical Information


Procedure
(All glassware was ovendried prior to use.)
26/04/12. Yb(OTf)3 (120 mg, 0.194 mmol) was added to a 3-necked flask containing well dried 3Å powdered MS under a nitrogen atmosphere. Dry toluene (30 mL) was added via canula before the sequential addition of benzaldehyde (0.10 mL, 0.97 mmol) and 3,4-dimethoxyphenethylamine (0.16 mL, 0.97 mmol). The reaction mixture was reflux heated to 110 °C from 10:00.
Reaction mixture (2 h)


Monitoring the Reaction Progress by TLC
All TLCs were eluted with 15%, MeOH/DCM, v/v and stained with ninhydrin. Lane 19-2 corresponds to the isolatable imine intermediate and 25-2 corresponds to the reaction mixture. Co = cospot.
TLC of reaction mixture (2 h)


Mini-workup (5 mL extraction)
Mass: 40.6 mg

After 4 days, the reaction mixture was allowed to cool. The reaction mixture was quenched with saturated sodium bicarbonate solution, and the organic fraction was removed. The basic aqueous layer was extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB25-2 (359 mg, 133%).

Summary and Conclusion


References
[1] K. Manabe, D. Nobutou, S. Kobayashi, Bioorg. Med. Chem. 2005, 13, 5154-5158.
[2] M. J. V. Eynden, K. Kunchithapatham, J. P. Stambuli, Journal of Organic Chemistry 2010, 75, 8542-8549.


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NOTES 27/04/12
- Still no product after >30 hours. Will leave over weekend.

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Attached Files
26th April 2012 @ 00:03
START: 23/04/12
FINISH: 24/04/12


Scheme%20KAB25-1.png

Hazard and Risk Assessment

Previous Experiments

Following Experiments

Chemical Information


Procedure
Dry dichloromethane (30 mL) was added under nitrogen to a flask containing Ytterbium(III) trifluromethanesulfonate (120.5 mg, 0.194 mmol, 0.2 equiv.) and well dried 3A powdered molecular sieves. Benzaldehyde (0.10 mL, 0.97 mmol, 1 equiv.) then 3,4-dimethoxyphenethylamine (0.16 mL, 0.97 mmol, 1 equiv.) were added to the mixture. The reaction mixture was stirred under nitrogen for 24 hours. The reaction was quenched by adding saturated sodium bicarbonate solution (30 mL). The organic fraction was separated, before the basic aqueous fraction was extracted with ethyl acetate (3 × 50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB24-1 as a yellow oil (392 mg, 150%).
1H-NMR of the crude product showed a mixture of the imine intermediate (identical to KAB19) and benzaldehyde (approximate ratio 1:0.15). The spectrum also contained a large water peak, which may account for the excess yield.


Monitoring the Reaction Progress by TLC


Summary and Conclusion

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NOTES Flask: 49.5964 g

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17th April 2012 @ 09:57
MNR4-1%20scheme.png
MNR4-1%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR4.pdf


A solution of 3,4-dimethoxyphenethylamine (24.0 mL, 132 mmol) in ethyl formate (130 mL, 1590 mmol) was heated to reflux for 13 h. The remaining ethyl formate and the by-product ethanol were removed under reduced pressure to give yellow liquid.

The crude 2-(3,4-Dimethoxyphenyl)ethylformamide and triethylamine (55.4 mL, 397 mmol) were dissoved in dry DCM (240 mL) and phosphoryl chloride (12.3 mL, 132 mmol) was added dropwise added at 0°C. The mixture was then stirred for 1 h at 0°C and a further 4 h at room temperature.
The mixture was quenched with water and neutralized with NaHCO3 solution. The organic layer was separated and the aqueous solution was extracted DCM (250 mL x4). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated afforded a dark brown oil.

Column 50-75% EtOAc/Hex

17.977 g, 94.o mmol, 71%

Material taken onto the next step