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30th March 2012 @ 04:13
Attempting to trap the enediamide for analysis and for catalyst screening.

MNR33-1%20scheme.png
mnr33-1%20table.PNG

Hazard and Risk Assessment
HIRAC MNR33.pdf


Procedure
MNR10-2 (0.43 g, 0.94 mmol) in toluene (50 mL) at -78 °C was treated with copper triflate (0.010 g, 0.09 mmol) and stirred at -78 °C. Following the reaction by TLC it looked like PS product was slowly beginning to form after 2 hours and no significant sign of enediamide (expected to a higher running spot on the TLC compared to starting material and PS product)
Attached Files
27th March 2012 @ 08:13
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Summary and Conclusion
Unknown if the cyclisation was successful. Value for yield unreliable. Presence of 2° amine and consumption of starting material suggested formation of expected product. No confirmation by H-NMR. The crude product decomposed overnight before it was purified by chromatography.
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START: 27/03/12
FINISH: 30/03/12

Background
See synaptic leap post: here.

Scheme%20KAB24-1.png
Table%20KAB24-1.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB24-1


Previous Experiments
Synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-4)
Synthesis of 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-1)

Following Experiments
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-2)

Chemical Information
2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (1, 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.
6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (2, KAB24-1) - SMILES: O=[N+]([O-])C1=CC=C(C2NCCC3=CC(OC)=C(OC)C=C32)C=C1, InChi: InChI=1S/C17H18N2O4/c1-22-15-9-12-7-8-18-17(14(12)10-16(15)23-2)11-3-5-13(6-4-11)19(20)21/h3-6,9-10,17-18H,7-8H2,1-2H3, InChIKey: GITFNMZGMQLGOX-UHFFFAOYSA-N.


Procedure
27/03/12. A suspension of KAB23-1 (610 mg, 1.94 mmol, 1 eq) in toluene (20 mL) was prepared before the slow addition of trifluoroacetic acid (6 mL, 78.4 mmol, 40 eq).
The pale yellow suspension turned clear and orange-red immediately after the addition of TFA. The reaction mixture was reflux heated to 110 °C from 18:45. After 15 minutes, the reaction turned clear yellow.
TLC indicated complete consumption of the starting material after 35 minutes (MeOH/DCM, 15%, v/v; ninhydrin stain).
TLC of reaction mixture (30 min)

The reaction mixture was promptly removed from the oil bath and allowed to cool.

28/03/12. After standing at rt for 13 hours, the reaction mixture was poured over ice then basified with NaOH (6 M), resulting in the brief formation of a white precipitate, which was presumably dissolved in the organic phase. The organic fraction was isolated and the aqueous fraction extracted with EtOAc (3 × 30 mL) then Et2O (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 paste, which showed signs of solidifying (~2 g wet). The crude product was put under a high vacuum for >7 hours, which solidified some of the product. The remainder was a paste.

Attempted to purify by silica gel column chromatography (5% MeOH/DCM). However collection of the first 10 fractions revealed product decomposition overnight (product had also went from a yellow solid to a brown gel). The product was taken no further. Experiment requires repeat.

Summary and Conclusion
Unknown if the cyclisation was successful. Value for yield unreliable. Presence of 2° amine and consumption of starting material suggested formation of expected product. No confirmation by H-NMR. The crude product decomposed overnight before it was purified by chromatography.


References
[1] R. Gitto, M. L. Barreca, L. De Luca, G. De Sarro, G. Ferreri, S. Quartarone, E. Russo, A. Constanti, A. Chimirri, Journal of Medicinal Chemistry 2003, 46, 197.


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NOTES 27/03/12
- Still working out assay conditions. Will need to monitor consumption of starting materials vs appearance of product. So far: Appearance of product - 15% MeOH/DCM, v/v.

NOTES 29/03/12
- Poorly soluble in CDCl3
- Proton NMR unclear of crude product unclear. Will need to purify by column chromatography.
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Attached Files
23rd March 2012 @ 04:10
MNR22-2%20scheme.png
mnr22-2%20table.PNG

Hazard and Risk Assessment:

As for MNR8-1

Procedure:

To a stirring suspension of paraformaldehyde (3.89 g, 130 mmol), 2,2-diethoxyethylamine (18,8 mL, 130 mmol) and benzoic acid (15.8 g, 114 mmol) in methanol (75 mL) at 0 °C was added MNR21-3 (17.0 g, 114 mmol) in methanol (10 ml) dropwise and stirred at room temperature over the weekend, 65 hours.

The reaction was concentrated and dissolved in Et2O (150 mL) then washed with water (100 mL) and brine (100 mL) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a dark brown oil, 43.88 g

Column #1 40-70% EtOAC/Hex (approx 500 ml silica, 500 ml fractions)

Frac 2-3 12.856 g
Frac 4-7 27.500 g
Frac 8-10 1.775 g

Total recovered - 42.111 g

All fraction need another column but this has got the quantities down to more manageable sizes.

mnr22-2_col1_frac2-3.pdf
mnr22-2_col1_frac4-7.pdf
mnr22-2_col1_frac8-10.pdf
Attached Files
22nd March 2012 @ 06:12
Mnr: 21-30
Repeat of MNR21-3 on the same scale.

MNR21-3%20scheme.png

mnr21-3%20table.PNG

DOI: 10.1002/chem.201002046

Hazard and Risk Assessment:
HIRAC MNR23-3.pdf


Water (60 mL) was added to a 500 mL round-bottomed flask. Sodium hydroxide (60.0 g, 1.5 mol) was added portionwise followed by a mixture of 2-phenylethylamine (24.3 mL, 0.19 mol), chloroform (16.0 mL, 0.19 mol), and benzyltriethylammonium chloride (400 mg, 1.8 mmol) in dichloromethane (60 mL)dropwise over 10 mins. The reaction mixture was then refluxed for 4 hours.

The reaction mixture was then allowed to cool to room temperature and was diluted with ice and water (50 mL), the organic layer was separated and retained, the aqueous layer was extracted with DCM (2 x 60 mL). The organic fractions were then combined and washed with HCl (1M) (3 x 100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude as a dark orange oil (23.90 g) The crude was passed through a short column (60-100 EtOAC) collecting the top running spot. After concentration, (2-isocyanoethyl)benzene (MNR21-4) was afforded as a dark yellow oil (17.618 g, 134.31 mmol, 70%)

Characterisation

mnr21-4_1H.pdf
mnr21-4_frac1.zip


1H NMR (400 MHz, CDCl3): d = 7.37-7.21 (m, 5H), 3.60 (tt, J = 10.6, 1.9 Hz, 2H), 2.98 (tt, J = 10.6, 1.9 Hz, 2H)

13C NMR MW34-1


13C NMR – MW34-1 (50 MHz, CDCl3): d = 156.6, 136.7, 128.7, 128.7, 127.2, 42.9 (t, J = 6.5) 35.6.

IR MW34-1


Vmax/cm-1 2147, 1454

Preparation of 2-Phenylethyl isocyanide (MW34-1)

*lab book entry closed
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Attached Files
22nd March 2012 @ 06:01
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Summary and Conclusion
Moderate yield (68%) and low conversion (9%) for the cyclisation reaction in neat methanesulfonic acid (140 °C, 20 hours).
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START: 22/03/12
FINISH: 26/03/12

Scheme%20KAB20-4.png


Hazard and Risk Assessment
As for KAB20-2 (here).

Previous/Related Experiments
AgOTf catalysed synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-1)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-3)

Following Experiments

Chemical Information
N-Benzylidene-N-phenethylamine (1, KAB18-1) - SMILES: N(=C/c1ccccc1)\CCc2ccccc2, InChI: InChI=1S/C15H15N/c1-3-7-14(8-4-1)11-12-16-13-15-9-5-2-6-10-15/h1-10,13H,11-12H2/b16-13+, InChIKey: OOBAKFDIGIHHOM-DTQAZKPQSA-N
1-Phenyl-1,2,3,4-tetrahydroisoquinoline (2, KAB20-4) - SMILES: c1ccc3c(c1)C(c2ccccc2)NCC3, InChI: InChI=1S/C15H15N/c1-2-7-13(8-3-1)15-14-9-5-4-6-12(14)10-11-16-15/h1-9,15-16H,10-11H2, InChIKey: PRTRSEDVLBBFJZ-UHFFFAOYSA-N
Methanesulfonic acid - SMILES: O=S(=O)(O)C, InChI: InChI=1S/CH4O3S/c1-5(2,3)4/h1H3,(H,2,3,4), InChIKey: AFVFQIVMOAPDHO-UHFFFAOYSA-N

Procedure
A mixture of KAB18-1 (194 mg, 0.93 mmol, 1 eq) and methanesulfonic acid (1.2 mL, 18.5 mmol, 20 eq) was reflux heated at 140 °C from 17:20.
After 19 hours the reaction mixture was poured over ice, then basified with NaOH (6 M), which turned the solution cloudy white. The precipitate was too fine to filter, so the aqueous layer was extracted with EtOAc (3 × 30 mL) and diethyl ether (30 mL). The organic layer were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give crude KAB20-4 as a dark brown oil (132 mg, 68%).

1H-NMR (300 MHz; CDCl3)
Raw H-NMR crude KAB20-4
H-NMR crude KAB20-4


Imine proton of KAB18-1 starting material: δ 8.20
Proton of cyclised THIQ at C1, KAB20-4: δ 5.14

Ratio of starting material to product ~ 1:0.10 = 9% conversion.

Summary and Conclusion
Moderate yield (68%) and low conversion (9%) for the cyclisation reaction in neat methanesulfonic acid (140 °C, 20 hours).

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NOTES 24/03/12
- Need to NMR sample
- Used the last of the KAB18-1 sample.

NOTES 23/03/12
- Some white crystals formed partway up the condensing tube. Will NMR in addition to crude sample.

NOTES 26/03/12
- POST YIELD!
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