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9th May 2012 @ 04:46
Mnr: 1-10

Hazard and Risk Assessment:

As for MNR8-1

Procedure:

To a stirring suspension of paraformaldehyde (3.17 g, 105.6 mmol), 2,2-diethoxyethylamine (15.4 mL, 105.6 mmol) and cyclohexanecarboxylic acid (13.5 g, 105.6 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-4 (20.2 g, 105.6 mmol) in methanol (10 mL) dropwise and stirred at room temperature for 48 hours.

The reaction was concentrated and dissolved in EtOAc (100 mL) then washed with water (75 mL) and brine (75 mL) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a pale yellow oil.

Column :- 25-100 % EtOAc/Hex

Frac 3 10.2 g as a clear oil, clean product Frac 4-8 17.138 g as a clear oil, clean product Frac 9-13 15.496 g as a slightly yellow oil, mostly product

Total recovered 42.834 g, 92.2 mmol, 87 %

Clean fractions were transferred in vials of approximately 2 g per vial and flasks were rinsed into the impure flask. Total remaining to be recolumn'd 17.9 g

It was found that "azeotroping" the clean product with Et2O several times resulted in a white foamy solid under vacuum. This however collapsed on warming to room temperature under vacuum back to the clear oil.

Characterisation

mnr08-2_1H.pdf
mnr8-2.zip

As a 50:50 mixture of rotamers

1H NMR (500 MHz, CDCl3): d = 7.09 (t, J = 5.3 Hz, NH), 6.80 (s, 0.5H), 6.79 (s, 0.5H), 6.74-6.70 (m, 2H),6.56 (t, J = 5.4 Hz, NH) 4.73 (t, J = 5.1 Hz, 0.5H), 4.55 (t, J = 5.1 Hz, 0.5H), 4.04 (s, 1H), 3.99 (s, 1H), 3.88 (s, 1.5H), 3.88 (s, 1.5H), 3.85 (s, 3H), 3.77-3.65 (m, 2H), 3.55-3.41 (m, 6H), 2.79-2.65 (m, 2H), 2.31-2.23 (m, 1H), 1.81-1.71 (m, 2H), 1.71-1.58 (m, 3H), 1.53-1.36 (m, 2H), 1.31-1.13 (m, 9H).

mnr08-2_13C.pdf
mnr8-2.zip

13C NMR (125 MHz, CDCl3): d= 178.1, 177.7, 169.6, 169.3, 149.1, 149.0, 147.8, 147.6, 131.3, 131. 0, 129.0, 128.2, 120.6, 120.5, 111.9, 111.7, 111.4, 111.3, 101.3, 100.5, 64.1, 63.5, 55.9, 55.8, 54.0, 52.3, 52.1, 50.9, 41.0, 40.8, 40.6, 40.2, 40.1, 35.3, 35.2, 29.3, 29.2, 29.0, 25.7, 25.6, 25.6, 25.5, 15.3.

 

IR 

7d IR MNR8-5.jpg
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3rd May 2012 @ 00:08
Mnr: 1-10
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 22 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.

*yield not noted

------------------------------------------------------------------

Reaction repeated on 21/08/12 - MNR4-5

A solution of 3,4-dimethoxyphenethylamine (24.0 mL, 132 mmol) in ethyl formate (130 mL, 1590 mmol) was heated to reflux for 22 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 reaction took a lot of quenching which was worrying. The organic layer was separated and the aqueous solution was extracted DCM (300 mL x4). The organic layers were combined, dried over magnesium sulphate, filtered and evaporated afforded a dark brown oil.

Crude NMR showed product compared to MNR4-3

mnr4-5_crude_1H.pdf
mnr4-3_dry.pdf


Crude TLC - 40%EtoAc/Hex

SANY0227.JPG


Column:- short column 20-30% EtOAc?Hex - product spot comes out before the yellow colour in the column starts to move, unexpected.

(250-500 mL fraction) Fracs 2-4 - 21.846 g, 114 mmol, 79%

frac2 flask - 8.169 g
frac3-4 flask - 13.677 g

The two fractions were kept apart as frac3-4 was slightly coloured although still only showing one spot by TLC. NMR shows that the two samples are identical.

NMR

mnr04-5_frac2_1H.pdf


mnr04-5_frac3-4_1H.pdf


*lab book page complete and closed 23/8/12
Attached Files
31st January 2012 @ 23:29
Mnr: 1-10
MNR10-2%20scheme.png

MNR10-2%20table.PNG

Hazard and Risk Assessment:
HIRAC MNR10.pdf


Procedure:

To a stirring suspension of paraformaldehyde (2.73 g, 91.0 mmol), 2,2-dimethoxyethylamine (13.2 mL, 91.0 mmol) and benzoic acid (11.11 g, 91.0 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-2 (17.4 g, 91.0 mmol) dropwise and stirred at room temperature for 40 hours.

The reaction was concentrated and dissolved in EtOAc (150 mL) then washed with water (75 mL) and brine (75 mL) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a yellow oil.

Crude :- 46.856 g

Column :- 50-100 % EtOAc/Hex

Frac 3-8 :- 36.126 g, 78.78 mmol, 87 %

Characterisation

mnr10-2_1H.pdf
mnr10-2_frac3-8.zip


As a 50:50 mixture of rotamers. Peaks not fully resolved at 300 K

1H NMR (500 MHz, CDCl3): d = 7.44-7.99 (m, 5H), 7.25 (br, NH), 6.84-6.66 (m, ,3H), 5.03 (br, 1H), 4.49 (br, 1H), 4.20 (br, 1H), 3.96 (br, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.66-3.15 (m, 8H), 2.85-2.72 (m, 2H), 1.23-1.03 (m, 6H).

mnr10-2_13C.pdf
mnr10-2_frac3-8.zip


13C NMR (125 MHz, CDCl3): d= 173.1, 168.9, 168.7, 149.1, 147.7, 135.4, 131.3, 130.3, 129.8, 128.5, 128.2, 127.0, 126.8, 120.7, 111.9, 111.4, 101.0, 100.5, 64.0, 63.4, 62.0, 55.9, 55.9, 55.4, 55.3, 53.4, 53.3, 51.4, 51.2, 40.7, 35.2, 15.4


______________________________________________________________________

23/08/12
MNR10-3

Procedure:

To a stirring suspension of paraformaldehyde (3.38 g, 112.43 mmol), 2,2-dimethoxyethylamine (16.4 mL, 112.43 mmol) and benzoic acid (13.73 g, 112.43 mmol) in methanol (90 mL) at 0 °C was added 2-(3,4-Dimethoxyphenyl)ethyl isocyanide MNR4-5 (21.5 g, 112.43 mmol) in methanol (20 mL) dropwise and stirred at room temperature for 41 hours.

The reaction was then concentrated and taken up in EtOAc (200 mL) then washed with water (150 mL) and brine (150 ml) then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude as a yellow oil (49.47 g, 96%)

Due to the crude recovered being less than 100% the aqueous fractions were extraced again with EtOAc (200 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give more crude as a yellow oil (1.364 g, 2.87 mmol, 3%)

Total crude recovered - 50.834 g, 110.86, 99%

TLC of crude mixture run in 50% and 100% EtOAc/Hex
SANY0237.JPG


Crude taken on without further purification.
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30th January 2012 @ 00:37
Mnr: 1-10
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.

Crude:- 30.519 g

Column:- 25-33% EtOAc/Hex

Frac 3-5 :- 21.751 g as a pale yellow oil (86 %)

Characterisation

mnr04-2_1H.pdf
mnr4-2frac3-5.zip


1H NMR (500 MHz, CDCl3): d = 6.84 (d, J = 8.7 Hz, 1H), 6.81-6.76 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.59 (t, J = 6.9 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H).

mnr04-2_13C_conc.pdf
mnr4-2_conc.zip



13C NMR (75 MHz, CDCl3): d= 156.4 (t, J = 5.2 Hz), 149.4, 148.3, 129.4, 120.9, 112.0, 111.4, 56.0, 43.4 (t, J = 6.3 Hz), 35.4.

HRMS (ESI (+)) Calcd. for [C33H40N3O6]+ (for [3M+H]+): 574.2912, found: 574.2914.

IR MW37-1


Vmax/cm-1 2939, 2147, 1515.

Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37)



Lab book page complete, MNR
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