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24th November 2011 @ 22:31
The modified Hoffman procedure for the preparation of (2-isocyanoethyl)benzene for later use in the Pictet-Spengler cyclisation to PZQ and the N-benzoyl analogue.

Scheme%204-1.png

KAB4-1%20table.tjpg

Risk Assessment
Risk Assessment


01/12/11

Procedure
Sodium hydroxide pellets (60 g) were gradually added to water (60 mL) in a 500 mL round bottom flask. A solution of benzyltriethylammonium chloride (400 mg, 1.76 mmol) in dichloromethane (DCM) (60 mL), chloroform (16 mL, 200 mmol) and 2-phenylethylamine (24.3 mL, 200 mmol) in a pressure equalising dropping funnel was added gradually over 12 minutes. The reaction mixture was heated at reflux (38-42 C) for 4 hours.

Reflux Timeline:
1:45 pm: The reaction mixture reached reflux temperature of ~40 C.
3:15 pm: Formation of a light brown froth-like-solid, sticking to the sides of the flask. Stirrer turned up. Reflux temperature fluctuating between 34-42 C.
3:30 pm: Reaction frothing more vigorously.
4:05 pm: Reaction mixture a darker brown, froth/solid light brown. Oil bath temperature holding steady around 40.0-40.6 C.
5:10 pm: More brown precipitate in reaction mixture.

5:45 pm: The reaction mixture was removed from the oil bath, diluted with ~50 mL of ice and water then transferred to a separating funnel before removal of some of the organic layer. The solution consisted of a brown emulsion and the organic-aqueous interface was not clear. Water (50 mL) and DCM (100 mL) was added to the solution and the emulsion began to dissolve. After settling for 5 min, the organic fraction was removed, the aqueous layer extracted with DCM (2 x 50 mL) and the organic fractions combined. The organic fractions were washed with hydrochloric acid (1 M, 3 x 100 mL) followed by brine (100 mL). After drying over magnesium sulfate, the solvent was removed under reduced pressure to give crude (2-isocyanoethyl)benzene as a viscous, dark brown oil. The crude product was sealed and stored in the freezer overnight.

Reaction Setup:
Start of reflux
Reaction mixture at 1.5 hours
Reaction mixture at 2.5 hours
Reaction mixture at 4 hours.
Emulsion prior to dilution
Crude product as an oil


Crude 250 mL round bottom flask weight: 100.803 g.

02/12/11

Purification
The crude oil was loaded on a 5 cm silica gel column (diameter 3 cm) and eluted with neat EtOAc to form a yellow-brown oil. The product seemed too dark in colour and the yield was higher than expected. The product was passed through another silica gel column (30 cm, 3 cm diameter, neat EtOAc). Clearer separation was achieved and the yellow filtrate was collected. The solvent was removed under reduced pressure to give KAB4-1 as a yellow-brown oil (16.6 g, 66 %).

Second column
Dilute purified KAB4-1


Flask + Product: 117.365 g.
Yield: 16.6 g
Percentage yield: 66 %

NMR Data
H-NMR of KAB4-1 (CDCl3)

(UPLOAD RAW HNMR DATA FOR KAB4-1)

***Procedure finished. The method for the isonitrile preparation was straightforward and agreed with the literature procedure outline and expected yield.

References
[1] H. Cao, H. Liu, A. Doemling, Chemistry-a European Journal 2010, 16, 12296. DOI: 10.1002/chem.201002046


Forward Experiments
Preparation of the PZQ analogue Ugi-intermediate (KAB5-1)
Preparation of the N-benzoyl PZQ analogue Ugi-intermediate (KAB6-1)

Related Experiments
Preparation of (2-isocyanoethyl)benzene (MNR21-1)

Links
Informal commentary
Linked Posts
Attached Files
Scheme
Risk Assessment
Table
Start of reflux
Reaction mixture at 1.5 hours
Scheme (amended)
Reaction mixture at 2.5 hours
Reaction mixture at 3.3 hours.
Reaction mixture at 4 hours.
Emulsion prior to dilution
Crude product as an oil
Second column
Dilute purified KAB4-1
H-NMR of KAB4-1 (CDCl3)
H-NMR of KAB4-1 (CDCl3)