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29th January 2012 @ 23:01
****Experiment concluded on 01/02/12

Scheme
Scheme%204-2.png

Hazard and Risk Assessment
As for KAB4-1 (here)

Following Experiments
Preparation of the PZQ peptide acetal Ugi-intermediate (KAB5-2)

Previous Related Experiments
Preparation of (2-isocyanoethyl)benzene (KAB4-1)

Procedure

31/01/12
Sodium hydroxide pellets (60 g) were added portionwise to water (60 mL) in a 500 mL, round bottom flask. A mixture of benzyltriethylammonium chloride (400 mg), chloroform (16 mL), 2-phenylethylamine (24.5 mL) in dichloromethane (DCM, 60 mL) was added dropwise over 10 minutes.
The reaction mixture was reflux heated at 40 °C from 10:10. At 14:10 (+4 hours) the reaction mixture was allowed to cool, then diluted with an ice/water slurry (50 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 × 50 mL). The organic layers were combined, washed with HCl (1 M, 3 × 100 mL) and NaCl solution (100 mL), dried over magnesium sulfate then concentrated under reduced pressure to give crude KAB4-2 as a dark brown oil (17.33 g). The crude product was put in the freezer overnight.
Reaction Setup
Reaction mixture after removal from heat
Crude KAB4-2


01/02/12
The crude KAB4-2 was diluted with 10 mL of EtOAc then eluted through a silica gel column with neat EtOAc. The filtrate was collected and concentrated under reduced pressure to give KAB4-2 as a dark brown, very pungent liquid (14 g, 55%).

Summary and Conclusion
The isocyanide preparation was successful (confirmed by 1H-NMR), though the yield was lower than expected. The NMR showed some EtOAc solvent contamination. Most of the product was used in the preparation of KAB5-2 (see "Following Experiment" above) and the remainder is to be used in the synthesis of KAB6-2 (see KAB6-1). Recommendation of immediate elution through a silica gel column following drying and filtration of the crude product in future (2-isocyanoethyl)benzene syntheses.

1H-NMR. (has some EtOAc contamination).
Raw H-NMR KAB4-2


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


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NOTES 30/01/12
- Total reaction time including preparation and workup is ~6 hours. Not enough time to complete today - will start first thing tomorrow.
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Attached Files
Scheme KAB4-2
Reaction Setup
Reaction mixture after removal from heat
Crude KAB4-2
Raw H-NMR KAB4-2