Van Leusen Reaction
The Van Leusen reaction allows the transformation of ketones into nitriles, aldehydes into oxazoles, and aldimines into imidazoles by the reaction of each substrate with tosylmethyl isocyanide (TosMIC).
Van Leusen Reaction
Reaction Mechanism
1. Initial deprotonation of TosMIC. 2. Attack onto the carbonyl carbon of the ketone followed by a 5-endo-dig cyclization. 3. Tautomerization followed by ring-opening and elimination of the tosyl group. 4. Final solvolysis generates the desired product.
Experimental Procedure
To a suspension of t–BuOK (2.67 equiv) in 30 mL of THF at -60 °C was added a solution of TosMIC (1.7 equiv) in THF (30 mL). After 15 min, a solution of the aldehyde (10 mmol, 1.0 equiv) in THF (20 mL) was added slowly. After 1 h, MeOH (15 mL) was added, and the reaction was then placed in a room temperature oil bath and heated to reflux for 2 h. The reaction was diluted with water and Et2O. The aqueous layer was extracted with Et2O. The combined organics were washed sequentially with sodium hydrosulfide solution (NaHS), brine, and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give the nitrile (71% yield).
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