Arndt-Eistert Homologation
The Arndt-Eistert reaction allows the homologation of carboxylic acids (elongation of carboxylic acids). It involves the reaction of activated carboxylic acids with diazomethane followed by a Wolff-rearrangement of the diazo ketone intermediate.
General features:
1. If the reaction is conducted in the presence of an alcohol or an amine, the homologated ester or amide is then generated. 2. The yields are generally good (50–80%) 3. The reaction tolerates a wide scope of non-acidic functional groups. Acidic groups would react with the diazomethane or diazo ketone intermediates.
Arndt-Eistert Homologation
Reaction Mechanism
1. Formation of the acid chloride. 2. Diazomethane reacts with the acid chloride to deliver the diazo ketone intermediate. 3. The diazo ketone undergoes Wolff Rearrangement: Loss of a molecule of nitrogen and formation of the corresponding ketene. 4. Nucleophilic attack to the ketene affords the homologated acid derivatives.
Example
Experimental Procedure
To a solution of the acyl chloride (0.64 mmol, 1.0 eq) in THF/acetonitrile (1:1, 13 mL) was added trimethylsilyldiazomethane (2.0 M in hexane, 2.0 eq) at 0 ºC. The reaction solution was allowed to warm to room temperature and stirred for 10 h. Acetic acid (2.7 eq) was then added. Removal of volatiles under vacuum afforded the crude methyldiazoketone product. To a solution of the crude methyldiazoketone (1.0 eq) in dioxane (4.5 mL) at room temperature was added H2O (20.0 eq) and silver benzoate (0.2 eq), and the resulting reaction mixture was stirred at 80 ºC for 10 h. After cooling down to room temperature, water, 1N aqueous HCl, and diethyl ether were added. The organic layer was separated, and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product (72% yield).
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