Ritter Reaction
The Ritter reaction is the acid-induced nucleophilic addition of a nitrile to a carbenium ion to deliver a N-alkyl amide.
General features:
1. The reaction is used for the preparation of acyclic amides and heterocycles such as lactams. 2. Alcohols that are easily ionized (secondary, tertiary, and benzylic alcohols) give the best results. 3. The nitrile substrate may not contain acid-sensitive functional groups that would be destroyed under the strongly acidic reaction conditions employed. Despite this, a wide range of aliphatic and aromatic nitriles will undergo the reaction.
Ritter Reaction
Reaction Mechanism
1. The hydroxyl group is protonated. 2. The C–O bond is heterolytically cleaved to generate a carbanion. 3. This cation is attacked by the nitrogen of the nitrile to form a nitrilium ion. 4. The nitrilium ion reacts with the conjugate base of the acid to give an imidate. 5. Final hydrolysis produces the amide.
Experimental Procedure
H2SO4 (20.0 eq) was added dropwise to a 0 °C solution of the alcohol (210 µmol, 1.0 eq) in TMSCN (15.0 eq). The reaction was stirred for 30 min at 0 °C and 30 min at rt. The solution was cooled to 0 °C and quenched by the sequential addition of sat aq Na2CO3 followed by 1.0 M NaOH. The solution was warmed to rt and stirred for 10 min. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were dried, filtered, and concentrated. The resulting residue was purified by flash column chromatography to afford the formamide as a single diastereomer (48% yield).
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