Hofmann Rearrangement
The Hofmann rearrangement is the conversion of primary carboxamides to the corresponding one-carbon shorter amines.
General features:
1. The reaction can form a wide range of products, including alkyl and arylamines. 2. Amides cannot contain base-sensitive functional groups; acid-sensitive groups (e.g., acetals) may be present. 3. The isocyanate intermediate is readily hydrolyzed under these reaction conditions; so, it can not be isolated. 4. There is complete retention of configuration when enantiopure amides are used.
Hofmann Rearrangement
Reaction Mechanism
1. Formation of the N-halogen amide. 2. Deprotonation of the N-haloamide by the base. 3. Formation of the alkali salt. 4. Concerted rearrangement to the isocyanate via bridged anion. 5. Hydration and decarboxylation deliver the corresponding amine.
Experimental Procedure
The amide (0.21 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4.1 mL), and H2O (4.1 mL) was added. To this solution was added crushed KOH (35.0 eq), and the suspension was allowed to stir for 5 min at room temperature. At this time, PIDA (1.2 eq) was added, and the solution turned light yellow. The suspension was allowed to stir at room temperature for 20 h at which time it was quenched with sodium bicarbonate and sodium thiosulfate. After stirring for 5 min at room temperature, the mixture was diluted with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield the crude reaction product that was purified using SiO2 gel preparatory thin-layer chromatography to yield the desired product (39% yield).
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