Inorganic Iodide Catalyzed Alkylation of Amines with Primary Alcohols

Alkylation of amines with readily accessible reagents is one of the most efficient strategies for synthesizing substituted amines. Primary alcohols, being widely abundant, are excellent electrophiles that can undergo dehydration to react with various nucleophilic reagents. However, using primary alcohols for direct alkylation of amines is challenging due to the kinetic and thermodynamic barriers associated with carbocation generation during alcohol dehydroxylation. Conventional approaches that involve the preactivation of primary alcohols to their derivatives (aldehydes, halides, or tosylates) suffer from poor step-and atom economy, limited functional group tolerance, or reliance on unstable metal complexes. In this work, we present a highly efficient method for the alkylation of amines using primary alcohols, catalyzed by the combination of HI and NaHSO4. This method leverages inexpensive catalysts and easily accessible alcohols as alkylation reagents, exhibiting excellent functional group tolerance and high catalytic reactivity. The method has been successfully applied to the alkylation of various amines, cascade construction of N-heterocycles, and late-stage concise synthesis of pharmaceuticals.