Direct Substitution Of The Hydroxy Groups In Alcohols

Readily available and inexpensive alcohols can be easily transformed into the corresponding halides, sulfonates, carboxylates, and phosphonates, which are able to react with a wide variety of nucleophiles under acid conditions. However, such indirect substitution of the hydroxyl groups in alcohols inevitably generates acidic byproducts that lead to more side reactions. In contrast, direct substitution of the hydroxyl groups in alcohols not only saves one step of synthetic manipulation, but also suppresses side reactions and exhibits atom-economy by generating byproduct water. Nevertheless, limited procedures have been disclosed for direct substitution of the hydroxy groups in alcohols owing to their poor leaving ability. Herein we disclose the direct substitution of the hydroxy groups in alcohols with serveral nucleophiles in the presence of acidic byproducts or external acidic catalysts. These studies significantly extend the synthetic applications of alcohols.The three-component reaction of alcohols, acyl chlorides, and hexamethyldisilazane has been developed through byproduct catalysis for the synthesis of polysubstituted amides. Trimethylchlorosilane is generated as a byproduct from acyl chlorides and hexamethyldisilazane, and is consequently decomposed by alcohols. The resulting HCl promotes the decomposition of alcohols and/or their derivatives to generate carbocations, which couple with N-silylamides generated in situ to afford amides. Benzylic and allylic alcohols serve as suitable substrates, and the replacement of acyl chlorides with chloroformates and sulfonyl chlorides results in the formation of N-alkyl carbamates and sulfonamides, respectively.The reaction of alcohols with sulfinyl chlorides has been developed through byproduct catalysis for the synthesis of benzylic and allylic sulfones. Initial reaction of alcohols with sulfinyl chlorides yield sulfinate esters that are ready to decompose in the presence of byproduct HCl, and the resulting carbocations and sulfinic'acids are coupled to afford sulfones. Alternatively, HCl promotes the decomposition of alcohols to generate carbocations and water, and the latter react with sulfinyl chlorides to afford sulfinic acids.The three-component reaction of terminal alkynes, benzylic alcohols, and simple arenes has been developed in the presence of a catalytic amount of triflic anhydride/ferric trichloride/silver nitrate. An array of both Z-and E-isomers of trisubstituted alkenes have been obtained with excellent stereoselectivity simply by switching the acidic catalyst system and reaction temperature. Regioselective attack of terminal alkynes by carbocations, generated in situ from benzylic alcohols in the prescence of acidic species, results in the formation of vinyl cations, which undergo an electiophilic aromatic substitution reaction with arenes to afford trisubstituted alkenes.The reaction of benzylic alcohols with alkenes has been developed in the presence of triflic anhydride for the synthesis of polysubstituted alkenes and indane derivatives with high stereoselectivity. In general, benzylic alcohols react with terminal alkenes to afford trisubstituted alkenes, and the reaction with 1,2-disubstituted and trisubstituted alkenes affords indane derivatives. In addition, the employment of alkenes generated in situ from the corresponding alcohols under the acidic reaction conditions also affords polysubstituted alkenes and indane derivatives with high stereoselectivity.The reaction of sulfonamides with alkenes (or the corresponding alcohols) has been developed in the presence of sulfuric acid for the synthesis of polysubstituted alkenes and indane derivatives with high stereoselectivity. The sp3 carbon-nitrogen bonds of sulfonamides are cleaved under acidic conditions to generate carbocations, which undergo olefination reaction or [3+2] annulation reaction with alkenes.