Palladium catalyzed chloroethoxylation of aromatic and heteroaromatic chlorides: an orthogonal functionalization of a chloroethoxy linker.

A novel disconnection based on cross-coupling chemistry was designed to access pharmaceutically relevant aryl-aminoethyl ethers. The developed palladium-catalyzed functionalization of aryl- and heteroaryl chlorides with a sodium tetrakis-(2-chloroethoxy) borate salt is orthogonal to the simple nucleophilic replacement of the chloro function of the ethylene linker. The transformation enables efficient 2-chloroethoxylation in the absence of an additional external base. Subsequent amine substitution of the alkyl halide affords 2-aminoethoxy arenes. The applicability of this method was demonstrated through the synthesis of various aryl- and heteroaryl-alkyl ethers, including the intermediates of marketed drug molecules.

Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil.

A simple and convenient method was developed for the introduction of a 2,2,2-trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2-trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium-catalyzed cross-coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil.