SYNTHESIS OF MULTISUBSTITUTED BENZOFURANS/INDOLES USING MULTICHLORINATED PHENOLS/ANILINES VIA PALLADIUM-CATALYZED SITE-SELECTIVE SONOGASHIRA COUPLING

Multisubstituted benzofurans/indoles are a critical class of compounds in the fields of pharmaceuticals and natural products. A useful method of preparing 2-substituted benzofurans/indoles is the Pd-catalyzed Sonogashira coupling of 2-halophenols/2-haloanilines and terminal alkynes, followed by cyclization. For the syntheses of multisubstituted benzofurans/indoles, the use of multichlorinated phenols/anilines as coupling partners is powerful because the synthetic steps required are reduced and all dichlorophenol and dichloroaniline positional isomers are commercially available and inexpensive. However, their use in benzofuran/indole synthesis is limited because of their low reactivity compared with those of the corresponding iodo or bromo compounds. Furthermore, site-selective Sonogashira coupling at the 2-position of the multihalogenated phenols/anilines is sterically and electronically challenging. To overcome these problems, dihydroxyterphenylphosphine (DHTP) has been developed as a ligand that enables the highly ortho-selective Sonogashira coupling of 2-chlorophenols/2-chloroanilines with terminal alkynes. Using the Pd-DHTP catalyst, chlorinated benzofurans/indoles are successfully obtained, which are easily converted to other derivatives by substitution of the chloro group. In this review, we summarize this and related studies to demonstrate the utility of this method.

Automated summary

Multisubstituted benzofurans/indoles are important compounds in the fields of pharmaceuticals and natural products. The Pd-catalyzed Sonogashira coupling of 2-halophenols/2-haloanilines and terminal alkynes followed by cyclization is a useful method for preparing 2-substituted benzofurans/indoles. The use of multichlorinated phenols/anilines as coupling partners is powerful for the synthesis of multisubstituted benzofurans/indoles, but their low reactivity and steric/electronic challenges limit their application. Dihydroxyterphenylphosphine (DHTP) has been developed as a ligand to overcome these problems and enable highly selective Sonogashira coupling at the 2-position. This review summarizes the utility of this method and related studies.