Room Temperature C–H Arylation of Benzofurans by Aryl Iodides

Abstract

A robust method of room temperature direct arylation for benzofuran is reported. This discovery allows for mild arylation by commercially available aryl iodides with complete C-2 regioselectivity and tolerates a range of functional groups, including heat sensitive groups. Mechanistically, a Heck-type oxyarylation product from a direct arylation process is reported as a key piece of evidence for a carbopalladation intermediate.

Hydride Relay Exchange Mechanism for the Heterocyclic C–H Arylation of Benzofuran and Benzothiophene Catalyzed by Pd Complexes

“…However, these works are limited by the small substrate range, slow kinetics at room temperature, limited commercial availability of the aryldiazonium salts, and violent decomposition . In 2021, Luscombe group reported a robust method for the direct α-arylation of benzofurans at room temperature catalyzed by Pd­(OAc) 2 with iodobenzene in the presence of 2 -p -nitrobenzoic acid and Ag 2 O in HFIP solvent (see Scheme B) . Meanwhile, although the selective heterocyclic C–H arylation of benzofuran and benzothiophene with iodobenzene at room temperature has been studied in experiments, the mechanism and origin of the regioselectivity for these reactions are still unclear.…”

“…The Pd–C coupling step is still the regioselectivity-determining step, the free energy barriers for the α-C-H and β-C-H arylation pathways of benzofuran are 15.7 and 19.0 kcal/mol, respectively. It is obvious that the α-C-H arylated product (α- P F ) of benzofuran catalyzed by the Pd complex is the major product, which agrees well with experimental results …”

Circular Discovery in Small Molecule and Conjugated Polymer Synthetic Methodology

“…Curious about the generality of this process, exploratory work was performed, eventually leading to improved conditions for benzofuran C–H arylation ( Scheme 13 ). 17 This small molecule report was inspired directly by our studies on adjacent polymerizations. While it is common for new polymerization methods to be informed by small molecule work, it is worth considering in what ways new polymerizations can inform new small molecule synthetic methods as well.…”

“…Much of this work leverages fundamental mechanistic insight to make finely tuned modifications. While electrophilic aromatic substitution (S E Ar) has been discussed, , and some examples exist for Heck-type coupling, ,, the concerted metalation–deprotonation (CMD) pathway has been indicated as the acting mechanism through which C–H bond activation in direct arylation occurs in the majority of cases (Scheme , I – IV ). − In these cases, the catalyst’s metal center forms a C–M bond at the same time as a ligated carboxylate group assists in deprotonating the C–H bond undergoing functionalization (Scheme , II ).…”

Recent Advances in Room-Temperature Direct C–H Arylation Methodologies

“…The Luscombe group recently succeeded in developing a robust methodology for a-arylation of benzofuran, another important heteroaryl scaffold (Scheme 13). 48 Though the reaction condition is very similar to the indole arylation method developed by the Larrosa group 31 except for the use of HFIP as the solvent instead of DMF, the reaction proceeds via a Heck-type arylation pathway (Scheme 13) instead of a radical mechanism as evidenced by the dark condition studies, deuterium scrambling, and KIE studies. Many functional groups such as -OH, NHAc, and -CHO, and halogens were well tolerated.…”