The directing group (DG)-assisted approach has so far been the major route to achieve selective C-H activation at both proximal and distal positions. While rhodium catalysts are highly effective in DG-assisted ortho-C-H arylation, meta-C-H arylation with rhodium has not yet been reported. In this study, we present the first example of Rh-catalyzed meta-C-H arylation of arenes. We found that the 2-cyanophenyl-based directing group, in conjunction with aryl boronic acids, selectively promotes meta-arylation with complete mono-selectivity. Despite significant advancements in meta-C-H activation for substrates with shorter linkers, such as hydrocinnamic acids, benzyl alcohols/amines, etc., meta-C-H activation of substrates with longer alkyl chains remains challenging with limited literature examples. We demonstrated that arenes with varying chain lengths, including conformationally flexible and less rigid ones such as 4-phenylbutanoic acid, 5-phenyl valeric acid, 6-phenylcaproic acid, 3-phenylpropanol, and 4-phenylbutanol underwent meta-arylation with high levels of regiocontrol. From a synthetic perspective, this approach could be valuable as it allows for the production of biaryl derivatives of flexible arenes with native functional groups at the meta-position. The synthetic utility of this strategy is demonstrated through the total synthesis of CNBCA, a bioactive compound possessing promising potency against the SHP2 enzyme activity in vitro.
Keywords: Linker length variation; Mechanistic study; Meta-C-H arylation; Rh-catalysis; distal C-H functionalization.
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