Pd-Catalyzed ipso,meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C–H Activation Cascade with Dimethyl Carbonate as the Methyl Source

• DOI: 10.1021/jacs.0c13057
• Publication Date: 2021-03-22T19:43:46Z
• Authors: Zhuo Wu; Feng Wei; Bin Wan; Yanghui Zhang
• Keywords: Chemical Sciences not elsewhere classified; novel strategy; Biophysics; Plant Biology; meta; dimethylated; Biochemistry; 01 natural sciences; K 2 CO 3; Substituted Iodoarenes; Environmental Sciences not elsewhere classified; iodo group; Genetics; methyl group; methylation methods; Methyl Source; Molecular Biology; iodoarene; Cancer; Pharmacology; Evolutionary Biology; methylating reagents; Computational Biology; Dimethyl Carbonate; 0104 chemical sciences; 3. Good health; ortho; palladium-catalyzed dimethylation r.; Medicine

A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.