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

Abstract

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.

The Deuterated “Magic Methyl” Group: A Guide to Site‐Selective Trideuteromethyl Incorporation and Labeling by Using CD3Reagents

“…Very recently, [D 6 ]dimethyl carbonate was introduced as a new trideuteromethylation reagent. The Zhang group developed a new strategy for site‐selective di(trideutero)methylation using ortho ‐substituted iodoarenes as substrates, K 2 CO 3 as a base, PdCl 2 as catalyst and [D 6 ]dimethyl carbonate as the trideuteromethyl source (Scheme 36a) [109] . [D 6 ]DMC is a very interesting reagent.…”

“…The Zhang group developed a new strategy for site‐selective di(trideutero)methylation using ortho ‐substituted iodoarenes as substrates, K 2 CO 3 as a base, PdCl 2 as catalyst and [D 6 ]dimethyl carbonate as the trideuteromethyl source (Scheme 36 a). [109] [D 6 ]DMC is a very interesting reagent. It can be readily prepared from CD 3 OD and CO and can be easily handled.…”

A Mild Heteroatom (O-, N-, and S-) Methylation Protocol Using Trimethyl Phosphate (TMP)–Ca(OH)2Combination

“…General methylation procedure A and workup procedure A (chromatography: petroleum ether/EtOAc, 10:1) afforded O-methylated product 15 32 (63 mg, 35% yield) as a white solid. 1 H NMR (500 MHz, CDCl 3 ):  = 7.87 (s, 2 H), 3.77 (s, 3 H), 2.33 (s, 6 H).…”

Frontispiece: The Deuterated “Magic Methyl” Group: A Guide to Site‐Selective Trideuteromethyl Incorporation and Labeling by Using CD3 Reagents

“…The Zhang group developed a new strategy for site-selective di(trideutero)methylation using ortho-substituted iodoarenes as substrates, K 2 CO 3 as a base, PdCl 2 as catalyst and [D 6 ]dimethyl carbonate as the trideuteromethyl source (Scheme 36a). [109] [D 6 ]DMC is a very interesting reagent. It can be readily prepared from CD 3 OD and CO and can be easily handled.…”