A unified approach to <i>meta</i> -selective methylation, mono-, di- and trifluoromethylation of arenes

Matched molecular series (MMS) are series of molecules that differ only by a single modification at a specific site. The synthesis of MMS is a desirable strategy in drug discovery campaigns. Small aliphatic motifs, notably methyl, mono-, di- and trifluoromethyl substituents (C₁ units), are known to have profound effects on the physiochemical properties and/or potency of drug candidates. In this context, we herein report a unique strategy for achieving direct <i>meta</i>-selective methylation, mono-, di-, and trifluoromethylation from the same parent compound. This approach takes advantage of a highly <i>meta</i>-selective ruthenium(ii)-catalyzed alkylation, followed by a subsequent photocatalyzed protodecarboxylation or silver-mediated fluorodecarboxylation to reveal the (fluoro)methyl moiety. This method enables the late-stage access to MMS in small molecules bearing a variety of orienting groups as well as bio-relevant molecules containing complex functionalities, bypassing the need for <i>de novo</i> synthesis to access individual compounds in a series. Moreover, key physiochemical properties of drug candidates were successfully modulated, highlighting opportunities to accelerate medicinal chemistry programs in a sustainable fashion.