Ruthenium-Catalyzed Monoselective C–H Methylation and d₃-Methylation of Arenes

Abstract

Site-selective installation of C−Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C−H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d 3 -methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity.

Transition-Metal-Catalyzed C–H Bond Activation for the Formation of C–C Bonds in Complex Molecules

“…Larrosa recently described the ruthenium-catalyzed monoselective C−H methylation and d 3 -methylation of arenes, using N,N,N-trimethyl anilinium salts as an easy to handle and stable electrophilic methyl source. 164 Using 5 mol % of RuBnN catalyst 1, one equiv of Na 2 CO 3 as a base, two equiv of NaI as an additive and one equivalent of the methylating ammonium salt in NMP at 50−70 °C, high levels of monoselectivity were achieved with 24 examples of methylation and 6 examples of deuteromethylation. This protocol was demonstrated on eight late-stage examples using ammonium salt Me 3 -143 bearing two trifluoromethyl groups.…”

The crucial role of silver(i)-salts as additives in C–H activation reactions: overall analysis of their versatility and applicability

“…Since the pioneering contribution by Murai and co-workers, 12 ruthenium-catalyzed C–H activation reactions have flourished significantly in the past two decades with major contributions from Ackermann, 1 j – m ,13 Dixneuf, 14 and Miura, 15 among others. 1 j – m ,16,17…”

Electrochemical Ruthenium‐Catalysed Directed C−H Functionalization of Arenes with Boron Reagents

“…The use of directing groups with transition‐metal catalysis enables regioselective C−H activation and functionalization under mild conditions, and has been explored extensively with Pd, [8] Rh, [9] Ir, [10] Ni, [11,12] Co, [12,13] and Fe [12,14] and Mn [15] . In this context, ruthenium has emerged as a versatile transition metal catalyst enabling arylation, [16–18] alkenylation [19–21] and alkylation reactions [22–26] . A wide range of nitrogen‐based directing group‐containing substrates and biologically active molecules can be functionalized using various electrophilic coupling partners, including halides, triflates and ammonium salts, [23,24,27] all under mild conditions.…”

“…[15] In this context, ruthenium has emerged as a versatile transition metal catalyst enabling arylation, [16][17][18] alkenylation [19][20][21] and alkylation reactions. [22][23][24][25][26] A wide range of nitrogenbased directing group-containing substrates and biologically active molecules can be functionalized using various electrophilic coupling partners, including halides, triflates and ammonium salts, [23,24,27] all under mild conditions. Through careful choice of reaction conditions and catalyst structure, regioselectivity for ortho-and meta-functionalisation enables access to a wide range of substitution patterns.…”