Intermolecular Anodic Oxidative Cross-Dehydrogenative C(sp³)–N Bond-Coupling Reactions of Xanthenes with Azoles

Abstract

A new anode strategy for accessing xanthen-9azoles via an electrochemical C(sp 3 )−H/N−H cross-coupling of xanthenes with azoles is described. This reaction proceeds efficiently with a broad scope of both xanthenes and N−H-free azoles under metal-and additional oxidant-free conditions and represents a new access to direct incorporation of important N-heterocycle units into the resulting xanthenes.X anthen-9-amines are important motifs existing in many important biologically active molecules, pharmaceuticals, and materials and find increasing applications in synthesis (Figure 1). 1−3 Accordingly, developing elegant approaches for construction of these molecules remains an ongoing point of interest for synthetic chemists. Traditional methods include transition-metal-catalyzed C−H amination 4 of xanthenes with nitrene precursors, which has emerged as the most common tool for the synthesis of xanthen-9-amines. However, such transformations suffer from heavy metal residues, toxic waste, and substrate prefunctionalization (Scheme 1a). Alternatively, the dehydrogenative cross-coupling reaction 5 is particularly attractive owing to its avoidance of the substrate prefunctionalization with highly atom-economy to construct various carbon−carbon bonds 6 and carbon−heteroatom bonds. 7 Among them, the direct C−H/N−H dehydrogenative crosscoupling of xanthenes represents one of the most efficient methods for accessing xanthen-9-amines. 8 However, most of these strategies require a combination of transition metals and excess amounts of external oxidants. Thus, there is an urgent need for developing improved synthetic pathways that can address these shortcomings.Recently, Zeng and co-workers developed an intermolecular electrochemical C(sp 3 )−H/N−H cross-coupling of xanthenes with amides to produce N-alkoxy-N-(9H-xanthen-9-yl)benzamide using 0.5 equiv of ferrocene as the redox catalyst under basic conditions (Scheme 1b). 9 Although this method has provided a conceptually novel strategy for the C(sp 3 )−N bond formation, it is restricted to narrow substrate scope with respect to only four examples of 9H-xanthene as well a special N-alkoxybenzamide. We envisioned that by employing the anodic oxidant the C(sp 3 )−H/N−H cross-coupling 10−12 might proceed successfully to enable the formation of the C−N bond under redox catalyst free conditions. Herein, we report a new anode strategy for the synthesis of xanthen-9azole derivatives (Scheme 1c) by C(sp 3 )−H/N−H dehydrogenative cross-coupling of xanthenes with various N−H-free azoles (e.g., 1H-indazoles, 1H-pyrazoles, 4H-pyrazolo-[3,4-

Photochemical and Electrochemical Strategies towards Benzylic C−H Functionalization: A Recent Update

“…In this work, the scope was limited to xanthene as in case of other substrates decomposition of the amide was observed. In 2019, two reports from Li [78] and Wang [79] further explored the electrochemical C−H functionalization of xanthenes. In both cases direct electrolysis of xanthenes led to the formation of an activated intermediate, either as a cation or a radical, which was subsequently trapped with the formation of a C−N bond.…”

Electrochemical Functionalization of Imidazopyridine and Indazole: An Overview

“…In the same year, Song & Li et al [41] . developed an electrochemical metal‐free strategy for alkyation of 1 H ‐indazoles 36 using intermolecular oxidative cross‐dehydrogenative coupling reaction.…”

Electrochemical Generation and Use in Organic Synthesis of C‐, O‐, and N‐Centered Radicals

“… Cross‐coupling reaction via stabilized radicals. a) Li's intermolecular anodic cross‐coupling of xanthenes with azoles [130] . b) Huang's synthesis of bis‐indolylmethanes from indoles and ethers [132] .…”

“…The anodic oxidative coupling reaction of xanthenes ( 184 ) with azoles ( 185 ) was successfully carried out through a dehydrogenative Csp 3 −N cross‐coupling (Scheme 20a) [130] . This reaction is triggered by formation of a double‐benzylic radical ( 186 ) at the xanthene, where simultaneously imidazole is also oxidized to form an N‐centered radical ( 187 ).…”