Rhodium(III)-Catalyzed Oxidative Cross-Coupling of Unreactive C(sp³)–H Bonds with C(sp²)–H Bonds

The development of the oxidative cross-coupling of unreactive C­(sp³)–H bonds with (hetero)­arene C­(sp²)–H bonds is considerably appealing, yet conceptually and practically challenging. Here, we disclose the rhodium-catalyzed oxidative heteroarylation of unactivated C­(sp³)–H bonds with heteroarene C­(sp²)–H bonds. This method provides a step-economic route to β-heteroarylated 2-ethylpyridine derivatives, which exhibits relatively broad substrate scope, high tolerance level of sensitive functional groups, and high selectivity. The protocol can also be extended to the coupling reaction between 8-methylquinoline derivatives and heteroarenes

Rhodium/Copper Cocatalyzed Highly <i>trans</i>-Selective 1,2-Diheteroarylation of Alkynes with Azoles via C–H Addition/Oxidative Cross-Coupling: A Combined Experimental and Theoretical Study

Transition metal-catalyzed addition of diaryl alkynes with arylating reagents for the synthesis of tetraarylethylenes generally encounters rigorous reaction conditions and relies on the use of prefunctionalized substrates such as organic halides or surrogates and organometallic reagents. In this work, we establish a highly <i>trans</i>-selective 1,2-diheteroarylation of alkynes with azoles via a rhodium/copper cocatalyzed C–H addition/oxidative coupling process. Moreover, the diheteroarylation developed herein could open a door for the synthesis of heteroarene-doped tetraarylethylenes, and the photoluminescence (PL) spectra in THF–water mixtures and solid powder verify that these tetra­(hetero)­arylethylenes are aggregation-induced emission (AIE) active, building a new AIE molecule library. With a combination of experimental and theoretical methods, the reaction mechanism for addition/oxidative cross-coupling of internal alkynes with azoles has been investigated. Theoretical calculations reveal that the metalation/deprotonation of azole could occur with either rhodium or copper species. When azolylrhodium is formed, an alkyne could insert into the Rh–C bond. Another azolyl group could then transfer to rhodium from azolylcopper compound. The subsequent intramolecular <i>trans</i>-nucleophilic addition generates the second C–C bond. Meanwhile, the putative pathway for the formation of the hydroheteroarylated byproduct has also been explained by theoretical calculations

Standardizing Substrate Selection: A Strategy toward Unbiased Evaluation of Reaction Generality

With over 10,000 new reaction protocols arising every year, only a handful of these procedures transition from academia to application. A major reason for this gap stems from the lack of comprehensive knowledge about a reaction’s scope, i.e., to which substrates the protocol can or cannot be applied. Even though chemists invest substantial effort to assess the scope of new protocols, the resulting scope tables involve significant biases, reducing their expressiveness. Herein we report a standardized substrate selection strategy designed to mitigate these biases and evaluate the applicability, as well as the limits, of any chemical reaction. Unsupervised learning is utilized to map the chemical space of industrially relevant molecules. Subsequently, potential substrate candidates are projected onto this universal map, enabling the selection of a structurally diverse set of substrates with optimal relevance and coverage. By testing our methodology on different chemical reactions, we were able to demonstrate its effectiveness in finding general reactivity trends by using a few highly representative examples. The developed methodology empowers chemists to showcase the unbiased applicability of novel methodologies, facilitating their practical applications. We hope that this work will trigger interdisciplinary discussions about biases in synthetic chemistry, leading to improved data quality

Copper- or Nickel-Enabled Oxidative Cross-Coupling of Unreactive C(sp³)–H Bonds with Azole C(sp²)–H Bonds: Rapid Access to β‑Azolyl Propanoic Acid Derivatives

β-Azolyl propanoic acid derivatives are frequently found in biologically active molecules and pharmaceuticals. Here, we report the oxidative heteroarylation of unactivated C­(sp³)–H bonds with azole C­(sp²)–H bonds via copper or nickel catalysis with the aid of removable bidentate auxiliary, which provides a rapid pathway to β-azolyl propanoic acid derivatives. A variety of azoles such as oxazole, benzoxazole, thiazole, benzothiazoles, benzimidazole, purine, and even [1,2,4]­triazolo­[1,5-<i>a</i>]­pyrimidine could be engaged in this protocol

Highly Selective Radical Relay 1,4-Oxyimination of Two Electronically Differentiated Olefins

Radical addition reactions of olefins have emerged as an attractive tool for the rapid assembly of complex structures, and have plentiful applications in organic synthesis, however, such reactions are often limited to polymerization or 1,2-difunctionalization. Herein, we disclose an unprecedented radical relay 1,4-oxyimination of two electronically differentiated olefins with a class of bifunctional oxime carbonate reagents via an energy transfer strategy. The protocol is highly chemo- and regioselective, and three different chemical bonds (C–O, C–C, and C–N bonds) were formed in a single operation in an orchestrated manner. Notably, this reaction provides rapid access to a large variety of structurally diverse 1,4-oxyimination products, and the obtained products could be easily converted into valuable biologically relevant δ-hydroxyl-α-amino acids. With a combination of experimental and theoretical methods, the mechanism for this 1,4-oxyimination reaction has been investigated. Theoretical calculations reveal that a radical chain mechanism might operate in the reaction