Herein, we report a two‐step process forming arene C−O bonds in excellent site‐selectivity at a late‐stage. The C−O bond formation is achieved by selective introduction of a thianthrenium group, ...which is then converted into C−O bonds using photoredox chemistry. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site‐selectively, which has not been shown via aryl halides.
Efficient diversification: The first site‐selective late‐stage aromatic C−O bond formation from arene C−H bonds proceeds in two steps via arylthianthrenium intermediates. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers.
We report diverse C–N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C–H functionalization. The scope of N-nucleophiles ranges from primary and ...secondary alkyl and aryl amines to various N-containing heterocycles, and the overall transformation is applicable to late-stage functionalization of complex, drug-like small molecules.
We report a nucleophilic substitution reaction of five-membered hetarylsulfonium salts that results in a change of the substitution pattern on the arene. The products of these cine-substitutions are ...hard to access synthetically otherwise. The sulfonium salts that serve as starting materials are generated by a highly site-selective C–H functionalization reaction.
A library of 29 homologous Ru-based olefin metathesis catalysts has been tested for ethenolysis of cyclic olefins toward the goal of selectively forming α,ω-diene using cis-cyclooctene as a ...prototypical substrate. Dissymmetry at the N-heterocyclic carbene (NHC) ligand was identified as a key parameter for controlling the selectivity. The best-performing catalyst bearing an N-CF3 group significantly outperformed the benchmark second-generation Grubbs catalyst in the ethenolysis of cis-cyclooctene. Application of this optimal catalyst to the ethenolysis of various norbornenes allows the efficient synthesis of valuable diene intermediates in good yields. The observed ligand effect trends could be rationalized through univariate and multivariate parameter analysis involving steric and electronic descriptors of the NHC ligand in the form of the buried volume and the 77Se NMR chemical shift, in particular the σ yy component of the shielding tensor of Se(NHC) model compounds, respectively. Natural chemical shift analysis of this chemical shielding tensor shows that σ yy probes the π-acceptor property of the NHC ligand, the essential electronic parameter that drives the relative rate of degenerate metathesis and selectivity in ethenolysis with catalysts bearing dissymmetric NHC ligands.
Starting from N-trifluoromethyl benzimidazole (1), a series of N-trifluoromethyl benzimidazolium salts 2a–f·HA have been prepared and fully characterized. These were engaged in the formation of ...Ir(CO)2(NHC)Cl, Rh(COD)(NHC)Cl, Se(NHC), and Au(NHC)Cl derivatives. IR analysis of Ir(CO)2(NHC)Cl complexes revealed that the trifluoromethyl substituent on nitrogen significantly decreases the σ-donating ability of the carbene carbon. On the other hand, the π-acceptor property of these novel ligands is enhanced. Examination of the 77Se NMR resonance of Se(NHC) adducts and the redox potentials of Rh(NHC)(COD)Cl complexes further supports this assumption. In addition, the efficiency of these new N-trifluoromethyl NHC ligands was investigated in π-acidic Au(I)-catalyzed hydroalkoxylation of cyclohexene. The gold complexes bearing NHCs 2a and 2c–e compete with Au(PPh3)Cl in terms of catalytic activity.
We report the synthesis of ruthenium metathesis catalysts containing unsymmetrical N-trifluoromethyl NHC ligands. These complexes have been fully characterized, and a Ru–F interaction has been ...identified in the solid state by X-ray crystallographic analysis for three catalysts with Ru–F distances between 2.629(2) and 2.652(2) Å. The influence of the N-trifluoromethyl NHC ligands on the initiation rates and activation parameters was studied. The activity of these catalysts was evaluated in benchmark olefin metathesis reactions and compared to the standard second-generation Grubbs catalyst. Remarkably, N-trifluoromethyl catalysts display an unusually high selectivity for the formation of terminal olefins (up to 90%) in the ethenolysis of ethyl oleate. Much improved selectivity is demonstrated for alternating copolymerization of cyclooctene and norbornene as well. These results underline the importance of electronic effects exerted by the NHC ligand.
A high throughput experimentation (HTE) study identified active Ru metathesis catalysts and reaction conditions for the ethenolysis of maleate esters to the respective acrylate esters. Catalysts were ...tested at various loadings (75–10’000 ppm) and temperatures (30–60 °C) with maleate esters dissolved in toluene (up to ca. 44 wt‐%) or neat and at variable partial pressures of ethylene (0.2–10 bar). Ruthenium catalysts containing a PCy3 ligand, such as 1st or 2nd generation Grubbs catalysts, as well as the state‐of‐the‐art catalysts containing cyclic alkyl amino carbene (CAAC) ligands, are generally inferior to Hoveyda–Grubbs 2nd generation catalyst in ethenolysis of maleates. Productive turnover numbers could exceed 1900 if the ethenolysis reaction is performed at low ethylene pressure (0.2–3 bar) and reach 5200 when a polymeric phenol additive was used. Such catalytic performance falls well within the window practiced in industry. Moreover, a crude technoeconomic analysis finds similar production cost for the ethenolysis route and conventional technology, that is, propene oxidation followed by esterification, justifying research to further improve the ethenolysis route.
Herein, we report a two‐step process forming arene C−O bonds in excellent site‐selectivity at a late‐stage. The C−O bond formation is achieved by selective introduction of a thianthrenium group, ...which is then converted into C−O bonds using photoredox chemistry. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site‐selectively, which has not been shown via aryl halides.
Effiziente Diversifizierung: Die erste regioselektive, spät anwendbare C‐O‐Bindungsbildung aus Aren‐C‐H‐Bindungen verläuft in zwei Stufen über Arylthianthrenium‐Zwischenprodukte. Elektronenreiche, elektronenarme und elektroneutrale Arene sowie komplexe, wirkstoffähnliche, niedermolekulare Verbindungen lassen sich in Phenole und verschiedene Ether umwandeln.
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