Synthesis of biaryls via the Suzuki-Miyaura coupling (SMC) reaction using nitroarenes as an electrophilic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl-nitro (Ar-NO) bond by palladium, which represents an unprecedented elemental reaction.

The Buchwald-Hartwig amination of nitroarenes was achieved for the first time by using palladium catalysts bearing dialkyl(biaryl)phosphine ligands. These cross-coupling reactions of nitroarenes with diarylamines, arylamines, and alkylamines afforded the corresponding substituted arylamines. A catalytic cycle involving the oxidative addition of the Ar-NO bond to palladium(0) followed by nitrite/amine exchange is proposed based on a stoichiometric reaction.

Metrics & MoreArticle Recommendations CONSPECTUS: Cross-coupling reactions are powerful synthetic tools to construct diverse chemical bonds often found in, for example, advanced materials and pharmaceuticals. Since their discovery, haloarenes have habitually been used as electrophilic coupling partners both in academic and industrial contexts. However, concerning the efficiency and the often-negative environmental impact of haloarene-based cross-coupling processes, more readily available, inexpensive, and environmentally friendly electrophiles have been explored. Nitroarenes, for example, are obtained from the facile nitration of aromatic compounds and, thus, represent one of the most easy-to-access feedstock electrophiles. Furthermore, their electron-deficient arene core can be functionalized easily and site-selectively through a wide variety of reactions. Yet, despite these advantages and even though the direct transformation of the NO 2 group would be an attractive option in cross-coupling chemistry, it has so far remained difficult to convert nitroarenes via a cleavage of the Ar−NO 2 bond given the inherent reactivity (or the lack thereof) of the nitro group. Such denitrative conversion has been performed by a conventional sequence of reduction, diazotization, and Sandmeyer reactions, which severely lacks efficiency and generality. This Account summarizes our recent research progress on cross-coupling reactions that employ nitroarenes as electrophiles. First, we developed the Suzuki−Miyaura coupling of nitroarenes using a palladium/BrettPhos catalyst. This reaction proceeds via an (at the time) unprecedented oxidative addition of the Ar−NO 2 bond, which was supported by experimental results and theoretical calculations. A widely accepted catalytic cycle for Pd-catalyzed cross-couplings has since been extended to include nitroarenes as electrophiles, which significantly increases substrate generality. Second, this denitrative coupling protocol was applied to various bond-forming reactions, namely, Buchwald−Hartwig amination, etherification, and hydrogenation reactions. Such diversification has enhanced the utility of nitroarenes as cross-coupling partners. To develop each reaction, it was necessary to modify the reaction conditions as required to overcome the obstacles deriving from nitro functionality including transmetalation and side reactions, as well as oxidative addition. Third, we designed a new Pd/NHC catalyst that exhibits higher activity than Pd/BrettPhos. The improved performance of Pd/NHC system was supported by its strong electron-donicity and structural robustness, and it allows the reduction of the catalyst loading significantly, thus increasing the efficacy and practicality of this method. The field of nitroarene-based cross-coupling has just started to flourish. In addition to our original work, several research groups have already adopted Pd/BrettPhos or Pd/NHC catalysts to develop new denitrative functionalizations. The utility of nitroarenes in the context of organic synthesis should be now...

N-Heterocyclic carbene (NHC) ligands effective for the cross-coupling of nitroarenes were identified.

The Pd-catalyzed reductive denitration of nitroarenes has been achieved via a direct cleavage of the C-NO bonds. The catalytic conditions reported exhibit a broad substrate scope and good functional-group compatibility. Notably, the use of inexpensive propan-2-ol as a mild reductant suppresses the competitive formation of anilines, which are normally formed by other conventional reductions. Mechanistic studies have revealed that alcohols serve as efficient hydride donors in this reaction, possibly through β-hydride elimination from palladium alkoxides.