Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C–H Bond Activation

Abstract

Direct C-H bond activation is an important reaction in synthetic organic chemistry. This methodology has the potential to simplify reactions by avoiding the use of prefunctionalized reagents. However, selectivity, especially site selectivity, remains challenging. Sequential reactions, in which different molecules or groups are combined in an ordered sequence, represent a powerful tool for the construction of complex molecules in a single operation. We have discovered and developed a synthetic methodology that combines selective C-H bond activation with sequential reactions. This procedure, which is now known as the "Catellani reaction", enables the selective functionalization of both the ortho and ipso positions of aryl halides. The desired molecules are obtained with high selectivity from a pool of simple precursors. These molecules are assembled under the control of a palladacycle, which is formed through the joint action of a metal (Pd) and an olefin such as norbornene. These two species act cooperatively with an aryl halide to construct the palladacycle, which is formed through ortho-C-H activation of the original aryl halide. The resulting complex acts as a scaffold to direct the reaction (via Pd(IV)) of other species, such as alkyl or aryl halides and amination or acylation agents, toward the sp(2) C-Pd bond. At the end of this process, because of steric hindrance, the scaffold is dismantled by norbornene extrusion. Pd(0) is cleaved from the organic product through C-C, C-H, C-N, C-O, or C-B coupling, in agreement with the well-known reactivity of aryl-Pd complexes. The cycle involves Pd(0), Pd(II), and Pd(IV) species. In particular, our discovery relates to alkylation and arylation reactions. Recently, remarkable progress has been made in the following areas: (a) the installation of an amino or an acyl group at the ortho position of aryl halides, (b) the formation of a C-B bond at the ipso position, (c) the achievement of meta-C-H bond activation of aryl rings bearing a chelating directing group by Pd(II)/Pd(IV)/norbornene catalysis, and (d) the activation of N-H and C-H bonds in sequence for indole 2-alkylation. In this Account, we explain the main features of this methodology, describe its synthetic potential, and illustrate some remarkable progress that has been made, emphasizing the most recent developments and applications in total synthesis.

Beyond Friedel and Crafts: Innate Alkylation of C−H Bonds in Arenes

“…An interesting and more general process has been described by Bach for the palladium‐catalyzed direct C2‐alkylation of indoles and electron‐deficient pyrroles through a norbornene‐mediated C−H activation‐ based on the Catellani reaction (Scheme ) . The use of palladium(II) sources such as Pd(OAc) 2 , PdCl 2 , Pd(MeCN) 2 Cl 2 , or Pd(OCOCF 3 ) 2 , in the presence of two equivalents of norbornene and an excess of alkyl halides as the alkylating agents at elevated temperature allows the C2‐selective direct alkylation of several indoles and electron‐deficient pyrroles in moderate to excellent yields.…”

Understanding Thermal and Photochemical Aryl–Aryl Cross‐Coupling by the AuI/AuIII Redox Couple

“…In recent years, the functionalization of C −H bonds has attracted considerable attention in organic synthesis . In particular, the oxidative coupling of different arenes by double C−H bond activation has been a topic of immense importance in modern organic synthetic chemistry .…”

Jenseits von Friedel und Crafts: immanente Alkylierung von C‐H‐Bindungen in Arenen

“…Ein allgemeinerer Prozess wurde von Bach für die palladiumkatalysierte direkte C2‐Alkylierung von Indolen und elektronenarmen Pyrrolen über eine Norbornen‐vermittelte C−H‐Aktivierung– basierend auf der Catellani‐Reaktion beschrieben (Schema ) . Die Verwendung von Palladium(II)‐Quellen wie Pd(OAc) 2 , PdCl 2 Pd(MeCN) 2 Cl 2 oder Pd(OCOCF 3 ) 2 in Gegenwart von 2 Äquivalenten an Norbornen und einem Überschuss an Alkylhalogenid als Alkylierungsmittel bei erhöhter Temperatur ermöglichte die C2‐selektive direkte Alkylierung mehrerer Indole und elektronenarmer Pyrrole in mäßigen bis hervorragenden Ausbeuten.…”