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 sp2 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.

Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C−H Bond Activation / DELLA CA', Nicola; Fontana, Marco; Motti, Elena; Catellani, Marta. - In: ACCOUNTS OF CHEMICAL RESEARCH. - ISSN 1520-4898. - 49:(2016), pp. 1389-1400. [10.1021/acs.accounts.6b00165]

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

DELLA CA', Nicola;FONTANA, Marco;MOTTI, Elena;CATELLANI, Marta
2016-01-01

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 sp2 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.
2016
Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C−H Bond Activation / DELLA CA', Nicola; Fontana, Marco; Motti, Elena; Catellani, Marta. - In: ACCOUNTS OF CHEMICAL RESEARCH. - ISSN 1520-4898. - 49:(2016), pp. 1389-1400. [10.1021/acs.accounts.6b00165]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2812070
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