Dipartimento di Chimica and CIRCC, Università di Parma , Parco Area delle Scienze 17/A, I-43124 Parma, Italy.
Acc Chem Res. 2016 Jul 19;49(7):1389-400. doi: 10.1021/acs.accounts.6b00165. Epub 2016 Jun 22.
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.
直接 C-H 键活化是合成有机化学中的重要反应。这种方法有可能通过避免使用预官能化试剂来简化反应。然而，选择性，特别是位点选择性，仍然具有挑战性。顺序反应是指不同的分子或基团按照有序的顺序结合在一起，它是在单个操作中构建复杂分子的有力工具。我们已经发现并开发了一种将选择性 C-H 键活化与顺序反应相结合的合成方法。这种方法现在被称为“Catellani 反应”，能够选择性地对芳基卤化物的邻位和对位进行官能化。所需的分子可以从简单的前体中高选择性地获得。这些分子在钯环的控制下组装，钯环是通过金属（Pd）和烯烃（如降冰片烯）的共同作用形成的。这两种物质与芳基卤化物协同作用，通过原始芳基卤化物的邻位 C-H 活化来构建钯环。所得的配合物充当支架，通过 Pd(IV) 引导其他物质（如烷基或芳基卤化物以及胺化或酰化试剂）与 sp(2)C-Pd 键反应。在这个过程的最后，由于空间位阻，支架通过降冰片烯的挤出而被拆除。Pd(0) 通过 C-C、C-H、C-N、C-O 或 C-B 偶联从有机产物中裂解，这与芳基-Pd 配合物的已知反应性一致。该循环涉及 Pd(0)、Pd(II) 和 Pd(IV) 物种。特别是，我们的发现涉及烷基化和芳基化反应。最近，在以下几个方面取得了显著进展：(a) 在芳基卤化物的邻位上安装氨基或酰基，(b) 在对位形成 C-B 键，(c) 通过 Pd(II)/Pd(IV)/降冰片烯催化实现芳环邻位 C-H 键的间位活化，(d) 吲哚 2-烷基化的顺序 N-H 和 C-H 键的活化。在本综述中，我们解释了这种方法的主要特点，描述了它的合成潜力，并说明了一些取得的显著进展，强调了在全合成中最近的发展和应用。
