Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C-H olefination

Abstract

The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (C-H) bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents. However, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. We report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient syntheses of 2-tetralone and naphthoic acid natural product cores.

Figure 1

(a) Comparison of the Mizoroki–Heck reaction and arene C–H olefination. (b) Schematic depiction of our position-selective C–H activation approach. (c) Substrates that were found to be unreactive under our original conditions but could be efficiently olefinated in the presence of amino acid ligands. (d) Non-steroidal anti-inflammatory drugs (NSAIDs) that can be directly ortho-olefinated. (e) Natural product components that can readily be synthesized using position-selective C–H olefination.

Figure 2

C–H olefination of phenylacetic acid substrates with ethyl acrylate (6a₁, 6b₁, and 6c to 6s) and with other olefin coupling partners (6a₂ to 6a₅ and 6b₂).

Figure 3

(a) Selected amino acid ligand screening data for position-selective C–H olefination. (The full ligand screening data are available in Table S8.) (b) Substrate scope for ligand-controlled position-selective C–H olefination. (c) Ligand-enabled C–H olefination with 2 mol% Pd(OAc)₂. (d) Amino acid ligand-enabled C–H olefination with problematic substrates. (Unless otherwise noted, the reaction conditions in 3.b to 3.d are identical to those described in 3.a.)

Figure 4

(a) Synthesis of 7,8-dimethoxytetalin-2-one. (b) Synthesis of the naphthoic acid component of neocarzinostatin (1). (c) Synthesis of the naphthoic acid component of kedarcidin (3).