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1.2 Intramolecular Heck Reactions

DOI: 10.1055/sos-SD-221-00020

Jammi, S.; Nottingham, C.; Guiry, P. J.Science of Synthesis: Metal-Catalyzed Cyclization Reactions, (2016155.

General Introduction

The vinylation of aryl/vinyl/alkyl halides or pseudohalides catalyzed by palladium(0), the Heck cross-coupling reaction, has developed into one of the most widely employed C—C bond-forming reactions in organic synthesis since its discovery in 1968 by Heck.[‌1‌‌3‌] The intramolecular version of this reaction was first realized by Mori and co-workers in 1977 through the formation of indole 1 (Scheme 1).[‌4‌] Since then the intramolecular Heck reaction has been extensively utilized in the construction of isolated, fused, bridged, or spiro rings of various sizes and as a key step in the total synthesis of many natural products.[‌5‌] Its application in cascade/domino processes has further increased the usefulness of the reaction in multiple bond formation to construct cyclic or polycyclic systems in both asymmetric and nonasymmetric modes. Additionally, tertiary or quaternary stereocenters can be established using the asymmetric intramolecular Heck reaction.[‌6‌‌8‌]

Scheme 1 Intramolecular Heck Reaction To Form an Indole[‌4‌]

The commonly accepted catalytic cycle for the intramolecular Heck reaction is believed to involve five major steps (Scheme 2). The first step is the oxidative addition of an aryl/vinyl/alkyl halide or pseudohalide to a palladium(0) complex 2 to form a palladium(II) complex 3. In the second step, dissociation of this palladium(II) complex, followed by coordination of a tethered alkene, leads to the formation of a π-complex 4 or 5. Depending on the reaction conditions, the mechanism involves the dissociation of either a halide (cationic route) or one of the ligands from the palladium(II) complex 3 (neutral route) to allow the coordination of the alkene. In the third step, syn-insertion of the alkene into the Pd—C bond of the π-complex occurs, providing σ-alkyl palladium(II) complexes 6/7 or 8/9. In the fourth step, syn-β-hydrogen elimination gives rise to the Heck products and the hydridopalladium complex 10 or 11. In the last step, catalytically active palladium(0) complex 2 is regenerated from the hydridopalladium complex 10 or 11 by base-assisted reductive elimination to complete the catalytic cycle.

Scheme 2 Catalytic Cycle for the Intramolecular Heck Reaction

In this chapter the best methods for the construction of cyclic systems using intramolecular Heck cyclizations, including enantioselective versions, are assembled. The examples discussed herein are categorized according to Baldwinʼs rules.[‌9‌] These guidelines categorize the reaction by the size of the ring formed, the method of cyclization (with exo for the double bond external to the cyclic structure or endo for an internal alkene), and the geometry of the carbon undergoing cyclization (e.g., trig for a trigonal/sp2 carbon).