The IntramolecularHeck Reaction

Abstract

Since the discovery of the Heck reaction, the process has gained widespread acceptance within the synthetic community both as a practical tool and a research area. The intramolecular Heck reaction has enjoyed a similar renaissance, particularly within the last decade. The reaction has emerged as a reliable method for efficiently constructing small, medium, and large rings. Since the reaction occurs under mild and nearly neutral conditions, the functional group tolerance is high. Tandem reactions, which are initiated by intramolecular Heck reactions, have been developed allowing for multiple ring formations, cyclization and intermolecular coupling, and a multitude of other ever‐expanding possibilities. Furthermore, congested tertiary and quaternary centers can be efficiently constructed diastereoselectively or enantioselectively during the ring‐forming reaction. The numerous advances in reaction technology and capability have led to frequent application of the reaction in complex molecule synthesis and combinatorial library preparation. For the purposes of this chapter, the intramolecular Heck reaction is defined as the palladium[0]‐catalyzed intramolecular coupling of an aryl or alkenyl halide or perfluorosulfonate with an alkene, alkyne, allene, or arene. The mechanism of the Heck reaction is an active area of research. Precise mechanistic details vary substantially depending upon catalyst, substrate, additives, and reaction conditions. The introduction given here is designed to give the chemist a basic understanding of the currently accepted mechanisms to aid in the rational selection and optimization of reaction conditions. Application to total synthesis of natural products and intramolecular Heck reactions on polymer supports are discussed.

Sequential Claisen Rearrangement and Intramolecular Heck Reaction as a Route to Medium-Ring Oxacycle-Fused Heterocycles

“…Exclusive 9-endo cyclisation has been observed previously in medium-ring heterocycle formation from substrates containing activated olefinic fragments. 21 The regioselectivity in the present instance is therefore noteworthy. Similarly, the iodobenzyl ether 16 (entry 3), derived from the rearranged phenol 15, also underwent 9-endo cyclisation under identical conditions to provide the oxonine derivative 17 (52%) as a colourless solid together with unreacted starting material.…”

Organolithium or Heck type cyclization of N-ortho-iodobenzyl-2-alkenylpyrrolidines to give indolizidines

“…Thus, 11b was treated with Pd(PPh 3 ) 4 (5%), n Bu 4 NCl (1.5 eq), NaHCO 3 (2.5 eq), in refluxing CH 3 CN or with Pd(PPh 3 ) 4 (30%), Et 3 N (2.2 eq) in toluene. In these cases a cyclized product could be detected by 1 H NMR spectroscopy of the crude reaction mixtures, but it could not be isolated or characterized, possibly due to instability. …”

“…Perhaps most common is the use of organopalladium species, typically formed by insertion of palladium(0) into an aromatic halide. 1 Cyclization onto an alkene is normally followed by β-elimination (of a palladium hydride species) to regenerate an alkene. An alternative methodology, developed extensively by Bailey and co-workers, makes use of an organolithium species, often formed by halogen-lithium exchange.…”

Palladium-catalyzed approach to the synthesis of five-membered O-heterocycles

“…The analogous carboetherification of hydroxy olefin proceeds with high diastereoselectivity for the generation of 2,5-trans-disubstituted tetrahydrofuran [120][121][122][123][124][125][126][127][128]94] several different alcohol substrates with varying alkene geometries and varied degrees of alcohol substitution (Scheme 57) [129][130][131][132][133][134][135].…”