Heck reaction carbocycle synthesis

The intramolecular Mizoroki-Heck reaction, although it had been known since 1977, when it was first used in the synthesis of heterocycles [7], started to be explored properly only around the mid 1980s. Its large use for the preparation of carbocycles began only in the late 1980s [8]. Since then, however, there has been a tremendous increase of interest in this intramolecular cyclization, culminating in its widespread utilization in total synthesis [9], This was mostly due to the development of asymmetric versions by two major contributors, namely Overman for the construction of heterocycles [9] (Chapter 12) and Shibasaki focusing on carbocyclic systems [10] (Chapter 16). 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

Dai WM, Shi JY, Wu JL (2008) Synthesis of 3-arylideneindolin-2-ones from 2-aminophe-nols by Ugi four-component reaction and Heck carbocyclization. Synlett 2716-2720... 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

As an interesting multicomponent reaction, an efficient palladium-catalyzed protocol for the synthesis of 3-atylidene-2-oxindoles was developed in 2010 by Balalaie and co-workers (Scheme 2.127). In this approach, a sequential one-pot six-component reaction via Ugi-Heck carbocyclization-Sonogashira-nucleophilic addition was used for the synthesis of the desired skeleton. 

Balalaie et al. described in 2010 a six-component reaction. The stereoselective synthesis of oxindole derivatives was carried out using a sequential one-pot Ugi/Heck carbocyclization/... 

---