Heck chemistry bond formation

In the last decade, organopalladium-catalysist C-C bond formation has become one of the most efficient approaches to synthesize organic molecules. The Heck reaction, in particnlar, is widely used as an important method to build biologically active compounds in synthetic chemistry and the pharmaceutical industry. 

The transformation that has come to be known as the Heck reaction is broadly defined as the palladium(O)-mediated coupling of an aryl or vinyl halide or triflate with an alkene. The basic mechanism for the Heck reaction of aryl halides or trifiates (as outlined in more detail in the Key Chemistry), involves initial oxidative addition of the chiral palladium(O) catalyst to afford a a-arylpalladium(II) complex. Coordination of an alkene and subsequent carbon-carbon bond formation by syn insertion provide a a-alkylpalladium(II) intermediate, which readily undergoes P-hydride elimination to release the alkene product. Finally, the hydridopalladium(II) complex has to be converted into the active palladium(O) catalyst to complete the catalytic cycle. 

During the last 30 years, numerous books, monographs, and reviews have been published on organo-palladium chemistry and palladium-catalyzed reactions such as the Heck, Suzuki, Stille, and Sonogashira reactions [1-52], These represent well-established methods for carbon—carbon bond formation in organic synthesis. 

Chapter 3 by Jie Jack Li presents a collection of very interesting total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. Five different types of palladium-mediated reactions are treated (I) oxidative cyclization reactions promoted by palladium (II) species (2) transmetallation reactions with organoboranes, organoslannanes, and organozinc reagents (3) inter- and intramolecular Heck reactions (4) reactions with it-allylpalladium as the intermediate and (5) reactions using C-N bond formation as the key step for the synthesis. 

Since the renaissance of solid-phase organic chemistry in 1992, carbon-carbon bond formation reactions on solid support have probably been the best studied reactions. Many different facets of the Suzuki, Heck and Stille reactions have been evaluated. The influence of linkers, catalyst, solvents, microwave, polymer-bound aryl halides or polymer-bound arylboronic acids (or stannanes) have been studied in detail. 

Transition-metal catalysts play an ever-increasing and important role in modem chemistry [3]. Numerous transition-metal-catalyzed coupling reactions have been developed and applied in the total synthesis of natural products, such as the Suzuki reaction, the Negishi reaction, the Heck reaction, and many others [4]. Interestingly, the power of transition-metal catalysts is even more visible in the area of domino reactions, where terms such as palladium walking show the value of transition metals in bond formations. 

First, the interaction of a Lewis acidic palladium 11) complex with a C(sp —H bond of an electron-neutral or electron-rich (het)arene might result in its electro-phiUc palladation (173 175 Scheme 7.42), a fundamental process later referred to as electrophilic C—H bond activation. In contrast, the oxidative addition of a C(sp )—X bond to palladium(O) is favored for electron-poor (het)arenes, thus providing an orthogonal entry into Mizoroki-Heck chemistry. After C—H activation, convenhonal alkene insertion (175 176) and P-hydride elimination (176 177) eventually lead to the formation of catalytically inactive palladium(O). In order to achieve catalytic turnover, however, paUadium(O) must be reoxidized to palladium(II). 

In addition to these methods, carbon-heteroatom bond formation can also be coupled with these Heck cyclizations. One of the more straightforward methods to couple carbon-heteroatom bond formation with Heck cyclization is via enamine generation. For example, the reaction of enolizable aldehydes or ketones with 2-haloanilines provides a route to the construction of enamines for subsequent Heck cyclization. A recent example of this reaction was reported by Nazare, who demonstrated that ortho-chloroanilines can react with enolizable ketones to generate indoles (Scheme 6.54) [74]. This chemistry proceeds in good yields with a diverse variety of symmetrical and unsymmetrical ketones, provided there is only one enamine isomer, and can be applied to a range of substituted indoles. Zhu has demonstrated that enolizable aldehydes can be used in the cyclization [75]. This latter approach can provide a very effective method to selectively incorporate a range of alkyl, aryl or functionalized units into the 3-indole position, many of which are not easily accessible via other routes. 

Metallomicellar-catalyzed reactions, inclnding hydrolysis, oxidorednction, and C—C bond formation, might characterize these snpramolecular objects as metalloenzyme mimics that use hydrophobic microenvironment and active centers in constrained domains. In this direction, formal approaches using Michaelis-Menten methods known for enzyme chemistry were applied to kinetics characterization of micellar catalysis. In addition, recent achievements of advanced organometallic reactions such as Heck, Suzuki, and Sonogashira couplings as well as olefin metathesis, directly in water and at room temperature, make the use of surfactants particularly promising to lower the environmental impact, which has become a requirement for the chemical industry in the past years. ... 

In the same year (2013), Doyle and co-workers reported an intramolecular version of the cyclization of the allenes.They combined allene chemistry with fluorination, and their report represents the first example of tandem C-C and C-F bond formation for the palladium-catalyzed carbofluorination of allenes. The intramolecular Heck-fluorination cascade provides mono-fluoromethylated heteroarenes, an important class of products in medicinal chemistry, in good yields (Scheme 2.88). The intermolecular variants for the three-component coupling of allenes, aryl iodides, and AgF were reported as well. Mechanistic studies indicate that C-F bond formation occurs by an outer sphere attack of fluoride on an allylpalladium fluoride intermediate. 

In instanees where a functionalized aromatic moiely is desired in the target structure, the Heck reaction of an atyl/vinyl halide/triflate with an alkene in the presenee of a palladium catalyst and base is an obvious choice and, indeed, has found application in the macrocycle arena. The first demonstration of a Pd(0) process on the solid phase actually involved Heck chemistry and was directed toward the synthesis of small libraries containing 20- to 24-membered macrocycles (94, Scheme 11.10). Analogous procedures were employed for the assembly of macrocyclic RGD mimet-ics °° and p-turn mimics (97, Figure 11.12, site of reaction and palladium species employed indicated) on the solid phase. For these conversions, it was postulated that an intramolecular hydrogen bond in the precursor assisted in the formation of the cycle. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

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