Heck chemistry

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

A very recent addition to the already powerful spectrum of microwave Heck chemistry has been the development of a general procedure for carrying out oxidative Heck couplings, that is, the palladium)11)-catalyzed carbon-carbon coupling of arylboronic acids with alkenes using copper(II) acetate as a reoxidant [25], In a 2003 publication (Scheme 6.6), Larhed and coworkers utilized lithium acetate as a base and the polar and aprotic N,N-dimethylformamide as solvent. The coupling... 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

Homogeneous Catalysis in Supercritical CO2 Using Dendrimer-Encapsulated Metal Particles Heck Chemistry... 

While BINAP had been used as the sole ligand of choice in the early days of asymmetric Heck chemistry, the introduction of the chiral P,N-li-gand 69 by Pfaltz and co-workes has led to another great improvement of the general methodology [22],... 

Earina V. High-turnover palladium catalysts in cross-coupling and Heck chemistry a critical overview. Adv. Synth. Catal. 2004 346 1553-1582. 

Whitcombe NJ, Hii KK, Gibson SE. Advances in the Heck chemistry of aryl bromides and chlorides. Tetrahedron 2001 57 7449-7476. 

Kerry K. Karukstis and Gerald R. Van Hecke, Chemistry Connections The Chemical Basis of Everyday Phenomena (New York Harcourt/Academic Press, 2000) Joe Schwarcz, The Genie in the Bottle (New York W. H. Freeman, 2001). 

Kerry K. Karukstis and Gerald R. Van Hecke, Chemistry Connections (New York Harcourt, 2000), p. 145. 

A variety of palladium(II) and palladium(O) complexes serve as effective precatalysts or precursors to the active palladium(O) catalyst. The most commonly used precatalysts in Heck chemistry are Pd(OAc)2, Pd2(dba)3, and PdCl2(PPh3)2. Typical catalyst loading is in the range of 5-10mol-%. The discovery of the unique catalytic activity of a dimeric palladacycle (Pd2(P(o-Tol)3)( Li-OAc)2) by Herrmann and Belle/ has set a milestone in palladium catalysis as it allows the use of even unreactive chloroaryl substrates intransformations. 

An important development in Heck chemistry arose from the recognition that a-palladium(II) intermediates can be exploited for transformations other than y3-hydride elimination [50]. Examples of potential reaction pathways include insertion of a second olefin (path A), anion capture (path B), or carbonylation (path C) (Scheme 6-22). Due to the... 

Yu K, Sommer W, Week M, Jones CW (2004) Silica and polymer-tethered Pd-SCS-pincer complexes evidence for precatalyst decomposition to form soluble catalyhc species in Mizoroki-Heck chemistry. J Catal 226 101... 

Wu, T.-C., Ramachandran, V. Pharmaceutical applications of Heck chemistry. Innovations in Pharmaceutical Technology 2000, 97-101. 

Ar-heterocycles as ligands in high-turnover palladium catalysts for cross-coupling and Heck chemistry 04MI47. 

Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, 7V-methylpyrrole, 7V-(phenylsulfonyl)pyrrole) react with... 

As will be seen throughout the book, carbon monoxide has become an important player in the extension of Heck chemistry to carbonylation reactions. And, since most of these involve CO at atmospheric pressure, this variation is quite accessible to the synthetic chemist. 

Examples of the former two reaction types are illustrated. An early Heck cyclization of 2-carboxy-2 -iododiphenylamine to 1-carbazolecarboxylic acid (73% yield) [346] has been generally overlooked by subsequent investigators. A microwave method is useful for the synthesis of azaindoles from aminopyridines and ketones [347], and a variety of cyclopent[/ ]indolones and carbazolones are available using this Heck chemistry [348, 349]. The requisite enamines can also be generated in situ by the addition of 2-haloani-lines to alkynes with TiC [350]. The aryl Heck variation affords carbazoles [351-353] including novel indolo[3,2-/ ]benzo[/ ]thiophenes [353]. 

Terminally functionalized PIB oligomers have been used in a thermomor-phic heptane/JV,N-dimethylacetamide mixture as supports for thermally stable SCS-Pd(II) Heck catalyst precursors. A PIB-supported SCS-Pd(II) Heck catalyst was prepared from the carboxyl-terminated PIB oligomer by the sequence of reactions shown in Eq. 61. The PIB-bound SCS-Pd(II) species 125 so ormed was then used to carry out Heck chemistry (Eq. 62). As was true for SCS-Pd(II) species on other polymers [154,155,162], this catalyst was only effective for aryl iodides or activated aryl bromides. However, the catalyst could be used through... 

Our work on latent biphasic systems has focused on linear polymers [165]. Initially these studies focused on poly(JV-alkylacrylamide)s like PNODAM because we had earlier shown that these lipophilic materials are very phase-selectively soluble in heptane [158,165]. This initial work used the PNODAM-bound SCS-Pd catalyst 116 in a DMA-heptane mixture with iodobenzene and acrylic acid as substrates and triethylamine as a base. This catalyst mixture was initially homogeneous at 25 On heating, Heck chemistry occurred to form cinnamic acid. Subsequent cooling of this reaction mixture formed a biphasic mixture even without addition of water because the reaction had formed some triethyl ammonium iodide, and this ammonium salt functioned as the perturbant. 

Recently, a wide range of organic reactions have been promoted by microwave irradiation," but in the field of Heck chemistry only a limited number of papers have appeared. " " "" Two types of microwave heating equipment have been used, a multimode reactor or a monomode reactor.The latter is more expensive but allows the placement of the reaction mixture at a fixed position of much higher continuous electric field strength than can be obtained in a multimode reactor." This is particularly important with Pd-catalyzed reactions since the reaction mixture must be heated to a high temperature in a reproducible and homogeneous fashion. 

Another example of an environmentally benign solvent for Heck chemistry is supercritical carbon dioxide (Scheme 44),[ 2],[i93] Undoubtedly, the future need for cleaner chemical processing is great. 

Shaughnessy, K.H., Kim, P. and Hartwig, J.F. (1999) A fluorescence-based assay for high-throughput screening of coupling reactions. Applications to Heck chemistry. J. Am. Chem. Soc., 121, 2123-32. 

Although Mizoroki-Heck chemistry also followed the same ligand-driven development, the results may appear puzzling. In 2000 we speculated [4] that the Mizoroki-Heck reachon is the best model process (a sharpening stone) for the development of new catalyhc systems, and that this development reciprocates in palladium catalysis as a whole. As is evident now, this metaphor should be read in a literal sense The sharpening stone sharpens other instruments, but not itself Palladium chemistry has indeed advanced dramahcally since then. New effective catalysts have been described for almost all palladium-catalysed reactions except the Mizoroki-Heck reaction, which turns out to be stubbornly reluctant to keep pace with other classical palladium-catalysed chemistry. 

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