Heck reaction applications

Primarily, enamines 85 are formed, which cyclize to indoles by intramolecular Heck reaction. Application of this method to pyruvic esters as carbonyl component leads to indole-2-carboxylates 86. 

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

For overviews of applications of the Heck reaction in natural products synthesis, see (a) Link, J. T. Overman, L. E. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F., Stang, P. J., Eds. Wiley-VCH New York, 1998 Chapter 6. (b) Brase, S. de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions Diederich, F., Stang, P. J., Eds. Wiley New York, 1998 Chapter 3.6. (c) Nicolaou, K. C. Sorensen, E. J. Classics in Total Synthesis VCH New York, 1996 Chapter 31. These authors refer to the Heck reaction as "one of the true "power tools" of contemporary organic synthesis" (p. 566). 

Scheme 6.7 Application of bis-NHC chelating ligands in the Mizoroki-Heck reaction...

As an application of this methodology to the syntheses of natural products, Sannicolo et al. have reported the preparation of benzazepine and tetra-hydroisoquinoline derivatives by silane-terminated intramolecular Heck reactions. These workers argued that one main disadvantage of the Heck reaction... 

Wang, Z.F., Xiao, P.F., Shen, B. and He, N.Y. (2006) Synthesis of palladium-coated magnetic nanoparticle and its application in Heck reaction. Colloids and Surfaces A Physicochemical and Engineering Aspects, 276 (1-3), 116-121. 

Zheng et al. treated potassium [l,2,4]diazaphospholides, obtained from the reaction of 3,5-disubstituted-[l,2,4]diazaphospholes with metallic potassium in THF, with [Cp RuCl]4 to afford [(T75-dp)RuCp ] type pseudoruthenocene complex (106) (Scheme 33). Sandwich structure with almost eclipsed orientation of two n-bonded ligands has been confirmed by X-ray crystal structure determination [110], Catalytic application of [(rf-dp)RuCp ] complexes in the Heck reaction has also been investigated [111]. 

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 synthetically useful application of an intramolecular microwave-assisted Heck reaction has been described by Gracias and coworkers (Scheme 6.9) [28], In their approach toward the synthesis of N-containing seven-membered heterocycles, the... 

In the Heck reactions discussed above it was essential to use polar aprotic solvents such as acetonitrile or DMF if high regioselectivity was to be achieved. In other Heck couplings the use of water as a solvent has recently gained attention. The advantages of water compared with standard organic solvents are many - it is, for example, cheap and nontoxic - but its usefulness extends only over a number of well-defined applications, partly because of problems with the solubility of the reactants and catalysts. The development of aqueous catalytic systems is, consequently, an important field [21]. 

Metal-catalyzed cross-couplings are key transformations for carbon-carbon bond formation. The applicability of continuous-flow systems to this important reaction type has been shown by a Heck reaction carried out in a stainless steel microreactor system (Snyder et al. 2005). A solution of phenyliodide 5 and ethyl acrylate 6 was passed through a solid-phase cartridge reactor loaded with 10% palladium on charcoal (Scheme 2). The process was conducted with a residence time of 30 min at 130°C, giving the desired ethyl cinnamate 7 in 95% isolated yield. The batch process resulted in 100% conversion after 30 min at 140°C using a preconditioned catalyst. 

The Heck reaction, first disclosed by the Mori and Heck groups in the early 1970s [65, 66], is the Pd-catalyzed coupling reaction of organohalides (or triflates) with olefins. Nowadays, it has become an indispensable tool for organic chemists. Inevitably, many applications to heterocyclic chemistry have been pursued and successfully executed. In one case, Ohta et al. reacted 2-chloro-3,6-dimethylpyrazine (49) with styrene to furnish ( )-2,5-dimethyl-3-styrylpyrazine (50) [67]. Here, only the E isomer was observed. The outcome will become apparent during the ensuing discussions on the mechanism. 

Normally, the oxidative addition of an aryl chloride to Pd(0) is reluctant to take place. But such a process is greatly accelerated in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(/-Bu)3 or tricyclohexylphosphine]. In late 1990s, Reetz [76] and Fu [77] successfully conducted intermolecular Heck reactions using arylchlorides as substrates, as exemplified by the conversion of p-chloroanisole to adduct 77 [77], The applications of this discovery will surely be reflected on future Heck reactions of non-activated heteroaryl chlorides. 

Since Heck reactions on metalated substrates are known (e.g., with organomercurials [105]), applications of these transformations to pyrrole chemistry have been reported. For example, mercuration of pyrrole 149 followed by exposure to methyl acrylate under Heck reaction conditions leads to 150 [106]. This Heck variation has been extended by Smith to mercurated porphyrins [107]. Pyrrolylacrylates like 150 have also been made using conventional Heck reactions on 3-iodopyrroles [108,109]. 

In the presence of tetramethyltin, 1-bromonauclefine reacts with CO in a Pd-catalyzed carbonylation to give the alkaloid naucletine [202], Dong and Busacca effected a new synthesis of tryptamines and tryptophols via a Rh-catalyzed hydroformylation of functionalized anilines that are prepared by a standard Heck reaction, as shown for the preparation of tryptamine sulfonamide 325 [423]. This reaction is applicable to ring-substituted tryptamines (Cl, Br, F. OMe, CF3). Likewise, the Rh-catalyzed carbonylation of o-alkynylanilines, which were prepared by a Pd-catalyzed Sonogashira coupling, leads to oxindoles (60-86% yields) [424],... 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(II) species. Pleixats and coworkers treated iodophenylsulfide 151, obtained from o-iodoaniline and crotyl bromide in two steps, with... 

The transition metal-catalyzed domino reactions will undoubtedly have a splendid future which is underlined by the increasing number of publications in this area Steglich et al. presented an approach to arcyriacyanin A via a domino Heck reaction between a bromo(indolyl)maleiimide and 4-bromoindole.1811 The synthesis of 33 -bifurans by Ling et al. was achieved using a novel palladium-catalyzed domino dimerization and subsequent cyclization of acetylenic ketones.1821 Other applications of a combination of Heck reactions for domino processes are the syntheses of aza-heterocydes developed by our group.1831... 

Several important industrial applications of the Heck reactions are known. The world s largest producer of Naproxen is Albemarle and they make Naproxen using two homogeneously catalysed steps, a Heck reaction and a palladium catalysed hydroxycarbonylation. The last step is carried out using palladium without chiral ligand and the enantiomers obtained are separated, see Figure 13.18. 

Application of the complexes 63 in the Mizoroki-Heck reaction did not reveal higher activity than the previously examined palladium(II) complexes. However, in the Suzuki-Miyaura reaction, a drastically increased activity was observed with complex 63. Catalysis starts without a measurable induction period at mild temperatures accompanied by an extraordinarily high turnover frequency (TOF) of 552 [mol product x mol Pd x h ] at the start of the reaction for the coupling of p-chlorotoluene and phenyl boronic acid [Eq. (48)]. ... 

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