The Heck-Mizoroki Reaction

5 Palladium-catalyzed C-C bond formation 2.3.5.1 The Mizoroki-Heck reaction 

The Mizoroki-Heck reaction, a palladium-catalyzed coupling of olefins with aryl or vinyl halides/triflates, is a powerful method for carbon-carbon bond formation. High efficiency is usually obtained only by starting from expensive aryl iodide (or bromide) or by using a fairly large amount of catalyst. Improvement of the catalytic activity as well as recovery and recycling of the catalyst is needed. 

Although the turnover number (TON) of this coupling remains low (18) and the temperature of the reaction is high (150°C), it represents an efficient use of ionic liquids because the reaction proceeds without the addition of a ligand or additive. When the same methodology was applied to the reaction between / -iodotoluene 

Furthermore, if [NBu4][OAc] is used as a base instead of sodium acetate to avoid the formation of sodium salts, the product can be distilled and the medium reused for further reactions. This recycling procedure is limited, however, by the precipitation of black palladium from the reaction mixture. 

The use of microwave ovens offers a solution to reducing the reaction time of organic transformations and leads to an increased yield compared with traditional methods. However, because the reaction medium is quickly heated to high temperatures, problems can occur as a result of an increase in the internal pressure in sealed vessels. Ionic liquids have proved to be an efficient aid for microwave heating. They can be heated for an extended period without signs of decomposition or an increase in pressure. Furthermore, when a small amount of ionic liquid is added to a volatile organic solvent, it can be heated to well above its boiling point. 

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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. 

The Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

Scheme 6.5 Catalytic cycle for the Mizoroki-Heck reaction...

Regarding bis-NHC chelating ligands, several structures that differ in the motifs used for the enlargement of the tether have been proposed as catalysts for the Mizoroki-Heck reaction. They range from non-functionalised aliphatic chains [23-25] to phenyl [26], biphenyl [27], binaphthyls [28] and to chains containing additional coordination positions like ethers [29], amines [30], and pyridines in an evolution towards pincer complexes [31-35], In most cases, the activity of aryl bromides in Mizoroki-Heck transformations was demonstrated to be from moderate to high, while the activation of chlorides was non-existent or poor (Scheme 6.7). 

Other classes of complexes that have been studied in depth in the Mizoroki-Heck reaction are those having a bidentate ligand containing both a NHC and a phosphine. The development of these structures was encouraged by early theoretical work from Rosch, who calculated that such ligands should be promising catalysts for this... 

As mentioned in the discussion of the reaction mechanism for this transformation, the active species is a dicoordinate Pd(0) complex, and it is unclear whether an associative or a dissociative process is operative for oxidative addition. In this context, different NHC complexes containing only one carbene ligand have been tested in the Mizoroki-Heck reaction. The most successful are those prepared by Beller, which were able to perform the Mizoroki-Heck reaction of non-activated aryl chlorides with moderate to good yields in ionic liquids (Scheme 6.13). The same compounds have also been applied to the Mizoroki-Heck reaction of aryldiazonium... 

For example, the Mizoroki-Heck reaction consists of the reaction of an unsaturated halide with alkenes under basic conditions catalyzed by a Pd source dissolved in... 

Silver salts are also employed to create more effective chiral catalysts by exchange of counter anions. For example, in the Mizoroki-Heck reaction of alkenyl or aryl halides, silver salts are employed to form effective chiral Pd intermediates by abstracting a halide group from the Pd11 precursor species (Scheme 53).227,228... 

Other successful examples of catalysts containing NHC ligands are found in palladium- and nickel-catalyzed carbon-carbon bond formations. The catalyst development with these metals has focused in particular on Heck-type reactions, especially the Mizoroki-Heck reaction itself [Eq. (42)] and various cross coupling reactions [Eq. (43)], e.g., the Suzuki-Miyaura reaction ([M] = and the Kumada-Corriu reaction ([M] = MgBr). " Related reactions like the Sonogashira coupling [Eq. (44)]326-329 Buchwald-... 

In the Mizoroki-Heck reaction aryl bromides and activated aryl chlorides could be employed with moderate turnovers. This holds true for both the complexes of monodentate such as 60 as well as the complexes of chelating ones... 

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)]. ... 

The Mizoroki-Heck reaction in liquid imidazolium salts as the solvent is a special case of an in situ system Under the reaction conditions NHC complexes of palladium are formed as the active catalyst from the solvent and the ligand-free palladium precursor. In general, ionic liquids are novel reaction media for homogeneous catalysis. They allow easy separation of product and catalyst after the reaction. ... 

Rahman et al used a novel high throughput reactor to produce substituted acetylene by the Sonogashira reaction and the Mizoroki-Heck reaction in series using the same IL in a one-pot operation. The products were obtained in good yields and the contamination from the previous reaction was not carried forward to the next. 

Interestingly, it then took almost 10 years until the chemical community became fully aware of the enormous synthetic utility of this transformation. Since then, the Mizoroki-Heck reaction (or simply Heck reaction) has become one of the most popular C-C bond-forming reactions, accounting for several thousand publications overall. 

M. Oestreich (Ed.), The Mizoroki-Heck Reaction, John Wiley Sons, Ltd, Chichester, 2009. 

Palladium-catalyzed arylation and vinylation of alkene is referred to as the Mizoroki-Heck reaction and is one of the most widely used Pd(0)-catalyzed C-C bond formations in organic synthesis. However, the reaction has not been extensively employed for C-glycosylation [96]. The example shown in O Scheme 67 outlines the reaction of iodopyridine and furanose gly-cal for the synthesis of C-nucleoside [97]. The mechanism began with the oxidative addition of iodopyridine to Pd(0) catalyst, and the resulting organo-palladium species was inserted by... 

For each of the immobilized catalysts, the reaction kinetics were slower for each recycle run relative to the fresh catalyst for the Mizoroki-Heck reaction of iodoben-zene with n-butyl acrylate. These resnlts indicated that it was likely some catalyst had deactivated or some palladinm had leached from the snpported catalyst. The use of insoluble supported catalysts allowed for the utilization of fdtration tests to provide additional insight into the catalyst stability. The filtration tests were conducted by filtering off the snpported catalyst and analyzing the remaining solntion for catalytic activity. These filtered solntions continned to show conversion after removal of the solid catalyst, indicating that at least some portion of the reactivity conld be attribnted to active palladinm that had leached from the snpported catalyst. 

The first report of C-C bond formation by C=C insertion, which we now call Heck olefination, was reported by Mizoroki in Japan in 1971 about a year before Heck s first paper appeared. Some refer to the Heck reaction as the Mizoroki-Heck reaction, but Mizoroki unfortunately died shortly after his original work was published. Since Heck and his co-workers vigorously pursued research on the mechanism and scope of this transformation after 1972, Heck s name is the only one usually attached to the process. T. Mizoroki, K. Mori, and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581 and R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. 

Kayaki, Y. Noguchi, Y. Ikariya, T. Enhanced product selectivity in the Mizoroki-Heck reaction... 

The Mizoroki-Heck Reaction, Wiley-VCH Verlag GmbH, Weinheim. 

The Mizoroki-Heck reaction was carried out in water/scCOz and ethylene glycol /scC02 using the typical sulfonated triphenylphosphine ligand TPPTS [56]. The reaction is claimed to occur under monophasic conditions although this seems unlikely under the C02 pressures and temperatures with the amounts of catalyst and co-solvent employed. Catalyst recycling was achieved by phase separation after... 

Pd-doped organic and carbon aerogels containing between 20 and 40 wt% Pd were demonstrated to be good catalysts in the Mizoroki-Heck reaction of iodobenzene with styrene and 3-butene-2-one in liquid phase to yield franv-l,2-diphenylethylene and frani-4-phenyl-3-butene-2-one, respectively [52], Finally, Eu-doped organic and carbon aerogels were active as catalysts in two Michael addition reactions the reaction of ethyl 2-oxocyclopentanecarboxylate with 2-butenone and with cyclopentenone. Moreover, these catalysts could be recovered and reused [53],... 

A non-covalent immobilization of Heck catalyst on silica (SILP concept) has been realized by Hagiwara et al. [217]. They used a silica surface, supported with Pd(OAc)2 dissolved in [BMIM][PFe]. This catalyst was appUed to the Mizoroki-Heck reaction of aryl halides with acrylate without a ligand in n-dodecane as solvent. It was six times reused and the overall TON reached 68 400 (for more details see Section 5.6). 

In the above example, CO2 is added after the reaction to facilitate only the separation. It can, however, be advantageous to add compressed CO2 during the reaction stage, even if it cannot dissolve the catalyst. Ikariya and co-workers reported an example of enhanced product selectivity in the Mizoroki-Heck reaction of ethylene with aryl halides under C02-liquid biphasic conditions [3]. In such reactions, the initially formed styrene derivatives can react with another aryl halide molecule to form stilbenes and 1,1-diphenylethylenes (Scheme 1). 

To recycle the palladium catalyst used for the Mizoroki-Heckreaction, a reaction using Pd/C as a heterogeneous catalyst was performed in [bmimJIPFe]. Ethyl cin-namate 86 was extracted simply from the ionic liquid using diethyl ether or hexane (Scheme 32). After the reaction, the Pd/C remained suspended in the ionic liquid, suitable for reuse. Since the EtsN+n formed in the course of the Mizoroki-Heck reaction accumulates in the [bmimJfPFe], slightly lower yields were obtained for successive runs. However, washing the ionic liquid with water removed any iodide salt present. 

Efforts have been made to explain the high rate acceleration of Mizoroki-Heck reactions in ionic liquids. The formation of the dialkylimidazol-2-ylidene palladium complex under conditions similar to those employed for the Mizoroki-Heck reaction has been studied. The C2-H proton of the imidazolium cation exhibits high acidity and can be deprotonated to form a carbene species, behaving as a good ligand for transition metals. Therefore, in the presence of a palladium salt and a base, [bmim][Br] formed the dimeric carbene complex 89, which further evolved to the monomeric c/x-90 and trans-9Q complexes. Each of these exists as an anti and a syn rotamer owing to the sterically demanding (V-alkyl substituents (Scheme 35 only the anti-90 rotamers are represented). 

The authors of this study demonstrated that similar species, along with an unidentified one, were present during the Mizoroki-Heck reaction. It was proved that isolated trans-90 behaved as an efficient catalyst for this reaction. Finally, when [bmim] [BF4] was used as the starting material, no palladium carbene complex was obtained. This observation might explain why Mizoroki-Heck reactions proceed more quickly in halide ionic liquids than in non-coordinating ones such as PFe salts. Ultrasound-promoted formation of carbene palladium complexes can also allow their in situ preparation at room temperature. ... 

The Suzuki-Miyaura cross-coupling reaction is a standard method for carbon-carbon bond formation between an aryl halide or triflate and a boronic acid derivative, catalyzed by a palladium-metal complex. As with the Mizoroki-Heck reaction, this cross-coupling reaction has been developed in ionic liquids in order to recycle and reuse the catalyst. In 2000, the first cross-coupling of a halide derivative with phenylboronic acid in [bmim] [BF4] was described. As expected, the reaction proceeded much faster with bromobenzene and iodobenzene, whereas almost no biphenyl 91 was obtained using the chloride derivative (Scheme 36). The ionic liquid allowed the reactivity to be increased, with a turnover number between 72 and 78. Furthermore, the catalyst could be reused repeatedly without loss of activity, even when the reaction was performed under air. Cross-coupling with chlorobenzene was later achieved - although with only a moderate yield (42%) - using ultrasound activation. 

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