Mizoroki-Heck-type product

By contrast, the COOH group is lost in the Rh(I)-catalyzed conjugate addition of 2,6-diflu-orinated benzoic acids to electron-poor olefins (Michael acceptors Scheme 22.7) [13]. Alkyl acrylates and A,iV-dimethylacrylamide have been found to give higher yields than methyl vinyl ketone [13], The use of aqueous toluene as the solvent avoids the formation of the Mizoroki-Heck-type product, whereby the reaction has thus far only been applied to fluorinated benzoic acids 5 [13],... 

Extrusion of CO from acyl-2-phenylpyridines is another way to form an Ar-C(sp ) bond. Rh(I) catalysis was found to be effective in the conversion of styryl ketones into the corresponding stil-benes [12]. Aroyl chlorides react with acyclic alkenes in the presence of a rhodium-ethylene complex, [ RhCljCjH lj Ij], in refluxing o-xylene under to give Mizoroki-Heck-type products [27a]. 

The scope of the synthetic procedure to substituted 1,3-butadienes 16 was later broadened by the same group, with the report of 18 examples of the 1 1 1 coupling of iodoarenes, diarylacetylenes, and monosubstituted alkenes. The mixture Pd(OAc)j, LiQ, and NaHCOj led to the desired products in moderate yields, although minor amounts of the Mizoroki-Heck-type product (ArCH=CHR) were also formed [30]. For the synthesis of 1,3,5-hexatriene derivatives 17, a modification of the former procedure consisting of using silver acetate as a base leads to the 1 2 1 coupling of iodoarenes. 

Edmondson et al. [138] developed a synthesis of 2,3-disubstituted indoles using an am-ination as the first step (Scheme 8.67). The reaction of 264 and 265 with catalytic amounts of Pd2(dba)3 and the ligand 268 gave compound 267 in high yield. To get to the final indole, a second charge of palladium had to be added after 12 h, otherwise only the amination product was isolated. It can be assumed that in the first step the enaminone 266 is formed, which then cyclizes in a Mizoroki-Heck-type reaction to give 267. In a similar way, reaction of 264 and 269 led to 270 by an acyl migration in the Mizoroki-Heck cyclization product. 

Toyota et al. [154] used a combination of a Wacker and a Mizoroki-Heck-type transformation for the construction of the cedrane skeleton. Thus, reaction of 303 using 10 mol% Pd(OAc)2 under an oxygen atmosphere led to the domino product 304 in 30% yield (Scheme 8.75). In addition, 58% of the monocyclized compound 305 was obtained. 

The use of pyridine (31) as additive allowed for more selective and efficient nickel-catalysed arylations of styrenes (Scheme 10.10) [32, 33]. Aryl and alkyl bromides gave good yields of isolated products. With respect to the latter, secondary alkyl bromides proved superior to primary ones. However, use of methyl acrylate (1) as substrate yielded predominantly products originating from conjugate additions, rather than Mizoroki-Heck-type reactions. 

Cobalt-catalysed electrochemical arylation reactions of acrylates were achieved by Gosmini and coworkers. The presence of 2,2 -bipyridine (Bpy, 63) was found crucial to reduce the formation of conjugate addition products in this transformation. Notably, this Mizoroki-Heck-type reaction proved applicable to aryl iodides and bromides and to an alkenyl chloride (Scheme 10.22) [48]. 

An early example for cobalt-catalysed Mizoroki-Heck-type reactions with aliphatic halides by Branchaud and Detlefsen showed that an intermolecular substitution of styrene (2) could be achieved with [Co(dmgH)2py] (70) (dmgH = dimethylglyoxime monoanion) as catalyst in the presence of visible light. This radical reaction led selechvely to the substitution products when using stoichiometric amounts of Zn (27) and pyridine (31) as additives (Scheme 10.24) [52]. 

The catalytic system proved not only applicable to alkyl hahdes, but also allowed for the intramolecular conversion of aryl halides. Interestingly, the corresponding Mizoroki-Heck-type cyclization products were formed selectively, without traces of reduced side-products (Scheme 10.27) [55]. Therefore, a radical reaction via a single electron-transfer process was generally disregarded for cobalt-catalysed Mizoroki-Heck-type reactions of aromatic hahdes. Instead, a mechanism based on oxidative addition to yield an aryl-cobalt complex was suggested [51]. 

In a related intramolecular rhodium-catalysed Mizoroki-Heck-type reaction of an alkene with an aryl iodide, Wilkinson s catalyst (84) gave significant amounts of side-products due to isomerization of the resulting double bond. In contrast to the corresponding palladium-catalysed transformation, the presence of Et4NCl had no beneficial influence either on the reactivity or on the selectivity [57]. 

As part of comparative studies, Iyer [47] reported the use of Vaska s complex [IrCl(CO)(PPh3)2l (92) in intermolecular Mizoroki-Heck-type reactions of methyl acrylate (1) and styrene (2). Aryl iodides could be used as electrophiles, while bromobenzene, chlorobenzene and aliphatic halides gave no desired product. The catalytic activity was found to be lower than that observed when using Wilkinson s complex [RhCl(PPh3)3] (84). Thus, a higher reaction temperature of 150 °C was mostly required. In contrast to the corresponding cobalt-catalysed reaction, however, Vaska s complex (92) proved applicable to orf/io-substituted aryl iodides (Scheme 10.33). 

The first example of an o/t/20-alkylation/Mizoroki-IIcck coupling was reported by Catellani [4] in 1997. Using the PNP dimer as a catalyst in the presence of an aryl halide, norbomene, an alkyl iodide, a terminal olefin and a base at room temperature, 1,2,3-trisubstituted benzenes (Scheme 16), were synthesized through alkylation of a palladacycle of type 35, followed by Mizoroki-Heck coupling with an arylpalladium(II) species of type 36. Although the synthetic scope of the reaction was limited, the importance of the report reveals an unprecedented catalytic transformation where two aryl C-H bonds are converted to sp2-sp3 C-C bonds followed by a standard Mizoroki-Heck coupling. The 1,2,3-trisubstitution pattern generated in the products would be very difficult to obtain via conventional methods. 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

As type 2 systems are maintained by rather high levels of soluble palladium concentrations in the reaction media, palladium from any support will be depleted rapidly. Recycling of a supported catalyst will thus be difficult. Aside from stable palladium complexes, there are a few supported systems which deliver reasonable type 2 performance. One of the most active systems was introduced by Molndr and Papp [105] with palladium(II) absorbed by ion-exchange onto montmorillonite clay. The precatalyst operates at high temperatures (150-160 °C) in the presence of NaaCOs in NMP and delivers high yields of Mizoroki-Heck products with, for example, phenyl bromide, 8 and 4-chloroacetophenone (47) at 0.001-0.1 mol% catalyst loading (47 48, Scheme 2.10). With more reactive substrates (e.g. phenyl bromide) this precatalyst survives two or three reuses, which shows that palladium is extracted from the support lattice at a sparing rate. 

The qnestion at to whether type 2 catalytic systems might be adjnsted to processing nonactivated aryl chlorides is of particular interest. Many investigations show that phenyl chloride and even electron-rich aryl chlorides are not totally nnreactive, and poor to modest yields of Mizoroki-Heck products were obtained in many systems. This prompts the important conclusion that aryl chlorides are able to (1) enter catalytic cycles in the absence of a catalyst bearing special ligands (see below) and (2) snccessfnlly rnn throngh a few turnovers but rapid catalyst deactivation prevents reliable operation. 

A number of intramolecular Mizoroki-Heck reactions yield the product consistent with a formal a r/-elimination of the HPdX [11], These experimental findings are in opposition to the generally accepted mechanism of a 5y -elimination however, a reasonable explanation is at hand in most cases. There are two main types of alkenyl derivatives which, if added to an CT-aryl- or cr-alkenylpalladium(II) complex, deliver the formal a ft-elimination product. The first case is intramolecular Mizoroki-Heck reactions with o ,jS-unsaturated carbonyl systems which result in the product of a formal 1,4-addition. The initially formed <7-(y3-aryl)- or <7-(/3-alkenyl)alkylpalladium complex should be long-lived enough to epimerize through a palladium(II) enolate intermediate and, thus, deliver the formal anr/-elimination product through conventional 5yn-elimination (Scheme 6.2). 

Intramolecular Mizoroki-Heck reactions with styrene-type alkenes constitute the second frequently met case. Finding suitable rationales in theses cases seems to be more intricate. There is some evidence for a mechanism involving a radical intermediate [11]. Most explanations, however, cite a facile epimerization at the benzylic position and, thus, furnishing the required cw-stereochemistry or a base-assisted reductive elimination of the palladium species (Scheme 6.3) [11]. In some cases, suitable substrates or conditions can lead to the a r/-elimination products via an Elcb-type mechanism [23,24]. 

Besides the different mechanistic pathways mainly depending on the substrate types, the Mizoroki-Heck reaction can also be run under several conditions with diverse additives which affect the outcome. A major achievement in this field was the discovery of the so-called Jeffery conditions [25-28]. Mizoroki-Heck reactions are indeed greatly accelerated by the use of inorganic bases in combination with a phase-transfer agent which allows lowered reaction temperatures. In some cases, Jeffery conditions can even lead to the endo-cyclizod product, whereas standard conditions give the exo-cyclized compound [8]. 

Substructure type A (Figure 6.3) has also been employed in total synthesis of some O-heterocyclic-containing natural products. Key intermediates 47 and 49 in the syntheses of (-)-galanthamine [61,62] and morphine or noroxymorphone [62,63] have been prepared by means of an intramolecular Mizoroki-Heck reaction (Scheme 6.16). 

Cyclizations of substructure type C (Figure 6.3) are also used in total synthesis of natural products bearing five-membered heterocycles, as shown by the example of (S)-camptothecin (83), a natural anticancer agent (Scheme 6.23) [71]. This pentacyclic alkaloid was synthesized in 10 steps, the last one being a 5-exo-intramolecular Mizoroki-Heck reaction. 

ShibasaM and coworkers [117] described the first enantioselective combination of this type in their synthesis of the natural product halenaquinone (225) possessing antibiotic, cardiotonic and protein tyrosine kinase inhibitory activities. The key step is an intermolecular Suzuki reaction of 222 and 223 followed by an enantioselective Mizoroki-Heck reaction in the presence of (5 )-BINAP to construct the third ring and the stereogenic quaternary centre present in 224. The reaction proceeded with a good cc-value of 85% but with a yield of only 20% (Scheme 8.56). 

Apart from the catalytic systems based on Pd/phosphines typically used in Mizoroki-Heck reactions, many other types of new palladium catalysts have been developed over the last decade. Avoiding the use of the phosphine ligands is a great advantage as they usually cannot be recovered and they frequently hamper the isolation and purification of the final product. One viable alternative is the use of ligand-free palladium catalysts usually in the form of Pd(OAc)2. At the high temperatures required for Mizoroki-Heck reactions, most ligand-free palladium complexes are unstable and have a tendency to form soluble Pd(0) nanoparticles [32]. The question arises as to the role played by the Pd nanopartides formed and whether... 

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