Intramolecular Mizoroki-Heck Arylations

Scheme 7.9 Intramolecular Mizoroki-Heck arylation of enamidine 20 and intermediates observed by ESI-MS.

Related reactions, that have been catalysed by NHC/Pd systems, are the intramolecular Mizoroki-Heck using catalysts formed in situ from imidazolium salts and a Pd(0) source [69], and the arylation of allylic alcohols by a benzothiazole-Pd complex [70,71] (Scheme 6.14). 

Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki-Heck ring closure <06JOC5340>. 

Various cyclic compounds can be prepared by the reaction of ketones with bifunctional aryl halides. The jS-naphthol derivative 52 was obtained by a-arylation of dibenzyl ketone (14) with o-bromobenzaldehyde derivative 51, followed by aldol condensation [38], Also the indole derivative 54 was synthesized by the reaction of cyclohexanone with 2-iodoaniline (53). Formation of 54 may be explained by enamine formation at first, followed by intramolecular Mizoroki-Heck reaction, rather than via a-arylation [39],... 

By the reaction of a,-unsaturated carbonyl compounds with the dibromide 55, cyclization occurs by a-arylation, followed by intramolecular Mizoroki-Heck reaction. For example, reaction of verbenone (61) with 55 using PPh3 generates 62 by y-arylation of 61, and subsequent intramolecular Mizoroki-Heck reaction affords the indane 63. The benzocyclobutane 67 was obtained unexpectedly... 

In a narrower sense, this review covers intramolecular Mizoroki-Heck [1] reactions forming carbocycles [2] that is, the palladium-catalyzed intramolecular coupling of vinyl/aryl (pseudo-)halides with an alkene tethered by a hydrocarbon chain. Ring closures furnishing heterocycles are covered in Chapter 6 also beyond the scope of this chapter are the domino/cascade or tandem (Chapter 8) and asymmetric processes (Chapters 12 and 16) dealing with formation of a carbocycle. 

In contrast to the substrate-type presented in Scheme 5.6, intramolecular Mizoroki-Heck reactions with cychc alkene moieties are quite common. Negishi and coworkers [21, 29] screened numerous substrates with different substitution patterns, out of which four are shown in Scheme 5.7. Cychzation of aryl iodide 35 proceeded well and furnished tricyclic 36 in good yield, including 10% of a double-bond isomer (not shown) (35 36). Mizoroki-Heck reactions of cyclohexenones 37 and 39 provided 68% and 82% yields respectively and, probably, due to conjugation with the carbonyl group in isomerically pure form (37,39 38,40). The two analogous cyclohexenone derivatives of aryl iodide 35 (not shown) cyclized under identical conditions in 50% and 71% yields respectively. Substrate 41a even allowed for formation of spirocyclic 42a in good yield, yet with poor... 

Cyclopentadiene 68 was formed in 63% yield by the Mizoroki-Heck cyclization of open-chain vinyl iodide 67 under classic reaction conditions (67 68, Scheme 5.14) [22], The analogous unsubstituted aryl iodide (not shown) provided a comparable yield (65%). Reaction in the /3-position of the a,/3-unsaturated carbonyl or carboxyl compound is not mandatory, as intramolecular Mizoroki-Heck reaction of 69 also proceeded well, forming tricyclic ketone 70 in 68% yield (69 70). 

In this section, only examples of Mizoroki-Heck reactions where a proper addition of the cr -aryl- or a -alkeny Ipalladium(II) complex to a double bond of an alkene or alkyne occurs are considered. As a consequence, an often-met deviation from the classic Mizoroki-Heck mechanism, the so-called cyclopalladation, will not be treated in further detail [12, 18]. However, as it is of some importance, especially in heterocycle formation and mainly because it will be encountered later during polycyclization cases, it shall be mentioned briefly below. Palladacycles are assumed to be intermediates in intramolecular Mizoroki-Heck reactions when j3-elimination of the formed intermediate cannot occur. These are frequently postulated as intermediates during intramolecular aryl-aryl Mizoroki-Heck reactions under dehydrohalogenation (Scheme 6.1). The reactivity of these palladacycles is strongly correlated to their size. Six-membered and larger palladacycles quickly undergo reductive elimination, whereas the five-membered species can, for example, lead to Mizoroki-Heck-type domino or cascade processes [18,19]. 

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). 

Lamaty and coworkers [132] described a nice combination of three palladium-catalysed transformations first, an intermolecular nucleophilic substitution of an allylic bromide to form an aryl ether second, an intramolecular Mizoroki-Heck type transformation in which the intermediate palladium(II) species is intercepted by a phenylboronic acid. Thus, reaction of a mixture of 2-iodophenol (255), methyl 2-bromomethylacrylate (256) and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-dihydrobenzofuran 257. Besides phenylboronic acid, several substituted boronic acids have also been used in this process (Scheme 8.65). 

The most common Mizoroki-Heck reaction mechanism is called the neutral mechanism, because its intermediates are uncharged. The catalytic cycle for the neutral manifold of the intramolecular Mizoroki-Heck reaction of alkenyl and aryl halides is shown in Scheme... 

Six-membered rings, particularly those with highly substituted benzylic stereocentres, are readily assembled by the asymmetric intramolecular Mizoroki-Heck reaction. In a seminal example, Shibasaki and coworkers [45] showed that (i )-alkenyl aryl triflate 75 can be cyclized in high yield with modest enantioselectivity to bicycle 76 (Scheme 12.18). 

For nongroup-selective examples, one of the first reports of an enantioselective intramolecular Mizoroki-Heck reaction was a polyene cyclization (Scheme 12.22) [23b], The trienyl triflate 5 underwent two intramolecular cyclization reactions to give the tricycle 6 in high yield and 45% ee. A cascade intramolecular Mizoroki-Heck-hydride capture sequence was used in the synthesis of retinoid derivatives from aryl iodide 100 to give benzofuran 101 in 80-81% ee [49]. Poor enantioselectivity was observed when neutral reaction conditions were employed. 

Since then, many research groups have described the benefit of ionic liquids as solvents in the Mizoroki-Heck reaction covering a large variety of substrates. Cacchi et al. [22] achieved a stereoselective coupling of aryl iodides and methyl cinnamates in a mixture of molten tetrabutylammonium acetate and bromide. Intramolecular Mizoroki-Heck reactions were conducted in l- -butyl-3-methylimidazolium tetralluoroborate ([BMIm]BF4) using PdCl2 as a precatalyst. Substituted benzofurans were obtained in satisfactory yields [23]. The ionic liquid containing the palladium catalyst could be reused several times with small decrease in activity. 

The final common class of coupling reactions to form C-C bonds described here is the coupling of an aryl halide with an olefin to cleave the C-H bond of the olefin and replace it with an aryl group. This reaction, which is shown generically in Equation 19.18, was first reported by Mizoroki the synthetic utility of this process and e most useful conditions for this process at the time were reported by Heck. ° This process is often called the "Heck reaction," or more appropriately the "Mizoroki-Heck reaction." " The Heck reaction is most commonly conducted with electron-deficient olefins, such as styrene or acrylate derivatives. The electronic properties of these substrates tend to favor formation of the conjugated products. The reaction can also be conducted effectively with ethylene a Heck reaction between 6-methoxy-2-bromonaphthalene and ethylene is one step of a short, catalytic commercial synthesis of naproxen. In contrast, intermolecular reactions of internal olefins typically form mixtures of regioisomeric products. Intramolecular Mizoroki-Heck reactions with intemal olefins are more common. Mizoroki-Heck reactions of aliphatic electrophiles have been reported, but remain rare. Applications of the Mizoroki-Heck reaction have been reviewed. ... 

The palladium-catalysed Mizoroki-Heck reaction is the most efficient route for the vinyla-tion of aryl/vinyl halides or triflates. This reaction, in which a C—C bond is formed, proceeds in the presence of a base (Scheme 1.1) [1, 2], Nonconjugated alkenes are formed in reactions involving cyclic alkenes (Scheme 1.2) [le, 2a,c,e,g] or in intramolecular reactions (Scheme 1.3) [2b,d-g] with creation of stereogenic centres. Asymmetric Mizoroki-Heck reactions may be performed in the presence of a chiral ligand [2], The Mizoroki-Heck reaction has been intensively developed from a synthetic and mechanistic point of view, as expressed by the impressive number of reviews and book chapters [1,2]. 

In 1990, Cabri el al. [40a] reported that the precursor Pd(OAc>2 associated with a biden-tate P P ligand as dppp (1,3-bis-diphenylphosphinopropane) appeared to be more efficient than PPhs in Mizoroki-Heck reactions performed from aryl Inflates and enol ethers (electron-rich alkenes) moreover, the regioselectivity in favour of the a-arylated alkenes was improved to 100%. Since that time, dppp associated with Pd(OAc)2 has been used extensively to catalyse Mizoroki-Heck reactions and to investigate the factors that control the regioselectivity [Ig, 40]. The chiral bidentate (7 )-Binap (2,2 -bis(diphenylphosphino)-1,1-binaphthyl) associated with Pd(OAc)2 has also been used by Shibasaki and coworkers [2b,d,41a] and Overman andPoon [41b] in intramolecular enantioselective Mizoroki-Heck reactions (also, see Link [2f] for an authorative review on the Overman-Shibasaki chemistry), as well as by Hayashi and coworkers [2a, 41c,d] to control the regioselectivity and enantioselectivity of intermolecular Mizoroki-Heck reactions performed from cyclic alkenes (see Schemes 1.3 and 1.2 (Z = O) respectively). 

It appears reasonable to predict that ArPdX(Cb)(PR3) complexes generated in the oxidative addition of ArX to Pd°(Cb)(PRj) would dissociate to ArPdX(Cb), which reacts with the alkene. Such a dissociation of the phosphine must be even easier than the intramolecular dissociation of the phosphine in the bidentate P Cb ligand proposed above. This is probably why mixed complexes Pd°(Cb)(PR3) are more efficient than Pd°(Cb)2 in Mizoroki-Heck reactions performed from aryl bromides [71, 76], even if they are less reactive than Pd°(Cb)2 in the oxidative addition. Indeed, the high stability of the Cb-Pd(II) bond combined with the easy dissociation of the phosphine in ArPdX(Cb)(PR3) favours the complexation/insertion of the alkene. 

In contrast to intramolecular carbonylative Mizoroki-Heck cyclizations, the intermolecular carbonylative reaction of aryl halides with alkenes has been much less explored. Figure 3.10 depicts one of these rare examples using a carbon monoxide pressure of 5 atm [62], Small... 

Scheme 6.1 Example of an intramolecular aryl-aryl Mizoroki-Heck reaction proceeding via a palladacycle.

Dongol and Tay [110] have recently made use of an intramolecular amination in the development of a one-pot synthesis of isoxazolidines starting from 0-homoallyl hydrox-ylamines 201 and aryl iodides. After a Mizoroki-Heck reaction, a subsequent C—N... 

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]. 

Scheme 10.27 Intramolecular cobalt-catalysed Mizoroki-Heck-type reaction with an aryl iodide.

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]. 

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