Domino Mizoroki-Heck Reactions

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. 

Cyclopropanes and cyclobutanes were only accessible via xo-type cyclizations, the former only within domino/cascade reactions (see Chapter 8) and the latter being realized by Erase [5a] in desymmetrizing Mizoroki-Heck cyclizations (see Chapter 13) and by Mulzer et al. [5b] five-membered and larger rings are formed in both modes. 

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]. 

In most of the palladium-catalysed domino processes known so far, the Mizoroki-Heck reaction - the palladium(0)-catalysed reaction of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - has been apphed as the starting transformation accordingly to our classification (Table 8.1). It has been combined with another Mizoroki-Heck reaction [6] or a cross-coupling reaction [7], such as Suzuki, Stille or Sonogashira reactions. In other examples, a Tsuji-Trost reaction [8], a carbonylation, a pericyclic or an aldol reaction has been employed as the second step. On the other hand, cross-couphng reactions have also been used as the first step followed by, for example, a Mizoroki-Heck reaction or Tsuji-Trost reactions, palladation of alkynes or allenes [9], carbonylations [10], aminations [11] or palladium(II)-catalysedWacker-type reactions [12] were employed as the first step. A novel illustrative example of the latter procedure is the efficient enantioselective synthesis of vitamin E [13]. 

Scheme 8.3 Allyisiiane-terminated domino Mizoroki-Heck reactions of 14a f.

Recently, Zhou and Larock [57] have also used a domino Mizoroki-Heck/Suzuki process in their syntheses of several tamoxifen analogues. They described a three-component coupling reaction of readily available aryl iodides, internal alkynes and arylboronic acids to give the expected tetrasubstituted olefins in good yields. For instance, the treatment of a mixture of iodobenzene, alkyne 92 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 93 in 90% yield. In this process, substituted aryliodides and... 

Scheme 8.26 Combination of a domino Mizoroki-Heck/Stille reaction with C—H activation.

As part of the total synthesis of the neurotoxin (-(-pumiliotoxin C [69], Minnaard and coworkers [70] used a domino Mizoroki-Heck/Tsuji-Trost reaction as the key step to prepare the perhydroquinoline 124 in 26% yield from 122 and 123 after hydrogenation (Scheme 8.31). Similarly, acyclic tosyl amides with vinyl bromides have been used to give the corresponding lactams in 49-82% yield [71]. 

The insertion of CO into a C(sp )-Pd or C(sp )-Pd species is a common procedure and it is applicable to a wide range of reactions, such as hydroformylation, carbonylation, hydroesterification and so on, thus being an ideal terminating transformation within a domino process starting, for example, with a Mizoroki-Heck reaction. 

In an approach towards a total synthesis of the marine ascidian metabolite perophorami-dine (125) and communesins (126) [72], Artman and Weinreb [73] developed a domino Mizoroki-Heck/carbonylation process. This allowed the construction of the C,E,F-ring system of 125 together with the C-20 quaternary centre and the introduction of a functionality at C-4. Thus, reaction of 127 in the presence of catalytic amounts of Pd(OAc)2 andP(o-Tol)3 under a CO atmosphere in AA -dimethylacetamide/MeOH gave 128 in 77% yield (Scheme 8.32). 

The combination of a Mizoroki-Heck reaction with a C—H activation is a domino process that has been encountered with increasing frequency in the past few years. This type of transformation takes place if the organo-palladium intermediate does not react in the usual way but activates an aryl- or vinyl-H bond in close vicinity, forming a new palladium(II) species that can react further with electrophiles or nucleophiles and giving rise to the formation of another C—C or C-Tieteroatom bond. 

When the initial aryl-palladium species has more than one possible proton in the vicinity, the C—H activation can take place several times. Carretero and coworkers [77] observed three C—H activations after the initial Mizoroki-Heck reaction nsing o, /i-nnsatnrated snlfones 134 and iodobenzene. Under normal conditions, the expected Mizoroki-Heck product 135 is formed however, using an excess of iodobenzene, 136 is obtained in high yield. In this transformation, three molecules of iodobenzene are incorporated into the final product. On the other hand, a later study showed that, under the same conditions, similar electron-deficient alkenes as enones do not nndergo this domino reaction instead, only the Mizoroki-Heck product is obtained [78]. A computational analysis of the transformation explained this finding with the difference in the energy of the transition states that ultimately lead to the five-membered ring palladacycle PdCl (Scheme 8.35). 

Scheme 8.35 Domino Mizoroki-Heck reaction/C—H activation of a, fi-unsaturated sulfones and Phi.

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

Since Mizoroki-Heck reactions allow the straightforward formation of 1,3-butadienes, the most common combination of a Mizoroki-Heck reaction in a domino process with a nonpalladium-catalysed transformation is that with a pericyclic reaction, especially a... 

The de Meijere group has investigated this domino process extensively [87], They prepared interesting spiro-compounds containing a cyclopropyl moiety using a combination of a Mizoroki-Heck and a Diels-Alder reaction with bicyclopropylidene 151 as starting material. The transformation can be performed as a three-component process. Thus, reaction of 151, iodobenzene and acrylate gave 152 in excellent yield. With vinyliodide, the tricyclic compound 153 was obtained (Scheme 8.40). 

Scheme 8.40 Domino Mizoroki-Heck reaction/cycloaddition.

A domino Mizoroki-Heck/Diels-Alder process described by the same group [88] implies the palladium(0)-catalysed reaction of 154 in the presence of acrylate or methyl vinyl ketone to give the corresponding bicyclic compounds 156 and 157 via the transient 155. Good yields were obtained only in the presence of potassium carbonate as base (Scheme 8.41). 

Similarly, the palladium-catalysed arylation of l,3-dicyclopropyl-l,2-propadiene 158 with iodobenzene in the presence of dimethyl maleale led to the diastereomeric cyclopropane derivatives 160 and 161 via 159 in 86% yield as a 4 l-mixture [89], Several other aryl halides and dienophiles have been used in this reaction. A nnmber of other examples of the use of bicyclic propylidenes in a Mizoroki-Heck/pericychc domino process were also reported later on by the same group [90] (Scheme 8.42). 

Scheme 8.45 Domino Mizoroki-Heck/anion-capture reaction.

Scheme 8.48 Domino Mizoroki-Heck/aldol reaction.

---