Intramolecular Mizoroki-Heck Reactions

The enantioselective spiro ring construction is an important issue because many natural compounds have chiral spiro centers [103,104]. Pd catalyses of Spiro cyclizations have been reported by asymmetric intramolecular Mizoroki-Heck reactions [105,106]. In spite of a similar potential, transition metal-catalyzed ene-type carbocyclization has never been applied to asymmetric spiro cyclizations [107-110]. 

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... 

Furthermore, Kiindig et al. [26] investigated intramolecular Mizoroki-Heck reactions at planar chiral arene tricarbonyl chromium complexes 29a—c, giving indanes substituted in the benzylic position in good yield (80% for = Me, 78% for = OH and 85% for R = OMe) (29a—c 30a—c. Scheme 5.5). 

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). 

Scheme 5.16 presents two conceptually interesting examples of Mizoroki-Heck reactions. In the first one, Ma and Negishi [41] showed that allenes are also suitable for intramolecular Mizoroki-Heck reactions 75a was cyclized in a 5-endo- g mode, providing benzofulvene (76a) in 69% yield (75a 76a, Scheme 5.16). Its cognate, 75b,...

Intramolecular Mizoroki-Heck reactions following a (formal) 6-endo-tiig pathway are, as with the 5-endo-tiig cyclizations (see above), not very common this circumstance is usually rationalized by Baldwin s rules [4]. Apart from occasional side-reactions of 5-cxo-trig-type cyclizations (see Section 5.2, Scheme 5.2), there were also several selective transformations reported. 

Aside from the common formation of five- and six-membered cycles, the intramolecular Mizoroki-Heck reaction also proved to be a reliable tool for the formation of medium-sized rings. 

The intramolecular Mizoroki-Heck reaction also allows for the synthesis of medium-sized and even large rings the latter were usually synthesized under high dilution conditions or on a solid support (Chapter 14). 

The intramolecular Mizoroki-Heck reaction, although it had been known since 1977, when it was first used in the synthesis of heterocycles [7], started to be explored properly only around the mid 1980s. Its large use for the preparation of carbocycles began only in the late 1980s [8]. Since then, however, there has been a tremendous increase of interest in this intramolecular cyclization, culminating in its widespread utilization in total synthesis [9], This was mostly due to the development of asymmetric versions by two major contributors, namely Overman for the construction of heterocycles [9] (Chapter 12) and Shibasaki focusing on carbocyclic systems [10] (Chapter 16). 

The formation of heterocycles by intramolecular Mizoroki-Heck reactions has been reviewed several times as a specific topic [11-16]. In this chapter, a classification by ting size has been established. The examples in the different subsections are organized according to specific substructures of the starting materials and according to types of heteroatom. 

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). 

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]. 

As seen before, regioselectivity in the intramolecular Mizoroki-Heck reaction can be controlled or directed by cautious choice of substrates and reaction conditions. In reality, the mechanism of the Mizoroki-Heck reaction is much more complex than the oversimplified... 

At the beginning of the 1980s, heterocycles via intramolecular Mizoroki-Heck reaction were prepared almost exclusively starting from haloarenes. Nowadays, a wide range of... 

There are more examples of 5-exo-cyclizatzion via intramolecular Mizoroki-Heck reaction than of any other compound class, among which substructure A (Figure 6.3) with an allyl side chain constitutes the most widespread substrate. 

Indoles or heterocycles containing an indole skeleton were the first products to be prepared by intramolecular heterocyclic Mizoroki-Heckreaction. In 1977, the first intramolecular Mizoroki-Heck reaction was reported by Mori et al. [7], who prepared indole 3 by cyclization of (Fl-methyl 4-(N-(2-bromophenyl)acetamido)but-2-enoate (1) in the presence of palladium acetate, triphenylphosphine and iVA/ A A -tetramethylethylenediamine (Scheme 6.4). 

A recent procedure describes a one-pot, two-step mutlicomponent reaction of bromoani-lines 13, aldehydes 14, acids 15 and isocyanides 16 yielding polysubstituted indoles 18 [34]. It is based on a Ugi four-component reaction yielding the precursor 17 for the in situ performed classical intramolecular Mizoroki-Heck reaction, thereby providing a facile access to highly substituted dihydro-indoles, l//-indoles and l//-indole-2-carboxyhc... 

A huge number of similar examples preparing indoles or related derivatives via intramolecular Mizoroki-Heck reactions can be found in the literature [35-39] enumerating them all would be impossible. 

As a lot of natural products contain fused A-heterocycles, intramolecular Mizoroki-Heck reactions have also been extensively used in total synthesis. Magallanesine (28) [48], an... 

Scheme 6.13 The 1 1 mixture of double bond isomers via intramolecular Mizoroki-Heck reaction.

Vickers and Keay [58] generated a stereogenic quaternary centre through intramolecular Mizoroki-Heck reaction in excellent yield. However, they obtained a 1 1 mixture of the two possible regioisomers (Scheme 6.13). 

Lautens and Fang [24] have reported an unusual intramolecular Mizoroki-Heck reaction with dihydronaphthalene substrate 43 involving a base-assisted ann-hydride elimination that gives tetracycle 45 in moderate yield (Scheme 6.15). 

Scheme 6.15 Intramolecular Mizoroki-Heck reaction involving a base-assisted anti-hydride elimination.

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. 

Scheme 6.21 Two examples of enamide substrates for intramolecular Mizoroki-Heck reactions.

Another often encountered substructure for intramolecular 5- xo-Mizoroki-Heck reactions is allyl side chain containing vinyl halide D (Figure 6.3) [73, 74], Based on this substrate structure, a series of 3-substituted pyrrolo[2,3-b]quinoxalines have been prepared via intramolecular Mizoroki-Heck reaction under Jeffery s ligand-free conditions in moderate to excellent yields (Scheme 6.25) [75]. 

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