Double Mizoroki-Heck Reaction Cascade

In 2003, Hu et al. developed a novel palladium-catalyzed Heck reaction of dienes with benzyl halides to generate dihydropyrroles [7a] (Schane 6.1). A series of benzylic halides were employed snccessfully, although electron-withdrawing snbstituents led to 

SCHEME 6.1 Heck reaction with double alkene insertion. 

In 2008, Ruck et al. developed a novel and efficient synthetic route to spiro-fused indance-oxindoles 9 by a palladium-catalyzed tandem Heck/C—H functionalization reaction [8] (Schone 6.2). Oxidative addition of the aryl bromide 8 to the palladium complex is followed by the intramolecular Heck insertion process through 5-exo-trig cycUzation to afford primary alkylpaUadium species 11. Reaction at the highlighted C—H bond provides six-monbered paUadacycle 12, and subsequent reductive elimination generates spiro-fused iudauce-oxindoles 9. 

SCHEME 6.2 Palladium-catalyzed tandem Heck/C—H functionalization. 

SCHEME 63 Palladium-catalyzed domino Heck reaction/C—H functionalization. 

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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]. 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

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