Heck reaction cascade carbopalladation

A couple of prototypical examples of the cyclic version of the Heck reaction, defined as a process consisting of alkene carbopalladation followed by -elimination, were reported during the 1984-1985 period [9,10]. Almost concurrently, seminal examples of both the non-Heck cyclic carbopallation reactions [10,30] were reported during the 1983-1985 period. Thus, with due respect paid to earlier discoveries of alkyne cyclooligomerization via cascade carbopalladation [7,8] as well as copolymerization [24] and cocyclization [25,... 

Cascade reactions arising from sequential carbopalladations are especially valuable for the construction of various carbo- and heterooligocyclic systans with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, as well as all-intramolecular reaction cascades (Sect. IV.3). In the carbopalladation step of the Heck reaction (Scheme 6) a new metal-carbon bond is formed, which, in principle, can undergo any of the typical reactions of a hydride elimination is not too fast. When the /S-hydride elimination is totally suppressed, the palladium species can undergo a number of reactions with the formation... 

D.i.b. Insertion of Another Alkenyl Unit In certain cases, however, the 3-exo-trig process may be retarded and an additional alkene moiety participates in the cascade carbopalladation. A pioneering example of this kind has been demonstrated by Overman and co-workers in their total synthesis of scopadulcic acid A, starting from an iodoaUcenyl-substituted methylenecycloheptene derivative (Scheme 24). The first intramolecular carbopalladation occurs across the disubstituted double bond of the exomethylene group, and the trisubstituted endocyclic double bond acts as the terminator to give a tricyclic system, which was further elaborated to the natural product (Scheme 24). It is remarkable that all three quaternary carbon centers can be created by intramolecular Heck reactions. 

A cascade Heck reaction with termination by nucleophiles is considered to start with an oxidative addition of a heteroatom-carbon bond (starter) onto a palladium(O) species (startup reaction), followed by carbopalladation of a nonaromatic carbon-carbon double or triple bond without subsequent dehydropalladation (relay), a second and possibly further carbopalladation of a carbon-carbon double or triple bond (second etc. relay). The terminating step is a displacement of the palladium residue by an appropriate nucleophile. It is crucial for a successful cascade carbopalladation that no premature dehydropalladation takes place, and that can be prevented by using alkynes and 1,1-disubstituted alkenes (or certain cycloalkenes) as relay stations since they give kinetically stable alkenyl- or neopentylpalladium intermediates, respectively. In addition, reaction of haloalkenes with alkenes in certain cases may form rr-allyl complexes, which are then trapped by various nucleophiles. 

In principle, carbonylative cyclization, that is, acylpalladation or Ac—Pd process, or noncarbonylative cyclization, that is, sample carbopalladation or C—Pd process, in the presence of CO and a Pd catalyst. Various possibilities with halo alkenes as representative substrates are shown in Scheme 2P Those processes that incorporate CO in the cyclization processes are discussed in Part VI including Sects. VI.4-VI.6. hi this section, those cases that do not incorporate CO during the cychzation processes but do so only after cyclization will be discussed. Such cychc carbopalladation-carbonylative termination tandem and cascade processes are represented by the Type II C—Pd process in Scheme 2, which may take place in competition with the other processes shown in Scheme 2, especially the cyclic Heck reaction (Type 1 C—Pd process) and cyclic carbopalladation involving cyclopropa-nation (Type 111 C— Pd process). 

In their pioneering work on the catalytic carbopalladation reaction of 1,2-heptadiene with phenyl iodide in the presence of a suitable base, Shimizu and Tsuji observed the formation of the corresponding substituted 1,3-dienes 62 via a / -hydride elimination from the 7z>allyl intermediate 61 [61]. Based on these observations, a three-component Heck-Diels-Alder cascade process has been developed by Grigg and co-workers [73]. A wide variety of aryl and heteroaryl iodides were used for the intermolecular reaction with dimethylallene to afford the corresponding 1,3-dienes. These subsequently react in situ with N-methylmaleimide to give the bicyclic adducts 63 (Scheme 8.30). 

When the carbopalladation of the bicyclopropylidene is performed in the presence of methyl acrylate, the reaction takes a different course (Scheme 8.34) [79]. The 1,3-diene intermediate 75 reacts in situ with the dienophile to give the spiro[2.5]octane derivative 76. An extension of this cascade Heck-Diels-Alder reaction involving l,3-dicyclopropyl-l,2-propadiene as the alkene partner, an alkenyl or aryl halide and a dienophile has been reported [80]. 

Scheme 8.28 Heck-type carbopalladation-initiated cascade reactions leading to various bi-, tri-, and tetracyclic systems [328-330].

Double, triple, and even quadruple Heck-Diels-Alder cascade reactions involving 1,4-diiodo-, 1,3,5-triiodo-, or 1,2,4,5-tetraiodobenzene, respectively, andbicyclo-propylidene (16) have been accomplished (cf. Scheme 8.5) [121b]. The efficiency of these sequences, in which each carbopalladation across the highly strained alkene is followed by a cyclopropylmethyl to homoallyl rearrangement with concomitant 3-hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 + 2] cycloaddition (Scheme 8.5), is quite remarkable [121bj. 

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