Cascade Heck Reactions

SCHEME 6.22 Palladium-catalyzed cascade reaction toward strained aromatic polycycles. 

SCHEME 6.24 Alkyne insertion/Suzuki coupling cascade. 

SCHEME 6.25 Palladium-catalyzed carbopalladation/Suzuki coupling of alkynes. 

SCHEME 6.26 Palladium-catalyzed cyclization/arylation cascade. 

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Scheme 6. Allylsilane-terminated cascade Heck reaction by Tietze et al.

TABLE 1. Inter—Intramolecular Cascade Heck Reaction to Form 9,10-Dibenzylidenedihydroanthracenes (for Details See Scheme 4)... 

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. 

Csscade Heck Reaction. Besides cycloisomerization and related reactions, Pd(0) species also catalyzes cascade Heck reactions, which offer attractive routes to a wide variety of polycyclic compounds (99-101). For example, pyra-nosides 107 has been synthesized through 5-exo trig double Heck annulation of bromo-diene 106 in the presence of a catalytic amovmt of Pd(OAc)2 and PPha (Scheme 54) (102). 

The Pd-catalyzed cascade Heck reaction of 5-methylenecycloheptene precursor 108 was utilized to construct the scopadulan ring system and chiral centers at C9 and C12 of the bicyclo-octane 109 and 110 for the first total synthesis of scopadulcic acid B, which is a powerful inhibitors of H+, K+ -adenosine triphosphatase and have potential for the treatment of peptic ulcers, gastritis, and esophagitis. (Scheme 55) (103,104). 

Under CO atmosphere, the cascade Heck reaction of enetetrayne 115 undergoes CO insertion at the last step of the cyclization sequence to afford pentacyclic lactone 116 (Scheme 57) (107). This methodology provided an efficient route for the synthesis of fused cyclic di- and polyenyl lactones. 

Domino or cascade reactions provide valuable approaches, especially to various carbo- and heterocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades, hi this section, the termination of these processes by alkenes, arenes, and related ir-bond systems such as alkynes and allenes will be described. A cascade Heck reaction is considered to consist of an oxidative addition of a heteroatom-carbon bond to palladium (starter), carbopalladation of a nonaromatic carbon-carbon double or triple bond without immediate dehydropalladation (relay), one, two, or more fimher car-bopalladation(s) of a carbon-carbon double or triple bond, and eventually ensuing dehydropalladation. Crucial for a cascade reaction of this kind to occur is the blockage or retardation of a dehydropalladation at one of the intermediate stages by using 1,1-disubsti-tuted alkenes and appropriately substimted cycloalkenes, bicycloalkenes, or alkynes as relays since they give kinetically stable alkyl- or alkenylpalladium intermediates, respectively. 

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