Intramolecular cascade carbopalladation, alkene

B. INTER-INTRAMOLECULAR CASCADE CARBOPALLADATIONS B.i. Termination by Alkenes... 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

Cascade carbopalladation sequences after attack on an alkene are most commonly terminated by dehydropallada-tion, if a / -hydride is available in a yy//-orientation. The intramolecular carbopalladation starting from the monocyclic diene 122 with a geminally disubstituted alkene terminator leads to a neopentylpalladium intermediate 123, which cannot undergo /J-dehydropalladation, but continue the cascade by a carbopalladation to eventually form the... 

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. 

For such cascades with intramolecular carbopalladations, smaller ring sizes (5 and 6) are preferred due to the entropic term thus, 1,1-disubstituted alkenes suitably located in the substrate preferably serve as the relay without formation of the larger ring size resulting from insertion into the terminal alkene moiety. 

In more complex reaction cascades an additional alkyne-insertion step can occur. Thus starting with intramolecular carbopalladation of a vinyl iodide to a carbon-carbon triple bond, followed by two intramolecular alkene-insertion steps and termination with dehydropalladation, a palladium-catalyzed synthesis of l-(5 -methylbicyclo[3.1.0]hex-T-yl)-5,5-bis(carboethoxy)cyclo-hexadiene (52) starting from l-iodo-4,4-bis(carboethoxy)-ll-methyldodeca-l,ll-dien-6-yne (51) is achieved. ... 

In this latter reaction mode, which is observed much more rarely than /3-dehydropal-ladation, a wide variety of ligands can be coupled to each other with the formation of new C—C, C—H, C— N, C—O, and C—Hal bonds. This section does not cover the numerous cascade couplings in which a number of successive intramolecular additions of 2 onto double bonds is eventually completed by /3-dehydropalladationt as well as the numerous [2 -I- 2 -I- 2] and [4 + 2] cyclotri- and cyclodimerizations of alkynes, enynes, and related compounds. " The Pd(0)-catalyzed Cope rearrangement also will not be considered here, as it proceeds via bis(i7 -allyl)palladium(ll) intermediates. The carbopalladation reactions of aUenes, which have been reviewed recently, are covered in Sect. IV.7. (For new examples see also refs. [10]-[12]). On the other hand, the numerous Pd-catalyzed formal [3 + 2] cycloadditions of trimethylenemethane (TMM) complexes may be classified as carbopalladations of alkenes without subsequent dehydropalladation. As the subject of this section has partially been covered in several newly published reviews, " the attention here will be on the most recent and interesting communications. 

The intramolecular carbopalladation starting from a 2-halo-1,6-enyne leads to a terminal aUcenylpalladium halide relay that can be trapped by an external alkene or alkyne. With the former, the cascade process leads to a 1,3,5-hexatriene that undergoes rapid 67T-electrocyclization to a flve-ring-annelated cyclohexadiene and this, in turn, is easily dehydrogenated to the corresponding aromatic compound (Scheme 15). With an external alkyne trapping the intermediate, a 1,3,5-hexatrienylpalladium intermediate will be formed and can either cyclize by intramolecular carbopalladation or 67r-electrocycliza-tion before termination by dehydropalladation will occur. ... 

D.i.a. Formation of Cyclopropane Derivatives by Two Successive Intramolecular Carbopalladations. Intramolecular carbopalladation starting from 1,( —l)-dienes with a suitable leaving group at the 2-position and a substituent at the (n-l)-position of the alkene terminator leads to a neopentylpalladium intermediate, which can only continue the cascade by a 3-eJto-tng-carbopalladation to eventually form bicyclo[(n—2). 1.0]alkenes. This sequence works equally well for ring sizes five, six, and seven in the first formed ring (Scheme 22) and even heterocyclic systems can be constructed by this mode (Scheme 22). 

Three simpler ort/io-substituted iodobenzene derivatives with two alkene moieties in the side chains have been cascade cycUzed to give methylenespiroalkane-annelated indanes (Scheme 26) and bicyclic systems (Scheme 27). This outcome clearly demonstrates that the intramolecular carbopalladations are determined by entropic factors, which always favor the formation of the smaller possible ring sizes. 

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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