Carbopalladation, approach

The formal addition of H-Pd-X across double bonds, followed by carbonylation, constitutes the simplest embodiment of the above strategy. Mechanistically speaking, hydrocarbonylation processes of unsaturated alcohols appear to be distinguishable according to two separate pathways (Scheme 21) the first (path a) involves in the key step an intramolecular carbopalladation of the double bond, and as such will be referred to as the carbopalladative approach the second (path b) involves instead an intermolecular hydropalladation of the double bond, and as such is referred to as the hydropalladative approach. The latter is the only one of the two that, according to the classification of this section, ought to be discussed here. 

SCHEME 8.3 Chroman and isochroman synthesis via a domino carbopalladation approach. 

SCHEME 8.5 Intermolecular domino carbopalladation approach using external alkynes. 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

A sequential process of carbopalladation and ring expansion of allenylcyclobuta-nols provides five-membered rings (Scheme 16.19) [24], The intramolecular version of this approach offers a facile synthetic method for 5,7- and 5,8-fused ring frameworks (Scheme 16.20) [24]. 

Negishi and co-workers demonstrated the feasibility of this carbopalladation mode on an allene in an intramolecular approach to medium and large rings [80]. The new C —C bond is fornied at the central carbon atom of the allene moiety to give a jr-allylpalladium complex, which in turn can be trapped by a variety of nucleophiles (arylstannanes to give arylated products, malonates, phenols, amines, etc.) (Scheme 3-27). The yields are remarkably good without using sophisticated nucleophile delivery techniques. 

Several groups have undertaken syntheses of (+)-lycoricidine 139 due to its structural similarity to the potential anticancer agent pancratistatin. Intramolecular carbopalladation has been a popular approach (Scheme 21). Prior to experimentation, the configuration of the stereocenter was considered important due to the potential of the hydrogen to be involved in /S-hydride elimination. In one example, aryl bromide 133 undergoes Heck cy-clization to yield the substitution product In this case, yyn-/S-hydride elimina-... 

Chernyak N, Tilly D, Li Z and Gevorgyan V. Cascade carbopalladation-annulation approach toward polyciclic derivatives of indole and indolizine. ARKIVOC. 2011 76-91. 

Another approach to the construction of five-membered nitrogen heterocycles by way of intermediate jt-allylpalladium complexes involves carbopalladation reactions of 1,3-or 1,4-dienes [85]. For example, Larock has described the coupling of N-tosyl-2-iodoaniline with 1,3-cyclohexadiene, which affords 119 in 87% yield (Eq. (1.48)). The allylpalladium complex 120 is a key intermediate in this transformation. Asymmetric versions of these reactions that generate pyrrolidine products have also been described [86]. Related Heck reactions that employ vinylcyclopropanes as diene surrogates have also been reported, although lengthy reaction times (3-4 days) are often required for transformations of these substrates [87]. 

Addition of CO to C=C and C=C bonds provides an alternative approach to lactones distinct from that of C—X and C—M carbonylation [6, 24]. In particular, hydrocarbonylation involves the formation of new C—H and C—C bonds (Scheme 2.12). Pd-catalyzed transformations of this type proceed through either hydropalladative or carbopalladative pathways [6]. In the carbopalladative mechanism, a Pd alkoxide undergoes carbonylation, yielding an acylpalladium species. Subsequent insertion into the C=C or C=C bond generates the desired lactone. Hydropalladation, on the other hand, is favored under reducing or acidic conditions and occurs via Pd hydride addition to the unsaturation, followed by CO insertion, and reductive elimination. 

Intermolecular carbopalladation of a triple bond as in 457 by an in sitw-formed organopalladium triflate and subsequent intramolecular nucleophibc trapping gives rise to indoles 458 (Scheme 8.86) [600]. The versatihty of this approach derives from the fact that the triflate may be varied in a wide range. 

Polycyclic Arenes. Trimethylsilylphenyl triflates have found widespread use as benzyne precursors in the preparation of polycyclic arenes. Triphenylenes are made via paUadium-catalyzed [2 + 2 + 2] cyclotrimerization of arynes, by paUadium-catalyzed annulation of the aryne and 2-halobiaryls, or via carbopalladation/carbocycUzation of arynes with substituted iodobenzenes (eq 2). All three approaches furnish substituted triphenylenes in high reported yields. Substituted phenanthrenes or naphthalenes are similarly prepared using 2-(trimethylsilyl) phenyl triflate as an aryne precursor. Treatment of the reagent with fluoride, a palladium catalyst, and a deactivated alkene, allyl halide, or internal aIk5Tie provides 9-substituted or 9,... 

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. 

The Holten group (then at Purdue University) reported carbopalladation chemistry that was adaptable to this approach to prostaglandins. In model studies, it was found that allylic amine 143 reacted with diethyl sodiomalonate, in the presence of stoichiometric amounts of lithium tetrachloropalladate, to give 146 after exposure to hydrogen. This reaction apparently involves an amine-directed electrophilic addition of electrophile (Pd ) and... 

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