Cyclohexane Heck reaction

A perhaps more exotic substrate for the Heck reaction is 1,2-cyclohexanedione [25], The reactivity of this molecule under Heck coupling conditions can probably be attributed to its resonance enol form. This reaction is attractive, because the literature contains relatively few examples of the preparation of 3-aryl-l,2-cyclohexane-diones. Yields varied from good to modest when classic heating and electron-rich aryl bromides were used, and reaction times typically ranged from 16 to 48 h. Similar yields were obtained under continuous microwave irradiation with a single-mode microwave reactor for 10 min at 40-50 W (Eq. 11.10) [25],... 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

Utilizing this principle, Heck reactions were performed [57]. The silica gel was derivatized with a CgHiy-trimethoxysilane to obtain the desired reversed phase properties, followed by treatment with palladium acetate and triph-enylphosphine in cyclohexane. After removal of the solvent, an air-stable catalyst supported on reversed-phase silica gel (RPSG) was formed. This supported catalyst was employed with variable success in Heck C-C coupling reactions, as depicted in Scheme 16. 

Sonogashira and Suzuki couplings that were effected in toluene, though the conversions in these reactions dropped from near quantitative values into the low 80% range after four to six cycles. The Heck reaction required more polar solvents hke DMA. In these solvents the membrane degraded - a problem that could be alleviated only if the reaction mixture was diluted with a large amount of cyclohexane. The conversions in the Heck reaction also notably decreased after only a few cycles. 

Intramolecular Heck reactions have frequently been used for the synthesis of cyclopen-tanoid structures. In nearly all cases reported so far, the ring closure occurs as a 5-exo process (for an exception, see Table 4, entry 6), for which 2-halo-l,6-heptadienes and related compounds are the appropriate starting materials. In some cases, however, these substrates cyclize by a 6-endo mode to give cyclohexane derivatives (see Sect. IV.2.2.1.B.V). 

Substrates of substructure C (Figure 6.3) have been used to prepare O-heterocycles as well. A recent survey studies the microwave-accelerated generation of conformationally restricted spiro[cyclohexane-l,r-isobenzofuran] derivatives via 5-cro-cyclization of the corresponding cyclohexenyl o-iodobenzyl ethers (Scheme 6.24) [21,72]. The double-bond position in the hexacycles could be controlled by thoughtful choice of starting material and reactions conditions. This study also constitutes one of the rare examples of electron-rich alkenes used in Mizoroki-Heck reactions [21,72]. 

Initial attempts to extend this methodology to the formation of cyclohexane derivatives were unsuccessful.The carbopalladation reaction of dimethyl 5-hexenylmalonate in the presence of phenyl iodide only gave rise to products issued from the classical Heck reaction (Table 2). No traces of the desired 6-exo cyclization product were detected. Further investigation, however, showed that the course of the reaction is strongly affected by the nature of the nucleophile. When one or both of the malonate esters were replaced by a nitrile, then no Heck reaction was observed under identical conditions. Instead, the cyclization products 31 were obtained. 

TABLE 2. Formation of Cyclohexanes versus Heck Reaction Depending on the Nature of the Active Methine Compound. 

A co-solvent that is poorly miscible with ionic Hquids but highly miscible with the products can be added in the separation step (after the reaction) to facilitate the product separation. The Pd-mediated Heck coupHng of aryl halides or benzoic anhydride with alkenes, for example, can be performed in [BMIMJfPF, ], the products being extracted with cyclohexane. In this case, water can also be used as an extrachon solvent, to remove the salt by-products formed in the reacdon [18], From a pracdcal point of view, the addidon of a co-solvent can result in cross-contamina-don, and it has to be separated from the products in a supplementary step (disdlla-don). More interestingly, unreacted orgaidc reactants themselves (if they have nonpolar character) can be recycled to the separadon step and can be used as the extractant co-solvent. 

Grigg et al. also introduced another Heck-type reaction. 2,6-Dibromo-hepta-1,6-dienes 80 cyclize to the same products 83 (n = 5) as do 2-bromo-1,6-dienes 78 (n = 5) when treated with the usual precatalyst mixture, yet containing a stoichiometric amount of triphenylphosphine [63,64], In this case, palladium dibromide rather than hydridopalladium bromide is eliminated in the final step of the cross-coupling reaction, and the palladium(II) salt is reduced by the phosphine to regenerate the reactive palladium(O) species. Completely selective exo-trig cyclizations occur in these examples, however, the respective cyclohexane derivatives with n = 6 are formed in poor yields. Additionally, it is sometimes difficult to separate the product from the phosphine oxide after aqueous work-up. This latter difficulty was circum-... 

B.M. Trost and co-workers conducted studies toward the total synthesis of saponaceolide B, an antitumor agent active against 60 human cancer cell lines. " One of the challenging structural features of this compound was the cis 2,4-disubstituted 1-methylene-3,3-dimethylcyclohexane ring. The key steps to construct this highly substituted cyclohexane ring were a diastereoselective Barbier reaction to install a vinyl bromide moiety followed by an intramolecular Heck cyclization reaction. 

Heck polycyclization of dienynes. Treatment of dienyne 1 bearing a vinyl bromide group with catalytic amounts of Pd(OAc)2 and P(Q,H5)3 and 2 cquiv. of silver carbonate in CH,CN at 80° results in the tricyclic cyclohexadicne 2 in 60% yield. A similar reaction occurs if the dicnync group is attached to a cyclohexane ring (3 — 4, equation I). 

Ionic liquids can also be advantageously used as solvents or co-solvents in conjunction with microwave irradiation for catalytic reactions [67]. Small amoimts of I Ls are sufficient to reduce the heating time of nonpolar solvents such as toluene or cyclohexane imder microwave conditions. In recent literature there are many examples in which microwaves and ionic liquids are associated to accelerate catalytic reactions (Heck [68], metathesis [69]). More recently, ILs have been used in sonochemical accelerations of Heck and Suzuki cross-coupling reactions [70, 71]. 

In 1961 Heck proposed what is now generally considered to be the correct monometallic mechanism for [HCo(CO)4]-catalyzed hydroformylation [10]. He also proposed, but did not favor, a bimetallic pathway involving an intermolecular hydride transfer between [HCo(CO)4] and [Co(acyl)(CO)4] to eliminate aldehyde product (Scheme 2). Most proposals concerning polymetallic cooperativity in hydroformylation have, therefore, centered on the use of inter- or intramolecular hydride transfers to accelerate the elimination of aldehyde product. Bergman, Halpem, Norton, and Marko have all performed elegant stoichiometric mechanistic studies demonstrating that intermolecular hydride transfers can indeed take place between metal-hydride and metal-acyl species to eliminate aldehyde products [11-14]. The monometallic [HCo(CO)4] pathway involving reaction of the acyl intermediate with H2, however, has been repeatedly shown to be the dominant catalytic mechanism for 1-aUcenes and cyclohexane [15, 16]. 

In 2007, Larhed and co-workers reported a palladium-catalyzed cyclization of o-halobenzyl cyclohexenyl ethers. " A number of new spiro[cyclohexane-l,l -isobenzofuran]-based compounds were synthesized by palladium(O)-catalyzed S-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of... 

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