Heck reaction twofold coupling

The multiple coupling of oligohaloarenes with alkenes was described early on by Heck and Nolley in one of their first papers on this new type of palladium-catalyzed cross-coupling reaction. Twofold coupling of 1,4-diiodobenzene with styrene furnished the 1,4-distyrylbenzene in 67% yield, shortly afterward, the double Heck... 

Heck in one of his first papers already demonstrated the feasibility of applying the palladium-catalyzed crosscoupling of aryl and alkenyl halides with alkenes repetitively on appropriate oligofunctional substrates. For example, twofold coupling of 1,4-diiodobenzene with styrene furnished 1,4-distyrylbenzene in 67% yield (Scheme 1). Since then, a large number of ortho-, meta-, and / r< -dihaloarenes and -heteroarenes have been subjected to twofold Heck reactions with various alkenes (Schemes 2-4). 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

The strategy of a vicinal twofold Heck reaction was applied on tetrabromo[2.2]para-cyclophanediene 164. After its fourfold coupling with styrene (165-H) or substituted styrenes 165-R, the products 166 can be 6jr-electrocyclized with subsequent aromatization (cf. Scheme 3-21) to the benzannelated [2.2]paracyclophanedienes 167, molecules with eight orthogonal biphenyl moieties (Scheme 3-43) [196a]. 

The twofold Heck arylation of ethylene and ethylene equivalents provides an easy access to stilbene derivatives (Scheme 11, Table 10). In the case of ethylene, the pressure has to be carefully controlled, otherwise styrene derivatives, which are the primary products in this process, will be found as major products. In general, shghtly pressurized (1-5 bar) reaction conditions are suitable for the twofold coupling and lead to stilbenes in up to 91% yield and with turnover numbers up to 18,200. The linear dependency on ethylene pressure in the arylation of ethylene with aroyl chlorides to give stilbenes (low pressure of ethenyl) or styrenes (high pressure) has been shown previously. ... 

Usually, monosubstituted or 1,1-disubstituted alkenes were used in the Heck reaction because of their increased reactivity (Table 8.3). The coupling of ethylene to a variety of bromoarenes is an elegant approach to substituted styrenes, and the twofold coupling of ethene can even give stilbenes such as 12-SOjH, which was commonly used as a laser dye, in good yields. The ratio between formed styrene and stilbene depends on the ethylene excess, which can be controlled by the applied pressure (Scheme 8.3) [111], Oligovinylarenes can be prepared from 1,2- (cf Scheme 8.13), 1,4-dibromoarenes [112, 113], 1,3,5-tribromobenzene, and 1,2,4,5-tetrabromobenzene [114]. 

Dihalothiophenes are also excellent substrates for twofold Heck couplings, even with 1,1-dimethylallene, the products of which can subsequently undergo a twofold Diels-Alder reaction [394]. Even fourfold Heck reactions applying a tetradiazonium salt with a tetraphenylmethane framework have been demonstrated with various alkenes to yield the corresponding fourfold coupled tetraarylmethane derivatives (Scheme 8.64) [395]. 

Arenediazoninm salts, which are readily available from a large stock of anilines, have proved to be valuable starting materials for Heck reactions since their reactivities exceed even those of the corresponding triflates and hence allow coupling at lower temperatures. Twofold Heck reactions of bisdiazonium salts with various substitution patterns have been investigated (Table... 

A clean twofold Heck coupling of unsubstituted butadiene 46 (R = H) in the 1- and 4-positions has not been reported. However, the initial carbopalladation product from 46 (R = H) and an in situ formed arylpalladium halide, the cr-allylpalladium halide 47 equilibrating with the corresponding 7r-allylpalladium halide, can efficiently be trapped with the anion formed by arylation of malononitrile or cyanoacetate to give 48, a product of reductive 1,4-arylation-alkylation of 1,3-butadiene 46 (R = H)." /3-Hydride elimination from the intermediate 47 (R H) can be accomplished when the reaction is carried out in the presence of silver acetate or thallium acetate, leading to the... 

In general, the Mizoroki-Heck coupling of aryl halides with both electron-rich and electron-poor terminal alkenes affords monoarylated products. With electron-deficient alkenes under selected reaction conditions, such as with excess of the aryl halide, with special catalysts at high temperatures or under high pressure, a twofold terminal arylation to give 1,1-diarylalkene derivatives may occur (Figure 3.41) [103]. Triple arylations... 

Similarly, 2,3-disubstituted anthraquinones were prepared from 2,3-dibromonaphthaquinone by a domino twofold Heck coupling/6x electrocychzation/dehydrogenation sequence that occurred in one pot (Scheme 16.7) [9]. Pd(0) present in these reactions might be responsible for the observed dehydrogenation of the product of electrocyclization. 

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