Heck reaction cross-coupling processes

Metal-catalyzed hydroarylation of alkynes catalyzed by electrophilic transition metal complexes has received much attention as a valuable synthetic alternative to the Heck and cross-coupling processes for the synthesis of alkenyl arenes (384). Metal trifluoromethanesulfonates (metal triflates) [M(OTQn M = Sc, Zr, In] catalyze the hydroarylation of alkynes via 71 complexation to give 1,1-diarylalkenes in very good yields (Scheme 32) (385). The reaction likely proceeds by a Friedel-Crafts mechanism via the alkenyl cation intermediate where the aryl starting material also serves as the solvent. 

An entirely different mode of interaction of electron-rich cyclopalladated Pd(II) complexes with water has been described, involving the oxidation of Pd(IV) species through oxidative addition of water to Pd(ll) with subsequent elimination of dihydrogen.It is not clear whether this process, proved for Pd complex with a very specific coordination sphere, may have a relation to a hypothetical involvement of Pd(ll)/Pd(IV) catalytic cycles in the reactions generally considered as Pd(0)/Pd(n) processes (Heck reaction, cross-coupling, etc.), particularly in those involving palladacycles as catalysts. ... 

On the other hand, true ligand acceleration (type 3 processes) shows preference for solvents of low polarity and lower Lewis basicity (toluene, dioxane and THF) with soluble tertiary amines as bases. In this respect, these Mizoroki-Heck reactions resemble cross-coupling processes, which also display strong preference for these solvents. Reactions in nonpolar solvents (toluene or xylene) have been known since Heck s seminal articles [8]. The halide remains a crucial subject of concern in reactions catalysed by phosphine complexes of palladium, aryl iodides prefer triarylphosphines and polar solvents, whereas reactions of aryl bromides and chlorides indeed prefer electron-rich trialkylphosphines and nonpolar solvents [63-65]. 

In a third form, the cross-coupling process forms a biaryl compoimd that possesses axial chirality as a result of slow atropisomerism (Equations 19.22 and 19.23). " In most cases, this reaction has been studied for the formation of 1,1 -binaphthyls (Equation 19.22), which are found in BINAP, BINOL, and related ligands. In a fourth form, ttie Heck reaction has been conducted in a manner that forms a product containing a new stereocenter (Equations 19.24-19.26). This type of enantioselective coupling has been the most widely used of the four in the synthesis of natural products. ... 

Heck Reactions Combined with Other Cross-Coupling Processes... 

Also exploiting an intramolecular C—S bond formation, Bryan et al. extended their investigation of gem-dihalovinylarene substrates in the synthesis of heterocycles to encompass a thiol analogue (Scheme 34.38, disconnection D-2). The combination of an unusual palladium-catalyzed S-alkenylation with a second cross-coupling process, such as a Suzuki, Heck, or Sonogashira reaction led to diversely functionalized benzothiophenes such as 67, produced in excellent yield (Scheme 24.40) [132], Routes incorporating a tandem carbonylation step [133] and a direct arylation [117] process have subsequently been reported. 

Palladium-catalyzed carbon-carbon cross-coupling reactions are among the best studied reactions in recent decades since their discovery [102, 127-130], These processes involve molecular Pd complexes, and also palladium salts and ligand-free approaches, where palladium(O) species act as catalytically active species [131-135]. For example, the Heck reaction with aryl iodides or bromides is promoted by a plethora of Pd(II) and Pd(0) sources [128, 130], At least in the case of ligand-free palladium sources, the involvement of soluble Pd NPs as a reservoir for catalytically active species seems very plausible [136-138], Noteworthy, it is generally accepted that the true catalyst in the reactions catalyzed by Pd(0) NPs is probably molecular zerovalent species detached from the NP surface that enter the main catalytic cycle and subsequently agglomerate as N Ps or even as bulk metal. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

Metal-catalyzed cross-couplings are key transformations for carbon-carbon bond formation. The applicability of continuous-flow systems to this important reaction type has been shown by a Heck reaction carried out in a stainless steel microreactor system (Snyder et al. 2005). A solution of phenyliodide 5 and ethyl acrylate 6 was passed through a solid-phase cartridge reactor loaded with 10% palladium on charcoal (Scheme 2). The process was conducted with a residence time of 30 min at 130°C, giving the desired ethyl cinnamate 7 in 95% isolated yield. The batch process resulted in 100% conversion after 30 min at 140°C using a preconditioned catalyst. 

As shown in the previous sections, a (cr-allenyl)palladium species, which is formed from a propargyl electrophile and a Pd(0) catalyst, reacts with a hard carbon nucleophile in a manner analogous to the Pd-catalyzed cross-coupling reaction to give a substituted allene. The results indicate that the reactivity of the (cj-allenyl)palladium species is similar to that of an alkenylpalladium intermediate. Indeed, it was found that the (cr-allenyl)palladium species reacted with olefins to give vinylallenes, a reaction process that is similar to that of the Heck reaction of alkenyl halides [54]. 

Alkylpalladium complexes generated by oxidative addition of Pd(0) to alkyl halides with a /3 hydrogen can undergo /3-elimination to yield an alkene and a Pd-hydrido complex (as in the Heck reaction Scheme8.7). Nevertheless, this process is relatively slow compared with transmetalations and reductive eliminations, and simple alkyl halides or tosylates with /3 hydrogen can be cross-coupled with carbon nucleophiles under optimized conditions if the nucleophile is sufficiently reactive [9, 73-75] (Scheme8.6). 

Inhibition by radical traps, such as TEMPO 17, was used to explain the involvement of radicals in the course of transition metal-catalyzed reactions (Fig. 7). Typical cross-coupling reactions, such as Heck or Suzuki-Miyaura reactions, proceeded even with nitroxyls as substrates, although the yields were sometimes low. Thus, nitroxyls do not necessarily interfere very much with the course of two-electron catalytic processes [79-81]. However, it must be critically mentioned that 17 and related nitroxides are both oxidants and reductants for metal species. 

Another gain in diversity is achieved by the combination of these cross couplings with uncatalyzed reactions. Because of their oligounsaturated character, the coupling products are obviously well suited for subsequent peri-cyclic reactions leading to additional cyclizations. These atom-efficient processes are especially attractive since they typically proceed with high chemo-, regio- and stereoselectivity [18]. This review is intended to cover Heck reactions and related palladium-catalyzed processes followed by Diels-Alder reactions, 1,3-dipolar cycloadditions or 6 -electrocyclizations. 

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