Heck couplings internal arylation

In 1975, three different protocols were available in the literature, each describing the synthesis of internal alkynes. Cassar described palladium- or nickel-mediated reactions between aryl or vinyl halides and alkynes complexes with phosphine as ligands in the presence of NaOMe [1]. As a second protocol, Heck pubhshed a variation of the Mizoroki-Heck couplings, in which the olefins were replaced by alkynes and coupled with (hetero)aryl, as weU as alkenyl bromides or iodides at 100 °C in the presence of a basic amine [2]. More than a decade earUer, Stephens and Castro had described the details of a palladium-free coupling of aryl iodides with cuprous acetylides in refluxing pyridine [3]. 

While this cyclization method does not allow the incorporation of substituents into the 3-position, as is available with internal alkynes, in analogous chemistry to that in Section 6.2.2, the palladium bound intermediate of cyclization can be intercepted with a range of external reagents to functionalize this site. These include aryl or vinyl halides, allylic substrates, carbonylation, and Heck coupling with alkenes [72]. 

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. 

The final common class of coupling reactions to form C-C bonds described here is the coupling of an aryl halide with an olefin to cleave the C-H bond of the olefin and replace it with an aryl group. This reaction, which is shown generically in Equation 19.18, was first reported by Mizoroki the synthetic utility of this process and e most useful conditions for this process at the time were reported by Heck. ° This process is often called the "Heck reaction," or more appropriately the "Mizoroki-Heck reaction." " The Heck reaction is most commonly conducted with electron-deficient olefins, such as styrene or acrylate derivatives. The electronic properties of these substrates tend to favor formation of the conjugated products. The reaction can also be conducted effectively with ethylene a Heck reaction between 6-methoxy-2-bromonaphthalene and ethylene is one step of a short, catalytic commercial synthesis of naproxen. In contrast, intermolecular reactions of internal olefins typically form mixtures of regioisomeric products. Intramolecular Mizoroki-Heck reactions with intemal olefins are more common. Mizoroki-Heck reactions of aliphatic electrophiles have been reported, but remain rare. Applications of the Mizoroki-Heck reaction have been reviewed. ... 

Given the expensive nature of Pd, other metals have been used as a replacement for this metal. In 2005, Li etal. [69] showed that copper(l) could be used as the catalyst for the Heck-Mizoroki reaction. They used 10 mol% Cul and 20 mol% l,4-diazabicyclo[2.2.2]octane (DABCO) for the coupling of a number of aryl iodides and an aryl bromide giving the corresponding internal olefins in moderate to good yields. The reaction conditions are shown in Scheme 1.25. The reaction mechanism that was proposed by these authors involved a four-centered transition state that was originally proposed by Castro and Stephens in 1963 (Scheme 1.26) [23]. 

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