Heck reaction With heterocycles

Iodination (I2/NaOH) of l,6-naphthyrid-5-one (47) gives the iodo derivative (48) (70% yield). This compound is converted to 5-chloro-8-iodo-l,6-naphthyridine (49) by the action of phosphorus oxychloride (64% yield). Heterocycle (49) undergoes a Heck reaction with ethyl acrylate in the presence of palladium acetate as a catalyst giving compound (51) (47% yield). Similarly, heterocycle (50) (obtained in 98% yield by treating compound (49) with sodium methoxide) gives ester (52) (88% yield) in a Heck reaction <86CPB2018>. 

Heck reactions with subsequent reduction ( hydride-ion capture ) [103, 105, 192] also have become valuable methods for the construction of various carbo- and heterocyclic skeletons. Such a reaction comes about when the. syn-addition of an aryl- or alkenylpalladium species to a multiple bond leads to an intermediate which does not or cannot undergo a rapid 5yn-jS-hydride elimination (Scheme 3-41) [105] (cf. [71b]. 

In the Heck reaction, aryl, heterocyclic and vinyl halides - " or aryl triflates react with excess carbon monoxide and primary or secondary amines to give substituted amides, in the presence of a palla-dium(II) catalyst (equation 41). Cis- and trans-vinyl halides react stereoselectively. 

Similarly, Heck reactions with allylic and homoaUylic alcohols in Scheme 46 lead to intermediary carbonyl compounds, which subsequently undergo heterocyclization either by formation of a hemiacetal (first example) or by cyclocondensation (second ex-ample). f In both cases the palladium catalyst is not involved in the heterocyclization step. 

Fiddy, S.G., Evans, J., Neisius, T. et al. (2007) Comparative experimental and EXAFS studies in the Mizoroki-Heck reaction with heteroatom-functionaUsed Al-heterocyclic carbene paUadium catalysts. Chem. Eur. J., 13, 3652-9. 

Scheme 6.14 Cascade of two intramolecular heterocyclic-forming Mizoroki-Heck reactions with anion capture.

Formation of six-membered cycles is the second most common case of heterocyclic Mizoroki-Heck reactions, with, as for the formation of five-membered rings, exo-cyclization reactions being largely favoured compared to c d( -cyclization reactions. As already noted for the five-membered cycles, there are more examples of iV-heterocyclic formation than of oxygen-containing heterocycles. 

In 1999, cyclopalladated tolylphosphine compounds were reported to show highly catalytic activities, not only for Heck reactions of which the turnover numbers (TONs) are up to 1,000,000, for example, but also for all other metal-catalyzed cross-coupling reactions [115, 116]. In 2005, Heck reactions with naphthyl phosphines [117] or 77-heterocyclic carbene phosphapalladacycles [118] were also reported to show highly catalytic activities, as evidenced by their TONs of up to 300,000 and 10,800, respectively. 

Aqueous media also facilitate the Heck reaction with iodo derivatives of various nitrogen-containing heterocycles [52]. 

Pd-catalysts with heterocyclic ligands as catalysts for Heck reaction 98CSR427. 

The Heck reaction, first disclosed by the Mori and Heck groups in the early 1970s [65, 66], is the Pd-catalyzed coupling reaction of organohalides (or triflates) with olefins. Nowadays, it has become an indispensable tool for organic chemists. Inevitably, many applications to heterocyclic chemistry have been pursued and successfully executed. In one case, Ohta et al. reacted 2-chloro-3,6-dimethylpyrazine (49) with styrene to furnish ( )-2,5-dimethyl-3-styrylpyrazine (50) [67]. Here, only the E isomer was observed. The outcome will become apparent during the ensuing discussions on the mechanism. 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many rt-electron-rich heteroaryls including furan, thiophene, benzo[ ]furan and benzo[6] thiophene [42, 43]. In reactions of chloropyrazines with furan, thiophene and pyrrole, disubstituted heterocycles were also isolated albeit in low yields. 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

Transition metal catalyzed insertion reactions offer a variety of alternate approaches for the preparation of heterocyclic rings, of which Heck reactions were utilised extensively to prepare rings with more than 6 atoms. At the end of this Chapter some examples of the use of insertion reactions in the formation of the carbacyclic part of condensed heterocyclic systems will also be presented. 

The common feature of the first set of examples discussed is the coupling of an arylpalladium complex, formed in oxidative addition, with a five membered heterocyclic ring via the formal displacement of a hydrogen atom. This reaction, formally a Heck coupling, is often called the heteroaryl Heck reaction . 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

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