Heck reaction heterocyclic compounds

The double-Heck-approach can also be employed for the preparation of novel heterocyclic compounds as 6/1-25 and 6/1-26 (Scheme 6/1.4) [24]. Thus, the palladium-catalyzed reaction of 6/1-21 and the cyclic enamide 6/1-22 gave a Oil-mixture of 6/1-23 and 6/1-24, which in a second Heck reaction using the palladacene 6/1-15 led to 6/1-25 and 6/1-26 in an overall yield of 44—49%. The synthesis can also be performed as a domino process using a mixture of Pd(OAc)2 and the palladacene 6/1-15. 

The palladium-catalyzed Heck [1], Suzuki [2] and Stille [3] reactions are robust and general methods for C-C bond-formation and have therefore emerged as important reactions in the synthesis of natural heterocyclic compounds. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

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. 

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>. 

The intramolecular asymmetric Heck reaction has featured in the synthesis of complex heterocyclic compounds. Bidentate ligands, such as diphosphines (especially BINAP) and phosphine—oxazolines, have been used as a chiral ligand of the asymmetric Heck reaction. Imbos et al. demonstrated that the mono-dentate phosphoramidite 513 was an effective ligand for the asymmetric Heck reaction of the prochiral cyclohexadienone 511 (Scheme 153).227 The reaction of 511 in the presence of catalytic amounts of Pd-(OAc)2 and the chiral phosphoramidite 513 gave the 4a-methoxy-4a//-benzo[c]chromen-2(6E/)-one 512 in 71% yield with 96% ee. By contrast, the reaction of... 

In contrast to facile reactions of aryl halides with alkenes and alkynes, reactions of aromatic compounds with aryl halides have received less attention. Only intramolecular arylation of benzene derivatives, except phenols, is known [1]. On the other hand, electron-rich heterocycles such as ffirans, thiophenes, pyrroles, oxa-zoles, imidazoles, and thiazoles undergo facile inter- and intramolecular arylation with aryl halides. These are called heteroaryl Heck reactions [2]. 

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. 

Also a multitude of novel heterocyclic compounds, such as 25 and 26, can be prepared by a double Mizoroki-Heck approach [23]. Thus, the palladium-catalysed reaction of 21 and... 

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. 

Starting in 1977, Mori and Ban " at Hokkaido University discovered that Pd can catalyze the intramolecular reaction of o-halo-iV-allylanilines to indoles under Heck reaction conditions. It was the first intramolecuar Heck reaction to the synthesis of heterocycles. For example, the compound 1, which was prepared from methyl a-bromocrotonate (3) and 2-bromo-A-acetylaniline 4, was adopted as a starting material. It was treated with Pd(OAc)2 (2 mol%) and PPhs (4 mol%) in the presence of tetramethylethylenediamine (TMEDA, 200 moI%) under a stream of nitrogen at 125 °C for 5.5 h methyl l-acetyl-3-indolyl acetate was obtained in a yield of 43% via an intramolecular Heck... 

As the first application of Heck reaction in making heterocyclic compounds — namely indole derivatives, the Mori-Ban reaction has been widely used in variety synthesis of indoles. In a program to synthesize CC-1065 analogs, Sundberg prepared indole 19 from o-bromo-JV-allylaniline 18 in an excellent yield using the Jeffrey s conditions. Silver carbonate and sodium carbonate were less effective than triethylamine. 

Syntheses of Heterocycles, Natural Products, and Other Biologically Active Compounds Applying Heck Reactions... 

As most biologically active compounds - natural and noimatural products - contain heterocyclic substractures, intramolecular C-C-bond-forming processes including Heck reactions have been applied to accompHsh heterocydization [564-566]. 

Syntheses of Heterocycles, Natural Products, and Other Biologically Active Compounds 619 Table 8.9 Some chiral ligands used in asymmetric Heck reactions [421] (Figure 8.5). 

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