Heterocyclic compounds intramolecular Heck reaction

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]. 

A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requiranents there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substructure typical for very many starting materials, which were transformed to heterocycles by intramolecular Heck-type reactions (X = halide, Het = heteroatom). This type of substructure with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active compounds. 

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]. 

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 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]. 

In 2004, Guy and co-workers reported the synthesis of five classes of heterocycles dihydrodibenzo[Z),/]azepine, -oxocine, and -thiocine and dibenzo[Z>,/]azepine and -oxepine using a strategy of allqrlation followed by highly selective intramolecular Heck arylation reaction. The heterotricyclic compounds were available in only two steps starting from... 

---