Heck reaction with heterocyclic halides

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. 

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. 

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. 

The Heck reaction is applicable to the synthesis of benzo-fused heterocycles including indolines, 1,2-dihydroquinolines, and benzopyrans. Influence of reaction conditions on diastereoselectivity is witnessed in the cyclization leading to geissoschizol and its isomer. Reaction of 2-cyanothiophene with aryl halides introduces the aryl group to the 5-position."... 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

The first high yielding one-pot tandem Hartwig-Buchwald-Heck cyclization was reported and applied to the synthesis of 2,3-disubstituted indoles [201]. Commercially available enone 123 was coupled with 1,2-dibromobenzene to provide A -arylcncaminonc 124 which subsequently cyclized to indole derivative 125 [201]. This reaction was widely applicable to a variety of electron rich, electron poor and neutral aromatic bromides and chlorides as well as heterocyclic halides. Excellent yields were obtained regardless of the substitution pattern on the aromatic halide. 

The ever-versatile Heck reaction (chapter 18) works well with most heterocycles providing one can put the halide or triflate in the right place on the heterocyclic ring. This example shows that an unprotected nucleoside 194, made by iodination of deoxyuridine, reacts cleanly with ethyl acrylate... 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reaction, whereby the alkyl halide or aryl halide is coupled to the unfunctionalized oxazole. First developed by Ohta and colleagues, it was demonstrated that a diverse array of aromatic heterocycles can be substrates in the reaction with chloropyrazines. While substitution was expected to occur at the 2-position, the reaction with chloropyrazine as the aryl halide resulted in substitution at the 5-position. When benzoxazole is used as the coupling partner, substitution is effected at the 2-position. More recently, a systematic study by Strotman and co-workers has demonstrated that slight modifications of the reaction conditions can allow completely regioselective coupling at either the 2- or 5-position. ... 

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]. 

Roland, S., Mangeney, P. and Jutand, A. (2006) Reactivity of Pd(0)(NHC)2 (NHC = A-heterocyclic carbene) in oxidative addition with aryl halides in Heck reactions. Synlett, 3088-94. 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

To overcome the ring closure of intermediate 10 giving rise to by-product 8 that was particularly encountered with secondary alkyl halides. Tautens and coworkers [22] developed conditions that favor the oxidative addition of alkyl hahdes. The methodology was widely applied to the intramolecular (Scheme 19.12) and intermolecular ortho alkylation of aromatic C-H bonds with secondary alkyl iodides and bromides [23]. Depending on the terminating reactions employed (the Heck reaction, direct arylation of heterocycles, and the Buchwald-Hartwig amination), a variety of valuable heterocydes were efficiently prepared. It should be pointed out that the reaction of enantioenriched substrates occurred with... 

Zeolites are very useful catalysts for a large variety of reactions, from acid to base and redox catalysis [27]. Hutchings et al. reported that bis(oxazoline)-modified Cu (II)-HY catalysts are effective for asymmetric carbonyl- and imino-ene reactions and aziridination of styrene [28, 29]. Recently Djakovitch and Kohler [30-34] found that Pd(II)-NaY zeolite activates aryl halides towards Heck olefination, a-arylation of malonate, and amination reactions. It is well known that alkali-exchanged faujasite zeolites are solid base catalysts [35]. Owing to the usefulness of zeolites in organic chemistry, and our interest, we recently reported the use of modified alkali-exchanged zeolite Y, NaY zeolite [36] with electron rich copper catalyst in the Y-arylation of nitrogen heterocycles with aryl halides to afford A -arylheterocycles in excellent yields under mild conditions without the use of any additive. 

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 substrnctnre typical for very many starting materials, which were transformed to heterocycles by intramolecnlar Heck-type reactions (X = halide, Het = heteroatom). This type of substrnctnre 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 componnds. 

In a narrower sense, this review covers intramolecular Mizoroki-Heck [1] reactions forming carbocycles [2] that is, the palladium-catalyzed intramolecular coupling of vinyl/aryl (pseudo-)halides with an alkene tethered by a hydrocarbon chain. Ring closures furnishing heterocycles are covered in Chapter 6 also beyond the scope of this chapter are the domino/cascade or tandem (Chapter 8) and asymmetric processes (Chapters 12 and 16) dealing with formation of a carbocycle. 

Later, Heck also reported the synthesis of amide from various aryl, heterocyclic, and vinylic halides and primary or secondary amines in the presence of a palladium catalyst.The reaction was carried out under an atmosphere of carbon monoxide, and a tertiary amine was generally added to neutralize the hydrogen halide formed in the reaction. The reaction is also highly stereospecific with cis- and trans-winyl halides (Table 3). 

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