Heck reaction heterocyclic carbopalladation

Another variant of the Heck reaction which is important in heterocyclic chemistry utilizes five membered heterocycles as olefin equivalent (2.2.)7 It is not clear whether the process, coined as heteroaryl Heck reaction follows the Heck mechanism (i. e. carbopalladation of the aromatic ring followed by //-elimination) or goes via a different route (e.g. electrophilic substitution by the palladium complex or oxidative addition into the C-H bond). Irrespective of these mechanistic uncertainties the reaction is of great synthetic value and is frequently used in the preparation of complex policyclic structures. 

Intramolecular carbopalladations, as in the Heck reaction, with subsequent reduction by a hydride source have established themselves as an indispensable tool for the construction of various carbocyclic and heterocyclic skeletons. Such a reaction comes about when the iyn-addition of an aryl- or alkenylpalladium species to a multiple bond leads to an intermediate that does not or cannot undergo a rapid 5yn-/3-hydride elimination such as certain cycloalkyl- (Scheme 21, Eq. 1), " neopentyl- (Eq. Eq. Eq. or TT-afiylpaUadium intermediates (Eq. The most efficient reagents for the reduction are formic acid in the presence of secondary or tertiary amines and alkali metal formates such as sodium formate. In some cases tin hydrides have successfully been employed (Scheme 33, Eqs. 3-5). 

Another approach to the construction of five-membered nitrogen heterocycles by way of intermediate jt-allylpalladium complexes involves carbopalladation reactions of 1,3-or 1,4-dienes [85]. For example, Larock has described the coupling of N-tosyl-2-iodoaniline with 1,3-cyclohexadiene, which affords 119 in 87% yield (Eq. (1.48)). The allylpalladium complex 120 is a key intermediate in this transformation. Asymmetric versions of these reactions that generate pyrrolidine products have also been described [86]. Related Heck reactions that employ vinylcyclopropanes as diene surrogates have also been reported, although lengthy reaction times (3-4 days) are often required for transformations of these substrates [87]. 

Domino or cascade reactions provide valuable approaches, especially to various carbo- and heterocyclic systems with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, inter-intra-, as well as all-intramolecular reaction cascades, hi this section, the termination of these processes by alkenes, arenes, and related ir-bond systems such as alkynes and allenes will be described. A cascade Heck reaction is considered to consist of an oxidative addition of a heteroatom-carbon bond to palladium (starter), carbopalladation of a nonaromatic carbon-carbon double or triple bond without immediate dehydropalladation (relay), one, two, or more fimher car-bopalladation(s) of a carbon-carbon double or triple bond, and eventually ensuing dehydropalladation. Crucial for a cascade reaction of this kind to occur is the blockage or retardation of a dehydropalladation at one of the intermediate stages by using 1,1-disubsti-tuted alkenes and appropriately substimted cycloalkenes, bicycloalkenes, or alkynes as relays since they give kinetically stable alkyl- or alkenylpalladium intermediates, respectively. 

Some heterocycles undergo facile inter- and intramolecular arylations. Two mechanistic explanations of the arylation are possible. The Heck-type reaction is one of them. Carbopalladation of one of two double bonds with Ar-Pd-X gives la, which is stabilized by jr-allylpalladium formation. Pd and jS-H is anti in la and hence syn f-H elimination is not possible. Therefore, in stereoisomerization from anti la to syn lb a relationship between Pd and jS-hydrogen occurs, and syn y3-H elimination from lb affords the arylation product (path a). Another explanation is electrophilic substitution with Ar-Pd-X. Since arylations occur mainly at electron-rich carbons of heterocycles, they can be understood as electrophilic substitutions (path b). In some cases, a Heck-type mechanism seems to be more reasonable. Certainly arylations proceed by one of these mechanisms depending on the electronic nature of the substrates and reaction conditions, and hence further mechanistic studies are necessary. 

This section gives a concise overview on the construction of heterocycles by Heck-type reactions all reactions covered here mechanistically start with an oxidative addition of a C-haUde or another appropriate C-heteroatom bond to a Pd(0) species and go on either with a carbopalladation step (intramolecular in Sect. B and intermolecular in Sect. C) or a cyclopalladation step (Sect. D). The examples presented in the subsections are organized according to types of starting materials, since certain substructures turned out to be typical. 

Compared to Figure 1, the substructures of Figure 3 have side chains elongated by one carbon atom. Heck-type cyclization of substrates that match these substructures should lead to six-membered heterocycles because the intramolecular carbopalladation in the sense of a 6-exo-trig reaction should clearly be favored against the 1-endo-trig pathway. 

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