Heck reaction carbopalladation

Tietze and coworkers [60] observed a combination of a Heck reaction and a C-H-activation by treatment of the alkyne 6/1-111 with Pd°. These authors aimed at compound 6/1-112, but 6/1-110 was obtained as a single product in high yield (Scheme 6/1.29). It can again be assumed that after oxidative addition a cis-carbopalladation of the triple bond takes place to give an alkenyl Pd intermediate which undergoes the C-H-insertion into the neighboring naphthalene and not into the aryl ether moiety. 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

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. 

Tethering an iodobenzene and a furane moiety through a y0-lactam led to the formation of a unique tetracyclic y0-lactam derivative (5.17.). Oxidative addition followed by the carbopalladation of the furane ring resulted in the closure of the seven membered core in a so called heteroaryl Heck reaction "... 

Keywords Carbopalladation, Asymmetric Heck reaction, Vinylation, Arylation... 

All reactions described in this section are explained by (i) the oxidative addition of a halide to generate the arylpalladium halide 14 (ii) insertion of an alkene to form 15, which is regarded as carbopalladation of alkenes and (iii) formation of the new alkene 16 by elimination of /I-hydrogen (dehydropalladation). The reaction was reported independently by Mizoroki [3] and by Heck [4], and is called the Mizoroki Heck or Heck reaction [5]. 

Whereas the intermolecular Heck reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and many cyclic compounds can be prepared by the intramolecular Heck reaction [37]. The stereospecific synthesis of an A ring synthon of la-hydroxyvitamin D has been carried out. Cyclization of the (7T)-alkene 88 gives the (fT)-exo-diene 90, and the (Z)-alkene 91 affords the (Z)-exo-diene 92 [38]. These reactions are stereospecific, and can be understood by cis carbopalladation to form 89 and the. sun-elimination mechanism. 

For the Heck reaction as discussed in Section III.2.1 the final position of the olefi-nic double bond of the products must not necessarily be the same as in the starting materials (for example Schemes 8, 9, and 10 of Section III.2.1) [1], The selectivity is often driven by stereochemical requirements, because the /1-hydrogen elimination step which forms the double bond proceeds exclusively in a syn manner (if a trans /3-hydrogen is eliminated, one should suspect major deviations from the general mechanism of the Heck reaction, for example electrophilic substitution instead of carbopalladation). An impressive example of a double bond migration is depicted in Scheme 1 - instead of olefins the coupling reaction of iodobenzene 1 with the olefmic alcohol 2 results in the isomeric aldehydes 3 and 4 as final products [2], Reactions of this type have emerged as valuable tools for the synthesis of carbonyl compounds and also as crucial steps in domino processes. 

Currently, there seems to be a widespread tendency to call many reactions proceeding via carbopalladation the Heck reaction. However, this practice is clearly incorrect, since the scope of carbopalladation is significantly wider than that of the Heck reaction. The alkyne carbopalladation reaction shown in Scheme 4, which is not accompanied by /J-dchydropalladation may not be viewed as an example of the Heck reaction. In fact, this chapter focuses its attention on various carbopalladation reactions that may not be considered as examples of the Heck reaction. Although some of such processes are combined with the Heck reaction in many cases. 

Although this chapter focuses its attention on cyclic carbopalladation reactions other than the cyclic Heck reaction, it might be useful to discuss here the following variants of the cyclic Heck reaction. For the vast topic of the cyclic Heck reaction including those variants discussed below, the reader are referred to the following chapters of the Handbook of Organopalladium Chemistry for Organic Synthesis [40]. 

One significant consequence of the formation of allylpalladium derivatives is that it represents an escape from the Heck reaction manifold permitting a wide variety of non-Heck processes via carbopalladation, which is the focal point of the rest of this chapter. 

Despite an earlier failure to achieve cyclic carbopalladation-carbonylative termination in competition with the cyclic Heck reaction [67] (Eq. 3 in Scheme 35), a series of investigations by Aggarwal [117-119] has provided useful solutions to this problem. In cases where the substrates contain a heteroatom group, such as O or NTs, the cyclic Heck reaction can be suppressed [117] (Eq. 1 in Scheme 37). This reaction has been applied to an asymmetric synthesis of avenaciolide [119] (Eq. 2 in Scheme 37). A more general solution to avoiding the cyclic Heck reaction is not to use a base, e.g., Et3N, and promote rehydropalladation to reserve /(-elimination through the... 

A couple of prototypical examples of the cyclic version of the Heck reaction, defined as a process consisting of alkene carbopalladation followed by -elimination, were reported during the 1984-1985 period [9,10]. Almost concurrently, seminal examples of both the non-Heck cyclic carbopallation reactions [10,30] were reported during the 1983-1985 period. Thus, with due respect paid to earlier discoveries of alkyne cyclooligomerization via cascade carbopalladation [7,8] as well as copolymerization [24] and cocyclization [25,... 

Palladium-catalyzed vinylations of aryl halides are generally referred to as the Heck reaction (for reviews on the Heck reaction see [34-40]), a versatile process that can be performed inter- and intramolecularly [41]. In the Heck reaction the carbon-carbon single bond forming step is an insertion of an al-kene into the aryl-Pd bond, i.e., a carbopalladation, giving rise to an alkyl-Pd species. If this insertion is terminated by /1-hydride elimination the expected vinylation product is the outcome of the classical Heck reaction. Likewise, reversible insertion of a highly strained olefin where the /1-hydride elimination is suppressed leads to an entry to multiple Pd-catalyzed bond forming processes. 

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