The Carbonylative Heck Reaction

3 Carbonylation of Alkenes and Alkynes 43.1 The Carbonylative Heck Reaction 

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In the next chapter we will discuss the carbonylative Heck reaction. Again, the reaction mechanism is different from those in the preceding chapters. 

The Carbonylative Heck Reaction is not the same as those that were traditionally called Heck carbonylations . Heck carbonylations normally include alkoxycarbonylation, aminocarbonylation and hydroxycarbonylation, while a carbonylative Heck reaction is more related to a Heck reaction. In the late 1960s, Richard Heck developed several coupling reactions of arylmercury compounds in the presence of either stoichiometric or catalytic amounts of palladium salts [1-7]. Based on this work in 1972, he described a protocol for the coupling of iodo-benzene with styrene, which today is known as the Heck reaction [8]. In contrast to this, the catalytic insertion of olefins into acylpalladium complexes is called a Carbonylative Heck reaction . Here the acylpalladium complexes can either by CO insertion or by the oxidative addition of benzoyl precursors [9, 10]. 

Additionally, the carbonylative Heck reaction was developed by Beller s group [29-31]. The reaction condition requires the higher loading of alkenes (6 equiv) and the presence of CO compared with Heck coupling. 

In contrast, the carbonylative Heck reaction, representing a variant of the palladium based multicomponent olefination reactions, has only been described to a hmited extent. Nevertheless, the resulting a,/ -unsaturated ketones serve as very important building blocks, as demonstrated by the many applications of the Michael addition, and constimte an attractive entry point to the assembly of heterocyclic compounds including pyridines, pyrimidines and pyrazoles etc [97, 98]. 

Scheme 7.2 Simplified mechanism of the carbonylative heck reaction...

Palladium(0)-catalyzed coupling reactions - i. e. the Heck and Sonogashira reactions, the carbonylative coupling reactions, the Suzuki and Stille cross-coupling reactions, and allylic substitutions (Fig. 11.1) - have enabled the formation of many kinds of carbon-carbon attachments that were previously very difficult to make. These reactions are usually robust and occur in the presence of a wide variety of functional groups. The reactions are, furthermore, autocatalytic (i.e. the substrate regenerates the required oxidation state of the palladium) and a vast number of different ligands can be used to fine-tune the reactivity and selectivity of the reactions. 

Another important line of investigation concerned the carbonyl insertion reaction, which was best defined in manganese chemistry (75, 16) and extended to acylcobalt tetracarbonyls by Heck and Breslow. The insertion may be through three-membered ring formation or by nucleophilic attack of an alkyl group on a coordinated CO group. 

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... 

The author would like to thank the many colleagues of the catalysis group at Hoechst AG for fiiendship and discussions. Special thanks go to Prof K Kiihlein 4io initiated and supported always the catalysis research at the Central Research Laboratories of Hoechst AG. I particularly thank our collaborators at the TU Miinchen Prof W. A. Herrmann and his coworkers and especially my co-workers M. Eckert, J. Krauter, T. Riermeier, F. VoUmuller, A. Zapf for their work and enthusiasm to join me in the areas of carbonylations, Heck reactions and two phase catalysis. 

In principle, carbonylative cyclization, that is, acylpalladation or Ac—Pd process, or noncarbonylative cyclization, that is, sample carbopalladation or C—Pd process, in the presence of CO and a Pd catalyst. Various possibilities with halo alkenes as representative substrates are shown in Scheme 2P Those processes that incorporate CO in the cyclization processes are discussed in Part VI including Sects. VI.4-VI.6. hi this section, those cases that do not incorporate CO during the cychzation processes but do so only after cyclization will be discussed. Such cychc carbopalladation-carbonylative termination tandem and cascade processes are represented by the Type II C—Pd process in Scheme 2, which may take place in competition with the other processes shown in Scheme 2, especially the cyclic Heck reaction (Type 1 C—Pd process) and cyclic carbopalladation involving cyclopropa-nation (Type 111 C— Pd process). 

A detailed investigation with 10 summarized in Table 2 indicates that premature esterification and cyclopropanation (Type HI C— Pd process in Scheme 2) can occur as dominant side reactions but that, under the optimized conditions (entry 7), both can be suppressed to insignificant levels (<3%). It is also important to note that, in marked contrast with the cyclic acylpalladation (Type n Ac—Pd) discussed in Sect. VI.4.1.1, monosubstituted alkenes that can readily participate in dehydropalladation (e.g., 11) cannot undergo the cyclic carbopalladation-carbonylative esterification tandem process (Type II C-Pd) since they merely undergo the cyclic Heck reaction (Type I C— Pd process in Scheme 14). The contrasting behavior mentioned above may be attributable to a chelation effect exerted by the carbonyl group in the acylpalladation (Scheme 15), which is lacking in the carbopalladation shown in Scheme 14. 

Alkenes that can provide hydrogen atoms /3 and syn to Pd, such as monosubstituted alkenes, may not be used in the cyclic carbopalladation-carbonylative trapping process, as the reaction is dominated by the cyclic Heck reaction. The difference between this process and the Type II Ac—Pd process (Sect. VI.4.1.1) may be attributable to a chelation effect in the latter preventing otherwise competitive dehydropalladation. 

In most of the palladium-catalysed domino processes known so far, the Mizoroki-Heck reaction - the palladium(0)-catalysed reaction of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - has been apphed as the starting transformation accordingly to our classification (Table 8.1). It has been combined with another Mizoroki-Heck reaction [6] or a cross-coupling reaction [7], such as Suzuki, Stille or Sonogashira reactions. In other examples, a Tsuji-Trost reaction [8], a carbonylation, a pericyclic or an aldol reaction has been employed as the second step. On the other hand, cross-couphng reactions have also been used as the first step followed by, for example, a Mizoroki-Heck reaction or Tsuji-Trost reactions, palladation of alkynes or allenes [9], carbonylations [10], aminations [11] or palladium(II)-catalysedWacker-type reactions [12] were employed as the first step. A novel illustrative example of the latter procedure is the efficient enantioselective synthesis of vitamin E [13]. 

The Mizoroki-Heck reaction promoted by microwave irradiation was first described by Laihed and Hallberg [205]. For easy catalyst recovery, solid-supported systems were often used. An a-heteroatom-substituted carbonyl linker has been utilized in solid-phase approaches to oxinolines by Pummerer cyclization [206]. The reaction performed with s/c = 20 in the presence of phosphine ligands (ratio ligand/palladium-precursor = 1 1) in 88-99% yield at 7 h reaction time. 

The first palladium-catalyzed copolymerization of carbon monoxide (CO) with olefins was described in 1982 [11], and as a consequence, carbonylative coupling reactions with alkenes were reported soon after. Notably, it was Negishi and Miller who discovered the first two examples of intramolecular carbonylative Heck reactions of 1-iodopenta-1,4-dienes by applying stoichiometric amounts of palladium [12]. 5-Methylenecyclopent-2-enones as the products were produced in moderate yields (Scheme 7.1). 

In this catalytic system, 58 % of faranones were formed instead of quinones if Pd(OAc)2/PPh3 was used. This latter work can be considered to be the first real palladium-catalyzed intramolecular carbonylative Heck reaction. In 1996, a full account using various vinyliodides was published by the same group [16-18]. 

Shortly thereafter, a more general palladium-catalyzed carbonylative Heck reaction of aryl halides was able to be developed by our group [34]. For the first time, various aromatic and aliphatic alkenes were used successfully in this system, and good yields of the corresponding a,jS-unsaturated ketones were obtained (41-90 %). Starting from easily available aryl iodides and bromides, interesting building blocks were obtained under mild conditions (Scheme 7.15). With respect to the reaction mechanism, the aryl palladium complex and acyl palladium complex were characterized by X-ray, and the mechanism was studied step by step. The results fit well with DFT calculations. 

In this chapter, we discussed carbonylative Heck reactions, or the reaction of C-X with alkenes. jS-hydride elimination is the step that distinguishes this type of carbonylation reaction from the other carbonylation reactions, from a mechanism point of view. 

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