Elimination reactions intermolecular Heck reaction

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

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. 

The product in Scheme 8, reminiscent of a prostaglandin, is the result of an intramolecular carbopalladation followed by an intermolecular Heck reaction, which becomes possible because the decisive intermediary alkylpalladium complex is lacking an appropriate hydrogen in synperiplanar position for the /3-H-elimination.f ... 

In 1996, the first examples of intermolecular microwave-assisted Heck reactions were published [85]. Among these, the successful coupling of iodoben-zene with 2,3-dihydrofuran in only 6 min was reported (Scheme 75). Interestingly, thermal heating procedures (125-150 °C) resulted in the formation of complex product mixtures affording less than 20% of the expected 2-phenyl-2,3-dihydrofuran. The authors hypothesize that this difference is the result of well-known advantages of microwave irradiation, e.g., elimination of wall effects and low thermal gradients in the reaction mixture. 

The use of cyclic alkenes as substrates or the preparation of cyclic structures in the Heck reaction allows an asymmetric variation of the Heck reaction. An example of an intermolecular process is the addition of arenes to 1,2-dihydro furan using BINAP as the ligand, reported by Hayashi [23], Since the addition of palladium-aryl occurs in a syn fashion to a cyclic compound, the 13-hydride elimination cannot take place at the carbon that carries the phenyl group just added (carbon 1), and therefore it takes place at the carbon atom at the other side of palladium (carbon 3). The normal Heck products would not be chiral because an alkene is formed at the position where the aryl group is added. A side-reaction that occurs is the isomerisation of the alkene. Figure 13.20 illustrates this, omitting catalyst details and isomerisation products. 

The main steps in the currently accepted catalytic cycle of the Heck reaction are oxidative addition, carbopalla-dation (G=G insertion), and / -hydride elimination. It is well established that both, the insertion as well as the elimination step, are m-stereospecific. Only in some cases has formal /r/ / i--elimination been observed. For example, exposure of the l,3-dibromo-4-(dihydronaphthyloxy)benzene derivative 16 and an alkene 1-R to a palladium source in the presence of a base led to a sequential intra-intermolecular twofold Heck reaction furnishing the alkenylated tetracyclic products 17 in good to excellent yields (Scheme 9). " In the rate-determining step, the base removes a proton in an antiperiplanar orientation from the benzylic palladium intermediate. The best amine base was found to be l,4-diazabicyclo[2.2.2]octane, which apparently has an optimal shape for this proton abstraction. 

Scheme 9 Sequential intra-intermolecular twofold Heck reaction involving a trans-/ -hydride elimination. ...

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

The development of the intermolecular cyclic version of the Heck reaction began in the late 1970s. It was immediately evident that the problem with reversible hydride eliminations complicated the use of endocyclic aUcenesf t " t ° and long chain acyclic... 

The investigation of the intermolecular version of the Mizoroki-Heck reaction with endo-cyclic alkenes began in the late 1970s [50-52], It was directly evident that the problem with reversible and repeating -hydride eliminations/migratory insertions complicated the use of cyclic alkenes in a manner similar to long-chain acyclic 1-alkenes [53], Mixtures of isomers were obtained. An example of a C—C bond formation-isomerization [54] process is shown in Figure 3.5. 

In addition to the several reports of intermolecular Fujiwara-Moritani reactions, there have been a nnmber of examples of intramolecular reactions, both stoichiometric and catalytic in palladinm. In considering an intramolecular oxidative Heck reaction, one can again draw a direct analogy to the classical Heck reaction (Figure 9.3). In the standard Heck reaction, a halogenated arene nndergoes an oxidative addition by palladium(0), followed by alkene insertion and jS-hydride elimination. In an oxidative version, a C—H bond of... 

The intermolecular version of the reaction can also be effective, and, under the right conditions, can give good yields even when the substrate, such as iodide 4.90, is capable of p-hydride elimination (Scheme 4.37). Curiously, the intramolecular carbonylative Heck reaction of styrene 4.03 proeeeded with net reduction of... 

Miura and coworkers reported the first palladium catalyzed intermolecular carbonylative Heck reaction of aryl iodides and five membered olefins in the presence of carbon monoxide (Scheme 1.28) [99]. The expected 2,5-dihydrofuran product was not observed in the carbonylative coupling of 4-iodoanisole and 2,3-dihydrofuran as depicted in Scheme 1.28. Instead, isomerization of the double bond via reinsertion of the palladium(II) hydride followed by another ]S-hydride elimination formed the vinyl ether exclusively. 

In their pioneering work on the catalytic carbopalladation reaction of 1,2-heptadiene with phenyl iodide in the presence of a suitable base, Shimizu and Tsuji observed the formation of the corresponding substituted 1,3-dienes 62 via a / -hydride elimination from the 7z>allyl intermediate 61 [61]. Based on these observations, a three-component Heck-Diels-Alder cascade process has been developed by Grigg and co-workers [73]. A wide variety of aryl and heteroaryl iodides were used for the intermolecular reaction with dimethylallene to afford the corresponding 1,3-dienes. These subsequently react in situ with N-methylmaleimide to give the bicyclic adducts 63 (Scheme 8.30). 

An alternate bimetallic pathway was also suggested, but not favored, by Heck and Breslow (also shown in Scheme 1). The acyl intermediate could react with HCo(CO)4 to undergo intermolecular hydride transfer, followed by reductive elimination of aldehyde to produce the Co-Co bonded dimer Co2(CO)s. A common starting material for HCo(CO)4-catalyzed hydroformylation, Co2(CO)g is well-known to react with H2 under catalysis reaction conditions to form two equivalents of HCo(CO)4. The bimetallic hydride transfer mechanism is operational for stoichiometric hydroformylation with HCo(CO)4 and has been proposed to be a possibility for slower catalytic hydroformylation reactions with internal alkenes.The monometallic pathway involving reaction of the acyl intermediate with H2, however, has been... 

Numerous examples of Heck-type reactions are known, where the common /3-H-elimination usually following the carbopalladation step is inhibited because of stractural or stereochemical reasons. Either the intermolecular reaction with an additional reagent or another cyclization reaction then terminates the Pd-catalyzed process. Such reactions are discussed below, again starting from substrates related to the substructure shown in Figure 1. 

Another potentially powerfnl sequence arises by combining one or two intramolecular Heck-type couplings with an intra- or intermolecular Diels-Alder addition (for early examples of inter-intermolecular one-pot domino Heck-Diels-Alder reactions see Refs. [49] and [50]). An all-intramolecular version of such a sequence has been shown to proceed reasonably smoothly for terminally alkoxycarbonyl-substituted 2-bromotrideca-l,ll-dien-6-ynes under palladium catalysis at 130 °C. At 80 °C, the sequential reaction stops after the two consecutive Heck-type cyclizations and subsequent /3-hydride elimination to give a 1,3,6-triene apparently only the ( )-isomer undergoes the intramolecular Diels-Alder reaction, as the (Z)-l,3,6-triene is observed accompanying the tetracyclic system obtained at 130 °C (Scheme 36). 

In 1961 Heck proposed what is now generally considered to be the correct monometallic mechanism for [HCo(CO)4]-catalyzed hydroformylation [10]. He also proposed, but did not favor, a bimetallic pathway involving an intermolecular hydride transfer between [HCo(CO)4] and [Co(acyl)(CO)4] to eliminate aldehyde product (Scheme 2). Most proposals concerning polymetallic cooperativity in hydroformylation have, therefore, centered on the use of inter- or intramolecular hydride transfers to accelerate the elimination of aldehyde product. Bergman, Halpem, Norton, and Marko have all performed elegant stoichiometric mechanistic studies demonstrating that intermolecular hydride transfers can indeed take place between metal-hydride and metal-acyl species to eliminate aldehyde products [11-14]. The monometallic [HCo(CO)4] pathway involving reaction of the acyl intermediate with H2, however, has been repeatedly shown to be the dominant catalytic mechanism for 1-aUcenes and cyclohexane [15, 16]. 

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