Heck-reaction

The reaction is of wide scope. Instead of ester groups as substituents at C-3 and C-5, other acceptor substituents—e.g. oxo, cyano, sulfonyl or nitro groups—can be employed in order to stabilize the 1,4-dihydropyridine system. 

Ruby in The Chemistry of Heterocyclic Compounds, Pyridine and its Derivatives, Vol. 14, Parti, (Ed. E. Klingsberg), Wiley, New York, 1960, p. 500-503. 

Bossert, H. Meyer, E. Wehinger, Angew. Chem. 1981, 93, 755-763 Angew. Chem. Int Ed. Engl. 1981, 20, 162. 

A catalytic amount of a reactive palladium(0)-complex 3 (i.e. PdLa in the catalytic cycle scheme shown below) is likely to be formed when the palladium(ll) acetate 2 oxidizes a small amount of the alkene  

The catalytic cycle of the Heck reaction can be formulated with four steps as follows  

The Heck arylation with arenediazonium salts was studied by Eberlin and coworkers through ESI-MS tandem mass spectrometry experiments. The group detected and structurally characterized the main cationic intermediates of this catalytic cycle direcfly from solution to the gas phase [52]. They proposed a detailed catalytic cycle of 

Roglans and coworkers [53,54] also studied the Heck reaction of arene diazonium salts using a palladium(O) complexes of 15-membered macrocyclic triolefines. 

Heck reaction, palladium-catalyzed cross-coupling reactions between organohalides or triflates with olefins (72JOC2320), can take place inter- or intra-molecularly. It is a powerful carbon-carbon bond forming reaction for the preparation of alkenyl- and aryl-substituted alkenes in which only a catalytic amount of a palladium(O) complex is required. 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

This reaction is not a bona fide Heck reaction per se for two reasons (a) the starting material underwent a Hg Pd transmetallation first rather than the oxidative addition of an aryl halide or triflate to palladium(O) (b) instead of undergoing a elimination step to give an enone, transformation 134 136 

The Heck reaction involves the coupling of an organopalladium species formed by oxidative addition to an alkene followed by /S-hydride elimination. The product is an alkene in which a vinyl hydrogen on the original alkene is replaced by die organic group on palladium. Thus aryl and alkenyl halides can be coupled to alkenes. 

Because the by-product of the coupling is a strong acid, bases are usually added to die reaction mixture to scavenge it. For example, 4-iodobromobenzene can be coupled with methyl acrylate to give the 4-bromocinnamate ester in 68% yield. This reaction takes advantage of the faster oxidative addition to the carbon-iodine bond to give a single product. 

The Heck reaction was discovered in the early 1970s and is extremely useful for rapidly assembling carbon skeletons. This reaction is unique to palladium A great deal of information is known about the reaction. For example, the success of the reaction depends on each of the three steps involved. Electron-donating groups decrease the reactivity of alkenyl halides and triflates toward Pd(0), whereas electron-withdrawing group increase the rate of oxidative addition. In cases where Pd(II) salts are used, it is assumed that they are converted to Pd(0) by some redox process. 

The insertion reaction is stereospecific and syn. Moreover the /S-hydride elimination is also syn. For acyclic alkenes there is free rotation in the organopalladium intermediate so that the more stable /ra .v-alkene is formed. Electron-withdrawing groups in the alkene also increase the rate of the insertion reaction and give higher yields generally, but the reaction is limited to relatively sterically unhindered alkenes. In general, polar solvents such as DMF or acetonitrile are most commonly used. There are several common additives which aid in the reaction. These include lithium or tetraalkylammonium chlorides and bromide, silver salts, or cuprous iodide, but exactly how they function is unknown at present. 

The conversion of carbonyl compounds to their enol triflates provides a very simple way to couple the carbonyl carbon to an alkene. In general, however, aryl 

The Heck reaction was discovered independently in the end of 1960s by T. Mizoroki and R. F. Heck . But Heck developed it into a synthetically useful reaction. Since then it has become one of the most important reactions for the synthesis ° of aromatic compounds substituted with alkenes. 

Although intermolecular Heck reactions are common, intramolecular Heck reactions can also be used for carbon-carbon coupling reactions. 

The intramolecular Heck reaction has been well established as a powerful tool for the construction of complex polycyclic ring systems in the context of natural product synthesis. 

If a Pd(II) source is used in the Heck reaction, it must be reduced to Pd(0) before entering the catalytic cycle. The initial oxidative addition of aryl halide to a Pd(0) catalyst affords 

Shibasaki and co-workers used (R)-BINAP as a chiral ligand for the enantioselective Heck cyclization of prochiral vinyl iodide 5.11 to cz5-decalin 5.12. Silver carbonate was used as a base and N-methyl-2-pyrrolidinone (NMP) as a solvent. 

The Heck reaction, first disclosed independently by Mizoroki and Heck in the early 1970s, is the Pd-catalyzed coupling reaction of organohalides (or triflates) with olefins. In recent years, this transformation has become an indispensable tool for organic chemists. Inevitably, many applications to heterocyclic chemistry have been pursued and successfully executed. The greatest utility of the intramolecular Heck reaction was captured in Section 3.2 in this chapter. Intermolecular Heck reactions will be focused on this section. 

Triptans have provided a futile ground for indole synthesis employing both the Heck and the intramolecular Heck reaction. In Glaxo s process synthesis of naratriptan, the reaction of 5-bromoindole with A -methyl-4-piperidone gave the A -methyl-tetrahydropyridinyl substituted indole. The Heck reaction between the 5-bromoindole and the A -methylvinylsulfonamide was carried out on 700-g scales. Both double bonds of the resulting diene were hydrogenated to give naratriptan hydrochloride as white crystals in 71% yield after recrystallization from hot water. 

In another example of intermolecular Heck reaction shown below, 4-bromoindole was coupled with a BOC-protected 7-vinyl-1,2,3,4-tetrahydronaph-thyridine olefin in 63% yield. The resulting alkene was manipulated to a potent otv a antagonist, a vitronectin receptor that has been identified as a promising potential target for the treatment of osteoporosis, diabetic retinopathy, and cancer. 

Three representative examples of intramolecualar Heck reaction are shown below. The first one is the Mori-Ban reaction the second is an intramolecualar Heck reaction taking place on the indole ring and the third one is an intramolecualar heteroaryl Heck reaction connecting two aromatic rings. 

The Mori-Ban reaction has been widely used in drug discovery and development. In the process synthesis of a selective PPARy modulator by Merck, the enamine was cyclized to afford the indole core.  

The Heck reaction is a Pd-catalysed coupling between aryl halides, tosylates or triflates with alkenes and is one of the most important C-C bond-forming reactions. Although in the original version no stereocentres were formed, the 

The Heck reaction is the palladium-catalyzed alkenylation or arylation of olefins.It has become one of the most widely used C-C bond forming tools in organic synthesis. 

In the early 1970s, T. Mizoroki and R. F. Heck independently discovered that aryl, benzyl and styryl halides react with olefinic compounds and elevated temperature in the presence of a hindered amine base and a catalytic amount 

As reports began to appear on the formation of halo(aryl)palladium-phosphine complexes, Heck hypothesized that these intermediates could replace the arylmercurial-palladium combination. Crucially, he also reasoned that the use of a base to quench the hydrogen halide generated would render the reaction catalytic. In the 1970s the use of palladium was considered exotic and the reaction a mere curiosity, which meant its importance was underestimated for decades. In 1982, Heck published a review that contained all known examples in a mere 45 pages. 

The general mechanism for the Heck reaction has been accepted for many years however numerous recent studies have shown the active catalytic species to vary dramatically depending on the ligands, reaction conditions and substrates. 

A Oxidative addition B Migratory insertion (syn) C C-C bond rotatbn 

The Heck reaction is one of the most versahle and useful tools in organic synthesis, and provides a direct route for the synthesis of many important olefins [99]. Normally, the Heck reaction employs a palladium catalyst in the presence of phosphine ligands and a base, under an inert atmosphere. However, as polar aprotic solvents remain the major media for the Heck reaction [100], this has greatly limited the reaction s industrial application. 

In the presence of TBAB and NaHCOj, PdfOAc) catalyzed the Heck arylation of acrylonitrile with a variety of aryl iodides at 80-90 °C in neat water, affording the corresponding (E)-cinnamonitriles in up to 89% yield [140]. The catalysis 

Ar= Ph, o-MeCsH4, o-MeOCeH4, p-MeCeH4, /77-MeCeH4, p-PhCOC0H4, 1-naphthyl X = Br, I 

Assisted by a nonionic amphiphile (PTS, 48), the catalyst 49 is very efficient for the Heck couplings of aryl iodides with styrene in water at room temperature [145]. Using EtjN as a base, in the presence of 15 wt% of PTS and 2 mol% of 49, a series 

Other polymeric catalysts have also been investigated. Examples are seen in the supported oxime-based Hgands 54 [151d] and 55 [151e]. Both are active for the Heck reaction in water. The latter was shown to be efficient for the coupling of heterocychc aryl bromides with tert-butyl acrylate or styrene under thermal or MW heating [15 le]. 

it may be concluded that the Heck reaction, being a base-driven process not involving any species that cannot tolerate the presence of water, is an appealing case to be tried in aqueous modes. However, historically, water has been allowed to enter Heck chemistry only relatively recently. The traditional technique for carrying out the Heck reaction is to use anhydrous polar solvents (DMF and MeCN are the most frequently used) and tertiary amines as bases. 

The role of water in the Heck reaction, as well as in other reactions catalyzed by Pd(0) in the presence of phosphine ligands, can be many-fold. Recent studies confirmed that it may play an important role in the transformation of catalyst precursor into Pd(0) species driving the catalytic cycle. The generation of zero-valent palladium species capable of oxidative addition by oxidation of phosphine ligands by the Pd(ll) catalyst precursor can be strongly affected by the water content in the reaction mixture, as is shown below for the reaction with BINAP ligand (BINAP-0 is BINAP monoxide) [91]  

Taking into account that the palladium catalyst is typically introduced into reaction mixtures in ca. 1 mol% amounts, trace amounts of water in a purportedly anhydrous solvent may play a key role in triggering the catalytic cycle. In this respect it is suspicious that Heck arylations are usually carried out in solvents like DMF or acetonitrile, which are famous for their hygro-scopicity and reluctance to be freed of residual water. 

The decisive evidence that water indeed helps to reduce Pd(ll) to Pd(0) by phosphine was obtained in experiments with O-enriched water. The reaction of PdCU with TPPTS in water gave a formally cationic complex [PdCl(TPPTS)3], and the respective amount of TPPTS oxide containing O that could have come only from the water molecule. 

The reaction of water-soluble acrylic acid with aryl iodides and bromides with both electron-donor and electron-withdrawing substituents can be easily carried out in DMF-H2O or HMPA-H2O mixtures with water content from 10 to 80% (v/v) at 70-100°C in the presence of Pd(OAc)2 as catalyst precursor and K2CO3 as base. The addition of (o-MeC6H4)3P ligand is required for aryl bromides. Some of these reactions can even be carried out in neat water  

Pd2(dba)3 catalyst is preferred over the more congested Pd(PPh3)4. Moreover, some reaction protocols allow for diffusion of the palladium catalyst into the resin prior to addition of other reagents. 

Unsuccessful couplings arose when resin-bound olefin was reacted with aryl triflates (presumably reflecting the lower reactivity observed in solution) and also when resin-bound iodide was reacted with ethyl propionate, where polymerized products were observed. Interestingly, attempts at transesterification as a means to release the products were unsuccessful. The stereochemistry (i.e., cis/trans) of the products was not addressed. 

If the allyl nitrogen were unalkylated, the reaction went in lower yield (60%) than its solution-phase counterpart (80%), and a variety of unidenti- 

Larock.38 The method allows for variation in the aromatic ring component. An interesting feature of this work, probably influenced by the ease of cleavage of the Rink linker, is that all characterization and yield calculations were done off-bead. 

Steric influences were proposed to account for the result shown above, but other observations suggest that it is the phenyl group that is important 

Researchers have described a new catalyst for the Heck reaction [573]. The 1 1 1 Au/Ag/Pd tri-metallic nanoparticles are more efficient than the traditional palladium complex catalysts for the following coupling reaction. 

Using a developed method, laser irradiation of colloidal mixtures of the three metals, these authors dispersed Au/Ag/Pd nanoparticles with average diameters 4.4 1.5 nm. These tri-metallic nanoparticles were assessed for activity in the synthesis of nabumetone [4-(6-methoxy-2-naphthalenyl)-2-butanone], a non-steroidal anti-inflammatory drug that has greater activity than aspirin and is comparable to naproxen and indomethacin. The 0.45-mol% Au/Ag/Pd was sufficient to catalyse the coupling of the 3-buten-2-ol 

Indeed, the observation that Pd black is often formed during Heck reactions led to detailed studies of the active species in many Heck reactions [96]. It was demonstrated that colloidal Pd, Pd that had not yet formed Pd black clusters 

This review is divided into four main sections, covering the Heck, Stille, and Suzuki reactions, with miscellaneous reactions being included at the end. Processes featuring alkynes in copper co-catalyzed Sonogashira-type couplings have been included in the section on Heck reactions. This review does not cover carbon-carbon bond formation processes using immobilized catalysts. Similarly, fluorous-phase syntheses and those on polyethylene glycol are excluded. 

Some special considerations apply when palladium complexes are to be used in solid-phase chemistry. Two obvious concerns are penetration of relatively large palladium complexes into resins and the effects of the resin microenvironment on dissociation of ligands from fully coordinated palladium complexes to give active species. The success of the chemistry reported to date has been an empirical test of these questions, but such factors may explain instances in which, for example, the ligandless 

PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT 

Heck vinylation of aryl halides is one of the most widely used methods for carbon-carbon bond formation. Bhanage et al. described a method for a Heck reaction of iodobenzene in a biphasic system of ethylene glycol/toluene. Several metal-TPPTS complexes were tested [24]. 

The toluene phase contained the reactants and products and the ethylene glycol phase the metal complex and KOAc. The reaction takes place in the ethylene glycol phase and at the interface [Eq. (5)]. In a typical experiment, 0.1 mmol of catalyst was dissolved in 10 mL of ethylene glycol, mixed with a solution of 10 mmol of iodobenzene and 10 mmol of butyl acrylate in 10 mL of toluene. These two phases were then mixed at 140 °C along with 10 mmol KOAc for several hours. Yields of 99% at 100% selectivity were obtained for the trans compound. 

Another biphasic Heck reaction was described by Beller et al. [25]. The medium consisted of xylene and ethylene glycol. The catalyst was a palladium complex with a carbohydrate-substituted triphenylphosphine (9 and 10). Aryl bromide (15 mmol), styrene (22.5 mmol), and NaOAc (16.5 mmol) were suspended in 10 mL of xylene and 10 mL of ethylene glycol. The catalyst precursor (Pd(OAc)2) and ligand (Pd/ ligand ratio 1 3) were added and the mixture was heated to 130 °C for 20 h. Both ligands A and B showed better results than the TPPTS ligand (cf Section 2.2.3.2) in the case of activated aryl bromides (for instance, p-nitrobromobenzene). However, for deactivated aryl bromides (for instance, 2-bromo-6-methoxynaphthalene) TPPTS proved to generate a more stable and thus more productive catalyst system. 

Recent studies show that Ni(0) catalyst is effective for the inter- or intramolecular Heck reaction leading to carbon-carbon bond formation [80]. 

Palladium-catalyzed coupling between organohalides or triflates with olefins. 

Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518. Richard Heck discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular hook, Heck had difficulties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida. 

Palladium Reagents in Organic Synthesis, Academic Press, London, 1985. (Book). 

Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books Mill Valley, CA, pp 103-113. (Book). 

the organic moiety of an aryl or vinyl halide or sulfonate replaces a hydrogen attached to an olefinic sp2-carbon atom. 

The first step in the cycle, analogous to the cross-coupling reactions, is the oxidative addition of an aryl (vinyl) halide or sulfonate onto the low oxidation state metal, usually palladium(O). The second step is the coordination of the olefin followed by its insertion into the palladium-carbon bond (carbopalladation). In most cases palladium is preferentially attached to the sterically less hindered end of the carbon-carbon double bond. The product is released from the palladium in a / -hydrogen elimination and the active form of the catalyst is regenerated by the loss of HX in a reductive elimination step. To facilitate the process an equivalent amount of base is usually added to the reaction mixture. 

As the entry of the aryl halide into the catalytic cycle is analogous to the cross-coupling reactions, the scope and limitations in the choice of this 

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. 

R = aryl, benzyl, vinyl (alkenyl), alkyl (no p hydrogen) R, R , R = alkyl, aryl, alkenyl X = Cl, Br, I, OTf, OTs, N2 ligand = trialkylphosphines, triarylphosphines, chiral phosphines base = 2° or 3° amine, KOAc, NaOAc, NaHCOa 

The mechanism of the Heck reaction is not fully understood and the exact mechanistic pathway appears to vary subtly with changing reaction conditions. The scheme shows a simplified sequence of events beginning with the generation of the active Pd catalyst. The rate-determining step is the oxidative addition of Pd into the C-X bond. To account for various experimental observations, refined and more detailed catalytic cycles passing through anionic, cationic or neutral active species have been proposed.  

Ecteinascidin 743 is a potent antitumor agent that was isolated from a marine tunicate. T. Fukuyama et al. applied the intramolecular Heck reaction as the key step in the assembly of the central bicyclo[3.3.1] ring system.Toward this end, the cyclic enamide precursor was exposed to 5 mol% of palladium catalyst and 20 mol% of a phosphine ligand in refluxing acetonitrile to afford the desired tricyclic intermediate in 83% isolated yield. 

The introduction of the C3 quaternary center was the major challenge during the total synthesis of asperazine by L.E. Overman and co-workers. To address this synthetic problem, a diastereoselective intramolecular Heck reaction was used. The a,(3-unsaturated amide precursor was efficiently coupled with the tethered aryl iodide moiety in the presence of 20 mol% Pd2(dba)3 CHCl3 and one equivalent of (2-furyl)3P ligand. The desired hexacyclic product was obtained as a single diastereomer in 66% yield. 

The total synthesis of the potent anticancer macrocyclic natural product lasiodiplodin was achieved in the laboratory of A. Furstner. The key macrocyclization step was carried out by the alkene metathesis of a styrene derivative, which was prepared in excellent yield via an intermolecular Heck reaction between an aryl triflate and high-pressure ethylene gas. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 121, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 129, Springer International Publishing Switzerland 2014 

5518-5526. Richard Heck discovered the Heck reaction when he was Hercules Corp. Heck won Nobel Prize in 2010 along with Akira Suzuki and Ei-ichi Negishi for palladium-catalyzed cross couplings in organic synthesis . 

R = Ph, 4-MeOPh, 4-(t-Bu)Ph, 4-N02Ph, 4-CIPh, piperonyl, 3,5-F2Ph, 3-pytidyl, Et ArX = Phi, PhBr, 4-N02Phl, 4-MeOPhl, 4-HOPh 

R = Et, 4-NO2PI1, n-hexyl, c-hexyl, 4-MeOPh Ar = 3-N02Ph, p-naphthyl, 2-MeOPh, 

MBH adducts have been employed successfully in various diastereo-/enantio-selective catalytic homogeneous hydrogenation processes by Brown and co-workers, Noyori and co-workers,Sato et and Yamamoto and 

Brown and co-workers have studied the Rh complex 137 catalyzed hydrogenation of a-(hydroxyalkyl)-V-methoxyacrylamides, and Ru complex 138 

Batra et al. have studied the catalytic hydrogenation of MBH adducts obtained from substituted 3-, 4- and 5-isoxazolecarboxaldehydes and their corresponding acetates in the presence of Raney-Ni and Pd-C. The hydrogenation of MBH adducts of substituted 5- and 3-isoxazolecarbaldehydes in the presence of Raney-Ni furnishes diastereoselectively syn enaminones 147 and 149, respectively, over anti, and in the presence of boric acid as an additive 

R = aryl, vinyl or alkyl group without (3-hydrogens on a sp carbon atom X = halide or triflate (OSO2CF3) 

The traditional technique for carrying out the Heck reaction is to use anhydrous polar solvents (eg., DMF and MeCN) and tert. amines as bases. 

It has been found that the Heck reaction can be accomplished under PTC conditions with inorganic carbonates as bases under mild conditions at room temperature. Such conditions can be used in case of substrates, like methyl vinyl ketone, which do not survive the usual conditions of Heck arylation (action of base at high temperature). Subsequently, it has been shown that the Heck reaction can be carried out in water and aqueous organic solvents, catalysed by simple palladium salts in presence of inorganic bases like K2CO3, Na2C03, NaHC03, KOH etc.  

A number of other application of the Heck reaction have been described in literature.  

Beller, M. Zapf, A. Riermeier, T. H. Transition Metals for Organic Synthesis (2nd edn.) 2004,1, 271-305. (Review). 

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Intramolecular reactions with alkenes. While the intermolecular reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and various cyclic compounds are prepared by the intramolecular Heck reaction. Particularly the... 

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Asymmetric Heck reaction of the conjugated diene 184 and subsequent acetate anion capture of the rr-allylpalladium intermediate afforded 185 in 80% ee. which was converted into the key intermediate 186 for the capnelle-... 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

A Heck reactions 1 l-Acetyl-3-bromoindole Methyl acrylate, PdiOAc), Ar,P, EtjN, DMF 50 [1]... 

Use of Qi-acetamidoacrylate esters in the Heck reaction allows for the introduction of a dehydroalanine side-chain. The dehydrotryptophans can be reduced catalytically, and this reduction can be done enantioselectively[17]. 

PaHadium-cataly2ed coupling reactions have important synthetic appHcations (210—212). The prototypical reaction is the Heck reaction (213) whereby an organoPd(II) undergoes coupling with an olefin (eq. 11). 

Pd-catalysts with heterocyclic ligands as catalysts for Heck reaction 98CSR427. 

Asymmetric Heck reaction in synthesis of heterocycles 97T7371. 

Synthesis of heterocycles using the intramolecular Heck reaction involving a formal nnd-elimination process 99H(51)1957. 

Legros et al. (2001T2507) carried out the synthesis of acetylquinolines (e.g. 130) via Heck reaction of 3-bromoquinoline (70) and -butyl vinyl ether (Scheme 16) employing either Pd(dba)2 or Pd(OAc)a as the catalyst. In each case it was found that the Heck reaction for this synthesis gave better overall yields than using the Stille reaction (see Section IV.C). Another advantageous point in favor of the Heck is that it avoids the use of toxic stannane. 

Employing Jefferey s ligandless conditions, Larock and Babu (87TL5291) synthesized quinolines and other nitrogen-containing heterocycles via the intramolcular Heck reaction strategy as exemplified by reaction 144 145. This reaction is similar to the Mori-Ban indole... 

In a six-step synthesis of (5)-camptothecin (20010L4255), the final step involved a C-ring closure using the Heck reaction. As shown in Scheme 17, 2-chloroquinoline 146 was treated with 15% (PPh3)2Pd(OAc)2 and two equivalents KOAc in CH3CN at 100 °C, affording (5)-campotothecin (147) in 64% yield. 

The regioselectivity of the addition of complex 4 to a substituted alkene is mainly influenced by steric factors. The substitution of hydrogen occurs preferentially at the carbon center which has the larger number of hydrogens. The Heck reaction... 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

This reaction also represents an example of the intramolecular Heck reaction, a variant that has gained some importance in recent years. Another instructive example of the potential of this reaction for the construction of ring systems has been reported by de Meijere and coworkers, taking advantage of a sequence of four consecutive intramolecular Heck reactions. The bromodiene-yne 18 reacts in a sequence of domino reactions within 3 d at 80 °C under Heck conditions to give the tetracyclic product 19 in 74% yield ... 

The Heck reaction is considered to be the best method for carbon-carbon bond formation by substitution of an olefinic proton. In general, yields are good to very good. Sterically demanding substituents, however, may reduce the reactivity of the alkene. Polar solvents, such as methanol, acetonitrile, N,N-dimethylformamide or hexamethylphosphoric triamide, are often used. Reaction temperatures range from 50 to 160 °C. There are various other important palladium-catalyzed reactions known where organopalladium complexes are employed however, these reactions must not be confused with the Heck reaction. 

Closely related to the Heck reaction is the Sonogashira reaction i.e. the palladium-catalyzed cross-coupling of a vinyl or aryl halide 20 and a terminal alkyne 21 ... 

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

Palladium-catalyzed carbon-carbon bond forming reactions like the Suzuki reac-tion as well as the Heck reaction and the Stille reaction, have in recent years gained increased importance in synthetic organic chemistry. In case of the Suzuki reaction, an organoboron compound—usually a boronic acid—is reacted with an aryl (or alkenyl, or alkynyl) halide in the presence of a palladium catalyst. 

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