Heck reaction alkenyl derivatives

To date, only double Heck reactions have been described, but triple Heck reactions are also possible [39]. Reaction of the alkynyl aryl iodide 6/1-55 with norbor-nene in the presence of Pd(OAc)2, triphenylphosphane and triethylamine as base led to the cyclopropanated norbornene derivate 6/1-59 as a single diastereomer in 40% yield (Scheme 6/1.13). It can be assumed that the alkenyl Pd-species 6/1-56 is first formed stereoselectively, and this undergoes a Heck reaction with norbornene... 

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. 

The palladium catalysed sequential alkylation-alkenylation of 5-iodoquinoline leads to the formation of the quinolooxepin ring system (5.20.), The process, closely related to the Catellani reaction,19 runs through an ort/zo-alkylation - Heck reaction sequence. The preparation of a series of benzoxepines has also been achieved in this manner, starting from such iodobenzene derivatives, where one of the or/7 o-positions was blocked by substitution.20... 

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

The domino Suzuki coupling-Heck reaction sequence involving dihydroaromatic alkenyl-substituted boronic esters (186) with diiodobenzene, bromoiodobenzene, or iodoaniline derivatives yields substituted phenanthrene (187) and phenanthridene derivatives regiospecifically (Scheme 52).218... 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

Likewise, Lautens and coworkers have demonstrated the strength of the concept of sequential alkylation-alkenylation by application to the synthesis of fused aromatic rings. Hence, in the presence of 10% of Pd acetate, 20% of tri-2-furylphosphane, two equivalents of norbornene, and two equivalents of cesium carbonate, bromoenoates and related derivatives, ortho-substituted aryl iodides react in boiling acetonitrile in the sense of a Pd-catalyzed ortho-alkylation-intramolecular Heck reaction to furnish fused aromatic carbocy-cles 47-53 in moderate to excellent yields (Scheme 17) [74]. 

The Murai reaction (Scheme 4), the replacement of an ortho-CH on an aromatic ketone by an alkyl group derived from a substrate olefin, is catalyzed by a variety of Ru complexes. This C bond formation occurs via chelate directed C-H bond activation (cyclometalation) in the first step, followed by alkene insertion into RuH and reductive elimination of the alkylated ketone. In a recent example of the use of a related cyclometalation in complex organic synthesis, Samos reports catalytic arylation (Suzuki reaction) and alkenylation (Heck reaction) of alkyl segments of a synthetic intermediate mediated by Pd(II). 

The Pd(0)-catalyzed reactions of propargylic compounds so far discovered can be classified into four types, I, II, III, and TV, from a mechanistic viewpoint. The allenyl intermediate complex 8 undergoes three types of transformation, depending on reactants. The reactions of Type I proceed by insertion of unsaturated bonds into the a-bond between palladium and sp carbon in 8. This a-bond has a reactivity similar to the a-bond formed by the oxidative addition of alkenyl halides to Pd(0) in the Heck reaction [3]. Therefore, reactions similar to those observed in the Heck reaction are expected to occur witli the intermediate 8. Alkenes and carbon monoxide are known to insert into the palladium-carbon a-bond. The allene derivatives 9 are formed by these reactions (Scheme 11.3). 

In 1999, Ravina and co-workers described the first example of an intermolecular Heck reaction on a pyridazine derivative [73]. Heating 5-bromo-2-methoxymethyl-6-phenylpyridazin-3(2//)-one (172) with styrene at 120°C for two days in a pressure tube, using Pd(OAc)2/PPh3 as the precatalyst and triethylamine as the base in acetonitrile, yielded 2-methoxymethyl-6-phenyl-5-(2-phenylvinyl)pyridazin-3(2//)-one in moderate yield (40%). Later, the same research group published more examples of Heck alkenylations on the same substrate with alkyl acrylates and acrylonitrile [93]. The catalyst and base were the same, but acetonitrile was replaced by DMF as the solvent. N-l protection of the pyridazin-3(2//)-one was essential for the alkenylation to occur since no formation of the desired reaction product could be observed on 5-bromo-6-phenylpyridazin-3(2//)-one (6) itself. Instead, Michael addition of the N-2 nitrogen on the alkyl acrylates and acrylonitrile occurred. Besides this... 

In the last decade significant progress has been made towards the development of new catalysts for palladium chemistry [167, 168]. Since the properties of the central metal palladium can be tuned by ligand variation, the introduction of new ligands was the key to success. The refinement of economically attractive aryl-X compounds is of general interest in fine chemical synthesis. As an example, the alkenylation of aryl-X derivatives (Heck reaction) [15, 16, 24, 105, 106, 169, 170, 171-182] has been called one of the true powerful tools of contemporary organic synthesis [18]. 

The reaction between aryl or alkenyl halides or arenediazonium salts and al-kenes catalyzed by palladium complexes, the so-called Heck reaction, has been performed in aqueous media. Arylation of styrene or acryHc acid derivatives occurred in high yields in the presence of a free-ligand palladium complex as catalyst and a base (Na2C03 or K2CO3) [96-98] and, eventually, a quaternary ammonium salt [Eq. (14)] [99,100]. 

Alkenyl iodides. Alkenylboronates derived from Heck reaction of the parent vinylboronate are a source of iodoalkenes. Both (Zj- and ( )-isomers are accessible. 

Similar to mercuration, Pd(OAc)2 undergoes facile palladation of aromatic com-povmds. The palladation product 162 is an unstable intermediate. It can be isolated only when stabilized by chelation. The palladation products of aromatics as reactive intermediates undergo three reactions. The reaction with alkenes to afford styrene derivatives 164 is the first one. Pd(II)-promoted alkenylation of aromatic compovmds, discovered by Fujiwara, is a stoichiometric Heck reaction. The second one is homocoupling to form biaryls. The acetoxylation of aromatic rings is the third reaction. These latter two reactions are treated in Chapter 2.7. 

D.i.b. Insertion of Another Alkenyl Unit In certain cases, however, the 3-exo-trig process may be retarded and an additional alkene moiety participates in the cascade carbopalladation. A pioneering example of this kind has been demonstrated by Overman and co-workers in their total synthesis of scopadulcic acid A, starting from an iodoaUcenyl-substituted methylenecycloheptene derivative (Scheme 24). The first intramolecular carbopalladation occurs across the disubstituted double bond of the exomethylene group, and the trisubstituted endocyclic double bond acts as the terminator to give a tricyclic system, which was further elaborated to the natural product (Scheme 24). It is remarkable that all three quaternary carbon centers can be created by intramolecular Heck reactions. 

Soon after, Cui, Wu, and co-workers reported a highly efficient oxidative Heck reaction for the synthesis of planar chiral ferrocene derivatives (Scheme 5.10). By employing a similar catalytic system, all kinds of 2-alkenylated ferrocene derivatives were easily accessed via Pd/MPAA catalyzed asymmetric C—H bond functionalization. It was suggested that the Pd° species was oxidized to Pd at the end of the catalytic cycle by Ai,Ai-dime-thylaminomethylferrocenium which is generated from Ai,Ai-dimethylamino-methyl-ferrocene oxidized by air. 

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