Aromatic and Vinylic halides

The results obtained with both aromatic bromides or iodides are usually fairly good when using palladium catalysts under mild conditions (Table II) chlorides do not react unless specially activated. 

Aromatic hahdes can be replaced by acid chlorides, thus enabling the so-called Rosenmund reaction [9]  

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Oxidative addition occurs readily with allylic halides. Donor ligands (tertiary phosphines, bipyridyl, halide ions) and anionic complexes are required for activation of aromatic and vinyl halides (4, 70). Certain aliphatic halides are also reactive. The intermediate species R—Ni—X... 

The radicals generated from esters of halogenodifluoroacetic acid or halogenodi-fluorophosphonic acid add onto olefins and enolates. When these reactions are intramolecular, they afford tetrahydrofurans. In the presence of copper dust, ethyl bromodifluoroacetate can couple with aromatic and vinyl halides or can add onto Michael acceptors (Figure 2.13). ... 

Palladium-Catalyzed Carboalkylations of Allylic, Aromatic, and Vinylic Halides... 

Free-radical-mediated four-component coupling reactions are rare. However, when an allyltin-mediated radical carbonylation is conducted in the presence of electron-deficient alkenes, four-component coupling reactions take place efficiently to give good yields of p-functionalized <5,fi-unsaturated ketones [40]. The wide scope of this four-component coupling reaction is noteworthy Primary, secondary, and tertiary alkyl bromides and iodides can be used as well as aromatic and vinylic halides. A variety of electron-deficient alkenes, such as methyl vinyl ketone, ethyl acrylate, acrolein, acrylonitrile, and vinyl sulfone, can be used as the acyl radical trap (Scheme 6.23). Fluorous allyltin compounds can also be used in four-component coupling reactions [41]. 

Catalytic nucleophilic substitution reactions comprise some of the most commonly used catalytic processes in S)mthetic organic chemistry. Substitutions at aromatic and vinylic halides and sulfonates, sho vn generically in Equation 19.1, are commonplace in the preparation of pharmaceutical candidates, have often been used in the s)mtheses of natural products, and have been used many times in the syntheses of sophisticated conjugated organic materials. These metal-catalyzed reactions are typically called cross-coupling reactions. ... 

Cross-coupling reactions of aromatic or vinylic halides and olefins catalyzed by palladium. 

Despite its utility, the Friedel-Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (atyl) halides and vinylic halides do not react because aryl and vinylic carbocations are too high in energy to form under Friedel-Crafts conditions. 

The reaction is highly catalytic in most instances and yields of substituted olefinic products are generally good to excellent at 100° or less. As in the related carbonylation reactions only aromatic, benzylic, and vinylic halides are useful in the reaction. Typical examples are shown in Table VIII. 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

Among the halides that react through this process are unactivated aromatic and heteroaromatic halides, vinyl halides, activated alkyl halides [nitroalkyl, nitroallyl, nitro-benzyl and other benzylic halides substituted with electron-withdrawing groups (EWG) as well as the heterocyclic analogues of these benzylic systems] and non-activated alkyl halides that have proved to be unreactive or poorly reactive towards polar mechanisms (bicycloalkyl, neopentyl and cycloalkyl halides and perfluoroalkyl iodides). 

In this review we will present the distinctive features of the proposed mechanism as well as main experimental and theoretical evidence for it. The reaction of organic halides will be further discussed according to the following sequence mechanistic features of the S l reaction in Section II, alkyl halides with electron-withdrawing groups in Section III, alkyl halides without electron-withdrawing groups in Section IV, aromatic halides in Section V and vinyl halides in Section VI. 

The introduction of a halogen atom into the nucleus of an unsaturated heterocycle serves at once as a valuable synthetic route to heterocyclic derivatives and as a revealing probe of substitution processes at unsaturated carbon.1 From a synthetic standpoint, aromatic and heterocyclic halides have become more attractive starting materials in recent years. Traditionally considered to be rather unreactive, these vinylic halides had been found suitable only in certain reactions... 

A listing of alkyne-nucleophile systems whose substitution kinetics have been studied is given in Table 24 for each of these systems. Rate constants and enthalpies and entropies of activation, if available, are tabulated. In order to compare the reactivity of haloalkynes with other organic halides we have also included in Table 24 related rate data for vinylic, aromatic and alkyl halides. 

In contrast, nucleophilic attack at an sp -carbon center with anionic 18-electron species like [Co(CO)4] and [Fe(CO)4] usually fails to activate aromatic or vinylic halides. Thus, catalytic carbonylations of aryl halides are initiated by oxidative addition of a C-X bond to an electronically unsaturated metal complex, normally a palladium [7], cobalt [8] or nickel complex [9]. The rate of this oxidative addition decreases along the sequence... 

Although aryl and vinyl halides have found vast applications in Heck coupling, aromatic diazonium salts, particularly the isolable tetrafluoroborates, proved successful in the work of Kikukawa et al. [23 a, b] and a one-pot reaction with the C-C-coupling step [23 c-e]. Extensions of this tandem diazotation Heck reaction technique were reported by Beller et al. (eq. (5)) [23 f], including heterogeneous Pd/carbon catalysts [23 g]. 

The mechanism of these reductions is a bimolecular nucleophilic substitution for the reaction of LAH with most primary and secondary halides [BK5, PCI]. A single-electron transfer (SET) has been proposed in the reduction of sterically hindered primary iodides [AD3, AGl, AWl], although some doubts have been cast [PCI] on this mechanism with bromocyclopropanes [HW2] and aromatic or vinyl halides [Cl], especially in the presence of CeClj [G02]. In this case, some rearrangements may be observed. SET does take place in the reduction of geminal dihalides by LAH [AIM] as well as in the reduction of bromocyclopropanes in the strict absence of molecular oxygen [PNl]. In the presence of oxygen, the C—Br bond of 2,2-diphenyl-l-bromocyclopropanecarboxylic acid is left unchanged [PN1 ]. 

The order of reactivity of organic halides is I > Br > Cl > F. Although organic iodides are the most reactive, they produce more Wurtz coupling products through the radical oxidative addition process. Thus, it is usually advisable to use the chlorides or bromides, except in the case of aromatic iodides and methyl iodide. 1-Alkenyl Grignard compounds are obtained by the direct reaction of magnesium and vinylic halides in THF [6], but the reaction is not completely stereospecific and the retention of the stereochemistry of haloalkenes varies from 60-90% [7]. The difficulty associated... 

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