Heck reaction aryl chlorides

Palladium(II) complexes provide convenient access into this class of catalysts. Some examples of complexes which have been found to be successful catalysts are shown in Scheme 11. They were able to get reasonable turnover numbers in the Heck reaction of aryl bromides and even aryl chlorides [22,190-195]. Mechanistic studies concentrated on the Heck reaction [195] or separated steps like the oxidative addition and reductive elimination [196-199]. Computational studies by DFT calculations indicated that the mechanism for NHC complexes is most likely the same as that for phosphine ligands [169], but also in this case there is a need for more data before a definitive answer can be given on the mechanism. 

HECK REACTIONS OF ARYL CHLORIDES CATALYZED BY PALLADIUM/TRI-tert-BUTYLPHOSPHINE (E)-2-METHYL-3-PHENYLACRYLIC ACID BUTYL ESTER AND (E)-4-(2-PHENYLETHENYL)BENZONITRILE... 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

Regarding bis-NHC chelating ligands, several structures that differ in the motifs used for the enlargement of the tether have been proposed as catalysts for the Mizoroki-Heck reaction. They range from non-functionalised aliphatic chains [23-25] to phenyl [26], biphenyl [27], binaphthyls [28] and to chains containing additional coordination positions like ethers [29], amines [30], and pyridines in an evolution towards pincer complexes [31-35], In most cases, the activity of aryl bromides in Mizoroki-Heck transformations was demonstrated to be from moderate to high, while the activation of chlorides was non-existent or poor (Scheme 6.7). 

As mentioned in the discussion of the reaction mechanism for this transformation, the active species is a dicoordinate Pd(0) complex, and it is unclear whether an associative or a dissociative process is operative for oxidative addition. In this context, different NHC complexes containing only one carbene ligand have been tested in the Mizoroki-Heck reaction. The most successful are those prepared by Beller, which were able to perform the Mizoroki-Heck reaction of non-activated aryl chlorides with moderate to good yields in ionic liquids (Scheme 6.13). The same compounds have also been applied to the Mizoroki-Heck reaction of aryldiazonium... 

Scheme 6.13 Mizoroki-Heck reaction of non-activated aryl chlorides and diazo compounds using Seller s catalytic systems...

Aryl chlorides are not very reactive under normal Heck reaction conditions but reaction can be achieved by inclusion of tetraphenylphosphonium salts with Pd(OAc)2 or PdCl2 as the catalysts.138... 

A study of the a-arylation of diazine mono iV-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very substantial improvement in yield <06AG(I)7781>. 

Scheme 6.2 Heck reactions of aryl chlorides involving air-stable phosphonium salts as ligand precursors.

Normally, the oxidative addition of an aryl chloride to Pd(0) is reluctant to take place. But such a process is greatly accelerated in the presence of sterically hindered, electron-rich phosphine ligands [e.g., P(/-Bu)3 or tricyclohexylphosphine]. In late 1990s, Reetz [76] and Fu [77] successfully conducted intermolecular Heck reactions using arylchlorides as substrates, as exemplified by the conversion of p-chloroanisole to adduct 77 [77], The applications of this discovery will surely be reflected on future Heck reactions of non-activated heteroaryl chlorides. 

While the sequence of steps for the Heck reaction remains the same for many catalysts, the kinetics may vary enormously and also the detailed composition of all intermediates may vary in the type and number of ligands. It had often been assumed that the oxidative addition is the slowest step and that may well be true for many systems based on PPh3 definitely for aryl chlorides it seems to be the rule. 

Because of their convenient preparation from palladium(II) salts and stable NHC-precursors (vide supra), paUadium(ll) complexes were first examined as potential catalysts for Heck-type reactions. Due to the high thermal stability, temperatures up to 150°C can be used to activate even less reactive substrates, like, e.g., aryl chlorides. Inunobilization of such catalysts has been shown recently (vide infra) ... 

In the Mizoroki-Heck reaction aryl bromides and activated aryl chlorides could be employed with moderate turnovers. This holds true for both the complexes of monodentate such as 60 as well as the complexes of chelating ones... 

The choice of an ionic liquid was shown to be critical in experiments with [NBuJBr (TBAB, m.p. 110°C) as a catalyst carrier to isolate a cyclometallated complex homogeneous catalyst, tra .s-di(ri-acetato)-bis[o-(di-o-tolylphosphino) benzyl] dipalladium (II) (Scheme 26), which was used for the Heck reaction of styrene with aryl bromides and electron-deficient aryl chlorides. The [NBu4]Br displayed excellent stability for the reaction. The recycling of 1 mol% of palladium in [NBu4]Br after the reaction of bromobenzene with styrene was achieved by distillation of the reactants and products from the solvent and catalyst in vacuo. Sodium bromide, a stoichiometric salt byproduct, was left in the solvent-catalyst system. High catalytic activity was maintained even after the formation of visible palladium black after a fourth run and after the catalyst phase had turned more viscous after the sixth run. The decomposition of the catalyst and the formation of palladium... 

A number of modified reaction conditions have been developed. One involves addition of silver salts, which activate the halide toward displacement.94 Use of sodium bicarbonate or sodium carbonate in the presence of a phase-transfer catalyst permits especially mild conditions to be used for many systems.95 Tetraalkylammonium salts often accelerate reaction.96 Solid-phase catalysts in which the palladium is complexed by polymer-bound phosphine groups have also been developed.97 Aryl chlorides are not very reactive under normal Heck reaction conditions, but reaction can be achieved by inclusion of triphenylphosphonium salts with Pd(OAc)2 or PdCl2 as the catalyst.98... 

The use of the heteroaryl Heck reactions extends beyond fine chemicals synthesis. Polythiophenes were prepared starting from 3-octyl-2-iodotiophene by heating in the presence of palladium acetate and tetrabutylammonium chloride (6.91.),122 The arylation of benzothiophene has also been achieved under the same conditions.123... 

The brownish-colored solid is air sensitive and should be handled and stored under inert gas atmospheres. Solutions are very air sensitive with precipitation of colloidal palladium. The 31P NMR (109.3 MHz, D20, 5°C) exhibits a singlet at <522.6 ppm. The IR displays the characteristic SO-vibrations at 1225 (sh, vst), 1200 (vst), 1039 (vst), and 622 (vst) cm-1. The compound has been intensively utilized for carbonylation of benzylic chlorides,26 aryl bromides,27 and 5-hydroxymethylfurfural,28 Heck-reactions,29 allylic substitution reactions,30 and oxidations.16... 

Scheme 2 shows a similar mechanistic pathway for a Heck reaction taking place on a Pd octahedral comer. This mechanism is based on that established for soluble Pd catalysts (ref. 5). Adsorption of the aryl halide (or aryl acid chloride after decarbonylation) gives the aryl Pd halide, 15, by way of the adsorbed intermediate, 14. Vinyl ether adsorption, as in 16, takes place as described in Scheme 1. Aryl insertion gives the halometalalkyl, 17, which on f) elimination to the available 4dxy orbital gives the aryl enol ether, 2 (or 1 depending on which hydrogen is eliminated in 17). The resulting halo palladium hydride, 18, then reacts with the tertiary amine to give the amine hydrochloride and regenerates the octahedral comer for further reaction.

Mukhopadhyay, S., Rothenberg, G., (oshi, A., Baidossi, M. and Sasson, Y. (2002) Heterogeneous palladium-catalyzed Heck reaction of aryl chlorides and styrene in water under mild conditions. Adv. Synth. Gated., 344, 348. 

Littke, A. F. Fu, G. C. A versatile catalyst for Heck reactions of aryl chlorides and aryl bromides under mild conditions./. Am. Chem. Soc. 2001, 123, 6989-7000. 

Because aryl phosphines are not only costly but can also act as aryl sources themselves, giving rise to unwanted byproducts, there has been steady interest in extending ligand-free Heck reactions to aryl bromides and aryl chlorides. Reetz and de Vries recently found that these can be performed with high efficiency using stabilized colloidal Pd catalysts [21]. If the palladium is kept at a low concentration between 0.01 and 0.1 mol%, precipitation of the Pd(0) is avoided and the colloids serve as a reservoir for the catalytically active species (Scheme 5). This economically attractive method has been successfully applied on an industrial scale by DSM [22]. 

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