Heck reaction complexes

Phospha-palladacycles are also powerful palladium catalysts for the Mizoroki-Heck reaction. Complexes like 3 (Figure 15.1) were successfully tested in Bu4NBr as solvent for the coupling of styrene (4) and chloroarenes (e.g. 5, X = Cl) in the presence of sodium acetate and [AsPh4]Cl, leading to 96% yield i(E)-6 (Z)-6 7 = 95 1 4) (Scheme 15.2)... 

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. 

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... 

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. 

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 ... 

In pyridinium chloride ionic liquids and in l,2-dimethyl-3-hexylimida2olium chloride ([HMMIMjCl), where the C(2) position is protected by a methyl group, only [PdClJ was observed, whereas in [HMIMjCl, the EXAFS showed the formation of a bis-carbene complex. In the presence of triphenylphosphine, Pd-P coordination was observed in all ionic liquids except where the carbene complex was formed. During the Heck reaction, the formation of palladium was found to be quicker than in the absence of reagents. Overall, the EXAFS showed the presence of small palladium clusters of approximately 1 nm diameter formed in solution. 

The use of imidazolium-based ionic liquids in Pd-catalyzed Heck reactions always carries with it the possibility of in situ formation of Pd-carbene complexes (for more details see Section 5.2.2.3). The formation of these under the conditions of the Heck reaction was confirmed by investigations by Xiao et al. [30], who described a significantly enhanced reactivity of the Heck reaction in [BMIM]Br in relation to the same reaction in [BMIM][Bp4] and explained this difference by the fact that formation of Pd-carbene complexes was observed only in the bromide melt. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

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. 

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 Pd-catalysed Heck reaction performed with thiourea as the Ugand exhibit good activities for some catalysts. As for carbene ligands [104], steric hindrance improves catalytic results. Thus, thioureas wearing bulky substituents afford the formation of air- and moisture-stable Pd complexes [105]. For example, the catalyst obtained with 2mol% Pd(dba)2 and Ar,M -dimesitylene-ethylene thiourea (Scheme 24) was still active even after 2 months in an air atmosphere. 

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). 

Other classes of complexes that have been studied in depth in the Mizoroki-Heck reaction are those having a bidentate ligand containing both a NHC and a phosphine. The development of these structures was encouraged by early theoretical work from Rosch, who calculated that such ligands should be promising catalysts for this... 

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... 

Table 7.2 Chiral NHC-Pd(II) complexes in asymmetric oxidative Heck reaction...

In 2004, Molander et al. developed another type of chiral sulfur-containing ligands for the intermolecular Heck reaction. Thus, their corresponding novel cyclopropane-based phosphorus/sulfur palladium complexes proved to be active as catalysts for the reaction between phenyltriflate and dihydrofuran, providing at high temperature a mixture of the expected product and its iso-merised analogue (Scheme 7.7). The major isomer C was obtained with a maximum enantioseleetivity of 63% ee. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

A novel phosphinito dipeptido ligand series were prepared, and fully characterized. These ligands readily form metal complexes with Pd(H) and Pt(II) precursors. The Pd(II) complexes were investigated for their suitability in asymmetric Heck reaction using 3,4-dihydrofuran as a substrate. 

Pd complexes 9-12 were tested for their catalytic behavior in the asymmetric Heck reaction involving the phenylation of 2,3-dihydrofuran (Scheme 3). The results are summarized in Table 2. The two isomeric products of 2-phenyl-2,5-dihydrofuran are formed with varying yields from 80% to 0%. The obtained ee s are high. Complex 12 is shown to be catalytically inactive. The lack of catalysis in complex 12 is rationalized by differences in the steric requirements between the diphenylphosphinites 1-3 (cone angle >140°) and the more sterically hindered cyclohexyl-phosphinite 4 (cone angle >170°) and the resulting stereochemistry on the Pd center. The ligands in complex 12 adopt a... 

General procedure for the Heck reaction. A mixture of iodobenzene (5 mol equ.), diisopropylethylamine (3 mol equ.), 2,3-dihydrofuran (1 mol eq.), and the complexes 9-12 (3 mol %) in degassed benzene was stirred at 70 °C. The progress of the reaction was monitored by GC. Upon completion, the mixture was filtered through basic alumina (58 mesh, Aldrich) to remove Pd and the products were identified using GCMS. 

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