Mizoroki-Heck reaction oxidative addition

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. 

The Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

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... 

Bulky ligands as above have also proved to be effective in other palladium-catalyzed reactions of aryl halides, e.g., amination [16-19], Suzuki-Miyaura reaction [20-22], Mizoroki-Heck reaction [23, 24], Migita-Kosugi-Stille reaction [25], and aryloxylation and alkoxylation [26-28] as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products [29, 30]. The effectiveness of the commercially available simple ligand, P(f-Bu)3, was first described for the amination by Nishiyama et al. [16]. 

Palladium-catalyzed arylation and vinylation of alkene is referred to as the Mizoroki-Heck reaction and is one of the most widely used Pd(0)-catalyzed C-C bond formations in organic synthesis. However, the reaction has not been extensively employed for C-glycosylation [96]. The example shown in O Scheme 67 outlines the reaction of iodopyridine and furanose gly-cal for the synthesis of C-nucleoside [97]. The mechanism began with the oxidative addition of iodopyridine to Pd(0) catalyst, and the resulting organo-palladium species was inserted by... 

Combination of the oxidative addition of aryl halide with olefin insertion followed by -hydrogen elimination provides a useful olefin arylation process catalyzed by a palladium complex (Mizoroki-Heck reaction) [63-65]. The essential part of the catalytic cycle is shown in Scheme 1.23. 

C-0 bond cleavage of aryl triflates or tosylates is also studied in relation to Mizoroki-Heck type reactions [101], Oxidative addition of PhOTf to Pd(PPh3)4 is 10 times slower than that of Phi. Since similar trend is observed for the catalytic Mizoroki-Heck reaction, the oxidative addition of aryl compound is considered to be the rate-determining step in the overall catalytic process. This feature suggests that the C-0 bond cleavage of aryl triflate proceeds by the concerted SNAr mechanism. However, since the triflate normally acts as a non-coordinating anion, thermally unstable cationic arylpalladium(II) complexes are formed in this reaction (Scheme 3.54). 

The catalytic precursor Pd (OAc)2 associated with a monophosphine such as PPhs is more efficient than Pd°(PPh3)4 in Mizoroki-Heck reactions. Two problems arise (i) how an active Pd(0) complex can be generated from Pd (OAc)2 associated with PPhs (ii) why the latter precursor is more efficient than Pd°(PPh3)4, whereas both are supposed to generate the same reactive species Pd°(PPh3)2 in the oxidative addition to aryl halides [17]. 

The oxidative addition is also slower when performed in the presence of an alkene, one of the components of the Mizoroki-Heck reaction. Owing to the reversible complexation of the reactive Pd°(PPh3)2(OAc) by the alkene which generates the nonreactive complex (jj —CH2=CHR)Pd°(PPh3)2(OAc) (R = Ph, C02Me), the concentration of Pd°(PPh3)2(OAc) decreases, making the oxidative addition slower (Scheme 1.16) [34]. 

This is illustrated in the mechanism of the Mizoroki-Heck reaction depicted in Scheme 1.22. Indeed, three main factors contribute to slow down the fast oxidative addition of Phi (i) the anion AcO delivered by the precursor Pd(OAc)2, which stabilizes Pd L2 as the less reactive Pd°L2(OAc) (ii) the base (NEts) which indirectly stabilizes Pd L2(OAc) by preventing its decomposition by protons to the more reactive bent Pd L2 (iii) the alhene by complexation of Pd°L2(OAc) to form the nonreactive ( -CH2=CHR)Pd°L2(OAc). On the other hand, the slow carbopalladation is accelerated by the base and by the acetate ions which generate ArPd(OAc)L2, which in turn is more reactive than the postulated ArPdIL2. The base, the alkene and the acetate ions play, then, the same dual role in Mizoroki-Heck reactions deceleration of the oxidative addition and acceleration of the slow carbopalladation step. Whenever the oxidative addition is fast (e.g. with aryl iodides or activated aryl bromides), this dual effect favours the efficiency of the catalytic reaction by bringing the rate of the oxidative addition closer to the rate of the carbopalladation [Im, 34]. 

The mechanism depicted in Scheme 1.22 is also valid for Mizoroki-Heck reactions performed with aryl triflates, since ArPd(OAc)L2 complexes are formed in the oxidative addition (Scheme 1.17b) [37]. This mechanism is also applicable when the catalytic precursor is not Pd(OAc)2 (e.g. Pd°(dba)2 and PPhs, PdCl2(PPh3)2 or Pd°(PPh3)4 (dba = rra 5,rra 5-dibenzylideneacetone)), but when acetate ions are used as base. AcO is indeed capable of coordinating to Pd°L2 complexes to give Pd°L2(OAc) [29] or react with ArPdIL2 to generate the more reactive ArPd(OAc)L2 [18]. 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

A catalytic cycle is proposed for Mizoroki-Heck reactions involving a P,C-palladacycle precursor based on the fact that a monoligated Pd(0) complex is formed from P,C-palladacycle precursors (see above). The structure of the Pd(0) complex 10 is close to thatof Pd° P(o-Tol)3 generated from Pd° P(o-Tol)3 2 as the minor but active species in oxidative additions of aryl bromides, as reported by Hartwig and Paul [62a]. The oxidative addition gives the dimeric complex [ArPd(/u.-Br) P(c>-Tol)3 ]2 in equilibrium with the former T-shaped complex ArPdBr P(c -Tol)3 prone to react with a nucleophile [62b,c]. Such a mechanism must be vahd for the Pd(0) complexes 10 or 13 generated in situ from the... 

Kinetics data on the oxidative addition are scarce. In 2003, Roland and cowoikers [71] used PdX2(Cb )2 (X = I, Cl) as an efficient precursor for Mizoroki-Heck reactions performed from aryl bromides at moderate temperatures (Scheme 1.45). Since Pd (Cb )2 could not be isolated, its reactivity with aryl halides was followed by cyclic voltammetry, the transient Pd°(Cb )2 being generated in the electrochemical reduction of the precursors PdX2(Cb )2 in DMF (Scheme 1.45). The rate constants k of the oxidative addition of aryl halides to Pd (Cb )2 have been determined (Table 1.3) [71]. 

It appears reasonable to predict that ArPdX(Cb)(PR3) complexes generated in the oxidative addition of ArX to Pd°(Cb)(PRj) would dissociate to ArPdX(Cb), which reacts with the alkene. Such a dissociation of the phosphine must be even easier than the intramolecular dissociation of the phosphine in the bidentate P Cb ligand proposed above. This is probably why mixed complexes Pd°(Cb)(PR3) are more efficient than Pd°(Cb)2 in Mizoroki-Heck reactions performed from aryl bromides [71, 76], even if they are less reactive than Pd°(Cb)2 in the oxidative addition. Indeed, the high stability of the Cb-Pd(II) bond combined with the easy dissociation of the phosphine in ArPdX(Cb)(PR3) favours the complexation/insertion of the alkene. 

Scheme 1.49 Ionic mechanism for Mizoroki-Heck reactions catalysed by a Pd(0) coordinated to one or two C—C saturated or C=C unsaturated fi-heterocyclic monocarbenes (only one way for the coordination of the alkene is presented). The reactive species is PdP(Cb) for a bulky carbene and Prf(Cb)2 for a nonbulky carbene. The aryl-palladium complex formed in the oxidative addition is always ligated by two Cb ligands delivered by the Pd(0) or PdfII) precursor even if Pcf(Cb) is the reactive species.

The efficiency of bulky and electron-rich phosphines in Mizoroki-Heck reactions seems to be due to their ability to generate monophosphine-Pd(O) or -Pd(II) complexes in each step of the catalytic cycle (Scheme 1.55). Steric factors are probably more important than electronic factors. One sees from Fu s studies that the last step of the catalytic cycle in which the Pd(0) complex is regenerated in the presence of a base may be rate determining. The role of this last step has been underestimated for a long time. Provided this step is favoured (e.g. with P-r-Bus as ligand and Cy2NMe as base), the oxidative addition of aryl chlorides would appear to be rate determining. However, Mizoroki-Heck reactions performed from the same aryl chloride with the same Pd(0) catalyst and same base but... 

The Mizoroki-Heck reaction is a subtle and complex reaction which involves a great variety of intermediate palladium complexes. The four main steps proposed by Heck (oxidative addition, alkene insertion, )3-hydride elimination and reductive elimination) have been confirmed. However, they involved a considerable number of different Pd(0) and Pd(Il) intermediates whose structure and reactivity depend on the experimental conditions, namely the catalytic precursor (Pd(0) complexes, Pd(OAc)2, palladacycles), the Ugand (mono- or bis-phosphines, carbenes, bulky monophosphines), the additives (hahdes, acetates), the aryl derivatives (ArX, ArOTf), the alkenes (electron-rich versus electron-deficient ones), which may also be ligands for Pd(0) complexes, and at least the base, which can play a... 

Kinetic data, however, are still missing for most steps which follow the oxidative addition for the precnrsors or ligands recently introduced in Mizoroki-Heck reactions (palladacy-cles, bnlky phosphines and carbenes). 

A common ground that is explicitly or implicitly defended in the majority of studies on Mizoroki-Heck reactions is that the limiting stage for the whole cycle is the oxidative addition step. By this criterion, the most important substrates, aryl halides, are subdivided into very reactive (aryl iodides and electron-deficient aryl bromides), less reactive (all other aryl bromides and electron-deficient aryl chlorides) and very unreactive (all other aryl chlorides). As evident as this classification may seem, it is not based on any solid proof. Indeed, if it were really so important, the oxidative addition step should have been characterized by very strong dependence on substituent effects in these substrates. However, this has not been observed in either Mizoroki-Heck reactions or in any other palladium-catalysed reaction of aryl hahdes. The Hammett reaction constant values p, whenever measured, are rather modest in valne [5]. Such values could hardly have accounted for the well-known enormous distance between the reactivity of, for example, a typical activated substrate 7 and a typical deactivated substrate 8 (Figure 2.1). 

In type 1 and type 2 Mizoroki-Heck reactions, high temperature is required when SRPCs are involved as palladium sources. In type 2 reactions, the need to speed up the oxidative addition step is more important when the palladium catalyst has no particular activating ligands. In this case, a lower rate of oxidative addition would result in the build-up of unsupported palladium(O) with concomitant deactivation. 

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