Mizoroki-Heck mechanism

In this section, only examples of Mizoroki-Heck reactions where a proper addition of the cr -aryl- or a -alkeny Ipalladium(II) complex to a double bond of an alkene or alkyne occurs are considered. As a consequence, an often-met deviation from the classic Mizoroki-Heck mechanism, the so-called cyclopalladation, will not be treated in further detail [12, 18]. However, as it is of some importance, especially in heterocycle formation and mainly because it will be encountered later during polycyclization cases, it shall be mentioned briefly below. Palladacycles are assumed to be intermediates in intramolecular Mizoroki-Heck reactions when j3-elimination of the formed intermediate cannot occur. These are frequently postulated as intermediates during intramolecular aryl-aryl Mizoroki-Heck reactions under dehydrohalogenation (Scheme 6.1). The reactivity of these palladacycles is strongly correlated to their size. Six-membered and larger palladacycles quickly undergo reductive elimination, whereas the five-membered species can, for example, lead to Mizoroki-Heck-type domino or cascade processes [18,19]. 

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... 

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... 

The first report of C-C bond formation by C=C insertion, which we now call Heck olefination, was reported by Mizoroki in Japan in 1971 about a year before Heck s first paper appeared. Some refer to the Heck reaction as the Mizoroki-Heck reaction, but Mizoroki unfortunately died shortly after his original work was published. Since Heck and his co-workers vigorously pursued research on the mechanism and scope of this transformation after 1972, Heck s name is the only one usually attached to the process. T. Mizoroki, K. Mori, and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581 and R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. 

The key intermediate should be a deuterated vinylpalladium species (H) generated via syn addition of D-Pd species (Scheme 9). This vinylpalladium intermediate H is similar in its structure to the Negishi intermediate in the Mizoroki-Heck-type cyclization of 2-iodo-1,6-dienes to six-membered carbo-cycles, which proceeds with olefmic geometry inversion[53-56]. Thus, the plausible mechanism follows a D-Pd syn addition, p-carbon elimination, and P H elimination mechanism effective in controlling olefin inversion via cyclopropane intermediate (E and then I). 

Scheme 1.23. Mechanism of palladium-catalyzed arylation of olefins (Mizoroki-Heck reaction).

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). 

These pioneering studies by Heck have opened the way to a new reaction later called the Mizoroki-Heck reaction (Scheme 1.1). In 1971, Mizoroki et al. reported preliminary results on the PdCh-catalysed arylation of alkenes by iodobenzene in the presence of potassium acetate as base (Scheme 1.5) [4]. No new contribution to the mechanism was proposed, except that palladium particles, formed in situ in the reaction or deliberately added, were suggested to be the active catalyst [4]. 

The mechanisms of Mizoroki-Heck reactions performed from aryl derivatives are presented herein by highlighting how the catalytic precursors, the bases and the ligands may affect the structure and reactivity of intermediate palladium(O) or palladium(II) complexes in one or more steps of the catalytic cycle and, consequently, how they may affect the efficiency and regioselectivity of the catalytic reactions. 

Mechanism of the Mizoroki-Heck Reaction when the Catalytic Precursor is Pd(OAc)2 in the Absence of Ligand... 

Some reagents of Mizoroki-Heck reactions may play the role of reducing agents, such as alkenes proposed by Heck [3b], according to the mechanism depicted in Scheme 1.9 intramolecular nucleophilic attack of acetate onto the alkene coordinated to Pd(OAc>2, followed by a jS-hydride elimination leading to HPdOAc and subsequent formation of Pd(0) in the presence of a base [3b, 11, 12]. 

A mechanism is now proposed for Mizoroki-Heck reactions involving Pd(OAc)2 as precursor associated with PPh3 (Scheme 1.22). From the rate constants of the main steps given in Scheme 1.22, it appears that, for comparable iodobenzene and styrene concentrations, the overall carbopalladation (complexation/insertion of the alkene) from PhPd(OAc)(PPh3)2... 

Scheme 1.22 Mechanism of Mizoroki-Heck reactions with Pd(OAc)2 as precursor associated with PPhs. Rate and equilibrium constants in DMF at 25 °C when ArX = Phi, R = Ph and base =...

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... 

Textbook neutral mechanism for the regioselectivity of Mizoroki-Heck tions (the n . .., , ... 

Scheme 1.29 Textbook ionic mechanism for the regioselectivity of Mizoroki-Heck reactions.

In more recent studies by Xiao and coworkers [40m,n], Mizoroki-Heck reactions catalysed by Pd(OAc)2 associated with dppp and performed from the eleclron-rich alkene ( -butylvinyl ether) and aryl halides (without any halide scavenger, i.e. under the conditions of the textbook neutral mechanism of Scheme 1.27 proposed by Cabri and Candiani [Ig]) give a mixture of branched and linear products in DMF, whereas the branched product is exclusively produced in ionic liquids (in the absence of halide scavengers) in a faster reaction. Whatever the medium, the cationic complex ArPd5(dppp)+ is always the sole reactive complex with electron-rich alkene (Scheme 1.33) [53]. Consequently, the regioselectivity should not vary with the experimental conditions. 

Scheme 1.35 Mechanism which rationalizes the regioselectivity of Mizoroki-Heck reactions in DMF when P P= dppp (the C—C internal rotation in complexes 3+, 3 +, 4 and 4 is omitted for more clarity).

Scheme 1,36 Mechanism of the Mizoroki-Heck reaction when the catalytic precursor is Pd(OAc)2 associated with dppp (i) when X = X = I, R = Ph, 0- -Bu (the formation of HPdS(dppp)+ may be by-passed if the base is strong enough to deprotonate the agostic H in the a-alkyl-PdS(dppp) complexes, see Scheme 1.37) (ii) when acetate is used as base with X = i,X= OAc, R = Ph, 0- -Bu, C02Me.

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