Oxidative Heck mechanism

There are two typical mechanisms generally applied for palladium-catalyzed C-H alkenylation. First, the oxidative Heck mechanism, initially proposed by Fujiwara and Moritoni [63]. 

Scheme 7.13 Proposed mechanism of the oxidative Heck reaction with as oxidising agent...

Another variant of the Heck reaction which is important in heterocyclic chemistry utilizes five membered heterocycles as olefin equivalent (2.2.)7 It is not clear whether the process, coined as heteroaryl Heck reaction follows the Heck mechanism (i. e. carbopalladation of the aromatic ring followed by //-elimination) or goes via a different route (e.g. electrophilic substitution by the palladium complex or oxidative addition into the C-H bond). Irrespective of these mechanistic uncertainties the reaction is of great synthetic value and is frequently used in the preparation of complex policyclic structures. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

In order to elucidate the mechanism of this reaction, a substrate probe was designed. Diastereomerically pure indole 140 was synthesized and subjected to the aerobic oxidative cyclization (Scheme 9.20). Annulated indole 141 was produced as a single diastereomer. The outcome of this reaction strongly suggested a mechanism involving initial palladation of the indole, followed by alkene insertion and )3-hydride elimination (an intramolecular Fujiwara-Moritani reaction). If the reaction proceeded by alkene activation followed by nucleophilic attack of the indole, then the opposite diastereomer would have been observed. This experiment confirmed that an oxidative Heck reaction pathway was operative in this aerobic indole annulation. 

As in the palladium(II)-catalysed indole annulation, a diastereomerically pure substrate was designed to help elucidate the mechanism of the benzofuran and dihydrobenzo-furan syntheses (Scheme 9.21). When aryl allyl ether 163 was treated with the palladium oxidation catalyst, dihydrobenzofuran 164 was produced as an exclusive di-astereomer in 60% yield. This observation confirmed that an oxidative Heck reaction pathway, featuring arene palladation, alkene insertion and /3-hydride elimination, was operative. 

A review on the developments in Pd-catalysed oxidative Heck reactions of organometallic compounds with alkenes emphasized that organometallic compounds derived from Group HI to Group VI are efficient substrates for the oxidative Heck reaction. The article discussed the mechanisms of several such studies. ... 

The Fujiwara-Moritani reaction enables the coupling of alkenes with arenes under oxidative conditions—also named oxidative Heck reaction (for the mechanism, see Ref [ 29]) Garcia-Rubia et al. used this Pd"-catalyzed oxidative direct C-H alkenylation to produce /rans-stilbene derivatives.As exemplified by their synthesis of pterostilene (Scheme 5-45), a partially methylated resveratrol derivative, a 2-pyridyl sulfinyl group efficiently promotes the Pd"-catalyzed ortho C-H olefination of arenes and can be readily removed or transformed into a thiol group. 

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. 

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... 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

As Scheme 23 illustrates, DMF reacts with POCI3 to form Vilsmeier reagent 158. Aryl-Pd-I species 159, generated by the oxidative addition of iodotoluene 160 to Pd(0) species, reacts with the reagent 158 to yield chloroiminium ion 162 via an adduct 161 through a hetero-Heck-type reaction mechanism, and liberates H-Pd-I species. Finally, the hydrolysis of chloroiminium ion 162 gives amide 163. 

Organopalladium(II) intermediates formed by oxidative addition of sp2 and sp3 organic halides and related compounds to Pd(0) species undergo a variety of synthetically useful reactions (e.g., Heck reaction) (191). For example, Pd complexes catalyze substitutive C—C bond formation between olefins and organic halides by the mechanism shown in Scheme 80 (192). The initially formed organo-Pd(II) intermediate adds across the C—C bond, and subsequent /3-elimination of Pd(II) hydride affords the final product. Other organic compounds that have electronegative... 

Recent development of the Heck reaction has also led to greater understanding of its mechanistic details. The general outlines of the mechanism of the Heck reaction have been appreciated since the 1970s and are discussed in numerous reviews [2,3]. More recently, two distinct pathways, termed the neutral and cationic pathways, have been recognized [2c-g,3,7,8,9]. The neutral pathway is followed for unsaturated halide substrates and is outlined in Scheme 8G. 1 for the Heck cyclization of an aryl halide. Thus, oxidative addition of the aryl halide 1.2 to a (bisphosphine)Pd(O) (1.1) catalyst generates intermediate 1.3. Coordination of... 

As discussed earlier, the generally accepted mechanism for the Heck reaction involves the steps of oxidative addition, coordination of the alkene, migratory insertion, and P-hydride elimination [2,3], With the intramolecular Heck reaction emerging as an important synthetic reaction over the past decade, the individual steps of this mechanism have come under closer scrutiny, and attention is beginning to be directed at determining the identity of the enantioselective step [41],... 

Fig. 16.18. Representative mechanism of the Pd-catalyzed C,C coupling of an organoboron compound. The elementary steps, discussed in the text, are (1) complexation, (2) oxidative addition, (3) transmetalation of the alkenylboron compound to afford an alkenylpalladium compound, (4) reductive elimination, and (5) dissociation of the coupled product from the metal. - Note Regarding the arrangement of the ligands around the metal center of the individual intermediates and the details of the transmetalation the present mechanistic analysis is less complete than the mechanistic analysis of other Pd-catalyzed C,C couplings, namely the Stille coupling (Figure 16.27) or Heck reaction (Figure 16.35, part II), which have been investigated in great detail.

---