Mizoroki-Heck reaction generation

By the reaction of a,-unsaturated carbonyl compounds with the dibromide 55, cyclization occurs by a-arylation, followed by intramolecular Mizoroki-Heck reaction. For example, reaction of verbenone (61) with 55 using PPh3 generates 62 by y-arylation of 61, and subsequent intramolecular Mizoroki-Heck reaction affords the indane 63. The benzocyclobutane 67 was obtained unexpectedly... 

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]. 

Instead, Pd° P(o-Tol)3 2 (9) is formed upon fast protonation of 7 followed by reductive elimination from complex 8 (Scheme 1.38) [28], Therefore, in DMF, the palladacycle 5 is reduced to a Pd° complex at a rather high negative potential that could be reached by zinc powder (Scheme 1.38). Such a strong reducing agent is, however, never present in Mizoroki-Heck reactions. No oxidation peak was detected when the cyclic voltammetry of 5 was performed directly towards oxidation potentials, establishing that a Pd(0) complex is not generated spontaneously from the palladacycle 5 in DMF at 25 °C. 

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... 

PdX2(Cb)2 (X = halide, acetate) precursors may be formed from a Pd(II) salt (e.g. Pd(OAc)2) and A-heterocyclic azolium salts which are deprotonated into the NHC ligand [Ip, 64, 66a—c]. They are also generated in situ when iV-heterocyclic azolium salts are used as ionic liquid solvents [66d,e]. Isolated stable NHC-ligated Pd(0) complexes [67] are also used as catalysts in Mizoroki-Heck reactions [68]. 

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]. 

DFT calculations by Rosch and cowoikers [74] showed that for PhPdCl(P Cb) complexes, where the bidentate hgand P Cb is a monophosphine Unked to an NHC, the reaction with an alkene proceeds via dissociation of the more labile phosphine that is, via a neutral Cb-linked ArPdX complex (Scheme 1.48). Later on, bidentate P Cb ligands generated in situ from phosphine-imidazohum salts proved to be efficient in Mizoroki-Heck reactions employing aryl bromides - even deactivated ones, as pioneered by Nolan and coworkers [Iq, 75]. Interestingly, the DFT calculations have paved the way to fhiitful experiments. 

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. 

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 room-temperature Mizoroki-Heck reaction can be extended to activated aryl bromides using electrochemically generated palladium(O) at high catalyst loading (30 mol%) [71]. 

As early as 1997, Antonietti and coworkers [167] showed that palladium nanoparticles supported by polystyrene-polyvinylpyrrolidone block copolymer effect the Mizoroki-Heck reaction while retaining a monodisperse size distribution throughout. Very recently, a similar effect was demonstrated for A-vinylimidazole-A-vinylcaprolactam copolymer, in the presence of which a monodisperse palladium sol was generated directly in the reacting system [168]. 

Vickers and Keay [58] generated a stereogenic quaternary centre through intramolecular Mizoroki-Heck reaction in excellent yield. However, they obtained a 1 1 mixture of the two possible regioisomers (Scheme 6.13). 

Substrates of substructure C (Figure 6.3) have been used to prepare O-heterocycles as well. A recent survey studies the microwave-accelerated generation of conformationally restricted spiro[cyclohexane-l,r-isobenzofuran] derivatives via 5-cro-cyclization of the corresponding cyclohexenyl o-iodobenzyl ethers (Scheme 6.24) [21,72]. The double-bond position in the hexacycles could be controlled by thoughtful choice of starting material and reactions conditions. This study also constitutes one of the rare examples of electron-rich alkenes used in Mizoroki-Heck reactions [21,72]. 

Jeffery has reported an alternative additive-based solution to yield Hy-abstracted products. Mizoroki-Heck reaction of allylic alcohols with aryl or alkenyl hahdes in the presence of silver salts (AgOAc or Ag2C03) results in selective Hy -abstraction [7]. Similar hydroxy-coordination to the cationic organopalladium intermediates are believed to be involved in this system. In this regard, the use of hypervalent iodonium salts is also effective for generating cationic palladium species [8]. 

Another attractive three-component procedure involves the versatile triazene linker T1 and generates spirooctene 30 from a Mizoroki-Heck reaction of immobilized iodoarene 29 with bicyclopropylidene in the presence of an acrylate derivative (Scheme 14.9) [27, 28], The triazene moiety can be cleaved to diazonium salts which, in turn, act as substrates for Mizoroki-Heck reactions with various alkenes to give spirooctenes 31. The latter can be obtained without the double bond in the coupled alkene if palladium on charcoal is used instead of palladium acetate, hi this case, the same catalyst promotes the Mizoroki-Heck reaction and the subsequent hydrogenation [28]. 

It is not necessary to use preformed and isolated palladium carbene complexes they can also be generated in situ [31]. When Pd(OAc)2 is dissolved in the presence of a base in [BMIm]Br, styrene was efficiently coupled with iodobenzene affording stilbene (complete conversion and 99% selectivity). The authors were able to isolate the thus-formed palladium carbene complex, derived from the ionic liquid solvent. The counter ion of the ionic liquid also plays an important role. Mizoroki-Heck reactions proceeded much faster in [BMIm]Br than in [BMIm]BF4. In the latter, precipitation of palladium black was encountered. The fact is explained by the necessity of the presence of a halide ion for the stabilization of the carbene-palladium complex [32]. 

Gedanken and coworkers [194] exploited power ultrasound to generate in situ amorphous-carbon-activated palladium metallic clusters that proved to be a catalyst for Mizoroki-Heck reactions (without phosphine ligands) of bromobenzene and styrene (yield to an appreciable extent of 30%). The catalyst is stable in most organic solvents, without showing any palladium powder segregation, even after heating them to 400 °C. 

In the Mizoroki-Heck reaction, the catalysis begins with the oxidative addihon of a C(sp )—X bond to a palladium(O) complex to give a C(sp )—Pd(II) complex common to almost all palladium(O)-catalyzed cross-coupling reachons (cf. Section 7.2.1). There are, however, alternative ways to generate the central o-aryl palladium(II) intermediate and to effect a Mizoroki-Heck-type process (Scheme 7.42). 

---