Cationic pathways, Heck reaction

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... 

Extensive studies by Amatore, Jutand, and co-workers have shed light on the structure and oxidative addition chemistry of a number of synthetically important palladium complexes [42], In particular, these workers have shown that the major species in a solution of Pd(dba)2 and BINAP is Pd(dba)BINAP and that oxidative addition of Phi to this complex generates (Bl-NAP)Pd(Ph)I [42d,43], In addition, it has been demonstrated that palladium halide complexes such as (PhjP jaryljPdCl do not dissociate the halide ligand in DMF solution [44], whereas the corresponding triflate complex is completely dissociated [44,45], As noted earlier, the nature of the oxidative addition intermediates defines two mechanistic pathways for the Heck reaction the neutral pathway for unsaturated halide substrates and the cationic pathway for unsaturated triflate substrates [2c-g,3,7-9]. Further, it is possible for halide substrates to be diverted to the cationic pathway by addition of Ag(I) orTh(I) salts [3], and it is possible to divert some triflate substrates to the neutral pathway by addition of halide additives [38]. Individual steps of these two pathways have recently received some scrutiny. 

The first detailed study of the individual steps of the cationic pathway of the intramolecular Heck reaction was recently described by Brown (Scheme 8G.21) [46], Oxidative addition of aryl iodide 21.1 to [l,l -bis(diphenylphosphino)ferrocene](cyclooctatetraene)palladium generated 21,2. Complex 21.2 was stable at room temperature and was characterized by X-ray crystallography no interaction between the palladium center and the tethered alkene was observed in this intermediate. Treatment of 21.2 with AgOTf at -78°C removed iodide from the palladium coordination sphere, which facilitated a rapid alkene coordination and subsequent... 

A key feature of the cationic mechanism is that removal (or dissociation) of an anionic ligand from the palladium coordination sphere allows alkene complexation to occur while maintaining coordination of both phosphines of a bisphosphine ligand. That both phosphines can be accommodated in a square-planar four-coordinate intermediate during the insertion step has provided a simple rationalization for the higher enantioselectivities often observed for the cationic pathway. Concrete information on the enantioselective step of asymmetric Heck reactions proceeding by the cationic pathway has not been reported to date. It is likely to be either coordination of the alkene to generate 20.S or the insertion step (20.5 —> 20.6, Scheme 8G.20). 

The neutral pathway differs from the cationic pathway in the absence of a vacant coordination site in the square-planar four-coordinate palladium(II) intermediate prior to alkene coordination. The key question is then how does alkene coordination take place. Early studies pointed out that Heck reactions of aryl or vinyl halides promoted by (bisphosphine)palladium complexes could be sluggish, and this sluggishness was attributed to a reluctance of one of the phosphines of the... 

To account for the differences in reactivity and enantioselectivity observed in Heck reactions of unsaturated triflates and halides, two distinct mechanistic pathways have been proposed (as shown in the margin). The "cationic" pathway is generally invoked to describe asymmetric Heck reactions of unsaturated triflates or halides in the presence of Ag(I) or T1(I) additives. In the absence of such additives the Heck reaction is expected to proceed through a "neutral" reaction pathway. The modest enantioselectivity often observed in Heck reactions of this type has been attributed to the formation of a neutral palladium-alkene complex by partial ligand dissociation. ... 

Scheme 6-2 Mechanism of Heck substitution reactions proceeding via the cationic pathway. ...

Silver and tliallium salts have been widely employed with halide substrates, either to increase the rate of a Heck reaction [84], to minimize double-bond isomerization in the product [75], or to modify regioselectivity or enantioselectivity [Ig]. These additives divert the Heck reaction to a pathway involving cationic palladium(II) intermediates. It is also possible to divert the Heck reaction of a triflate precursor from the cationic pathway to the neutral pathway (see Scheme 6-1) by the addition of halide salts. In one, possibly exceptional, case studied in our laboratoiy, the addition of halide salts dramatically improves enantioselectivity [65]. 

The mechanism of the Heck reaction is not fully understood and the exact mechanistic pathway appears to vary subtly with changing reaction conditions. The scheme shows a simplified sequence of events beginning with the generation of the active Pd catalyst. The rate-determining step is the oxidative addition of Pd into the C-X bond. To account for various experimental observations, refined and more detailed catalytic cycles passing through anionic, cationic or neutral active species have been proposed. ... 

The key step in the catalytic cycle with regard to enantioselectivity is clearly B), association of the alkene 2 and insertion of it into the Pd-R bond. As with the Heck reaction itself, the mechanism for this process remains a matter for conjecture, with the overall rationale currently in favor having been proposed in 1991 by Ozawa and Hayashi [18] and independently by Cabri [19] (although the cationic pathway via 8 and 9 had been proposed as early as 1990 [20]). Its development and subsequent evolution has recently been reviewed by the latter author [ 12]. 

In reactions that proceed via the cationic manifold (164 - 165 v 166 -> 167 - 168) the alkene can bind to the metal and undergo Heck reaction while both phosphines remain bound to palladium. In most cases, reactions that proceed via the cationic pathway provide better enantioselectivity, presumably because the ligand maintains two points of contact to the metal during the entire carbon-carbon bond-formation process. 

Research into the mechanism of the Heck reaction continues and the understanding of the reaction is increasing. Recent research has revealed that in some intramolecular cases another mechanism is observed. Cationic intermediate 68 can be accessed by associative displacement via the pentacoordinate intermediate 70, leading to high enantioselectivity from a reaction that might be thought to proceed via a neutral pathway. Other studies have also identified key roles for pentacoordinate intermediates as well as anionic complexes.f ... 

Scheme 11.5 Cationic versus neutral pathway for the asymmetric intermolecular Mizoroki-Heck reaction.

To rationalize the enantioselective intramolecular Mizoroki-Heck reaction, other mechanistic pathways have been invoked, including the cationic pathway and nenlial pentacoor-dinate intermediates. The different pathways explain the influences that substrate, Ugands and additives have upon selectivity. As with many catalytic asymmetric systems, optimization of enantioselectivity is achieved through a combination of experimentation and the application of mechanistic knowledge. 

For alkenyl and aryl halides, a neutral mechanistic manifold has been invoked in which one arm of the phosphine ligand must dissociate (13- 17) to create a vacant site on palladium for alkene coordination (17- 18) [6,11]. The lower enantioselectivities observed for Mizoroki-Heck reactions occurring via the neutral pathway have been attributed to this ligand dissociation. To achieve higher enantioselectivities, the reaction of alkenyl and aryl halides may be directed into the cationic manifold by the addition of the silver or thallium... 

Much of the recent hteiature on the mechanism of the enantioselective intramolecular Mizoroki-Heck reaction has focused on the anionic mechanism, o-iodoanilide substrates, pathways involving neutral pentacoordinate palladium intermediates and the influence of additives. The new examples and mechanistic findings indicate that the potential may exist to control the stereoselectivity of the intramolecular Mizoroki-Heck reaction through pathways other than the cationic mechanism. However, further research is needed to obtain the level of effectiveness of the traditional cationic pathway. 

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