Neutral pathways, Heck reaction

A challenge in the development of direct alkenylation reactions is preventing undesirable homocoupling pathways that are common under oxidative conditions. A neutral oxidative Heck reaction to directly C2 alkenylate thiazoles and benzothiazoles was reported, which proceeds in the presence of Pd(OAc)2,l,10-phenanthroline, and AgN03. Strongly acidic or basic conditions failed to generate the C2 alkenylated product, and in-... 

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 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... 

These results led other investigators to propose that the Heck reaction proceeds via an ionic pathway or a neutral variant, depending on the starting materials and on 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 6-1 Mechanism of Heck substitution reactions proceeding via the neutral 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]. 

Scheme 1 shows the desired Heck reaction of alkoxy-DSB 1 with 2. The formation of 3 is accompanied by two destructive pathways the reductive debromination of 1 to 4 as a side reaction and the protodesilylation to 5 as a subsequent reaction. Particularly the latter limits the reaction conditions in terms of time and temperature. The phosphine is a decisive factor in this system consisting of three reactions a fine-tuning of the reaction conditions is possible via electronic and steric effects of the substituents in the phosphine electron-rich trialkylphosphines 6 and 7 strongly favor the reduction. Fast coupling reactions were observed with tris-o-tolylphosphine 8, the chelating diphosphine dppe 9 being even more efficient in terms of turnover, yield, and suppression of side reactions. Compared with Heck reactions of polycyclic or electron-deficient arenes with 2 [21, 22], the yield of 3 is only moderate. The reactivity of bromo-distyrylbenzenes 1 and 12 -14 in the coupling reaction is controlled by the substituents on the opposite side of the n-system (Fig. 1, Table 2) a compensation for the electron-donating alkoxy groups by a cyanide (13) or exchange of donors with electronically neutral alkyl side chains strongly improves the yields.

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. ... 

However, clear evidence of the IL effect was found for the regioselective arylation of olefins. It is generally accepted that the Heck reaction may proceed via two pathways, a neutral pathway leading to the preferential formation of linear olefins and an ionic counterpart more likely to give rise to branched olefins. Thus, Pd(OAc)2 and l,3-bis(diphenylphosphino)propane (DPPP) immobilized in [G4GiIm]BF4 promote the exclusive a-arylation of several classes of electron-rich olefins with a wide range of aryl iodides and bromides in the absence of halide scavengers (Scheme 3). ... 

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.

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. 

Scheme 12.5 Potential neutral pathways of the intramolecular Mizoroki Heck reaction with a bidentate ligand.

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