Of Heck reactions

Rhodium(i) complexes are excellent catalysts for the 1,4-addition of aryl- or 1-alkenylboron, -silicon, and -tin compounds to a,/3-unsaturated carbonyl compounds. In contrast, there are few reports on the palladium(n) complex-catalyzed 1,4-addition to enones126,126a for the easy formation of C-bound enolate, which will result in /3-hydride elimination product of Heck reaction. Previously, Cacchi et al. described the palladium(n)-catalyzed Michael addition of ArHgCl or SnAr4 to enones in acidic water.127 Recently, Miyaura and co-workers reported the 1,4-addition of arylboronic acids and boroxines to a,/3-unsaturated carbonyl compounds. A cationic palladium(n) complex [Pd(dppe)(PhCN)2](SbF6)2 was found to be an excellent catalyst for this reaction (dppe = l,2-bis(diphenyl-phosphine)ethane Scheme 42).128... 

The transition metal-catalyzed domino reactions will undoubtedly have a splendid future which is underlined by the increasing number of publications in this area Steglich et al. presented an approach to arcyriacyanin A via a domino Heck reaction between a bromo(indolyl)maleiimide and 4-bromoindole.1811 The synthesis of 33 -bifurans by Ling et al. was achieved using a novel palladium-catalyzed domino dimerization and subsequent cyclization of acetylenic ketones.1821 Other applications of a combination of Heck reactions for domino processes are the syntheses of aza-heterocydes developed by our group.1831... 

Table 5.1 Inductively coupled plasma analysis of Heck reaction filtrates. (Reproduced from ref. 13, with permission.)...

Representative examples of Heck reactions are depicted in Scheme 8.8. Terminal alkenes react faster than internal alkenes, and the formation of mixtures of products resulting from further arylation or vinylation of the initial product is therefore only observed when a large excess of halide and long reaction times are employed. Electron-poor alkenes usually react more rapidly than electron-rich alkenes, and the new C-C bond is usually formed at the most electron-deficient carbon atom. 

Conditions of Heck reactions with alkenes have been made considerably more mild through the addition of tetrabutylammonium halides and weak bases such as KOAc or K2C03. The reagents have been employed in polar aprotic solvents such as DME, or under phase transfer conditions in their presence, yields are often increased and, in the case of iodides, reactions may be accomplished even at room temperature285-288. 

Ionic liquids have been pointed out as better solvents for this type of Heck reaction than classic organic solvents [72], In fact, the coupling of aryl chlorides was first achieved in tetraalkylamonium bromides at 140-150 °C using monocarbene-Pd(O) complexes as catalyst. 

Alkenyl triflates are capable of Heck reactions, too, as can be seen in Figure 13.28. 

Figure 3-2 Some biologically active compounds prepared by application of Heck reactions with asymmetric induction. (The dashed lines indicate bonds formed by palladium-catalyzed coupling).

Summaries of Heck reactions involving alkenes are given in Tables 3-3 and 3-4. 

Thus, the regioselectivity of Heck reactions with unsymmetrical alkenes can be manipulated favorably by appropriate variations of the catalyst cocktail . T e impact of silver(I) and thallium(I) salts [97] on Pd-catalyzed reactions extends beyond just increasing... 

In light of the enormous versatility of Heck reactions, one should ask why no commercial application has been seen as yet ... 

Fig. 14.5 Generation of addressable libraries on chips (a) Scheme of Heck reaction under employment of an transition metal catalyst (Reprinted with permission from Tian et al.33 Copyright (2005) American Chemical Society) (b) Scheme of reductive amination reactions (Reprinted with permission from Tesfu et al.34 Copyright (2006) American Chemical Society)...

The development of new catalysts for Heck arylations of unactivated aryl chloride substrates has also been a recent focus of research in this area. In late 1990s, Reetz [75] and Fu [76] successfidly conducted intermolecular Heck reactions using aryl chlorides as substrates, as exemplified by the conversion of p-chloroanisole to adduct 78 [76], A few examples of Heck reactions involving unactivated heteroaryl chlorides have also been described [77],... 

This sort of Heck reaction is normally done in a more convenient way. Though Pd(0) really starts off the cycle, Pd(II) is involved and Pd(OAc)2 [or (Ph3P)2Pd(OAc)2] is a more convenient reagent than Pd(PPh3)4. This same product can be made in excellent yield under very mild conditions without any phosphine at all.20 An explanation of the necessary reduction of Pd(II) to Pd(0) is in the workbook. 

A bonanza of Heck reactions was used by Tietze25 in the synthesis of cephalostatin analogues. Corey-Fuchs reaction on the aldehyde 167 gives the alkene 168 from which the trans Br atom is stereoselectively removed by Pd-catalysed tin hydride reduction to give the Z-vinyl bromide 169. This reaction is discussed below under Stille coupling. 

The electron-rich nature of heterocycles such as indoles, furans and thiophenes allows a different type of Heck reaction to be carried out. In this oxidative modification, the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. 

The transient involvement of norbomene in Heck reaction via its carbopalladation and help to functionabzation of the ortho position(s) is highly profitable. Its further exploitation includes oalkylation at the site of Heck reaction and amination. ... 

The electron-rich nature of heterocycles such as indoles, furans, and thiophenes allows a different type of Heck reaction to be carried out. " In this oxidative modification the aryl palladium derivative is generated by electrophilic palladation with a palladium(II) reagent. This process is not catalytic in the standard way, but can be made so by the addition of a reoxidant selective for Pd(0) note, that the catalytic Pd(0) could not effect the first (electrophilic) ring palladation. " ... 

More recently, Najera et al. performed a number of Heck reactions of deactivated aryl halides and styrenes under phosphane-free conditions using oxime-derived palladacycles or palladium acetate as catalyst [113], Coupling can be performed either vith chcyclohexylmethylamine as base and TBAB as PTC catalyst or in neat vater vith triethylamine in N,N-dimethylacetamide (DMA) solutions under the action of MW irradiation. 

This points to the fact that the rate of the catalytic reaction must be extremely high, since most of the Pd is in the form of PdNPs. This type of Heck reaction... 

The majority of the papers on Suzuki and Sonogashira reactions catalysed by supported palladium do not focus on mechanistic aspects and the corresponding contributions are thus limited in this respect Nevertheless, it is reasonable to assume from the limited number of such investigations that the principal conclusions from detailed mechanistic studies of Heck reactions by supported catalysts are valid also for this group of coupling reactions the active species is Pd leached into solution during the reaction and re-deposited at the end (see next section). 

There is evidence in some cases that C-C coupling by heterogeneous catalysts also occurs by soluble metal colloids (or smaller species) leached from solid supports, such as silica. In the 1970s, the catalytic activity of palladium black for C-C coupling was already reported by Mizoroki et al. [11,12], Various examples of Heck reactions with heterogeneous catalysts have been reported since then [13]. Therefore, while heterogeneous catalysts are not the main focus of this section, they are addressed where appropriate. 

Bradley et al. employed P VP-stabilized palladium colloids, which were pretreated with the base and the olefin at the reaction temperature prior to addition of the aryl halide (Table 1) [19]. The colloids were prepared by stirring [Pd(dba)2] in the presence of PVP at variable hydrogen pressures, affording particles of different average particle size (diameter 1.7 0.5 nm to 3.7 0.3 nm). The initial activities of Heck reactions catalyzed by these colloids of different average particle size were correlated with the number of low-coordinated atoms, i.e., comer and edge atoms in the palladium particles rather than all surface atoms. A general difficulty in such considerations is that the particles are not monodisperse, and also are not ideal cuboctahedra. 

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