Catalysts and Ligands

Some of the most commonly used catalysts or pre-catalysts are [Pd(PPhj)4],35 [Pd2(dba)3] (dba = dibenzylideneacetone),36 [PdCl2(NCMe)2],37 [PdCl2(PPh3)2],3 [Pd(CH2Ph)Cl(PPh3)2], [PdCl2(dppf)] 

Particularly useful for the activation of aryl chlorides are palladium complexes of the bulky phosphine P(t-Bu)3,4 which is readily available. 

Bedford and co-workers have demonstrated that palladium complexes of the simple, inexpensive tricyclohexylphosphine display very high activity in the Stille coupling of non-activated and deactivated aryl chlorides [Equation (5.3.6)]The use of K3PO4 is necessary to promote the coupling. 

SnRsR themselves and (ill) finally it helps the removal of tin by-prodncts from the reaction mixture [Equation (5.3.8)].5° 

The reaction of 8-bromoguanines with aryl- and hetero-aryl tin compounds in the presence of a palladium catalyst leads to the formation of the corresponding 8-aryl(heteroaryl)guanines. It was found 

A wide range of experimental conditions for the CuAAC have been employed since its discovery, underscoring the robustness of the process and its compatibility with most functional groups, solvents, and additives, regardless of the source of the catalyst. The most commonly used protocols and their advantages and limitations are discussed below, and representative experimental procedures are described at the end of this chapter. 

Different copper(I) sources can be utilized in the reaction, as recently summarized in necessarily partial fashion by Meldal and Torn0e [12]. Copper(I) salts (iodide, bromide, chloride, acetate) and coordination complexes such as [Cu(CH3CN)4]Pp6 and [Cu(CH3CN)4]OTf [40, 41] have been commonly employed [6]. In general, however, we recommend against the use of cuprous iodide because 

The reaction can also be catalyzed by Cu(I) ions supplied by elemental copper, thus further simplifying the experimental procedure-a small piece of copper metal (wire or turning) is all that is added to the reachon mixture, followed by shaking or stirring for 12-48 h [6, 23, 50]. Aqueous alcohols (methanol, ethanol, tert-butanol), tetrahydrofuran, and dimethylsulfoxide can be used as solvents in this procedure. Cu(ll) sulfate may be added to accelerate the reaction however, this is not necessary in most cases, as copper oxides and carbonates, the patina on the metal surface, are sufficient to initiate the catalytic cycle. Although the procedure based on copper metal requires longer reaction times when performed at ambient temperature, it usually provides access to very pure triazole products 

The Cu(I) oxidation state is the least thermodynamically stable form of copper, and many copper(I) complexes can be readily oxidized to catalytically inactive copper(II) 

Several Cu(I) complexes with N-heterocyclic carbene ligands have been described as CuAAC catalysts at elevated temperature in organic solvents, under heterogeneous aqueous conditions (when both reactants are not soluble in water), and under neat conditions [75]. These catalyst show high activity under the solvent-free conditions, achieving turnover numbers as high as 20 000. However, their activity in solution-phase reactions is significantly lower than that of other catalytic systems (for example, a stoichiometric reaction of the isolated copper(I) acetylide/NHC complex with benzhydryl azide required 12 h to obtain 65% yield of the product [76], whereas under standard solution conditions even a catalytic reaction would proceed to completion within 1 h). 

The category of hard donor ligands for CuAAC is dominated by amines. In many 

HR are catalyzed by Pd(0) complexes of phosphines. Mainly commercially available Pd(PPh3)4, Pd2(dba 3 and Pd(OAc 2 are used as precursors of Pd(0) catalysts with or without phosphines. When overligated Pd(PPh3)4 is used, reactions of congested molecules may be slow due to the presence of too many ligands, which inhibit coordination of reactants. Pd(OAc)2, Pd(dba 2 and even Pd on carbon are used with phosphines. 

Bulky tri(o-tolyl)phosphine was used first by Heck [11]. A palladacycle obtained from it is known as the Herrmann complex (XVIII-1) and is used extensively in HR [12]. Also, palladacycles XVIII-7 [13] and XVIII-2 [14] are high performance catalysts. Turnover numbers as high as 630-8900 were achieved by tetraphosphine Tedicyp (X-1) [15]. Recently, the remarkable effect of electron-rich and bulky phosphines, typically P(t-Bu)3 and other phosphines shown in Tables 1.4, 1.5 and 1.6, have been vmveiled. Smooth reactions of aryl chlorides using these ligands are treated later. Electron-rich ligands accelerate oxidative addition of aryl chlorides, and reductive elimination is accelerated by bulky ligands. HR can be carried out in an aqueous solution by use of a water-soluble sulfonated phosphine (TPPMS, II-2) [16]. 

Sometimes, AsPhs shows better effeet than PPhs. In the synthesis of epibatidine (30) by hydroarylation of the azabicyelie alkene 28 with 2-ehloro-5-iodopyridine (29) in the presenee of formic acid, the best result was obtained using AsPh3 [17]. 

In addition, electron-rich and bulky heterocyclic carbenes are attracting attention as effective phosphine mimics [18], Using carbene ligand XVI-6, HR of aryl bromides proceeds at 120 °C [19] and that of diazonium salts 31 at room temperature [20], A new phosphine-imidazolium salt (XVI-14) was found to catalyze HR efficiently [21]. 

Occasionally reactions proceed with phosphine-free Pd(0) catalysts. Some phosphines are more expensive than Pd and more difficult to recover than Pd. Therefore, an ideal catalyst is a phosphine-free Pd(0) catalyst. Reactions of reactive halides and pseudohalides such as aryl iodides, diazonium salts and acyl chlorides proceed under phosphine-free conditions. 

The (E)-bromides in 1,1-dibromo-l-alkenes can be stereoselectively coupled with aryl- or al-kenylboronic acids to give the corresponding (Z)-l-aryl(or alkenyl)-l-bromo-l-alkenes. Tris(2- 

Najera et al. [92] have reported that for the coupling of aryl halides with organoboronic adds, complexes 23-26 are adequate catalysts, giving TONs between 102 and 10s. These pallada-cycles exhibit greater aerial and thermal stability than palladium]0) complexes. 

Most recently, Monteiro et al. have reported that cyclopalladated compounds derived from the ortho-metalation of benzylic tert-butyl thioethers are excellent catalyst precursors for the Suzuki cross-coupling reaction of aryl bromides and chlorides with phenylboronic acid under mild reaction conditions. A broad range of substrates and functional groups are tolerated in this protocol, and high catalytic activity is attained (Eq. (58)) [93]. 

The Suzuki reaction of aryl bromides and chlorides is efficiently catalyzed by palladium/ phosphite complexes generated in situ. The influence of the ligand, base, and various additives was examined. The process tolerates various functional groups, and catalyst turnovers of up to 820,000 were obtained, even with deactivated aryl bromides [94]. 

Palladium-catalyzed Suzuki cross-coupling reactions can be conducted in the ambient temperature ionic liquid, l-butyl-3-methylimidazolium tetrafluoroborate (29), in which unprecedented reactivities are witnessed, and which allows easy product isolation and catalyst recycling (Eq. (60)) [96]. 

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The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

Fig. 2.20 Chiral Pd-NHC catalysts and ligands used for the asymmetric allyhc alkylation...

Variation in catalyst and ligand can lead to changes in both regio- and enantio-selectivity. For example, the hydroboration of vinyl arenes such as styrene and 6-methoxy-2-vinylnaphthalene can be directed to the internal secondary borane by use of Rh(COD)2BF4 as a catalyst.166 These reactions are enantioselective in the presence of a chiral phosphorus ligand. 

Many other catalysts and ligands have been examined for the enantioselective reduction of a-acetamidoacrylates and related substrates. Phosphoramidites derived from BINOL and the cyclic amines piperidine and morpholine give excellent results.35... 

Metal-catalyzed C-H bond formation through isomerization, especially asymmetric variant of that, is highly useful in organic synthesis. The most successful example is no doubt the enantioselective isomerization of allylamines catalyzed by Rh(i)/TolBINAP complex, which was applied to the industrial synthesis of (—)-menthol. A highly enantioselective isomerization of allylic alcohols was also developed using Rh(l)/phosphaferrocene complex. Despite these successful examples, an enantioselective isomerization of unfunctionalized alkenes and metal-catalyzed isomerization of acetylenic triple bonds has not been extensively studied. Future developments of new catalysts and ligands for these reactions will enhance the synthetic utility of the metal-catalyzed isomerization reaction. 

Figure 5 Catalysts and ligands for epoxide opening reactions.

Future challenges of major interest will be the creation of new catalysts and ligand types, and the identification of new catalytic reactions. While HTE can clearly be used to speed up this research, the large number of experiments associated with HTE has led in the past - and will continue to lead in the future -to totally unexpected findings. Ultimately, further applications outside the area of enantioselective catalysis are also expected. 

Figure 11.2 Catalysts and ligands for carbonyl reduction by borane.

If a specific catalyst is not available at the right time, and in the appropriate quantity, it wiU not be applied due to time limitations for process development Today, a sizable number of homogeneous catalysts and ligands (especially for hydrogenation) are available commercially in technical quantities. 

The crude reaction mixture was purified by column chromatography by using petroleum ether EtOAc (6 4—5 5 ) as eluent to afford (R)-lansoprazole (0.312 g, 84 %) as well as (DHQD)2-PYR (0.084 g). Recovered catalyst and ligand were reused without any loss in activity and selectivity. 

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