Palladium Sources

The palladium precursors for the catalytically active complexes can be classified as palladium(O) and palladium(II) compounds. 

The most often used palladium(O) precursors are Pd2(dba)3 or Pd(dba)2 (dba = dibenzylidenacetone this is released during the formation of the active complex). 

The application of immobilized palladium sources has also been reported recently. 

A plethora of ligands is available for palladium-catalyzed C—N bond formations, using a seemingly unlimited variety of combinations of amines and organic 

XantPhos and DPEPhos are remarkable Ugands which were developed by van Leeuwen and coworkers [50]. These Ugands are especiaUy useful in the coupUngs of various amine derivatives, such as amides [51, 52], hydrazines [53], oxazoUdinones [54] and ureas [55]. Furthermore, appUcations of XantPhos to the diphenylamine synthesis [48], and coupUngs of alkylarylamines [56], as weU as 

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Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

Fagnou and co-workers reported on the use of a palladium source in the presence of different phosphine ligands for the intramolecular direct arylation reaction of arenes with bromides [56]. Later, they discovered that new conditions employing palladium complex 27 promoted the direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls including different functionalities as ether, amine, amide and alkyl (Scheme 7.11) [57]. 

The nature of the palladium source was found to have a profound effect on the rate of the coupling reaction. In particular, Pd(OAc)2 provided a significantly faster reaction rate than all other palladium sources [17]. It is interesting to note that either a 1 1 or 2 1 ratio of ligand to Pd provided competent in situ generated catalysts however the preformed catalyst Pd[(Pt-Bu3)2] [23] afforded -80% conversion whereas with [PdBr(Pt-Bu3)]2 [24], the reachon went to completion. These observations indicate that the acetate plays an important role in the catalytic system. 

Use of the above conditions in conjunction with the enol tosylate 32, provided only low yields of 22, prompting an extensive screening of structurally diverse phosphine ligands/solvents and palladium sources to attempt to define suitable conditions. Quite quickly a number of conditions were found to be effective, with chelating diphosphines being superior to monodentate phosphines (Table 9.7). In... 

Table 1 Time dependent performance in direct carbonylation of phenol using lead based catalysts with varying palladium sources (0.25 mM Pd, 12 eq. PbO, 5.6 eq. Ce(acac)3, 400 eq. TBAB).

Palladium-catalyzed carbon-carbon cross-coupling reactions are among the best studied reactions in recent decades since their discovery [102, 127-130], These processes involve molecular Pd complexes, and also palladium salts and ligand-free approaches, where palladium(O) species act as catalytically active species [131-135]. For example, the Heck reaction with aryl iodides or bromides is promoted by a plethora of Pd(II) and Pd(0) sources [128, 130], At least in the case of ligand-free palladium sources, the involvement of soluble Pd NPs as a reservoir for catalytically active species seems very plausible [136-138], Noteworthy, it is generally accepted that the true catalyst in the reactions catalyzed by Pd(0) NPs is probably molecular zerovalent species detached from the NP surface that enter the main catalytic cycle and subsequently agglomerate as N Ps or even as bulk metal. 

A series of benzo[fc]benzo[2,3-cfjthiophen-6,9-diones 12 has been prepared in modest yields by palladium mediated cyclization of the precursors 13. However, the necessity to use stoichiometric amounts of the palladium source precludes cost effective preparation of the targets. The required substrates 13 may be constructed by palladium catalyzed reactions between the appropriate phenols with 2,3-dimethylbenzoquinone <06SC3319>. 

Following the pioneering work by Alterman, several microwave-assisted palladium-catalyzed aminations have been reported for a number of different substrates, using different types of palladium sources and ligands. The examples shown in Scheme 6.59 include bromoquinolines [124], aryl triflates [125], and intramolecular aminations in the synthesis of benzimidazoles [126]. In all cases, the use of micro-wave irradiation dramatically reduced the required reaction times and in many cases also improved the yields. Several authors have also found that the microwave-driven reaction required significantly less catalyst than its conventionally heated counterpart [126]. 

A palladium-catalyzed protocol for carbon-sulfur bond formation between an aryl triflate and para-methoxybenzylthiol was introduced by Macmillan and Anderson (Scheme 6.66) [138], Using palladium(II) acetate as a palladium source and 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (BINAP) as a ligand, microwave heating of the two starting materials in N,N-dimethylformamide at 150 °C for 20 min in the presence of triethylamine base led to the formation of the desired sulfide in 85% yield. 

The catalyst reported by Drent [48] was generated in situ by mixing a palladium source with the ligand. A palladium source is broadly defined as a complex or any form of palladium metal whereby upon mixing with the ligand an active catalyst is formed. Many palladium sources are possible, but the sources exemplified by Drent aretris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3),bis(dibenzylideneacetone) palladium(O) (Pd(dba)2), or palladium(II) acetate. 

The reaction starts with an oxidative addition of an allylic compound to palladium(O) and a Tt-allyl-palladium complex forms. Carboxylates, allyl halides, etc. can be used. In practice one often starts with divalent palladium sources, which require in situ reduction. This reduction can take place in several ways, it may involve the alkene, the nucleophile, or the phosphine ligand added. One can start from zerovalent palladium complexes, but very stable palladium(O) complexes may also require an incubation period. Good starting materials are the 7t-allyl-palladium intermediates ... 

Buchwald has shown that, in combination with palladium(II) acetate or Pd2(dba)3 [tris(dibenzylideneacetone)dipalladium], the Merrifield resin-bound electron-rich dialkylphosphinobiphenyl ligand (45) (Scheme 4.29) forms the active polymer-supported catalysts for amination and Suzuki reactions [121]. Inactivated aryl iodides, bromides, or even chlorides can be employed as substrates in these reactions. The catalyst derived from ligand (45) and a palladium source can be recycled for both amination and Suzuki reactions without addition of palladium. 

The main steps in the currently accepted catalytic cycle of the Heck reaction are oxidative addition, carbopalla-dation (G=G insertion), and / -hydride elimination. It is well established that both, the insertion as well as the elimination step, are m-stereospecific. Only in some cases has formal /r/ / i--elimination been observed. For example, exposure of the l,3-dibromo-4-(dihydronaphthyloxy)benzene derivative 16 and an alkene 1-R to a palladium source in the presence of a base led to a sequential intra-intermolecular twofold Heck reaction furnishing the alkenylated tetracyclic products 17 in good to excellent yields (Scheme 9). " In the rate-determining step, the base removes a proton in an antiperiplanar orientation from the benzylic palladium intermediate. The best amine base was found to be l,4-diazabicyclo[2.2.2]octane, which apparently has an optimal shape for this proton abstraction. 

The Sonogashira coupling of haloazines can be effected by a series of catalyst systems. Recently a lot effort was devoted to the development of a recyclable catalyst system. Kotschy and co-workers recently reported the use of palladium on charcoal as a convenient palladium source for this process, which allows for the separation and reuse of the catalyst at the end of the reaction (7.35.), The authors also demonstrated that, in spite of the absence of any substantial catalyst leaching, the catalytic activity of the reused Pd/C decreases on each run,49 a surprising phenomenon which was attributed to the dissolution and reprecipitation of the active catalyst in the course of the process. Pd(OH)2 on charcoal exhibited a similar activity in the Sonogashira coupling of bromopyridines.50... 

Polar, aprotic solvents such as DMF were necessary for the formation of (126). [Pd(diphos)2] (104) gave the best performance as catalyst. Using [Pd(DBA)2] (105) as palladium source, a number of mono- and bi-dentate nitrogen, phosphorus and arsenic ligands were investigated and Me2PCH2CH2PMe2 was found to be nearly as effective as diphos. The reaction of C02 with a bis(i73-allyl) complex of palladium was believed to be a key step in the process (equation 158). 

The use of [Pd(DBA)2] (105) as palladium source or the use of other phosphine ligands led to no formation of lactone (128). The product selectivity was very poor, and (128) was never the major product. The C02 fixation step may be as shown in equation (159) by analogy with other reactions. 

For this particular cis-decalin synthesis, it was eventually found that best results were obtained with the corresponding vinyl triflates and Pd(BINAP) (Scheme 8G.5) [l 3). As illustrated in these examples, the reaction of unsaturated triflates under cationic conditions typically is done in a nonpolar solvent, in the presence of an inorganic base such as K2C03 or a tertiary amine Pd(OAc)2 and Pd dba CHC have been the most widely used palladium sources. 

It has been shown that combination of bromoallylation reaction and Heck cyclization is a useful methodology for the preparation of a variety of fused bicyclic (3-lactams of nonconventional structure [95], Starting from acetates 164 and using palladium acetate as the palladium source, DMF as solvent, potassium carbonate as base, and triphenylphosphine, the reaction occurred. The reaction conditions were further optimized and typical results for the preparation of bicyclic (3-lactams 165-168 are summarized in Schemes 57. 

Catalytically active particles can be formed from various palladium sources under supercritical reaction condition, which could be helpful for the particle dispersion. Therefore, those materials show high catalytic activity, selectivity, and stability for a broad range of substrates. Additionally, the PEG matrix effectively stabilizes and immobilizes the catalytically active particles, whereas the unique solubility and mass transfer properties of scC02 allow continuous processing at mild conditions, even with low-volatility substrates. 

Commonly used metal salts and palladium precursors include Pd(OAc)2, Pd (acac)2 (acac = acetylacetonato) and Pd2(dba)3 or Pd(dba)2 (dba = dibenzylide-neacetone). If a Pd(II) salt is used as pre-catalyst, reduction by base or by excess phosphine ligand is required. The exact nature of the reducing agent is somewhat contended, but it is often assumed that the phosphine takes up this role, for which evidence has been reported [26]. A typical catalytic system consists of a palladium source and an aryl- or alkylphosphine (typically PPh3), in at least 2 eq., as ligand. The addition of bases, typically amines and alkoxides, is often found to be beneficial for activity, which is also reflected in the patent literature [27-29]. The bases are thought to facilitate in the attack of the nucleophile in the rate-determining step and, in the case of the amines, in the reduction of Pd(II) to Pd(0). 

Pyrazole-based COX-inhibitors were synthesized using Pd/C as a heterogeneous and ready-filterable palladium source. Electron-deficient boronic acids coupled well while orf/zo-substitulcd and electron-rich boronic acid were less reactive (Scheme 62) [146]. The same team also developed a two-step and one-pot procedure for the synthesis of styrene-based nicotinic acetylcholine receptor antagonists. 

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