Palladium(II) Acetate1

Pd(OAc)2

[3375-31-3]  · C4H6O4Pd  · Palladium(II) Acetate  · (MW 224.52) (trimer)

[53189-26-7]

(homogenous oxidation catalyst3 that, in the presence of suitable co-reagents, will effect the activation of alkenic and aromatic compounds towards oxidative inter- and intramolecular nucleophilic attack by carbon, heteroatom, and hydride nucleophiles1,3,4,5)

Alternate Name: bis(acetato)palladium; diacetatopalladium(II); palladium diacetate.

Physical Data: mp 205 °C (dec).

Solubility: sol organic solvents such as chloroform, methylene chloride, acetone, acetonitrile, diethyl ether. Dissolves with decomposition in aq HCl and aq KI solutions. Insol water and aqueous solutions of NaCl, NaOAc, NaNO3 as well as in alcohols and petroleum ether. Decomposes when heated with alcohols.

Form Supplied in: orange-brown crystals; generally available.

Preparative Methods: preparation of palladium diacetate from palladium sponge was developed by Wilkinson et al.2

Purification: palladium nitrate impurities can be removed by recrystallization from glacial acetic acid in the presence of palladium sponge.

Handling, Storage, and Precautions: can be stored in air. Low toxicity.

General Considerations.

Salts of palladium that are soluble in organic media, for example Pd(OAc)2, Dilithium Tetrachloropalladate(II), and PdCl2(RCN)2, are among the most extensively used transition metal complexes in metal-mediated organic synthesis. Palladium acetate participates in several reaction types, the most important being: (i) PdII-mediated activation of alkenes towards nucleophilic attack by (reversible) formation of PdII-alkene complexes, (ii) activation of aromatic, benzylic, and allylic C-H bonds, and (iii) as a precursor for Pd0 in Pd0-mediated activation of aryl, vinyl, or allyl halides or acetates by oxidative addition to form palladium(II)-aryl, -vinyl and -(p)-allyl species, respectively.1b All reactions proceed via organopalladium(II) species which can undergo a number of synthetically useful transformations.

Alkenes complexed to PdII are readily attacked by nucleophiles such as water, alcohols, carboxylates, amines, and stabilized carbon nucleophiles (eq 1). Attack occurs predominantly from the face opposite to that of the metal (trans attack), thus forming a new carbon-nucleophile bond and a carbon-metal s-bond.

The s-complex obtained is usually quite reactive and unstable, and can undergo a number of synthetically useful transformations such as b-hydrogen elimination (eq 1) to give a vinyl substituted alkene and insertion of CO (eq 1) or alkenes (eq 1) into the carbon-palladium bond, which permit further functionalization of the original alkene. The same general chemistry is observed for complexes generated from Pd0 (eq 2). Heck vinyl couplings and carbonylations together with allylic nucleophilic substitution reactions are among the synthetically most interesting reactions employing palladium acetate.5

The transformations in eqs 1 and 2 ultimately produce palladium(0), while palladium(II) is required to activate alkenes (eq 1). Thus, if such a process is to be run using catalytic amounts of the noble metal, a way to rapidly regenerate palladium(II) in the presence of both substrate and product is required. Often this reoxidation step is problematic in palladium(II)-catalyzed nucleophilic addition processes, and reaction conditions have to be tailored to fit a particular type of transformation. A number of very useful catalytic processes, supplementing the processes that employ stoichiometric amounts of the metal, have been developed.1,3-5

Oxidative Functionalization of Alkenes with Heteroatom Nucleophiles.

Oxidation of Terminal Alkenes to Methyl Ketones.

The oxidation of ethylene to acetaldehyde with water acting as the nucleophile using a PdIICl2-CuIICl2 catalyst (see Palladium(II) Chloride and Palladium(II) Chloride-Copper(II) Chloride) under an oxygen atmosphere is known as the Wacker process. On a laboratory scale the reaction conveniently allows the transformation of a wide variety of terminal alkenes to methyl ketones.6 Some synthetic procedures that employ Pd(OAc)2 in chloride-free media have been developed (eq 3).

By this, both the use of the highly corrosive reagent combination PdCl2-CuCl2 and the occurrence of chlorinated byproducts are avoided. The stoichiometric oxidant used in these reactions can be a peroxide,7 1,4-Benzoquinone,8 or molecular Oxygen.8a,9 An electrode-mediated process has also been described.10

Other Heteroatom Nucleophiles.

Alcohols and carboxylic acids also add to metal-activated alkenes,1a and processes for the industrial conversion of ethylene to vinyl acetate and acetals are well established.1c However, these processes have not been extensively used with more complex alkenes. In contrast, a number of intramolecular versions of the processes have been developed, a few examples of which are given here. Allylphenols cyclize readily in the presence of palladium(II) to form benzofurans (eq 4). Catalytic amounts of palladium acetate can be used if the reaction is carried out under 1 atm of molecular oxygen with copper diacetate as cooxidant, or in the presence of t-Butyl Hydroperoxide. If instead of palladium acetate a chiral p-allylpalladium acetate complex is used, the cyclization proceeds to yield 2-vinyl-2,3-dihydrobenzofuran with up to 26% ee.11

Methyl glyoxylate adducts of N-Boc-protected allylic amines cyclize in the presence of a catalytic amount of palladium acetate and excess Copper(II) Acetate to 5-(1-alkenyl)-2-(methoxycarbonyl)oxazolidines (eq 5).12 These heterocycles are easily converted to unsaturated N-Boc protected b-amino alcohols through anodic oxidation and mild hydrolysis.

Nitrogen nucleophiles such as amines, and in intramolecular reactions amides and tosylamides, readily add to alkenes complexed to PdII derived from PdCl2(RCN)2 (see Palladium(II) Chloride) with reactivity and regiochemical features paralleling those observed for oxygen nucleophiles.3,4 Intramolecular nucleophilic attack by heteroatom nucleophiles also occurs in conjunction with other palladium-catalyzed processes presented in the following sections.

Allylic C-H Bond Activation.

Internal alkenes, in particular cyclic ones, can be transformed into allylic acetates in a palladium-catalyzed oxidation (eq 6).13 With benzoquinone as stoichiometric oxidant or electron transfer mediator,9a the allylic acetoxylation proceeds with high selectivity for the allylic product and usually in excellent yield.

This one-step transformation of an alkene to an allylic acetate compares well with other methods of preparation such as hydride reduction of a,b-unsaturated carbonyl compounds followed by esterification. The scope and limitations of the reaction have been investigated.14 The allylic acetoxylation proceeds via a p-allylpalladium intermediate,15 and as a result, substituted and linear alkenes generally give several isomeric allylic acetates. With oxygen nucleophiles the reaction is quite general, and reactants and products are stable towards the reaction conditions. This is normally not yet the case with nitrogen nucleophiles, although one intramolecular palladium-catalyzed allylic amination mechanistically related to allylic acetoxylation has been reported.16

Functionalization of Conjugated Dienes.

Electrophilic transition metals, particularly palladium(II) salts which do not form stable complexes with 1,3-dienes, do activate these substrates to undergo a variety of synthetically useful reactions with heteroatom nucleophiles.17 Some examples are presented below.

Telomerization.

Conjugated dienes combine with nucleophiles such as water, amines, alcohols, enamines and stabilized carbanions in the presence of palladium acetate and Triphenylphosphine to produce dimers with incorporation of one equivalent of the nucleophile.1,18 Telomerization of butadiene (eq 7) yields linear 1,6- and 1,7-dienes and has been used for the synthesis of a variety of naturally occurring materials.19

Oxidative 1,4-Functionalization.

The regio- and stereoselective palladium-catalyzed oxidative 1,4-functionalization of 1,3-dienes (eq 8) constitutes a synthetically useful process.20-23

A selective catalytic reaction that gives high yields of 1,4-diacetoxy-2-alkenes occurs in acetic acid in the presence of a lithium carboxylate and benzoquinone. The latter reagents act as the activating ligand and reoxidant for palladium(0).24 The reaction can be made catalytic also in benzoquinone by the use of Manganese Dioxide,20 electrochemistry,25 or metal-activated molecular oxygen9a as stoichiometric oxidant. If the reaction is carried out in alcoholic solvent in the presence of a catalytic amount of a nonnucleophilic acid, cis-1,4-dialkoxides can be obtained.23 An important feature of the 1,4-diacetoxylation reaction is the ease by which the relative sterochemistry of the two acetoxy substituents can be controlled (eq 9).

The first step in the reaction sequence is a regioselective and stereoselective trans-acetoxypalladation of one of the double bonds, thus forming a p-allylpalladium(II) intermediate, which is then attacked by a second nucleophile. By variation of the concentration of chloride ions, reactions selective for either the trans-diacetate or the cis-diacetate (eq 9) can be accomplished. The use of other chloride salts resulted in poor selectivity. The selectivity for the trans product at chloride-free conditions is further enhanced if the reaction is carried out in the presence of a sulfoxide co-catalyst.26 Enzymatic hydrolysis of the cis-meso-diacetate yields cis-1-acetoxy-4-hydroxy-2-cyclohexene in more than 98% ee,27 thus giving access to a useful starting material for enantioselective synthesis.28

In a related catalytic procedure, run in the presence of a stoichiometric amount of Lithium Chloride (eq 10), it is possible to obtain cis-1-acetoxy-4-chloro-2-alkenes with high 1,4-selectivity and in high chemical yield.21 A selective nucleophilic substitution of the chloro group in the chloroacetate, either by palladium catalysis or by classical methods (eq 10), and subsequent elaboration of the acetoxy group, offer a number of useful transformations.22 The methodology has been applied to, for example, a synthesis of a naturally occurring 2,5-disubstituted pyrrolidine, some tropane alkaloids, and perhydrohistrionicotoxin.29

The use of two different nucleophiles can lead to unsymmetrical dicarboxylates.30 Palladium-catalyzed oxidation of 1,3-cyclohexadiene in acetic acid in the presence of CF3CO2H/LiO2CCF3, with MnO2 and catalytic benzoquinone, yielded 70% of trans-1-acetoxy-4-trifluoroacetoxy-2-cyclohexene (more than 92% trans), with a selectivity for the unsymmetrical product of more than 92%. 1,3-Cycloheptadiene afforded the cis addition product in 58% yield with a selectivity for the unsymmetrical product of more than 95%. Since the two carboxylato groups have different reactivity, for example toward hydrolysis, further transformations can be carried out at one allylic position without affecting the other.

Intramolecular versions of the 1,4-oxidations have been developed.31 In these reactions the internal nucleophile can be a carboxylate, an alkoxide, or nitrogen functionality, and the result of the first nucleophilic attack is the regioselective and stereoselective formation of a cis-fused heterocycle (eq 11).

The second attack can be directed as described above to yield either an overall trans or cis product in >70% yield. With internal nucleophiles linked to the 1-position of the 1,3-diene, spirocyclization occurs. The synthetic power of the method has been demonstrated in the total syntheses of heterocyclic natural products,32 and further developed into a tandem cyclization of linear diene amides (eq 12) to yield bicyclic compounds with trisubstituted nitrogen centers.33

Functionalization of Alkenes with Palladium-Activated Carbon Nucleophiles.

Heck Coupling.5

The Heck reaction is the common name for the coupling of an organopalladium species with an alkene and includes both inter- and intramolecular reaction types. However, no general reaction conditions exist and the multitude of variations can sometimes seem confusing.

The original version of the Heck reaction involved the coupling of an alkene with an organomercury(II) salt in the presence of stoichiometric amounts of palladium(II),34 a method still used in nucleoside chemistry.35 The finding that the organomercury reagent can be replaced by an organic halide, however, greatly increased the versatility of the process.36 The modified process is catalyzed by zerovalent palladium, either in the form of preformed tertiary phosphine complexes or, preferentially, formed in situ from palladium acetate (eq 13).

To keep the active catalyst in solution, reactions are often carried out in the presence of tertiary phosphines such as Triphenylphosphine,37 or rather tri(o-tolyl)phosphine,38 which is now the phosphine most widely employed in Heck coupling reactions.5 Other ligands successfully employed include tris(2,6-dimethoxyphenyl)phosphine and the bidentate ligands 1,2-Bis(diphenylphosphino)ethane (dppe), 1,3-Bis(diphenylphosphino)propane (dppp), 1,4-Bis(diphenylphosphino)butane (dppb), and 1,1-Bis(diphenylphosphino)ferrocene (dppf). Coupling reactions can occur in homogenous aqueous media if a water-soluble palladium ligand, trisodium 3,3,3-(phosphinetriyl)tribenzenesulfonate, is employed. This greatly facilitates workup procedures, and good yields of coupled products were obtained from reacting aryl and alkyl iodides with alkenes, alkynes, and allylic acetates.39 In all cases, an inert atmosphere and the presence of a base, normally Triethylamine, is required.

Phase-Transfer Conditions.

The Heck conditions described above are not useful, however, for a large number of alkenic substrates.40 A sometimes serious drawback is the high temperature (ca. 100 °C) often required. Upon addition of tetrabutylammonium chloride (phase-transfer conditions or Jeffery conditions), aromatic halides or enol triflates react under mild conditions with vinylic substrates or allylic alcohols.5,41 Variations of these conditions include the optional or additional presence of silver or thallium salts. The effect of using different salts, bases, catalysts, solvents, and protecting groups in the coupling of aminoacrylates with iodobenzene has been studied.42

Cross Coupling.

In cross-coupling reactions, an aryl, vinyl, or acyl halide or triflate undergoes a palladium-catalyzed Heck-type coupling to an aryl-, vinyl-, or alkyl-metal reagent (eq 14) to give a new carbon-carbon bond.5

Mg, Zn, and Zr are examples of metals used in cross-coupling reactions,43 but, in particular, organostannanes have been employed in mild and selective palladium acetate-catalyzed couplings with organic halides and triflates.44 Aryl arenesulfonates undergo a cross-coupling reaction with various organostannanes in the presence of palladium diacetate, dppp, and LiCl in DMF.45 An advantage of the arylsulfonates over triflates is that the former are solids whereas the latter are liquids. Also, arylboranes and boronic acids also undergo a palladium-catalyzed cross-coupling with alkyl halides, although the catalysts of choice are Tetrakis(triphenylphosphine)palladium(0), Dichloro[1,4-bis(diphenylphosphino)butane]palladium(II), or Dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II).46

Arylation of Alkenes by Coupling and Cross Coupling.

Alkenes can be functionalized with palladium-activated arenes, yielding styrene derivatives in a process applicable to a wide range of substrate combinations. An early demonstration of the possibilities of the Heck arylation was the coupling of 3-bromopyridine with N-3-butenylphthalimide (eq 15), the first step of four in a total synthesis of nornicotine.47

N-Vinylimides readily undergo palladium-catalyzed vinylic substitution with aryl bromides to yield 2-styryl- and 2-phenylethylimines. With aryl iodides (eq 16), the reaction proceeds even in the absence of added phosphine,48 which opens the possibility of a sequential disubstitution of bromoiodoarenes.

Vicinal dibromides undergo a twofold coupling reaction with monosubstituted alkenes to yield 1,3,5-trienes (eq 17). The reaction, catalyzed by palladium acetate in the presence of triphenylphosphine and triethylamine, can also be applied to aromatic tri-and tetrabromides.49

A double coupling of 2-amidoacrylates with 3,3-diiodobiphenyl constitutes a key step in a short preparation of a biphenomycin B analog.50 Palladium acetate-catalyzed double coupling reactions of 1,8-diiodonaphthalene with substituted alkenes and alkynes under phase-transfer conditions are useful also for the synthesis of various acenaphthene and acenaphthylene derivatives.51

1,2-Disubstituted alkenes are generally less reactive towards coupling than are monosubstituted alkenes. However, the use of the more reactive aryl iodides can result in reasonable yields of the coupled product, usually as a mixture of (E) and (Z) isomers.52 The reaction has been applied to a coupling of 2-iodoaniline derivatives with Dimethyl Maleate (eq 18), the product of which spontaneously cyclizes to form quinolone derivatives in 30-70% yield. If, instead, the 2-iodoaniline is coupled with Isoprene or cyclohexadiene in the presence of palladium acetate, triphenylphosphine, and triethylamine, indole and carbazole derivatives are obtained by a coupling followed by intramolecular nucleophilic attack by the heteroatom.53

2-Alkylidenetetrahydrofurans can be prepared via intramolecular oxypalladation and subsequent coupling by treatment of aryl or alkyl alkynic alcohols with n-Butyllithium followed by palladium acetate and triphenylphosphine. The reaction proceeds to yield furans in moderate yields.54

Formation of Dienes and Enynes by Coupling and Cross Coupling.

The vinylation of methyl acrylate, methyl vinyl ketone, or acrolein with (E) or (Z) vinylic halides under phase-transfer conditions gives high yields of (E,E) (eq 19) or (E,Z) (eq 20) conjugated dienoates, dienones, and dienals, respectively.55 Coupling of vinyl halides or triflates with a,b- or b,g-unsaturated acids under phase-transfer conditions yields vinyl lactones.56

Commercially available trimethylvinylsilanes can be vinylated using either vinyl triflates or vinyl iodides in the presence of silver salts, in a reaction catalyzed by palladium acetate in the presence of triethylamine. The resulting 3-substituted 1-trimethylsilyl-1,3-dienes are obtained in reasonable to good yields.57

Alkenylpentafluorosilicates derived from terminal alkynes react readily with allylic substrates in a palladium-catalyzed cross-coupling reaction to yield (E)-1,4-dienes (eq 21).58 Treatment of 1-alkenylstannanes with t-BuOOH in the presence of 10% of palladium acetate gives 1,3-dienes (eq 22), whereas coupling between 1- and 2-alkenylstannanes provides 1,4-dienes in good yields (eq 23).59

Cross coupling of enol triflates under neutral conditions with allyl-, vinyl-, or alkynylstannanes in the presence of palladium diacetate and triphenylphosphine proceeds to give high yields of 1,4- and 1,3-dienes and 1,3-enynes, respectively (eq 24).60

Terminal alkynes react to form 1-en-3-ynes in a process catalyzed by palladium acetate and tris(2,6-dimethoxyphenyl)phosphine. A number of functional groups such as internal alkenes, esters, and alcohols are tolerated, and good yields of homo- (eq 25) as well as hetero-coupled enynes (eq 26) are obtained.61

An interesting approach to 1-en-5-ynes is the palladium-catalyzed tandem coupling of a cis-alkenyl iodide, a cyclic alkene, and a terminal alkyne (eq 27). With norbornene as the alkene, the coupling occurs in a stereodefined manner, and the enyne products are obtained in good yields.62 Potassium Cyanide can be used instead of an alkyne to yield the corresponding cyanoalkene.63

Formation of Aldehydes, Ketones, and Allylic Dienols by Coupling to Allylic Alcohols.

Allylic alcohols can be coupled with aryl or vinyl halides or triflates. The outcome of the reaction depends on the coupling agent and the reaction conditions. Thus arylation of allylic alcohols under Heck conditions constitutes a convenient route to 3-aryl aldehydes and 3-aryl ketones (eq 28).64

Coupling of primary allylic alcohols with vinyl halides carried out under phase-transfer conditions (cat Pd(OAc)2 in the presence of Ag2CO3 and n-Bu4NHSO4 in acetonitrile) gave 4-enals,65 whereas secondary allylic alcohols, when treated with a vinyl halide or enol triflate, afforded conjugated dienols with good chemoselectivity, regiochemistry, and stereoselectivity.66 Since the coupling reaction under these conditions proceeds without touching the carbon bearing the alcohol functional group, it was possible to prepare optically active dienols from vinyl iodides and optically active allylic alcohols (eq 29).67

Formation of Allyl and Aryl Primary Allylic and Homoallylic Alcohols from Vinyl Epoxides and Oxetanes.

Vinylic epoxides can be coupled with aryl (eq 30) or vinyl (eq 31) iodides or triflates to form allylic alcohols in 40-90% yield.68 When employing palladium acetate as the catalyst, a reducing agent such as sodium formate is required in addition to the salts normally present under phase transfer conditions.

Vinyloxetane couples with aryl or vinyl iodides or triflates to form homoallylic alcohols under essentially the same reaction conditions (eq 32).69 The process has also been applied to the preparation of aryl-substituted 3-alkenamides from 4-alkenyl-2-azetidinones (eq 33).70

Homoallylic alcohols can also be prepared using a one-pot transformation of homopropargyl alcohols. Intramolecular hydrosilylation followed by a palladium-catalyzed coupling of the in situ generated alkenoxysilane with an aryl or alkenyl halide, in the presence of fluoride ions, affords the alcohol product.71 This process has also been applied to the preparation of 1,3-dienes.

Carbonylation.

Carbon monoxide readily inserts into Pd-C s-bonds. The resulting acylpalladium intermediate can react intermolecularly or intramolecularly with amines or alcohols to form ketones, amides, or esters, respectively, or with alkenes to yield unsaturated ketones.1a,5 Thus treatment of vinyl triflates with Pd(OAc)2, PPh3, and MeOH in DMF results in one-carbon homologation of the original ketone to a,b-unsaturated esters.72 Benzopyrans with a cis-fused g-lactone can be prepared in high yield from o-disubstituted arenes by carbonylation of the intermediate formed upon intramolecular attack of the phenol on the terminal alkene (eq 34). The sequence affords the cis-fused lactone, regardless of the relative stereochemistry of the hydroxide and the methylenepalladium in the intermediate.73

Vinyl triflates undergo carbonylative coupling with terminal alkynes to yield alkenyl alkynyl ketones in a reaction catalyzed by palladium acetate and dppp in the presence of triethylamine.74 When applied to 2-hydroxyaryl iodides (eq 35), subsequent attack by the hydroxyl group on the alkyne yielded flavones and aurones. The cyclization result depends on the reaction conditions. 1,8-Diazabicyclo[5.4.0]undec-7-ene as base in DMF yields mainly the six-membered ring flavone, whereas the only product observed when employing potassium acetate in anisole was the five-membered ring aurone.75

Chiral a,b-unsaturated oxazolines can be obtained by a carbonylation-amidation of enol triflates or aryl halides with chiral amino alcohols (eq 36).76 The palladium catalyst can be either Pd(PPh3)4, Bis(dibenzylideneacetone)palladium(0) and PPh3, or Pd(OAc)2 and dppp in the presence of triethylamine.

N-Substituted phthalimides are obtained from coupling o-dihalo aromatics with carbon monoxide and primary amines. The best catalysts for this reaction, however, were PdCl2L2 species.77

Formation of Heterocyclic Compounds.

Coupling reactions of 2-halophenols or anilines with molecules containing functionalities that allow the heteroatom nucleophile to form a heterocycle either by intramolecular oxy- or amino-palladation of an alkene, or by lactone or lactam formation, has already been mentioned in the preceding sections.78 In addition to these powerful techniques, carbon-heteroatom bonds can be constructed in steps prior to the cyclization. For example, the enamine 3-((2-bromoaryl)amino)cyclohex-2-en-1-one undergoes a palladium-catalyzed intramolecular coupling to yield 1,2-dihydrocarbazoles in moderate yields.79 Intramolecular coupling of 2-iodoaryl allyl amines gave high yields of indoles under phase-transfer conditions (eq 37).80 The corresponding aryl allyl ethers require the additional presence of sodium formate in order to give benzofurans in good yields (eq 38).

The principle has been applied to the preparation of pharmaceutically interesting heterocyclic compounds,81 and to the assembly of fused or bridged polycyclic systems containing quaternary centers.82

Formation of Carbocycles.

By Intramolecular Heck Coupling.

1-Bromo-1,5-dienes and 2-bromo-1,6-dienes cyclize in the presence of Piperidine and a palladium acetate-tri-o-tolylphosphine catalyst to produce cyclopentene derivatives (eq 39).83 2-Bromo-1,7-octadiene, when subjected to the same reaction conditions, cyclized to yield a mixture of six and five-membered ring products, whereas competing dimerization and polymerization was observed for the more reactive 2-bromo-1,5 dienes.

The influence of phosphine ligands, added salts, and the type of metal catalyst on the selectivity of the cyclization have been studied.84 With K2CO3 as base, Wilkinson's catalyst (Chlorotris(triphenylphosphine)rhodium(I)) showed higher selectivity for the formation of 1,2-dimethylenecyclopentanes over 1-methylene-2-cyclohexenes than the palladium acetate-triphenylphosphine catalyst.

The palladium-catalyzed cyclization of acyclic polyenes to form polycyclic systems (eq 40) constitutes a very powerful further development of the above method. s-Alkylpalladium intermediates, produced in an intramolecular Heck reaction, can be efficiently trapped by neighboring alkenes to give bis-cyclization products of either spiro or fused geometry. The second cyclization also produces a s-alkylpalladium intermediate which can also be trapped.

1-Iodo-1,4- and -1,5-dienes can be transformed into a-methylenecyclopentenones and -hexenones, respectively, by palladium-catalyzed carbonylation and subsequent intramolecular coupling.85 Better results, however, were obtained using Tetrakis(triphenylphosphine)palladium(0).

Via (p-Allyl)palladium Intermediates.

Allylic substitution, by nucleophilic attack on (p-allyl)palladium complexes generated from allylic substrates, are most often catalyzed by Pd0-phosphine complexes.86,87 There are, however, a few examples of intramolecular reactions where the active catalyst is generated in situ from palladium acetate. For example, ethyl 3-oxo-8-phenoxy-6-octenoate reacts to yield cyclic ketones in the presence of catalytic amounts of palladium diacetate and a phosphine or phosphite ligand (eq 41).88 The product distribution between five- or seven-membered rings depends on the ligand employed and the solvent used. With a chiral phosphine, (E)-methyl 3-oxo-9-methoxycarbonyloxy-7-nonenoate was cyclized to give (R)-3-vinylcyclohexane with 41-48% ee.89

Another example is based on the palladium-catalyzed 1,4-chloroacetoxylation methodology,21,22,29 where a common intermediate, by proper choice of reaction conditions, can be transformed into cis- or trans-annulated products.89

By Cyclization of Alkenyl Silyl Enol Ethers.

Treatment of alkenyl silyl enol ethers with stoichiometric amounts of palladium acetate induces an intramolecular attack to form carbacycles (eqs 42 and 43). Good to high yields of a,b-unsaturated ketones were obtained.90

With slightly different substrates, the observed products were not a,b-unsaturated ketones but nonconjugated bicycloalkenones.91 The method, which affords bridged (eq 44) as well as spirocyclic (eq 45) bicycloalkenones in acceptable to good yields, has been applied to the preparation of bicyclo[3.3.1]nonadienones92 and to a total synthesis of quadrone.93

By Cyclization of Simple Dienes.

Treatment of 1,5-dienes with catalytic amounts of Pd(OAc)2 and benzoquinone with MnO2 as stoichiometric oxidant in acetic acid leads to an oxidative cyclization reaction (eqs 46, 47).94 The reaction normally yield cyclopentanes with acetate and exomethylene groups in a 1,3-configurational relationship.95

The selectivity of the reaction depends strongly upon the structure of the starting alkene. Substituents in the 1,3- and/or 4-positions of the diene are tolerated, but not in the 2- and 5-positions; thus the reaction most likely proceeds via an acetoxypalladation of the 1,2-double bond followed by insertion of the 5,6-alkene into the palladium-carbon s-bond and subsequent reductive elimination.96 The cyclization is compatible with the presence of several types of functional groups such as alcohols, acetate (even in the allylic position), ethers, nitriles, and carboxylic acids. An improved diastereoselectivity was observed in reactions carried out with chiral nucleophiles in the presence of water-containing molecular sieves.97 The synthetic utility of the reaction was demonstrated by a synthesis of diquinanes.98

By Cycloisomerization of Enynes.

When 1,6-enynes, prepared by a Pd(PPh3)4-catalyzed coupling of an allylic carboxylate with dimethyl propargylmalonate anion, is treated with a catalytic amount of a palladium(II) species, a carbocyclization leading to cyclopentanes carrying an exocyclic double bond occurs (eq 48).99 Yields of 1,4-dienes ranging from 50% to 85% are observed. If the enyne has oxygen substituents in the allylic positions, the reaction instead yields a 1,3-diene (eq 49).100 Cycloisomerization could also be induced for internal enynes carrying alkynic electron-withdrawing substituents.101

By Cycloaddition.

Palladium acetate, combined with (i-PrO)3P, catalyzes the [2 + 3] cycloaddition of trimethylenemethane to alkenes carrying electron-withdrawing substituents (eq 50). The yields of five-membered carbocycle varied from 35-89%.102 With 1,3-dienes, a [4 + 3] cycloaddition gave seven-membered ring products in good yield (eq 51), and in some cases excellent diastereomeric ratios were observed.102

By Cyclopropanation.

Alkenes undergo a cyclopropanation reaction with diazo compounds (caution)103 such as Diazomethane or Ethyl Diazoacetate in the presence of a catalytic amount of palladium acetate.104 With diazomethane, a selective cyclopropanation of terminal double bonds can be obtained (eq 52).105

With diazo esters, the regioselectivity in transition metal-catalyzed cyclopropanation of dienes and trienes was generally not as good with palladium acetate as with a rhodium carboxylate catalyst,106 although both palladium and rhodium carboxylates were better catalysts for the reaction than Copper(II) Trifluoromethanesulfonate. a,b-Unsaturated carbonyl compounds also undergo palladium-catalyzed cyclopropanation, yielding the corresponding cyclopropyl ketones (eq 53) and esters (eq 54).107

Asymmetric cyclopropanations of a,b-unsaturated carboxylic acid derivatives with CH2N2 proceeds in greater than 97.6% diastereomeric excess when Oppolzer's sultam is used as a chiral handle.108 The stereoselectivity of the reaction was found to be temperature dependent, with the best results obtained at higher temperatures. A coupling of norbornene and a cis-alkenyl iodide in the presence of a hydride donor resulted in a cyclopropanation of the norbornene (eq 55).65

Other examples of palladium-catalyzed cyclopropanation are intramolecular processes catalyzed by, for example, Dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II),109 Tetrakis(triphenylphosphine)palladium(0),110 or Bis(allyl)di-m-chlorodipalladium.111

Oxidations.

Carbonyl Compounds by Oxidation of Alcohols and Aldehydes.

Salts of palladium, in particular PdCl2 in the presence of a base, catalyze the CCl4 oxidation of alcohols to aldehydes and ketones. Allylic alcohols carrying a terminal double bond are transformed to 4,4,4-trichloro ketones at 110 °C, but yield halohydrins at 40 °C. These can be transformed to the corresponding trichloro ketones under catalysis of palladium acetate (eq 56).112 The latter transformation could be useful for the formation of ketones from internal alkenes provided the halohydrin formation is regioselective.

Secondary alcohols can be oxidized in high yield to the corresponding ketones by bromobenzene in a reaction catalyzed by palladium acetate in the presence of a base and a phosphine ligand. These reaction conditions, when applied to D2-, D3-, and D4-unsaturated secondary alcohols, yielded product mixtures. When the stoichiometric oxidant was bromomesitylene and a Pd(OAc)2:PPh3 ratio of 1:2 was used, the oxidation proceeded smoothly for a wide variety of alcohols (eqs 57 and 58).113

Oxidation of aldehydes in the presence of Morpholine proceeded effectively to yield 50-100% of the corresponding morpholine amides.114

a,b-Unsaturated Ketones and Aldehydes by Oxidation of Enolates.

Palladium diacetate-mediated dehydrosilylation of silyl enol ethers proceeds to yield unsaturated ketones in high chemical yield and with good selectivity for the formation of (E)-alkenes (eqs 59 and 60).115 Although stoichiometric amounts of Pd(OAc)2 are employed, this method for dehydrogenation has been employed in key steps in the total synthesis of some polycyclic natural products.116

Oxidation of primary vinyl methyl ethers yields a,b-unsaturated aldehydes. The method has been applied to a transformation of saturated aldehydes to one-carbon homologated unsaturated aldehydes (eq 61) by a Wittig reaction and subsequent palladium acetate-mediated oxidation.117 The oxidations, which were carried out in NaHCO3-containing aqueous acetonitrile, yielded 50-96% of the unsaturated aldehydes.

Allyl b-keto carboxylates and allyl enol carbonates undergo a palladium-catalyzed decarboxylation-dehydrogenation to yield a,b-unsaturated ketones in usually high chemical yield and with good selectivity.118 Following this approach, it was possible to obtain 2-methyl-2-cyclopentenone in two steps from diallyl adipate in a procedure that could be convenient for large-scale preparations (eq 62).119

Activation of Phenyl and Benzyl C-H bonds: Oxidation of Aromatics.

If palladium diacetate is heated in an aromatic solvent, oxidation of the solvent by cleavage-substitution of a C-H bond occurs, resulting in a mixture of products.120 Depending on the reaction conditions, biaryls and phenyl or benzyl acetates are isolated. Seemingly small changes can result in large changes in product distribution (eq 63). For example, the oxidation of toluene by a palladium(II) salt yields benzyl acetate in reactions mediated by palladium acetate, whereas bitolyls are the major products in reactions carried out in the presence of chloride ions (eq 63).121

Oxygen Nucleophiles.

A reagent such as permanganate oxidizes toluene to benzoic acid,122 whereas benzylic oxidation by palladium acetate results in benzyl alcohol derivatives. The oxidation is favored by electron-releasing substituents in the phenyl ring.123 Catalytic amounts of palladium acetate and tin diacetate, in combination with air, effects an efficient palladium-catalyzed benzylic oxidation of toluene and xylenes. For the latter substrates, the a,a-diacetate is the main product.124 A mixed palladium diacetate-copper diacetate catalyst has also been found to selectively catalyze the benzylic acyloxylation of toluene (eq 64).125

Benzene can be oxidized to phenol by molecular oxygen in the presence of catalytic amounts of palladium diacetate and 1,10-phenanthroline (eq 65).126 If potassium peroxydisulfate is used as a stoichiometric oxidant with 2,2-bipyridyl as a ligand, a process yielding mainly m-acetoxylated aromatics results (eq 66).127

Palladium diacetate in Trifluoroacetic Acid (Pd(O2CCF3)2) gives a mixture of o- and p-trifluoroacetoxylated products.128 The reagent is also capable of oxidizing saturated hydrocarbons such as adamantane and methane. In the presence of carbon monoxide and with sodium acetate as co-catalyst, carbonylation of aromatic C-H bonds occurs, eventually yielding acid anhydrides.129

Naphthalenes and methylbenzenes can be oxidized to p-quinones by aqueous H2O2 in acetic acid catalyzed by a PdII-DOWEX polystyrene resin. Yields and selectivities are generally higher for the methylnaphthalenes (50-65% p-quinone) than for methylbenzenes (3-8%).130

Carbon Nucleophiles.

Palladium-mediated homocoupling of substituted arenes generally yields mixtures of all possible coupling products. If the reaction is carried out with a catalytic amount of palladium diacetate and with Thallium(III) Trifluoroacetate as stoichiometric oxidant (eq 67), aryls carrying substituents such as alkyl or halide afford mainly the 4,4-biaryls in yields ranging from 60% (R = ethyl) to 98% (R = H).131 Biaryls can also be formed without the palladium catalyst.132

Oxidative substitution of aromatics with a heteroatom substituent in a benzylic position generally yields o-substituted products.1b,5 The reaction probably proceeds via a cyclopalladated phenylpalladium species (eq 68), which decomposes to form substituted products. For example, the alkylation of a number of acetanilides proceeds with high selectivity for the o-alkylated product.133

With t-butyl perbenzoate as hydrogen acceptor, it is possible to couple benzene or furans with alkenes. In the absence of alkene, benzoxylation of the aromatic compound is observed.134

When heated in palladium acetate-containing acetic acid, diphenyl ether, diphenylamine, benzophenone, and benzanilide gave high yields of cyclized products (eq 69). A large number of ring substituents were tolerated in the cyclization.135

Oxidation of benzoquinones and naphthoquinones by palladium diacetate in arene-containing acetic acid gave the corresponding aryl-substituted quinones (eq 70).136 Treatment of 1,4-naphthoquinone with aromatic heterocycles, for example furfural, 2-acetylfuran, 2-acetylthiophene, and 4-pyrone, yielded the corresponding 2-heteroaryl-substituted 1,4-naphthoquinones.

Palladium-Catalyzed Reductions.

Reduction of Alkynes.

Alkynes are selectively reduced to (Z)-alkenes by a reduction catalyst prepared from NaH, t-C5H11OH, and Pd(OAc)2 (6:2:1) in THF. The reactions, carried out in the presence of quinoline under near atmospheric pressure of H2, are self-terminating at the semihydrogenated stage, and are more selective than the corresponding reductions catalyzed by Lindlar's catalyst. Omitting the t-C5H11OH gave a catalyst that effected complete reduction.137

Alkenyldialkylboranes from internal alkynes undergo palladium acetate-catalyzed protonolysis to yield (Z)-alkenes under neutral conditions and (E)-alkenes in the presence of Et3N.138

Hydrogenolysis of Allylic Heterosubstituents.

Chemoselective removal of an allylic heterosubstituent in the presence of sensitive functional groups is a sometimes difficult transformation since nucleophilic displacement with hydride donors is efficient only if the heterosubstituent is a good leaving group or the hydride donor is powerful. However, removal of an allylic heterosubstituent is a reaction readily performed by Pd0.87 The resulting (p-allyl)palladium complexes are readily attacked by hydride nucleophiles (eq 71). Thus, mild hydride donors such as Sodium Borohydride or Sodium Cyanoborohydride can be employed.139 Treatment of allylic oxygen, sulfur, and selenium functional groups with a combination of Pd(PPh3)4 and Lithium Triethylborohydride yielded the corresponding hydride-substituted compounds with good regio- and stereoselectivity, with the more highly substituted (E)-alkene as the predominant product (eq 71).140 Similar results are observed for all hydride donor systems but one: that derived from formic acid yields predominantly or exclusively the less substituted alkene (eq 71).142

The regio- and stereoselective hydride attack on the more substituted terminus of (p-allyl)palladium complexes derived from allylic formates has been applied to the palladium acetate-n-Bu3P-catalyzed formation of ring junctions in hydrindane, decalin, and steroid systems, and to stereospecific generation of steroidal side-chain epimers.141

Deoxygenation of Carbonyls.

Carbonyl compounds can be deoxygenated to form alkenes in a palladium-catalyzed reduction of enol triflates (eq 72). The reaction is quite general, and has been applied to aryl as well as alkyl enol triflates.142

Related Reagents.

Sodium Hydride-Palladium(II) Acetate-Sodium t-Pentoxide; Thallium(III) Trifluoroacetate--Palladium(II) Acetate.


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Helena Grennberg

University of Uppsala, Sweden



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