Direct arylations palladium acetate

Several reports have been made of a successful catalyzed addition/ substitution reaction resulting in direct attachment of phosphorus to aromatic rings. The preparation of mixed triarylphosphines has been accomplished by the reaction of tin- or silicon-substituted diphe-nylphosphines with aryl halides catalyzed by palladium reagents.74 A similar transformation has also been reported using nickel catalysis.75 The addition/substitution of diphenylphosphine to triflate functionalized phenolic linkages has been of use for the preparation of substances as analogues of tyrosine-related amino acid derivatives, accomplished with catalysis by palladium acetate (Equation 4.29).76... 

Although the Sonogashira reaction is normally performed with a copper cocatalyst, a copper-free, one-pot procedure for direct coupling with l-aryl-2-trimethylsilylacetylenes has been developed <2005T2697>. The procedure uses a mixture of palladium acetate and tri(o-tolyl)phosphine as catalyst in the presence of tetra- -butylammonium chloride... 

Vinyl ethers yield acylated vinyl ethers when they are reacted with aroyl chlorides or 3-thienylcarbo-nyl chloride, triethylamine and a palladium acetate catalyst at 60-70 C (equation 43).103 The products of this reaction are useful 1,3-dicaibonyl equivalents. At higher temperatures the reaction yields arylated vinyl ethers. It is interesting that the acylations of vinyl ethers are regioselective while the direct aryla-tions are usually not.104... 

A nonclassical substrate for the Heck reaction is 2,3-epoxycyclohexanone. The reactivity of this molecule under Heck coupling conditions is most likely attributed to its in situ isomerization to 1,2-cyclohexanedione. The 1,2-diketone subsequently reacts with aryl bromides as an olefin via the enol tautomer. Thus, within 5 to 30 min of directed microwave heating of the aqueous PEG mixture, up to 13 different C3-arylations were conducted using less than 0.05 mol % palladium acetate and no phosphine ligand (Scheme 12) [51]. 

Such an arylation reactioncanneverthelessberendered regioselectiveifcoordinating atoms are present in the starting molecule at the appropriate position, directing the C-H activation at this position. Thus, 2-arylbenzoxazoles have been regioselectively arylated in the presence of palladium acetate and silver acetate (Scheme 10.54).86... 

The presence of chelating groups in those complexes is necessary to stabilize the intermediate aryl-palladium complex for isolation but it does not seem necessary to cause palladation. The chelating group does, however, tremendously accelerate the palladation. Aromatic compounds reactive to electrophilic substitution apparently undergo palladation with palladium acetate in acetic acid solution fairly readily at 100 °C or above. Of course, the arylpalladium acetates presumably formed, are not stable under these conditions, and they decompose very rapidly into biaryls and palladium metal 34,35,36) ag do aryl palladium salts prepared by the exchange route 24>. If the direct palladation is carried out in the presence of suitable olefins, arylation can be achieved, so far, however, only in poor yields, arid with concurrent loss of stereospecificity and formation of isomers and other side products 37.38). 

Two methodologies for the direct C-2 arylation of thiazoles have been reported. The first one is mediated by both palladium and copper <07T1970>. Thus, the C-2 arylation of thiazole and benzothiazole with aryl iodides is carried out using copper iodide (2 equiv.) and a catalytic amount of palladium acetate under base-free conditions. The other method involves copper-catalyzed arylation with aryl iodides in the presence of lithium t-butoxide <07JA12404>. In general, reactions with lithium tert-butoxide provide better yields than those with potassium fert-butoxide. In addition, arylation with phenyl bromide, chloride or tosylate fails to provide any desired arylation products. 

Head-to-tail dimerisation of methyl acrylate to the dimethyl ester of 2-methylenepentane-dioic acid (126) occurred in 82-85% yield in the presence of catalytic amounts of P(RNCH2CH2)3N with R = PP, Bu or Bz but the less sterically hindered proazaphosphatrane with R = Me, gave oligomer or pol-ymer. The proazaphosphatrane, P(RNCH2CH2)3N with R = Bu also acts as an effective ligand for the palladium-catalyzed direct arylation of ethyl cyano-acetate (127) with aryl bromides (e.g. 128) to form (129) in high yield. ... 

O/t/20-arylation of benzoic acids is often preferable to ortho-arylation of benzamides if conversion of the amide moiety to other functional groups is desired. However, only a few reports have dealt with the orf/io-functionalization of free benzoic acids due to challenges that involve such transformations. The reactions can be complicated by decarboxylation of the product and the starting material. Despite those difficulties, several methods for direct o/t/io-arylation of benzoic acids have been developed. Yu has shown that arylboronates are effective in arylation of benzoic acids under palladium catalysis [59], The reactions require the presence of palladium acetate catalyst, silver carbonate oxidant, and benzoquinone. Even more interestingly, the procedure is applicable to the arylation of unactivated sp3 C-H bonds in tertiary carboxylic acids such as pivalic acid (Scheme 13) if aryl iodide coupling partner is used. Aryl trifluoroborates can also be used [60],... 

In 1981, Itahara reported the palladium acetate-mediated direct arylation of pyrroles and indoles with arenes [59], With (sub)stoichiometric Pd(OAc)2 in benzene and acetic acid, arylation of 1-benzoylpyrrole and 1-acetylindole occurred with moderate to excellent conversions, but gave generally low yields of the desired cross-coupling products (Scheme 14). Direct arylation of isoxazole in the presence of stoichiometric amount of Pd(OAc)2 was also reported by Nakamura et al. [60]. 

Recently, Zhang and coworkers reported a direct palladium-catalyzed C-2 arylation of indoles with potassium aryltrifluoroborate salts [204]. Remarkably, the direct arylation took place at room temperature when acetic acid was used as the solvent. 

Oestxeich found that the direct arylation of indolines could be accomplished without over oxidation to the corresponding indole under palladium-catalysis with air (open flask), oxygen (balloon), or copper(II) acetate as the oxidant. Indolines can be unsubstituted or substituted as C2/C3 and the reaction performs well on gram scale (250, 18 examples, 18—90% isolated yield) (140L6020).A directed C2-functionalization/C7-alkenylation was discovered by Xu,Yi, and colleagues. With a rhodium catalyst, indole derivatives were functionalized with acetates at C2 (22 examples, 62—92% yield) the newly obtained products could be alkenylated at C7 with a rhodium/copper system (251,3 examples, 68—78% yield) (14CC6483). 

Arylation of Quinoline N-Oxides and Pyridines N-Oxides. An efficient protocol to directly arylate quinoline A-oxides was developed using palladium acetate as the catalyst and potassium carbonate as the hase. A survey of different phosphines demonstrated that the sterically less encumbered di-tert-butyl(methyl)phosphonium tetrafluoroborate provides higher yields relative to tri-iert-hutylphosphine. Using this protocol, 15 quinohne A-oxides were arylated in good to excellent yields (eq 1). ... 

Arylation of Thiazoles and Oxazoles. The protocol that was previously developed for the C-H activation of azine and diazine (V-oxides with aryl triflates was used to effect the arylation of flve-membered ring heterocycles, such as oxazoles and thiazoles. In contrast to another protocol that was previously reported by the same group, the transformation did not require an V-oxide function. However, in order to direct the arylation at the C4-position, to prevent the formation of a mixture of regioisomers, and to minimize the generation of diarylated products, a C5-chloride was used as a blocking group. The procedure, which is promoted by palladium acetate and di-tert-butyl(methyl)phosphonium tetrafluoroborate, uses an aryl bromide as the electrophile. 

Arylation of Other Heterocycles. Y)i-tert-hutyl(methyl)phosphonium tetrafluoroborate has also been used for the C-H arylation reaction of other heterocycles. For exart5)le, the direct C5-arylation of imidazo[l,5-a]pyrazines was disclosed using this ligand, in combination with palladium acetate as the catalyst (eq 24). ... 

More complex mechanisms may involve the deprotonation of a substrate that is bound to the transition metal. The bidentate nature of the acetate anion is critical in some palladium-catalyzed direct arylation/C-H activation reactions. In these reactions, the acetate moiety participates in a concerted metalation-deprotonation (CMD) step wherein a transition metal-bound acetate group removes a proton from an aryl C(sp2)-H bond as the metal-C(sp2) bond is being formed (eq 32). Many acetate bases have been used (e.g., KOAc, NaOAc, CsOAc, and CsPiv), and the optimal base used in these reactions is generally determined during the optimization process. 

Arene Amination. Alternative methods for the A-arylation of N-H-containing heterocycles that proceed directly with arenes (i.e., where aryl halides are not required) have emerged in the literature. In a recently reported procedure, a succinimide derivative was iV-arylated using palladium acetate as the catalyst, tri-ferf-butylphosphine as the ligand, and (diacetoxyiodo)benzene as a stoichiometric oxidant. This reaction allows the formation of ster-ically controlled products with monosubstituted arenes, yielding mainly meta- and / ara-arylated products and di- and trisubsti-tuted arenes, mostly providing the products of arylation at the meta-position (eq 15). ... 

C-H Activation. Tri-terf-butylphosphine, combined with palladium acetate, acts as an effective catalytic system for the direct Ar-H arylation of heterocycles. This system has been applied for the functionalization of various five- and six-membered ring heterocycles containing one or more heteroatoms. A base (CS2CO3,... 

Palladium-catalyzed Direct Arylation of Pyridine N-Oxides, Pyrazine N-Oxides, Pyridazine N-Oxides, Pyrimidine N-Oxides, and Thiazole N-Oxides. Pyridine W-oxides can be efficiently ary-lated at the C2 position using aryl halides as the electrophile, palladium acetate as the catalyst, tri-tert-butylphosphonium tetraflu-oroborate as the ligand, and potassium carbonate as the base (eq 19). In this protocol, 3 equiv of pyridine Al-oxide are utilized to generate the corresponding 2-aryl derivatives. ... 

The comhination of palladium acetate and tn-tert-hutylphosphonium tetrafluorohorate was moreover found to be remarkably efficient in the site-selective sp direct Ar-H arylation of azine and diazineiV-oxides possessing a methyl group... 

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