Palladium acetate arylation/oxidation

Intramolecular Heck reactions are particularly efficient and have been used considerably in organic synthesis.In situ reduction of palladium acetate and oxidative addition of the resulting palladium(O) into the aryl iodide 210 gave an... 

When furan or substituted furans were subjected to the classic oxidative coupling conditions [Pd(OAc)2 in refluxing HOAc], 2,2 -bifuran was the major product, whereas 2,3 -bifuran was a minor product [12,13]. Similar results were observed for the arylation of furans using Pd(OAc)2 [14]. The oxidative couplings of furan or benzo[i]furan with olefins also suffered from inefficiency [15]. These reactions consume at least one equivalent of palladium acetate, and therefore have limited synthetic utility. 

Menendez et al. reported the synthesis of murrayafoline A (7) by palladium(II)-mediated oxidative double C-H activation of a diarylamine assisted by microwave irradiation (585). The aniline derivative 598 was obtained by O-methylation of 5-methyl-2-nitrophenol (625) followed by catalytic hydrogenation. The required diarylamine 654 was obtained by N-arylation of the aniline derivative 598 with phenyllead triacetate (653) in the presence of copper(II) acetate. Under microwave-assisted conditions, in the presence of more than the stoichiometric amount of palladium(II) acetate and a trace of dimethylformamide, the diarylamine 654 was cyclodehydrogenated to murrayafoline A (7) (585) (Scheme 5.47). 

The Heck reactions depicted so far all involve the coupling of halopyridines and other olefins. The alternate approach, coupling of a vinylpyridine with an aryl halide is also feasible, although less commonly employed. 4-Vinylpyridine was coupled successfully with diethyl 4-bromobenzylphosphonate (7.50.) in the presence of a highly active catalyst system consisting of palladium acetate and tn-o-tolylphosphine to give the desired product in 89% yield, which was used for grafting the pyridine moiety onto metal oxides.70... 

Applications of this reaction are not limited to advanced materials, but can be applied to natural product synthesis. Indeed, indoles have quite recently (in 2008) been arylated in the presence of palladium acetate and silver oxide (Scheme 10.52).84... 

Commercially available palladium compounds in the presence of various ligands have often been used as catalysts (Table 3-1). The first choice is often the air-stable and relatively inexpensive palladium acetate however, several of the other published variants can be preferable in certain applications. It is commonly assumed that the palladium(II) species is reduced in situ by the solvent, the alkene [11], the amine [12] or the added ligand (frequently a phosphane, which is oxidized to a phosphane oxide) [13]. In some cases, highly dispersed elemental palladium on charcoal can be applied. In the case of alkenyl or aryl bromides, phosphanes are necessary to avoid precipitation of palladium black (c.f., however. Section 3.2.4.), whereas iodides have been reported to be less reactive in the presence of phosphanes. Triflates have been found to be more reactive in the presence of chloride ions, as the chloride ligand is more easily removed from palladium than the tiiflate ion [14], However, this also has become questionable, because successful coupling reactions of alkenyl triflates have been performed in the absence of chloride ions [15]. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

Imidazole /V-oxide substrates may be used in a similar fashion. Initial investigations revealed that the use of palladium acetate in conjunction with an electron deficient 4-fluorophenylphosphine in acetonitrile at 70 °C provides C2 arylation in high yields. With the goal of achieving the same reactivity at or near room temperature it was determined that the use of palladium acetate in conjunction with a Buchwald ligand, catalytic copper bromide and 30 mol% pivalic acid in acetonitrile could also achieve high yields of C2 arylation at 25 °C. As was the case with thiazole V-oxides. if the C2 and C5 positions of the imidazole are blocked C4 arylation may also be achieved in synthetically useful yield (Scheme 15). 

Several reports have appeared describing anilide arylation by arenes that do not involve coupling of a C-H bond with a C-Hal bond and thus will be discussed only briefly. Buchwald has shown that oxidative arylation of anilides takes place in presence of 5-10 mol% of palladium acetate and catalytic DMSO in trifluoroacetic acid solvent by using oxygen as the terminal oxidant [52], Pivalanilides afford the best results. Notably, only about four equivalents of the arene component are required for efficient arylation. However, regioisomer mixtures were obtained if monosubstituted arenes were used as the coupling components. 

Shi has reported a method for /V-alkylanilidc arylation by simple arenes [53], The reaction conditions include heating the anilide with excess arene in propionic acid in the presence of catalytic palladium acetate and copper triflate under oxygen atmosphere. Use of monosubstituted arenes leads to the formation of isomer mixtures however, from the point of atom economy C-H/C-H couplings are the most efficient way for formation of C-C bonds if oxygen is used as the terminal oxidant. Shi has also reported that anilides can be coupled with arylboronic acids and trialkoxyaryl-silanes [54, 55], Silver and copper salts are used as terminal oxidants. 

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],... 

Arylation of indoles can also be carried out via arylpalladium acetates generated from boronic acids or trifluoroborate salts " and palladium acetate. The reactions are catalytic in palladium, cycling of the Pd(ll) being effected by the use of a re-oxidant (Cu(ll)/air). The reaction works well on NH and A-methyl indoles but fails with the A-acetyl derivative. 

A construction of the carbazole framework involving copper(ll)-catalyzed aryla-mine arylation and palladium(ll)-mediated oxidative cyclization has been reported by Menendez et al. (Scheme 41) [190, 191]. The diarylamines 95 were obtained by copper(ll) acetate-catalyzed N-arylation of arylamines 31 with phe-nyllead triacetate (183) using Barton s conditions [192]. Subsequent oxidative cyclization using palladium(ll) acetate under microwave irradiation afforded the carbazoles 32. This procedure was applied to the synthesis of murrayafoline A (188) [190]. 

Palladium-mediated oxidative arylation of thiophene has also been reported <8SJ0CS272>. Thus, treatment of 2-formylthiophene with palladium acetate in a mixture of acetic add and benzene gave 2-formyl-4-phenylthiophene (30%), 2-formyl-5-phenylthiophene (5%) and 5,5 -diformyl-2,2 -bithienyl (16%). It has been suggested that preliminary palladation of benzene would lead to 4-phenylation of the thiophene, while palladation of the thiophene would produce the 5-phenylated product. 

Examples of the formylation of aryl halides with synthesis gas catalyzed by palladium complexes are summarized in Equation 19.90. These reactions relied upon the development of ligands with particular steric and electronic properties. The dia-damantyl-n-butyl phosphine shown in the equation, in combination with palladium acetate, leads to the formation of aromatic aldehydes in high yields from electron-rich and electron-poor aryl bromides. Reactions of nitroarenes and 2-bromopyridine provided the aldehydes in low yield, but other examples occurred in satisfactor) yield with only 0.1-0.75 mol % catalyst. The identity of the base is important in this process, and TMEDA was the most effective base. The mechanism of this process was not proposed in the initial work, but is likely to occur by oxidative addition of the aryl halide, insertion of the carbon monoxide into the palladium-aryl bond, and a combination of hydrogenolysis of the acyl intermediate and elimination of hydrogen halide to regenerate palladium(O). The base would then be involved in the hydrogenol5 sis and consumption of hydrogen halide. 

Fused thiophene-cyclopentanes 39 can be synthesized by intramolecular dual C-H activation of 2-arylthiophenes 38 (Scheme 17, Table 10) [67]. The cross-coupling proceeds moderately well using palladium(ll) acetate as catalyst and silver (1) carbonate as oxidant. When the thiophene moiety is not substituted at positimi 2, homocoupling occurs easily. However, in contrast to this direct route, a two-step sequence consisting of a prior bromination and a subsequent palladium-catalyzed arylation is much more effective forming the fused thiophene-cyclopentane 39 in a yield of 83%. 

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). ... 

A modified protocol involving pivahc acid as an additive was developed in order to perform the arylation of pyridine A-oxides with aryl triflates as the electrophile. Similar to other Het-H functionalization reactions, palladium acetate is used as the catalyst in conjunction with di-/eri-hutyl(methyl)phosphonium tetrafluoroborate as the ligand, leading to the efficient arylation of a diverse set of pyridine (eq 4), pyridazine (eq 5), pyrimidine (eq 6), and pyrazine A-oxides (eq 7). This method also minimizes... 

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. 

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