Palladium oxidative arylations

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

More recently, reductive elimination of aryl ethers has been reported from complexes that lack the activating substituent on the palladium-bound aryl group (Equation (55)). These complexes contain sterically hindered phosphine ligands, and these results demonstrate how steric effects of the dative ligand can overcome the electronic constraints of the reaction.112,113 Reductive elimination of oxygen heterocycles upon oxidation of nickel oxametallacycles has also been reported, but yields of the organic product were lower than they were for oxidatively induced reductive eliminations of alkylamines from nickel(II) mentioned above 215-217... 

The Heck reaction involves the coupling of an organopalladium species formed by oxidative addition to an alkene followed by /S-hydride elimination. The product is an alkene in which a vinyl hydrogen on the original alkene is replaced by die organic group on palladium. Thus aryl and alkenyl halides can be coupled to alkenes. 

Scheme 2. Oxidative arylation of alkenes by electrophilic palladium (I I).

In a recent review it was argued that such additives of copper, benzoquinone, and HPMOV are not really needed all that is needed is the presence of oxidation-resistant ligands that prevent palladium metal formation [15]. Indeed, activation of the C-H bond is not as slow as, for example, the Wacker reaction of ethene in which reoxidation of palladium must be performed by copper oxidation, although in this catalytic system the additives may still play a role in stabilizing the intermediate low-valent palladium species and thus prevent catalyst decomposition. This thesis was corroborated by the work of de Vos and Jacobs, who showed that addition of benzoic acid to the oxidative arylation reaction in the presence of oxygen led to superior results in the coupling of a variety of substituted arenes with acrylates, cinnamates, and ,/f-unsaturated ketones. Very good yields and TON up to 762 were obtained at 90 °C. A mixture of the o, m, and p isomers is obtained if substituted arenes are used [16]. 

As can be seen in the scheme below, a series of substituted 2-(2-aminothiazol-4-yl)-benzo[ ]furans with inhibitory activity for leukotriene B4 were made from benzofurans via acylation, followed by Hantzsch thiazole formation <070BC3083>. 2-Substituted benzo[ ]furans could also be generated via an aerobic oxidative coupling of 2-unsubstituted benzo[ ]furans with arenes through the palladium-catalyzed double C-H activation <07OL3137>. In addition, 2,3-diarylbenzo h I uran could be constructed by a palladium-catalyzed arylation of benzo[6]furan with an aryl chloride in the presence of a bulky, and electron-rich phosphine <07OL1449>. 

The generally accepted mechanism for the amine arylation is shown in Scheme 1. The catalytic cycle begins with the oxidative addition of the aryl halide (or sulfonate) by Pd (0). The palladium (II) aryl amide can be formed either by direct displacement of the halide (or sulfonate) by the amide or via the intermediacy of a palladium (II) alkoxide [19]. Reductive elimination of the C-N bond results in the formation of the desired arylamine and regeneration of the Pd (0) catalyst [lie,20]. 

Palladium-catalyzed arylation and vinylation of alkene is referred to as the Mizoroki-Heck reaction and is one of the most widely used Pd(0)-catalyzed C-C bond formations in organic synthesis. However, the reaction has not been extensively employed for C-glycosylation [96]. The example shown in O Scheme 67 outlines the reaction of iodopyridine and furanose gly-cal for the synthesis of C-nucleoside [97]. The mechanism began with the oxidative addition of iodopyridine to Pd(0) catalyst, and the resulting organo-palladium species was inserted by... 

Magnesium probably undergoes oxidative insertion more easily than the other metals we use, but lithium, used as wire, hammered-out sheets, or even slices3 inserts quite easily into alkyl or aryl halides, particularly in THF solution.4 A one-electron donor like lithium probably follows a similar pathway to Mg but with single electron arrows. Palladium forms aryl Pd(II) derivatives in the same way,5 but the Pd must be added as a soluble complex like Pd(Ph3P)4. Other transition metals are much less successful. 

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. 

This transformation matured to being a highly efficient tool for the synthesis of substituted alkenes [116-118]. Thus, for instance, effective palladium-catalyzed regioselective oxidative arylation of alkenes [119] were developed, which enabled oxidative coupling to proceed at ambient temperature (Scheme 9.46). 

The pioneering studies by Moritani and co-workers set the stage for further applications of palladium-catalyzed C—H bond functionalizations to oxidative C (sp2)-C(sp2) bond-forming processes. Thus, catalyzed oxidative arylations for biaryl syntheses could be accomplished with either stoichiometric [120] or catalytic [121] amounts of palladium complexes. 

More promising results were obtained for cross-dehydrogenative arylations with heteroarenes, since pronounced differences in reactivities gave improved chemos-electivity. In elegant studies it was shown that palladium-catalyzed oxidative arylations of indoles could be accomplished with unactivated arenes, which were used as solvents, in the presence of Cu(OAc)2 as terminal oxidant [130]. Notably, these reactions proceeded with high regioselectivities, leading predominantly to arylations at position C-3 (Scheme 9.51). 

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. 

Indeed, a variety of heterocyclic compounds, such as thiophenes, dithiophenes, pyrroles, indoles, or carbazoles can be involved as carbon-centered nucleophiles in these reactions to modify the pyrimidine ring (Scheme 31) [120-122]. For instance, it has been shown that 5-bromopyrimidine reacts with dithiophene into the corresponding 5-substituted pyrimidine due to palladium-catalyzed aryl-aryl C-C cross-coupling reaction. On the other hand, 5-bromo-4-dithiophenyl-substituted pyrimidine was prepared from the same starting material through the SH (addition-oxidation) reaction catalyzed by a Lewis acid in the presence of potassium... 

Scheme 3 Palladium-catalyzed arylation of pyridine iV-oxides...

As in the palladium(II)-catalysed indole annulation, a diastereomerically pure substrate was designed to help elucidate the mechanism of the benzofuran and dihydrobenzo-furan syntheses (Scheme 9.21). When aryl allyl ether 163 was treated with the palladium oxidation catalyst, dihydrobenzofuran 164 was produced as an exclusive di-astereomer in 60% yield. This observation confirmed that an oxidative Heck reaction pathway, featuring arene palladation, alkene insertion and /3-hydride elimination, was operative. 

Prior to the discovery of the aryl-Heck reaction (Chapter 72), the direct Pd-promoted oxidative cyclization of diaryl amines to carbazoles was well known. In 1975 Akennark reported this reaction (Scheme 1, eqnation 1) [1], In addition, A -phenylanthranUic acid gave carbazole-l-carboxylic acid (60%). Miller and Moock used Pd(OAc)j to cyclize 6-anilino-5,8-dimethylisoquinoIine to eUipticine in low yield [2]. The second advance in this chemistry was reported independently by Bittner [3] and Furukawa [4], who described the Pd-mediated (stoichiometric) oxidative conversion of 2-anilino-l,4-benzoquinones and 2-anilino-l,4-naphthoquinones to the corresponding carbazole-l,4-diones and benzo[ ]carbazole-l,6-diones (equations 2, 3). Furukawa s studies included syntheses of several carbazolequinone alkaloids. In 1995 Akermark and colleagues developed catalytic versions (i.e., using tert-butyl hydrogen peroxide [TBHP] or oxygen) of this cyclization (equation 3) [5,6], which elevated the importance of this palladium oxidative cyclization, mainly because of the expense of Pd(OAc)2. Somewhat earlier, Knbiker used cupric acetate as a reoxidant in a synthesis of carbazole-l,4-quinones [7]. 

Scheme 1.12 Palladium

Scheme 1.13 Palladium-catalyzed oxidative arylation of alkenes with arenes (Fujiwara,...

Interestingly, an intramolecular palladium-catalyzed oxidative arylation for a dibenzofuran synthesis was reported earlier Shiotani, A. and... 

In contrast with arylations of other heterocycles, the palladium-catalyzed arylation of benzoxazoles at C-2 proceeds readily at ambient temperature (Scheme 11.21) [67]. Although, as in other cases no kinetic isotope effect was found for 59a, a Hammett plot revealed a correlation with ct with a positive p, which indicates that a phenolate intermediate is formed in this reaction. Therefore, this reaction has been shown to proceed by a totally different mechanism. According to experimental results and DFT calculations, the reactions proceed by the deprotonation of benzoxazoles 59 to form 61, which is in equilibrium with o-phenoxyisocyanide 62. Coordination of the oxidative addition product PdI(Ph)L2 to the isocyanide then forms 63 which cyclizes to form palladate 64, from which the 2-phenylbenzoxazoles 60 are formed by reductive ehmination. 

The intermolecular oxidative arylation of olefins has been reported in most cases with acrylic acid derivatives. This process could be developed as an alternative to the Heck reaction, which occurs with aryl halides. Several groups have reported versions of this oxidative C-C bond formation. Fujiwara reported intermolecular examples of this reaction catalyzed by palladium and copper (Equation 18.64). Intermolecular versions of this reaction have also been reported with ruthenium catalysts and as the oxidant. Other oxidative reactions in which electron-rich arenes add to olefins (Equation 18.66) have been reported as stoidiiometric steps of natural products syntheses, and later as a catalytic process. ... 

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