Palladium reductive 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... 

Reduction of /V-alkoxycarbonyl-2-azabicyclo[2.2.0]hcx-5-cnc with hydrogen and palladium on charcoal catalyst gave the corresponding bicyclo[2.2.0]hexanes <2003JOC1626>. Reductive arylation occurred when /V-alkoxycarbo-nyl-2-azabicyclo[2.2.0]hexane was treated with 2-chloro-5-iodopyridine in the presence of palladium(m) acetate, triphenylphosphine, piperidine, formic acid, and dimethylformamide (DMF) to give mainly 175 and 176 but in moderate and variable yields (28-58%) <2000T9233>. 

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]. 

In the coupling of more challenging substrates, reduction of the aryl halide is frequently observed [21]. Specifically, in the reaction of electron-rich aryl halides or sulfonates, reduced arene is a major by-product. Presumably, this side-product arises when the palladium amide can undergo /1-hydride elimination to generate an imine and a palladium (II) aryl hydride (Scheme 2). Subse-... 

Palladium-catalyzed reductive arylations of alkenes have also been applied to intramolecular additions70 75 77. 

Taking this into account, the influence of the support is of minor importance for reactions of aU aryl bromides. Similar good results can be obtained with activated carbon, MgO, Ti02, AI2O3, Si02 etc. Differences found in the literature are probably due to different Pd dispersion, palladium reduction degree or water content. For the activation of non-activated aryl chlorides a fine-tuning of the support and the reaction conditions may be necessary. 

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. 

BusP as ligand.Poor yields in the reductive cyclization method—when competitive cyclization is possible—and also the need for milder reaction conditions in the cyclization step urged Emoto et al. to report an alternative method based on sequential palladium-catalyzed aryl amination (Scheme 10). The substrate for the cyclization was 2-amino-2 -bromo-diphenylamine, obtained by selective bromination and reduction of the well-known 2-nitrodiphenyl-amines or by coupling of 2-bromoaniline with a l-bromo-2-nitrobenzene and subsequent reduction. Treatment of 2-bromo-2 -nitrodiphenylamine with catalytic amounts of palladium(II) and BINAP as ligand afforded the desired phenazines in good yields. ... 

Steric properties of the ligand have a more pronounced effect on the rate of reductive elimination. Arylpalladium phenoxide complexes containing a stericaUy hindered monophosphine P(Fc)(I-Bu)2 (Fc = ferrocenyl) underwent reductive elimination of diaryl ethers, even when the palladium-bound aryl group was unactivated, as shown in Eq. Arylpalladium phenoxide intermediates containing P(t-Bu)3 as ligand under-... 

The electronic effects on the reductive elimination of aryl ethers from BlNAP-ligated palladium complexes (Eq. 6) was studied by Widenhoefer and Buchwald. Because the reductive elimination of acycUc ethers required activated palladium-bound aryl groups, the scope of the arylpalladium alkoxide complexes was limited. An example of elimination from an oxametallacycle that contained an nnactivated aryl group demonstrated that the formation of cycUc ethers may become more general. Nonetheless, studies on these systems showed that the factors that control elintination of ethers are similar to those that control elimination of amines. For example, alkoxide complexes that are more electron rich at the alkoxide oxygen underwent faster reductive elimination than those that are more electron poor. Elimination of diaryl ethers from arylpalladium phenoxides did not occur. 

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