Anilines palladium® acetate

Benzyloxy-6-bromo-4-nitro-JV-(2-propeny])aniline (5.82 g, 16 mmol), tetra-ii-butylammonium bromide (5.16 g, 16 mmol) and titjN (4.05 g, 40 mmol) were dissolved in DMF (15 ml). Palladium acetate (72 mg, 2 mol%) was added and the reaction mixture was stirred for 24 h. The reaction mixture was diluted with EtOAc, filtered through Cclite, washed with water, 5"/o HCl and brine, dried and evaporated in vacuo. The residue was dissolved in CHjClj and filtered through silica to remove colloidal palladium. Evaporation of the eluate gave the product (4.32 g) in 96% yield. 

Figure 5.26 Catalytic activity of a UV-decomposed palladium acetate catalyst. Nitrobenzene conversion ( ) aniline selectivity ( ) [60].

Reactions that involve significant bond formation in the ratedetermining step are in general expected to exhibit large and negative volumes of activation. This was for instance found for a series of cyclometallation reactions of benzylidenebenzylamines, -anilines, and -propylamine with palladium acetate in toluene and acetic acid solution (171, 172). The cyclometallated compounds are formed via C-H electrophilic bond activation to produce different types of metalla-... 

Four solvent-soluble poly(aniline-co-thiophene) materials have been prepared by coupling thiophene derivatives with 4-n-butyl aniline using palladium acetate as catalyst. Mn s of up to 17,500 daltons with a PDI of 1.1 were obtained. 

Several metals have been reported of being able to hydroaiylate alkynes as in the examples shown below. Thus, di-substituted-propargyl anilines can be cyclized either in the presence of copper(I) chloride at reflux or by a mixture of palladium acetate and trifluoroacetic acid. ... 

In general it is not advisable to have the palladium-catalysed coupling reaction as last or penultimate step in view of the need to reduce palladium levels in the final product to below 10 ppm. Based on this reasoning, Taiwanese chemists patented an alternative route towards Lapatinib in which the furan ring is coupled to the quinazoline moiety before attachment of the substimted aniline (Scheme 23) [69]. Thus, coupling between the furfural-boronic acid 99 and aryl halide 103 catalysed by a catalyst prepared in situ from palladium acetate and one equivalent of tri-t-butylphosphine (2 mol%) gave the biaryl compound 104 in 98% HPLC yield. 

Heating l-(4-hydroxy-2-pyridyl)pyridinium chloride in aniline and acetic anhydride gives a product that, on hydrogenation over palladium-charcoal, proved to be 2-aminopyridine. ... 

The coupling of anilines with arylboronic acids has been described in a process catalysed by palladium acetate without the need for ligands, bases, or salts. The mechanism shown in Scheme 17, where S represents solvent, involves in situ formation of the dia-zonium salt from the aniline, and formation of an arylpalladium alkoxo complex which allows the transmetallation step with arylboronic acids. It has been shown that a free amine may be used as a DG in a palladium-catalysed reaction promoted by soluble silver salts. The latter aid the formation of intermediates, (136), which may undergo cyclopalladation followed by transmetallation with an arylboronic acid and reductive elimination. Related work has shown thatbiaryl-2-amines may react with aryl iodides in the presence of palladium acetate and silver acetate to give mono- or di-arylated species such as (137). 

Indoles.—Formation. Phenacyltriphenylarsonium bromide, Ph3AsCH2COPh Br , reacts with aniline to give 2-phenylindole. o-Tolyl isocyanide (306) is selectively lithiated at the methyl group by lithium di-isopropylamide at —78°C warming the product to room temperature, followed by aqueous workup, yields indole almost quantitatively. The ester (307) cyclises to the indole (308) in the presence of palladium acetate and triphenylphosphine. Treatment... 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

Catalytic hydrogenation over palladium in acetic acid and sulfuric acid at room temperature and 2.5 atm reduced nitroacetophenones and their homologs and derivatives all the way through the alkyl anilines in yields of 78.5-95% [904]. 

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). 

Furukawa et al. reported the total synthesis of murrayaquinone A (107) by a palladium(II)-mediated oxidative cyclization of the corresponding 2-arylamino-5-methyl-l,4-benzoquinones. 2-Anilino-5-methyl-l,4-benzoquinone (842) was prepared starting from 2-methyl-l,4-benzoquinone 841 and aniline 839, along with the regio-isomeric 2-anilino-6-methyl-l,4-benzoquinone (844). The oxidative cyclization of 2-anilino-5-methyl-l,4-benzoquinone (842) with stoichiometric amounts of palla-dium(ll) acetate provided murrayaquinone A (107) in 64% yield. This method was also applied to the synthesis of 7-methoxy-3-methylcarbazole-l,4-quinone (113) starting from 3-methoxyaniline (840) (623). Seven years later, Chowdhury et al. reported the isolation of 7-methoxy-3-methylcarbazole-l,4-quinone (113) from the stem bark of Murraya koenigii and named it koeniginequinone A (113) (49) (Scheme 5.101). 

One of the carbazole-l,4-quinones, 3-methoxy-2-methylcarbazole-l,4-quinone (941), required for the total synthesis of carbazomycin G (269), was already used as a key intermediate for the total synthesis of carbazoquinocin C, and was obtained by the addition of aniline (839) to 2-methoxy-3-methyl-l,4-benzoquinone (939), followed by oxidative cyclization with catalytic amounts of palladium(II) acetate (545,645) (see Schemes 5.124 and 5.125). Similarly, in a two-pot operation, 4-meth-oxyaniline (984) was transformed to 3,6-dimethoxy-2-methylcarbazole-l,4-quinone... 

Under an atmosphere of nitrogen a flask was charged with the step 2 product (18.70 mmol), aniline (39.27 mmol), palladium dibenzanthracene (0.37 mmol), t-butylphosphine (0.75 mmol), and 100 ml toluene. The reaction mixture stirred for 10 minutes and was then treated with sodium t-butoxide (38.33 mmol) and continued stirring for 24 hours. The mixture was diluted with 3 liters of toluene and filtered through a plug of silica and celite, concentrated, and a dark brown oil obtained. The residue was purified by flash column chromatography on silica gel using a mixture of ethyl acetate/hexanes, 1 10, respectively, and 6.8 g product isolated as a pale yellow powder. 

To a suspension of 36.56 g of 3-fluoro-4-morpholinyl-nitrobenzene and 48.84 g of ammonium formate in 110 mL of tetrahydrofuran and 440 mL of methanol under nitrogen was added 0.524 g of 10% palladium on carbon. After stirring the mixture for 3 hours, the mixture was filtered through diatomaceous earth, and the filter pad was washed with ethyl acetate. The filtrate was concentrated to a volume of about 450 mL and then 200 mL of water was added. This was extracted with 300 mL of ethyl acetate, then the organic layer was washed with of water and then with brine, dried (MgS04), and concentrated to give a brown solid of 3-fluoro-4-morpholinyl-aniline. 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

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