Mechanism of the coupling reaction

Lithiation at C2 can also be the starting point for 2-arylatioii or vinylation. The lithiated indoles can be converted to stannanes or zinc reagents which can undergo Pd-catalysed coupling with aryl, vinyl, benzyl and allyl halides or sulfonates. The mechanism of the coupling reaction involves formation of a disubstituted palladium intermediate by a combination of ligand exchange and oxidative addition. Phosphine catalysts and salts are often important reaction components. 

Figure 27.9 Mechanism of the coupling reaction of dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP), to give geranyl diphosphate (GPP).

The mechanism of the coupling reaction has been very exhaustively studied. Summarising first what has already been mentioned, it must be noted that the reaction is not confined to the aromatic series, for diazo-compounds condense also with enols and with the very closely related aliphatic aci-nitro-compounds. The final products of these reactions are not azo-compounds, but the isomeric hydrazones formed from them by rearrangement. 

Although the precise mechanism of the coupling reaction is not thoroughly established, one can visualize the formation of (71) as arising from initial fragmentation of the C(16)—C(21) bond of (69), followed by condensation of vindoline with the more accessible a face of the iminium ion (73). The impact of the Polonovski approach in this area is emphasized by the fact that all other attempts to couple vindoline with 16,21-seco derivatives of catharanthine lead invariably to formation of the unnatural dimer. A Polonovski reaction was also a key step in the subsequent elaboration of anhydrovinblastine (71) to (68). ... 

This reaction suffers all the problems outlined above since these routes rely on chlorine to activate the aromatic ring towards nucleophilic attack. It has recently been discovered at Monsanto that the base catalyzed coupling of aniline and nitrobenzene via NASH chemistry is a superior route for the production of intermediates like 2.24 Understanding the mechanism of the coupling reaction,25 and in particular, the oxidation of a-complex intermediate, 4, has allowed for the development of a commercial process based on this chemistry. 

The mechanism of the coupling reaction resembles an S l reaction and begins with a silver-ion-assisted ionization of the carbon-bromine bond of the glycosyl donor to give a carbocation (Mechanism 23.3). 

The following experiments were made concerning the mechanism of the coupling reaction mediated by metallic nickel. The reaction of iodopentafluorobenzene with nickel powder prepared from nickel iodide was investigated in detail. Iodopentafluorobenzene was found to react with nickel at room temperature however, decafluorobiphenyl could not be detected in the reaction mixture. Triphenylphosphine (2 equiv) was then added to the mixture to trap the arylnickel intermediate as the phosphine complex, and a usual workup afforded bis(triphenylphosphine) bis(pentafluorophenyl)nickel(II) in 45% yield. As the diarylnickel(II) species seemed to be derived by disproportionation from an initially formed oxidative adduct, (pentafluorophenyl)nickel(II) iodide, the trapping of the arylnickel(II) iodide was tried. In the presence of 2 equiv of triethylphos-phine, the reaction of iodopentafluorobenzene with nickel was carried out at room temperature, and bis(triethylphosphine)(pentafluorophenyl)-nickel(II) iodide was isolated in 15% yield. 

What is the mechanism of the coupling reaction of Rgure 23.47 Remember that other cumulated double bonds (p. 512) such as ketenes (p. 515), isocyanates (p. 918), and isothiocyanates (p. 1198) all react rapidly with nucleophiles. The related DCC is no exception, and it is attacked by amines to give molecules called guanidines. Carboxylates are nucleophiles too, and will also add to DCC (Fig. 23.48). 

The mechanism of the coupling reaction involves initial formation of a triorganocopper intermediate, followed by coupling and loss of RCu. The coupling is not a typical polar nucleophilic substitution reaction of the sort considered in the next chapter. 

The mechanism of the coupling reactions is not known in detail. They formally involve one-electron oxidation of the alkyl moiety to the equivalent of a radical, followed by combination of two such groups. Both the oxidation and coupling probably take place while the alkyl group remains in the metal coordination sphere, so that free-radical intermediates are not necessarily involved. 

In 2002, Trauner and coworkers reported the total synthesis of (—)-frondosin B (Scheme 16.19) [39]. In their synthesis, a palladium-catalyzed C-H alkenylation of benzofuran with an enol triflate was used for the construction of the seven-membered ring in frondosin B. Treatment of triflate 95 with catalytic Pd(PPh3) and f-PrjNEt in Af,Af-dimethylacetamide (DMAc) afforded cyclized product 97 in 70% yield. Although the mechanism of the coupling reaction is still unclear, the catalytic cycle might involve (i) C-OTf oxidative addition of 95 to Pd(0),... 

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