Sonogashira cross coupling Mechanism

The mechanism of the Sonogashira cross-coupling follows the expected oxidative addition-reductive elimination pathway. However, the structure of the catalytically active species and the precise role of the Cul catalyst is unknown. The reaction commences with the generation of a coordinatively unsaturated Pd species from a Pd " complex by reduction with the alkyne substrate or with an added phosphine ligand. The Pd " then undergoes oxidative addition with the aryl or vinyl halide followed by transmetallation by the copper(l)-acetylide. Reductive elimination affords the coupled product and the regeneration of the catalyst completes the catalytic cycle. 

Scheme 14. (a) Sonogashira cross-coupling reaction mechanism, (b) Click chemistry [2 + 3]... 

Duchene and Parrain developed a one-pot allylic amina-tion/palladium-catalyzed Sonogashira cross-coupling and heterocyclization process for the preparation of 1,2,4-trisub-stituted and 1,3-disubstituted pyrroles starting from diiodo-butenoic acid, a primary amine, and a terminal alkyne [49], Scheme 3.27 shows a plausible mechanism for this transformation. The initial C—N allylic amination, followed by a Sonogashira cross-coupling and an intramolecular hydroam-ination, affords a dihydroexoalkylidene pyrrole XIX, which rearranges into pyrrole 39. The reaction is influenced by the... 

The Sonogashira cross-coupling reaction, consisting of oxidative addition, cis-trans isomerization, transmetallation and reductive elimination has been modelled, using the DFT B3LYP/cc-pVDZ method, for Pd(diphosphane)-catalysed reaction between bro-mobenzene and phenylacetylene with CuBr as a co-catalyst and trimethylamine as a base. The reaction mechanism in both the gas phase and in CH2CI2 solution has been studied using the polarized continuum model (PCM) method. ... 

The generally accepted textbook mechanism of the Sonogashira cross-coupling reaction suggests a synergism between Cu- and Pd-cycles [9,28]. The Cu-additives are commonly assumed to form organocopper intermediates that in turn assist and faciUtate the transmetallation step of the Pd-catalyzed transformation (see... 

SCHEME 3.13 Mechanism for the Sonogashira cross coupling reaction using diethylamine as base. 

The mechanism of the Sonogashira reaction has not yet been established clearly. This statement, made in a 2004 publication by Amatore, Jutand and co-workers, certainly holds much truth [10], Nonetheless, the general outline of the mechanism is known, and involves a sequence of oxidative addition, transmetalation, and reductive elimination, which are common to palladium-catalyzed cross-coupling reactions [6b]. In-depth knowledge of the mechanism, however, is not yet available and, in particular, the precise role of the copper co-catalyst and the structure of the catalytically active species remain uncertain [11, 12], The mechanism displayed in Scheme 2 includes the catalytic cycle itself, the preactivation step and the copper mediated transfer of acetylide to the Pd complex and is based on proposals already made in the early publications of Sonogashira [6b]. 

Scheme 2. Mechanism of the Sonogashira reaction for Pd/ Cu-catalyzed cross-coupling of sp2-C halides with terminal acetylenes.

Some of the optimized procedures for Stille and Sonogashira reactions involve the addition of copper cocatalysts to accelerate the cross-coupling procedures. A word of caution should be provided on the role of these additives in Pd-catalyzed amination procedures. Beletskaya and Davydov have reported the arylation of benzotriazole and of diary-lamines in polar organic or aqueous organic solvents using a combination of palladium and copper as catalyst.The arylation of amino acids has been reported under similar conditions.However, these reaction conditions are similar to classic Ullmann procedures for the synthesis of arylamines, except for the addition of palladium to the reaction mixture. In one case, subsequent work showed that the palladium species was not an essential component and that copper alone was the true catalyst in their reactions. An unusual accelerating effect of amino acid coordination to copper was used to explain the low-temperature Ullmann conditions. Beletskaya, however, showed that lower yields and a mixture of N1 and N2 arylation products were observed from the reactions of benzotriazole in the absence of copper and no reaction was observed in the absence of palladium. The conditions for this chemistry are, however, distinct enough from those of the majority of the aryl halide aminations to support the idea that a different mechanism may operate. 

Scheme 1.8 (a) General conditions for the Songashira-Hagihara cross-coupling reaction, (b) The proposed mechanism for the Sonogashira-Hagihara cross-coupling arylation procedure [12, 24]. 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

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