Sonogashira catalytic cycle

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Sonogashira has proposed a catalytic cycle (Figure 4) which shows 1) the reduction of the palladium complex, 2) coordination of the aryl halide and acetylene with the palladium (0) complex and 3) the reductive elimination of the substituted aryl acetylene and regeneration of the active catalyst.(10)... 

Figure 3.44 Catalytic cycle for the Pd-catalyzed Sonogashira cross-coupling the cuprous acetylide intermediate is highlighted in gray.

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 5.49 Catalytic cycle of the Suzuki, Stille, Negishi and Sonogashira reactions.

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. 

One can imagine that the Sonogashira coupling proceeds by a catalytic cycle very similar to the Stille coupling. The transmetallation step of the Stille coupling is replaced with a ligand substitution reaction, in which a deprotonated alkyne displaces X- from the Pd(II) complex. The alkyne may be deprotonated by the Et3N that is present in the reaction mixture. 

Alkyne cross-coupling reactions over the last 25 years have become one of the most valuable assets in the synthetic chemist s toolbox. The now famous Sonogashira coupling (50, 114) of terminal alkynes with aryl or vinyl halides is readily achieved with a palladium catalyst, a copper(l) cocatalyst, and amine base. In the catalytic cycle (Scheme 14a), copper-and palladium-alkyne complexes are the key intermediates that lead to coupling of R and R units via the alkyne. Analogously, the Stille coupling... 

The same group extended this methodology to incorporate a Sonogashira reaction into the domino sequence [14]. As a result, oxindole 40 could be synthesized from propiolamide 38 and 2 equiv of aryl iodide 39 in the presence of catalytic Pd(PPh3)4/CuI via a domino Sonogashira reaction/carbopaUadation/C-H activation sequence (Scheme 3.10). Overall three C-C bonds were formed from distinct catalytic cycles using only one catalyst. UnsymmetricaUy substituted oxindoles were also synthesized by a one-pot/two-step protocol where the second aryl iodide was simply added to the same reaction vessel after the Sonogashira reaction of the first aryl iodide. 

Despite all the synthetic developments, relatively little detailed mechanistic work has been performed on Sonogashira carbonylations until the present. The generally accepted mechanism is shown in Scheme 5.25. The typical reaction begins with the oxidative addition of ArX to a palladium(0) complex to form an aryl palladium(II) intermediate. The subsequent insertion of CO leads to the respective palladium acyl complex. Transmetallation, and finally reductive elimination, releases the product and a new catalytic cycle can be started. Notably, all species passing through the cycle are believed to be in a reversible equilibrium. 

Scheme 1.41 The Sonogashira coupling thorough a Au(l)/Au(lll) catalytic cycle in the presence of selectfluor.

An interesting variant of the sila-Sonogashira-Hagihara reaction avoiding any transition metal catalysts has more recently been reported by Portella et al [332]. The catalytic cycle was implemented under fluoride activation while replacing... 

Direct Alkynylation. Ni-catalyzed direct alkynylation on azoles has been achieved without assistance of halogen-mediated activation by using oxygen as oxidant in the catalytic cycle. TIPS-acetylene was added to a variety of nonhalogenated azoles to produce the Sonogashira coupling products (eq 25). ... 

The requisite entry into the main catalytic cycle is a Pd(0) species (12) which can either be added as [Pd (PPh3)4] or similar, or generated in situ from a Pd(Il) pre-catalyst and excess phosphine or alkyne. In Sonogashira s original condition, it is likely that the active Pd(0) catalyst 12 was generated... 

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