Aryl Sonogashira

Closely related to the Heck reaction is the Sonogashira reaction i.e. the palladium-catalyzed cross-coupling of a vinyl or aryl halide 20 and a terminal alkyne 21 ... 

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 ... 

Cationic phosphine ligands containing guanidiniumphenyl moieties were originally developed in order to make use of their pronounced solubility in water [72, 73]. They were shown to form active catalytic systems in Pd-mediated C-C coupling reactions between aryl iodides and alkynes (Castro-Stephens-Sonogashira reaction) [72, 74] and Rh-catalyzed hydroformylation of olefins in aqueous two-phase systems [75]. 

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. 

A microwave-assisted Cu-catalyzed Sonogashira-type protocol on aryl iodide substrates without the involvement of a palladium catalyst has also been published (Scheme 54) [71]. Reactions were executed using Cut and CS2CO3 in NMP at 195 °C. The application seems to be fairly limited since there are indications that only (hetero)arylacetylenes are suitable coupHng partners for this protocol. In addition, aryl bromides react more sluggishly than aryl iodides. Moreover, even on aryl iodides the reaction times required are on the order of hours. 

We synthesized uniform CU2O coated Cu nanoparticles from the thermal decomposition of copper acetylacetonate, followed by air oxidation. We successfully used these nanoparticles for the catalysts for Ullmann type amination coupling reactions of aryl chlorides. We synthesized core/shell-like Ni/Pd bimetallic nanoparticles from the consecutive thermal decomposition of metal-surfactant complexes. The nanoparticle catalyst was atom-economically applied for various Sonogashira coupling reactions. 

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

Table 4.7 Sonogashira coupling of aryl halides with terminal acetylenes in the presence of PdCbiPPhj) catalyst [120].

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

The first examples of NHC-Pd complexes applied to the Sonogashira reaction were reported to show a limited scope in the coupling of aryl iodides and activated aryl bromides with acetylene [23,33,52]. However, the use of A-carbamoyl-substituted heterocyclic carbene Pd(ll) complexes expanded the use to alkyl-acetylenes and deactivated aryl iodides and bromides [124] (Scheme 6.40). 

More recently, a study with di- and mono-carbene Pd(II) complexes has demonstrated that the Sonogashira coupling of activated and non-activated aryl iodides can be carried out in an aqueous, aerobic medium and in the absence of amines. These results suggest that the moisture-sensitive copper-acetylide may not be present in this particular transformation, and that a Pd-acetyhde could be formed by deprotonation of the coordinated alkyne instead of transmetallation [130]. 

There are a number of procedures for coupling of terminal alkynes with halides and sulfonates, a reaction that is known as the Sonogashira reaction.161 A combination of Pd(PPh3)4 and Cu(I) effects coupling of terminal alkynes with vinyl or aryl halides.162 The reaction can be carried out directly with the alkyne, using amines for deprotonation. The alkyne is presumably converted to the copper acetylide, and the halide reacts with Pd(0) by oxidative addition. Transfer of the acetylide group to Pd results in reductive elimination and formation of the observed product. 

A potentially interesting development is the microwave-assisted transition-metal-free Sonogashira-type coupling reaction (Eq. 4.10). The reactions were performed in water without the use of copper(I) or a transition metal-phosphine complex. A variety of different aryl and hetero-aryl halides were reactive in water.25a The amount of palladium or copper present in the reaction system was determined to be less than 1 ppm by AAS-MS technique. However, in view of the recent reassessment of a similarly claimed transition-metal-free Suzuki-type coupling reaction, the possibility of a sub-ppm level of palladium contaminants found in commercially available sodium carbonate needs to be ruled out by a more sensitive analytical method.25 ... 

A palladium catalyst with a less electron-rich ligand, 2,2-dipyridyl-methylamine-based palladium complexes (4.2), is effective for coupling of aryl iodides or bromides with terminal alkynes in the presence of pyrrolidine and tetrabutylammonium acetate (TBAB) at 100°C in water.37 However, the reactions were shown to be faster in NMP solvent than in water under the reaction conditions. Palladium-phosphinous acid (POPd) was also reported as an effective catalyst for the Sonogashira cross-coupling reaction of aryl alkynes with aryl iodides, bromides, or chlorides in water (Eq. 4.18).38... 

Besides palladium catalysts, nickel was also found to be an effective catalyst for the Sonogashira reaction in aqueous media. Recently, Beletskaya et al. reported a Ni(PPh3)2Cl2/CuI-catalyzed Sonogashira coupling reaction of terminal acetylenes with aryl iodides in aqueous dioxane in high yields (Eq. 4.19).39... 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

Aryl hydrazide-based linker 79 was developed as a traceless handle that released products under mild oxidative conditions (Scheme 42) [91]. Polymeric bound p-iodophenylhydrazide was subjected to a variety of Pd°-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille). Oxidation with Cu(OAc)2 in MeOH and pyridine released the final products in 50-96% yield. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

Muller and coworkers developed a concise domino process in which termination of an intramolecular arylation of an alkyne was achieved by a Sonogashira alkynyla-... 

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

In spite of the common conception that Ni catalysts are useless in the Sonogashira reaction, NiCl2(PPh3) has been disclosed as being able to catalyze the cross-coupling of aryl iodides with terminal acetylenes in aqueous dioxane, in the presence of Cul.147... 

Through the years, the development of transition metal-catalyzed methodologies, notably involving cyclotrimerization and Sonogashira or Heck cross coupling, has paved the way for rapid and efficient access to aryl glycoclusters with desired and controlled valency. 

Scheme 6.30 Domino Sonogashira sequence for the synthesis of bis(aryl)-alkynes.

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