Aryl halides Sonogashira reaction

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 ... 

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. 

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. 

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 ... 

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. 

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. 

Halopyridines, like simple carbocyclic aryl halides, are viable substrates for Pd-catalyzed crosscoupling reactions with terminal acetylenes in the presence of Pd/Cu catalyst. The Sonogashira reaction of 2,6-dibromopyridine with trimethylsilylacetylene afforded 2,6-bis(trimethylsilyl-ethynyl)pyridine (130), which was subsequently hydrolyzed with dilute alkali to provide an efficient access to 2,6-diethynylpyridine (131) [106]. Extensions of the reactions to 2-chloropyridine, 2-bromopyridine, and 3-bromopyridine were also successful albeit at elevated temperatures [107]. 

The Sonogashira reaction is a C-C coupling reaction of terminal alkynes with aryl or vinyl halides in presence of Pd(0) metal and/or Cu(i) catalyst. These compounds are useful in synthesizing species having pharmaceutical... 

Hierso et al reported a copper-free, Sonogashira reaction for a number of activated and deactivated aryl halides with alkyl-/aryl acetylenes and using a variety of metallic precursors, bases and tertiary phosphanes in [bmim][BF4]. They found that a combination of [Pd(/7 -C3H5)Cl]2/PPh3 with 1 % pyrrolidine in the absence of copper showed the highest activity. 

The Sonogashira reaction of 2-iodothiophene with 2-methyl-3-butyne-2-ol or trimethylsilylacetylene under phase transfer conditions using sodium hydroxide as base led to the formation of the expected products, which released their end group spontaneously under the applied conditions giving rise to the intermediate formation of 2-ethynylthiophene. This terminal acetylene, in turn, reacted with another molecule of aryl halide, yielding either non symmetrical or symmetrical diarylethynes. When 2-methyl-3-butyn-2-ol was used as acetylene equivalent68 it was possible to introduce a benzothiophene moiety in the second step, while the reaction of 2-iodothiophene and trimethylsilylacetylene led to the formation of l,2-bis(2 -thienyl)acetylene (6.47.),69... 

In 2006, Li and Wang reported the palladium-free, silver-catalyzed Sonogashira-type coupling of aryl halides and terminal alkynes. The reaction proceeds in high yield in the presence of catalytic silver iodide, triphenylphosphine, and potassium carbonate. Although the mechanism remains unclear, it is evident that the silver acetylide has a role, as the acetylide is formed on mixing of the reagents (Scheme 1.54).122... 

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) and aryl-ated by aryl triflates (bromides, iodides). These reactions are called Cacchi coupling reactions if the reaction is catalyzed by Cu(I) and Pd(0) and if triflate reagents are employed, Sonogashira-Hagihara coupling reactions if the reaction is catalyzed by Cu(I) and Pd(0) and halides are employed as substrates, and Stephens-Castro coupling reactions for the more specialized case of the noncatalyzed coupling of copper acetylides with aryl halides. 

The coupling of terminal alkynes with aryl or vinyl halides under palladium catalysis is known as the Sonogashira reaction. This catalytic process requires the use of a palladium(0) complex, is performed in the presence of base, and generally uses copper iodide as a co-catalyst. One partner, the aryl or vinyl halide, is the same as in the Stille and Suzuki couplings but the other has hydrogen instead of tin or boron as the metal to be exchanged for palladium. 

---