The Sonogashira Reaction

The Sonogashira reaction couples the sp-hybridized carbon of a terminal alkyne to aryl and alkenyl halides. The reaction requires a palladium catalyst and a catalytic amount of Cul. The reaction is carried out in an amine solvent. 

R = aryl, vinyl = aryl, alkenyl, alkyl, SiRs X = I, Br, Cl, OTf 

Since its introduction almost four decades ago, a tremendous number of modifications of Sonogashira s original protocol have been reported to improve yields, to increase the reactivity of unactivated electrophiles or stericaUy demanding substrates under mild reaction conditions, or to suppress the formation of homo-coupled products. Significant improvements have mostly been achieved by tailoring the catalytic and cocatalytic metal species, metal-complexing ligands, and amine bases used (see later discussion). 

While the Pd cycle is well understood, little is known about the reaction sequence involving copper species (Cycle B). It is widely accepted that the initial 

This general mechanistic scheme is not limited to the use of Pd as a catalyst. In fact, it has been shown that the Sonogashira reaction can be catalyzed by numerous 

In particular, iron-containing salts and nanoparticles hold great promise to serve as inexpensive and nontoxic catalytic centers in combination with comparatively simple ligands [29]. However, for many of the reported results, it remains to be clarified as to whether the observed Sonogashira activity of these metals might have resulted from minute amounts of Pd impurities in the reagents used (see later discussion). 

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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 ... 

A variety of catalysts, solvents and amines as base can be employed for the Sonogashira reaction. Typical conditions are, e.g. tetrakis(triphenylphosphine)palladium(0)... 

For the further decoration of the pyrazinone scaffold via transition metal-catalyzed chemistry, the Sonogashira reaction [45-50] has also been investigated on the C-3 position of the pyrazinone, applying microwave irradiation conditions (Scheme 17) [29]. It was found that microwave irradiation at 120 °C for 15 min of a mixture of the starting material, Pd(OAc)2, Cul and PPha in TEA/DMF were the appropriate reaction conditions. 

The performance of the Sonogashira reaction is claimed to be the first example of a homogeneously metal-catalyzed reaction conducted in a micro reactor [120], Since the reaction involves multi-phase postprocessing which is needed for the separation of products and catalysts, continuous recycling technology is of interest for an efficient production process. Micro flow systems with micro mixers are one way to realize such processing. 

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... 

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). 

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. 

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... 

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... 

F. Perez-Balderas and F. Santoyo-Gonzalez, Synthesis of deeper calix-sugar-based on the Sonogashira reaction, Synlett, 11 (2001) 1699-1702. 

It is speculated that an alkynylcopper species, which undergoes the transmetalation process more readily, is generated during the reaction with the aid of an amine. The aliphatic amine also serves as a reducing agent to generate Pd(0). For recent reviews on the Sonogashira reaction, see references [60] and [61]. 

The Sonogashira reaction has enjoyed tremendous success in the synthesis of almost all types of heteroarylacetylenes because of the extremely mild reaction conditions and great tolerance of nearly all types of functional groups. A representative reaction with conditions akin to Sonogashira s original conditions is shown below [62] ... 

The Sonogashira reaction frequently serves as a platform for the construction of indoles, and we will explore this application in Chapter 3, but it also is a valuable method for the preparation of alkynyl pyrroles. 

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]. 

Additional examples of the Sonogashira reactions of pyridine triflates include coupling of 2-pyridyltriflate and 3-hydroxy-3-methylbut-l-yne to afford alkyne 141 [114], The carbinol adduct could be readily unmasked to give 2-ethynylpyridine via a basic-catalyzed retro-Favorsky elimination of acetone. Due to the volatility of 2-ethynylpyridine, use of a high boiling liquid such as paraffin oil for the basic hydrolysis made the distillation more convenient [115]. 

Advantage has been taken of the aforementioned observations in the synthesis of a terthiophene natural product, arctic acid (147) [123]. Pd-catalyzed carbonylation of bromobisthiophene 25, obtained from the Kumada coupling of 2-thienylmagnesium bromide and 2,5-dibromothiophene, gave bithiophene ester 144, which was converted to iodide 145 by reaction with iodine and yellow mercuric oxide. Subsequent propynylation of 145 was then realized using the Sonogashira reaction with prop-l-yne to give bisthienyl alkyne 146, which was subsequently hydrolyzed to 5 -(l-propynyl)-2,2 -bithienyl-5-carboxylic acid (147), a natural product isolated from the root of Arctium lappa. 

Alkynylfurans are readily prepared via the Sonogashira reactions of halofurans [66, 67]. Due to activation of the a-positions, regioselective Sonogashira reaction can be achieved at C(2) rather than C(3) [35,68]. 

A noticeable failure of the Sonogashira reaction of 3-bromobenzofuran was recorded by Yamanaka and coworkers [75], Only resinous materials were obtained from 3-bromobenzofuran even though the same reaction worked well (58-96% yields) for 3-iodobenzothiophene. 

In 1987, Yamanaka s group described a Pd-catalyzed reaction of halothiazoles with terminal acetylenes [51]. While the yield for the Sonogashira reaction of 2-bromo-4-phenylthiazole (89) with phenylacetylene to afford 90 was moderate (36% after desilylation), the coupling of 4-bromothiazole and 5-bromo-4-methylthiazole with phenylacetylene gave the desired internal acetylenes 91 and 92 in 71% and 65% yield, respectively. 

The Sonogashira reaction of 2-substituted-5-acetyl-4-thiazolyl triflate 97 and phenylacetylene led to 3-alkynylthiazole 98, which subsequently underwent a 6-endo-dig annulation in the presence of ammonia to produce pyrido[3,4-c]thiazole 99 [54],... 

In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [22a]. Submission of 4-bromo- and 5-bromo-4-methyloxazoles to the Sonogashira reaction conditions with phenylacetylene led to the expected internal acetylenes. 

In contrast, an excellent yield was obtained for the reaction between 5-iodoimidazole and propargyl alcohol in the absence of Cul to install the 5-alkynyl derivative [10, 41], The adduct was then deprotected to 5-alkynyl- l-P-D-ribofuranosylimidazole-4-carboxamide 58, an antileukemic agent. It is noteworthy that if the Sonogashira reaction was conducted in the presence of Cul, the yield dropped to 19%. 

In triiodoimidazole 21, a selective Suzuki coupling was achieved at C(2), whereas a selective halogen-metal exchange in a diiodoimidazole 23 was realized at C(5). In addition, the Sonogashira reactions of haloimidazoles appear to be very substrate-dependent. 

The Sonogashira reaction of 2-chloropyrazine 1-oxide gave only recovered starting material. Pentylation and octylation of 2-chloropyrazine 1-oxide also failed [9]. Possible explanations for these results were either catalyst agglomeration or metal formation from pyrazinylpalladium... 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Likewise, when 98 was refluxed with aqueous KOH in dioxane, the corresponding 2-phenylfurono[2,3-6]quinoxaline was produced in 67% yield [52], The Sonogashira reactions of chloro- and dichloroquinoxalines and trimethylsilylacetylene (56, 57] or but-3-yn-2-ol [58] have also been documented. 

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