Sonogashira reactions

Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Castro-Stephens reaction. 

Note that EtsN may reduce Pd(II) to Pd(0) as well, where EtsN is oxidized to imin-ium ion at the same time  

Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot-Chodkiewicz coupling and Castro-Stephens reaction. The Castro-Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 258, Springer International Publishing Switzerland 2014 

Sakamoto, T. Nagano, T. Kondo, Y. Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 

Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F. de Meijere, A., Eds. Wiley-VCH Weinheim, 2004 Vol. 1, 319. (Review). 

Sonogashira K. Tohda, Y. Hagihara, N. Tetrahedron Lett. 1975, 4467. Richard Heck discovered the same transformation using palladium but without the use of copper J. Organomet. Chem. 1975, 93, 259. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 241, Springer-Verlag Berlin Heidelberg 2009 

1 copper acetyl id e 2 sp halide °hen added 3. disubstituted alkyne 

The union of an sp and an sp center does not create any new stereochemistry, making for an attractive retrosynthetic disconnection in certain situations. In cases where E- or Z-geometry exists in the aryl halide component (e.g., 4), the stereochemical integrity of the olefin is retained during a Sonogashira coupling.  

A large number of ligands for palladium have been employed, though the largest and most important class is the monodentate phosphines. Multi-dentate phosphanes, palladacycles, and A-heterocyclic carbenes are emerging areas of ligand development and application. A stoichiometric amount of base is necessary to turn the catalytic system over, but in practice two or 

Mechanism of Sonogashira Reaction with Copper Co-Catalyst 

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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The condensation of 4-ethynyl-1,3-dimethyl-5-aminomethylpyrazole with iodo-benzene in the standard conditions of the Heck-Sonogashira reaction caused no complications and the yield of disubstituted acetylene was 87% (86TH1) (Scheme 68). 

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)... 

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]. 

Extended tetrathiafulvalenes with acetylenic cores are interesting compounds because of their redox and chromophoric properties. Such molecules are both interesting from materials and supramolecular chemistry perspectives. A tetraethynylethene-extended tetrathiafulvalene, for instance, was prepared using a microwave-promoted Sonogashira reaction [72]. Coup-... 

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. 

Pyrazinone bearing a phenylalkynyl substituent at position C-3, was prepared in 47% yield via Sonogashira reaction with 7 equiv of phenylacetylene in a mixture of toluene/triethylamine (2 1) using Pd[P(Ph3)2]Cl2 and Cul as the catalyst system (Scheme 37). 

Scheme 37 Scaffold decoration via Sonogashira reaction on solid support...

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... 

Figure 4.69 Flow scheme of a Sonogashira reaction performed in a micro flow system [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). 

Concerning other metals, Sonogashira coupling products have also been observed in the reaction of Ag(l)-carbenes [133] and Au(I)-supported carbenes [134] in low to moderate yields, but only under harsh conditions (more than 100°C). In this regard, NHC based catalysts for Sonogashira reactions have been supported on different materials that include clays [135], polymers [136] and peptides [137]. 

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. 

The coupling of terminal alkynes with organic halides, known as the Castro-Stephens-Sonogashira reaction, has wide applications in synthesis. The most widely used method is the Sonogashira coupling, using a combination of palladium and copper as the catalyst.13 Recently,... 

Palladium/charcoal also could serve as a catalyst for Sonogashira reactions of peptides in aqueous media. Recently, Granja et al. used palladium/carbon associated with 4-diphenylphosphinobenzoic acid (4-DPPBA) or triphenylphosphine ligand to catalyze such a reaction in aqueous DMF (Eq. 4.16).34... 

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... 

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. 

Domino transition metal-catalyzed processes can also start with a cross-coupling reaction most often, Suzuki, Stille and Sonogashira reactions are used in this context They can be combined with another Pd-catalyzed transformation, and a number of examples have also been reported where a pericydic reaction, usually a Diels-Alder reaction, follows. An interesting combination is also a Pd-catalyzed borina-tion followed by a Suzuki reaction. 

Thus, Alami and coworkers [102] have shown that benzylhalides as 6/1-201 can react with 1-alkynes as 6/1-202 in the presence of Pd° and Cul in a Sonogashira reaction which is followed by a Heck and a second Sonogashira reaction to give tetra-substituted alkenes 6/1-203 in yields of 22 to 90% (Scheme 6/1.52). 

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... 

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