The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.

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<math chem>\begin{array}{c} {} \\ {\color{Red}\ce{R^1} }\ce{-X} + \ce{H}{-\color{Blue}\!{\equiv}\!\ce{-R^2} } \ \ce{->[\text{[Pd] cat., [Cu] cat.}][\text{base, rt}]} \ {\color{Red}\ce{R^1} }{\color{Blue}-\!{\equiv}\!\ce{-R^2} } \end{array}</math><br />&nbsp;

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! The Sonogashira reaction

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:* <span style="color:red">R<sup>1</sup></span>: aryl or vinyl

:* <span style="color:blue">R<sup>2</sup></span>: arbitrary

:* X: I, Br, Cl or OTf

The Sonogashira cross-coupling reaction has been employed in a wide variety of areas, due to its usefulness in the formation of carbon–carbon bonds. The reaction can be carried out under mild conditions, such as at room temperature, in aqueous media, and with a mild base, which has allowed for the use of the Sonogashira cross-coupling reaction in the synthesis of complex molecules. Its applications include pharmaceuticals, natural products, organic materials, and nanomaterials. which is a treatment for psoriasis and acne, and in the preparation of SIB-1508Y, also known as Altinicline, a nicotinic receptor agonist.

History

The alkynylation reaction of aryl halides using aromatic acetylenes was reported in 1975 in three independent contributions by Cassar, Dieck and Heck as well as Sonogashira, Tohda and Hagihara. All of the reactions employ palladium catalysts to afford the same reaction products. However, the protocols of Cassar and Heck are performed solely by the use of palladium and require harsh reaction conditions (i.e. high reaction temperatures). The use of copper-cocatalyst in addition to palladium complexes in Sonogashira's procedure enabled the reactions to be carried under mild reaction conditions in excellent yields. A rapid development of the Pd/Cu systems followed and enabled myriad synthetic applications, while Cassar-Heck conditions were left, maybe unjustly, all but forgotten. The reaction's remarkable utility can be evidenced by the amount of research still being done on understanding and optimizing its synthetic capabilities as well as employing the procedures to prepare various compounds of synthetic, medicinal or material/industrial importance. and a search for the term "Sonogashira" in SciFinder provides over 1500 references for journal publications between 2007 and 2010.

The palladium cycle

  • Palladium precatalyst species are activated under reaction conditions to form a reactive Pd<sup>0</sup> compound, A. The exact identity of the catalytic species depends strongly upon reaction conditions. With simple phosphines, such as PPh<sub>3</sub> (n=2), and in case of bulky phosphines (i.e., ) it was demonstrated that monoligated species (n=1) are formed. Furthermore, some results point to the formation of anionic palladium species, [L<sub>2</sub>Pd<sup>0</sup>Cl]<sup>−</sup> , which could be the real catalysts in the presence of anions and halides.
  • The active Pd<sup>0</sup> catalyst is involved in the oxidative addition step with the aryl or vinyl halide substrate to produce Pd<sup>II</sup> species B. Similar to the above discussion, its structure depends on the employed ligands. This step is believed to be the rate-limiting step of the reaction.
  • Complex B reacts with copper acetylide, complex F, in a transmetallation step, yielding complex C and regenerating the copper catalyst.
  • The structure of complex C depends on the properties of the ligands. For the facile reductive elimination to occur, the substrate motifs need to be in close vicinity, i.e. cis-orientation, so there can be trans-cis isomerisation involved. In reductive elimination the product tolane is expelled from the complex and the active Pd catalytic species is regenerated.

The copper cycle

  • The copper cycle is not entirely well described. It is suggested that the presence of a base results in the formation of a π-alkyne complex E. This increases the acidity of the terminal proton and leads to the formation of copper acetylide, complex F, upon deprotonation.
  • Acetylide F is then involved in the transmetallation reaction with palladium intermediate B.

The mechanism of a copper-free Sonogashira variant

Although beneficial for the effectiveness of the reaction, the use of copper salts in "classical" Sonogashira reaction is accompanied with several drawbacks, such as the application of environmentally unfriendly reagents, the formation of undesirable alkyne homocoupling (Glaser side products), and the necessity of strict oxygen exclusion in the reaction mixture. Thus, with the aim of excluding copper from the reaction, a lot of effort was undertaken in the developments of Cu-free Sonogashira reaction. Along the development of new reaction conditions, many experimental and computational studies focused on elucidation of reaction mechanism. Until recently, the exact mechanism by which the Cu-free reaction occurs was under debate, with critical mechanistic questions unanswered.

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center|642px|Mechanism for the Cu-free Sonogashira reaction. The cross-coupling is carried out at room temperature with a base, typically an amine, such as [[diethylamine,

Catalysts

Typically, two catalysts are needed for this reaction: a zerovalent palladium complex and a copper(I) halide salt. Common examples of palladium catalysts include those containing phosphine ligands such as Tetrakis(triphenylphosphine)palladium(0)|. Another commonly used palladium source is [, but complexes containing bidentate phosphine ligands, such as , , and (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride| have also been used. Pd<sup>II</sup> catalysts are reduced to Pd<sup>0</sup> in the reaction mixture by an amine, a phosphine ligand, or another reactant in the mixture allowing the reaction to proceed. For instance, oxidation of triphenylphosphine to triphenylphosphine oxide can lead to the formation of Pd<sup>0</sup> in situ when is used.

Copper(I) salts, such as CuI, react with the terminal alkyne and produce a copper(I) acetylide, which acts as an activated species for the coupling reactions. Cu(I) is a co-catalyst in the reaction, and is used to increase the rate of the reaction. This coupling can be carried out starting from anilines by formation of the diazonium salt followed by in situ

Sonogashira coupling, where anilines are transformed into diazonium salt and furtherly converted into alkyne by coupling with phenylacetylene.

Alkynes

Various aromatic alkynes can be employed to yield desired disubstituted products with satisfactory yields. Aliphatic alkynes are generally less reactive.

Bases

Due to the crucial role of base, specific amines must be added in excess or as solvent for the reaction to proceed. It has been discovered that secondary amines such as piperidine, morpholine, or diisopropylamine in particular can react efficiently and reversibly with trans&ndash; complexes by substituting one ligand. The equilibrium constant of this reaction is dependent on R, X, a factor for basicity, and the amine's steric hindrance. The result is competition between the amine and the alkyne group for this ligand exchange, which is why the amine is generally added in excess to promote preferential substitution.

Protecting groups

Trimethylsilylacetylene is a commonly used reagent in Sonogashira couplings. Being a liquid it is a more convenient reagent than the gaseous acetylene, and the trimethylsilyl group prevents addition onto the other end of the acetylene group. The trimethylsilyl group can then be removed using TBAF, yielding a monosubstituted acetylene. It may also be removed using DBU in situ, allowing the monosubstituted acetylene to react further with another aryl halide to form diphenylacetylene and derivatives.

Reaction variations

Copper-free Sonogashira coupling

While a copper co-catalyst is added to the reaction to increase reactivity, the presence of copper can result in the formation of alkyne dimers. This leads to what is known as the Glaser coupling reaction, which is an undesired formation of homocoupling products of acetylene derivatives upon oxidation. As a result, when running a Sonogashira reaction with a copper co-catalyst, it is necessary to run the reaction in an inert atmosphere to avoid the unwanted dimerization. Copper-free variations to the Sonogashira reaction have been developed to avoid the formation of the homocoupling products. There are other cases when the use of copper should be avoided, such as coupling reactions involving substrates which potential copper ligands, for instance free-base porphyrins.

Catalyst variations

Silver co-catalysis

In some cases stoichiometric amounts of silver oxide can be used in place of CuI for copper-free Sonogashira couplings. It has also been reported that gold can be used as a heterogeneous catalyst, which was demonstrated in the coupling of phenylacetylene and iodobenzene with an Au/CeO<sub>2</sub> catalyst. In this case, catalysis occurs heterogeneously on the Au nanoparticles, with Au(0) as the active site. Selectivity to the desirable cross coupling product was also found to be enhanced by supports such as CeO<sub>2</sub> and La<sub>2</sub>O<sub>3</sub>.

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<math chem>\begin{array}{c} {} \\ {\color{Blue}\ce{R}-\!\!\!{\equiv}\!}\ce{-H} + {\color{Red}\ce{Ar}-\!\!\!{\equiv}\!-}\ce{X ->[\ce{FeCl3}\text{, DMEDA}][\begin{matrix}\ce{Cs2CO3}\text{, toluene} \\ 135^\circ\text{C, 72h} \end{matrix}]} \ {\color{Blue}\ce{R}-\!\!\!{\equiv}\!}{\color{Red}\ce{-H \end{array}</math>

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! Palladium-free Sonogashira reaction catalysed by iron

Studies have shown that organic and inorganic starting materials can also contain enough (ppb level) palladium for the coupling.

Gold and palladium co-catalysis

A highly efficient gold and palladium combined methodology for the Sonogashira coupling of a wide array of electronically and structurally diverse aryl and heteroaryl halides has been reported.

The orthogonal reactivity of the two metals shows high selectivity and extreme functional group tolerance in Sonogashira coupling. A brief mechanistic study reveals that the gold-acetylide intermediate enters into palladium catalytic cycle at the transmetalation step.

Dendrimeric palladium complexes

The issues dealing with recovery of the often expensive catalyst after product formation poses a serious drawback for large-scale applications of homogeneous catalysis. Some recent examples can be found about the use of dendritic palladium complex catalysts for the copper-free Sonogashira reaction. Thus, several generations of bidentate phosphine palladium(II) polyamino dendritic catalysts have been used solubilized in triethylamine for the coupling of aryl iodides and bromides at 25-120&nbsp;°C, and of aryl chlorides, but in very low yields.

[[File:Polymeric phosphine ligand.png|thumb|A recyclable polymeric phosphine ligand Despite recovery by filtration, polymer catalytic activity decreased by approximately 4-8% in each recycle experiment.

Nitrogen ligands

Pyridines and pyrimidines have shown good complexation properties for palladium and have been employed in the formation of catalysts suitable for Sonogashira couplings. The dipyrimidyl-palladium complex shown below has been employed in the copper-free coupling of iodo-, bromo-, and chlorobenzene with phenylacetylene using N-butylamine as base in THF solvent at 65&nbsp;°C. Furthermore, all structural features of this complex have been characterized by extensive X-ray analysis, verifying the observed reactivity.

More recently, the dipyridylpalladium complex has been obtained and has been used in the copper-free Sonogashira coupling reaction of aryl iodides and bromides in N-methylpyrrolidinone (NMP) using tetra-n-butylammonium acetate (TBAA) as base at room temperature. This complex has also been used for the coupling of aryl iodides and bromides in refluxing water as solvent and in the presence of air, using pyrrolidine as base and TBAB as additive, although its efficiency was higher in N-methylpyrrolidinone (NMP) as solvent.

thumb|center|Coupling of a diiodo substrate catalysed by the dipyridylpalladium complex.

N-heterocyclic carbene (NHC) palladium complexes

N-heterocyclic carbenes (NHCs) have become one of the most important ligands in transition-metal catalysis. The success of normal NHCs is greatly attributed to their superior σ-donating capabilities as compared to phosphines, which is even greater in abnormal NHC counterparts. Employed as ligands in palladium complexes, NHCs contributed greatly to the stabilization and activation of precatalysts and have therefore found application in many areas of organometallic homogeneous catalysis, including Sonogashira couplings.

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| center|200px|An example of palladium(II) derived complex with N-heterocyclic ligand

| center|300px|An example of cationic PdNHC complex for efficient catalysis of Sonogashira reaction in water.

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| An example of palladium(II) derived complex with normal NHC ligand.

| Efficient iPEPPSI catalyst for Cu-free Sonogashira reaction in water.

Applications in synthesis

Sonogashira couplings are employed in a wide array of synthetic reactions, primarily due to their success in facilitating the following challenging transformations:

Alkynylation reactions

The coupling of a terminal alkyne and an aromatic ring is the pivotal reaction when talking about applications of the copper-promoted or copper-free Sonogashira reaction. The list of cases where the typical Sonogashira reaction using aryl halides has been employed is large, and choosing illustrative examples is difficult. A recent use of this methodology is shown below for the coupling of iodinated phenylalanine with a terminal alkyne derived from d-biotin using an in situ generated Pd<sup>0</sup> species as catalyst, which allowed the preparation of alkyne-linked phenylalanine derivative for bioanalytical applications. There are also examples of the coupling partners both being attached to allyl resins, with the Pd<sup>0</sup> catalyst effecting cleavage of the substrates and subsequent Sonogashira

coupling in solution.

[[File:Alkynylation.svg|thumb|center|Alkynylation of phenylalanine. Several of the most recent and promising applications of this coupling methodology toward the total synthesis of natural products exclusively employed the typical copper-cocatalyzed reaction.

An example of the coupling of an aryl iodide to an aryl acetylene can be seen in the reaction of an iodinated alcohol and tris(isopropyl)silylacetylene, which gave an alkyne, an intermediate in the total synthesis of the benzindenoazepine alkaloid bulgaramine.

thumb|center|Sonogashira reaction in the total synthesis of bulgaramine. An example is the synthesis of the [[benzylisoquinoline alkaloids (+)-(S)-laudanosine and (–)-(S)-xylopinine. The synthesis of these natural products involved the use of Sonogashira cross-coupling to build the carbon backbone of each molecule.

[[File:Natural Products (+)-(S)-laudanosine and (–)-(S)-xylopinine.svg|thumb|center|Natural products (+)-(S)-laudanosine and (–)-(S)-xylopinine synthesized using the Sonogashira cross-coupling reaction.

  • The preparation of alk-2-ynylbuta-1,3-dienes from the cross-coupling of a diiodide and phenylacetylene, as shown below.

[[File:Shao-J-Org-Chem-2005.png|thumb|center|Synthesis of an alk-2-ynylbuta-1,3-diene accomplished by Sonogashira coupling. As of 2008, Altinicline has undergone Phase II clinical trials.

[[File:Application of Sonogashira.svg|thumb|center|Use of the Sonogashira cross-coupling reaction in the synthesis of SIB-1508Y.

[[File:Bakherad-Tetrahedron-Lett-2008.png|thumb|center|Synthesis of imidazopyridine derivatives.