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. Among the cross-coupling reactions it follows in the number of publications right after Suzuki and Heck reaction and a search for the term "Sonogashira" in Scifinder provides over 1500 references for journal publications between 2007 and 2010. The Sonogashira reaction has become so well known that often all reactions that use modern organometallic catalyst to couple alkyne motifs are termed some variant of "Sonogashira reaction", despite the fact that these reactions are not carried out under true Sonogashira reaction conditions.Mechanism
TheThe palladium cycle
* Palladium precatalyst species are activated under reaction conditions to form a reactive Pd0 compound, A. The exact identity of the catalytic species depends strongly upon reaction conditions. With simple phosphines, such as PPh3 (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, 2Pd0Cl">2Pd0Clsup>− , which could be the real catalysts in the presence of anions and halides. * The active Pd0 catalyst is involved in theThe 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. It was proven in 2018 by Košmrlj et al. that the reaction proceeds along the two interconnected Pd0/PdII catalytic cycles. * Similar to the original mechanism, the Pd0 cycle begins with the oxidative addition of theReaction conditions
The Sonogashira reaction is typically run under mild conditions. The cross-coupling is carried out at room temperature with a base, typically an amine, such as diethylamine, that also acts as the solvent. The reaction medium must be basic to neutralize the hydrogen halide produced as the byproduct of this coupling reaction, so alkylamine compounds such as triethylamine and diethylamine are sometimes used asCatalysts
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 . Another commonly used palladium source is , but complexes containing bidentate_phosphine_ligands,_such_as_,_,_and_(1,1'-Bis(diphenylphosphino)ferrocene)palladium(II)_dichloride.html" ;"title="Diphosphines">bidentate phosphine ligands, such as , , and (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride"> have also been used. The drawback to such catalysts is the need for high loadings of palladium (up to 5 mol %), along with a larger amount of a copper co-catalyst. PdII complexes are in fact pre-catalysts since they must be reduced to Pd(0) before catalysis can begin. PdII complexes generally exhibit greater stability than Pd0 complexes and can be stored under normal laboratory conditions for months. PdII catalysts are reduced to Pd0 in the reaction mixture by anAryl halides and pseudohalides
The choice of aryl halide or pseudohalide substrate (sp2-carbon) is one of the factors that mainly influence the reactivity of the Sonogashira catalytic system. The reactivity of halides is higher towards iodine, and vinyl hallides are more reactive than analogous aryl halides. Aryl triflates can also be employed instead of aryl halides.Arenediazonium precursors
Arenediazonium salts have been reported as an alternative to aryl halides for the Sonogashira coupling reaction. Gold(I) chloride has been used as co-catalyst combined with palladium(II) chloride in the coupling of arenediazonium salts with terminal alkynes, a process carried out in the presence of bis-2,6-diisopropylphenyl dihydroimidazolium chloride (IPr NHC) (5 mol%) to ''in situ'' generate a NHC–palladium complex, and 2,6-di-tert-butyl-4-methylpyridine (DBMP) as base in acetonitrile as solvent at room temperature. 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 satisfactorily 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''– 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.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 uponInverse Sonogashira coupling
In an inverse Sonogashira coupling the reactants are an aryl or vinyl compound and an alkynyl halide.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.Nickel catalysts
Recently, a nickel-catalyzed Sonogashira coupling has been developed which allows for the coupling of non-activated alkyl halides to acetylene without the use of palladium, although a copper co-catalyst is still needed. It has also been reported that gold can be used as a heterogeneous catalyst, which was demonstrated in the coupling ofGold 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 have 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. Structures known as metallodendrimers combine the advantages of homogeneous and heterogeneous catalysts, as they are soluble and well defined on the molecular level, and yet they can be recovered by precipitation, ultrafiltration, or ultracentrifugation. 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 °C, and of aryl chlorides, but in very low yields. The dendrimeric catalysts could usually be recovered by simple precipitation and filtration and reused up to five times, with diminished activity produced by dendrimer decomposition and not by palladium leaching being observed. These dendrimeric catalysts showed a negative dendritic effect; that is, the catalyst efficiency decreases as the dendrimer generation increases. The recyclable polymeric phosphine ligand shown below is obtained from ring-opening metathesis polymerization of a norbornene derivative, and has been used in the copper co-catalyzed Sonogashira reaction of methyl piodobenzoate and phenylacetylene using as a palladium source. 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 °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.''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. Interesting examples of abnormal NHCs are based on the mesoionic 1,2,3-triazol-5-ylidene structure. An efficient, cationic palladium catalyst of PEPPSI type, i.e., ''i''PEPPSI (i''nternal'' pyridine-enhanced precatalyst preparation stabilization and initiation) was demonstrated to efficiently catalyse the copper-free Sonogashira reaction in water as the only solvent, under aerobic conditions, in the absence of copper, amines, phosphines and other additives.Metal-Oxide Catalysts
Recent developments in heterogeneous catalysis enabled the use of these metal oxide materials such as Cuprous-oxide nanocatalysts, in flow processing technologies which can reduce the economical production of active pharmaceutical ingredients and various other fine chemicals.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(0) species as catalyst, which allowed the preparation of alkynelinked phenylalanine derivative for bioanalytical applications. There are also examples of the coupling partners both being attached to allyl resins, with the Pd(0) catalyst effecting cleavage of the substrates and subsequent Sonogashira coupling in solution.Natural products
Many metabolites found in nature contain alkyne or enyne moieties, and therefore, the Sonogashira reaction has found frequent utility in their syntheses. 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 the iodinated alcohol and the tris(isopropyl)silylacetylene, which gave alkyne, an intermediate in the total synthesis of the benzindenoazepine alkaloid bulgaramine. There are other recent examples of the use of aryl iodides for the preparation of intermediates under typical Sonogashira conditions, which, after cyclization, yield natural products such as benzylisoquinoline or indole alkaloids An example is the synthesis of theEnynes and enediynes
The 1,3-enyne moiety is an important structural unit for biologically active and natural compounds. It can be derived from vinylic systems and terminal acetylenes by using a configuration-retention stereospecific procedure such as the Sonogashira reaction. Vinyl iodides are the most reactive vinyl halides to Pd0 oxidative addition, and their use is therefore most frequent for Sonogashira cross-coupling reactions due to the usually milder conditions employed. Some examples include: *The coupling of 2-iodo-prop-2-enol with a wide range of acetylenes. *The preparation of an alk-2-ynylbuta-1,3-dienes from the cross-coupling of a diiodide and phenylacetylene, as shown below.Pharmaceuticals
The versatility of the Sonogashira reaction makes it a widely used reaction in the synthesis of a variety of compounds. One such pharmaceutical application is in the synthesis of SIB-1508Y, which is more commonly known as Altinicline. Altinicline is aRelated reactions
* Cross-coupling reactions ** Castro-Stephens coupling ** Heck reaction **References
{{Alkynes Condensation reactions Carbon-carbon bond forming reactions Palladium Organometallic chemistry Name reactions