View source for Sonogashira coupling

{{Short description|Cross-coupling reaction used in organic synthesis}}
{{Reactionbox
| Name = Sonogashira coupling
| Type = Coupling reaction
| NamedAfter = [[Kenkichi Sonogashira]]
| Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = sonogashira-coupling
| RSC_ontology_id = 0000137
}}
| Section4 = {{Reactionbox Related
| Similar = [[Sonogashira coupling#Copper-free Sonogashira coupling|Copper-free Sonogashira coupling]]
| Alternative = Heck-Cassarcoupling, Heck alkynylation
}}
}}
The '''Sonogashira reaction''' is a [[cross-coupling reaction]] used in [[organic synthesis]] to form [[carbon–carbon bond]]s. 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]].<ref name="Development">{{citation |author=Sonogashira, K. |journal=[[J. Organomet. Chem.]] |title= Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp<sup>2</sup>-carbon halides |year=2002 |volume=653 |issue=1–2 |pages=46–49 |doi= 10.1016/s0022-328x(02)01158-0}}</ref>

{| class="wikitable" 
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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]].<ref name="Development" /> Specific examples include its use in the synthesis of [[tazarotene]],<ref name=King-2005>{{citation |author=King, A.O. |author2=Yasuda, N. |journal=[[Org. Process Res. Dev.]] |title= A Practical and Efficient Process for the Preparation of Tazarotene |year=2005 |volume=9 |issue=5 |pages=646–650 |doi= 10.1021/op050080x}}</ref> which is a treatment for [[psoriasis]] and [[acne]], and in the preparation of SIB-1508Y, also known as [[Altinicline]],<ref name="King-2004">{{citation |author1=King, A. O. |author2=Yasuda, N.  |title=Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals Organometallics in Process Chemistry |year=2004 |volume=6 |pages=205–245 |doi=10.1007/b94551 |series=[[Top. Organomet. Chem.]] |isbn=978-3-540-01603-8 }}</ref> a [[nicotinic receptor]] [[agonist]].

==History==

The alkynylation reaction of aryl halides using aromatic acetylenes was reported in 1975 in three independent contributions by Cassar,<ref name="Cassar">{{citation |author=Cassar, L. |journal=[[J. Organomet. Chem.]] |title= Synthesis of aryl- and vinyl-substituted acetylene derivatives by the use of nickel and palladium complexes |year=1975 |volume=93 |issue=2 |pages=253–257 |doi= 10.1016/S0022-328X(00)94048-8}}</ref> Dieck and [[Richard F. Heck|Heck]]<ref name="Dieck-Heck">{{citation |author1=Dieck, H.A. |author2= Heck, R.F. |journal=[[J. Organomet. Chem.]] |title= Palladium catalyzed synthesis of aryl, heterocyclic and vinylic acetylene derivatives |year=1975 |volume=93 |issue= 2 |pages=259–263 |doi= 10.1016/S0022-328X(00)94049-X}}</ref> as well as [[Kenkichi Sonogashira|Sonogashira]], Tohda and Hagihara.<ref name="Sonogashira-TetrahedronLett-1975">{{citation |author1=Sonogashira, K. |author2=Tohda, Y. |author3=Hagihara, N. |journal=[[Tetrahedron Lett.]] |title=A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines |year=1975 |volume=16 |issue=50 |pages=4467–4470 |doi=10.1016/s0040-4039(00)91094-3}}</ref> 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.<ref name="Recent Advances">{{citation |author1=Chinchilla, R. |author2=Nájera, C. |journal=[[Chem. Soc. Rev.]] |title=Recent advances in Sonogashira reactions  |year=2011 |volume=40 |issue=10 |pages=5084–5121 |doi=10.1039/c1cs15071e |pmid=21655588}}</ref> 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.<ref name="Recent Advances" /> Among the cross-coupling reactions it follows in the number of publications right after Suzuki and Heck reaction<ref name="Seechurn-AngewChemIndEd-2012">{{citation |author1=Seechurn, C. C. C. |author2=Kitching, M. O. |author3=Colacot, T. J. |author4=Snieckus, V. |journal=[[Angew. Chem. Int. Ed.]] |title=Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize  |year=2012 |volume=51 |issue=21 |pages=5062–5085 |doi=10.1002/anie.201107017 |pmid=22573393}}</ref> and a search for the term "Sonogashira" in [[SciFinder]] provides over 1500 references for journal publications between 2007 and 2010.<ref name="Recent Advances" />

The Sonogashira reaction has become so well known that often all reactions that use modern organometallic catalyst to couple alkyne motifs are termed some [[Sonogashira coupling#Reaction variations|variant of "Sonogashira reaction"]], despite the fact that these reactions are not carried out under true Sonogashira reaction conditions.<ref name="Recent Advances" />

==Mechanism==
[[File:Sonogashira-reaction-mechanism.png|thumb|right|315px|Catalytic cycle for the Sonogashira reaction<ref name="Recent Advances" />]]
The [[reaction mechanism]] is not clearly understood, but the textbook mechanism revolves around a palladium cycle which is in agreement with the "classical" [[cross-coupling]] mechanism, and a copper cycle, which is less well known.<ref name="Booming">{{citation |author1=Chinchilla, R. |author2=Nájera, C. |journal=[[Chem. Rev.]] |title=The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry |year=2007 |volume=107 |issue=3 |pages=874–922 |doi=10.1021/cr050992x |pmid=17305399}}</ref>

===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., {{chem|P(''o''-Tol)|3}}) it was demonstrated that monoligated species (n=1) are formed.<ref name="Synthesis, Characterization">{{citation |author1=Stambuli, J. P. |author2=Buhl, M. |author3=Hartwig, J. F. |journal=[[J. Am. Chem. Soc.]] |title= Synthesis, Characterization, and Reactivity of Monomeric, Arylpalladium Halide Complexes with a Hindered Phosphine as the Only Dative Ligand |year=2002 |volume=124 |issue=32 |pages=9346–9347 |doi=10.1021/ja0264394 |pmid=12167009 }}</ref> 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.<ref name="Anionic">{{citation |author1=Amatore, C. |author2=Jutand, A. |journal=[[Acc. Chem. Res.]] |title=Anionic Pd<sup>0</sup> and Pd<sup>II</sup> Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions |year=2000 |volume=33 |issue=5 |pages=314–321 |doi=10.1021/ar980063a |pmid=10813876 |citeseerx=10.1.1.612.7347 }}</ref>
* 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 [[Cis–trans isomerism|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|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 coupling|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.<ref name="Soheili-OrgLett-2003">{{citation |author1=Soheili, A. |author2=Albaneze-Walker, J. |author3=Murry, J. A. |author4=Dormer, P. G. |author5=Hughes, D. L. |journal=[[Org. Lett.]] |title=Efficient and General Protocol for the Copper-Free Sonogashira Coupling of Aryl Bromides at Room Temp |year=2003 |volume=5 |issue=22 |pages=4191–4194 |doi=10.1021/ol035632f|pmid=14572282 }}</ref> Until recently, the exact mechanism by which the Cu-free reaction occurs was under debate, with critical mechanistic questions unanswered.<ref name="Recent Advances" /> It was shown in 2018 by Košmrlj et al. that the reaction proceeds along the two interconnected Pd<sup>0</sup>/Pd<sup>II</sup> catalytic cycles.<ref name="Gazvoda-NatCommun-2018">{{cite journal |last1=Gazvoda |first1=M. |last2=Virant |first2=M. |last3=Pinter |first3=B. |last4=Košmrlj |first4=J. |title=Mechanism of copper-free Sonogashira reaction operates through palladium-palladium transmetallation |journal=[[Nat. Commun.]] |year=2018 |volume=9 |issue=1 |page=4814 |doi=10.1038/s41467-018-07081-5|pmc=6240041 |pmid=30446654|bibcode=2018NatCo...9.4814G }}</ref><ref name=Virant-thesis-2019>{{cite thesis |type=PhD |last=Virant |first=Miha |date=2019|title=Development of homogeneous palladium catalytic systems for selected transformations of terminal acetylenes |publisher=[[University of Ljubljana]] |url=https://repozitorij.uni-lj.si/Dokument.php?id=124988&lang=slv}}</ref>

{| class="wikitable" 
|- align="center" 
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[[File:Cu-free-mechanism.png|center|642px|Mechanism for the Cu-free Sonogashira reaction.<ref name="Gazvoda-NatCommun-2018"/><ref name=Virant-thesis-2019/>]]
|- align="center"
! Mechanism for the Cu-free Sonogashira reaction.<ref name="Gazvoda-NatCommun-2018"/><ref name=Virant-thesis-2019/>
|}

* Similar to the original mechanism, the Pd<sup>0</sup> cycle begins with the oxidative addition of the [[aryl halide]] or triflate to the Pd<sup>0</sup> catalyst, forming complex '''B''' and activating aryl halide substrate for the reaction.
* Acetylene is activated in the second, Pd<sup>II</sup> mediated cycle. Phenylacetylene was proven to form Pd monoacetylide complex '''D''' as well as Pd bisacetylide complex '''F''' under mild reaction conditions.
* Both activated species, namely complexes '''B''' and '''F''', are involved in the [[transmetallation]] step, forming complex '''C''' and regenerating '''D'''.
* The resulting products of [[reductive elimination]], disubstituted alkyne product as well as regenerated Pd<sup>0</sup> catalytic species, complete the Pd<sup>0</sup> catalytic cycle.

It was demonstrated that amines are competitive to the phosphines and can also participate as ligands L in the described reaction species. Depending on the rate of the competition between amine and phosphines, a dynamic and complex interplay is expected when using different coordinative bases.<ref name = "Copper-free 2">{{citation |author1=Tougerti, A. |author2=Negri, S. |author3=Jutand, A. |journal =[[Chem. Eur. J.]]|title=Mechanism of the Copper-Free Palladium-Catalyzed Sonogashira Reactions: Multiple Role of Amines |year=2007|volume=13|issue=2 |pages=666–676| doi =10.1002/chem.200600574|pmid=16991183 }}</ref><ref name = "Plenio-AngewChemIntEd-2008">{{citation |author1=Plenio, H. |journal =[[Angew. Chem. Int. Ed.]] |title=Catalysts for the Sonogashira Coupling—The Crownless Again Shall Be King  |year=2008|volume=47|issue =37 |pages=6954–6956| doi=10.1002/anie.200802270|pmid =18683173 }}</ref><ref name="Gazvoda-NatCommun-2018" /><ref name=Virant-thesis-2019/>

==Reaction conditions==
The Sonogashira reaction is typically run under mild conditions.<ref name="Cond">{{citation |author1=Kohnen, A. L |author-link2=Rick L. Danheiser |author2=Danheiser, R. L. |author3=Denmark S. E. |author4=Liu X. |journal=[[Org. Synth.]] |title=Synthesis of Terminal 1,3-Diynes Via Sonogashira Coupling of Vinylidene Chloride Followed by Elimination. Preparation of 1,3-Decadiyne |year=2007 |volume=84 |pages=77–87 |doi=10.15227/orgsyn.084.0077|pmc=2901882 |pmid=20628544}}</ref> The cross-coupling is carried out at room temperature with a base, typically an amine, such as [[diethylamine]],<ref name="Sonogashira-TetrahedronLett-1975" /> 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 [[amine|alkylamine]] compounds such as [[triethylamine]] and [[diethylamine]] are sometimes used as [[solvent]]s, but also DMF or ether can be used as solvent. Other bases such as potassium carbonate or cesium carbonate are occasionally used. In addition, deaerated conditions are formally needed for Sonogashira coupling reactions because the palladium(0) complexes are unstable in the air, and oxygen promotes the formation of homocoupled acetylenes. Recently, development of air-stable organopalladium catalysts enable this reaction to be conducted in the ambient atmosphere. In addition, R.M Al-Zoubi and co-workers successfully developed a method with high regioselectivity for 1,2,3-trihaloarene derivatives in good to high yields under ambient conditions.<ref>{{cite journal |last1=Al-Zoubi |first1=Raed |title=Palladium-catalyzed highly regioselective mono and double Sonogashira cross-coupling reactions of 5-substituted-1,2,3-triiodobenzene under ambient conditions† |journal=[[RSC Adv.]] |date=16 April 2020 |volume=10 |issue=28 |page=16376 |doi=10.1039/d0ra01569e |bibcode=2020RSCAd..1016366A |doi-access=free |pmid=35498858 |pmc=9053030 }}</ref>

===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 ligand]]s such as [[Tetrakis(triphenylphosphine)palladium(0)|{{chem2|[Pd(PPh3)4]}}]]. Another commonly used palladium source is [[Bis(triphenylphosphine)palladium chloride|[{{chem2|Pd(PPh3)2Cl2]}}]], but complexes containing [[Diphosphines|bidentate phosphine ligands]], such as {{chem2|[Pd([[dppe]])Cl2]}}, {{chem2|[Pd([[dppp]])Cl2]}}, and [[(1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride|{{chem2|[Pd(dppf)Cl2]}}]] have also been used.<ref name="Booming" /> The drawback to such catalysts is the need for high loadings of palladium (up to 5&nbsp;mol %), along with a larger amount of a copper co-catalyst.<ref name="Booming" /> 
Pd<sup>II</sup> complexes are in fact [[pre-catalyst]]s since they must be reduced to Pd<sup>0</sup> before catalysis can begin. Pd<sup>II</sup> complexes generally exhibit greater stability than Pd<sup>0</sup> complexes and can be stored under normal laboratory conditions for months.<ref name="Copper-free">{{citation |author1=Bohm, V. P. W. |author2=Herrmann, W. A. |journal=[[Eur. J. Org. Chem.]] |title=A Copper-Free Procedure for the Palladium-Catalyzed Sonogashira Reaction of Aryl Bromides with Terminal Alkynes at Room Temperature |year=2000 |volume=200 |issue=22 |pages=3679–3681 |doi=10.1002/1099-0690(200011)2000:22<3679::aid-ejoc3679>3.0.co;2-x}}</ref> 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.<ref name="Carbon-Carbon">{{citation |author1=Yin, L. |author2=Liebscher, J. |journal=[[Chem. Rev.]] |title=Carbon-Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts |year=2006 |volume=107 |issue=1 |pages=133–173 |doi=10.1021/cr0505674|pmid=17212474 }}</ref> For instance, oxidation of [[triphenylphosphine]] to [[triphenylphosphine oxide]] can lead to the formation of Pd<sup>0</sup> ''[[in situ]]'' when {{chem2|[Pd(PPh3)2Cl2]}} is used.

Copper(I) salts, such as [[Copper(I) iodide|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.<ref name="Recent Advances" />

===Aryl halides and pseudohalides===
The choice of aryl halide or pseudohalide substrate (sp<sup>2</sup>-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 halides are more reactive than analogous aryl halides. The coupling of aryl iodides proceeds at room temperature, while aryl bromides require heating.
[[File:Reactivity in Sonogashira Cross-Coupling.svg|thumb|center|800px|The rate of reaction of sp<sup>2</sup> carbons. Vinyl iodide > vinyl triflate > vinyl bromide > vinyl chloride > aryl iodide > aryl triflate > aryl bromide >>> aryl chloride.<ref name="Booming" />]]
This difference in reactivity can be exploited to selectively couple an aryl iodide but not an aryl bromide, by performing the reaction at room temperature.<ref name="Booming"/> An example is the symmetrical Sonogashira coupling of two equivalents of [[1-bromo-4-iodobenzene]] with [[trimethylsilylacetylene]] (with the [[trimethylsilyl group]] removed ''in-situ'') to form [[bis(4-bromophenyl)acetylene]].<ref name="one-pot"/>
[[File:Symmetrical sonogashira 1-bromo-4-iodobenzene.png|thumb|center|600px|Symmetrical Sonogashira coupling of 1-bromo-4-iodobenzene with trimethylsilylacetylene with in situ TMSA deprotection to form bis(4-bromophenyl)acetylene.<ref name="one-pot"/>]]

Aryl triflates can also be employed instead of aryl halides.

====Arenediazonium precursors====
[[Diazonium compound|Arenediazonium salt]]s 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&nbsp;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.<ref>{{cite journal | author = Panda B., Sarkar T. K. | year = 2010 | title = Gold and palladium combined for the Sonogashira-type cross-coupling of arenediazonium salts |journal=[[Chem. Commun.]] | volume = 46 | issue = 18 | pages = 3131–3133 | doi = 10.1039/c001277g | pmid = 20361097 }}</ref> 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;{{chem2|RPdX(PPh3)2}} complexes by substituting one {{chem2|PPh3}} ligand. The equilibrium constant of this reaction is dependent on R, X, a factor for basicity, and the amine's steric hindrance.<ref name="Reduction">{{citation |author1=Jutand, A. |author2=Négri, S. |author3=Principaud |author4=A. |journal=[[Eur. J. Inorg. Chem.]] |title=Formation of ArPdXL(amine) Complexes by Substitution of One Phosphane Ligand by an Amine in trans-ArPdX(PPh3)2 Complexes |year=2005 |pages=631–635 |doi=10.1002/ejic.200400413 |volume=2005|issue=4 }}</ref> 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.<ref>{{cite encyclopedia|title=Trimethylsilylacetylene| encyclopedia=EROS|author=Godson C. Nwokogu |author2=Saskia Zemolka |author3=Florian Dehme |year=2007|doi=10.1002/047084289X.rt288.pub2| isbn=978-0-471-93623-7}}</ref> 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 [[1,8-Diazabicyclo(5.4.0)undec-7-ene|DBU]] in situ, allowing the monosubstituted acetylene to react further with another aryl halide to form [[diphenylacetylene]] and derivatives.<ref name="one-pot">{{cite journal |last1=Mio |first1=Matthew J. |last2=Kopel |first2=Lucas C. |last3=Braun |first3=Julia B. |last4=Gadzikwa |first4=Tendai L. |last5=Hull |first5=Kami L. |last6=Brisbois |first6=Ronald G. |last7=Markworth |first7=Christopher J. |last8=Grieco |first8=Paul A. |date=2002 |title=One-Pot Synthesis of Symmetrical and Unsymmetrical Bisarylethynes by a Modification of the Sonogashira Coupling Reaction |journal=[[Organic Letters]] |volume=4 |issue=19 |pages=3199–3202 |doi=10.1021/ol026266n|pmid=12227748 }}</ref>

==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 gas|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.<ref name="Copper-free" /><ref name="Efficient, Copper-Free">{{citation |author1=Mery, D. |author2=Heuze, K. |author3=Astruc, D. |journal=[[Chem. Commun.]] |title=A very efficient, copper-free palladium catalyst for the Sonogashira reaction with aryl halides |year=2003 |volume=15 |issue=15 |pages=1934–1935 |doi=10.1039/B305391C |pmid=12932040 }}</ref>  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 [[porphyrin]]s.<ref name="Booming" />

===Inverse Sonogashira coupling===
In an '''inverse Sonogashira coupling''' the reactants are an aryl or vinyl compound and an alkynyl halide.<ref name=Dudnik-2010>{{cite journal |last1=Dudnik |first1=A.|last2=Gevorgyan | first2= V. |title=Formal Inverse Sonogashira Reaction: Direct Alkynylation of Arenes and Heterocycles with Alkynyl Halides |year=2010 |volume=49 |pages=2096–2098 |journal=[[Angew. Chem. Int. Ed.]] |issue=12|doi=10.1002/anie.200906755 |pmc=3132814 |pmid=20191647}}</ref>

===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.<ref name="Booming" />

====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.<ref name="Ni-Catalyzed">{{citation |author1=Vechorkin, O. |author2=Barmaz, D. |author3=Proust, V. |author4=Hu, X. |journal=[[J. Am. Chem. Soc.]] |title=Ni-Catalyzed Sonogashira Coupling of Nonactivated Alkyl Halides: Orthogonal Functionalization of Alkyl Iodides, Bromides, and Chlorides |year=2009 |volume=131 |issue=34 |pages=12078–12079 |doi=10.1021/ja906040t |pmid=19670863 }}</ref> 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.<ref name="Catalysis">{{citation |author1=Gonzalez-Arallano, C. |author2=Abad, A. |author3=Corma, A. |author4=Garcia, H. |author5=Iglesias, M. |author6=Sanchez, F. |journal=[[Angew. Chem. Int. Ed.]] |title=Catalysis by Gold(I) and Gold(III): A Parallelism between Homo- and Heterogeneous Catalysts for Copper-Free Sonogashira Cross-Coupling Reactions |year=2007 |volume=46 |issue=9 |pages=1536–1538 |doi=10.1002/anie.200604746 |pmid=17226890 }}</ref><ref name="Gold">{{citation |author1=Corma, A. |author2=Juarez, R. |author3=Boronat, M. |author4=Sanchez, F. |author5=Iglesias, M. |author6=Garcia, H. |journal=[[Chem. Commun.]] |title=Gold catalyzes the Sonogashira coupling reaction without the requirement of palladium impurities |year=2011 |volume=47 |issue=5 |pages=1446–1448 |doi=10.1039/C0CC04564K |pmid=21183985 }}</ref> In this case, catalysis occurs heterogeneously on the Au nanoparticles,<ref name="Gold" /><ref name="heterogeneousgold">{{citation |author=Kyriakou, G. |author2=Beaumont, S. K. |author3=Humphrey, S. M. |author4=Antonetti, C. |author5=Lambert, R. M. |journal=[[ChemCatChem]] |title=Sonogashira Coupling Catalyzed by Gold Nanoparticles: Does Homogeneous or Heterogeneous Catalysis Dominate?|year=2010 |volume=2 |issue=11 |pages=1444–1449 |doi=10.1002/cctc.201000154|s2cid=96700925 }}</ref> with Au(0) as the active site.<ref name="Goldzero">{{citation |author=Beaumont, S. K. |author2=Kyriakou, G. |author3=Lambert, R. M. |journal=[[J. Am. Chem. Soc.]] |title=Identity of the active site in gold nanoparticle-catalyzed Sonogashira coupling of phenylacetylene and iodobenzene. |year=2010 |volume=132 |issue=35 |pages=12246–12248  |doi=10.1021/ja1063179|pmid=20715838 |url=http://dro.dur.ac.uk/12203/1/12203.pdf }}</ref> 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>.<ref name="Goldzero" /> Additionally, iron-catalyzed Sonogashira couplings have been investigated as relatively cheap and non-toxic alternatives to palladium. Here, FeCl<sub>3</sub> is proposed to act as the transition-metal catalyst and Cs<sub>2</sub>CO<sub>3</sub> as the base, thus theoretically proceeding through a palladium-free and copper-free mechanism.<ref name="iron">{{citation |author1=M. Carril |author2=A. Correa |author3=C. Bolm | journal =[[Angew. Chem.]] |title=Iron-Catalyzed Sonogashira Reaction |year=2008 |volume=120|issue=26 |pages = 4940–4943|doi=10.1002/ange.200801539|bibcode=2008AngCh.120.4940C }}</ref>
{| class="wikitable" 
|- align="center" 
||
<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>
|- 
! Palladium-free Sonogashira reaction catalysed by iron<ref name="iron" />
|}

While the copper-free mechanism has been shown to be viable, attempts to incorporate the various transition metals mentioned above as less expensive alternatives to palladium catalysts have shown a poor track record of success due to contamination of the reagents with trace amounts of palladium, suggesting that these theorized pathways are extremely unlikely, if not impossible, to achieve.<ref>{{citation |author=Thorsten Lauterbach |author2=Madeleine Livendahl |author3=Antonio Rosellon |author4=Pablo Espinet |author5=Antonio M. Echavarren | journal =[[Org. Lett.]] |title=Unlikeliness of Pd-Free Gold(I)-Catalyzed Sonogashira Coupling Reactions| year=2010 |volume=12| issue =13 |pages = 3006–3009|doi=10.1021/ol101012n|pmid=20515017 }}</ref>

Studies have shown that organic and inorganic starting materials can also contain enough ([[Parts-per notation|ppb]] level) palladium for the coupling.<ref name=ppb-level-palladium>{{cite journal|author1=Tolnai, L. G.|author2=Gonda, ZS.|author3=Novák, Z.|title=Dramatic Impact of ppb Levels of Palladium on the "Copper-Catalyzed" Sonogashira Coupling|journal=[[Chem. Eur. J.]] |year = 2010|volume=16|issue=39|pages=11822–11826|doi=10.1002/chem.201001880|pmid=20821769}}</ref>

====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.<ref name="GoldPd">{{citation |author1=Panda, B. |author2=Sarkar, T. K. |journal=[[Synthesis (journal)|Synthesis]] |title=Gold and Palladium Combined for the Sonogashira Coupling of Aryl and Heteroaryl Halides |year=2013 |volume=45|issue=6|pages=817–829 |doi=10.1055/s-0032-1318119 }}</ref>
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.<ref name="Booming" /> 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.<ref name="AstrucAdvSynth2005">{{cite journal |last1=Astruc |first1=Didier |last2=Heuzé |first2=Karine |last3=Gatard |first3=Sylvain |last4=Méry |first4=Denise |last5=Nlate |first5=Sylvain |last6=Plault |first6=Lauriane |title=Metallodendritic Catalysis for Redox and Carbon—Carbon Bond Formation Reactions: A Step towards Green Chemistry. |journal=[[Adv. Synth. Catal.]] |date=February 2005 |volume=347 |issue=2–3 |pages=329–338 |doi=10.1002/adsc.200404247}}</ref> 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.<ref name="AstrucChemComm2003">{{cite journal |last1=Heuzé |first1=Karine |last2=Méry |first2=Denise |last3=Gauss |first3=Dominik |last4=Astruc |first4=Didier |title=Copper-free, recoverable dendritic Pd catalysts for the Sonogashira reaction |journal=[[Chem. Commun.]] |date=2003 |issue=18 |pages=2274–2275 |doi=10.1039/B307116M|pmid=14518871 }}</ref>
[[File:Polymeric phosphine ligand.png|thumb|A recyclable polymeric phosphine ligand<ref name="Luh2003"/>]]
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. A recyclable polymeric phosphine ligand is obtained from ring-opening metathesis polymerization of a norbornene derivative, and has been used in the copper co-catalyzed Sonogashira reaction of methyl ''p''-iodobenzoate and phenylacetylene using {{chem2|Pd(dba)2*CHCl3}} as a palladium source.<ref name="Luh2003">{{cite journal |last1=Yang |first1=Yun-Chin |last2=Luh |first2=Tien-Yau |title=Polymeric Phosphine Ligand from Ring-Opening Metathesis Polymerization of a Norbornene Derivative. Applications in the Heck, Sonogashira, and Negishi Reactions |journal=[[J. Org. Chem.]] |date=December 2003 |volume=68 |issue=25 |pages=9870–9873 |doi=10.1021/jo035318z|pmid=14656129 |url=http://ntur.lib.ntu.edu.tw/bitstream/246246/172095/1/65.pdf }}</ref> 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.<ref name = "Xray">{{cite journal |journal=[[J. Organomet. Chem.]] |doi=10.1016/S0022-328X(01)01083-X |title=Bis(pyrimidine)-based palladium catalysts: Synthesis, X-ray structure and applications in Heck–, Suzuki–, Sonogashira–Hagihara couplings and amination reactions |year=2001 |last1=Buchmeiser |first1 =Michael R. |last2=Schareina | first2=Thomas |last3=Kempe |first3=Rhett |last4=Wurst |first4=Klaus |volume=634 |pages=39–46}}</ref>

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,<ref name = "Gil-Molto-Tetrahedron-2005">{{citation |author1=Gil-Moltó, J. |author2=Karström, S. |author3=Nájera, C. |journal=[[Tetrahedron (journal)|Tetrahedron]] |title=Di(2-pyridyl)methylamine–palladium dichloride complex covalently anchored to a styrene-maleic anhydride co-polymer as recoverable catalyst for C–C cross-coupling reactions in water |year=2005 |volume=61 |issue=51 |pages=12168–12176 |doi=10.1016/j.tet.2005.08.122 }}</ref> although its efficiency was higher in ''N''-methylpyrrolidinone (NMP) as solvent.

[[File:Najera, Org Lett 2003.png|thumb|900px|center|Coupling of a diiodo substrate catalysed by the dipyridylpalladium complex.<ref name = "Gil-Molto-EurJOrgChem-2005">{{citation |author1=Gil-Moltó, J. |author2=Nájera, C. |journal=[[Eur. J. Org. Chem.]] |title=Palladium(II) Chloride and a (Dipyridin-2-ylmethyl)amine-DerivedPalladium(II) Chloride Complex as Highly Efficient Catalysts for the Synthesisof Alkynes in Water or in NMP and of Diynes in the Absence of Reoxidant |year=2005 |volume=2005 |issue=19 |pages=4073–4081 |doi=10.1002/ejoc.200500319 }}</ref>]]

====''N''-heterocyclic carbene (NHC) palladium complexes====

[[N-Heterocyclic carbene|''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.<ref name="Booming" /><ref name="Gazvoda-Chem-Commun-2016">{{citation |author1=Gazvoda, M. |author2=Virant, M |author3=Pevec, A. |author4=Urankar, D. |author5=Bolje, A. |author6=Kočevar, M. |author7=Košmrlj, J. |journal=[[Chem. Commun.]] |title= A mesoionic bis(Py-''tz''NHC) palladium(II) complex catalyses green Sonogashira reaction through an unprecedented mechanism |year=2016 |volume=52 |issue=8 |pages=1571–1574 |pmid=26575368 |doi= 10.1039/c5cc08717a|doi-access=free }}</ref><ref name="Crudden">{{cite journal |last1=Crudden |first1=Cathleen M. |last2=Allen |first2=Daryl P. |title=Stability and reactivity of N-heterocyclic carbene complexes |journal=[[Coord. Chem. Rev.]] |date=December 2004 |volume=248 |issue=21–24 |pages=2247–2273 |doi=10.1016/j.ccr.2004.05.013}}</ref>

{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
|-
|-
| [[File:Pd-NHC-1.png|center|200px|An example of palladium(II) derived complex with ''N''-heterocyclic ligand]]
| [[File:PyNHC-PEPPSI-water.png|center|300px|An example of cationic PdNHC complex for efficient catalysis of Sonogashira reaction in water.]]
|-
| An example of palladium(II) derived complex with normal NHC ligand.<ref name = "Pd-NHC">{{citation |author1=Batey, R. A. |author2=Shen, M. |author3=Lough, A. J. |journal=[[Org. Lett.]] |title=Carbamoyl-Substituted ''N''-Heterocyclic Carbene Complexes of Palladium(II): Application to Sonogashira Cross-Coupling Reactions |year=2002 |volume=4|issue=9|pages=1411–1414 |doi=10.1021/ol017245g |pmid=11975591 }}</ref>
| Efficient ''i''PEPPSI catalyst for Cu-free Sonogashira reaction in water.<ref name="Gazvoda-Chem-Commun-2016" />
|}

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'' '''p'''yridine-'''e'''nhanced '''p'''recatalyst '''p'''reparation '''s'''tabilization and '''i'''nitiation) 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.<ref name="Gazvoda-Chem-Commun-2016" />

====Metal oxide catalysts====
Recent developments in heterogeneous catalysis enabled the use of metal oxide materials such as [[cuprous oxide]] nanocatalysts in flow processing technologies, which can enable the economical production of active pharmaceutical ingredients and various other fine chemicals.<ref name="Cu2O-Catalyzed">{{citation |author1=Ravi Teja Addanki Tirumala. |author2=Andishaeh P. Dadgar. |author3=Farshid Mohammadparast. |author4=Sundaram Bhardwaj Ramakrishnan. |author5=Tong Mou. |author6=Bin Wang. |author7=Marimuthu Andiappan. |journal=[[Green Chemistry (journal)|Green Chemistry]] |title=Homogeneous versus heterogeneous catalysis in Cu2O-nanoparticle-catalyzed C–C coupling reactions |year=2019 |volume=21 |issue=19 |pages=5284–5290 |doi=10.1039/C9GC01930H |pmid=19670863 }}</ref>

==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.<ref name = "alkyne">{{cite journal |author=Corona C. |author2=Bryant B.K. |author3=Arterburn J.B. |pages=1883–1886 |journal=[[Org. Lett.]] |year=2006 |volume=8 |doi=10.1021/ol060458r |title=Synthesis of a Biotin-Derived Alkyne for Pd-Catalyzed Coupling Reactions |issue=9 |pmid=16623575 |pmc=2523258 }}</ref> 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.<ref>{{cite journal |author1=Tulla-Puche J. |author2=Barany G |year=2005 |title=Development of resin-to-resin transfer reactions (RRTR) using Sonogashira chemistry |journal=[[Tetrahedron (journal)|Tetrahedron]] |volume=61 |issue=8 |page=2195 |doi=10.1016/j.tet.2004.12.029}}</ref>

[[File:Alkynylation.svg|thumb|center|800px|Alkynylation of phenylalanine.<ref name="alkyne" />]]

===Natural products===

Many metabolites found in nature contain alkyne or enyne moieties, and therefore, the Sonogashira reaction has found frequent utility in their syntheses.<ref name=Hong-2006>{{cite journal |author1 = Hong, B.-C. |author2= Nimje, R. Y. |title=Catalytic C-C Bond Formation in Natural Products Synthesis: Highlights From The Years 2000-2005 |year = 2006 |journal=[[Curr. Org. Chem.]] |volume=10 |issue= 17 |page=2191-2225 |doi=10.2174/138527206778742605}}</ref> 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.<ref name="bulgaramine">{{cite journal |last1=Chinchilla |first1=Rafael |last2=Nájera |first2=Carmen |date=2007 |title=The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry† |journal=[[Chemical Reviews]] |volume=107 |issue=3 |pages=874–922 |doi=10.1021/cr050992x|pmid=17305399 }}</ref>

[[File:Bulgaramine.png|thumb|center|800px|Sonogashira reaction in the total synthesis of bulgaramine.<ref name="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 <ref name=Mujahidin-2005/> or indole alkaloids<ref name=Pedersen-2005>{{cite journal |author=Pedersen, J. M. |author2=Bowman, W. R. |author3=Elsegood, M. R. J. |author4=Fletcher, A. J. |author5=Lovell, P. J |title=Synthesis of Ellipticine: A Radical Cascade Protocol to Aryl- and Heteroaryl-Annulated[b]carbazoles |year=2005 |journal=[[J. Org. Chem.]] |volume =70 |issue=25 |pages=10615–10618 |doi=10.1021/jo0519920 |pmid=16323886 }}</ref> 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.<ref name="Mujahidin-2005">{{cite journal|last=Mujahidin|first=Didin |author2=Doye, Sven |title=Enantioselective Synthesis of (+)-(''S'')-Laudanosine and (−)-(''S'')-Xylopinine|journal=[[Eur. J. Org. Chem.]] |date=1 July 2005 |volume=2005 |issue=13 |pages=2689–2693 |doi=10.1002/ejoc.200500095}}</ref>

[[File:Natural Products (+)-(S)-laudanosine and (–)-(S)-xylopinine.svg|thumb|center|800px|Natural products (+)-(''S'')-laudanosine and (–)-(''S'')-xylopinine synthesized using the Sonogashira cross-coupling reaction.<ref name="Mujahidin-2005" />]]

====Enynes and enediynes====

The 1,3-enyne moiety is an important structural unit for biologically active and natural compounds.{{citation needed|date=December 2018}} 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 Pd<sup>0</sup> 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-iodoprop-2-en-1-ol with a wide range of acetylenes.<ref name=Thongsornkleeb-2005>{{cite journal |author1=Thongsornkleeb, C. |author2=Danheiser, R.L. |year=2005 |title=The coupling of 2-iodo-prop-2-enol with a wide range of acetylenes such as TMSA to give enynyl alcohol, which can be oxidized to the corresponding R-alkynylated acroleins |journal=[[J. Org. Chem.]] |volume=70 |issue=6 |pages=2364–2367 |doi=10.1021/jo047869a |pmid=15760233 |pmc=2897060}}</ref>
*The preparation of alk-2-ynylbuta-1,3-dienes from the cross-coupling of a diiodide and phenylacetylene, as shown below.<ref name="Shao-J-Org-Chem-2005">{{citation |author1=Shao, L.-X. |author2=Shi, M. |journal=[[J. Org. Chem.]] |title= Facile Synthesis of 2-Alkynyl Buta-1,3-dienes via Sonogashira Cross-Coupling Methodology |year=2005 |volume=70 |issue=21 |pages=8635–8637 |doi= 10.1021/jo051434l|pmid=16209628 }}</ref>

[[File:Shao-J-Org-Chem-2005.png|thumb|center|560px|Synthesis of an alk-2-ynylbuta-1,3-diene accomplished by Sonogashira coupling.<ref name="Shao-J-Org-Chem-2005"/>]]

====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 a [[nicotinic acetylcholine receptor]] agonist that has shown potential in the treatment of Parkinson's disease, Alzheimer's disease, Tourette's syndrome, schizophrenia, and attention deficit hyperactivity disorder (ADHD).<ref name="King-2004" /><ref name="Practical">{{citation |author1=Bleicher, L.S. |author2=Cosford, N.D.P. |author3=Herbaut, A. |author4=McCallum, J. S. |author5=McDonald, I. A. |journal=[[J. Org. Chem.]] |title=A Practical and Efficient Synthesis of the Selective Neuronal Acetylcholine-Gated Ion Channel Agonist (''S'')-(−)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y) |year=1998 |volume=63 |issue=4 |pages=1109–1118 |doi=10.1021/jo971572d }}</ref> As of 2008, Altinicline has undergone Phase II clinical trials.<ref>{{cite journal|last=Wang|first=David X. |author2=Booth, Heather |author3=Lerner-Marmarosh, Nicole |author4=Osdene, Thomas S. |author5=Abood, Leo G.|title=Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency|journal=[[Drug Dev. Res.]] |date=1 September 1998|volume=45|issue=1|pages=10–16|doi=10.1002/(SICI)1098-2299(199809)45:1<10::AID-DDR2>3.0.CO;2-G}}</ref><ref>{{cite journal|title=Randomized placebo-controlled study of the nicotinic agonist SIB-1508Y in Parkinson disease|journal=[[Neurology_(journal)|Neurology]]|date=14 February 2006|volume=66|issue=3|pages=408–410|doi=10.1212/01.wnl.0000196466.99381.5c|pmid=16476941|last1=Parkinson Study|first1=Group|s2cid=31720763}}</ref>

[[File:Application of Sonogashira.svg|thumb|center|800px|Use of the Sonogashira cross-coupling reaction in the synthesis of SIB-1508Y.<ref name="King-2004" />]]

The Sonogashira cross coupling reaction can be used in the synthesis of imidazopyridine derivatives.<ref name="Bakherad-Tetrahedron-Lett-2008">{{citation |author1=Bakherad, M. |author2=Nasr-Isfahani, H. |author3=Keivanloo, A. |author4=Doostmohammadi, N. |journal=[[J. Organomet. Chem.]] |title= Pd–Cu catalyzed heterocyclization during Sonogashira coupling: synthesis of 2-benzylimidazo[1,2-''a'']pyridine |year=2008 |volume=49 |issue=23 |pages=3819–3822 |doi=10.1016/j.tetlet.2008.03.141}}</ref>

[[File:Bakherad-Tetrahedron-Lett-2008.png|thumb|center|1000px|Synthesis of imidazopyridine derivatives.<ref name="Bakherad-Tetrahedron-Lett-2008" />]]

==Related reactions==
* [[Coupling reaction|Cross-coupling reactions]]
** [[Castro-Stephens coupling]]
** [[Heck reaction]]
** [[Stille reaction]]
** [[Suzuki reaction]]
** [[Negishi coupling]]
** [[Kumada coupling]]
* [[Transmetalation]]

==References==
{{Reflist|colwidth=30em}}
{{Alkynes}}

[[Category:Condensation reactions]]
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Palladium]]
[[Category:Organometallic chemistry]]
[[Category:Name reactions]]