Sonogashira coupling

Sonogashira coupling
Named after	Kenkichi Sonogashira
Reaction type	Coupling reaction
Identifiers
Organic Chemistry Portal	sonogashira-coupling
RSC ontology ID	RXNO:0000137

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide.^[1]

${\displaystyle {\begin{matrix}{}\\{\ce {R-\!{\equiv }\!-H}}+{\color {Red}{\ce {R'}}}\!-\!{\ce {X->[{\text{Pd cat., Cu cat.}}][{\text{base, rt}}]R-\!{\equiv }\!}}{\color {Red}{\ce {-R'}}}\end{matrix}}}$

• R': Aryl or Vinyl
• 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.^[1] Specific examples include its use in the synthesis of tazarotene,^[2] which is a treatment for psoriasis and acne, and in the preparation of SIB-1508Y, also known as Altinicline,^[3] which is a potential treatment for Parkinson's disease, Alzheimer's disease, Tourette syndrome, schizophrenia, and attention deficit hyperactivity disorder (ADHD).

History

The Sonogashira cross-coupling reaction was first reported by Kenkichi Sonogashira, Yasuo Tohda, and Nobue Hagihara in their 1975 publication.^[4] It is an extension to the Cassar and Dieck and Heck reactions, which afford the same reaction products, but use harsh reaction conditions, such as high temperature, to do so. Both of these reactions make use of a palladium catalyst to carry out the coupling, while Sonogashira uses both palladium and copper catalysts simultaneously. This results in the increased reactivity of the reagents and the ability of the reaction to be carried out at room temperature, making the Sonogashira cross-coupling reaction a highly useful reaction, particularly in the alkynylation of aryl and alkenyl halides.^[5] The reaction's remarkable utility can be evidenced by the amount of research still being done on understanding and optimizing its synthetic capabilities. A search for the term "Sonogashira" in Scifinder provides over 1500 references for journal publications between 2007 and 2010.^[5] It has become so well known that often, all reactions that use a palladium(0) catalyst to couple a sp² and even sp³ halide or triflate with a terminal alkyne, regardless of whether or not a copper co-catalyst is used, are termed "Sonogashira reactions," despite the fact that these reactions are not carried out under true Sonogashira reaction conditions.^[5]

Mechanism

The reaction mechanism is not clearly understood but the textbook mechanism revolves around a palladium cycle and a copper cycle that is less well known.^[6]

Catalytic cycle for the Sonogashira reaction^[5]

The palladium cycle

• An inactive palladium Pd^II catalyst is activated by a reduction to the Pd⁰ compound.
• The active palladium catalyst is the 14 electron compound Pd⁰L₂, complex A, which reacts with the aryl or vinyl halide in an oxidative addition to produce a Pd^II intermediate, complex B. This step is believed to be the rate-limiting step of the reaction.
• Complex B reacts in a transmetallation with the copper acetylide, complex F, which is produced in the copper cycle, to give complex C, expelling the copper halide, complex G.
• Both organic ligands are trans oriented and convert to cis in a trans-cis isomerization to produce complex D.
• In the final step, complex D undergoes reductive elimination to produce the alkyne, with regeneration of the palladium catalyst.

The copper cycle

• It is suggested that the presence of base results in the formation of a pi-alkyne complex, complex E, which makes the terminal proton on the alkyne more acidic, leading to the formation of the copper acetylide, compound F.
• Compound F continues to react with the palladium intermediate B, with regeneration of the copper halide, G.

Mechanistic studies suggest that these catalytic cycles represent the preferred reaction pathway, however there is debate about the exact identity of some intermediates, which may depend upon reaction conditions. For example, it has been shown that monoligated Pd⁰(PR₃) complexes (B) can be formed when dealing with bulky phosphanes and have been suggested as possible catalytic species in coupling reactions.^[7] In contrast, some results point to the formation of anionic palladium species, which would be the real catalysts instead of the coordinatively unsaturated Pd⁰L₂. Generally seen in the presence of anions and halides, it is known that Pd⁰(PPh₃)₂ does not exist in solution when generated in the presence of halide anions because they coordinate the Pd⁰ center to form anionic species of the type [L₂Pd⁰Cl]⁻ which can participate in cross-coupling reactions.^[8]

Catalysts

Typically, two catalysts are needed for this reaction: a zerovalent palladium complex and a halide salt of copper(I). Examples of such palladium catalysts include compounds in which palladium is ligated to phosphines (Pd(PPh₃)₄). A common derivative is Pd(PPh₃)₂Cl₂, but bidentate ligand catalysts, such as Pd(dppe)Cl, Pd(dppp)Cl₂, and Pd(dppf)Cl₂ have also been used.^[6] 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.^[6] Pd^II is often employed as a pre-catalyst since it exhibits greater stability than Pd⁰ over an extended period of time and can be stored under normal laboratory conditions for months.^[9] The Pd ^II catalyst is reduced to Pd⁰ in the reaction mixture by either an amine, a phosphine ligand, or a reactant, allowing the reaction to proceed.^[10] The oxidation of triphenylphosphine to triphenylphosphine oxide can also lead to the formation of Pd⁰ in situ when catalysts such as bis(triphenylphosphine)palladium(II) chloride are used.

Copper(I) salts, such as copper iodide, 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.^[5]

Reaction conditions

The Sonogashira reaction is typically run under mild conditions.^[11] The cross-coupling is carried out at room temperature with a base, typically an amine, such as diethylamine,^[4] 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 as solvents, 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.

Depending on the sp²-carbon halide-or triflate used, these reaction conditions have varying results.

The rate of reaction of sp² carbons. Vinyl iodide > vinyl triflate > vinyl bromide > vinyl chloride > aryl iodide > aryl triflate > aryl bromide >>> aryl chloride.^[6]

Complications

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-RPdX(PPh₃)₂ complexes by substituting one PPh₃ ligand. The equilibirium constant of this reaction is dependent on R, X, a factor for basicity, and the amine's steric hindrance.^[12] 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.

Scope and limitations

The Sonogashira coupling is applied in the synthesis of cross-conjugated oligo(phenylene enynylene)s^[13] and phenanthroline derivatives.^[14]

Inverse Sonogashira Coupling

In an inverse Sonogashira coupling the reactants are an aryl or vinyl compound and an alkynyl halide.^[15]

Copper-free reaction

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.^[9][16] The exact mechanism by which the copper-free reaction occurs is still under debate.^[5] One mechanism seems to indicate the following:

• As in the original mechanism, oxidative addition of the aryl halide or triflate to the Pd(0) catalysts.
• Since the amines associated with this reaction are not basic enough to deprotonate the reacting alkyne, it is believed that complexation to the Pd(0) catalyst requires displacement of one ligand to create an intermediate complex.
• As a result, this new intermediate can then facilitate deprotonation of the terminal alkyne proton and subsequent ligand exchange with the leaving group X.
• Reductive elimination gives rise to the desired coupling product.

Proposed copper-free mechanism for Sonogashira Reaction.^[16]

Due to mounting evidence that amines may also be involved in various steps exclusive of (via a new mode of reactivity) and/or preceding deprotonation events, an alternate mechanism suggests the following:

• Amines can interfere with the oxidative addition through an accelerating effect brought upon to the formation of more reactive [Pd(0)L(amine)] complexes.
• As a result, they can also substitute one ligand in the complex formed after the addition.
• Depending on the rate of the competition between amine and alkyne in the substitution of one ligand in this complex, an interplay between the original mechanism and the newer one seems likely.

Alternative copper-free mechanism.^[17]

The crucial difference between the two mechanisms is that the former would be preferred if the amine is a weaker ligand than the reacting alkyne, while the latter mechanism would be preferred if the amine were a better ligand than the alkyne.^[17]

Catalyst variations

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.^[18] 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/CeO₂ catalyst.^[19][20] In this case, catalysis occurs heterogeneously on the Au nanoparticles,^[20][21] with Au(0) as the active site.^[22] Selectivity to the desirable cross coupling product was also found to be enhanced by supports such as CeO₂ and La₂O₃.^[22] Additionally, iron-catalyzed Sonogashira couplings have been investigated as relatively cheap and non-toxic alternatives to palladium. Here, FeCl₃ is proposed to act as the transition-metal catalyst and Cs₂CO₃ as the base, thus theoretically proceeding through a palladium-free and copper-free mechanism.^[23]

${\displaystyle {\begin{matrix}{}\\{\ce {{R-\!{\equiv }\!-H}+Ar-X->[{\ce {FeCl3,\ dmeda}}][{\ce {Cs2CO3,\ PhMe}}]R-\!{\equiv }\!-Ar}}\\{}\end{matrix}}}$ at 135 °C, 72 h^[23]

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 reagants with trace amounts of palladium, suggesting that these theorized pathways are extremely unlikely, if not impossible, to achieve.^[24]

Studies shown that organic and inorganic starting materials can also contain enough (ppb level) palladium for the coupling.^[25]

Gold and Palladium Combined

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.^[26] 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.

Use of arenediazonium

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.^[27] 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.

Palladium-phosphorus 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 metalodendrimers 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.^[28] 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 phosphanated 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.^[29] 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 phosphane ligand shown below is obtained from ring-opening metathesis polymerization of a norbornene derivative, and has been used in the copper cocatalyzed Sonogashira reaction of methyl piodobenzoate and phenylacetylene using Pd(dba)₂•CHCl₃ as a palladium source.^[30] Despite recovery by filtration, polymer catalytic activity decreased by approximately 4-8% in each recycle experiment.

Palladium-nitrogen complexes

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.

Dipyrimidyl-palladium complex.

Furthermore, all structural features of this complex have been characterized by extensive X-ray analysis, verifying the observed reactivity.^[31]

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. It is interesting to note that 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,^[32] although its efficiency was higher in N-methylpyrrolidinone (NMP) as solvent. An example of this complex's use is shown in the double coupling of o-diiodobenzene and phenylacetylene to give dialkynylated benzene.

Copper-free synthesis of dialkynylated benzene.^[32]

N-heterocyclic carbene (NHC) palladium complexes

Nucleophilic N-heterocyclic carbenes (NHCs) behave like typical σ-donor ligands that can substitute 2-electron ligands (i.e., amines, phosphanes) in metal coordination chemistry, and at times even more efficiently; therefore, they have found application to numerous areas of organometallic homogeneous catalysis.^[33] The most easily available are stable carbenes derived from imidazole, not the least because numerous imidazolium precursor compounds can be made along various reliable routes, with the combination of the imidazolium salt with a palladium source under basic conditions generating the NHC-palladium complex. At 1 mol%, the NHC-derived palladium(II) complex shown below has been shown to promote the coupling of aryl bromides at 80 °C in DMF using triethylamine as base, although requiring the presence of catalytic amounts of copper(I) iodide and triphenylphosphine as well.^[34]

An example of palladium(II) derived complex with N-heterocyclic ligand.^[34]

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.^[35] 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.^[36]

Alkynylation of phenylalanine.^[35]

Natural products

Many metabolites found in nature contain alkyne or enyne moieties, and therefore, the Sonogashira reaction has found frequent utility in their syntheses.^[37] 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 ^[38] or indole alkaloids^[39] 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.^[40]

Natural products (+)-(S)-laudanosine and (–)-(S)-xylopinine synthesized using the Sonogashira cross-coupling reaction.^[40]

Enynes and enediynes

The 1,3-enyne moiety is an important structural unit for biologically active and natural compounds. It is 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 such as TMSA to give enynyl alcohol, which can be oxidized to the corresponding R-alkynylated acroleins ^[41]
• The preparation of an alk-2-ynylbuta-1,3-dienes from the cross-coupling of a diiodide and phenylacetylene, as shown below.^[42]

Synthesis of an alk-2-ynylbuta-1,3,-diene accomplished by Sonogashira coupling.^[42]

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).^[3][43] As of 2008, Altinicline has undergone Phase II clinical trials.^[44][45]

Use of the Sonogashira cross-coupling reaction in the synthesis of SIB-1508Y.^[3]

Related reactions

• Castro-Stephens coupling
• Heck reaction
• Stille reaction
• Suzuki reaction
• Negishi coupling
• Kumada coupling
• Transmetalation

References

1. Sonogashira, K. (2002), "Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp²-carbon halides", J. Organomet. Chem., 653: 46–49, doi:10.1016/s0022-328x(02)01158-0
2. King, A. O., Yasuda, N. (2005), "A Practical and Efficient Process for the Preparation of Tazarotene", Top. Organomet. Chem., 9: 646–650, doi:10.1021/op050080x
3. King, A. O.; Yasuda, N. (2004), "Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis of Pharmaceuticals Organometallics in Process Chemistry", Top. Organomet. Chem., 6: 205–245, doi:10.1007/b94551
4. Sonogashira, K.; Tohda, Y.; Hagihara, N. (1975), "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines", Tetrahedron Lett., 16: 4467–4470, doi:10.1016/s0040-4039(00)91094-3
5. Chinchilla, R.; Nájera, C. (2011), "Recent advances in Sonogashira reactions", Chem. Soc. Rev., 40: 5084–5121, doi:10.1039/c1cs15071e
6. Chinchilla, R.; Nájera, C. (2007), "The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry", Chem. Rev., 107: 874–922, doi:10.1021/cr050992x, PMID 17305399
7. Stambuli, J. P.; Buhl, M.; Hartwig, J. F. (2002), "Synthesis, Characterization, and Reactivity of Monomeric, Arylpalladium Halide Complexes with a Hindered Phosphine as the Only Dative Ligand", J. Am. Chem. Soc., 124: 9346–9347, doi:10.1021/ja0264394
8. Amatore, C.; Jutand, A. (2000), "Anionic Pd(0) and Pd(II) Intermediates in Palladium-Catalyzed Heck and Cross-Coupling Reactions", Acc. Chem. Res., 33: 314–321, doi:10.1021/ar980063a
9. Bohm, V. P. W.; Herrmann, W. A. (2000), "A Copper-Free Procedure for the Palladium-Catalyzed Sonogashira Reaction of Aryl Bromides with Terminal Alkynes at Room Temperature", Eur. J. Org. Chem., 200: 3679–3681, doi:10.1002/1099-0690(200011)2000:22<3679::aid-ejoc3679>3.0.co;2-x
10. Yin, L.; Liebscher, J. (2006), "Carbon-Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium Catalysts", Chem. Rev., 107: 133–173, doi:10.1021/cr0505674
11. Kohnen, A. L; Danheiser, R. L.; Denmark S. E.; Liu X. (2007), "Synthesis of Terminal 1,3-Diynes Via Sonogashira Coupling of Vinylidene Chloride Followed by Elimination. Preparation of 1,3-Decadiyne" (PDF), Org. Synth., 84: 77–87, doi:10.15227/orgsyn.084.0077, PMC 2901882, PMID 20628544
12. Jutand, A.; Négri, S.; Principaud; A. (2005), "Formation of ArPdXL(amine) Complexes by Subsitution of One Phosphane Ligand by an Amine in trans-ArPdX(PPh3)2 Complexes", Eur. J. Inorg. Chem., 2005: 631–635, doi:10.1002/ejic.200400413
13. Joon Cho, Yuming Zhao, and Rik R. Tykwinski Arkivoc (NZ-1369J) pp 142-150 2005 Online Article
14. 3-(2,5-Diethyl-4-iodo-phenylethynyl)-[1,10]-phenanthroline Davood Habibi Molbank 2005, M421 Online Article
15. Dudnik, A.; Gevorgyan, V. (2010). "Formal Inverse Sonogashira Reaction: Direct Alkynylation of Arenes and Heterocycles with Alkynyl Halides". Angewandte Chemie International Edition in English. 49 (12): 2096–2098. doi:10.1002/anie.200906755. PMC 3132814. PMID 20191647.
16. Mery, D.; Heuze, K.; Astruc, D. (2003), "A very efficient, copper-free palladium catalyst for the Sonogashira reaction with aryl halides", Chem. Commun., 15: 1934–1935, doi:10.1039/B305391C
17. Tougerti, A., Negri, S.; Jutand, A. (2007), "Mechanism of the Copper-Free Palladium-Catalyzed Sonagashira Reactions: Multiple Role of Amines", Chem.–Eur. J., 13: 666–676, doi:10.1002/chem.200600574
18. Vechorkin, O.; Barmaz, D.; Proust, V., Hu, X. (2009), "Ni-Catalyzed Sonogashira Coupling of Nonactivated Alkyl Halides: Orthogonal Functionalization of Alkyl Iodides, Bromides, and Chlorides", J. Am. Chem. Soc., 131: 12078–12079, doi:10.1021/ja906040t
19. Gonzalez-Arallano, C.; Abad, A.; Corma, A.; Garcia, H.; Iglesias, M.; Sanchez, F. (2007), "Catalysis by Gold(I) and Gold(III): A Parallelism between Homo- and Heterogeneous Catalysts for Copper-Free Sonogashira Cross-Coupling Reactions", Angew. Chem. Int. Ed., 46: 1536–1538, doi:10.1002/anie.200604746
20. Corma, A.; Juarez, R.; Boronat, M.; Sanchez, F.; Iglesias, M.; Garcia, H. (2011), "Gold catalyzes the Sonogashira coupling reaction without the requirement of palladium impurities", Chem. Commun., 47: 1446–1448, doi:10.1039/C0CC04564K
21. Kyriakou, G., Beaumont, S. K., Humphrey, S. M., Antonetti, C. and Lambert, R. M. (2010), "Sonogashira Coupling Catalyzed by Gold Nanoparticles: Does Homogeneous or Heterogeneous Catalysis Dominate?", Chemcatchem, 2: 1444–1449, doi:10.1002/cctc.201000154
22. Beaumont, S. K., Kyriakou, G., Lambert, R. M. (2010), "Identity of the active site in gold nanoparticle-catalyzed Sonogashira coupling of phenylacetylene and iodobenzene.", J. Am. Chem. Soc, 132: 12246–12248, doi:10.1021/ja1063179
23. M. Carril; A. Correa; C. Bolm (2008), "Iron-Catalyzed Sonogashira Reaction", Angew. Chem., 120: 4940–4943, doi:10.1002/ange.200801539
24. Thorsten Lauterbach†, Madeleine Livendahl†, Antonio Rosellon†, Pablo Espinet‡* and Antonio M. Echavarren†* (2010), "Unlikeliness of Pd-Free Gold(I)-Catalyzed Sonogashira Coupling Reactions", Org. Lett., 12: 3006–3009, doi:10.1021/ol101012n
25. Tolnai, L., G.; Gonda, ZS.; Novák, Z. (2010). "Dramatic Impact of ppb Levels of Palladium on the "Copper-Catalyzed" Sonogashira Coupling". Chemistry A European Journal. 16 (39): 11822–11826. doi:10.1002/chem.201001880.
26. Panda, B.; Sarkar, T. K. (2013), "Gold and Palladium Combined for the Sonogashira Coupling of Aryl and Heteroaryl Halides", Synthesis, 45 (6): 817–829, doi:10.1055/s-0032-1318119
27. Panda, B.; Sarkar, T. K.(2010),"Gold and palladium combined for the Sonogashira-type cross-coupling of arenediazonium salts" Chem. Commun., 46, 3131–3133, doi: 10.1039/c001277g
28. Astruc, D.; Heuze´, K.; Gatard, S.; Me´ry, D.; Nlate, S.; Plault, L. AdV. Synth. Catal. 2005, 347, 32
29. Heuze´, K.; Me´ry, D.; Gauss, D.; Astruc, D. Chem. Commun. 2003, 2274.
30. Yang, Y.-C.; Luh, T.-Y" J. Org. Chem 2003, 68, 9870
31. Buchmeiser, Michael R.; Schareina, Thomas; Kempe, Rhett; Wurst, Klaus (2001). "Bis(pyrimidine)-based palladium catalysts: Synthesis, X-ray structure and applications in Heck–, Suzuki–, Sonogashira–Hagihara couplings and amination reactions". J. Organomet. Chem. 634: 39–46. doi:10.1016/S0022-328X(01)01083-X.
32. Nájera, C.; Gil-Moltó, J.; Karström, S.; Falvello, L. R. (2003), "Di-2-pyridylmethylamine-Based Palladium Complexes as New Catalysts for Heck, Suzuki, and Sonogashira Reactions in Organic and Aqueous Solvents", Org. Lett., 5 (9): 1451–1454, doi:10.1021/ol0341849
33. Crudden, C. M.; Allen, D. P. Coord. Chem. ReV. 2004, 248, 224
34. Batey, R. A.; Shen, M.; Lough, A. J. (2002), "Carbamoyl-Substituted N-Heterocyclic Carbene Complexes of Palladium(II):  Application to Sonogashira Cross-Coupling Reactions", Org. Lett., 4 (9): 1411–1414, doi:10.1021/ol017245g
35. Corona, C.; Bryant, B. K.; Arterburn, J. B. Org. Lett. 2006, 8, 1883
36. Tulla-Puche, J.; Barany, G. Tetrahedron 2005, 61, 2195
37. Hong, B.-C.; Nimje, R. Y. Curr. Org. Chem. 2006, 10, 2191.
38. Mujahidin, D.; Doye, S. Eur" J. Org. Chem 2005, 2689
39. Pedersen, J. M.; Bowman, W. R.; Elsegood, M. R. J.; Fletcher, A. J.; Lovell, P. J" J. Org. Chem 2005, 70, 10615.
40. Mujahidin, Didin; Doye, Sven (1 July 2005). "Enantioselective Synthesis of (+)-(S)-Laudanosine and (−)-(S)-Xylopinine". European Journal of Organic Chemistry. 2005 (13): 2689–2693. doi:10.1002/ejoc.200500095.
41. Thongsornkleeb, C.; Danhaiser, R. L" J. Org. Chem 2005, 70, 2364
42. Shao, L.-X.; Shi, M" J. Org. Chem 2005, 70, 8635
43. Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.; McDonald, I. A. (1998), "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)", J. Org. Chem., 63: 1109–1118, doi:10.1021/jo971572d
44. Wang, David X.; Booth, Heather; Lerner-Marmarosh, Nicole; Osdene, Thomas S.; Abood, Leo G. (1 September 1998). "Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency". Drug Development Research. 45 (1): 10–16. doi:10.1002/(SICI)1098-2299(199809)45:1<10::AID-DDR2>3.0.CO;2-G.
45. Parkinson Study, Group (14 February 2006). "Randomized placebo-controlled study of the nicotinic agonist SIB-1508Y in Parkinson disease". Neurology. 66 (3): 408–410. doi:10.1212/01.wnl.0000196466.99381.5c. PMID 16476941.