874 Chem. Rev. 2007, 107, 874−922 The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry† Rafael Chinchilla* and Carmen Na´jera* Departamento de Quı´mica Orga´nica and Instituto de Sı´ntesis Orga´nica (ISO), Universidad de Alicante, Facultad de Ciencias, Apartado 99, 03080 Alicante, Spain Received September 25, 2006 Contents 1. Introduction 874 2. Mechanistic Considerations 875 3. Catalysts and Reaction Conditions 877 3.1. Palladium−Phosphorus Complexes 877 3.1.1. Unsupported Palladium−Phosphorus 877 Complexes 3.1.2. Supported Palladium−Phosphorus 881 Complexes 3.2. Palladium−Nitrogen Complexes 882 3.2.1. Unsupported Palladium−Nitrogen 882 Complexes Rafael Chinchilla (right) was born in Alicante and studied chemistry at 3.2.2. Supported Palladium−Nitrogen Complexes 883 the University of Alicante, from which he received B.S. (1985) and Ph.D. 3.3. Palladium−P,N- and Palladium−P,O 884 (1990) degrees. After a postdoctoral stay at the University of Uppsala, Complexes Sweden (1991−1992), he moved back to the University of Alicante, where 3.4. N-Heterocyclic Carbene (NHC) Palladium 884 he was appointed Associate Professor in 1997. He is coauthor of 70 Complexes papers and four patents. He is cofounder of the new chemical company MEDALCHEMY, S. L. as a spin-off of the University of Alicante. His current 3.4.1. Unsupported NHC Palladium Complexes 884 research interests include asymmetric synthesis, amino acid and peptide 3.4.2. Supported NHC Palladium Complexes 885 synthesis, and solid-supported reagents. 3.5. Palladacycle Catalysts 885 3.5.1. Unsupported Palladacycles 885 Carmen Na´jera (left) was born in Na´jera (La Rioja). She graduated from the University of Zaragoza in 1973 and obtained her doctorate in chemistry 3.5.2. Supported Palladacycles 886 from the University of Oviedo in 1979, followed by postdoctoral stays at 3.6. Ligand-Free Palladium Catalysts 886 the ETH (Zurich), the Dyson Perrins Laboratory (Oxford), Harvard 3.6.1. Unsupported Ligand-Free Palladium 886 University, and Uppsala University. She became Associate Professor in Catalysts 1985 at the University of Oviedo and Full Professor in 1993 at the 3.6.2. Solid-Supported Ligand-Free Palladium 887 University of Alicante. She is coauthor of more than 200 papers and 30 Catalysts reviews, and has been visiting professor at different universities, such as 3.7. Palladium Nanoparticles as Catalysts 888 University of Arizona (Tucson, AZ, USA), Universidad Nacional del Sur (Bahia Blanca, Argentina), Universite´ Louis Pasteur (Strassbourg, France), 3.8. Other Transition-Metal Complexes 888 and Ecole Nationale Superie´ure de Chimie de Paris (France). Prof. Na´jera 3.9. Transition-Metal-Free Reactions 889 has received the 2006 Janssen Cilag Organic Chemistry Prize from the 4. Applications 889 Spanish Royal Chemical Society of Chemistry and the 2006 Rosalind 4.1. Alkynylation of Arenes 889 Franklin International Lectureship from the English Royal Society. She is 4.2. Alkynylation of Heterocycles 891 cofounder of the new chemical company MEDALCHEMY, S. L. as a spin- off of the University of Alicante. Her current research interest is focused 4.3. Synthesis of Enynes and Enediynes 894 on sulfones, amino acids, polymer-supported reagents, asymmetric 4.4. Synthesis of Ynones 896 catalysis, and palladium catalysis. 4.5. Synthesis of Carbocyclic Systems 897 4.6. Synthesis of Heterocyclic Systems 898 4.7. Synthesis of Natural Products 903 1. Introduction 4.8. Synthesis of Electronic and Electrooptical 906 Molecules The array of transition-metal-catalyzed cross-coupling 4.9. Synthesis of Molecules for Nanostructures 911 reactions can easily be considered nowadays cornerstones 5. Conclusions 913 in the field of organic synthesis.1,2 Among them, the 6. Acknowledgments 914 palladium-catalyzed sp2-sp coupling reaction between aryl 7. References 914 or alkenyl halides or triflates and terminal alkynes, with or without the presence of a copper(I) cocatalyst, has become the most important method to prepare arylalkynes and † Dedicated to Professor Miguel Yus on the occasion of his 60th birthday. conjugated enynes, which are precursors for natural products, * To whom correspondence should be addressed. Phone: +34 965903728. Fax: +34 965903549. E-mail: [email protected]; [email protected]. URL: pharmaceuticals, and molecular organic materials (Scheme www.ua.es/dqorg. 1).3 10.1021/cr050992x CCC: $65.00 © 2007 American Chemical Society Published on Web 02/17/2007 The Sonogashira Reaction Chemical Reviews, 2007, Vol. 107, No. 3 875 Scheme 1 unstable aryl or vinyl iodides are used. Moreover, if the organic halide system is “activated”, that is, electron-poor, the situation is even more favorable. Thus, deactivated aryl bromides are difficult starting materials for coupling reac- tions, whereas the cheapest aryl chlorides, if not strongly activated, represent a real challenge for any cross-coupling methodology.12 The two earlier studies on this topic were reported Although the most recent reviews about the Sonogashira independently by Heck4 and Cassar5 in 1975. Heck’s reaction are fairly recent, covering up to 2002,3 a simple procedure was based on the known Mizoroki-Heck reaction computer search of the keyword “Sonogashira” in chemical for the palladium-catalyzed arylation or alkenylation of databases reveals a similar amount of citations from 2003 alkenes, and consisted of performing the coupling employing to the present compared to the amount during the period of a phosphane-palladium complex as a catalyst and triethyl- time from the discovery of this reaction (1975) to 2002. This amine or piperidine as a base and solvent. Cassar’s procedure indicates that in the last few years this has been a really involved the use of a phosphane-palladium catalyst in fast-moving topic, with a fierce search for better catalysts, combination with sodium methoxide as a base and DMF as more convenient reaction conditions, and an understanding solvent. Both methods generally required high temperature of the reaction mechanism, and also with a remarkable (up to 100 °C). In the same year, Sonogashira and Hagihara increase in the use of this cross-coupling reaction for the reported that addition of a catalytic amount of copper(I) synthesis of interesting or promising compounds. iodide greatly accelerates the reaction, thus enabling perfor- This review covers the developments in the Sonogashira mance of the alkynylation at room temperature,6 an observa- cross-coupling reaction, as well as applications of this tion related to the already known coupling between copper methodology since 2003, although older works can be acetylides and phenyl or vinyl halides (the so-called Stephens- commented on if necessary. In the cases for which some Castro reaction).7 Therefore, the Sonogashira-Hagihara reviews on particular related topics have been published more protocol (more often simply known as Sonogashira coupling) recently, only the literature after them will be considered. became the most popular procedure for the alkynylation of When dealing with applications of this methodology, this aryl or alkenyl halides. It is necessary to note that even review will not be fully comprehensive, although very primary alkyl bromides or iodides8a and secondary alkyl extensive, as a complete coverage of all the literature bromides8b have been alkynylated using a Sonogashira containing an application of a Sonogashira reaction is almost protocol, although this type of sp3-sp coupling is very recent impossible and would make this review never-ending. and remains almost unexplored. The addition of copper salts as cocatalysts in the typical 2. Mechanistic Considerations Sonogashira cross-coupling reactions also has drawbacks, apart from including in the reacting mixture another envi- The exact mechanism of the homogeneous copper-cocata- ronmentally unfriendly and difficult to recover reagent. Thus, lyzed Sonogashira reaction is unknown, with some obscure the in situ generation of copper acetylides under the reaction points and not unequivocally proven assertions still remain- conditions often generates homocoupling products of the ing. Although physical measures suggest plausible mecha- terminal alkyne (the so-called Glaser coupling),9 along with nistic paths based on the identification of some of the the main reaction product, upon exposure to oxidative agents transient species formed in the homogeneous catalytic or air. This side reaction is especially problematic when the reactions, it is a very difficult task to isolate and characterize terminal acetylene is difficult to obtain or expensive, and the organometallic intermediates from a homogeneous although it has been shown that the presence of a reductive mixture to validate a mechanism beyond any doubt. There- atmosphere formed by difficult-to-handle hydrogen can fore, some techniques have been developed to study this diminish homocoupling,10 as well as the slow addition of coupling process using heterogeneous catalysts in order to the acetylene,11 significant efforts have being dedicated to detect surface transient organometallic intermediates.13 How- develop coupling procedures working in the absence of ever, unexpected findings can add further complications to copper salts. These procedures generally aim to increase the the always difficult study of mechanisms. Thus, the always reactivity of the catalytic system, thus making the presence useful kinetic measures could be in some cases dampened of copper unnecessary. All these copper-free methodologies by details such