Sonogashira coupling

The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide. The Sonogashira reaction is a cross-coupling reaction used in organic synthesis to form carbon–carbon bonds. It employs a palladium catalyst as well as copper co-catalyst to form a carbon–carbon bond between a terminal alkyne and an aryl or vinyl halide. 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. Specific examples include its use in the synthesis of tazarotene, which is a treatment for psoriasis and acne, and in the preparation of SIB-1508Y, also known as Altinicline, a nicotinic receptor agonist. 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. 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. 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. 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. 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 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. 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 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 an amine, a phosphine ligand, or another reactant in the mixture allowing the reaction to proceed. For instance, oxidation of triphenylphosphine to triphenylphosphine oxide can lead to the formation of Pd0 in situ when is used.