Sonogashira-Hagihara reaction coupling

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) in the presence of catalytic amounts of a palladium(O) complex (or a precursor thereof) and usually an additional substoichiometric amount of copper(I) iodide (Cul), and they can be arylated by aryl triflates (bromides, iodides). These reactions are called Cacchi coupling reactions if triflate reagents are employed, and Sonogashira-Hagihara coupling reactions if halides are used. 

Cacchi and Sonogashira-Hagihara coupling reactions occur only if a primary, secondary, or tertiary amine is present, and it is best to have the amine present in large excess. Under these conditions the acetylene will form at least a small equilibrium amount of an ammonium acetylide. Aside from this, a substoichiometric amount of Cul is almost always added to capture the small equilibrium concentration of the ammonium acetylide as a copper acetylide. The copper acetylide represents a substantially improved nucleophile in comparison to the free acetylene. Without the Cul addition, the acetylide content of the reaction mixture is so small that a reaction occurs only at higher temperatures (for an example, see Figure 13.23). 

In 2011, Lipshutz s team reported the successful application of the amphiphile TPGS-750-M for the realization of Sonogashira-Hagihara coupling reactions (as well as Heck-Mizoroki, Suzuki-Miyaura, Buchwald-Hartwig, Negishi-like couplings, C-H activation reactions, and so on... 

BuendiaJ, Darses B, Dauban P. Tandem catalytic C(sp )-H amination/sila-Sonogashira-Hagihara coupling reactions with iodine reagents. Angew Chem Int Ed. 2015 54 5697-5701. 

There are several stereoisomers in disubstituted [2.2]paracyclophane, such as ortho-, meta-, para-, pstudo-ortho-, pseudo-m fa-, pseudo-para-, and pseudo-g mma/-disubstituted [2.2]paracyclophanes. Iron-catalyzed dibromination of commercially available [2.2]paracyclophane yields the mixtures of the dibromo[2.2]paracyclo-phane isomers, and pseudo-para-dibromo[2.2]paracyclophane 9 can be obtained by recrystallization as it has the poorest solubility in common organic solvents [76]. Thermal isomerization of 9 in triglyme afforded the psowdo-ortho isomer 38, as shown in Scheme 10. This transformation is an equilibrium reaction when the reaction was allowed to cool to room temperature, pseudo-para isomer 9 was precipitated as a result of its low solubility and was readily separated by simple filtration to obtain pseudo-arf/za isomer 38 in moderate isolated yield [76]. V ondo-ortho-dibromo[2.2]paracyclophane 38 was converted into pseudo-arf/ a-diethynyl[2.2] paracyclophane 40 via pseudo-arf/ a-diformyl[2.2]paracyclophane 39 (Scheme 10) [77]. Sonogashira-Hagihara coupling polymerization of 40 with 12 afforded the corresponding jc-stacked polymer 41 in 23 % isolated yield with the of 3,800 [78]. 

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

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