Copper-free Sonogashira coupling reaction conditions

Liang B, Dai M et al (2005) Copper-free Sonogashira coupling reaction with PdCl in water under aerobic conditions. J Org Chem 70 391-393... 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

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). 

It was also found that the Sonogashira reaction [69] takes place under aqueous alkaline conditions in the presence of the PS-PEG-supported palladium complex 59 [95]. The combination of the resin catalyst 59, cesium hydroxide [96], and water is essential to promote high yielding coupling of 69. Using copper-free conditions, a one-step preparation of the benzofurans 70 was achieved in water via coupling of 2-iodophenol 68 (X=OH) and the terminal alkynes (Scheme 23). 

Tri-t-butyl phosphine can be more effective in the coupling of reluctant aryl bromides (Scheme 2.118). Bulky electron-rich biaryl phosphine ligands, such as 2385, can also promote the Sonogashira reaction of difficult aryl chlorides (Scheme 2.119). ° Interestingly, in this case, the presence of copper(I) salts inhibited the reaction, and the copper-free version provided better yields. Aryl tosylates, easily prepared from phenols, also couple under these conditions (Scheme 2.120). 

Recently it has been observed that NCBs have been used as a support for heterogeneous catalyst due to its hollow core, mesoporous and ball-like structure. Park et al. [70] developed Pd(OAC)2 catalyst supported on NCBs and applied it for the synthesis of 2-substituted benzofuran from u-iodo phenol and various substituted terminal alkynes using Sonogashira cross-coupling reaction under copper and ligand-free condition. 

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