Sonogashira Coupling

Sonogashira Coupling

The Sonogashira coupling is a prominent cross-coupling reaction used in organic synthesis to form carbon-carbon bonds between a terminal alkyne and an aryl or vinyl halide. This reaction is facilitated by a palladium catalyst and often employs a copper co-catalyst, although copper-free variants exist. The reaction is named after Kenkichi Sonogashira, who, along with co-researchers, reported the reaction in 1975[1].

Mechanism

The mechanism of the Sonogashira coupling, particularly the copper-free variant, involves two interconnected Pd(0)/Pd(II) catalytic cycles. Initially, the oxidative addition of the aryl halide or triflate to the Pd(0) catalyst forms a complex that activates the aryl halide substrate. Acetylene is activated in a Pd(II) mediated cycle, forming Pd monoacetylide and Pd bisacetylide complexes under mild conditions. These activated species participate in a transmetallation step, leading to the formation of a disubstituted alkyne product and the regeneration of the Pd(0) catalytic species[1].

Applications

The Sonogashira coupling has a wide range of applications due to its ability to form carbon-carbon bonds under mild conditions, such as room temperature and in aqueous media. It is used in the synthesis of pharmaceuticals, natural products, organic materials, and nanomaterials. Notable examples include the synthesis of tazarotene, a treatment for psoriasis and acne, and the preparation of SIB-1508Y, a nicotinic receptor agonist[1]. The reaction is also a key step in the total synthesis of complex natural products and in the construction of materials with electrooptical and electronic properties[2][7].

Catalysts

The original Sonogashira coupling employs a palladium catalyst in conjunction with a copper co-catalyst. However, due to environmental concerns and the drawbacks associated with copper, such as the formation of undesirable byproducts and the need for strict oxygen exclusion, copper-free variants have been developed. These copper-free reactions utilize palladium catalysts alone, and recent advancements have focused on the development of heterogeneous palladium-containing catalysts for this purpose[1][9].

Reactions

The Sonogashira reaction typically requires anhydrous and anaerobic conditions, but newer procedures allow for more relaxed conditions. The reaction is generally carried out at room temperature with a base, often an amine, which also acts as the solvent. The reaction medium must be basic to neutralize the hydrogen halide produced as a byproduct[4]. The selectivity of the coupling can be controlled by the electronic and steric effects of the substrates, and if these effects are adjusted, the coupling can be carried out in a stepwise, regioselective fashion[2].

In summary, the Sonogashira coupling is a versatile and widely used reaction in organic synthesis, with ongoing research aimed at improving its efficiency and environmental friendliness.

Citations:

[1] https://en.wikipedia.org/wiki/Sonogashira_coupling

[2] https://pubs.rsc.org/en/content/articlehtml/2014/qo/c3qo00086a

[3] https://pubs.acs.org/doi/10.1021/cr050992x

[4] https://www.organic-chemistry.org/namedreactions/sonogashira-coupling.shtm

[5] https://www.mdpi.com/2073-4344/10/1/25

[6] https://www.sciencedirect.com/topics/immunology-and-microbiology/sonogashira-reaction

[7] https://chem.libretexts.org/Bookshelves/Inorganic_Chemistry/Supplemental_Modules_and_Websites_%28Inorganic_Chemistry%29/Catalysis/Catalyst_Examples/Sonogashira_Coupling

[8] https://pubs.acs.org/doi/10.1021/acsanm.9b02017

[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8695108/

[10] https://byjus.com/chemistry/sonogashira-coupling/

[11] https://onlinelibrary.wiley.com/doi/full/10.1002/aoc.2931

[12] https://www.sciencedirect.com/topics/chemistry/sonogashira-cross-coupling

[13] https://www.nature.com/articles/s41467-018-07081-5