AMITY UNIVERSITY SUZUKI AND SONOGASHIRA CROSS COUPLING REACTION RAJASTHAN SUZUKI AND SONOGASHIRA CROSS COUPLING REACTION PRESENT BY Subhrangsu Sekhar Dey M.Sc - Applied Chemistry @ 2014-2016

Transmetallation: Transfer of alkyl group from one metal to another Introduction of Cross Coupling Reaction Typically use a transition metal catalyst and an organometallic precursor Most involve a “transmetallation step” Transmetallation: Transfer of alkyl group from one metal to another Typical trend: Can transfer from more electropositive to less electropositive metals

Suzuki Cross Coupling Reaction Reported in 1979 by Akira Suzuki and N. Miyaura Commonly referred to as the Suzuki cross-coupling Palladium catalyzed cross-coupling between organoboron compounds and organic halides leading to the formation of carbon-carbon bonds.

REACTION MECHANISM

OXIDATIVE ADDITION The rate determining step of the catalytic cycle Couples the palladium catalyst to the alkyl halide which gives rise to the organopalladium complex The complex is initially in the cis conformation but isomerizes to the trans conformation Stereochemistry with vinyl halides are retained but inversion of stereochemistry occurs with allylic or benzylic halides

TRANSMETALATION The role of base is to activate the boron-containing reagent, and also facilitate the formation of R1Pd- OR from R1Pd-X. Reaction does not occur in the absence of base. Exact mechanism is unclear.

REDUCTIVE ELIMINATION This final step gives the desired product and it also regenerates the palladium catalyst so that it can participate again in the catalytic cycle. Require the complex to revert back to the cis conformation before reductive elimination can occur

ADVANTAGES Mild Reaction Conditions Availability of common boronic acids Inorganic by-products are easily removed from reaction mixture. Stereoselective Less toxic than other competitive methods, (ie. Boronic acids are environmentally safer and less toxic than organostannanes) Reaction will take place in the presence of other functional groups (ie. protecting group is not always necessary) Relatively cheap reagents, easy to prepare, and GREEN!

Typically use a palladium catalyst in the 0 oxidation state: Typically, triphenylphosphine and triorthotolylphosphine is the ligand used to activate the palladium. Can also be ligandless such as Pd/C Easier to handle (other ligands may be air-sensitive) Remove by simple filtration (recover, purify, and reuse) In recent years, Nickel catalysts have become popular: Not as expensive as Pd More abundant than Pd Need higher catalyst loading Mechanism not fully understood VARIATION The first nickel catalyzed cross-coupling reaction was reported by Miyaura and co-workers in 1996 using aryl chlorides and boronic acids, Miyaura and Inada reported in 2000 that an cheaper TRIPHENYL, fact that this reaction can be run in biphasic(aqueous and organic

APPLICATION INDUSTRIAL APPLICATION Polyene antibiotic Cost-effective for use in the synthesis of intermediates for pharmaceuticals or fine chemicals. SYNTHETIC APPLICATION Isolated from the bacterium Myxococcus xanthus. The Suzuki coupling has been used on a citronellal derivative for the synthesis of caparratriene, a natural product that is highly activeagainst leukemia. The last step in thesynthesis of Myxalamide A Observed to have antibiotic and antifungal activity

Sonogashira cross-coupling reaction The Sonogashira cross-coupling reaction was first reported by Kenkichi Sonogashira, Yasuo Tohda, and Nobue Hagihara in their 1975 publication. Sonogashira uses both palladium and copper catalysts simultaneously which inceases the reactivity. Highly useful reaction in the alkynylation of aryl and alkenyl halides

MECHANISM

Copper-free reaction/Variation SCOPE AND LIMITATION The Sonogashira coupling is applied in the synthesis of cross-conjugated oligo(phenylene enynylene)s and phenanthroline derivatives. Copper-free reaction/Variation Unwanted dimerization To avoid the formation of the homocoupling products

APPLICATION Its applications pharmaceuticals, natural products, organic materials, and nanomaterials. Sonogashira reaction use in the synthesis of tazarotene, which is a treatment for psoriasis and acne The preparation of SIB-1508Y, also known as Altinicline, which is a potential treatment for Parkinson’s disease, Alzheimer’s disease, Tourette syndrome, schizophrenia, and attention deficit hyperactivity disorder (ADHD).

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