Negishi coupling

Chemical reaction

The Negishi coupling is a widely employed transition metal catalyzed cross coupling reaction. The reaction couples organic halides or triflates with organozinc compounds, forming carbon carbon bonds (C C) in the process. A palladium (0) species is generally utilized as the metal catalyst, though nickel is sometimes used. A variety of nickel catalysts in either Ni0 or NiII oxidation state can be employed in Negishi cross couplings such as Ni(PPh3)4, Ni(acac)2, Ni(COD)2 etc. The leaving group X is usually chloride, bromide, or iodide, but triflate and acetyloxy groups are feasible as well. X = Cl usually leads to slow reactions. The organic residue R = alkenyl, aryl, allyl, alkynyl or propargyl. The halide X' in the organozinc compound can be chloride, bromine or iodine and the organic residue R' is alkenyl, aryl, allyl, alkyl, benzyl, homoallyl, and homopropargyl. The metal M in the catalyst is nickel or palladium
The ligand L in the catalyst can be triphenylphosphine, dppe, BINAP, chiraphos or XPhos. Palladium catalysts in general have higher chemical yields and higher functional group tolerance. The Negishi coupling finds common use in the field of total synthesis as a method for selectively forming C C bonds between complex synthetic intermediates. The reaction allows for the coupling of sp3, sp2, and sp carbon atoms, (see orbital hybridization) which make it somewhat unusual among the palladium catalyzed coupling reactions. Organozincs are moisture and air sensitive, so the Negishi coupling must be performed in an oxygen and water free environment, a fact that has hindered its use relative to other cross coupling reactions that require less robust conditions (i. e. Suzuki reaction). However, organozincs are more reactive than both organostannanes and organoborates which correlates to faster reaction times. The reaction is named after Ei ichi Negishi who was a co recipient of the 2010 Nobel Prize in Chemistry for the discovery and development of this reaction. Negishi and coworkers originally investigated the cross coupling of organoaluminum reagents in 1976 initially employing Ni and Pd as the transition metal catalysts, but noted that Ni resulted in the decay of stereospecifity whereas Pd did not. Transitioning from organoaluminum species to organozinc compounds Negishi and coworkers reported the use of Pd complexes in organozinc coupling reactions and carried out methods studies, eventually developing the reaction conditions into those commonly utilized today. Alongside Richard F. Heck and Akira Suzuki, El ichi Negishi was a co recipient of the Nobel Prize in Chemistry in 2010, for his work on "palladium catalyzed cross couplings in organic synthesis".

The Negishi coupling is not employed as frequently in industrial applications as its cousins the Suzuki reaction and Heck reaction, mostly as a result of the water and air sensitivity of the required aryl or alkyl zinc reagents. In 2003 Novartis employed a Negishi coupling in the manufacture of PDE472, a phosphodiesterase type 4D inhibitor, which was being investigated as a drug lead for the treatment of asthma. The Negishi coupling was used as an alternative to the Suzuki reaction providing improved yields, 73% on a 4.5 kg scale, of the desired benzodioxazole synthetic intermediate.

Where the Negishi coupling is rarely used in industrial chemistry, a result of the aforementioned water and oxygen sensitivity, it finds wide use in the field of natural products total synthesis. The increased reactivity relative to other cross coupling reactions makes the Negishi coupling ideal for joining complex intermediates in the synthesis of natural products. The major drawback of the Negishi coupling, aside from its water and oxygen sensitivity, is its relative lack of functional group tolerance when compared to other cross coupling reactions. (−) stemoamide is a natural product found in the root extracts of ‘’Stemona tuberosa’’. These extracts have been used Japanese and Chinese folk medicine to treat respiratory disorders, and (−) stemoamide is also an anthelminthic. Somfai and coworkers employed a Negishi coupling in their synthesis of (−) stemoamide. The reaction was implemented mid synthesis, forming an sp3 sp2 c c bond between β,γ unsaturated ester and an intermediate diene 4 with a 78% yield of product 5. Somfai completed the stereoselective total synthesis of (−) stemoamide in 12 steps with a 20% overall yield. Kibayashi and coworkers utilized the Negishi coupling in the total synthesis of Pumiliotoxin B. Pumiliotoxin B is one of the major toxic alkaloids isolated from Dendrobates pumilio, a Panamanian poison frog. These toxic alkaloids display modulatory effects on voltage dependent sodium channels, resulting in cardiotonic and myotonic activity. Kibayashi employed the Negishi coupling late stage in the synthesis of Pumiliotoxin B, coupling a homoallylic sp3 carbon on the zinc alkylidene indolizidine 6 with the (E) vinyl iodide 7 with a 51% yield. The natural product was then obtained after deprotection. δ trans tocotrienoloic acid isolated from the plant, Chrysochlamys ulei, is a natural product shown to inhibit DNA polymerase β (pol β), which functions to repair DNA via base excision. Inhibition of pol B in conjunction with other chemotherapy drugs may increase the cytotoxicity of these chemotherapeutics, leading to lower effective dosages. The Negishi coupling was implemented in the synthesis of δ trans tocotrienoloic acid by Hecht and Maloney coupling the sp3 homopropargyl zinc reagent 8 with sp2 vinyl iodide 9. The reaction proceeded with quantitative yield, coupling fragments mid synthesis en route to the stereoselectively synthesized natural product δ trans tocotrienoloic acid. Smith and Fu demonstrated that their method to couple secondary nucleophiles with secondary alkyl electrophiles could be applied to the formal synthesis of α cembra 2,7,11 triene 4,6 diol, a target with antitumor activity. They achieved a 61% yield on a gram scale using their method to install an iso propyl group. This method would be highly adaptable in this application for diversification and installing other alkyl groups to enable structure activbity relationship (SAR) studies. Kirschning and Schmidt applied nickel catalyzed negishi cross coupling to the first total synthesis of carolactone. In this application, they achieved 82% yield and dr = 10:1.

Alkylzinc reagents can be accessed from the corresponding alkyl bromides using iodine in dimethylacetamide (DMAC). The catalytic I2 serves to activate the zinc towards nucleophilic addition. Aryl zincs can be synthesized using mild reaction conditions via a Grignard like intermediate. Organozincs can also be generated in situ and used in a one pot procedure as demonstrated by Knochel et al.