Heterocycles Negishi coupling

In efforts to prepare substituted methylthio-2V-heterocycles, researchers at Dupont discovered a new type of Negishi coupling reaction in which benzylic zinc reagents were found to undergo a Pd-catalyzed cross-coupling reaction at the C—S site. 2-(Methylthio) pyrimidine 50 was found to be a particularly reactive substrate for this reaction. Indeed, a 71% isolated yield using 1 mol% Pd( PPh J was obtained with benzyl zinc bromide and 2-(methylthio)pyrimidine in THF. This new cross-coupling method provides a convenient alternative to the use of pyrimidine halides [24]. 

The heterocycles may be pyridine, pyridazine, pyrimidine (positional isomers) and the organo-zinc reagents 233 were made from the bromo-compounds. Six compounds such as 234 were made by Negishi coupling.34... 

Finally, the efficient Negishi coupling of unactivated aryl, heterocyclic, vinyl chlorides as well as aryl dichlorides catalyzed by binuclear and mononuclear NHC-Ni complexes was recently described by Chen and co-workers (Equation (10.18)). Elaborated heteroarene-functionalized NHC were found to be highly effective for the preparation biaryls and terphenyls in good to excellent yields under mild conditions. Notably, the binuclear nickel catalysts showed higher activities than mononuclear analogues, probably because of a bimetallic cooperative effect. 

The reaction of alkynylzinc or zincates with azides has been reported to deliver metallotriazoles that can be further functionalized using a Negishi coupling reaction [142]. Although the mechanism has not been discussed, formation of a metalated heterocycle might be related to the one proposed by Krasinski (Scheme 57). 

SCHEME 110. Negishi cross-coupling with heterocyclic zinc reagents... 

Phospholes and other related heterocycles are an important class of main group compounds. The chemistry of phospholes and their preparation has been reviewed extensively by Mathey.3 We provide details here for a simple, one-pot procedure for the preparation of 1-phenyl-2,3,4,5-tetramethylphosphole applying zirconocene chemistry.4 The procedure involves reduction of (n-CsHsteZrCIa with butyllithium in the presence of 2-butyne which (as reported initially by Negishi, et al.s) forms a zirconium metallacycle. Addition of dichlorophenylphosphine to this reaction mixture produces the phosphole. One other procedure for the preparation of 1-phenyl-2,3,4,5-tetramethylphosphole has been reported by Nief, et al.2 That procedure involved aluminum chloride - coupling of 2-butyne, followed by reaction with dichlorophenylphosphine to form a chlorophospholium tetrachloroaluminate which was then reduced with tributylphosphine to produce the phosphole in 68% yield. 

A modification of the Negishi cross-coupling has also been used for a wide range of nitrogen heterocycles. In accordance to that, the zinc reagent derived from protected iodoaniline can be treacted with a-substituted carbethoxy vinyl-triflates to produce quinolin-2-ones. ... 

Spiro-linked compounds containing heterocyclic units have been prepared for many apphcations. In general, there are two synthetic pathways to build up heterocyclic spiro compounds. On the one hand, cross-coupling reactions like the Negishi, Kharash, Stille, Suzuki, or Sonogashira coupling reaction can be utilized to connect the heterocychc subunit with the central spiro core [118]. On the other hand, the heterocycle can be built up from spiro precursors containing heteroatoms. 

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