Synthesis and Reactions of Novel Heteroarylzirconocene Reagents

Abstract

The cross-coupling of metallated heteroaromatic species with aryl and heteroaryl halides is a powerful and highly desirable transformation in both the synthesis of pharmaceutical compounds as well as materials development. However, current methodology in this area has some limitations, particularly with organometallic reagents derived from 2-halopyridines, 2-haloquinolines, and other similar heteroaromatic compounds. Suzuki cross-coupling reactions of 2-pyridyl boronic acids or esters is often reported to be low yielding due to protodeborylation. In particular, the preparation of the corresponding heteroaromatic boronic reagents is often associated with low yields. Although Negishi cross-coupling reactions are often reported to be high yielding, the generation of heteroaromatic Negishi reagents require the use of expensive and user unfriendly Rieke® Zinc. The Stille reaction is the least desirable because of the highly toxic tin waste streams generated. Zirconium is a non-toxic, inexpensive, and abundant metal that exists primarily in the Zr(IV) oxidation state and its application in organic synthesis has been extensively studied. However, the preparation of heteroaromatic zirconocene reagents and their application in organic synthesis have not been reported. In 1986, Negishi reported the generation of a Zr(II) species, in situ, by reacting Cp₂Zr(IV)Cl₂ with 2 equivalents of n-BuLi followed by a [beta]-H abstraction process. We anticipated that the oxidative addition of a heteroaromatic halide to the Negishi reagent, "Cp₂Zr(II)", would generate the desired heteroaromatic zirconocene reagents. These novel reagents were successfully generated and used in palladium-catalyzed cross-coupling reactions.