Cross-coupling reactions of unactivated alkyl halides

Abstract

My graduate research at MIT has been focused on the development of palladium- or nickel-catalyzed cross-coupling reactions using unactivated alkyl electrophiles (e.g., halides and sulfonates). Although aryl and alkenyl electrophiles have been commonly used in such processes, the utility of alkyl substrates has been underdeveloped, and merits further exploration. We have developed the first palladium-based catalyst that is effective for Negishi couplings of primary alkyl electrophiles. A single protocol (2%Pd₂(dba)₃/8%P(Cyp)₃/NMI in THF/NMP at 80⁰C) can be applied to a broad spectrum of electrophiles, including chlorides, bromides, iodides, and tosylates. Concerning the scope of the nucleophilic components, an array of alkyl-, alkenyl-, and arylzinc halides can be coupled. The process is tolerant of a variety of functional groups, including esters, amides, imides, nitriles, and heterocycles. Furthermore, geometrically- defined alkenylzinc species, generated from titanium-mediated hydrozincation of internal alkynes, can be directly used in the process. Despite the progress in nickel- and palladium-catalyzed C(sp³)-C(sp³) bond formation, the methods had been limited to primary alkyl electrophiles.

(cont.) No doubt, the ability to use more challenging, secondary ones will further augment the usefulness of these metal- catalyzed processes. To this end, we have determined that Ni(cod)₂/s-Bu-Pybox can catalyze room-temperature Negishi couplings of an array of functionalized alkyl bromides and iodides. To the best of our knowledge, this is the first nickel- or palladium- catalyzed cross-coupling procedure for unactivated, [beta]-hydrogen-containing secondary alkyl halides. In addition, preliminary studies using substrate-based probes suggest that the oxidative addition proceeds through a radical pathway. This may explain the unparalleled reactivity of the nickel catalyst. As an extension of the nickel catalysis, we have established that the combination of Ni(cod)₂ and bathophenanthroline can effect Suzuki reactions of secondary halides and organoboronic acids. These organoboron reagents are particularly widely used in the cross-coupling chemistry, owing to their chemical stability, biological non-toxicity, and commercial availability. Again, mechanistic evidence has been collected to support the involvement of organic radicals during the oxidative addition step.