The First Negishi Cross-Coupling Reaction of Two Alkyl Centers

Org. Lett., 7 (17), 3805 -3807, 2005.

Palladium-catalyzed cross-coupling reactions of unsaturated organohalides and sulfonates with organometallic reagents are well established and powerful methods for construction of carbon-carbon bonds.¹ While coupling of alkyl organometallic reagents has been known for some time, the use of unactivated alkyl chlorides, bromides, or tosylates as coupling partners posed a greater challenge,² isolated early examples notwithstanding.³ Until recently, there was no general and efficient catalytic protocol for alkyl-alkyl cross-coupling reactions.

Previous work by Fu and co-workers demonstrated that Pd(PR₃)₂ (R = cyclohexyl, cyclopentyl) is an effective catalyst for Negishi⁴ and Suzuki⁵ cross-couplings of primary alkyl halides (Cl, Br, I) and tosylates. Kambe and co-workers disclosed Pd-1,3-diene catalysts for Kumada couplings of unactivated alkyl halides (Cl, Br) and tosylates.⁶ In addition, catalysts based on Ni^6,7 or other transition metals (Fe, Cu)^3,8 have been used successfully in alkyl-alkyl cross-coupling protocols.

The main problems when attempting to couple haloalkanes are the reluctance of saturated carbon-halogen bonds to undergo oxidative addition^2b compared to aryl, vinyl, or allyl halides and competing -H elimination from the oxidative addition intermediate, which results in unwanted alkene formation.

Further, this is also the first reported room-temperature palladium-catalyzed Negishi alkyl-alkyl coupling reaction.