Thursday, July 17, 2008

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 Ni6,7 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 addition2b 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.


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