Corey–House synthesis

[1][2][3] In principle, a carbanion equivalent such as an organolithium or Grignard reagent can react directly (without copper) with an alkyl halide in a nucleophilic substitution reaction to form a new carbon–carbon bond.

However, aside from the use of metal acetylides as nucleophiles, such a process rarely works well in practice due to metal–halogen exchange and/or the formation of large amounts of reduction or elimination side-products.

The scope of the Corey-House synthesis is exceptionally broad, and a range of lithium diorganylcuprates (R2CuLi, R = 1°, 2°, or 3° alkyl, aryl, or alkenyl) and organyl (pseudo)halides (RX, R = methyl, benzylic, allylic, 1°, or cyclic 2° alkyl, aryl, or alkenyl and X = Br, I, OTs, or OTf; X = Cl is marginal) will undergo coupling as the nucleophilic and electrophilic coupling partners, respectively.

The Corey-House synthesis process is the reaction between the organocopper reagent, usually a lithium dialkylcuprate as prepared above, and a second alkyl (pseudo)halide or an aryl iodide.

This results in the formation of a C–C bond between the two organic fragments: From the stoichiometry, it is apparent that one equivalent of the R group is wasted as an ill-characterized alkylcopper species (likely polymeric; usually converted to RH upon aqueous workup) in the most common form of the Corey–House synthesis.

[7] However, aryl bromides, iodides and sulfonates, which do not ordinarily undergo nucleophilic substitution in the absence of a transition metal, can be used successfully as coupling partners.

Under recently discovered conditions, using TMEDA as the ligand for copper and lithium methoxide as a base additive, it is now possible to couple 1°, 2°, and 3° Grignard reagents with 1° and 2° alkyl bromides and tosylates in high yields with nearly exclusive stereoinversion.

[11] While the coupling of organocopper compounds and allyl bromide was reported as early as 1936 by Henry Gilman (Iowa State University),[12] this reaction was fully developed by four organic chemists (two at Harvard and two at MIT):