The Corey–House synthesis (also called the Corey–Posner–Whitesides–House reaction and other permutations) is an organic reaction that involves the reaction of a lithium diorganylcuprate (<chem>R_{2}CuLi</chem>) with an organic halide or pseudohalide (<chem>R'-X</chem>) to form a new alkane, as well as an ill-defined organocopper species and lithium (pseudo)halide as byproducts.
:Li<sup>+</sup>[R–Cu–R]<sup>−</sup> + –X → R– + "R–Cu" + LiX
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. As a solution to this problem, the Corey–House reaction constitutes a general and high yielding method for the joining of two alkyl groups or an alkyl group and an aryl group.
Scope
The scope of the Corey-House synthesis is exceptionally broad, and a range of lithium diorganylcuprates (R<sub>2</sub>CuLi, 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. 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.
Catalytic version
In 1971, Jay Kochi reported that Grignard reagents and alkyl bromides could be coupled using a catalytic amount of lithium tetrachlorocuprate(II), a process that was extended to alkyl tosylates by Schlosser and Fouquet. In the catalytic process, the Grignard reagent undergoes transmetalation with the copper salt or complex to generate an organocuprate as a catalytic intermediate, which then undergoes reaction with the (pseudo)halide electrophile to form the coupling product and release the copper and complete the catalytic cycle.
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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. Even β-branched 2° alkyl tosylates react to give coupling product in moderate yield, greatly expanding the scope of the catalytic Corey–House synthesis (Kochi–Schlosser coupling).
Background
While the coupling of organocopper compounds and allyl bromide was reported as early as 1936 by Henry Gilman (Iowa State University), this reaction was fully developed by four organic chemists (two at Harvard and two at MIT):
- E.J. Corey (Harvard University), research advisor of Gary Posner
- Gary H. Posner (Johns Hopkins University), a student of Harvard University at the time
- George M. Whitesides (Massachusetts Institute of Technology; later Harvard University), junior colleague of Herbert House
- Herbert O. House (Massachusetts Institute of Technology; later Georgia Institute of Technology)
See also
- Gilman reagent
- Wurtz reaction