Wednesday, January 13, 2010

Nickel catalyzed aryl-X - alkyl-X coupling from a new group

Looking through current organic methodology literature, we all see tons of 'copper-catalyzed this' and 'ligandless palladium-catalyzed cross-coupling' that and even now the onset of 'direct C-H functionalization' blablabla.  Of course that stuff is important, and my own methodology involves this kind of chemistry, but it's just a matter of fine-tuning all of the reaction conditions to work with the electronics of your particular substrate.  We are continuously hard-pressed to find truly general reaction conditions that we can throw at any ol' aryl halide and get coupling to form a C-C bond.

One of the issues with traditional cross-coupling reactions is preparing the cross-coupling partners; usually we try to mix R-X, with X being Cl (ideally), Br, I or OTf, with a second molecule that has to have a transmetallating group or otherwise activating group (boronic acid/ester, organocuprate generated in situ, etc.; see Sonogashira, Suzuki, Negishi, Buchwald-Hartwig or Hartwig-Buchwald coupling depending on who you talk to, and Stille, to name a few of these cross-coupling named reactions with preformed coupling partners).  Toss in some ligand, base, and transition metal complex and you've got a catalytic system for C-C bond formation.



To circumvent the necessity of this group, direct functionalization of an sp2 C-H bond is becoming quite popular and works well for some substrates (see work of Lautens, the late Fagnou, DaugulisSames, Cheng, Bellina/Rossi, and Mori, just to name a few of the many).  This requires intense screening and optimization, however, and possibly requires directing groups; a few examples (linked to references) are arylation (popular), alkylation, cyanation, hydroxylation, and allylation.

The glory of JACS has recently given us R-X / R-X coupling between aryl iodides and alkyl iodides catalyzed by nickel reported by the brand new Weix group at the University of Rochester, "Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Alkyl Halides" (DOI: 10.1021/ja9093956).  The authors sought to find a system that minimized the common cross-coupling complications - homocoupling and/or reduction byproducts, having to use an excess of one of the coupling partners, and using a stoichiometric amount of a reagent required for the transmetallation.  Aryl and alkyl halides have been coupled before through organometallic intermediates like alkyl-ZnI or alkyl-MgBr, but the tolerance for acidic protons such as OH and the slow timescale of insertion by the Mn0 reductant provide evidence that the mechanism is more direct, without such an intermediate species.  Check out the paper for the decent substrate scope.

The reaction and conditions are as follows:



My favorite example?  The conditions tolerate a boronic ester which you DEFINITELY wouldn't get using palladium, so you can build your own reagent to be used in a future Suzuki.  Woohoo!  I look forward to the future publications of this group.


3 comments:

Constructive criticism welcome; criticism for judgement's sake, not.