Chaos!

Anyone check out asaps for J. Agric. Food Chem.?  There's actually some good stuff lurking in there.  Not just hilarious TOC graphics of chaotic olive oil.

A Novel Method To Quantify the Adulteration of Extra Virgin Olive Oil with Low-Grade Olive Oils by UV-Vis

J. Agric. Food Chem., Article ASAP

DOI: 10.1021/jf903308u

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, Daugulis, Sames, 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.

Reaction of the Week #2 - Strecker reaction & amino acid synthesis

I selected the Strecker synthesis based on a recent Nature paper by Jacobsen and coworkers using an asymmetric Strecker synthesis to create unnatural α-amino acids. The classical Strecker reaction, first reported in 1850 (!), involves the reaction of a carbonyl acompound (ketone or aldehyde) with ammonia (to create the free amine) or primary or secondary amines to form an α-amino nitrile, which can be followed by acidification to hydrolize the nitrile group to a carboxylic acid.  (The intermediate may also be reduced to produce 1,2-diamines or undergo α-substitution chemistry following deprotonation at the α-position, provided there is an available proton). The mechanism/sequence concluding with acid-catalyzed, sans the formation of the iminium and acid stepwise, is shown below.

The entire sequence can be achieved in one pot.  This reaction and the synthesis of amino acids can be easily rendered asymmetric using a chiral Lewis acid or an organocatalyst (in the latter, the additive would coordinate to the imine nitrogen...it would obviously have to be trisubstituted/neutral for this to occur) and another basic moiety at the appropriate distance would associate with the proton from HCN, pulling H away and direct the CN to whichever side of the imine it is closest to.  Anionic CN sources are generally a problem because of the toxicity of the CN anion, and so improvements and modifications to the reaction are continuously made.  Examples of reagents include Bu₃SnCN, TMSCN (which is expensive and difficult to handle), Et₂AlCN, and HCN; while KCN and NaCN are desirable as they are inexpensive and easily handled cyanide salts, they are not typically seen presumably due to their low solubility in organic solvents unless buffered aqueous medium is used, according to the authors of the Nature paper.

A neat caveat to α-amino nitriles is that if they are treated with a heavy metal salt (such as a Ag(I) salt), a Brönsted or Lewis acid, cyanide can be a leaving group to reform iminium which is trappable by a nucleophile - when the nucleophile is organometallic, the reaction is the Bruylants reaction.

Jacobsen and coworkers have developed a chiral catalyst derived from (S)-tert-leucine (read: inexpensive and accessible) to achieve asymmetric imine hydrocyanation.  Using 2 equivalents of TMSCN, 2 equivalents of MeOH, and 0.5 mol% of the catalyst in 0.2 M toluene at -30C for 20 hours, excellent yields were achieved with good to excellent ee with the exception of only a few of the reported substrates which were still in good yield.

A nice graphic that explains the enantioselectivity was presented in the paper:

Another example which is included in the entry in Kürti and Czakó text is in the synthesis of (-)-α-kainic acid, a neurotoxic compound that induces seizures (it is used in research commonly to induce seizures in rats).  It is a kainate receptor agonist (hence its name), and since the kainate receptor is one of the "ionotropic glutamate receptors" it is understandably a stimulant (glutamate is an excitatory neurotransmitter).  The Strecker reaction in this case is mediated by zirconium with the Schwartz reagent to form imine, which was not isolated but directly treated with cyanotrimethylsilane to produce the α-amino nitrile.  Hydrolysis to the acid and concomitant epimerization selectively led to (-)-α-kainic acid.

I hope you like the festive-colored kainic acid!