Aldehydes and ketones form intermediate π complexes with the Gilman reagent, Me2CuLi, at low temperatures in tetrahydrofuran.

Typical aldehydes and ketones form π complexes with Me2CuLi at low temperatures in tetrahydrofuran. They range in stability from fleeting intermediates at -100 °C to entities that persist up to -20 °C. Three subsequent reaction pathways have been identified.

First X-ray crystal structure and internal reference diffusion-ordered NMR spectroscopy study of the prototypical Posner reagent, MeCu(SPh)Li(THF)3.

Grow slow: The usual direct treatment of MeLi and CuSPh did not yield X-ray quality crystals of MeCu(SPh)Li. An indirect method starting from Me2CuLi⋅LiSPh and chalcone afforded the desired crystals by the slow reaction of the intermediate π-complex (see scheme). This strategy produced the first X-ray crystal structure of a Posner cuprate. A complementary NMR study showed that the contact ion pair was also the main species in solution.

Rapid injection NMR reveals η3 'π-allyl' Cu(III) intermediates in addition reactions of organocuprate reagents.

By using rapid injection NMR, it has now been possible to prepare and characterize the η(3) 'π-allyl' copper(III) intermediate that has been proposed for addition reactions of organocopper(I) reagents and α,ß-unsaturated carbonyl compounds.

Base-mediated stereospecific synthesis of aryloxy and amino substituted ethyl acrylates.

The stereospecific synthesis of aryloxy and amino substituted E- and Z-ethyl-3-acrylates is of interest because of their potential in the polymer industry and in medicinal chemistry. During work on a copper-catalyzed cross-coupling reaction of ethyl (E)- and (Z)-3-iodoacrylates with phenols and N-heterocycles, we discovered a very simple (nonmetallic) method for the stereospecific synthesis of aryloxy and amino substituted acrylates. To study this long-standing problem on the stereoselectivity of aryloxy and amino substituted acrylates, a series of O- and N-substituted nucleophiles was allowed to react with ethyl (E)- and (Z)-3-iodoacrylates. Screening of different bases indicated that DABCO (1,4-diazabicyclo[2.2.2]octane) afforded successful conversion of ethyl (E)- and (Z)-3-iodoacrylates into aryloxy and amino substituted ethyl acrylates in a stereospecific manner. Herein are the details of this DABCO-mediated stereospecific synthesis of aryloxy and amino substituted E- or Z-acrylates.

Minimization of organocuprate complexity through self-organization: remarkable orientation effect in mixed cuprate π complexes.

They "know" where to go: a powerful orientation effect has been observed in complexes of mixed organocuprates [R(T)R(NT)CuLi] and substrates with C-C, C-N, and C-S double bonds (see scheme; Th=thienyl). The preferred geometry of the intermediate complex sets up the facile addition of R(T) to the double bond, rather than addition of the "dummy ligand", R(NT) .

Complexes of Gilman reagents with C-S and C-N double bonds: sigma or pi bonding?

Upon rapid injection, a variety of thiocarbonyl compounds react with the Gilman reagent Me(2)CuLi at -100 degrees C inside the probe of an NMR spectrometer to give high yields of complexes. Typical examples of substrates include carbon disulfide, methyl dithioacetate, methyl dithiobenzoate, thiobenzophenone, ethylene trithiocarbonate, and phenyl isothiocyanate. Evidence suggesting the formal oxidation state of copper in these complexes to be Cu(III) is presented. The last example was particularly interesting, since it involved a transient intermediate that was identified as a complex with a C-N double bond. Methyl isothiocyanate gave a stable C-N double-bond complex.

Preparation of sigma- and pi-allylcopper(III) intermediates in SN2 and SN2' reactions of organocuprate(I) reagents with allylic substrates.

The first pi-allyl complexes of CuIII have been prepared and characterized by using rapid injection nuclear magnetic resonance spectroscopy (RI-NMR). The prototype, (eta3-allyl)dimethylcopper(III), was prepared by injection of allyl chloride into a THF-d8 solution of iodo-Gilman reagent, Me2CuLi.LiI (A), spinning in the probe of an NMR spectrometer at -100 degreesC. A sigma-allyl ate complex, lithium (eta1-allyl)trimethylcuprate(III), was prepared in high yield by including 1 equiv of tributylphosphine in the reaction mixture or by using allyl acetate as the substrate. Cyano ate complex, lithium cis-(eta1-allyl)cyanodimethylcuprate(III) was obtained in high yield by injecting allyl chloride or allyl acetate into the cyano-Gilman reagent, Me2CuLi.LiCN (B), in THF-d8 at -100 degrees C. Reactions of A with allylic substrates show a definite dependence on leaving group (chloride vs acetate), whereas those of B do not. Moreover, these reagents have different regioselectivities, which in the case of A vary with temperature. Finally, the exclusive formation of cis-cyano sigma-allyl CuIII intermediates in both the 1,4-addition of B to alpha-enones and its SN2alpha reaction with allylic substrates now makes sense in terms of pi-allyl intermediates in both cases, thus unifying the mechanisms of these two kinds of conjugate addition.

Neutral organocopper(III) complexes.

Neutral organocopper(III) complexes have been prepared from organocuprate(I) reagents and alkyl halides in the presence of certain strongly electron donating ligands.

Opening the 'black box': oscillations in organocuprate conjugate addition reactions.

Under the conditions of a rapid injection experiment, the conjugate addition reactions of butyl Gilman reagents with 2-cyclohexenone undergo oscillations of a complex nature.

The role of isomorphism in synthetic analysis. Pruning the search tree by finding disjoint isomorphic substructures.

Isomorphism is an equivalence relation that is less stringent than identity (equality), and it is useful for synthetic analysis, since it allows one to find reflexive routes for targets even when they do not have an element of symmetry.

The Use of 15 N NMR Spectroscopy To Resolve the "Higher Order Cyanocuprate" Controversy: 15 N, 6 Li, and 13 C NMR Spectroscopic Investigations of CuCN-Derived Butyl Cuprates.

Structure 1 is the major component obtained by the reaction of two equivalents of RLi and one equivalent of CuCN; other proposed structures can now be ruled out on the basis of 15 N NMR spectroscopic and theoretical studies. Thus, these useful synthetic reagents should be considered as cyano-Gilman reagents R2 CuLi⋅LiCN and not "higher order cyanocuprates" R2 Cu(CN)Li2 .

π-Complexes from acyl cyanides and lithium dimethylcuprate(I).

Rapid injection of pyruvonitrile or benzoyl cyanide into solutions of Me2CuLi in THF-d8 at -100 °C gave complexes that were stable at this temperature. 1D NMR with multiply labelled substrates ((13)C/(15)N) and 2D NMR ((1)H/(13)C) identified them as the first cuprate-carbonyl π-complexes.

Organocuprate(III) chemistry: synthesis and reactivity of amido, cyano, phosphido and thiolato ate complexes of copper(III).

Lithium tetramethylcuprate(III) 1 reacts readily at -100 degrees C with appropriate sources of H(+) or X(+) (X = Br, I) to remove a methyl and in some cases incorporate the counterion (e.g., arylthio or cyano) to give stable complexes. These derivatives can in turn serve as starting materials for other Cu(III) complexes.

Serendipity strikes again--efficient preparation of lithium tetramethylcuprate(III) via rapid injection NMR.

Lithium tetramethylcuprate(III), Me(4)CuLi, the Cu(III) analog of the Gilman reagent, has been prepared in high yield from halo-Gilman reagents Me(2)CuLi.LiX (X = Cl, Br, I) and 2,3-dichloropropene and found to have surprising thermal stability. The cyano-Gilman reagent (X = CN) follows a different pathway.

Remarkable effect of silyl groups on asymmetric induction in a conjugate addition reaction with O-methylnorephedrine-based N-silylamidocuprates.

Scalemic N-silylamidocuprates, prepared from O-methylnorephedrine in a two-flask procedure, are exceedingly reactive and give excellent enantiomeric excesses with chalcone, a classic substrate for studies of organocuprate conjugate addition. For example, the butyl N-diphenylmethylsilylamidocuprate (T = Bu) affords a 99.2% ee (99% yield) of (S)-3-butyl-1,3-diphenyl-1-propanone. The remarkably high yields with this and other silyl ligands are attributed to the extraordinary activating effect of a beta-silicon atom on organocuprate reactions. The high ee is a consequence of the larger size of the silyl ligands compared to that of the unsubstituted or methyl-substituted analogues.

Subtle factors are important: radical formation and transmetallation in reactions of butyl cuprates with cyclohexyl iodide.

The reactions of Bu(2)CuLi[middle dot]LiI and Bu(2)CuLi.LiCN with cyclohexyl iodide are critically dependent upon subtle factors such as the surface properties of the reaction vessel, nature of the solvent still and lot of 'ultrapure' copper salt in addition to major effects such as the Li counterion.

Organic synthesis--art or science?

The LHASA rules for finding strategic bonds in polycyclic target structures are analyzed with respect to the following question: Do the strategic bonds tend to give the greatest simplification upon disconnection, as measured by recently introduced indices of molecular complexity? The answer is yes, at least for the more general rules. This result implies that the bonds most useful for retrosynthetic disconnection can now be identified by a simple calculation rather than by application of a body of rules. It is concluded that organic synthesis, as far as described by these rules, has a mathematical basis and consequently can be considered a science as well as an art.

Rapid-injection NMR study of iodo- and cyano-Gilman reagents with 2-cyclohexenone: observation of pi-complexes and their rates of formation.

Rapid-injection is a very useful technique for the preparation of temperature-sensitive and air-sensitive compounds in the cold, nitrogen-filled probe of an NMR spectrometer. We have used this method to prepare solutions of pi-complexes from 2-cyclohexenone and prototypical cuprates Me2CuLi.LiI and Me2CuLi.LiCN, and we have assigned structures on the basis of 1H and 13C NMR. In each case two pi-complexes were observed, and in the former, their rates of formation were measured by rapid-injection 1H NMR and EXSY spectroscopy. These results provide insights into the normal and anomalous conjugate addition reactions of organocuprates.