Accessing Grignard Reluctant Aldehyde in 2-Oxoaldehyde by Organocuprates to Give [1,2] Addition and Oxidative Coupling Reactions.

Novel finding of aldehyde in 2-oxoaldehyde (2OA) is presented as it unprecedentedly disinclines to react with Grignard reagents but reacts with moderate organocuprate reagents in anaerobic condition to give [1,2] addition (α-hydroxyketones) reaction. In the presence of air, the reaction produces an efficient protocol for the synthesis of 1,2-diones through a copper-catalyzed oxidative cross-coupling reaction at room temperature. Mechanistic studies indicate that α-hydroxy ketone perhaps is generated before the hydrolysis step/acid work-up process. The α-keto group of 2OA causes to exhibit this peculiar aldehyde behavior toward these organometallic reagents.

Room-Temperature Amination of Chloroheteroarenes in Water by a Recyclable Copper(II)-Phosphaadamantanium Sulfonate System.

Buchwald-Hartwig amination of chloroheteroarenes has been a challenging synthetic process, with very few protocols promoting this important transformation at ambient temperature. The current report discusses about an efficient copper-based catalytic system (Cu/PTABS) for the amination of chloroheteroarenes at ambient temperature in water as the sole reaction solvent, a combination that is first to be reported. A wide variety of chloroheteroarenes could be coupled efficiently with primary and secondary amines as well as selected amino acid esters under mild reaction conditions. Catalytic efficiency of the developed protocol also promotes late-stage functionalization of active pharmaceutical ingredients (APIs) such as antibiotics (floxacins) and anticancer drugs. The catalytic system also performs efficiently at a very low concentration of 0.0001 mol % (TON = 980,000) and can be recycled 12 times without any appreciable loss in activity. Theoretical calculations reveal that the π-acceptor ability of the ligand PTABS is the main reason for the appreciably high reactivity of the catalytic system. Preliminary characterization of the catalytic species in the reaction was carried out using UV-VIS and ESR spectroscopy, providing evidence for the Cu(II) oxidation state.

Catalytic Asymmetric Epoxidation of Aldehydes with Two VANOL-Derived Chiral Borate Catalysts.

A highly diastereo- and enantioselective method for the epoxidation of aldehydes with α-diazoacetamides has been developed with two different borate ester catalysts of VANOL. Both catalytic systems are general for aromatic, aliphatic, and acetylenic aldehydes, giving high yields and inductions for nearly all cases. One borate ester catalyst has two molecules of VANOL and the other only one VANOL. Catalysts generated from BINOL and VAPOL are ineffective catalysts. An application is shown for access to the side-chain of taxol.

Self-Assembly of a Library of Polyborate Chiral Anions for Asymmetric Catalytic Quinoline Reduction.

The 'template' polyborate BOROX catalysts are shown to mediate the asymmetric transfer hydrogenation of 2-quinolines. The rapid and simple generation of a large family of BOROX catalysts with significantly altered asymmetric pockets is described. A transition state model that explains the enantioselectivity is proposed.

Catalytic asymmetric synthesis of alkynyl aziridines: both enantiomers of cis-aziridines from one enantiomer of the catalyst.

Alkynyl aziridines can be obtained from the catalytic asymmetric aziridination (AZ reaction) of alkynyl imines with diazo compounds in high yields and high asymmetric inductions mediated by a chiral boroxinate or BOROX catalyst. In contrast to the AZ reaction with aryl- and alkyl-substituted imines, alkynyl imines react to give cis-substituted aziridines with both diazo esters and diazo acetamides. Remarkably, however, the two diazo compounds give different enantiomers of the cis-aziridine from the same enantiomer of the catalyst. Theoretical considerations of the possible transition states for the enantiogenic step reveal that the switch in enantiomers results from a switch from Si-face to Re-face addition to the imine, which in turn is related to a switch from reaction with an E-imine in the former and a Z-isomer of the imine in the latter.

Isotope effects and mechanism of the asymmetric BOROX Brønsted acid catalyzed aziridination reaction.

The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring-closing transition structures.

How the binding of substrates to a chiral polyborate counterion governs diastereoselection in an aziridination reaction: H-bonds in equipoise.

The stereochemistry-determining step of the self-assembled chiral Brønsted acid-catalyzed aziridination reactions of MEDAM imines and three representative diazo nucleophiles has been studied using ONIOM(B3LYP/6-31G*:AM1) calculations. The origin of cis selectivity in the reactions of ethyldiazoacetate and trans selectivity in reactions of N-phenyldiazoacetamide can be understood on the basis of the difference in specific noncovalent interactions in the stereochemistry-determining transition state. A H-bonding interaction between the amidic hydrogen and an oxygen atom of the chiral counterion has been identified as the key interaction responsible for this reversal in diastereoselectivity. This hypothesis was validated when a 3° diazoamide lacking this interaction showed pronounced cis selectivity both experimentally and calculationally. Similar trends in diastereoselection were observed in analogous reactions catalyzed by triflic acid. The broad implications of these findings and their relevance to chiral Brønsted acid catalysis are discussed.

Controlled diastereo- and enantioselection in a catalytic asymmetric aziridination.

Chiral polyborate based Brønsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.