NHC-catalyzed enantioselective access to ß-cyano carboxylic esters via in situ substrate alternation and release.

A carbene-catalyzed asymmetric access to chiral ß-cyano carboxylic esters is disclosed. The reaction proceeds between ß,ß-disubstituted enals and aromatic thiols involving enantioselective protonation of enal ß-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched ß-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

Carbene-Catalyzed Access to Thiochromene Derivatives: Control of Reaction Pathways via Slow Release of Thiols from Disulfides.

Substrates containing disulfide bonds, which are more stable and less smelling, could be used as thiophenol precursors in organic synthesis. Herein, an N-heterocyclic carbene (NHC)-catalyzed reaction between α-bromoenals and 2,2'-dithiodibenzaldehydes was developed. Through the sustained release strategy, the side reaction can be effectively inhibited, and the chiral thiochromene derivatives can be obtained with good yields and high optical purities. Application studies showed encouraging results when the desired products were explored for antimicrobial utilities in pesticide development.

Carbene-Catalyzed Activation of 2-Aminobenzaldehyde for Access to Chiral Fluorescent Quinazolinone.

A carbene-catalyzed reaction to synthesize a chiral quinazolinone with a new activation mode of an "aniline-like" N-H moiety is disclosed. Addition of the nitrogen atom of diphenyl o-aminobenzaldehydes via NHC activation to imines leads to chiral quinazolinones with high yields and optical purities. The acidity of the N-H moiety was extremely increased through the formation of an acyl azolium intermediate, which was investigated by DFT calculations. Moreover, the chiral quinazolinones were found to have high fluorescence quantum efficiency.

Carbene-Catalyzed Enantioselective Sulfonylation of Enone Aryl Aldehydes: A New Mode of Breslow Intermediate Oxidation.

A carbene-catalyzed sulfonylation reaction between enone aryl aldehydes and sulfonyl chlorides is disclosed. The reaction effectively installs sulfone moieties in a highly enantioselective manner to afford sulfone-containing bicyclic lactones. The sulfonyl chloride behaves both as an oxidant and a nucleophilic substrate (via its reduced form) in this N-heterocyclic carbene (NHC)-catalyzed process. The NHC catalyst provides both activation and stereoselectivity control on a very remote site of enone aryl aldehyde substrates. Water plays an important role in modulating catalyst deactivation and reactivation routes that involve reactions between NHC and sulfonyl chloride. Experimental studies and DFT calculations suggest that an unprecedented intermediate and a new oxidation mode of the NHC-derived Breslow intermediate are involved in the new asymmetric sulfonylation reaction.

Carbene-Catalyzed Activation of Formyl-phenylacetic Esters for Access to Chiral Dihydroisoquinolinones.

A carbene-catalyzed reaction to synthesize chiral dihydroisoquinolinones via an o-quinodimethane (o-QDM) intermediate is disclosed. o-QDM reacts with cyclic sulfonic imines via annulation to afford highly enantioenriched dihydroisoquinolinone products. ESI-HRMS studies suggest a stepwise Mannich addition and acylation reaction pathway, and the pathways of the catalytic and uncatalyzed background reactions are evaluated via DFT calculations.

Carbene-Catalyzed Enantioselective Addition of Thioamides to Bromoenals for Access to Thiazinone Heterocycles.

A carbene-catalyzed reaction between α-bromoenals and thioamides was developed. Key steps include enantioselective 1,4-addition of thioamide sulfur atoms to α,ß-unsaturated acyl azolium intermediate. Subsequent intramolecular annulation eventually affords thiazinone heterocycles with high optical purities. The introduction of Lewis acid additives such as Cu(OTf)2 to this NHC catalytic reaction could provide small but consistent improvements to reaction enantioselectivities.

NHC-Catalyzed Chemoselective Reactions of Enals and Aminobenzaldehydes for Access to Chiral Dihydroquinolines.

An N-heterocyclic carbene (NHC)-catalyzed reaction between α-bromoenals and 2-aminoaldehydes has been developed. Key steps include chemoselective reaction of the NHC catalyst with one of the aldehyde substrates (the bromoenal) to eventually generate an α,ß-unsaturated acylazolium intermediate. Addition of the nitrogen atom of aminoaldehyde to the unsaturated azolium ester intermediate followed by intramolecular aldol reaction, ß-lactone formation, and decarboxylation leads to chiral dihydroquinolines with high optical purity. The dihydroquinoline products, which are quickly prepared by using this method, can be readily transformed into a diverse set of functional molecules such as pyridines and chiral piperidines.

Addition of a Carbene Catalyst to Indole Aryl Aldehyde Activates a Remote δ-sp2 Carbon for Protonation and Formal [4+2] Reaction.

The addition of a carbene catalyst to an indole aryl aldehyde leads to the activation of a remote sp2 carbon that is five atoms away from the catalyst. The unsaturated Breslow intermediate formed between the catalyst and substrate undergoes an internal redox reaction and remote carbon protonation to generate an analogous azolium vinyl enolate intermediate. Subsequent [4+2] reaction with cyclic imine substrates eventually affords multicyclic pyridoindoles as nearly single diastereomers with excellent enantioselectivities.

Addition of N-Heterocyclic Carbene Catalyst to Aryl Esters Induces Remote C-Si Bond Activation and Benzylic Carbon Functionalization.

Through the incorporation of a silicon atom to an aryl carboxylic ester substrate, the resulting C-Si bond can be activated via the addition of a carbene catalyst on a remote site. This strategy allows for efficient functionalization of the benzylic sp3-carbons of aryl carboxylic esters.