Qing-An Chen

Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles Activated by Brønsted Acids

The first highly enantioselective hydrogenation of simple indoles was developed with a Brønsted acid as an activator to form the iminium intermediate in situ, which was hydrogenated using Pd(OCOCF(3))(2)/(R)-H8-BINAP catalyst system with up to 96% ee. The present method provides an efficient route to enantioenriched 2-substituted and 2,3-disubstituted indolines.

Dihydrophenanthridine: A New and Easily Regenerable NAD(P)H Model for Biomimetic Asymmetric Hydrogenation

A new and easily regenerable NAD(P)H model 9,10-dihydrophenanthridine (DHPD) has been designed for biomimetic asymmetric hydrogenation of imines and aromatic compounds. This reaction features the use of hydrogen gas as terminal reductant for the regeneration of the DHPD under the mild condition. Therefore, the substrate scope is not limited in benzoxazinones; the biomimetic asymmetric hydrogenation of benzoxazines, quinoxalines, and quinolines also gives excellent activities and enantioselectivities. Meanwhile, an unexpected reversal of enantioselectivity was observed between the reactions promoted by the different NAD(P)H models, which is ascribed to the different hydride transfer pathway.

Convergent Asymmetric Disproportionation Reactions: Metal/Brønsted Acid Relay Catalysis for Enantioselective Reduction of Quinoxalines

A convergent asymmetric disproportionation of dihydroquinoxalines for the synthesis of chiral tetrahydroquinoxalines using a metal/Brønsted acid relay catalysis system has been developed. The use of hydrogen gas as the reductant makes the convergent disproportionation an ideal atom-economical process. A dramatic reversal of enantioselectivity was observed in the reduction of quinoxalines because of the different steric demands in the 1,2- and 1,4-hydride transfer pathways.

Biomimetic Asymmetric Hydrogenation: In Situ Regenerable Hantzsch Esters for Asymmetric Hydrogenation of Benzoxazinones

A catalytic amount of Hantzsch ester that could be regenerated in situ by Ru complexes under hydrogen gas has been employed in the biomimetic asymmetric hydrogenation of benzoxazinones with up to 99% ee in the presence of chiral phosphoric acid. The use of hydrogen gas as a reductant for the regeneration of Hantzsch esters makes this hydrogenation an ideal atom economic process.

Highly Enantioselective Partial Hydrogenation of Simple Pyrroles: A Facile Access to Chiral 1-Pyrrolines

A highly enantioselective Pd-catalyzed partial hydrogenation of simple 2,5-disubstituted pyrroles with a Brønsted acid as an activator has been successfully developed, providing chiral 2,5-disubstituted 1-pyrrolines with up to 92% ee.

Iridium‐Catalyzed Asymmetric Hydrogenation of Pyridinium Salts

As one of the most straightforward and powerful approaches for the preparation of optically active compounds, asymmetric hydrogenation has been successfully used for different types of aromatic compounds, including quinolines, isoquinolines, quinoxalines, indoles, pyrroles, furans, imidazoles, and aromatic carbocyclic ring, with excellent enantioselectivities. Despite these advances, direct hydrogenation of simple pyridines is still a challenge. The inherent problems are apparent: First, substrates and corresponding products that possess strong coordination ability might cause the deactivation of catalysts. Second, pyridines have a stabilizing aromatic structure that might impede the reduction. Therefore, only limited examples of hydrogenation of specific pyridine derivatives bearing powerful electron-withdrawing substituent at the 2or 3-position have been previously described. In 2000, Studer et al. reported the first homogeneous rhodium-catalyzed asymmetric hydrogenation of pyridines, but only poor enantioselectivity was obtained. Zhang and co-workers described an efficient three-step rhodium-catalyzed asymmetric hydrogenation of nicotinates. Subsequently, the group of Rueping documented the first enantioselective organocatalytic transfer hydrogenation of 3-cyanoor carbonyl-substituted pyridines using Hantzsch esters as hydrogen sources, and our group also employed [{Ir(cod)Cl}2]/(S)-MeO-biphep/I2 catalyst system for asymmetric hydrogenation of specific pyridines with excellent enantioselectivities. Additionally, an elegant asymmetric hydrogenation of activated pyridines, that is, N-iminopyridinium ylides, was developed by Charette et al. As chiral piperidines are important building blocks for the synthesis of biologically active molecules and natural products, the development of an efficient strategy for the highly challenging hydrogenation of the simple pyridines is still of great significance. Iminium salts generally exhibit higher activity than the corresponding imines in hydrogenation, therefore we envisioned that the activation of simple pyridines as the corresponding N-benzyl-pyridinium bromides would effectively eliminate coordination ability of the substrate and thus the reactivity could be greatly enhanced. Moreover, the stoichiometric amount of hydrogen bromide generated in situ would effectively inhibit the coordination ability of the desired product through the formation of its piperidine hydrogen bromide salt (Scheme 1). Also, the benzyl protecting groups could be conveniently removed by hydrogenolysis. Herein, we disclose the iridium-catalyzed asymmetric hydrogenation of 2-substituted pyridinium salts with excellent enantioselectivity.

An Enantioselective Approach to 2,3-Disubstituted Indolines through Consecutive Brønsted Acid/Pd-Complex-Promoted Tandem Reactions

Tandem reactions and consecutive catalysis (or relay catalysis) have been receiving considerable attention in organic synthesis due to their abilities of constructing multiple new chemical bonds to build complex chiral molecules in a single operation. Transition-metal-catalyzed asymmetric hydrogenation is one of the most widely used and reliable catalytic methods for preparation of chiral molecules. The combination of Brønsted acid/transition-metal-catalyzed tandem reactions involving asymmetric hydrogenation as key step remains rare, although Krische and co-workers reported the C C bond formation with metal hydride as the catalytic species. Chiral 2,3-disubstituted indolines are significant building blocks in biologically active natural products and pharmaceutically active compounds. Generally, these compounds are synthesized from either dynamic resolution or multiplestep reactions. The most straightforward and atom economic means towards chiral indolines may be the asymmetric hydrogenation of substituted indole derivatives. Recently, some significant progress has been achieved by us and other groups for the highly enantioselective hydrogenation of substituted indoles using chiral Pd, Rh, Ru, and Ir complexes as catalysts. Very recently, we developed a facile approach to chiral 2,3-disubstituted indolines through dehydration-triggered asymmetric hydrogenation of 3-(a-hydroxyalkyl)indoles. Despite these contributions, the tedious procedure for the preparation of the substrates limits its synthetic applications. So, the search for a rapid, simple, and divergent method for synthesizing chiral 2,3-disubstituted indolines is still highly desirable. Considering reductive alkylation (Friedel–Crafts/dehydration/reduction) of 2-substituted indoles and aldehydes can rapidly lead to 2,3-disubstituted indoles, we envisioned that combination of reductive alkylation of 2-substituted indoles and asymmetric hydrogenation of 2,3-disubstituted indoles can lead to a rapid and divergent approach to chiral 2,3-disubstituted indolines (Scheme 1). Herein, we describe the enantioselective access to chiral 2,3-disubstituted indolines through consecutive Brønsted acid/Pd-complex-

Regioselective hydroacylation of 1,3-dienes by cobalt catalysis.

We describe a cobalt-catalyzed hydroacylation of 1,3-dienes with non-chelating aldehydes. Aromatic aldehydes provide 1,4-addition products as the major isomer, while aliphatic aldehydes favor 1,2-hydroacylation products. The kinetic profile supports an oxidative cyclization mechanism involving a cobaltacycle intermediate that undergoes transformation with high regio- and stereoselectivity.

Enantioselective Pd-catalyzed hydrogenation of fluorinated imines: facile access to chiral fluorinated amines.

An enantioselective hydrogenation of simple fluorinated imines has been developed using Pd(OCOCF(3))(2)/(R)-Cl-MeO-BIPHEP as a catalyst, and up to 94% ee was achieved. This method provides an efficient route to enantioenriched fluorinated amines.

Rhodium-Catalyzed Enantioselective Hydroamination of Alkynes with Indolines

The hydroamination of internal alkynes via tandem rhodium catalysis gives branched N-allylic indolines with high regio- and enantioselectivity. An acid switch provides access to the linear isomer in preference to the branched isomer by an isomerization mechanism. Mechanistic studies suggest formation of an allene intermediate, which undergoes hydroamination to generate allylic amines instead of the enamine or imine products typically observed in alkyne hydroaminations.