Iridium-Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Pyridines, Pyrazines, Quinolines, and Isoquinolines

Abstract

The first Ir-catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines, pyrazines, quinolines, and isoquinolines has been developed. Enabled by in situ formed chiral Ir-catalyst, the dearomatized products were isolated in high levels of yield (up to 99% yield) and enantioselectivity (up to 99% ee). It is worth noting that the Me-THQphos ligand is much more efficient than other tested ligands for the dearomatization of pyrazines and certain quinolines. Mechanistic studies of the dearomatization reaction were carried out, and the results suggest the feasibility of an alternative process which features the formation of a quinolinium as the key intermediate. The mechanistic findings render this reaction a yet unknown type in the chemistry of Reissert-type reactions. In addition, the utility of this method was showcased by a large-scale reaction and formal synthesis of (+)-gephyrotoxin.

Catalytic Asymmetric Dearomatization by Transition-Metal Catalysis: A Method for Transformations of Aromatic Compounds

“…However, our recent research efforts demonstrated that electron-deficient arenes could also be involved in asymmetric allylic dearomatization reactions (Scheme 13). 45,46 In our mechanistic design plan, allylic carbonates 54 derived from pyridines, pyrazines, quinolines, and isoquinolines first react with chiral Ir catalyst to yield the corresponding p-allyliridium intermediates. The concomitantly generated methoxide anion abstracts the acidic a-proton in the substrates, making the nitrogen in the heterocycle a strong nucleophilic site as a result of the resonance of the negative charge (path a).…”

“…Ir-Catalyzed Asymmetric Allylic Dearomatization of Electron-Deficient Arenes Originally reported by the You group. 45,46 intermediate VI could be isolated or captured by in situ transformation. In addition, the synthetic utility of this reaction was also demonstrated by a facile synthesis of compound 56, which is a key intermediate in the synthesis of (+)-gephyrotoxin.…”

Basic approaches to the synthesis of pyrrolo[1,2-a]quinolines derivatives: a review

“…A further direction of research was developed in the study of complexes of transition metals, such as Pd [23][24][25], Cu [26][27][28][29][30][31], Cu/Pd [32], Rh [33], Ir [34], Pt [35], Fe/Au [36], Sm [37], Ce [38], etc. They are used as catalysts for the derivation of pyrrolo[1,2-a]quinoline derivatives; however, despite their potential utility, none of these procedures can directly provide end products with a lack of heavy metal admixtures [39][40][41][42].…”

Iridium‐Catalyzed Intramolecular Asymmetric Allylic Dearomatization Reaction of Benzoxazoles, Benzothiazoles, and Benzimidazoles

“…However,e nantiomerically pure small molecules have attracted increasing attention from medicinal chemists owing to their versatile interaction modes and tremendous potential in drug development. [11,12] However,t he successful cases were limited to six-membered-ring nitrogen-containing aromatic compounds,s uch as pyridines,p yrazines,q uinolines, and isoquinolines.T he dearomatization of five-memberedring Nheteroaromatic compounds had not been explored. [4] Meanwhile,dearomatized structures of benzoxazoles,benzothiazoles,a nd benzimidazoles are found as core skeletons in natural products (e.g.s trellidimine;S cheme 1) and biologically active small molecules (Scheme 1A-C).…”

“…[5][6][7][8] During our research on the development of transitionmetal-catalyzed allylic dearomatization reactions, [9] which are ap owerful class of catalytic asymmetric dearomatization (CADA) reactions, [10] we recently realized iridium-catalyzed allylic dearomatization reactions of electron-deficient Nheteroaromatic compounds. [11,12] However,t he successful cases were limited to six-membered-ring nitrogen-containing aromatic compounds,s uch as pyridines,p yrazines,q uinolines, and isoquinolines.T he dearomatization of five-memberedring Nheteroaromatic compounds had not been explored. [13] Herein we report the successful application of the iridiumcatalyzed asymmetric allylic dearomatization strategy to various five-membered-ring nitrogen-containing aromatic compounds,i ncluding benzoxazoles,b enzothiazoles,a nd benzimidazoles.…”