Transition-Metal-Catalyzed Asymmetric Allylic Dearomatization Reactions

Abstract

Dearomatization reactions serve as powerful methods for the synthesis of highly functionalized, three-dimensional structures starting with simple planar aromatic compounds. Among processes of this type, catalytic asymmetric dearomatization (CADA) reactions are attractive owing to the large number of aromatic compounds that are readily available and the fact that they enable direct access to enantiopure polycycles and spirocycles, which frequently are key structural motifs in biologically active natural products and pharmaceuticals. However, as a consequence of their high stabilities, arenes only difficultly participate in dearomatization reactions that take place with high levels of enantioselectivity. Transition-metal-catalyzed asymmetric allylic substitution reactions have been demonstrated to be powerful methods for enantioselective formation of C-C and C-X (X = O, N, S, etc.) bonds. However, the scope of these processes has been explored mainly using soft carbon nucleophiles, some hard carbon nucleophiles such as enolates and preformed organometallic reagents, and heteroatom nucleophiles. Readily accessible aromatic compounds have been only rarely used directly as nucleophiles in these reactions. In this Account, we present the results of studies we have conducted aimed at the development of transition-metal-catalyzed asymmetric allylic dearomatization reactions. By utilizing this general process, we have devised methods for direct dearomatization of indoles, pyrroles, phenols, naphthols, pyridines, and pyrazines, which produce various highly functionalized structural motifs bearing all-carbon quaternary stereogenic centers in a straightforward manner. In mechanistic investigations of the dearomatization process, we found that the five-membered spiroindolenines serve as intermediates, which readily undergo stereospecific allylic migration to form corresponding tetrahydro-1H-carbazoles upon treatment with a catalytic amount of TsOH. It is worth noting that no notable loss of the enantiomeric excess of the spiroindolenine derivatives takes place during the rearrangement process as a consequence of the intervention of a "three-center-two-electron"-type transition state, a proposal that has gained support from the results of DFT calculations. Equally intriguing, upon tuning of the electronic nature of the tethers, pyrroles or indoles undergo unprecedented Ir or Ru catalyzed intramolecular allylic alkylation promoted dearomatization/migration reactions. The operation of this novel reaction pathway provides additional information leading to a greater mechanistic understanding of the transition-metal-catalyzed enantioselective intramolecular functionalizations of pyrroles and indoles. The combined results of this effort provide not only methods for the efficient synthesis of highly enantioenriched fused and spiro polycycles but also novel strategies in the field of asymmetric catalysis.

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

“…Very recently, isolation and full characterization of the key aza-spiroindolenine intermediates were accomplished by further tuning of the electronic property of the N-tether. 27 Subjecting racemic N-Ts-tethered indol-3-yl allylic carbonate (rac)-13 to similar reaction conditions led to three isolatable diastereomers of aza-spiroindolenine intermediates (14), whose structures were confirmed by X-ray crystallographic analysis. A set of improved reaction Scheme 2.…”

Highly Regio‐ and Enantioselective Synthesis of N‐Substituted 2‐Pyridones: Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination

“…[7] Despite the significant progress made with transition-metalcatalyzed allylic dearomatization reactions, [8] only recently has the strategy been found to be compatible with electrondeficient arenes. [7] Despite the significant progress made with transition-metalcatalyzed allylic dearomatization reactions, [8] only recently has the strategy been found to be compatible with electrondeficient arenes.…”

Palladium‐Catalyzed Dearomative Cyclocarbonylation by CN Bond Activation

“…[7] Our investigations began with the direct cyclocarbonylation of N,N-diisopropyl-3-(pyridin-2-yl)prop-2-en-1-amine (1a)intoluene by palladium catalysis under CO atmosphere at 120 8 8C( Table 1). After an extensive screening of catalysts, to our great delight, the desired product 2a was obtained in 67 %y ield in the presence of ac atalytic amount of PdI 2 (5 mol %) and CO (10 atm).…”

“…Inspired by this promising lead, we next sought to improve the efficiencyo f the reaction. Va rious phosphine ligands were then screened in combination with PdI 2 as the catalyst precursor,a nd the transformation was found to be sensitive to the bite angle of the bis(phosphine) ligand (entries [7][8][9][10][11][12][13][14].…”

“…[7] We reasoned that the dearomatization process could be further enhanced in the presence of CO,o wing to the lower electron density at Pd(CO). [8] Moreover,COwould prefer to insert into the less hindered planar pyridyl N À Pd bond, and the R 2 N À moiety contained in metal complex II could then act as an intramolecular base to promote the subsequent Heck reaction.…”