Asymmetric Dearomatization Reaction Research Articles

Chiral Brønsted Acid-Catalyzed Intramolecular Asymmetric Dearomatization Reaction of Indoles with Cyclobutanones via Cascade Friedel-Crafts/Semipinacol Rearrangement.

The highly efficient synthesis of chiral indolines fused with an azabicyclo[2.2.1]heptanone moiety is achieved by an asymmetric dearomatization reaction of indoles with cyclobutanones. A new chiral imidodiphosphorimidate (IDPi) catalyst is synthesized and exhibits extraordinary activity in promoting a cascade Friedel-Crafts/semipinacol rearrangement. Target molecules are prepared in good yields (up to 95%) with excellent enantioselectivity (up to 98% ee) with operational convenience. Combined experimental and computational studies provide detailed mechanistic insights into the energy landscape and origin of the stereochemical induction of the reaction.

Catalytic Asymmetric Dearomative [2 + 2] Photocycloaddition/Ring-Expansion Sequence of Indoles with Diversified Alkenes.

Developing novel strategies for catalytic asymmetric dearomatization (CADA) reactions is highly valuable. Visible light-mediated photocatalysis is demonstrated to be a powerful tool to activate aromatic compounds for further synthetic transformations. Herein, a catalytic asymmetric dearomative [2 + 2] photocycloaddition/ring-expansion sequence of indoles with simple alkenes was reported, providing a facile access to enantioenriched cyclopenta[b]indoles with good to high yields and enantioselectivities by means of chiral lanthanide photocatalysis. This protocol exhibited a broad substrate scope and good functional group tolerance, as well as potential applications in the synthesis of bioactive molecules. Mechanistic studies, including control experiments, UV-vis absorption spectroscopy, emission spectroscopy, and DFT calculations, were carried out, shedding insights into the reaction mechanism and the origin of enantioselectivity.

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Catalytic Asymmetric Cascade Dearomatization of Indoles via a Photoinduced Pd‐Catalyzed 1,2‐Bisfunctionalization of Butadienes

AbstractPhotoinduced Pd‐catalyzed bisfunctionalization of butadienes with a readily available organic halide and a nucleophile represents an emerging and attractive method to assemble versatile alkenes bearing various functional groups at the allylic position. However, enantiocontrol and/or diastereocontrol in the C−C or C−X bond‐formation step have not been solved due to the open‐shell process. Herein, we present a cascade asymmetric dearomatization reaction of indoles via photoexcited Pd‐catalyzed 1,2‐biscarbonfunctionalization of 1,3‐butadienes, wherein asymmetric control on both the nucleophile and electrophile part is achieved for the first time in photoinduced bisfunctionalization of butadienes. This method delivers structurally novel chiral spiroindolenines bearing two contiguous stereogenic centers with high diastereomeric ratios (up to >20 : 1 dr) and good to excellent enantiomeric ratios (up to 97 : 3 er). Experimental and computational studies of the mechanism have confirmed a radical pathway involving excited‐state palladium catalysis. The alignment and non‐covalent interactions between the substrate and the catalyst were found to be essential for stereocontrol.

Catalytic Asymmetric Cascade Dearomatization of Indoles via a Photoinduced Pd-Catalyzed 1,2-Bisfunctionalization of Butadienes.

Photoinduced Pd-catalyzed bisfunctionalization of butadienes with a readily available organic halide and a nucleophile represents an emerging and attractive method to assemble versatile alkenes bearing various functional groups at the allylic position. However, enantiocontrol and/or diastereocontrol in the C-C or C-X bond-formation step have not been solved due to the open-shell process. Herein, we present a cascade asymmetric dearomatization reaction of indoles via photoexcited Pd-catalyzed 1,2-biscarbonfunctionalization of 1,3-butadienes, wherein asymmetric control on both the nucleophile and electrophile part is achieved for the first time in photoinduced bisfunctionalization of butadienes. This method delivers structurally novel chiral spiroindolenines bearing two contiguous stereogenic centers with high diastereomeric ratios (up to >20 : 1 dr) and good to excellent enantiomeric ratios (up to 97 : 3 er). Experimental and computational studies of the mechanism have confirmed a radical pathway involving excited-state palladium catalysis. The alignment and non-covalent interactions between the substrate and the catalyst were found to be essential for stereocontrol.

Asymmetric dearomatization of benzyl 1-naphthyl ethers via [1,3] O-to-C rearrangement.

A catalytic asymmetric dearomatization reaction of benzyl 1-naphthyl ethers accelerated by a chiral N,N'-dioxide/Co(II) complex is disclosed. The reaction proceeds via an enantioselective [1,3] O-to-C rearrangement through a tight ion-pair pathway, providing a wide array of α-naphthalenone derivatives bearing an all-carbon quaternary center in high yields with excellent ee values.

Catalytic asymmetric dearomatization of phenols via divergent intermolecular (3 + 2) and alkylation reactions.

The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers.

Catalytic Asymmetric Synthesis of Aza-Quaternary Carbon Cyclohexadieneones Enabled by Aminative Dearomatization of Phenols.

Reported herein is the catalytic asymmetric aminative dearomatization reaction of common phenols. As opposed to the well-studied indoles and naphthols, phenols are supposed to be challenging substrates for catalytic asymmetric dearomatization reactions in terms of their strong aromaticity and regioselectivity issues. Under the catalysis of a chiral phosphoric acid, the C4-regiospecific aminative dearomatization of phenols with azodicarboxylates readily occurred at ambient temperature, delivering an array of biologically and synthetically important aza-quaternary carbon cyclohexadieneones in good yields and with excellent enantioselectivities (29 examples, up to 98% yield, and >99% ee).

Organocatalytic Asymmetric Dearomatization Reaction for the Construction of Axially Chiral Urazole Embedded Naphthalenones

AbstractHerein we disclose a catalytic asymmetric dearomatization reaction of β‐naphthols with 4‐aryl‐1,2,4‐triazole‐3,5‐diones. A chiral phosphoric acid with spiro motif was found to be effective for this reaction. The chiral urazole embedded naphthalenones having both axial and central chirality were obtained in good to high yields (70–85%) with high diastereo‐ and enantioselectivities (>20:1, 8–96% ees), having C−N rotational energy barrier 31.54 K.Cal.mol−1 and t1/225 °C=589.8 years. The scope of the reaction was broad and few applications including a bromo‐amination reaction have been demonstrated.magnified image

Recent Advances in Asymmetric Dearomatization Reactions Induced by Chiral Hypervalent Iodine Reagents

Recent Advances in Asymmetric Dearomatization Reactions Induced by Chiral Hypervalent Iodine Reagents

Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions

Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions

Chemo-, regio- and enantioselective dearomative (3+2) reaction of non-functionalized 1-naphthols

The catalytic asymmetric dearomatization reaction of non-functionalized arenes poses a long-standing synthetic challenge to organic chemists because of the relative ease of rearomatization via the departure of a proton. In this work, the direct dearomatization of non-functionalized 1-naphthols was achieved through a phosphoric acid-catalyzed asymmetric (3+2) annulation reaction with azoalkenes. The reported convergent method allows the use of readily available simple 1-naphthols without pre-functionalization under mild conditions, furnishing a variety of tricyclic hexahydrobenz[e]indole derivatives in good yields and excellent enantioselectivities (75%–96% yields and 92%–99% ee). Density functional theory (DFT) calculations were performed to gain insights into the origins of the observed chemo-, regio-, and enantioselectivities. It is noteworthy that using azoalkenes as 1,3-dipole surrogates, in combination with powerful chiral phosphoric acid (CPA) catalysis, was key to the success of current reaction.

A tandem asymmetric oxidation-oxa-Michael sequence for dearomatization of β-naphthols

A catalytic asymmetric hydroxylative dearomatization reaction has been disclosed, and the products can smoothly transform into spiroannulation adducts by simply treated with a base under mild conditions. Novel in-situ generated magnesium catalytic methods are developed by application of combinational ligands. Related concise transformaitons of the spiroannulation adducts have been carried out.

Asymmetric Direct/Stepwise Dearomatization Reactions Involving Hypervalent Iodine Reagents.

A remarkable growth in hypervalent iodine-mediated oxidative transformations as stoichiometric reagents as well as catalysts has been well-documented due to their excellent properties, such as mildness, easy handling, high selectivity, environmentally friendly nature, and high stability. This review aims at highlighting the asymmetric oxidative dearomatization reactions involving hypervalent iodine compounds. The present article summarizes asymmetric intra- and intermolecular dearomatization reactions using chiral hypervalent iodine reagents/catalysts as well as hypervalent iodine-mediated dearomatization reactions followed by desymmetrization.

Asymmetric dearomatization catalysed by chiral Brønsted acids via activation of ynamides.

Chiral Brønsted acid-catalysed asymmetric synthesis has received tremendous interest over the past decades, and numerous efficient synthetic methods have been developed based on this approach. However, the use of chiral Brønsted acids in these reactions is mostly limited to the activation of imine and carbonyl moieties, and the direct activation of carbon-carbon triple bonds has so far not been invoked. Here we show that chiral Brønsted acids enable the catalytic asymmetric dearomatization reactions of naphthol-, phenol- and pyrrole-ynamides by the direct activation of alkynes. This method leads to the practical and atom-economic construction of various valuable spirocyclic enones and 2H-pyrroles that bear a chiral quaternary carbon stereocentre in generally good-to-excellent yields with excellent chemo-, regio- and enantioselectivities. The activation mode of chiral Brønsted acid catalysis revealed in this study is expected to be of broad utility in catalytic asymmetric reactions that involve ynamides and the related heteroatom-substituted alkynes.

Organocatalytic Asymmetric Dearomatization Reaction for the Synthesis of Axial Chiral Allene-Derived Naphthalenones Bearing Quaternary Stereocenters.

The highly regio-, diastereo-, and enantioselective dearomatization reaction of 1-substituted 2-naphthols and β,γ-alkynyl-α-imino esters with complete atom economy is disclosed via chiral phosphoric acid catalysis. This protocol provides facile and efficient access to asymmetric construction of a broad range of axially chiral allene-derived naphthalenones bearing quaternary stereocenters in good yields with high diastereoselectivities and enantioselectivities.

Silver‐Catalyzed Asymmetric Dearomatization of Electron‐Deficient Heteroarenes via Interrupted Barton–Zard Reaction

AbstractHerein we report a catalytic asymmetric dearomatization reaction of electron‐deficient heteroarenes with α‐substituted isocyanoacetates through an interrupted Barton–Zard reaction. A range of optically active pyrrolo[3,4‐b]indole derivatives was obtained in good yields (up to 97 %) with high stereoselectivities (up to >20:1 dr and 97 % ee), using a catalytic system consisting of a cinchona‐derived amino‐phosphine and silver oxide. This reaction features wide substrate scope and mild conditions, and provides a new strategy for developing asymmetric dearomatization reactions.

Silver‐Catalyzed Asymmetric Dearomatization of Electron‐Deficient Heteroarenes via Interrupted Barton–Zard Reaction

Herein we report a catalytic asymmetric dearomatization reaction of electron-deficient heteroarenes with α-substituted isocyanoacetates through an interrupted Barton-Zard reaction. A range of optically active pyrrolo[3,4-b]indole derivatives was obtained in good yields (up to 97 %) with high stereoselectivities (up to >20:1 dr and 97 % ee), using a catalytic system consisting of a cinchona-derived amino-phosphine and silver oxide. This reaction features wide substrate scope and mild conditions, and provides a new strategy for developing asymmetric dearomatization reactions.

Advances in Catalytic Asymmetric Dearomatization.

Asymmetric catalysis has been recognized as the most enabling strategy for accessing chiral molecules in enantioenriched forms. Catalytic asymmetric dearomatization is an emerging and dynamic research subject in asymmetric catalysis, which has received considerable attention in recent years. The direct transformations from readily available aromatic feedstocks to structurally diverse three-dimensional polycyclic molecules make catalytic asymmetric dearomatization reactions of broad interest for both organic synthesis and medicinal chemistry. However, the inherent difficulty for the disruption of aromaticity demands a large energy input during the dearomatization process, which might be incompatible with the conditions generally required by asymmetric catalysis. In this Outlook, we will discuss representative strategies and examples of catalytic asymmetric dearomatization reactions of various aromatic compounds and try to convince readers that by overcoming the above obstacles, catalytic asymmetric dearomatization reactions could advance chemical sciences in many respects.

Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions.

We summarize in this review the recent development of chiral phosphoric acid (CPA)-catalyzed asymmetric dearomatization reactions. A wide array of electron-rich arenes (indoles, phenols, naphthols, benzothiophenes, benzofurans, etc.) and electron-poor arenes (pyridines, quinolines, isoquinolines, etc.) has been proved reactive towards various reaction partners in the presence of a CPA catalyst, enabling asymmetric dearomatization reactions that lead to structurally-diverse polycyclic molecules. The reactions are grouped according to the roles of the arenes in the reactions (as nucleophiles or electrophiles) and the types of reaction partners. This review closes with a personal perspective on the dynamic research area of asymmetric dearomatization reactions by CPAs.