Synthesis of 3-propargyl isoindolinones by Pd/Cu-catalyzed enantioselective Heck/Sonogashira reaction of enamides.

Herein, we report an enantioselective Pd/Cu-catalyzed sequential Heck/Sonogashira coupling reaction of electron-rich enamides with terminal alkynes as substrates. This transformation proceeds smoothly to afford 3-propargyl isoindolinone derivatives bearing quaternary stereogenic centers in moderate to good yields (43-77% yield) and good to excellent enantioselectivity (up to 93% ee). Functional groups such as halogen atoms (F, Cl, and Br), thienyl, and silyl moieties are tolerated well.

Cobalt-Catalyzed Intramolecular Enantioselective Reductive Heck Reaction toward the Synthesis of Chiral 3-Trifluoromethylated Oxindoles.

Herein, a cobalt-catalyzed intramolecular enantioselective reductive Heck reaction is disclosed. Starting from --iodoaryl-2-(trifluoromethyl)acrylamides, a plethora of chiral oxindoles bearing trifluoromethylated quaternary stereogenic centers at the C3-position are achieved in moderate to good yields (up to 88% yield) and good to excellent enantioselectivities (up to 94% ee) by employing zinc/silane as reducing agent. Other than the trifluoromethyl group, a number of chiral oxindoles bearing alkyl, aryl, and ester groups at C3-position were also obtained albeit in relatively lower enantioselectivities (68-78% ee).

Copper-Catalyzed Dearomative [3 + 2] Annulation of Indoles with 2-Iodoacetic Acid.

An efficient copper-catalyzed dearomative [3 + 2] annulation of indoles with 2-iodoacetic acid is developed. By employing Cu(OTf)/2,2'-bis(2-oxazoline) as the catalyst and LPO as the oxidant, a series of indoline-fused butyrolactones were synthesized in moderate to good yields. The reaction features mild conditions, a broad substrate scope, and readily available starting materials.

Copper-catalyzed asymmetric 1,2-arylboration of enamines: access to chiral borate-containing 3,3'-disubstituted isoindolinones.

An enantioselective copper-catalyzed 1,2-arylboration reaction of enamines has been developed by employing ()-xyl-BINAP as a chiral ligand. A number of chiral borate-containing 3,3'-disubstituted isoindolinones were obtained in moderate to good yields and good to excellent enantioselectivities from the reactions of -(-iodobenzoyl)enamines and bis(pinacolato)diboron (Bpin) under mild reaction conditions. Synthetic transformations of the products were conducted to demonstrate the practicality of this reaction.

Pd-Catalyzed Enantioselective Desymmetrizing 1,7-Enyne Cycloisomerization of Alkyne-Tethered Cyclopentenes.

An enantioselective Pd-catalyzed intramolecular desymmetrizing cycloisomerization of -(cyclopent-3-en-1-yl)propiolamides has been developed by employing a new chiral phosphoramidite ligand. A series of structurally unique bridged azabicycles are achieved in moderate to excellent yields with good / selectivity and high enantioselectivity. Synthetic transformations are conducted to demonstrate the practical utility of this reaction.

Pd-Catalyzed Asymmetric Intramolecular Dearomatizing Reductive Heck Reaction of Indoles.

An enantioselective Pd-catalyzed intramolecular dearomative reductive Heck reaction of -(-bromoaryl) indole-3-carboxamide is developed. By employing Pd(dba)/SPINOL-based phosphoramidite as the chiral catalyst and HCONa as the hydride source, a series of enantioenriched spiro indolines bearing vicinal stereocenters were afforded in moderate to good yields with excellent enantioselectivities. The reductive Heck reaction of formal tetrasubstituted alkene bearing β-hydrogens is therefore realized by inhibiting β-H elimination.

Copper-catalyzed intramolecular dearomative aza-Wacker reaction of indole.

Herein, we describe a copper-catalyzed intramolecular dearomative amination of indoles a formal aza-Wacker reaction. This protocol provides an efficient method to access aza-polycyclic indoline molecules bearing exocyclic CC bonds in moderate to excellent yields in the presence of molecular oxygen as an oxidant. It is worth noting that indolin-3-ones are achieved when employing C3-non-substituted indoles as substrates.

Palladium-Catalyzed Dearomative Heck/Suzuki Coupling of C2-Deuterated or C2-Nonsubstituted Indoles.

A palladium-catalyzed dearomative diarylation of C2-deuterated or C2-nonsubstituted indoles through domino Heck/Suzuki coupling is established. Relying on electron-deficient phosphite ligand, side reactions including intermolecular Suzuki coupling and intramolecular C-D/H arylation are inhibited and a wide range of 2,3-diarylated indolines bearing vicinal tertiary stereocenters including deuterated ones are afforded in moderate to excellent yields (up to 94%) and excellent diastereoselectivities (>20:1). The catalyst loading can be lowered to 0.

Pd-Catalyzed Intramolecular Dearomative [4 + 2] Cycloaddition of Naphthalenes with Arylalkynes.

A Pd-catalyzed intramolecular dearomative [4 + 2] cycloaddition reaction of naphthalenes with arylalkynes is developed. The protocol provides a straightforward method to access a range of polycyclic dihydronaphthalenes containing two vicinal all-carbon stereocenters in moderate yields under mild conditions in an air atmosphere. The deuterium labeling experiment suggests a pathway involving electrophilic dearomatization followed by Friedel-Crafts cyclization.

Nickel-Catalyzed Enantioselective Dearomative Heck-Reductive Allylic Defluorination Reaction of Indoles.

Herein, we describe a nickel-catalyzed asymmetric dearomative aryl-difluoroallylation reaction of indoles with α-trifluoromethyl alkenes as an electrophilic coupling partner. The reaction proceeds via a cascade sequence involving dearomative Heck cyclization and reductive allylic defluorination. A series of -difluoroallyl substituted indolines are obtained in moderate to good yields (36-77% yield) with excellent enantioselectivity (up to 99% ee).

Cobalt-catalyzed enantioselective desymmetrizing reductive cyclization of alkynyl cyclodiketones.

A highly enantioselective cobalt-catalyzed desymmetrizing reductive cyclization of alkynyl cyclodiketones has been developed. Under mild reaction conditions by employing HBpin as a reducing agent and ferrocene-based PHOX as a chiral ligand, a series of polycyclic tertiary allylic alcohols bearing contiguous quaternary stereocenters are achieved in moderate to excellent yields with excellent enantioselectivities (up to 99%). Broad substrate scope and high functional group compatibility are observed in this reaction.

Dearomatizing [2+2+1] Spiroannulation of Indoles with Alkynes.

A palladium-catalyzed dearomatizing [2+2+1] spiroannulation of indoles with two molecular internal alkynes is developed in the presence of Cu(OAc)/O as the oxidant, in which a domino sequence including C-H activation of indole followed by consecutive Heck reactions is involved. A range of 3,3'-spiroindolines bearing tetrasubstituted cyclopentadiene moieties and exocyclic C═C bonds at C2 are obtained in moderate to excellent yields.

Enantioselective Pd-catalyzed dearomative reductive Heck and domino Heck-Suzuki reactions of 2-CF-indoles.

Highly enantioselective palladium-catalyzed dearomative reductive Heck reaction and domino Heck-Suzuki reaction of 2-CF-indoles have been developed. Using Pd(OAc)/()-Synphos as the catalyst and EtSiH as a hydride source, a variety of indolines bearing a 2-trifluoromethyl quaternary stereocenter were obtained a dearomative reductive Heck reaction. Alternatively, using Pd(dba)/phosphoramidite as the catalyst and ArBNa as a coupling partner, structurally diverse indolines containing two vicinal carbon stereocenters were afforded through the domino dearomative Heck-Suzuki reaction.

Aromatic π-Components for Enantioselective Heck Reactions and Heck/Anion-Capture Domino Sequences.

Olefin functionalization represents one of the most important synthetic transformations in organic synthesis. Over the past decades, palladium-catalyzed enantioselective Heck reactions, and Heck/anion-capture domino sequences through olefin carbopalladation followed by termination of the resulting alkyl-Pd species have been extensively developed. Extension of the coupling partners from classical olefins to other π-components would enable further advances and open new space in this field.

Enantioselective Dearomative [3 + 2] Umpolung Annulation of -Heteroarenes with Alkynes.

Enantioselective [3 + 2] annulation of -heteroarenes with alkynes has been developed via a cobalt-catalyzed dearomative umpolung strategy in the presence of chiral ligand and reducing reagent. A variety of electron-deficient -heteroarenes, including quinolines, isoquinolines, quinoxaline, and pyridines, and internal or terminal alkynes are employed in this reaction, showing a broad substrate scope and good functionality tolerance. Annulation of electron-rich indoles with alkynes is also developed.

Palladium-Catalyzed Enantioselective Heteroarenyne Cycloisomerization Reaction.

The extensively developed ene-type enantioselective cycloisomerization of classical 1,n-enynes provides an efficient approach to chiral cyclic 1,4-dienes. In contrast, the catalytic asymmetric heteroarenyne (heteroarene-alkyne) cycloisomerization involving the dearomative transformation of endocyclic aromatic C=C bonds remains unknown. Herein, we communicate a PdH-catalyzed enantioselective heteroarenyne cycloisomerization reaction of alkyne-tethered indole substrates (formal 1,5- and 1,6-enynes).

Dearomative 1,4-difunctionalization of naphthalenes via palladium-catalyzed tandem Heck/Suzuki coupling reaction.

Dearomative functionalization reactions represent an important strategy for the synthesis of valuable three-dimensional molecules from simple planar aromatics. Naphthalene is a challenging arene towards transition-metal-catalyzed dearomative difunctionalization reactions. Reported herein is an application of naphthalene as a masked conjugated diene in a palladium-catalyzed dearomative 1,4-diarylation or 1,4-vinylarylation reaction via tandem Heck/Suzuki sequence.

3,3'-Disubstituted Oxindoles Formation via Copper-Catalyzed Arylboration and Arylsilylation of Alkenes.

Arylboration and arylsilylation reactions of -(2-iodoaryl)acrylamides with bis(pinacolato)-diboron (Bpin) or PhMeSi-Bpin are developed by using simple CuOAc as the sole catalyst. A range of boron- or silane-bearing 3,3'-disubstituted oxindoles are obtained in moderate to excellent yields. The reaction is proposed to proceed via a domino sequence involving intermolecular olefin borylcupration or silylcupration followed by intramolecular coupling of an alkyl-Cu intermediate with aryl iodide.

A Pd-catalyzed domino Larock annulation/dearomative Heck reaction.

A palladium-catalyzed domino Larock annulation/dearomative Heck reaction is developed, which delivers a range of tetracyclic indoline derivatives in moderate to excellent yields through a Larock annulation of N-bromobenzoyl o-iodoanilines with alkynes and a subsequent intramolecular dearomative Heck reaction. This protocol provides a straightforward route to structurally diverse indolines from readily available starting materials by forming two new rings and three chemical bonds in a single step.

Synthesis of tetracyclic indolin-3-ones through Pd-catalyzed intramolecular deacetylative dearomatization of 3-acetoxy-indoles.

An efficient palladium-catalyzed intramolecular deacetylative dearomatization reaction of 3-acetoxyindoles has been developed. A range of tetracyclic indolin-3-ones bearing C2-quaternary stereocenters are achieved in good yields, showing a wide substrate scope for this reaction. A preliminary enantioselective reaction is established to furnish the product in 63% ee by using (,,)-phosphoramide-PE as a chiral ligand.

Domino Reaction between Nitrosoarenes and Ynenones for Catalyst-Free Preparation of Indanone-Fused Tetrahydroisoxazoles.

A catalyst-free domino reaction to synthesize highly functionalized indanone-fused tetrahydroisoxazole from easily accessed nitrosoarene and 1,6-ynenone with good chemo- and regioselectivity was disclosed. This unprecedented domino reaction represents a new strategy for multifunctionalization of an internal alkyne with nitrosoarene by formation of two rings and four bonds in a single operation.

Palladium-Catalyzed Enantioselective Intramolecular Dearomative Heck Reaction.

Enantioselective intramolecular dearomative Heck reactions have been developed by Pd-catalyzed cross-coupling of aryl halides or aryl triflates with the internal C═C bond of indoles, benzofurans, pyrroles, and furans. A variety of structurally unique spiroheterocycles and benzofused heterocycles having N/O-substituted quaternary carbon stereocenters, and exocyclic olefin moieties were afforded in moderate to excellent yields with good to excellent enantioselectivities, showing a broad scope of the present protocol. A series of new BINOL- and H8-BINOL-based phosphoramidite ligands were synthesized and proved to be efficient chiral ligands in the reactions of C2-tethered substrates to form spiroheterocycles.

Enantioselective Dearomative Difunctionalization of Indoles by Palladium-Catalyzed Heck/Sonogashira Sequence.

Palladium-catalyzed enantioselective dearomative arylalkynylation of N-substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL-based phosphoramidite as the chiral ligand. A wide range of 2,3-disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).

Spirooxindole synthesis via palladium-catalyzed dearomative reductive-Heck reaction.

Palladium-catalyzed intramolecular dearomative reductive-Heck reaction of C2-substituted indoles is developed, which provides access to structurally diverse 3,2'-spiropyrrolidine oxindoles. By changing the hydride source to AcONa base, direct C3-arylation products [2,3-b]quinolinones are achieved in good yields. The reaction of C2-substituted benzofuran is also realized, delivering the desired spiro-product.

Rapid Access to 2-Methylene Tetrahydrofurans and γ-Lactones: A Tandem Four-Step Process.

A one-pot tandem process involving hydrolysis, Knoevenagel condensation, Michael addition, and Conia-ene (HKMC) reactions has been developed for the rapid synthesis of indanone-fused 2-methylene tetrahydrofurans from the reaction of enynals and propynols. In this process, two rings and four bonds are generated with 100 % atom-economy and high step-efficiency. The resulting tetrahydrofurans were readily oxidized into α-methylene γ-lactones, which are one of the most important substructures in natural and bioactive compounds.