Gold‐Catalyzed Cascade Cyclization of 2‐Alkynyl‐N‐Propargylanilines by Rearrangement of a Propargyl Group

Gold catalysis enables direct construction of tetracyclic fused indolines through the migration of a propargyl substituent from an aniline nitrogen atom to the C3‐position of an indole from 2‐alkynyl‐N‐propargylanilines. This reaction provides rapid access to fused three‐dimensional indolines in a single operation with the formation of four bonds and three rings.     

An efficient approach to fused indolines via a copper(I)-catalyzed reaction of sulfonyl azide with 2-ethynylaryl methylenecyclopropane

A cascade reaction of 2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides a novel and efficient route for the generation of fused indolines.     

Enantioselective synthesis of 2-methyl indolines by palladium catalysed asymmetric C(sp3)-H activation/cyclisation

The first example of the enantioselective methyl C-H activation by an intramolecular ArPdX species and subsequent cyclisation was developed. Palladium catalysts using commercially available chiral diphosphines yield good ee's (up to 93% ee) in the synthesis of 2-methyl indolines from 2-halo N-isopropyl anilides. This approach was also employed for the synthesis of enantioenriched cyclohexyl fused indolines with moderate enantioselectivities.     

Enantioselective gold-catalyzed synthesis of polycyclic indolines

The synthesis of architecturally complex polycyclic fused indolines is achieved in a chemo-, regio-, and stereodefined manner, via an enantioselective gold-catalyzed cascade hydroindolination/iminium trapping synthetic sequence. Highly functionalized tetracyclic fused furoindolines (2) and dihydropyranylindolines (4) are synthesized in moderate to good yields and enantiomeric excesses of up to 87%.     

Intermolecular dearomative oxidative coupling of indoles with ketones and sulfonylhydrazines catalyzed by I2: synthesis of [2,3]-fused indoline tetrahydropyridazines

A convergent construction of [2,3]-fused indoline tetrahydropyridazines via an I₂/tert-butyl hydroperoxide (TBHP) catalyzed three-component dearomative oxidative coupling of indoles, hydrazines and acetophenone was established in moderate to good yields. This protocol provides a new approach for the synthesis of these biologically interesting fused indolines.     

Electrooxidation Enables Selective Dehydrogenative [4+2] Annulation between Indole Derivatives

Dearomative annulation of indoles has emerged as a powerful tool for the preparation of polycyclic indoline‐based alkaloids. Compared with well‐established methods towards five‐membered‐ring‐fused indolines, the six‐membered‐ring‐fused indolines are rarely accessed under thermal conditions. Herein, a dearomative [4+2] annulation between different indoles is developed through an electrochemical pathway. This transformation offers a remarkably regio‐ and stereoselective route to highly functionalized pyrimido[5,4‐b]indoles under oxidant‐ and metal‐free conditions. Notably, this electrochemical approach maintains excellent functional‐group tolerance and can be extended as a modification tactic for pharmaceutical research. Preliminary mechanism studies indicate that the electrooxidation annulation proceeds through radical–radical cross‐coupling between an indole radical cation and an N‐centered radical generated in situ.     

Synthesis of Enantioenriched Indolines by a Conjugate Addition/Asymmetric Protonation/Aza‐Prins Cascade Reaction

A conjugate addition/asymmetric protonation/aza‐Prins cascade reaction has been developed for the enantioselective synthesis of fused polycyclic indolines. A catalyst system generated from ZrCl₄ and 3,3′‐dibromo‐BINOL enables the synthesis of a range of polycyclic indolines in good yields and with high enantioselectivity. A key finding is the use of TMSCl and 2,6‐dibromophenol as a stoichiometric source of HCl to facilitate catalyst turnover. This transformation is the first in which a ZrCl₄?BINOL complex serves as a chiral Lewis‐acid‐assisted Brønsted acid.     

Recent advances in asymmetric synthesis of 2-substituted indoline derivatives

Recent advances in asymmetric synthesis of 2-substituted indoline derivatives are discussed.     

Stereoselective synthesis of tetracyclic indolines via gold-catalyzed cascade cyclization reactions

A reliable synthetic route to fused polycyclic indolines is documented by the development of a stereoselective gold catalyzed cascade cyclization of indole propargylic alcohols.     

Asymmetric Dearomatization of Indole Derivatives with N‐Hydroxycarbamates Enabled by Photoredox Catalysis

Dearomatization of indoles provides efficient synthetic routes for substituted indolines. In most cases, indoles serve as nucleophiles. Reported here is an asymmetric dearomatization reaction of indole derivatives that function as electrophiles. The combination of a photocatalyst and chiral phosphoric acid open to air unlocks the umpolung reactivity of indoles, enabling their dearomatization with N‐hydroxycarbamates as nucleophiles. A variety of fused indolines bearing intriguing oxy‐amines were constructed in excellent yields with moderate to high enantioselectivities. Mechanistic studies show that the realization of two sequential single‐electron transfer oxidations of the indole derivatives is key, generating the configurationally biased carbocation species while providing the source of stereochemical induction. These results not only provide an efficient synthesis of enantioenriched indoline derivatives, but also offer a novel strategy for further designing asymmetric dearomatization reactions.     

Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP

Highly enantioselective hydrogenation of N-protected indoles was successfully developed by use of the rhodium catalyst generated in situ from [Rh(nbd)₂]SbF₆ and the chiral bisphosphine PhTRAP, which can form a trans-chelate complex with a transition metal atom. The PhTRAP–rhodium catalyst required a base (e.g., Cs₂CO₃) for the achievement of high enantioselectivity. Various 2-substituted N-acetylindoles were converted into the corresponding chiral indolines with up to 95% ee. The hydrogenations of 3-substituted N-tosylindoles yielded indolines possessing a stereogenic center at the 3-position with high enantiomeric excesses (up to 98% ee).     

Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine

A ligand‐promoted catalytic [4+2] annulation reaction using indole derivatives and donor‐acceptor (D‐A) cyclobutanes is reported, thus providing an efficient and atom‐economical access to versatile cyclohexa‐fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)‐akuammicine and the formal total synthesis of (±)‐strychnine from the same common‐core scaffold.     

Phosphine‐Catalyzed Enantioselective Dearomative [3+2]‐Cycloaddition of 3‐Nitroindoles and 2‐Nitrobenzofurans

Over the past years, the metal‐catalyzed dearomative cycloaddition of 3‐nitroindoles and 2‐nitrobenzofurans have emerged as a powerful protocol to construct chiral fused heterocyclic rings. However, organocatalytic dearomative reaction of these two classes of heteroarenes has become a long‐standing challenging task. Herein, we report the first example of phosphine‐catalyzed asymmetric dearomative [3+2]‐cycloadditio of 3‐nitroindoles and 2‐nitrobenzofurans, which provide a new, facile, and efficient protocol for the synthesis of chiral 2,3‐fused cyclopentannulated indolines and dihydrobenzofurans by reacting with allenoates and MBH carbonates, respectively through a dearomative [3+2]‐cycloaddition.     

Design and synthesis of a tetracyclic pyrimidine-fused benzodiazepine library

Method development for a heterocyclic library which entails novel scaffolds of benzodiazepines fused with various heterocycles, such as pyrimidines, indolines, and tetrahydroquinolines, was accomplished. The new synthetic strategy is based on an electrophilic cyclization reaction involving an iminium intermediate formed by the corresponding aminopyrimidine with a carbonyl compound to give the desired heterocycles in high yields. Subsequent replacement of the chloro group in the resulted structures with a nucleophile, such as boronic acids, amines, alcohols and thiols, led to a library of privileged compounds with up to eight accessible diversity points.     

Conformational insights into furo- and thieno[2,3-b]indolines derived from coupling constants and molecular modeling

The extent to which conformational preferences of fused heterocyclic five-membered rings change with the nature of the heteroatom (O and S) was investigated in furo- (1, 2) and thieno[2,3-b]indolines (3, 4) by the combined use of 1H NMR spectroscopy and density functional theory (DFT) calculations. In contrast to the behavior observed for pyrroloindolines, the furo- and thienoindolines exist in solution in only one conformer, with structures in the 2E-2T3 (1,2) and 2T3-E (3,4) North/West region of the pseudorotational wheel, and with pseudorotation phase angles (P) of 315.8, 311.6, 337.2 and 331.6 degrees, respectively.     

Reaction of a Fischer base and its derivatives with benzoylacetaldehydes

The corresponding 2-(3-benzoyl-2-propen-1-ylidene)indolines, which exist in the form of merocyanines and do not display tendencies to undergo intramolecular cyclization to the spiro form, were obtained as a result of the reaction of 1,3,3-trimethyl-2-methyleneindoline and its analogs with p-substituted benzoylacetaldehydes.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 202–206, February, 1981.     

Platinum‐Catalyzed Friedel–Crafts‐Type C−H Coupling–Allylic Amination Cascade to Synthesize 3,4‐Fused Tricyclic Indoles

A novel platinum‐catalyzed cascade cyclization reaction was developed by intramolecular Friedel–Crafts‐type C?H coupling of aniline derivatives with a propargyl carbonate unit‐allylic amination sequence. Treatment of various propargyl carbonates tethered to meta‐aniline derivatives with a Pt(dba)₃/DPEphos catalyst system afforded the corresponding 3,4‐fused tricyclic 3‐alkylidene indolines in 42–99 % yield, which were transformed into 3,4‐fused indole derivatives by reaction with trifluoroacetic acid. The reaction products exhibited antiproliferative activities against cancer cells, but not normal cells, revealing the potential usefulness of this reaction for medicinal chemistry.     

One-pot synthesis of substituted indolines via a copper-catalyzed sequential multicomponent/C-N coupling reaction

One-pot synthesis of 2-(N-sulfonylimino)indolines has been developed. The procedure combines the copper-catalyzed three-component reaction of sulfonyl azides, o-bromophenylacetylenes, and amines and the copper-catalyzed intramolecular C-N coupling in one sequence, which afforded the products in moderate to good yields. The resulting 2-(N-sulfonylimino)indolines could be easily transformed to pharmaceutically valuable oxindoles (indolin-2-ones).     

Synthesis of 6-methoxyindoles and indolines. Regioselective c-6 bromination of indolines and subsequent nucleophilic substitution with a methoxyl group

Regioselective bromination of the 6-position of indolines was investigated. Treatment of indolines with bromine in sulfuric acid in the presence of silver sulfate or with bromine in superacid afforded the 6-bromoindolines, which were converted to 6-methoxyindolines and indoles.     

One-pot cyclization of 2-aminophenethyl alcohols: a novel and direct approach to the synthesis of N-acyl indolines

A unique one-pot cyclization of 2-aminophenethyl alcohols with carboxylic acids in the presence of PPh3, CCl4, and NEt3 furnished the formation of N-acyl indolines in good to excellent yields. This new approach provides an efficient, scalable, low-cost, and direct access to the biologically important indolines which are further oxidizable to indoles and oxindoles.