The preparation of 5-indolyl-Mannich bases: an expedient source of 5-(chloromethyl)indoles

Regioisomeric analogues of gramine, 5-(dialkylaminomethyl)indole-2-carboxylates were prepared by the Fischer indolization of 4-(dialkylaminomethyl)phenylhydrazones easily obtained from diazotized 4-(dialkylaminomethyl)anilines by the Japp-Klingemann reaction. These formal Mannich bases are valuable synthetic intermediates affording 5-(chloromethyl)indoles on reaction with acetyl chloride at rt within a few minutes in quantitative yields.     

Enantioselective Dearomatization of Indoles by an Azoalkene-Enabled (3+2) Reaction: Access to Pyrroloindolines

The enantioselective dearomatization of indoles by an organocatalytic (3+2) reaction has been established. The reaction makes use of simple indole derivatives as substrates, and employs azoalkenes reaction partners. A wide range of pyrroloindolines containing an all-carbon quaternary stereogenic center were readily prepared in high yields and with excellent enantioselectivities.     

Enantioselective Dearomatization of Indoles by an Azoalkene‐Enabled (3+2) Reaction: Access to Pyrroloindolines

The enantioselective dearomatization of indoles by an organocatalytic (3+2) reaction has been established. The reaction makes use of simple indole derivatives as substrates, and employs azoalkenes reaction partners. A wide range of pyrroloindolines containing an all‐carbon quaternary stereogenic center were readily prepared in high yields and with excellent enantioselectivities.     

An efficient, microwave-assisted, one-pot synthesis of indoles under Sonogashira conditions

A microwave-assisted, one-pot, three-component coupling reaction for the synthesis of indoles has been developed. The reaction is carried out in two steps under standard Sonogashira coupling conditions from an N-substituted/N,N-disubstituted 2-iodoaniline and a terminal alkyne, followed by the addition of acetonitrile and an aryl iodide. A variety of polysubstituted indoles have been prepared in moderate to excellent yields using the present method.     

Palladium and copper cocatalyzed tandem N-H/C-H Bond functionalization: synthesis of CF3-containing indolo- and pyrrolo[2,1-a]isoquinolines

A palladium- and copper-catalyzed tandem N-H/C-H bond functionalization reaction of ortho-(2-chlorovinyl)bromobenzenes with indoles and pyrroles has been developed. A variety of CF(3)-containing indolo- and pyrrolo[2,1-a]isoquinolines were prepared in moderate to good yields via the cyclization of 1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)benzenes with indoles and pyrroles.     

PMA-SiO2–Mediated MCR in PEG-400: A Greener aza-Friedel–Crafts Reaction Leading to 3-Arylmethyl/Diarylmethyl Indoles

A greener approach for the synthesis of 3-arylmethyl/diarylmethyl indoles has been achieved via a PMA-SiO₂-mediated three-component reaction (the aza-Friedel–Crafts reaction) involving indoles, aldehydes, and N,N-disubstituted anilines in PEG-400. A variety of indole derivatives were prepared by using this operationally simple and straightforward methodology in acceptable yields.     

Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

Tandem reactions of Pd‐catalyzed cross‐coupling of 3‐(2‐isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich‐type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich‐type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich‐type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.     

Asymmetric Dearomatization of Indoles through a Michael/Friedel–Crafts‐Type Cascade To Construct Polycyclic Spiroindolines

A highly efficient asymmetric dearomatization of indoles was realized through a cascade reaction between 2‐isocyanoethylindole and alkylidene malonates catalyzed by a chiral N,N′‐dioxide/Mg^II catalyst. Fused polycyclic indolines containing three stereocenters were afforded in good yields with excellent diastereo‐ and enantioselectivities through a Michael/Friedel–Crafts/Mannich cascade. When 2‐substituted 2‐isocyanoethylindoles were used, spiroindoline derivatives were obtained through a Michael/Friedel–Crafts reaction.     

Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by Cu(Ⅱ)-imine complex

A series of new ligands L₁-L₇ were readily prepared in one step.Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by a novel Cu（Ⅱ）-L complex has been developed.The remarkable advantages of this reaction are mild reaction conditions,simple workup procedure,high yields of products and the use of ethanol as a green solvent.     

Mannich Reaction of Indole with Cyclic Imines in Water

An efficient MsOH promoted direct Mannich reaction of indoles with α-nonsubstituted aliphatic cyclic imines has been developed. The reactions were performed in water and the obtained piperidin-2-yl-indoles act as a useful precursor for the synthesis of various alkaloid-like derivatives.     

Pyrrolo- and pyrido[1,2-a]indoles via an intramolecular wittig reaction

Several pyrrolo- and pyrido[1,2-a]indoles were prepared via an intramolecular Wittig reaction in good yields. This reaction sequence represents a facile entry into the mitosene ring system.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

Palladium-/copper-catalyzed regioselective amination and chloroamination of indoles

A palladium-/copper-catalyzed intermolecular C-H amination reaction of indoles has been developed. This reaction proceeds in good to excellent yields to produce a variety of 2-amino-substituted indoles and exhibits excellent regioselectivity at room temperature. Furthermore, chloroamination of indoles provides a simple method for the construction of C-N and C-Cl bonds in one step.     

Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation. The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of triethylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectivities (up to 91% ee). The products could be further converted to the heteroatomic mimics of prostaglandins via reaction with primary amines.     

Oxidative Asymmetric Aza‐Friedel–Crafts Alkylation of Indoles with 3‐Indolinone‐2‐carboxylates Catalyzed by a BINOL Phosphoric Acid and Promoted by DDQ

An asymmetric aza‐Friedel–Crafts alkylation reaction between indoles and indolenines that were derived in situ from 3‐indolinone‐2‐carboxylates has been developed by using 3,3′‐bis(triphenylsilyl)‐1,1′‐binaphthyl‐2,2′‐diyl hydrogen phosphate as a catalyst. The reaction proceeded under mild conditions and provided chiral indol‐3‐yl‐3‐indolinone‐2‐carboxylate derivatives in good yields with excellent ee values (up to 98.6 %). Similarly, the Mannich‐type addition of indoline‐3‐ones to indolenines provided heterodimers with vicinal chiral quaternary centers. This method was successfully applied to the construction of the core structure of trigonoliimine C.     

Copper-catalyzed cross dehydrogenative coupling reactions of tertiary amines with ketones or indoles

A novel cross dehydrogenative coupling (CDC) reaction of N,N-dimethylanilines with methyl ketones by cooperative copper and aminocatalysis has been developed, which leads to the formation of β-arylamino ketones in 42-73% yields. Moreover, the copper-catalyzed alkylation of free (NH) indoles with N,N-dimethylanilines via CDC reaction is also presented, affording alkylated indoles in 52-78% yields.     

Enantioselective Continuous‐Flow Production of 3‐Indolylmethanamines Mediated by an Immobilized Phosphoric Acid Catalyst

A polystyrene‐supported 1,1’‐bi‐2‐naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel–Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3‐indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98 % enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous‐flow operation (6 h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous‐flow experiment that involved sequential pumping of different substrate combinations.     

Rapid Assembly of Functionalised Spirocyclic Indolines by Palladium‐Catalysed Dearomatising Diallylation of Indoles with Allyl Acetate

Herein, we report the application of allyl acetate to the palladium‐catalysed dearomatising diallylation of indoles. The reaction can be carried out by using a readily available palladium catalyst at room temperature, and can be applied to a wide range of substituted indoles to provide access to the corresponding 3,3‐diallylindolinines. These compounds are versatile synthetic intermediates that readily undergo Ugi reactions or proline‐catalysed asymmetric Mannich reactions. Alternatively, acylation of the 3,3‐diallylindolinines with an acid chloride or a chloroformate, followed by treatment with aluminium chloride, enables 2,3‐diallylindoles to be prepared. By using ring‐closing metathesis, functionalised spirocyclic indoline scaffolds can be accessed from the Ugi products, and a dihydrocarbazole can be prepared from the corresponding 2,3‐diallylindole.     

Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis

Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially available Lewis acids. The reaction proceeded through a stepwise pathway involving a nucleophilic addition of indoles to BCBs followed by an intramolecular Mannich reaction to form rigid indoline-fused polycyclic structures, which resemble polycyclic indole alkaloids. This new reaction tolerated a wide range of indoles and BCBs, thereby allowing the one-step construction of various rigid indoline polycycles containing up to four contiguous quaternary carbon centers.     

Brønsted acid catalyzed Diels-Alder reactions of 2-vinylindoles and 3-nitrocoumarins: an expedient synthesis of coumarin-fused tetrahydrocarbazoles

A Brønsted acid catalyzed Diels-Alder reaction of 2-vinylindoles and 3-nitrocoumarins has been described. The methodology allows a rapid and expedient synthesis of a variety of coumarin-fused polycyclic indoles in good yields (up to 82%) with high diastereoselectivities (up to >19:1).