2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

Cyclooxygenase‐2 (COX‐2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX‐2‐selective 2,3‐disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2‐carbaborane‐3‐phenyl‐1H‐indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta‐carbaboranyl‐substituted derivatives lacked COX inhibitory activity, an ortho‐carbaboranyl analogue was active, but showed a selectivity shift toward COX‐1.     

Facile Creation of 3‐Indolyl‐3‐hydroxy‐2‐oxindoles by an Organocatalytic Enantioselective Friedel–Crafts Reaction of Indoles with Isatins

The first direct enantioselective Friedel–Crafts reaction of indoles with isatins has been developed. The process is catalyzed by simple cupreine under mild reaction conditions and affords synthetically and biologically interesting, chiral 3‐indolyl‐3‐hydroxy‐2‐oxindoles in good yields (68–97%) and with high enantioselectivities (76–91%).     

Chiral Phosphoric Acid‐Catalyzed Enantioselective Aza‐Friedel–Crafts Alkylation of Indoles with γ‐Hydroxy‐γ‐lactams

An enantioselective aza‐Friedel–Crafts reaction of indoles with γ‐hydroxy‐γ‐lactams using a chiral phosphoric acid catalyst is reported. The approach described herein provides an efficient access to 5‐indolylpyrrolidinones in good to quantitative yields and excellent enantioselectivities (up to >99% ee). The results suggest that the reaction may proceed via N‐acyliminium intermediates associated with the chiral phosphoric acid anion.     

Palladium‐Catalyzed Direct Denitrogenative C‐3‐Arylation of 1H‐Indoles with Arylhydrazines using Air as the Oxidant

A novel palladium‐catalyzed approach to direct C‐3‐arylation of 1H‐indoles with arylhydrazines using air as the oxidant via C N bond cleavage has been developed. Various substituents are tolerated in this system in moderate to good yields. This reaction could also be compatible with a larger scale. Thus, this strategy using arylhydrazines as arylating reagents provides a powerful method for constructing substituted 3‐aryl‐1H‐indoles.     

Intramolecular Photochemical Cross‐Coupling Reactions of 3‐Acyl‐2‐haloindoles and 2‐Chloropyrrole‐3‐carbaldehydes with Substituted Benzenes

Highly efficient syntheses of indolo[2,1‐a]isoquinolines, indolo[2,1‐a][2]benzazepines, pyrrolo[2,1‐a]isoquinolines and pyrrolo[1,2‐a]benzazepines in excellent yields have been achieved by the intramolecular photochemical cross‐coupling reactions of 3‐acyl‐2‐halo‐N‐(ω‐arylalkyl)indoles and 2‐chloro‐N‐(ω‐arylalkyl)pyrrole‐3‐carbaldehydes in acetone. A new heterocyclic ring system – pyrrolo[1,2‐d][1,4]benzoxazepine – has also been constructed for the first time in this work by the photocyclization of 2‐chloro‐N‐(2‐phenoxyethyl)pyrrole‐3‐carbaldehyde.     

Microwave‐Assisted Facile Synthesis of Furo[3,2‐b]indole Derivatives via Silver(I)‐Mediated [3+2] Cycloaddition

A robust one‐pot process has been developed for the synthesis of a variety of furo[3,2‐b]indoles from readily available o‐propargylaminoacetophenones via silver(I)‐mediated [3+2] cycloaddition.     

A Photochemical Route to Benzo[a]carbazoles via Domino Elimination/Electrocyclization of 2‐Aryl‐3‐(1‐tosylalkyl)indoles

The photochemical synthesis of benzo[a]carbazoles from easily synthesizable 2‐aryl‐3‐(1‐tosylalkyl)indoles is presented. Irradiation of these substrates in polar aprotic solvents (acetone or THF) gives selectively the target products in satisfactory yields. This versatile and efficient procedure promises to be a useful alternative to the multistep strategies reported in the literature.     

Heterogeneous Palladium Catalysts Applied to the Synthesis of 2‐ and 2,3‐Functionalised Indoles

Heterogeneous palladium catalysts ([Pd(NH₃)₄]²⁺/NaY and [Pd]/SBA‐15) were applied to the synthesis of 2‐functionalised indoles, giving generally high conversions and selectivities (>89% yield) using only 1 mol % [Pd]‐catalyst under standard reaction conditions (polar solvent, 80 °C). For the synthesis of 2,3‐functionalised indoles by cross‐coupling arylation, the [Pd]/SBA‐15 catalyst was found to be particularly interesting, producing the expected compound with =35% yield after 12 days of reaction, which is comparable to the homogeneous catalyst, Pd(OAc)₂ (=48% yield). In the course of the study, the dual reactivity of the indole nucleus was demonstrated: aryl bromides gave clean C C coupling while aryl iodides led to a clean C N coupling.     

Reaction of 3‐(1‐Arylsulfonylalkyl)‐indoles with Easily Enolisable Derivatives Promoted by Potassium Fluoride on Basic Alumina

Active methylene compounds and nitro derivatives react with 3‐(1‐arylsulfonylalkyl)‐indoles in the presence of potassium fluoride on basic alumina at room temperature leading to the corresponding adducts in good yields. Under basic conditions, sulfonylindoles suffer elimination of arenesulfinic acid leading to an intermediate vinylogous imine that promptly adds stabilized carbanions. The obtained 3‐indolyl derivatives are pivotal intermediates for the synthesis of indole‐based alkaloids and amino acids.     

Chiral Imidodiphosphoric Acids‐Catalyzed Friedel–Crafts Reactions of Indoles/Pyrroles with 3‐Hydroxy‐indolyloxindoles: Enantioselective Synthesis of 3,3‐Diaryloxindoles

The first enantioselective Friedel–Crafts alkylation of indoles and pyrroles with 3‐hydroxy‐3‐indolyloxindoles to access two novel types of 3,3‐diaryloxindoles catalyzed by chiral imidodiphosphoric acids has been reported. A range of quaternary carbon centered 3,3‐diaryloxindoles were synthesized in high yield (up to >99%) with excellent enantioselectivity (up to 98% ee) at low catalyst loadings (as low as 0.5 mol%). The Friedel–Crafts reaction between indoles and 3‐hydroxy‐3‐indolyloxindoles is amenable to gram scale syntheses.

     

A New One‐Pot Synthesis of Polysubstituted Indoles from Pyrroles and β‐Nitroacrylates

The reaction of β‐nitroacrylates with pyrroles, under solvent‐ and catalyst‐free conditions, allows the formation of Friedel–Crafts adducts which, after in situ treatment with Amberlyst 15 in isopropyl alcohol under reflux, provide polysubstituted indoles, via a benzannulation reaction, in a one‐pot process.     

Copper‐Catalyzed Activation of Dioxygen: Oxidative Cyclization of 2‐Arylindoles

A series of unusual six‐ring‐fused heterocycles containing indole and quinoline skeletons was successfully synthesized by a copper‐catalyzed reaction from 2‐arylated indoles. Two new bonds were regioselectively formed from C H and C H coupling. ¹⁸O‐Labelled experiments revealed that the dioxygen is not only the oxidant but also the reactant.     

3‐Naphthylindole Construction by Rhodium(II)‐Catalyzed Regioselective Direct Arylation of Indoles with 1‐Diazonaphthalen‐2‐(1H)‐ones

The regioselective direct 3‐arylation of indoles with 1‐diazonaphthalen‐2‐(1H)‐ones was developed by means of a rhodium(II) pivalate‐catalyzed cross‐coupling reaction. This procedure provided a variety of novel 3‐naphthylindoles in high yield. The direct coupling of benzofuran, pyrrole or furan with 1‐diazonaphthalen‐2‐(1H)‐ones afforded 2‐ or 3‐naphthyl substituted heterocycles.

     

Iridium‐Catalyzed Selective Synthesis of 4‐Substituted Benzofurans and Indoles via Directed Cyclodehydration

A directed cyclization‐dehydration cascade of α‐aryloxy ketones and α‐arylamino ketones was efficiently catalyzed by a cationic iridium‐BINAP complex, which afforded various types of 4‐substituted benzofurans and indoles in high yields with complete regioselectivity. The newly developed protocol also enabled the enantioselective preparation of chiral 4‐acetyloxindole using a chiral iridium catalyst.     

An Aluminum Triflate‐Catalyzed Intramolecular Reaction Sequence Toward Concise Construction of the Tetrahydropyrido[1,2‐a]indol‐6‐one Skeleton

An aluminum triflate‐catalyzed intramolecular reaction sequence involving protonation and Mannich‐like nucleophilic addition of indoles toward the concise construction of the tetrahydropyrido[1,2‐a]indol‐6‐one skeleton is reported. This new reaction pattern employs a carbon atom as nucleophile to form a C C bond which bears one or even two quaternary carbons and leads to the dearomatization of indoles with high atom economy.

     

Nitrones as Trapping Reagents of α,β‐Unsaturated Carbene Intermediates – [1,2]Oxazino[5,4‐b]indoles by a Platinum‐ Catalyzed Intermolecular [3+3] Cycloaddition

Some readily available Boc‐protected 2‐(3‐methoxy‐1‐propynyl)anilines and nitrones in platinum‐catalyzed reactions deliver [1,2]oxazino[5,4‐b]indoles. Twelve examples with yields of 41–95% are reported. Different substituents like nitro, trifluoromethyl, fluoro, bromo, and ester groups are tolerated. With regard to the mechanism, this reaction probably combines an initial intramolecular cyclization/elimination to vinylcarbenoid species and a subsequent stepwise intermolecular [3+3] cycloaddition with the nitrones.     

Gold‐Catalysed Direct Couplings of Indoles and Pyrroles with 1,3‐Dicarbonyl Compounds

The gold‐catalysed direct couplings of indoles 1 and pyrroles 5 with 1,3‐dicarbonyls 2 is described. This new method for C C bond formation allows high functional group tolerance, regioselectivity, and scope under relatively mild conditions. Moreover, the 3‐alkenylindoles 3 can be readily available through gold‐catalysed sequential cyclization/alkenylation reaction of 2‐alkynylanilines derivatives 4 with 1,3‐dicarbonyls 2 .     

Expedient Introduction of β‐Methoxyacrylate Unit onto 3‐Substituted Indoles and Application of the Resulting Indole‐Dienes in Organocascade toward Indolino‐Polycyclics

An efficient methodology for introducing a β‐alkoxy acrylate unit onto the indolic C‐2 position of 3‐substituted indoles has been realized by oxidative radical alkylation of indoles with a xanthate bearing dialkyl acetal functionality and subsequent elimination of alcohol by treatment with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). The indole‐dienes thus prepared are quite stable and can be stored at room temperature for several months without obvious deterioration. Next, the indole‐dienes were successfully applied in an asymmetric cascade reaction with propargyl aldehyde catalyzed by MacMillan’s imidazolidinone and trichloroacetic acid (TCA), affording tetracyclic spiroindolines or tricyclic hydrocarbazoles in good to excellent yields with excellent ees. The practicality of this cascade was demonstrated by a gram scale preparation of a tetracyclic spiroindoline product with as low as 1 mol% catalyst loading and further elaboration of this spiroindoline compound into valuable intermediates for alkaloid synthesis.

     

Boron Trifluoride‐Promoted Indium(III) Triflate‐Catalyzed Sequential One‐Pot Synthesis of (1,2‐Diaryl‐2‐oxoethyl)malonates from trans‐2‐Aryl‐3‐nitrocyclopropane‐1,1‐dicarboxylates and Activated Arenes

A sequential one‐pot synthesis of Michael adducts of aroylmethylidenemalonates with activated aromatics is described. The method involves treatment of trans‐2‐aryl‐3‐nitro‐cyclopropane‐1,1‐dicarboxylates with boron trifluoride etherate to form aroylmethylidenemalonates in situ and then addition of activated aromatics such as indoles, carbazole, pyrrole, thiophenes, methoxybenzenes and benzodioxole followed by a catalytic amount of indium(III) triflate to the same reaction vessel. To prove the synthetic potential of the resulting Michael adducts, one of the adducts was transformed into a pharmaceutically interesting dihydropyridazinone derivative.

     

Rhodium(III)‐Catalyzed Regioselective Direct C‐2 Alkenylation of Indoles Assisted by the Removable N‐(2‐Pyrimidyl) Group

The C‐2‐alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C‐2‐alkenylindoles through rhodium(III)‐catalyzed direct C H functionalization of indoles with acrylates under air by employing a metal‐directing group strategy. This strategy gives a rare selectivity for the alkenylation N‐(2‐pyrimidyl)indoles at the C‐2 position and provides the functionalized C‐2‐ alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C‐2‐alkenylindoles.