Indoles In High Yields Research Articles

Sequential Aerial Oxidation and Atom‐Economical C‐3 Chalcogenation of Indolines Facilitated by Potassium tert‐Butoxide

AbstractAn operationally straightforward and highly efficient potassium tert‐butoxide facilitated protocol for the C‐3 chalcogenation of indolines under catalyst and additive‐free conditions has been established under ambient temperature. The salient features of the process include the development of transition metal‐free, oxidant‐free and iodine‐free, atom‐economic and cost‐effective reaction conditions at room temperature in DMSO as solvent for regioselective generation of 3‐chalcogenyl indoles in high yields. The mechanistic interpretation through controlled experiments and analysis of intermediates suggests the prevalence of the ionic pathway. The reaction is scalable to gram‐scale without a significant decrease in product yield, indicating its potential for large‐scale applications. This protocol offers a practical and environment friendly approach to accessing a diverse range of 3‐arylthioindoles and 3‐arylselenylindoles withstanding electron releasing and withdrawing substituents in good to excellent yields. Interestingly, the biological evaluation of the 3‐arylselenylindole products exhibited significant activity against breast cancer and triple‐negative breast cancer cell lines MCF‐7, and MDA‐MB 231. These results indicate the derivatives to be potent candidates for further SAR study.

Cu(I) Complexes Catalyzed the Dehydrogenation of N-Heterocycles.

A copper-catalyzed method for the dehydrogenation of various nitrogen-containing heterocycles to furnish quinolines and indoles has been developed. A range of 1,2,3,4-tetrahydroquinolines underwent dehydrogenation by employing 2 mol % of copper complex Cat 3 as a catalyst and using O2 as an oxidant at 120 °C in 1,2-dichlorobenzene to afford the desired quinolines. The method enables the dehydrogenation of a variety of indolines in the presence of 2 mol % of copper complex Cat 2, using 10 mol % of TEMPO as an additive and O2 as an oxidant under room temperature in tetrahydrofuran to furnish indoles in high yields. Mechanistic studies suggested that the dehydrogenative activity is ascribed to the formation of a copper(II) active species from copper(I) complexes oxidized by O2, which was proved by high-resolution mass spectrometry (HRMS). The copper-catalyzed dehydrogenation reaction proceeds via a superoxide radical anion (·O2-) as proved by electron paramagnetic resonance (EPR) spectrometry. In situ infrared spectroscopy revealed that the dihydroquinoline intermediate was formed in the dehydrogenation of 1,2,3,4-tetrahydroquinolines.

Enantioselective Synthesis of an All-Carbon Quaternary Stereocenter by Chiral Brønsted Acid-Catalyzed Friedel-Crafts-Type Reaction between Pyrroles and 3-Indolylmethanols.

We have developed a chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts alkylation reaction between pyrroles and indolylmethanols. Wide substrate scope was observed, and a chiral all-carbon quaternary center was constructed at the 3 position of indoles in high yields with high to excellent enantioselectivities (up to 99% ee).

One-Pot Synthesis of 3-Substiuted Indoles from 2-(2-Nitro-1-phenylethyl)cyclohexanone Derivatives

Herein, a one-pot synthesis of 3-substituted indoles from 2-(2-nitro-1-phenylethyl)cyclohexanone derivatives catalyzed by Pd/C is reported. The starting materials can be easily prepared by the reaction of substituted ketones and nitroalkenes. The facile experimental procedure comprises the treatment of 2-(2-nitro-1-phenylethyl)cyclohexanone derivatives with H2 as a hydrogen donor in the presence of 10 mol % Pd/C. Subsequently, the exchange of H2 with CH2═CH2 as a hydrogen acceptor affords a variety of 3-substituted indoles in high yields. The formation of intermediate nitrones is essential for a smooth reaction.

Synthesis and Reactions of 3-Halogenated 2-CF3-Indoles.

Halogenation of 2-trifluoromethylindole afforded 3-chloro-, 3-bromo- and 3-iodo derivatives in up to 98% yield. Methyl-, benzyl- and tosyl-groups can be installed at the nitrogen atom of prepared indoles in high yields by base catalyzed reaction with the corresponding alkylating (sulfonylating) reagents. A high synthetic utility of the prepared haloindoles in the reaction with various nucleophilies was shown. The reaction with 4-methylthiophenol and copper cyanide afforded the corresponding sulfides and nitriles in high yield. Palladium catalyzed cross-coupling with phenyl boronic acid and phenylacetylene gave the corresponding 3-phenyl-2-CF3-indoles and acetylenic derivatives in 72-98% yield.

Additive-Controlled Divergent Synthesis of Indole and 4H-Benzo[d][1,3]oxazine Derivatives: Palladium-Catalyzed Carbonylative Cyclization of 2-Alkynylanilines and Benzyl Chlorides.

A palladium-catalyzed divergent carbonylative synthesis of indoles and 4H-benzo[d][1,3]oxazines from 2-alkynylanilines and benzyl chlorides with benzene-1,3,5-triyl triformate (TFBen) as the CO source has been developed. The reaction using AlCl3 as the additive produced various indoles in high yields, while a series of 4H-benzo[d][1,3]oxazines was achieved in moderate yields with AcOH as the additive.

Stereoselective Synthesis of Cyclohepta[b]indoles by Visible‐Light‐Induced [2+2]‐Cycloaddition/retro‐Mannich‐type Reactions

AbstractA novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible‐light‐induced, photocatalyzed [2+2]‐cycloaddition/ retro‐Mannich‐type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single‐electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical‐cation state to form cyclohepta[b]indoles.

Stereoselective Synthesis of Cyclohepta[b]indoles by Visible-Light-Induced [2+2]-Cycloaddition/retro-Mannich-type Reactions.

A novel method for the concise synthesis of cyclohepta[b]indoles in high yields was developed. The method involves a visible-light-induced, photocatalyzed [2+2]-cycloaddition/ retro-Mannich-type reaction of enaminones. Experimental and computational studies suggested that the reaction is a photoredox process initiated by single-electron oxidation of an enaminone moiety, which undergoes subsequent cyclobutane formation and rapidly fragmentation in a radical-cation state to form cyclohepta[b]indoles.

Copper-Catalyzed Addition of Grignard Reagents to in situ Generated Indole-Derived Vinylogous Imines.

Chiral indole derivatives are ubiquitous motifs in pharmaceuticals and alkaloids. Herein, the first protocol for catalytic asymmetric conjugate addition of Grignard reagents to various sulfonyl indoles, offering a straightforward approach for the synthesis of chiral 3‐sec‐alkyl‐substituted indoles in high yields and enantiomeric ratios is presented. This methodology makes use of a chiral catalyst based on copper phosphoramidite complexes and in situ formation of vinylogous imine intermediates.

Synthesis of Pyrido[2,3‐b]indole Derivatives via Rhodium‐Catalyzed Cyclization of Indoles and 1‐Sulfonyl‐1,2,3‐triazoles

AbstractAcyloxy‐substituted α,β‐unsaturated imines generated in situ from triazoles can act as aza‐[4 C] synthons and be trapped by indoles in a stepwise [4 + 2] cycloaddition reaction, thus providing rapid access to valuable pyrido[2,3‐b]indoles in high yields. Attractive features of this reaction system include operational simplicity, readily available substrates, construction of sterically demanding quaternary centers, and convenient derivatization using triflate.magnified image

A synthetic route to 1,4-disubstituted tetrahydro-β-carbolines and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reaction of aziridines and epoxides with indoles/aldehydes.

A simple and efficient synthetic route to various 1,4-disubstituted tetrahydro-β-carbolines and tetrahydropyrano[3,4-b]indoles in high yields and stereoselectivity via LiClO4-catalyzed SN2-type ring opening of aziridines and epoxides with indoles followed by p-toluenesulfonic acid (PTSA) catalyzed Pictet-Spengler reaction is described.

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

AbstractWe report herein the first examples of a palladium‐catalyzed enantioselective Cacchi reaction for the synthesis of indoles bearing a chiral C2‐aryl axis. In the presence of a catalytic amount of Pd(OAc)2 and (R,R)‐QuinoxP* ligand, reaction of N‐aryl(alkyl)sulfonyl‐2‐alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3‐disubstituted indoles in high yields and enantioselectivity. The indole ring is constructed de novo in this process and a complexation‐induced chirality transfer is proposed to account for the observed enantioselectivity.

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

We report herein the first examples of a palladium-catalyzed enantioselective Cacchi reaction for the synthesis of indoles bearing a chiral C2-aryl axis. In the presence of a catalytic amount of Pd(OAc)2 and (R,R)-QuinoxP* ligand, reaction of N-aryl(alkyl)sulfonyl-2-alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3-disubstituted indoles in high yields and enantioselectivity. The indole ring is constructed de novo in this process and a complexation-induced chirality transfer is proposed to account for the observed enantioselectivity.

Transformation of fluorinated 2-alkynylanilines by various catalytic systems

Simple and efficient approaches to the synthesis of fluorinated benzoazaheterocycles with good yields are reported. Firstly a series of polyfluorinated 2-alkynylanilines – the versatile building blocks – was synthesized by the Sonogashira reaction of o-iodoaniline with terminal alkynes. Then the transformations of the obtained 2,3,4-trifluo-6-alkynilanilines in the presence of KOH or PdCl2 in MeCN, and in the presence of monohydrate of p-toluenesulfonic acid (p-TSA•H2O) in MeOH, EtOH or benzene were investigated. It was found that Ph- and n-Bu-containing alkynylanilines by action of PdCl2 in MeCN underwent an intramolecular cyclization reaction to produce the corresponding indoles in high yields. The reaction of KOH with alkynes containing the tertiary alcohol function at the triple bond produced the unsubstituted on the pyrrole ring indole. It was found that fluorinated 2-alkynilanilines can be transformated into indoles, 2-arylketones and 2,3-dihydroquinolines by action of p-TSA•H2O in boiling alcohols, depending on the substituent at the triple bond. The use of benzene as a solvent in the reaction of p-TSA•H2O with polyfluorinated alkynes, bearing an alcohol group resulted in representative series of 2,3-dihydroquinolinones containing a substituents R1 and R2 in the 2nd position of their structure (R = H, H; Me, Me; H, i-Pr; H, Ph).

Copper-Catalyzed Decarboxylative N-Arylation of Indole-2-carboxylic Acids

A novel decarboxylative N-arylation of indole-2-carboxylic acids with aryl halides is developed. The reaction proceeds efficiently in the presence of Cu2O as the catalyst to give the corresponding N-aryl indoles in high yields. This synthetic method shows good functional group tolerance and offers an alternative route to construct N-aryl indoles.

Solventless Mechanosynthesis Of Bis(Indolyl)Methanes

Ball-milling technique as a solvent-free and an alternative green process was investigated for the eco-benign synthesis of bis(indolyl)methanes (BIMs) from various aldehydes and selected ketones with indoles in high yields. The present methodology has several advantages such as simple procedure, good yields, mild conditions, and reduced environmental consequences. The silica gel acts both as a grinding medium and an acid catalyst. The utility of this technique was demonstrated by synthesizing library of 17 BIMs including two natural products trisindoline and tris(1H-indol-3-yl)methane.

Highly enantioselective synthesis of functionalized azepino[1,2-a]indoles via NHC-catalyzed [3+4] annulation.

The enantioselective [3+4] annulation of 3-formylindol-2-methyl-malonates with 2-bromoenals catalyzed by NHCs is described to afford functionalized azepino[1,2-a]indoles in high yields with excellent enantioselectivities. This method, in which the 3-formyl group in indoles acts as a necessary mediating group, provided cycloaddition products under mild conditions.

Sequential [1 + 4]- and [2 + 3]-Annulation of Prop-2-ynylsulfonium Salts: Access to Hexahydropyrrolo[3,2-b]indoles.

A powerful sequential [1 + 4]- and [2 + 3]-annulation has been developed using prop-2-ynylsulfonium salts and sulfonyl-protected o-amino aromatic aldimines, affording a series of hexahydropyrrolo[3,2-b]indoles in high yields. Prop-2-ynylsulfonium salts act as C2 synthons in the reaction, and fused rings containing two five-membered azaheterocycles can be constructed in a single operation with readily accessible starting materials.

Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylanilides: Synthesis of 3-Substituted Indoles by 1,2-Carbon Migration.

We developed ruthenium-catalyzed cycloisomerization of alkynylanilides that gave 3-substituted indoles in high yields. The reaction proceeded via the disubstituted vinylidene ruthenium complex that was formed by the 1,2-carbon migration.

Synthesis of 3‐Aryl‐2‐(trifluoromethyl)indoles via Copper‐Catalyzed Hydroarylation and Subsequent Cadogan Cyclization

AbstractThe copper‐catalyzed hydroarylation of (trifluoromethyl)alkynes with (o‐nitrophenyl)boronic acids selectively afforded trisubstituted (trifluoromethyl)alkenes bearing an o‐nitrophenyl group. The obtained hydroarylation products were converted into 3‐aryl‐2‐(trifluoromethyl)indoles in high yields via molybdenum‐catalyzed Cadogan cyclization. Similarly, the hydroarylation product prepared from (o‐nitrophenyl)(trifluoromethyl)alkyne and (p‐anisyl)boronic acid also underwent Cadogan cyclization, albeit with a longer reaction time, affording the desired indole product in a high yield.magnified image