Indoline Derivatives Research Articles

Gold Catalyzed [3+2] Oxidative Annulation of 1,3‐Enynes with Indoles

AbstractAn efficient new method has been developed for the synthesis of ketone‐integrated cyclopentene‐fused indoline derivatives with a high regioselectivity through gold‐catalyzed oxidative cyclo‐coupling of 1,3‐enynes with indoles by using 2,6‐dichloropyridine N‐oxide as the terminal oxidant. A plausible mechanism has been proposed, in which, a cascade process of nucleophilic trapping of the vinyl gold carbene surrogate with indole followed by the subsequent intramolecular cyclization provides the dearomative formal [3+2] cycloaddition product. In addition, a scale‐up reaction and further derivation via cyclopentene's epoxidation & hydrazone derivative's 1,5‐ electrocyclization have been performed.

Electrochemical Selenized Reaction of N-Arylbicyclo[1.1.0]butane-1-carboxamides: Access to 3-(Arylselanyl)spiro[cyclobutane-1,3'-indolin]-2'-one Derivatives.

A novel selenized reaction of N-arylbicyclo [1.1.0]butane-1-carboxamides with diselenide for the synthesis of polycyclic indoline derivatives is developed under electrochemical conditions. The synthesis is achieved by the bicyclo[1.1.0]butane strain-release reaction and intramolecular cyclization process. In addition, this approach features a wide range of substrates, good group tolerance, shorter reaction time, and mild conditions.

Merging Organocatalysis with 1,2-Boronate Rearrangement: A Lewis Base-Catalyzed Asymmetric Multicomponent Reaction.

Catalytic asymmetric multicomponent 1,2-boronate rearrangements provide a practical approach for synthesizing highly valuable enantioenriched boronic esters. When applied to alkenyl or heteroaryl boronates, these reactions have relied mainly on transition-metal catalysis. Herein, we present an organocatalytic, Lewis base-catalyzed asymmetric multicomponent 1,2-boronate rearrangement, involving indoles, boronic esters, and Morita-Baylis-Hillman carbonates, leading to enantioenriched, highly substituted indole and indoline derivatives. Using cinchona alkaloid-based catalysts, high selectivity has been achieved, enabling expansion of the chemical space around pharmaceutically relevant indole and indoline derivatives.

Synthesis of Heptacyclic Compounds through C-H Bond Activation-Initiated Cascade Reactions.

Presented herein is an atom- and step-economical method enabling the precise assembly of a heptacyclic scaffold containing both azocine and indoline units through the cascade reactions of indolin-1-yl(aryl)methanimines with diazo indanediones. The formation of products involves C-H bond activation and double carbene insertion followed by intramolecular condensation, retro-[2 + 2] cycloaddition, and recyclization. This cascade reaction not only provided a concise and straightforward strategy for the synthesis of the otherwise difficult to obtain heptacyclic compounds from readily available substrates but also disclosed an unprecedented reaction mode for indoline derivatives and diazo compounds. In general, this novel synthetic protocol has advantages, such as easily obtainable substrates, structurally sophisticated products, concise synthetic procedure, good compatibility with diverse functional groups, and ready scalability. Moreover, the products thus obtained showed decent antiproliferative activity against three human cancer cell lines.

Thermal‐Induced Synthesis of Cyclobute[b]indolines via Intramolecular Formal [2+2] Cycloaddition of Enamines and Triazole‐derived Ketenimines

AbstractA de novo synthesis of cyclobutene‐fused indoline derivatives via thermally induced intramolecular cyclization was reported. This approach efficiently yields valuable high‐strained cyclobute[b]indolines in moderate to high yields and enables further transformation into other valuable heterocycles, demonstrating its potential in organic synthesis.

Visible-Light-Mediated Activation of Remote C(sp3)-H Bonds by Carbon-Centered Biradical via Intramolecular 1,5- or 1,6-Hydrogen Atom Transfer.

In this study, we introduce a novel intramolecular hydrogen atom transfer (HAT) reaction that efficiently yields azetidine, oxetane, and indoline derivatives through a mechanism resembling the carbon analogue of the Norrish-Yang reaction. This process is facilitated by excited triplet-state carbon-centered biradicals, enabling the 1,5-HAT reaction by suppressing the critical 1,4-biradical intermediates from undergoing the Norrish Type II cleavage reaction, and pioneering unprecedented 1,6-HAT reactions initiated by excited triplet-state alkenes. We demonstrate the synthetic utility and compatibility of this method across various functional groups, validated through scope evaluation, large-scale synthesis, and derivatization. Our findings are supported by control experiments, deuterium labeling, kinetic studies, cyclic voltammetry, Stern-Volmer experiments, and density functional theory (DFT) calculations.

Visible‐Light‐Mediated Activation of Remote C(sp3)−H Bonds by Carbon‐Centered Biradical via Intramolecular 1,5‐ or 1,6‐Hydrogen Atom Transfer

AbstractIn this study, we introduce a novel intramolecular hydrogen atom transfer (HAT) reaction that efficiently yields azetidine, oxetane, and indoline derivatives through a mechanism resembling the carbon analogue of the Norrish‐Yang reaction. This process is facilitated by excited triplet‐state carbon‐centered biradicals, enabling the 1,5‐HAT reaction by suppressing the critical 1,4‐biradical intermediates from undergoing the Norrish Type II cleavage reaction, and pioneering unprecedented 1,6‐HAT reactions initiated by excited triplet‐state alkenes. We demonstrate the synthetic utility and compatibility of this method across various functional groups, validated through scope evaluation, large‐scale synthesis, and derivatization. Our findings are supported by control experiments, deuterium labeling, kinetic studies, cyclic voltammetry, Stern–Volmer experiments, and density functional theory (DFT) calculations.

Azidoindolines—From Synthesis to Application: A Review

Azide-containing compounds, organic azides, showcases a variety of reactivities, making them highly convenient and chameleonic intermediates. An indoline derivative has been proven to be of great significance in drug discovery due to its sp3-rich property. In this context, it is interesting to perform such vigorous azidation on medicinal-relevant indoles/indolines, resulting in the production of sp3-rich azidoindolines. The potential biological activity, in combination with the sp3-rich indoline bearing the azido moiety, makes azidoindolines an attractive synthetic target for medicinal and synthetic chemists. This review describes recent advances in the synthesis and application of azidoindolines: (1) iodine-mediated azidations, (2) metal-catalyzed azidations, (3) electrochemical azidations, (4) photochemical azidations, (5) azidation using a combination of an oxidant and an azide source, and (6) nucleophilic azidation.

Microdroplet-accelerated cycloaddition of gaseous phenylacetylene and indoline derivatives to form tricyclic quinolines

Microdroplets have exhibited distinct acceleration effects on many reactions, but most of which involve dissolved reactants within the droplets. Here, we modified a sub-atmospheric pressure electrospray ionization source (SAP-ESI) as a reactor to perform the cycloadditions of gaseous phenylacetylene and indoline derivatives to yield tricyclic quinolines. The reactions were found to proceed rapidly with the assist of charged microdroplets in a nitrogen atmosphere. Real-time and on-site capture of the intermediates and products by mass spectrometry reveals the reaction mechanism at the microdroplet interface, which is somewhat different from the conventional catalytic cycloaddition processes. In particular, the radical cations of dimer phenylacetylenes are first generated in microdroplets and then promote the catalyst-free cycloaddition. This research showcases the new potential of microdroplet chemistry to advance gas-phase reactions.

Easy Access to Functionalized Indolines and Tetrahydroquinolines via a Photochemical Cascade Cyclization Reaction.

Herein, the development of a light-mediated synthesis of functionalized indolines and tetrahydroquinolines is reported. These structural motifs are considered as highly valuable targets, attributed to their widespread occurrence in pharmaceuticals and natural products. The gold-mediated approach offers a direct route to functionalized indolines in yields of up to 81% under mild photochemical conditions. Thereby, easily accessible Boc-protected N-aryl-allylamine and homoallylamine derivatives were reacted with sp3-hybridized haloalkanes in an intermolecular cascade cyclization reaction. A broad scope of substrates, including a variety of different substituents on the aromatic backbone as well as various haloalkanes, could be utilized. Indoline derivatives, which are functionalized in position 2, are also accessible by applying ortho-allylic anilines. Moreover, the synthetic appeal was demonstrated for a total synthesis of the anti-inflammatory agent AN669 in three reaction steps in an overall yield of 64%.

Hybrids of imidazole with indoline derivatives: Microwave assisted synthesis, molecular docking studies, possible biological activities

A new hybrids of imidazole with Indole derivative 1-methyl-3-((1-(2-methyl-1H-Imidazole.-1yl)-methyl)-1H-indol-5-yl)imino)indolin-2-one(3a-o) was prepared by microwave-assisted technique via alkylation and Schiff's and Mannich base mechanism. The chemical structures of the synthesized products were confirmed by IR, 1HNMR and Mass spectra. The in vitro anticancer activity was evaluated via MTT assay technique, as well as their anthelmintic activity by utilising Indian earth warms. Most of the compounds 1-methyl-3-((1-(2-methyl-1H-Imidazole-1yl)-methyl)-1H-indol-5-yl)imino)indolin-2-one demonstrated greater anthelmintic action than the other compounds. The compounds 1,5-dimethyl-3-((1-(2-methyl-1H-Imidazole-1-yl)-methyl)-1H-indol-5-yl)-imino)-indole-2-one and 1-benzyl-5--chloro-3-((1-((2-methyl-1H--imidazole-1-yl) methyl)-1H-indol-5-yl) imino)indolin-2-one exhibit good anticancer action. Lastly, whenever the interaction pattern and selectivity towards the EGFR activity site have been examined, the molecular docking experiments of novel indole derivatives demonstrated good alignment only with biological findings.

Palladium-Catalyzed Carbothiolation by Using Thioesters with Formation of a Quaternary Carbon

AbstractA Pd-catalyzed carbothiolation using thioesters, with the formation of a quaternary carbon, is described. Carbothiolation using thioesters was problematic due to a direct-coupling side reaction that produced a sulfide, but this side reaction was successfully suppressed by an appropriate selection of the thioester and the reaction conditions. In the preparation of chroman or coumaran derivatives by this method, the reaction using S-phenyl 4-methoxybenzenecarbothioate Pd(PPh3)4, and Cs2CO3 at 100 °C in toluene afforded the desired products in good yields (77–92%). The carbothiolation reaction also proceeded with esters of alkanethiols in higher yields (56–93%) than those obtained from the previously reported carbothiolation using triisopropylsilyl (TIPS) thioethers (12–63%). The developed Pd-catalyzed carbothiolation is applicable in the preparation of a wide range of products, including a tetralin derivative and an indoline derivative. The Pd-catalyzed carbothiolation using thioesters was found to be comparable with a previously reported carbothiolation using TIPS thioethers in terms of the yield and substrate scope, and to be a superior alternative owing to the stability and lower cost of thioesters.

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles.

A convenient and efficient method for the synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with excellent yield and enantioselectivity.

Construction of C2‐C3 Contiguous Stereogenic Centers in Indoline Derivatives by 1,3‐Dipolar Cycloaddition

AbstractWe report a reduction‐condensation‐1,3‐dipolar cycloaddition sequence to create C2‐C3 contiguous stereogenic centers in indoline derivatives. This method includes a one‐pot procedure starting from easily obtainable nitroketones and can be applied to intrarmolecular cycloaddition to give highly functionalized isoxazolidines. Both a length of methylene tether and olefinic substituents strongly affect the cycloaddition mode (exo/endo approach) to give highly stereo‐controlled tri‐ and tetracyclic systems through a single operation. Intermolecular cycloaddition is also applicable to the construction of 3 stereocenters in range of 47–87 % yield.

Cu‐Catalyzed Intramolecular Borylation‐Cross Coupling Reaction of Unactivated Alkenes to Borylated Indolines

AbstractCu‐catalyzed intramolecular borylation‐cross coupling reaction of alkenes was developed. Racemic and chiral borylated indolines were achieved by borylation‐cross coupling of alkenes with B2pin2 via simultaneous construction of C−C and C−B bonds by Cu/phosphine ligand system. With CuOAc and DPPE ligand, a series of 3‐substituted borylated indoline derivatives were concisely synthesized in good to excellent yields in short time under mild conditions. Asymmetric synthesis was investigated by ligand screening, and the chiral 3‐substituted borylated indoline was obtained in 80% yield and 80:20 er with (R, R)‐Me‐Duphos. Application of 3‐substituted borylated indolines has been demonstrated by a gram scale synthesis and further functionalization.

Synthesis of cinnamoyl tethered indoline derivatives with anti-inflammatory and antioxidant activities

Aimed to improve the anti-inflammatory activities of natural antioxidant caffeic acid phenethyl ester, the thirty derivatives of cinnamoyl tethered indoline were synthesized. The structure-activity relationship indicated that the fragments of catechol and 5-Cl-indolinyl were beneficial for the higher dual-activities of antioxidant and anti-inflammation. The most potent compound 4b suppressed the secretions of inflammatory cytokines IL-6 and TNF-α, inhibited inducible nitric oxide synthase (iNOS) expression, upregulated the antioxidant gene HO-1 expression and antioxidant enzyme SOD level, and inhibited oxidative stress marker MDA level. Besides, 4b and its acetate prodrug 4′b could effectively attenuate paw edema more than CAPE. In regard to anti-inflammatory mechanism, 4b suppressed the NF-κB activation associated with phosphorylation of p65 subunit and degradation of IκBα. In summary, this study provided a new anti-inflammatory derivative 4b which was worthy of further research.

Nickel-Catalyzed Tandem Cyclization of 1,6-Diynes with Indolines/Indoles through Dual C-H Bond Activation.

A nickel-catalyzed site-selective tandem cyclization of 1,6-diynes with substituted indolines or indoles through consecutive dual C-H bond activation is described. In the reaction, substituted fused indole and carbazole derivatives were observed in good to excellent yields, in which three consecutive C-C bonds formed in one pot. Later, in the presence of DDQ, the aromatization of the indoline derivative was converted to the indole derivative. A possible reaction mechanism involving dual C-H bond activation as a key step was proposed to account for the present reaction.

Pd-Catalyzed Intramolecular Cyclization–Thiocarbonylation Cascade Using Thioesters

AbstractA Pd-catalyzed intramolecular cyclization–thiocarbonylation cascade using thioesters is described. The developed cascade reaction afforded chromane, coumaran, indoline, and oxindole derivatives with a chiral quaternary carbon atom at the benzylic position in high to excellent yields. Relative to those observed in the previously reported relevant cascade using TIPSSPh, the yields with thioesters are almost the same or higher, depending on the substrate. Moreover, the use of thioesters significantly reduces the reaction time to less than one hour. Therefore, AcSPh is advantageous over TIPSSPh in terms of reaction time, atom economy, and cost effectiveness.

Indapamide analogue a promising drug: Synthesis, a novel crystal structure, HSA/DFT/XRD, greener pastures biological study

A new indoline derivative, N-allyl-4-chloro-3-(N,N-diallylsulfamoyl)-N-(2-methylindolin-1-yl)benzamide (ASIB), indapamide analogue, has been synthesized via the N-allylation reaction and characterized by ESI-MS, IR, 1H & 13C NMR. The geometric parameters of the title compound, whose crystallographic structure has been defined by X-ray diffraction, have been calculated by Density Functional Theory (DFT), B3LYP, 6–311++G(d,p) basis set. For these operations, the data obtained by X-ray diffraction was used as initial values, and the calculated geometric parameters and experimental results were compared. In order to understand intermolecular interactions, Molecular Electrostatic Potential (MEP) and Hirshfeld Surface Analysis (HSA) studies were figured out for the molecule. Frontier Molecular Orbitals (FMO's) were created, and Energy Gap between Lowest Unoccupied Molecular Orbital (LUMO) and Highest Occupied Molecular Orbital (HOMO) was calcculated. Adapting Greener Pastures Biological Study (GPBS) aims to conduct a fair comparative study using accessible computer-aided software. ASIB, Indapamide, Asunaprevir, Danoprevir, and Vaniprevir were docked together using the same conditions and parameters to ensure a fair comparison. The binding scores against 6LU7 were −6.6, −7.1, −8.4, 7.6, and −7.9 kcal/mol−1 for ASIB, Indapamide, Asunaprevir, Danoprevir, and Vaniprevir, respectively. A relation between the molecule's binding score was due to the hydrophobic and hydrogen interactions between the ligand and the receptor's active amino acid residues. Worth pointing out here that the free energy and environmentally friendly in Silico molecular docking method aims mainly to rank ASIB, and Indapamide with respect to the approved drugs used in this study. Results support further investigation of ASIB as non-toxic a Diuretic, anti-COVID-19 and powerful antiviral drug as an indapamide derivative. Way2drug-PASS, Pro Tox-II and SwissADME are online software tools used in this study. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of ASIB and its starting material (Indapamide) were compared.

The design, synthesis, and inhibition of Clostridioides difficile spore germination by acyclic and bicyclic tertiary amide analogs of cholate

Clostridioides difficile infection (CDI) is a major identifiable cause of antibiotic-associated diarrhea. In our previous study (J. Med. Chem., 2018, 61, 6759–6778), we have identified N-phenyl-cholan-24-amide as a potent inhibitor of spore germination. The most potent compounds in our previous work are N-arylamides. We were interested in the role that the conformation of the amide plays in activity. Previous research has shown that secondary N-arylamides exist exclusively in the coplanar trans conformation while tertiary N-methyl-N-arylamides exist in a non-planar, cis conformation. The N-methyl-N-phenyl-cholan-24-amide was 17-fold less active compared to the parent compounds suggesting the importance of the orientation of the phenyl ring. To lock the phenyl ring into a trans conformation, cyclic tertiary amides were prepared. Indoline and quinoline cholan-24-amides were both inhibitors of spore germination; however, the indoline analogs were most potent. Isoindoline and isoquinoline amides were inactive. We found that the simple indoline derivative gave an IC50 value of 1 μM, while the 5′-fluoro-substituted compound (5d) possessed an IC50 of 400 nM. To our knowledge, 5d is the most potent known spore germination inhibitor described to date. Taken together, our results indicate that the trans, coplanar conformation of the phenyl ring is required for potent inhibition.