Synthesis of Tetrazolo[5,1-a]isoquinolines via a Suzuki-Miyaura Coupling Reaction/[3 + 2] Cycloaddition Sequence.

An efficient copper-catalyzed method for the synthesis of tetrazolo[5,1-a]isoquinolines has been developed starting from alkenyl-1,2-bis(boronates). The domino reaction underwent a Suzuki-Miyaura cross-coupling reaction and an azidation followed by an in situ [3 + 2] cycloaddition. Regioselective synthesis has been demonstrated by inverting the Suzuki-Miyaura cross-coupling reaction and the azidation.

N-Substituted piperazine-coupled imidazo[2,1-b]thiazoles as inhibitors of Mycobacterium tuberculosis: Synthesis, evaluation, and docking studies.

An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).

6-Strand to Stable 10/12 Helix Conformational Switch by Incorporating Flexible ß-hGly in the Homooligomers of Camphor Derived ß-Amino Acid: NMR and X-Ray Crystallographic Evidence.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel ß-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible ß-hGly spacer at alternate positions (1 : 1 ß-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing ß-amino acids of either alternate chirality or alternate ß2/ß3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[ß-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions.

Fullerene C70 as Photoredox Catalyst for the Synthesis of Pyrrolo[2,1-a]isoquinolines by 1,3-Dipolar Cycloaddition-Aromatization Sequence.

Herein, fullerene (C70 ) is introduced as an effective photoredox catalyst for the construction of a highly functionalised pyrrolo[2,1-a]isoquinoline framework by 1,3-dipolar cycloaddition-aromatisation reaction sequence. The ability of C70 to efficiently harvest visible light, its long-triplet state lifetime, good photostability, and strong singlet oxygen generation potential (Φ▵ ≈1), make it an efficient photoredox catalyst. Upon photoirradiation, C70 promotes the formation of singlet oxygen and superoxide radical by energy transfer (EnT) and single electron transfer (SET) mechanism. The superoxide radical acts as a potential oxidant in the formation of azomethine ylide through the oxidation-deprotonation tandem process. Azomethine ylide further participates in [3+2]-cycloaddition reaction protocol with alkene/alkyne to give the corresponding pyrrolo[2,1-a]isoquinolines. Interestingly, this protocol allows the activation of a wide range of substrates giving access to a diverse library of 48 well-decorated pyrrolo[2,1-a]isoquinolines with good functional group tolerance.

Construction of Octahydro-4H-cyclopenta[b]pyridin-6-one Skeletons using Pot, Atom, and Step Economy (PASE) Synthesis.

Cascade aza-Piancatelli reaction and [3+3]/[4+2] cycloaddition reactions are carried out using the ideality principles of pot, atom, and step economy (PASE) synthesis. The reaction resulted in generation of octahydro-4H-cyclopenta[b]pyridin-6-one scaffolds. Moreover, octahydro-5,7a-epoxycyclopenta[cd]isoindol-4-one frameworks of gracilamine alkaloid and a novel decahydro-1H-dicyclopenta[cd,hi]isoindol-6-one were also realized in good yields with excellent regio- and diastereo-selectivities.

Synthesis of Fused Tetracyclic Compounds via Oxidative Annulation: Access to Copper-Catalyzed Indolo[1,2-a]quinolines and to Ruthenium-Catalyzed Isoquinolin-1[2H]-ones.

A facile double oxidative annulation of (en-3-yn-1-yl)phenylbenzamides was developed allowing us to synthetize fused tetracyclic compounds. Under copper catalysis, the reaction proceeds with high efficiency and leads to new indolo[1,2-a]quinolines via a decarbonylative double oxidative annulation. On the other hand, under ruthenium catalysis, new isoquinolin-1[2H]-ones were obtained via a double oxidative annulation.

Ir(III)-Catalyzed Dual C-H Activation of 2-Aryl Phthalazinediones and 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides for the Construction of Spiro-Fused Cyclic Frameworks.

An Ir(III)-catalyzed double C-H activation strategy has been developed for the synthesis of highly rigid spiro frameworks by means of ortho-functionalization of 2-aryl phthalazinediones and 2,3-diphenylcycloprop-2-en-1-ones using the Ir(III)/AgSbF6 catalytic system. Similarly, 3-aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides undergo smooth cyclization with 2,3-diphenylcycloprop-2-en-1-ones to afford a diverse range of spiro compounds in good yields with excellent selectivity. Additionally, 2-arylindazoles provide the corresponding chalcone derivatives under similar reaction conditions.

Dual gold-catalyzed regioselective synthesis of benzofulvenes via 5-endo dig cyclization.

An efficient dual gold-catalyzed regioselective synthesis of benzofulvenes has been developed from substituted allyloxy 1,5-diynes via 5-endo dig cyclization. In this intramolecular organic transformation a new C-C bond formation occurs and moderate to very good yields are obtained in one pot.

Radical-mediated sulfonylative/thiolative cyclization of biaryl enones to phenanthrone derivatives.

An approach for the assembly of phenanthrone derivatives bearing all carbon quaternary centres has been developed through visible light-promoted tandem sulfonylation/intramolecular-arylation of biaryl enones with sulfonyl chlorides. A series of sulfonylated 10,10-dialkylphenanthrones were obtained in good yields. In addition, the approach has been extended to thiotrifluoromethyl (SCF3) and thiocyanato (SCN) radicals to obtain the corresponding phenanthrones under oxidative conditions. The synthetic utility was also illustrated by the scalability and further transformations of the product.

BF3·OEt2-catalyzed synthesis of 2,2'-spirobi-2H-1-benzopyrans from 2H-chromenes.

A new BF3·OEt2-catalyzed approach was developed for the construction of 2,2'-spirobi-2H-1-benzopyrancarboxylates by reacting ethyl 2-(chloromethyl)-2-hydroxy-2H-chromene-3-carboxylates with salicylaldehydes. The reactions proceeded through the formation of C-C and C-O bonds in one pot. Structure assignment of compound 3c was confirmed by single crystal X-ray analysis.

Unexpected ring opening of pyrazolines with activated alkynes: synthesis of 1H-pyrazole-4,5-dicarboxylates and chromenopyrazolecarboxylates.

1H-Pyrazole-4,5-dicarboxylates and chromenopyrazole carboxylates were prepared by reacting pyrazolines with activated alkynes under neat conditions without a catalyst. The products were formed via unexpected ring opening of pyrazolines with the elimination of styrene/ethylene. These types of transformations are unknown and the products formed were confirmed using their spectral/analytical data. In addition, the structures of compounds 5e and 5n were confirmed by single-crystal X-ray analysis. Control experiments were conducted to support the proposed reaction mechanism.

Direct Access for the Regio- and Stereoselective Synthesis of N-Alkenylpyrazoles and Chromenopyrazoles.

A highly regio- and stereoselective method was developed for the preparation of N-alkenylpyrazoles and chromenopyrazoles by the reaction of N-tosylhydrazones and salicyl N-tosylhydrazones with alkynes under neat conditions in the presence of La(OTf)3. The present study was found to be efficient and convenient for direct access to N-alkenylpyrazoles and chromenopyrazoles through C-C, C-N, and C-O bond forming reactions. Structure assignment of N-alkenylpyrazole compound 5c was confirmed by X-ray analysis.

Gold-catalyzed synthesis of 1H-isochromene-4-carbaldehydes via oxidative cascade cyclization.

An efficient gold-catalyzed formation of indenylidene-derived 1H-isochromene-4-carbaldehydes from substituted 1,5,10-triyne-O-silanes was developed under mild reaction conditions. In this reaction, gold-catalyzed selective oxidation, 1,2-migration, nucleophilic addition and then 5-endo-dig cyclization took place regioselectively. The indenylidene-derived isochromene-4-carbaldehydes were synthesized in moderate to very good yields via the formation of new C-C and C-O bonds in one pot.

Chemoselective [3 + 2] annulation of oxime acetate with 2-aryl-3-ethoxycarbonyl-pyrroline-4,5-dione: an entry to pyrrolo[2,3-b]pyrrole derivatives.

A novel chemoselective [3 + 2] annulation reaction of easily accessible ketoxime acetate with 2-aryl-3-ethoxycarbonyl pyrroline-4,5-dione has been developed for the synthesis of unknown pyrrolo[2,3-b]pyrrole frameworks. This method involves copper-mediated N-O bond cleavage followed by the formation of carbon-carbon and carbon-nitrogen bonds. This operationally simple protocol provides broader functional group compatibility and good yields.

Tandem Prins cyclization for the synthesis of indole fused spiro-1,4-diazocane scaffolds.

A novel strategy has been developed for the synthesis of indole fused spiro-1,4-diazocane derivatives. Using a tandem Prins cyclization, this is the first report on the synthesis of eight-membered spirodiazocane scaffolds, which are less accessible due to ring strain but more relevant to drug discovery.

Correction: Tandem Prins cyclization for the synthesis of indole fused spiro-1,4-diazocane scaffolds.

Correction for 'Tandem Prins cyclization for the synthesis of indole fused spiro-1,4-diazocane scaffolds' by Chandrashekhar Rapelli et al., Org. Biomol. Chem., 2020, 18, 6710-6715, DOI: 10.1039/D0OB01384F.

Access to pyrrolo[2,1-a]isoindolediones from oxime acetates and ninhydrin via Cu(i)-mediated domino annulations.

A copper-mediated domino condensation reaction of readily accessible oxime acetates with ninhydrin is reported to afford pyrrolo[2,1-a]isoindolediones via new C-C & C-N bond formations. A wide range of oxime acetates were shown to generally participate in the reaction to produce the condensed products in excellent yields. The necessary control experiments were performed and the mechanism is proposed to involve sequentially the formation of iminium radical via Cu-mediated N-O bond cleavage of oxime acetates, addition of the radical to ninhydrin and rearrangement via ring expansion.

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents.

(+)-Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3-triazoles 10-44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1-A35 under copper catalysis to give triazoles 10-44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 µM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 µM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 µM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.

Synthesis, in vitro, and in vivo (Zebra fish) antitubercular activity of 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides.

We, herein, describe the synthesis of a series of novel aryl tethered 7,8-dihydroquinolin-5(6H)-ylidenehydrazinecarbothioamides 4a-v, which showed in vitro and in vivo antimycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Rv. The intermediates dihydro-6H-quinolin-5-ones 3a-v were synthesized from ß-enaminones, reacting with cyclochexane-1,3-dione/5,5-dimethylcyclohexane-1,3-dione and ammonium acetate using a modified Bohlmann-Rahtz reaction conditions. They were further reacted with thiosemicarbazide to give the respective hydrazine carbothioamides 4a-v. All the new analogues 4a-v, were characterized by their NMR and mass spectral data analysis. Among the twenty-two compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), two compounds, 4e and 4j, exhibited the highest inhibition with an MIC of 0.39 µg/mL. Compounds 4a, 4g, and 4k were found to inhibit Mtb at an MIC of 0.78 µg/mL. Hydrazinecarbothioamides 4a-k, exhibited enhanced activity than dihydroquinolinones 3a-k. The observed increase in potency provides a clear evidence that hydrazinecarbothioamide is a potential pharmacophore, collectively imparting synergistic effect in enhancing antitubercular activity of the dihydroquinolinone core. The in vivo (Zebra fish) antimycobacterial screening of the in vitro active molecules led to the identification of a hit compound, 4j, with significant activity in the Mtb nutrient starvation model (2.2-fold reduction). Docking studies of 4j showed a hydrogen bond with the P156 residue of the protein.

Gold-catalyzed formation of aryl-fused pyrazolooxazepines via intramolecular regioselective 7-exo-dig cyclization.

An efficient method was developed for the synthesis of substituted aryl-fused pyrazolooxazepines from ortho-O-propargyl aryl pyrazoles by gold catalysis. In this organic transformation a new C-N bond was formed regioselectively via 7-exo-dig cyclization. Moderate to good yields of aryl-fused pyrazolooxazepine derivatives were obtained with significant molecular complexity in one-pot.