Efficient and stereoselective one-pot synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic fused benzoxazinyl-oxazolidinones (20 examples) were obtained in good to excellent yields and high enantioselectivities with facile operation. Furthermore, four stereoisomers were afforded respectively in high ee values (>97.8%) via using different chiral 2,3-epoxy-4-trityloxybutanol. This methodology has been applied to the synthesis of key intermediates of drug candidates.

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization.     

Pyridine-2-carboxylic acid as an effectual catalyst for rapid multi-component synthesis of pyrazolo[3,4-b]quinolinones

Green synthesis of pyrazolo[3,4-b]quinolinones was designed using bioproduct pyridine-2-carboxylic acid (P2CA) as a green and efficient catalyst. The multi-component reaction of aldehydes, 1,3-cyclodiones and 5-amino-1-phenyl-pyrazoles regioselectively produced pyrazolo[3,4-b]quinolinones in excellent yield (84–98%). Recyclization of the catalyst was also investigated. The electronic effect of the various substituents in aromatic rings indicated that the reaction proceeded through the carbocation intermediate. This newly designed protocol very quickly constructed products conventionally under milder conditions.

Green synthesis of pyrazolo[3,4-b]quinolinones was designed using bioproduct pyridine-2-carboxylic acid (P2CA) as a green and efficient catalyst.     

Synthesis of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridines via one-pot sequential Suzuki–Miyaura coupling

A practical synthesis of diarylpyrazolo[3,4-b]pyridine derivatives by a combination of chemoselective Suzuki–Miyaura cross-coupling reactions was developed. The sequential arylation strategy can be performed in a one-pot manner without much loss of efficiency when compared to the corresponding stepwise synthesis. These conditions are applicable to the coupling of a wide variety of aryl and heteroaryl-boronic acids with pyrazolo[3,4-b]pyridines with high selectivity of the C3 over the C6 position, thus enabling the rapid construction of a diverse array of medicinally important diarylpyrazolo[3,4-b]pyridines.

An efficient method to produce diarylpyrazolo[3,4-b]pyridines derivatives via combination of chemoselective Suzuki–Miyaura cross-coupling reactions has been developed.     

Sonochemistry in an organocatalytic domino reaction: an expedient multicomponent access to structurally functionalized dihydropyrano[3,2-b]pyrans,spiro-pyrano[3,2-b]pyrans,and spiro-indenoquinoxaline-pyranopyrans under ambient conditions

A highly convenient and sustainable one-pot approach for the diversely-oriented synthesis of a variety of medicinally privileged amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives on the basis of a domino three-component reaction of readily available carbonyl compounds including aryl aldehydes or isatins, active methylene compounds, and kojic acid as a Michael donor using secondary amine catalyst l-proline under ultrasound irradiation in aqueous ethanolic solution at ambient temperature has been developed. This methodology can involve the assembly of C–C, C C, C–O, C–N bonds via a one-pot operation, and following this protocol, a series of novel amino-substituted spiro[indeno[1,2-b]quinoxaline-11,4-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylates have been synthesized. The practical utility of this method was found to be very efficient for scale-up reaction and other useful transformations. The methodology provides significant advantages including mild reaction conditions, energy-efficiency, short reaction time, fast reaction, simple work-up procedure, broad functional group tolerances, utilization of reusable catalyst, green solvent system, being metal-free, ligand-free, waste-free, inexpensive, etc. Excellent chemical yields have been achieved without using column chromatography. To address the issues of green and more sustainable chemistry, several metrics including Atom Economy (AE), Reaction Mass Efficiency (RME), Atom efficiency, E-factor, Process Mass Intensity (PMI), and Carbon Efficiency (CE) have been quantified for the present methodology that indicates the greenness of the present protocol.

Amino-substituted 4,8-dihydropyrano[3,2-b]pyran-3-carbonitriles, and spiro[indoline-3,4′-pyrano[3,2-b]pyran]-3-carbonitrile/carboxylate derivatives has been synthesised under ultrasound irradiation in aqueous ethanolic solution at rt.     

Anion–cation co-operative catalysis by artificial sweetener saccharine-based ionic liquid for sustainable synthesis of 3,4-dihydropyrano[c]chromenes, 4,5-dihydropyrano[4,3-b]pyran and tetrahydrobenzo[b]pyrans in aqueous medium

In this study, a saccharine-based ionic liquid [Bmim]Sac has been found to be a sustainable catalyst for the synthesis of 3,4-dihydropyrano[c]chromenes, 4,5-dihydropyrano[4,3-b]pyran and tetrahydrobenzo[b]pyrans scaffolds through Domino Knoevenagel–Michael reaction. The easy recovery of the catalyst and high yield of the products make the protocol attractive, sustainable and economical. A mechanistic hypothesis is discussed using the concept of cooperative catalysis based on the dual (electrophilic/nucleophilic) activation of reactants by [Bmim]Sac. Furthermore, dual hydrogen bonding of saccharinate anions plays an important role in the activation of nucleophiles.

Artificial sweetener saccharine based ionic for sustainable synthesis of 3,4-dihydropyrano[c]chromenes, 4,5-dihydropyrano[4,3-b]pyran and tetrahydrobenzo[b]pyrans in aqueous medium scaffolds through Domino Knoevenagel–Michael reaction.     

On water catalyst-free synthesis of benzo[d]imidazo[2,1-b] thiazoles and novel N-alkylated 2-aminobenzo[d]oxazoles under microwave irradiation

A highly efficient unprecedented catalyst-free microwave-assisted procedure for synthesizing benzo[d]imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazol in green media was developed. The transformation provided rapid access to functionalized benzo[d]imidazo[2,1-b]thiazoles from 2-aminobenzothiazole and N-alkylated 2-aminobenzo[d]oxazole from 2-aminobenzoxazole scaffolds under mild transition-metal-free conditions. This synthetic manipulation is expected to greatly expand the repertoire of reaction types in heterocyclic chemistry and pave the way for new syntheses of bioactive compounds.

A highly efficient unprecedented catalyst-free microwave-assisted procedure for synthesizing benzo[d]imidazo[2,1-b]thiazoles and N-alkylated 2-aminobenzo[d]oxazol in green media was developed.     

Three-component microwave-assisted synthesis of 3,5-disubstituted pyrazolo[3,4-d]pyrimidin-4-ones

A practical three-component method for the synthesis of pyrazolo[3,4-d]pyrimidin-4-ones was developed. The reaction was performed in a one-pot manner under controlled microwave irradiation using easily accessible methyl 5-aminopyrazole-4-carboxylates, trimethyl orthoformate, and primary amines. Under the optimized conditions, challenging substrates, such as N-1 unsubstituted 5-aminopyrazole-4-carboxylates with another substituted amino group in position 3, reacted selectively affording 5-substituted 3-arylamino-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones. The reaction tolerated a range of primary amines, including anilines. The advantages of the developed protocol include short reaction time, pot- and step-economy, and convenient chromatography-free product isolation. The structural features of representative products were explored by X-ray crystallography.

A practical three-component method for the synthesis of pyrazolo[3,4-d]pyrimidin-4-ones was developed.     

Indoleninyl-substituted pyrimido[1,2-b]indazoles via a facile condensation reaction

A new series of pyrimido[1,2-b]indazoles bearing indolenine moieties was synthesized through a simple condensation reaction with up to 94% yield. The present method features the versatile formation of a pyrimidine ring with a broad range of substrates, great functional group compatibility and facile synthetic operation. The work offers opportunities in drug development as well as in materials science.

A facile synthesis of fused nitrogen tricyclic based pyrimido[1,2-b]indazoles featuring indolenines is presented.     

Convenient construction of tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles and tetrahydroindolizino[8,7-b]indoles via one-pot domino reaction

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes. Under similar conditions, the one-pot reaction of tryptamines, alkyl propiolates and β-nitroalkenes resulted in functionalized tetrahydroindolizino[8,7-b]indoles. The reaction mechanism involved sequential generation of β-enamino ester, Michael addition, Pictet–Spengler reaction and annulation process. The reaction showed high atomic economy and met the goals of sustainable chemistry.

The functionalized tetrahydrochromeno[4′,3′:2,3]indolizino[8,7-b]indoles were conveniently synthesized in high yields by one-pot domino reaction of tryptamines, alkyl propiolates and 2-aryl-3-nitro-2H-chromenes.     

One-pot multicomponent synthesis of thieno[2,3-b]indoles catalyzed by a magnetic nanoparticle-supported [Urea]4[ZnCl2] deep eutectic solvent

In this study, we have developed the synthesis of thieno[2,3-b]indole dyes via a multicomponent reaction of cheap and available reagents such as sulfur, acetophenones, and indoles using a magnetic nanoparticle-supported [Urea]₄[ZnCl₂] deep eutectic solvent as a green catalyst. The synthesis of a series of diversely functionalized thieno[2,3-b]indole has been successfully performed in a one-pot reaction. Among a total of 25 compounds synthesized, there are 21 new compounds with full characterization such as FT-IR, ¹H and ¹³C NMR, HRMS (ESI). Due to the deep eutectic solvent coated surface of the magnetic nanoparticles, the catalyst could be recovered by an external magnet and reused in five consecutive runs without a considerable decrease in catalytic activity.

We have developed the synthesis of thieno[2,3-b]indole dyes via a multicomponent reaction of cheap and available reagents using a magnetic nanoparticle-supported [Urea]₄[ZnCl₂] deep eutectic solvent as a green catalyst.     

Environmentally friendly domino multicomponent strategy for the synthesis of pyrroloquinolinone hybrid heterocycles

An efficient and elegant assembly of pyrene/aryl fused pyrrolo[2,3-b]quinolinone and pyrrolizino[3,2-b]quinolinone hybrid heterocycles was achieved via a domino multicomponent reaction strategy using a solid state melt reaction (SSMR) condition. The 1,3-dipole component was generated in situ from N-methylgylcine/l-proline and isatin, while the Baylis–Hillman adduct prepared from pyrene-1-carbaldehyde and various benzaldehydes is used as the dipolarophile. The domino protocol comprises 1,3-dipolar cycloaddition and a consequent double annulation reaction process. The advantages of this cascade protocol include environmentally friendly conditions, the avoidance of toxic organic solvents, simple work-up and good to excellent product yields.

An efficient and elegant assembly of pyrene/aryl fused pyrrolo[2,3-b]quinolinone and pyrrolizino[3,2-b]quinolinone hybrid heterocycles was achieved via a domino multicomponent reaction strategy using a solid state melt reaction (SSMR) condition.     

Regioselective,one-pot,multi-component,green synthesis of substituted benzo[c]pyrazolo[2,7]naphthyridines

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component “on-water” reaction of isatin, malononitrile and 3-aminopyrazole. The Knoevenagel condensation of isatin with malononitrile resulted in the formation of arylidene, which subsequently underwent Michael addition with 3-aminopyrazole followed by basic hydrolysis, cyclization, decarboxylation and aromatization to give the target naphthyridines in good to excellent yields. The one-pot multi-component protocol was also employed to obtain the said naphthyridines in a lower yield (10–15%) than obtained by basic hydrolysis of spiro-intermediates. The present study shows attractive features such as the use of water as a green solvent, short reaction time, reduced waste products and transition metal free C–C and C–N bond formation. The structures of the synthesized derivatives were established through FTIR, ¹H-NMR, ¹³C-NMR spectroscopy and ESI-mass spectrometry.

An efficient and environmentally benign synthetic protocol has been developed for the synthesis of benzo[c]pyrazolo[2,7]naphthyridine derivatives through regioselective multi-component “on-water” reaction of isatin, malononitrile and 3-aminopyrazole.     

Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4′-pyrano[2,3-c]pyrazol], spiro[indoline-3,5′-pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3′-indoline] and spiro[benzo[g]chromene-4,3′-indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity.

Synthesis of spirooxindole pyrans by a sequential four-component reaction of nitroketene dithioacetals, alkylamine/benzylamine, isatin, and active methylene compounds.     

Transition-metal-free base catalyzed intramolecular cyclization of 2-ynylphenols for efficient and facile synthesis of 2-substituted benzo[b]furans

A transition-metal-free base catalyzed intramolecular cyclization of 2-ynylphenols was developed for the facile synthesis of 2-substituted benzo[b]furans. Various 2-aryl and 2-alkyl substituted benzo[b]furans can be obtained with good to excellent yields using readily available Cs₂CO₃ as the catalyst under mild reaction conditions. The broad substrates scope and the typical maintenance of vigorous efficiency on gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[b]furans derivatives.

An efficient and practical transition-metal-free synthesis of 2-substituted benzo[b]furans catalyzed by readily accessible base was developed with broad substrates scope.     

Synthesis of Schiff and Mannich bases of new s-triazole derivatives and their potential applications for removal of heavy metals from aqueous solution and as antimicrobial agents

An efficient, simple, and one-pot double Mannich reaction was performed for the synthesis of cyclized 2-methyl-6-substituted-6,7-dihydro-5H-s-triazolo[5,1-b]-1,3,5-thiadiazines via a reaction of 5-methyl-1H-s-triazole-3-thiol (1) with formaldehyde and primary aliphatic amines in ethanol at room temperature, while with primary aromatic amines, uncyclized 3-methyl-1-((substituted-amino)methyl)-1H-s-triazole-5-thiols were produced. Under Mannich reaction conditions, 4-amino-3-methyl-s-triazole-5-thiol (8) reacted with formaldehyde only in boiling ethanol or at room temperature to afford 3-methyl-5,6-dihydro-s-triazolo[3,4-b]-1,3,4-thiadiazole without incorporation of secondary amine. Furthermore, after reaction of compound 8 with aromatic aldehydes under different reaction conditions, uncyclized Schiff''s bases were produced. Therefore, reaction of these Schiff''s bases with primary or secondary amines with formaldehyde in ethanol at room temperature afforded the corresponding Mannich bases 13–14. The structures of all new compounds were confirmed using spectral analysis. Furthermore, most of the synthesized derivatives showed high efficiency for removal of Pb²⁺, Cd²⁺, Ca²⁺, and Mg²⁺ from aqueous solutions, as well as antimicrobial activity.

An efficient synthesis of Schiff and Mannich bases of new s-triazole derivatives under mild conditions has been developed for the removal of Pb²⁺, Cd²⁺, Ca²⁺, and Mg²⁺ from aqueous solutions and as antimicrobial agents.     

The synthesis of anticancer sulfonated indolo[2,1-a]isoquinoline and benzimidazo[2,1-a]isoquinolin-6(5H)-ones derivatives via a free radical cascade pathway

A facile CuBr₂ induced radical relay addition/cyclization of activated alkenes with substituted-thiosulfonates has been achieved, leading to a broad range of sulfonated indolo[2,1-a]isoquinolines and benzimidazo[2,1-a]isoquinolin-6(5H)-ones in moderate to good yields. In particular, some compounds exhibit bioactivity against cancer cell lines. This protocol shows advantages of low-cost, base-free, simple operation, and broad functional group tolerance.

A facile CuBr₂ induced tandem radical reaction has been achieved, leading to sulfonated indole and benzimidazole derivatives.     

Synthesis and characterization of amino glucose-functionalized silica-coated NiFe2O4 nanoparticles: a heterogeneous,new and magnetically separable catalyst for the solvent-free synthesis of pyrano[3,2-c]chromen-5(4H)-ones

A novel, efficient and one-pot multi-component procedure for the synthesis of simple pyrano[3,2-c]chromen-5(4H)-ones or pyrazolyl pyrano[3,2-c]chromen-5(4H)-ones via reaction of aryl aldehydes, acetophenones and 4-hydroxycoumarin promoted by amino glucose-functionalized silica-coated NiFe₂O₄ nanoparticles under solvent-free conditions without using any other harmful organic reagents was reported. The structure of this nanoparticle was characterized by transmission electron microscopies, X-ray diffraction and Fourier transform infrared spectroscopies. The catalyst could easily be separated from the reaction mixture by using an external magnetic field and it was reusable. The high purity of the desired products, eco-friendliness, short reaction time and easy workup procedure can be mentioned as the other advantages of this method.

We have developed NiFe₂O₄@SiO₂@glucose amine as a new, mild and efficient avenue for the synthesis of pyrano[3,2-c]chromen-5(4H)-ones.     

Facile synthesis of 2-substituted benzo[b]furans and indoles by copper-catalyzed intramolecular cyclization of 2-alkynyl phenols and tosylanilines

A catalytic amount of CuCl and Cs₂CO₃ was employed to synthesize a variety of 2-substituted benzo[b]furans and indoles by an intramolecular cyclization of 2-alkynyl phenols and tosylanilines. This protocol features mild conditions, high yields and broad substrate scope, which makes it a practical method for the synthesis of 2-substituted benzo[b]furans and indoles.

A facile and inexpensive copper-catalyzed method was developed for the synthesis of 2-substituted benzo[b]furans and indoles.     

ACI/EG eutectic mixture mediated synthesis,characterization and in vitro osteoblast differentiation assessment of spiropyrrolo[1,2-b]isoquinoline analogues

An eco-friendly acetylcholine iodide–ethylene glycol (ACI/EG) deep eutectic mixture mediated green protocol has been developed for the synthesis of hitherto unexplored multi-functionalized linear tricyclic spiropyrrolo[1,2-b]isoquinoline analogues. The effects of the synthesized compounds on the osteoblast differentiation of hBMSC-TERT cell lines were investigated and promising results were observed with significant IC₅₀ values. In addition, molecular modeling simulations were also performed with the 3D structure of BMP-2 to reveal binding interactions and orientations of highly potent spiropyrrolo[1,2-b]isoquinoline analogues.

An eco-friendly acetylcholine iodide–ethylene glycol (ACI/EG) deep eutectic mixture mediated green protocol has been developed for the synthesis of unexplored multi-functionalized linear tricyclic spiropyrrolo[1,2-b]isoquinoline analogues.     

Green synthesis and characterisation of novel [1,3,4]thiadiazolo/benzo[4,5]thiazolo[3,2-a]pyrimidines via multicomponent reaction using vanadium oxide loaded on fluorapatite as a robust and sustainable catalyst

We synthesised materials with different loadings of vanadia on fluorapatite (V₂O₅/FAp), fully characterised their structural properties using various spectral techniques including TEM, BET, XRD, FT-IR, SEM and EDX and assessed their prowess as catalysts. The 2.5% V₂O₅/FAp exhibited excellent activity for the synthesis of novel [1,3,4]thiadiazolo[3,2-a]pyrimidines and benzo[4,5]thiazolo[3,2-a]pyrimidines. The one-pot three-component fusion reaction between chosen substrates of 1,3,4-thiadiazole-amines or 2-amino-benzothiazole, aldehydes and active methylene compounds in ethanol solvent at room temperature gave an excellent yield of products (90–97%) in a swift reaction (25–30 min). The advantages of this protocol are rapid synthesis, mild reaction conditions, green solvent, easy work-up, eco-friendliness, reusability of catalyst and no need for column chromatography.

We synthesized material with different loading of vanadia on fluorapatite (V₂O₅/FAp), and excellent activity was showed for the synthesis of pyrimidine derivatives (90–97%) in ethanol medium for short reaction time.