Aryl Isothiocyanates Research Articles

Elemental Sulfur Promoted Cyclization of o‐Chloronitrobenzenes and Aryl Isothiocyanates to Furnish 2‐Aminobenzothiazoles

AbstractMethods to afford 2‐aminobenzothiazoles often involve the use of o‐aminothiophenols or aniline‐typed precursors. Herein we describe a method to furnish 2‐aminobenzothiazoles through the cyclization of o‐chloronitrobenzenes and aryl isothiocyanates with the assistance of elemental sulfur. From the perspective of step economy, our strategy allows for the direct use of nitroarene precursors without further reduction to anilines. The scope of the reaction with respect to both substrates was investigated, and it was found that electronic properties of the aryl isothiocyanate was important for obtaining acceptable yields.

Hypervalent Iodine Catalyzed Cascade C−H Functionalization: An Atom‐Economical Strategy to Access Diverse 2‐Substituted Benzothiazoles

AbstractA metal‐free 4,5‐difluoro‐2‐iodobenzoic acid catalyzed C−H functionalization strategy has been developed for the synthesis of 2‐(hetero)aryl benzothiazoles from aryl isothiocyanates and unfunctionalized arenes/thiophenes/furans at room temperature. The procedure entails one‐pot cascade carbon−carbon and carbon−sulfur bond formation facilitated by triflic acid, which serves as both a Brønsted acid and a ligand source at the in situ generated I(III) center. This process is atom‐economical and offers benefits over existing protocols for synthesizing benzothiazoles in terms of ease of use, eco‐friendliness, and not requiring the typical use of aryl aldehyde/carboxylic acid precursors. Mechanistic studies were carried out, and the synthetic utility of the protocol was demonstrated for the synthesis of the benzothiazole‐based antitumor drug GW‐610.

Ultrasound-assisted Synthesis of Novel 4-[3-acetyl-2-(N-alkyl(aryl)acetamido)-1,3, 4-thiadiazol-5-yl]-3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazoles: Anticancer Activities, Apoptotic, Cell Cycle, Molecular Docking, and ADMET Studies

Abstract: A novel series of 4-[3-acetyl-2-(N-alkyl(aryl)acetamido)-1,3,4-thiadiazol-5-yl]-3-(2-oxo-2Hchromen- 3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazoles (2a-i) and 3 was synthesized in good yields. The methodology was depended on a one-pot four-components reaction of hydrazine hydrate, alkyl(aryl) isothiocyanate, 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (1), and acetic anhydride in acetic acid under ultrasound irradiation. The spectral tools confirmed the structures of all synthesized compounds. Using the standard SRB method, the designed compounds were screened for their in vitro cytotoxicity properties against PC3, HepG2, and HCT116 human cancer cell lines. Products 2a and 2c worked best against all cancer cells tested, as well as doxorubicin. Apoptosis and cell cycle analyses were performed for the bioactive products 2a and 2c. Both products strongly impacted all tumor cells in the late apoptotic pathway and significantly inhibited all cancer cell types under investigation in both the S and G2 phases. After that, a molecular docking study was carried out on products 2a and 2c to investigate how they interact with the CDK-8 receptor. The ADMET prediction suggested that these bioactive products may be effective anticancer treatments.

Synthesis of 3,5-Disubstituted-1,2,4-thiadiazoles via NaH-DMF-Promoted Dehydrogenative Intramolecular N-S Bond Formation.

A facile transition-metal-free synthesis of 3,5-bis(het)aryl/arylaminothiadiazoles has been reported. The overall protocol involves base-mediated tandem thioacylation of amidines with dithioesters or aryl isothiocyanates in DMF solvent and subsequent in situ intramolecular dehydrogenative N-S bond formation of thioacylamidine intermediates under an inert atmosphere. A probable mechanism involving a carbamoyl anion, generated by deprotonation of DMF, acting as a radical initiator has been suggested.

A Practical Method for the Synthesis of Mesoionic 1,3-Diaryltetrazolium Derivatives Bearing a para-Substituted Phenyl Group at the 1- or 3-Position from Anilines

AbstractA simple, economical, and safe method for the synthesis of mesoionic 1,3-diaryltetrazolium derivatives bearing a para-substituted phenyl group at the 1- or 3-position via thiosemicarbazides was established. Such compounds were directly obtained from the corresponding para-substituted anilines instead of aryl isothiocyanates and arylhydrazines. The newly synthesized mesoionic compounds were successfully converted into the corresponding nitrosotetrazolium salts, which were utilized as catalysts for oxidation of an aliphatic alcohol and analyzed by cyclic voltammetry to determine the correlation between the catalytic efficiencies and redox potentials. The proposed method can be widely applied and is valuable for investigating the substituent effects in mesoionic and related compounds.

Synthesis, anti-HIV and cytotoxicity evaluation of chiral 2,5-disubstituted 1,3,4-thiadiazole derivatives bearing the sulfonamide scaffold

Abstract In the present study, chiral 2-(4-substiuted phenyl)amino-5-[1-(4-substituted benzenesulphonamido)alkyl]-1,3,4-thiazdiazoles 5a–x were synthesized from enantiopure l-amino acids in a multistep sequence. The starting acids were reacted with arylsulphonyl chlorides to produce N-arylsulfonyl amino acids 1a–h, followed by esterification to obtain the corresponding esters 2a–h. Treatment of esters with hydrazine hydrate afforded the corresponding hydrazides 3a–h. The coupling of hydrazides with aryl isothiocyanates followed by cyclization gave the target thiadiazoles 5a–x in good yields. The new synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells using MTT assay. Compounds 5s, 5v and 5w showed IC50 values of > 1.58, >1.98 and > 2.04 μm with SI > 1, respectively, indicating that these compounds were cytotoxic at concentrations values of 1.58, 1.98 and 2.04 μm, respectively.

Elemental Sulfur Promoted Cyclization of Aryl Hydrazones and Aryl Isothiocyanates Yielding 2-Imino-1,3,4-thiadiazoles.

We report a method for using elemental sulfur to facilitate the cyclization of aryl hydrazones and aryl isothiocyanates, affording biorelated 2-imino-1,3,4-thiadiazoles. Reactions progressed in the presence of elemental sulfur, N-methylmorpholine base, and DMSO solvent, while were tolerant of a wide range of functionalities including halogen, nitro, cyano, methylsulfonyl, and heterocyclic groups. The method appears to offer a general pathway for using simple, cheap, and stable reagents to afford triaryl-substituted 2-imino-1,3,4-thiadiazoles under relatively mild conditions.

Naphthyl cyanoketene N,S-acetals in glycoside synthesis: a new preparative route to a new class of N-naphthylcyanoacrylamide thioglycosides and their conversions to naphthyl–pyrazole hybrids

The novel N-naphthylcyanoacrylamide thioglycosides 4 were readily prepared by the reaction of N-napthylcyanoacetamide 1 with aryl isothiocyanates in the presence of potassium hydroxide, followed by coupling of the produced salts 2 with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galacto-pyranosyl bromides 3. The N-naphthyl acrylamide thioglycoside 12 was prepared by the reaction of N-napthylcyanoacetamide 1 with glucose isothiocyante 10 in the presence of potassium hydroxide, followed by alkylation of the produced salt 11 with methyl iodide. The reaction of thioglycoside compounds 4 with hydrazines afforded the corresponding naphthyl-pyrazole hybrids.

Cobalt ferrite nanoparticles for annulation of C3-substituted nitroarenes and aryl isothiocyanates.

The synthesis of medicinally relevant N-aryl-substituted 2-aminobenzothiazoles often uses 2-aminothiophenol derivatives, which are not commercially abundant, as starting materials. Herein, we report a method for the annulation of C3-substituted nitroarenes and aryl isothiocyanates towards the synthesis of 2-aminobenzothiazoles. Reactions proceeded in the presence of cobalt ferrite nanoparticles as a catalyst, DABCO as a base, and DMF as a promoter. The cobalt ferrite nanoparticles could be recovered after each run and reused up to 3 times while the product yield was not diminished. Our method appears to be the first example of the direct use of substituted nitroarenes for yielding 2-aminobenzothiazoles.

A solvent-free and catalyst-free reaction of o-aminobenzophenone with aryl isothiocyanates: expedient access to congested 4-phenyl-4-hydroxyquinazolin-2-thione derivatives.

An efficient method to construct 4-phenyl-4-hydroxyquinazolin-2-thiones 3via solvent-free and catalyst-free addition of o-aminobenzophenone 1 with aryl isothiocyanates 2 under thermal conditions has been developed, providing new congested 4-phenyl-4-hydroxyquinazolin-2-thiones 3 in practically quantitative yields via simple purification by filtration/recrystallization. Extension of these conditions to o-aminoacetophenone 4 in place of o-aminobenzophenone 1 led to 4-methylenequinazoline-thione 5 as a result of a subsequent dehydration reaction.

Additive-free synthesis of S-substituted isothioureas via visible-light-induced four-component reaction of α-diazoesters, aryl isothiocyanates, amines and cyclic ethers

An additive-free and environmentally friendly strategy has been realized for the construction of S-substituted isothioureas through visible-light-induced multicomponent reaction starting from α-diazoesters, aryl isothiocyanates, amines and cyclic ethers. This methodology features simple operation, mild reaction conditions, favorable functional group tolerance, easily available starting materials and high efficiency.

A Cost-effective and Green Synthesis of Isothiocyanates

Abstract: Irritant, expensive, or toxic desulfurating agents are usually used in the synthesis of isothiocyanates from amines, CS2, and appropriate bases, accompanied by a tedious workup. A more practical and green method has been developed. Cheap and non-toxic CaO was used as both a base and a desulfurating agent in the synthesis of isothiocyanates. Both alkyl and aryl isothiocyanates are easily synthesized in moderate to high yield from amines, CS2, and CaO under mild conditions. A simple and practical synthetic approach for isothiocyanates from amines, CS2, and CaO was developed. CaO acts as both a base and a desulfurating agent in the reactions, simplifying the reaction system and reducing cost as well as side products. Moderate to high yields were obtained at room temperature in 48 hours which included alkyl and aryl isothiocyanates.

Excited state dynamics of 1,2,4-triazolyl-thio-pentane-2,4-dione system and their conversion to biologically active novel triazole-S-pyrazole hybrids

The current study focuses on designing and synthesis of novel 1,2,4-triazole appended pyrazoles linked to each other through sulphur atom. Herein we report the condensation of nicotinic hydrazide and isonicotinic hydrazide with aryl isothiocyanate derivatives to obtain carbothioamides which are cyclised to yield 4-aryl-5-(pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives under alkaline conditions. Further, condensation of thiones with 3-chloro-pentane-2,4-dione generated novel 1,2,4-triazolyl-thio-pentane-2,4-dione system which was studied for keto-enol tautomerism with the help of spectral data (FT-IR, NMR and Mass). Low energy barrier between three different tautomers (chelated enol, keto, non-chelated enol) resulted in transformation of chelated enol ⇌ non-chelated enol ⇌ keto form upon UV-irradiation. Solvent effects on excited state intramolecular proton transfer (ESIPT) in dione 5a have been studied and the experimental findings were documented with TD-DFT studies. The generated 1,3-diketones were treated with hydrazine hydrate to obtain triazolyl-S-pyrazole hybrids 6. Structure of the synthesized compounds was identified on the basis of spectroscopic data. Single crystal X-ray diffraction (SC-XRD) studies of the representative compound 6a predicts the strong intermolecular hydrogen bonding interaction between N2H2 of pyrazole ring of one molecule and N4 of triazole ring (N2H2…N4) of the other molecule which accounts for the crystal stability. Moreover, triazolyl-S-pyrazole hybrids were also assessed for their antibacterial activities and some derivatives have shown promising activity against E. coli.

DNA-Compatible Synthesis of Thiazolidione Derivatives via Three-Component Annulation and Knoevenagel Condensation.

Thiazolidione, conferring drug-like properties, is an important heterocycle that widely exists in medicinally relevant molecules. In this work, by efficiently assembling various DNA-tagged primary amines, abundant aryl isothiocyanates, and ethyl bromoacetate, we present a DNA-compatible three-component annulation to generate a 2-iminothiazolidin-4-one scaffold, which was further decorated via Knoevenagel condensation by employing (hetero)aryl and alkyl aldehydes. These thiazolidione derivatives should find broad use in focused DNA-encoded library construction.

Cooperative Capture Synthesis of Functionalized Heterorotaxanes─Chemical Scope, Kinetics, and Mechanistic Studies.

The self-assembly of molecularly interlocked molecules offers new opportunities for creating bioactive molecules for applications in medicine. Cooperative capture synthesis of heterorotaxanes in water is an attractive methodology for developing multifunctional supramolecular imaging agents or drugs, but derivatizing the rotaxane scaffold with biologically active vectors like peptides and proteins, or reporter probers like radioactive metal ion complexes and fluorophores, requires the installation of reactive functional groups. Here, we explored the chemical scope of β-cyclodextrin (β-CD) derivatization on the cucurbit[6]uril (CB[6])-mediated cooperative capture synthesis of hetero[4]rotaxanes with the objective of identifying which reactive groups can be used for further functionalization without compromising the efficiency of rotaxane synthesis. Nine β-CD derivatives featuring an electrophilic leaving group (tosylate), aliphatic amines, a carboxylic acid, aliphatic azides, anilines, and aryl isothiocyanate were evaluated in the synthesis of hetero[4]rotaxanes. Experimental measurements on the kinetics of rotaxane synthesis were combined with detailed computational studies using the density functional theory to elucidate the mechanistic pathways and rate determining step in the cooperative capture process. Computational studies on the structure and bonding also revealed why intermolecular interactions between the β-CD and CB[6] macrocycles improve the rate and efficiency of rotaxane formation through cooperative capture. Understanding the mechanistic details and synthetic scope will facilitate broader access to functionalized hetero[4]rotaxanes for applications in biomedicine and beyond.

Spectroscopic, X-ray, mechanistic and DFT studies on formation of novel benzoimidazole-4-ones from cyclohexenyl carbothioamides

Spectroscopic studies of cyclohexenyl carbothioamides 2, obtained from condensation of 1,3-cyclohexandione with aryl isothiocyanates, predicted the proton transfer behaviour in solid, solution and gaseous phases. DFT studies in gaseous and solution phase shows good congruence with the experimental findings. Condensation of cyclohexenyl carbothioamide 2a with hydrazine hydrate unexpectedly embellished novel 2-(4-chlorophenyl)amino)-2,5,6,7-tetrahydro-4H-benzo[d]imidazol-4-one 4a and 2-(bis((4-chlorophenyl)amino)methylene)cyclohexane-1,3-dione 3a instead of the presumable 2H and 1H-indazole derivatives 5a and 6a, respectively. The proposed mechanism of formation of unconventional products 3a and 4a supported by experimental results is described. Spectroscopic investigations such as FT-IR, Mass and NMR (1H, 13C, DEPT-135, HSQC, COSY, NOESY) along with X-ray crystallographic results established the structure of two derived novel products 3a and 4a. The interesting feature of this study is NN bond cleavage of strained transit diazetidine ring and formation of CN bond leading to generation of novel benzoimidazol-4-one derivative 4a. Hirshfeld surface analysis of entitled compounds is reported.

Iron(III)-Catalyzed Regioselective Synthesis of Electron-Rich Benzothiazoles from Aryl Isothiocyanates via C–H Functionalization

We report herein a direct synthetic route for the preparation of 2-arylbenzothiazoles using aryl isothiocyanates and electron-rich arenes. The synthetic route involves triflic acid promoted addition of the arenes to aryl isothiocyanates followed by FeCl3-catalyzed C-S bond formation via C-H functionalization. The approach provides the advantage of synthesis of benzothiazoles without the conventional use of aryl aldehyde/carboxylic acid precursors employing the less expensive iron(III) catalyst.

Synthesis of aryloxyacetylthiourea derivatives for the development of radicle elongation inhibitor of parasitic weeds

Aryloxyacetylthiourea, 1-(3,4-dichlorophenyl)-3-(2-phenoxyacetyl)thiourea (PI-28), has attracted attention as a lead compound for the development of radicle elongation inhibitors in Orobanche minor seeds germination. In this study, we synthesized PI-28 and its derivatives in two steps using commercially available phenols, 2-chloroacetamide, and N-aryl isothiocyanates. In this method, 2-aryloxyacetanilides, which are also attractive as bioactive compounds, were obtained as byproducts. According to the result of the control experiment, the formation of byproducts was due to the loss of isothiocyanate moiety from the formed aroyloxyacetylthioureas caused by the action of another aryl isothiocyanate during the reaction. Moreover, we have developed a one-pot synthesis method for PI-28 derivatives with comparable overall yields.

TFE assisted mechanochemical synthesis of new pyrazolones from Meldrum acid carbothioamides-Experimental and theoretical studies

Facile synthesis of Meldrum acid carbothioamides 3 from condensation of Meldrum acid and aryl isothiocyanates under ultrasonication is reported. The structure of carbothioamides was investigated in solid and solution state from X-ray diffraction and spectroscopic studies, respectively. Studies on photo-tautomerism emanating from proton switching between O and S under UV irradiation have been reported. S-methyl derivatives 4 of carbothioamides 3 were also prepared and solid state structure of the representative compound was described. Novel synthetic mechanochemical route to synthesis of functionalized pyrazolones 5 from reaction of carbothioamides 3 or their S-methyl derivatives and hydrazine hydrate in presence of 2,2,2-trifluoroethanol has been developed. The structure and proton tautomerism of pyrazolones has been assigned on spectroscopic grounds and authenticated by single crystal X-ray diffraction (SCXRD) studies. The tautomeric equilibrium between different forms of pyrazolone 5a has been studied by ab initio calculations. Experimental studies are in congruous with theoretical results. Further, synthesis of new thiazole derivatives 6 and thiazolidin-5-one derivatives 7 linked with Meldrum's acid (MA) moiety was achieved from reaction of 3 with 3-chloro-2,4-pentanedione and chloroacetyl chloride, respectively. Spectroscopic studies confirmed the structure of new developed products.

Antimalarial Activity of Tri- and Tetra-Substituted Anilino Pyrazoles

Pyrazole core represents a privilege scaffold in medicinal chemistry; a number of pyrazole compounds are endowed with various pharmacological activities in different therapeutic areas including antimalarial treatment. Supported by this evidence, a series of 5-anilino-3-(hetero)arylpyrazoles were evaluated for their antiplasmodial activity in in vitro assays. The compounds were synthesized according to regioselective and versatile protocols that combine active methylene reagents, aryl isothiocyanates and (substituted)hydrazines. The considered derivatives 2 allowed the definition of consistent structure-activity relationships and compounds 2b,e,k,l were identified as the most interesting derivatives of the series showing micromolar IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium strains. Additionally, the most active anilino-pyrazoles did not show any cytotoxicity against tumor and normal cells and were predicted to have favorable drug-like and pharmacokinetic properties.