Acyl Isothiocyanates Research Articles

Lewis base-catalyzed [3 + 2] annulation of β-oxo-acrylamides with acyl isothiocyanates: facile access to 2-iminothiazolidin-4-one derivatives

A novel and efficient protocol for the Cs2CO3-catalyzed [3 + 2] annulation of β-oxo-acrylamides with acyl isothiocyanates has been developed under mild reaction conditions. This strategy offers a streamlined route to access 2-iminothiazolidin-4-one derivatives with yields of 53–83 %. The annulation is characterized by being transition-metal-free, atom-economic, and operationally straightforward.

Acyl Isothiocyanates of 2-Allyl- and 2-Benzylmaleopimarimide: Synthesis of 1,3,4-Thiadiazoles

Acyl Isothiocyanates of 2-Allyl- and 2-Benzylmaleopimarimide: Synthesis of 1,3,4-Thiadiazoles

Synthesis and spectral characteristics of hydrazinocarbonothioyl derivatives of maleopimaric acid

Reaction of acyl isothiocyanates of 2-allyl- and 2-benzylmaleopimarimides with 3-carboxy- and 2,4-dinitrophenylhydrazines and hydrazides of some aromatic acids (benzoic, 4-hydroxy- and 4-methoxybenzoic, nicotinic, isonicotinic) furnished linear hydrazinocarbonothioyl derivatives of these maleopimarimides in high yields. Structure of the synthesized compounds was determined by 1H,13C, 1H-13C HSQC, 1H-13C HMBC, COSY, NOESY, and 1H-15N HMBC NMR spectroscopy methods.

Synthesis, Biochemical Characterization, and in-Silico Investigations of Acyl-3-(Ciprofloxacinyl) Thioureas as Inhibitors of Carbonic Anhydrase-II

A new series of 1-(acyl/aroyl)-3-(ciprofloxacinyl) thioureas (5a–o) was synthesized by the reaction of ciprofloxacin (4) in dry acetone with acyl isothiocyanate intermediate (3). The synthesized compounds were characterized by FT-IR, 1H-NMR, and 13C-NMR. Furthermore, the synthesized compounds were tested for inhibitory potential against carbonic anhydrase (CA-II) and 15 lipoxygenase (LOX) enzymes. The tested compounds exhibited maximum inhibition of CA-11 with moderate anti-inflammatory potential, at the same concentration, i.e. 100 µM, therefore, can be considered as the selective inhibitors of CA-II. Among the tested derivatives 5g showed remarkable inhibitory activity against CA enzyme with IC50 value of 0.97 ± 0.11 µM and this derivative exhibited approximately 40% inhibition of 15-LOX, indicating that compound has moderate anti-inflammatory properties. The molecular docking studies, density functional theory (DFT) calculations, and molecular dynamic (MD) simulation studies were performed to evaluate their binding affinities, stability, and chemical reactivity within the active pocket of the targeted enzymes. The docking analysis and MD simulation studies revealed that the most active inhibitor 5g showed important interactions within the binding pockets of CA-II and may be responsible for the inhibitory activity of the compound toward the targeted enzymes. Therefore, the screened derivatives provided an outstanding platform for further development of CA inhibitors.

Lewis base-catalyzed cascade [4 + 2]-annulation reaction of N-alkoxy acrylamides and acyl isothiocyanates: facile access to 2-imino-1,3-thiazinone derivatives.

A formal [4 + 2]-cycloaddition reaction of N-alkoxy acrylamides and acyl isothiocyanates was developed via a Lewis base-catalyzed cascade aza-nucleophilic addition/thio-Michael addition process under mild conditions. This study provides a facile approach for preparing 2-imino-1,3-thiazinone derivatives in moderate to excellent yields and enriches the field of heterocyclic acrylamide chemistry. The reported method features metal-free reaction conditions, high atom economy, and easy operation. Moreover, the reaction was successfully scaled up and derivatization reactions were successfully performed.

Substituted acyl thioureas and acyl thiosemicarbazides: synthesis and biological activity (minireview)

Acyl isothiocyanates and their functional derivatives (acyl thioureas and acyl thiosemicarbazides) are an important group of organic compounds that are widely used in the synthesis of heterocycles and in chemistry as catalysts, ligands, colorimetric hemosensors, etc. In recent years, there has been an increased interest towards this class of compounds as promising biologically active compounds, especially since the latest advances in medicinal chemistry for them are not sufficiently studied.
 The aim. To summarize and systematize information for the last 10 years on methods of synthesis and biological activity of substituted acyl thioureas and acyl thiosemicarbazides.
 Materials and methods. Web-tools for finding scientific information (Reaxys, Scopus, Google Scholar, ScienceResearch, SciFinder, Web of Science, etc.).
 Results and discussion. Literature sources related to the methods of synthesis of substituted acyl thioureas and acyl thiosemicarbazides were systematized and analyzed. The main approaches for the formation of these compounds are revealed: stepwise formation from carboxylic acids, through acyl chlorides and acyl isothiocyanates followed by nucleophilic addition of amines or hydrazides of carboxylic acids ("one-pot synthesis"), nucleophilic addition of amines or hydrazides of carboxylic acids directly to acyl isothiocyanates and parallel microwave synthesis using acyl isothiocyanates and amines as reagents. The possibility of their use as ligands for the formation of complex compounds with transition metal ions was discussed. In the review biological activity of these structures, namely antimicrobial, fungicidal, antitumor, antiviral, antifungal and other activities was detailazed.
 Conclusions. The basic approaches to the synthesis of substituted acylthuoureas and acyl thiosemicarbazides which include the application of carboxylic acids, their derivatives (acyl halides and isothiocyanates) and N-nucleophiles as initial compounds were discussed. It was shown that aforementioned class of the compounds reveals the versatile biological activity and are promising for further structural modification aimed to the search of novel drugs

Combustion Synthesis of Nano Fe2O3 and its Utilization as a Catalyst for the Synthesis of Nα-Protected Acyl Thioureas and Study of Anti-bacterial Activities.

A simple and eco-friendly nano Fe2O3 heterogeneous catalytic system is described for the synthesis of acyl thiourea derivatives from corresponding in situ generated acyl isothiocyanates and amino acid esters in acetone obtained in good yields. The structures of synthesized acyl thioureas were confimed by 1H NMR, 13C NMR, mass, and FTIR analysis. Fe2O3 NPs has been prepared via a solution combustion route using ascorbic acid as the reducing agent and ferric nitrate as the source of iron. The prepared nano material has been characterized by XRD, SEM, UV-Visible, and FTIR analysis. More prominently, the Fe2O3 and other impurities are removed though a simple work-up and the material prepared shows to be effective in catalyzing the conversion of reactants to products in good yields. Further, some of the synthesized acyl thioureas were evaluated for in vitro antibacterial activity against Staphylococcus aureus and Escherichia coli.

Synthesis of novel hybrid pharmacophore of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides as potent carbonic anhydrase-II and 15-lipoxygenase inhibitors.

A series of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides (5a-j) were synthesized by the reaction of sulphanilamide in dry acetone with freshly prepared alkyl and acyl isothiocyanates (5a-j). The structures of products were confirmed by IR, 1 H, and 13 C NMR. The synthesized compounds were screened as inhibitors of the bovine erythrocyte carbonic anhydrase isoform II (bCA II) and 15-lipoxygenase enzyme (15-LOX). Most of the derivatives showed significant activity against bCA-II while only few compounds were found active against 15-LOX. Molecular docking studies of most active compounds were carried out against bCA II as well as 15-LOX to rationalize the binding mode and interactions of compound in the active sites. Additionally, the pharmacokinetic properties of the compounds were predicted through computational tools, which reflect that these compounds possess acceptable pharmacokinetic profile and good drug-likeness.

Cycloaddition of Aroyl Isothiocyanate: A Novel Synthesis of Triazine, Oxazine, Pyrimidine, and Pyridine Derivatives

A simple and direct synthetic methodology for a novel series of azines and their annulated systems was performed. Heterocyclization of acyl isothiocyanate 2 with urea or malononitrile gave s‐triazine 4 and 1,3‐oxazine 7 derivatives, respectively. The reaction of heteroallene 1 with acetylacetone tolerated 2‐thioxopyridine derivative 9. The latter compound underwent heterocyclization with urea, hydrazine hydrate, or phenyl hydrazine to give the annulated pyridines 10–12. Pyrimidinethione 14 was resulted from reaction of acylisothiocyanate with enamine 13. Condensation of compound 14 with hydrazine hydrate, phenyl hydrazine, urea, and 3‐nitrobenzaldehyde in the presence of ethyl cyanoacetate or sodium hydroxide afforded 15–20, respectively.

Facile Synthesis of 2,4-Disubstituted Thiooxazoles and 2,4-Disubstituted Oxazole Sulfonyl Chlorides via Acyl Isothiocyanates and TMS-Diazomethane

An expedient method for the direct conversion of acyl isothiocyanates to 2,4-disubstitued thiooxazoles and 2,4-disubstituted oxazole sulfonyl chlorides is described. The method takes advantage of an early observation by Sheehan and the reaction of diazomethane with isocyanates to form oxazolones. However, in this case an acyl isothiocyanate is utilized as well as the readily available TMS-diazomethane to provide access to the desired 4-substituted sulfur derivatives. The 2,4-disubstituted oxazole systems synthesized represent novel thiooxazoles and oxazole sulfonyl chlorides not previously described.

Reactivity and diverse synthetic applications of acyl isothiocyanates

Isothiocyanates constitute a group of heterocumulenes containing N=C=S functionality that is of immense importance in organic synthesis. The presence of carbonyl group in acyl isothiocyanates imparts unique reactivity to acyl isothiocyanates. The chemistry of acyl isothiocyanates, in particular, is very rich and diverse, and has been employed in synthesis of a number of biologically important heterocycles. This review article discusses the acyl isothiocyanate chemistry leading to the synthesis of biologically important heterocyclic skeletons. These include highly functionalized thiazoles, thiadiazoles, triazoles, benzimidazoles, dithiolane, spiro-fused oxazolines, triazines, and oxazines, etc. The role of acyl isothiocyanates as acylating agent and thiocyanate transfer reagent is also discussed.

Synthesis and Intramolecular Cyclization of N-acyl- and N-allyl-N'-(2-oxo-1,2-dihydro-pyridin-3-yl)thiourea

The reaction of 3-amino-4,6-dimethylpyridin-2(1H)-one and 3-amino-4-phenylpyridin-2-one with acyl isothiocyanates (benzoyl-, 4-bromobenzoyl-, and methacryloyl isothiocyanates) and with allyl isothiocyanate has been studied. The N-carbamothioyl methacrylamides and N-allylthioureas obtained undergo intramolecular heterocyclization reactions to give the corresponding 1,3-thiazin-4-one and 1,3-thiazoline derivatives. It was found that the starting 3-amino-4,6-dimethylpyridin-2(1H)-one shows antiradical activity but the synthesized thioureas do not.

SYNTHESIS AND INTRAMOLECULAR CYCLIZATION OF N -ACYL- AND N -ALLYL- N '-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)THIOUREA

The reaction of 3-amino-4,6-dimethylpyridin-2(1 H )-one and 3-amino-4-phenylpyridin-2-one with acyl isothiocyanates (benzoyl-, 4-bromobenzoyl-, and methacryloyl isothiocyanates) and with allyl isothiocyanate has been studied. The N -carbamothioyl methacrylamides and N -allylthioureas obtained undergo intramolecular heterocyclization reactions to give the corresponding 1,3-thiazin-4-one and 1,3-thiazoline derivatives. It was found that the starting 3-amino-4,6-dimethylpyridin-2(1 H )-one shows antiradical activity but the synthesized thioureas do not. How to Cite Kulakov, I. V.; Nikitina, O. S.; Fisyuk, A. S.; Goncharov, D. S.; Shul'gau, Z. T.; Gulyaev, A. E. Chem. Heterocycl. Compd. 2014 , 50 , 670. [ Khim. Geterotsikl. Soedin. 2014 , 729.] For this article in the English edition see DOI 10.1007/s10593-014-1519-y

ChemInform Abstract: Synthesis and Structure of New Imidazo‐ and Pyrazolo[5,1‐d][1,2,3,5]thiatriazines Based on the Reaction of Diazoazoles with Acyl Isothiocyanates Controlled by S···O Interaction.

AbstractCycloaddition reactions of 5‐diazopyrazoles and 5‐diazoimidazoles with acyl isothiocyanates give thiatriazine derivatives.

Synthesis and structure of new imidazo- and pyrazolo[5,1-d][1,2,3,5]thiatriazines based on the reaction of diazoazoles with acyl isothiocyanates controlled by S⋯O interaction

5-Diazoimidazoles and 5-diazopyrazoles have been shown to react with acyl isothiocyanates yielding the imidazo- and pyrazolo[5,1-d][1,2,3,5]thiatriazines stabilized by a nonbonded S⋯O interaction. In contrast to acyl isothiocyanates, alkyl-, aryl-, and arylsulfonyl isothiocyanates do not react with 5-diazoazoles. The nature and the strength of stabilizing intramolecular interaction between non-bonded S and O atoms have been studied by X-ray analysis for mono crystals and DFT calculations for selected azolo[5,1-d][1,2,3,5]thiatriazines. The interaction was described in terms of Weinhold covalence ratio factors, NBO, and AIM schemes. The reaction discovered was used to develop an efficient approach toward the new 8-substituted 4-ethoxycarbonylimino-4-benzoyl- and 4-(3,4,5,6-tetrafluorobenzoyl)iminoimidazo(pyrazolo)[5,1-d][1,2,3,5]thiatriazines.

Reaction of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acyl isothiocyanates

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.

Rearrangements of Acyl, Thioacyl, and Imidoyl (Thio)cyanates to Iso(thio)cyanates, Acyl Iso(thio)cyanates to (Thio)acyl Isocyanates, and Imidoyl Iso(thio)cyanates to (Thio)acyl Carbodiimides, RCX-YCN ⇌ RCX-NCY ⇌ RCY-NCX ⇌ RCY-XCN (X and Y = O, S, NR′)

Two types of rearrangements have been investigated computationally at the B3LYP/6-311+G(d,p) level. The activation barriers for rearrangement of acyl thiocyanates RCO-SCN to the corresponding isothiocyanates RCO-NCS are 30-31 kcal/mol in agreement with the observation that the thiocyanates are in some cases isolable albeit very sensitive compounds. Alkoxycarbonyl-, (alkylthio)carbonyl- and carbamoyl thiocyanates are isolable and have higher calculated barriers (ca. 40 kcal/mol) toward rearrangement to isothiocyanates, whereas all thioacyl thiocyanate derivatives are rather unstable compounds with barriers in the range 20-30 kcal/mol for rearrangement to the isothiocyanates. Acyl-, alkoxycarbonyl-, and carbamoyl cyanates R-CO-OCN are predicted to be in some cases isolable compounds with barriers up to ca. 40 kcal/mol for rearrangement to the isocyanates RCO-NCO. All of the rearrangements of this type involve the HOMO of a nearly linear (thio)cyanate anion and the LUMO of the acyl cation, in particular the acyl C═X π* orbital. The second type of rearrangement involves 1,3-shifts of the groups R attached to the (thio)acyl groups, that is, acyl isothiocyanate-thioacyl isocyanate and imidoyl isothiocyanate-thioacyl carbodiimide rearrangements. These reactions involve four-membered cyclic, zwitterionic transition states facilitated by lone pair-LUMO interactions between the migrating R group and the neighboring iso(thio)cyanate function. Combination of the two rearrangements leads to the general reaction scheme RCX-YCN ⇌ RCX-NCY ⇌ RCY-NCX ⇌ RCY-XCN (X and Y = O, S, NR').

Synthesis of aza-aromatic hydroxylamine- O-sulfonates and their application to tandem nucleophilic addition–electrophilic 5- endo- trig cyclization

Hydroxylamine- O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine- O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition–electrophilic 5- endo- trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G ∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine- O-sulfonates and N-(5-methoxy-2 H-[1,2,4]thiadiazolo[2,3- a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2 H-[1,2,4]thiadiazolo[3,2- a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC 50 in the range 1.47–2.97 μM).

ChemInform Abstract: Reaction of 2-Amino-2-deoxy-D-glucose with Aryl and Acyl Isothiocyanates, and Aryl Isocyanates: Structure of the Intermediate Products.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Syntheses of Functionalized Pyrimidines from the Products of Addition of Triphenylphosphoranylideneacetonitrile to Acyl Isothiocyanates

The products of addition of accessible phosphorus-containing ylide Ph3 $${\mathop P\limits^+}$$ - $${\mathop C\limits^\_}$$ HCN to acyl and alkoxycarbonyl isocyanates readily cyclize under the action of methanolic HCl. This reaction was used for preparing a broad range of new 5-phosphonium derivatives of di- and trifunctionalized pyrimidine bases. Among them, the corresponding tertiary phosphonium salts containing no labile hydrogen atoms are especially important. Under mild conditions, they undergo dephosphorylation in the presence of alkalis to give 4-mercapto, 4,6-dimercapto-, and 2,4,6-trimercaptopyrimidine derivatives which are difficult or impossible to prepare by traditional routes.