Cycloaddition reactions of heterocyclic azides with 2-cyanoacetamidines as a new route to ,-diheteroarylcarbamidines.

A novel and efficient base-catalyzed, transition-metal-free method for the synthesis of diheterocyclic compounds connected by an amidine linker, including apart from the common 1,2,3-triazole ring, either an additional pyrimidinedione, 4-nitroimidazole, isoxazole, 1,3,4-triazole, 2-oxochromone or thiazole ring, has been developed. The process was facilitated by a strong base and includes the cycloaddition reaction of 3,3-diaminoacrylonitriles (2-cyanoacetamidines) to heterocyclic azides followed by a Cornforth-type rearrangement to the final products. The reaction is tolerant to various -monosubstituted 3,3-diaminoacrylonitriles and to different heterocyclic azides.

Cyanothioacetamides as a synthetic platform for the synthesis of aminopyrazole derivatives.

It was shown that the reaction of 2-cyanothioacetamides with hydrazine involves both cyano- and thioamide groups, and 3,5-diaminopyrazoles are formed. In the reaction of 2-cyano-3-(dimethylamino)-,-dimethylprop-2-enethioamides with hydrazine and its derivatives, the interaction proceeds with the participation of cyano- and enamine groups, not affecting the thiocarbamoyl group, and leads to the formation of 4-thiocarbamoylpyrazoles. A synthesis method has been developed and a series of 1-substituted-4-thiocarbamoyl pyrazoles has been thus synthesized.

Tandem Cycloaddition of Azides to 3,3-Diaminoacrylonitriles (2-Cyanoacetamidines) and Cornforth-Type Rearrangement as an Approach to 5-Amino-1,2,3-triazole-4--substituted Imidamides.

An efficient base-catalyzed, metal-free method for the synthesis of 5-amino-1,2,3-triazole-4--sulfonyl- and arylimidamides, directed by the structure of the amidine group, has been developed. It is based on a previously unknown tandem process involving cycloaddition reaction to 3,3-diaminoacrylonitriles (2-cyanoacetamidines) with aryl(alkyl)sulfonyl or aryl azides and Cornforth-type rearrangement. During the reaction optimization, different factors were found to facilitate the title reaction, which include the use of a strong base and -mono- or ,'-disubstituted 3,3-diaminoacrylonitriles.

Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles.

The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2)ylidenes are formed.

Differentiation between Isomeric 4,5-Functionalized 1,2,3-Thiadiazoles and 1,2,3-Triazoles by ESI-HRMS and IR Ion Spectroscopy.

A large variety of 1,2,3-thiadiazoles and 1,2,3-triazoles are used extensively in modern pure and applied organic chemistry as important structural blocks of numerous valuable products. Creation of new methods of synthesis of these isomeric compounds requires the development of reliable analytical tools to reveal the structural characteristics of these novel compounds, which are able to distinguish between isomers. Mass spectrometry (MS) is a clear choice for this task due to its selectivity, sensitivity, informational capacity, and reliability.

Exploration of Fungicidal Activity and Mode of Action of Ferimzone Analogs.

Lead discovery and molecular target identification are important for developing novel pesticides. Scaffold hopping, an effective approach of modern medicinal and agrochemical chemistry for a rational design of target molecules, is aiming to design novel molecules with similar structures and similar/better biological performance. Herein, 24 new ferimzone derivatives were designed and synthesized by a scaffold-hopping strategy.

Synthesis, Fungicidal Activity and Plant Protective Properties of 1,2,3-Thiadiazole and Isothiazole-Based -acyl--arylalaninates.

The addition of active groups of known fungicides, or systemic acquired resistance inducers, into novel compound molecules to search for potential antifungal compounds is a popular and effective strategy. In this work, a new series of -acyl--arylalanines was developed and synthesized, in which 1,2,3-thiadiazol-5-ylcarbonyl or 3,4-dichloroisothiazol-5-ylcarbonyl (fragments from synthetic plant resistance activators tiadinil and isotianil, respectively) and a fragment of -arylalanine, the toxophoric group of acylalanine fungicides. Several new synthesized compounds have shown moderate antifungal activity against fungi in vitro, such as , and .

Rhodium-Catalyzed Transannulation of 4,5-Fused 1-Sulfonyl-1,2,3-triazoles with Nitriles. The Selective Formation of 1-Sulfonyl-4,5-fused Imidazoles versus Secondary C-H Bond Migration.

The reactivity of readily available 4,5-fused-1-sulfonyl-1,2,3-triazoles was examined in the Rh(II)-catalyzed transannulation reaction with nitriles. We have come across the interesting observation that 1-sulfonyl cycloalkeno[][1,2,3]triazoles that possess β-hydrogens resist intramolecular β-hydride migration and could serve as a new source of Rh-iminocarbenoids for intermolecular Rh(II)-catalyzed transannulation reactions. As a result, 1-sulfonyl cyclohexeno-, cyclohepteno-, dihydropyrano-, 5-phenyltetrahydrobenzo-, and 4,5-dihydronaphtho[]imidazoles were synthesized from various nitriles in good yields.

Thioisomünchnones versus Acrylamides via Copper-Catalyzed Reaction of Thioamides with Diazocarbonyl Compounds.

A novel carbenoid-mediated approach to thioisomünchnones was developed by intermolecular copper-catalyzed reactions of diazoacetamides with aromatic and heteroaromatic thioamides bearing a pyrrolidine moiety. The direction of the reaction can be switched toward 2-amino-2-heteroarylacrylamides by replacing the pyrrolidine with an aniline group or by the use of 2-cyano-2-diazoacetamides. The proposed mechanism and DFT calculations allowed us to rationalize the effect of substituents on the reaction direction.

Selective Synthesis of Azoloyl -1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights.

Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl--1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with -sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of -1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines.

Synthesis, Fungicidal Activity, and Molecular Docking of 2-Acylamino and 2-Thioacylamino Derivatives of 1-benzo[]imidazoles as Anti-Tubulin Agents.

This work deals with the synthesis and evaluation of fungicidal activity of benzimidazole derivatives, which are structural analogues of commercial anti-tubulin fungicides. A number of -acyl and -thioacyl derivatives of 2-amino-1-benzo[]imidazole were prepared, and their fungicidal activity against 13 strains of phytopathogenic fungi was studied. The most active compounds against the majority of the studied strains were , , and , and the EC values of these compounds were in the range 2.

Design, Synthesis, and Evaluation of the Antifungal Activity of Novel Pyrazole-Thiazole Carboxamides as Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) is regarded as a promising target for fungicide discovery. To continue our ongoing studies on the discovery of novel SDH inhibitors as fungicides, novel pyrazole-thiazole carboxamides were designed, synthesized, and evaluated for their antifungal activity. The results indicated that compounds , , and showed excellent activities against with EC values from 1.

Water/Alkali-Catalyzed Reactions of Azides with 2-Cyanothioacetamides. Eco-Friendly Synthesis of Monocyclic and Bicyclic 1,2,3-Thiadiazole-4-carbimidamides and 5-Amino-1,2,3-triazole-4-carbothioamides.

The reactions of thioamides with azides in water were studied. It was reliably shown that the reaction of 2-cyanothioacetamides with various types of azides in water in the presence of alkali presents an efficient, general, one-step, atom-economic, and eco-friendly method for the synthesis of 1,2,3-thiadiazol-4-carbimidamides and 1,2,3-triazole-4-carbothioamides . This method can be extended to the one-pot reaction of sulfonyl chlorides and 6-chloropyrimidines with sodium azide, leading to final products in higher yields, that is, avoiding the isolation of unsafe sulfonyl azides.

Rh(II)-mediated domino [4 + 1]-annulation of α-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes.

A new approach towards the synthesis of multisubstituted thiophenes is elaborated based on Rh(II)-catalyzed domino reactions of acyclic diazoesters with α-cyanothioacetamides. It provides a way for the preparation of 5-amino-3-(alkoxycarbonylamino)thiophene-2-carboxylates, 2-(5-amino-2-methoxycarbonylthiophene-3-yl)aminomalonates and (2-cyano-5-aminothiophene-3-yl)carbamates with the preparative yields of up to 67%. It was also shown that α-cyanothioacetamides easily interact with dirhodium carboxylates to give rather stable 2:1 complexes, resulting in an evident decrease in the efficiency of the catalytic process at moderate temperatures (20-30 °C).

Identification and interconversion of isomeric 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles in conditions of electrospray ionization.

1,2,3-Triazoles and 1,2,3-thiadiazoles have been receiving permanent interest due to their exciting chemical reactivity and interesting biological properties including antibacterial, anticancer and antiviral activities. There are four compounds bearing 1H-1,2,3-triazole core in clinical studies which may appear in the market of drugs in nearest future. Definitely reliable methods of their identification and quantification should be developed by that time.

Switchable Synthesis of 4,5-Functionalized 1,2,3-Thiadiazoles and 1,2,3-Triazoles from 2-Cyanothioacetamides under Diazo Group Transfer Conditions.

High yield solvent-base-controlled, transition metal-free synthesis of 4,5-functionalized 1,2,3-thiadiazoles and 1,2,3-triazoles from 2-cyanothioacetamides and sulfonyl azides is described. Under diazo transfer conditions in the presence of a base in an aprotic solvent 2-cyanothioacetamides operating as C-C-S building blocks produce 5-amino-4-cyano-1,2,3-thiadiazoles exclusively. The use of alkoxide/alcohol system completely switches the reaction course due to the change of one of the reaction centers in the 2-cyanothioacetamide (C-C-N building block) resulting in the formation of 5-sulfonamido-1,2,3-triazole-4-carbothioamide sodium salts as the only products.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides.

Reactions of β-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. ()-β-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as isomers during the reaction of ()-β-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides.

Synthesis of 1,2,3-Thiadiazole and Thiazole-Based Strobilurins as Potent Fungicide Candidates.

Strobilurin fungicides play a crucial role in protecting plants against different pathogens and securing food supplies. A series of 1,2,3-thiadiazole and thiazole-based strobilurins were rationally designed, synthesized, characterized, and tested against various fungi. Introduction of 1,2,3-thiadiazole greatly improved the fungicidal activity of the target molecules.

The new facile and straightforward method for the synthesis of 4H-1,2,3-thiadiazolo[5,4-b]indoles and determination of their antiproliferative activity.

A series of 4H-1,2,3-thiadiazolo[5,4-b]indoles were synthesized by novel tandem of oxidative cyclization of 3-alkoxycarbonylhydrazonoindoline-2-thiones, 1,5-H-shift and elimination of tert-butoxy(ethoxy)carbonyl group. The simple method for their modifications by the reactions with electrophilic agents were elaborated and as a result of the synthetic investigation a number of N-alkyl-, N-acyl- and N-sulfonyl-4H-1,2,3-thiadiazolo[5,4-b]indoles were prepared in good yields. Preliminary biological tests for the three examples of synthesized compounds with different substituents at the nitrogen atom indole ring have shown that the biological behavior of the investigated 1,2,3-thiadiazolo[5,4-b]indoles is substantially directed by this structural fragment.

A novel three-component reaction designed by the combinatorial method: heteroarenes, isothiocyanates and isocyanides.

The novel three-component reaction of isoquinoline with isothiocyanates and isocyanides leads to a variety of new imidazoisoquinolines. The zwitterionic ground state of these new ring systems is established by means of NMR and X-ray analysis. Use of phthalazine instead of isoquinoline gives access to imidazole annulated phthalazines.

Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic diamines. Synthesis and intramolecular cyclization of bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides.

Bis[1,2,3]triazolo[1,5-f:5',1'-b][1,3,6]thiadiazepine and [1,5-g:5',1'-b][1,3,7]thiadiazocine ring systems have been synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates and products were supported by different NMR spectroscopic methods (1H coupled 13C NMR, 2D HETCOR, HMBC and 1D INADEQUATE experiments) and mass spectrometry.

Reactions of 5-mercaptoazoles and pyridine-2-thiones with acetylenic esters. Selectivity of the formation of novel fused thiazin-4-ones and thiazolidin-4-ones.

A systematic study of the reactions of dimethyl acetylenedicarboxylate (DMAD) and methyl propynoate with 5-mercaptoazoles and pyridine-2-thiones has been carried out and as a result, a number of novel imidazo[1,5-b]thiazin-4-ones 6a,b, pyrazolo[1,5-b] thiazin-4-ones 15a-f, imidazo[1,5-b]thiazol-4-ones 7a,b and thiazolo[3,2-a]pyridines 21a-c have been prepared. The influence of the size of the ring of the starting "cyclic" thioamides on the size of the fused ring in the reaction products has been established. The preferred formation of a six-membered thiazine ring took place in the reactions of 5-mercaptoazoles.

Pericyclic versus Pseudopericyclic 1,5-Electrocyclization of Iminodiazomethanes. An ab Initio and Density Functional Theory Study.

Density functional (B3LYP/6-311+G) and ab initio (MP2/6-311+G and MP4(SDTQ)/6-311+G//MP2/6-311+G) calculations on the ring closure reactions of (E)- and Z-iminodiazomethane ((E)-5, (Z)--5), vinyldiazomethane 7, and formyldiazomethane 9 to 1H-1,2,3-triazole 6, 3H-pyrazole 8, and 1,2,3-oxadiazole 10, respectively, are reported. (E)-5 cyclizes via a low barrier (ca. 10 kcal mol(-)(1)) pseudopericyclic nonrotatory transition state.

Ab initio and density functional calculations on the pericyclic vs pseudopericyclic mode of conjugated nitrile ylide 1, 5-electrocyclizations.

Ab initio (MP2/6-311+G and MP4(SDTQ)/6-311+G//MP2/6-311+G) and density functional (B3LYP/6-311+G) calculations on the ring closure reactions of conjugated nitrile ylides 1a-e, 3, and 6 to the corresponding oxazoles 2a, 5, 7, and 8; thiazoles 2b and 4; imidazole 2c; and pyrroles 2d and 2e, respectively, are reported. Vinyl nitrile ylides 1d and 1e cyclize with a substantially higher barrier than nitrile ylides containing a heteroatom. Geometric features as well as electronic structures as obtained by NBO analysis are indicative of a pericyclic, monorotatory 1, 5-electrocyclization of 1d and 1e.