Synthesis of 2-azirine-2,2-dicarboxylic acids and their derivatives.

Methods for the preparation of 3-aryl-2-azirine-2,2-dicarboxylic acids and their amides, esters, and azides by FeCl-catalyzed isomerization of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides into 3-aryl-2-azirine-2,2-dicarbonyl dichlorides followed by their reaction with nucleophiles are reported. Two approaches to the preparation of 3-aryl-5-chloroisoxazole-4-carbonyl chlorides have been developed.

Dual-Reporter SARS-CoV-2 Replicon for Screening Viral Polymerase Inhibitors.

To design a safe cellular system for testing inhibitors targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, a genetic construct was engineered containing viral cDNA with two blocks of reporter genes while the genes encoding structural S, E, and M proteins were absent. The first reporter block, consisting of Renilla luciferase and green fluorescent protein (Rluc-GFP), was located upstream of the SARS-CoV-2 5'-UTR. Meanwhile, the second block represented by firefly luciferase and red fluorescent protein (Fluc-RFP) was positioned downstream of the transcription regulatory sequence (TRS-N).

DBU-Promoted Cyclizations of Cyclopentyl-Substituted Oxazapolyenes to Cyclopentapyridones and Hydroxypyrroles: Experimental and DFT Study.

1,1-Di(alkoxycarbonyl)-4-cyclopentyl-2-azabuta-1,3-dienes react with DBU to form two types of heterocyclic products: 1-cyclopenta[]pyrid-1-ones and 3-hydroxy-1-pyrroles. These previously unobserved transformations proceed through the formation of 1-azapentadienyl anion which undergoes 1,6-shift of the alkoxycarbonyl group to the cyclopentyl moiety followed by 1,6-cyclization to form the cyclopentapyridone (path ) and 1,5-cyclization accompanied by 1,3-shift of the methoxy group followed by dialkyl carbonate elimination to afford the hydroxypyrrole (path ). The mechanisms of the reactions were studied using DFT calculations.

Rhodium-Catalyzed Double Dearomatization of 1,2,3-Triazole-Isoxazole Dyads: Synthesis of Nonfused 1-1,3-Diazepines.

A double dearomatization of dyads consisting of 1-sulfonyl-1,2,3-triazoles and 3-aryl-5-methoxyisoxazoles was applied for the efficient synthesis of nonfused 1-1,3-diazepines. The plausible mechanism of the cascade reaction includes transformation of the 1,2,3-triazole to rhodium azavinyl carbene, the -selective hydride shift to form the 1-azabuta-1,3-diene moiety, rhodium-catalyzed ring contraction of the isoxazole to azirine, and pseudopericyclic four-atom ring expansion of the azirine. The synthetic utility and antiproliferative activity of the 1,3-diazepines obtained have been demonstrated.

Cyclocondensation of 2-(α-Diazoacyl)-2-azirines with Amidines in Diazo Synthesis of Functionalized Naphtho[1,2-]imidazoles.

A diazo approach toward functionalized naphtho[1,2-]imidazole derivatives has been developed. It involved a new reaction of arylamidines with 2-(α-diazoacyl)-2-azirines giving 5-aryl-4-(α-diazoacyl)-1-imidazoles under mild conditions in good yields. The mechanism of annulation of azirines with amidines is discussed based on DFT calculations.

Stable 2-Azaallyl Salts as a Bridge between 2-Azirines and Densely Functionalized 2-Pyrroles.

An efficient protocol for the synthesis of stable 2-azaallyl anion salts by the reaction of alkyl 2-bromo-2-azirine-2-carboxylates with trimethylsilyl cyanide/BuNF has been developed. The domino reaction proceeds in four steps via the cleavage of the azirine C-C bond to provide the tetrabutylammonium salts of stereochemically pure 2-azaallyl anions having U-configuration relative to the cyano groups. The anions with an -substituted aryl group or styryl group exist as a mixture of two geometrical isomers across the N2-C3 bond.

Acridine-Isoxazole and Acridine-Azirine Hybrids: Synthesis, Photochemical Transformations in the UV/Visible Radiation Boundary Region, and Anticancer Activity.

Easy-to-handle -hydroxyacridinecarbimidoyl chloride hydrochlorides were synthesized as convenient nitrile oxide precursors in the preparation of 3-(acridin-9/2-yl)isoxazole derivatives via 1,3-dipolar cycloaddition with terminal alkynes, 1,1-dichloroethene, and acrylonitrile. Azirines with an acridin-9/2-yl substituent attached directly or via the 1,2,3-triazole linker to the azirine C2 were also synthesized. The three-membered rings of the acridine-azirine hybrids were found to be resistant to irradiation in the UV/visible boundary region, despite their long-wave absorption at 320-420 nm, indicating that the acridine moiety cannot be used as an antenna to transfer light energy to generate nitrile ylides from azirines for photoclick cycloaddition.

Divergent Synthesis of Pyrazolo[1,5-]pyridines and Imidazo[1,5-]pyridines via Reagent-Controlled Cleavage of the C-N or C-C Azirine Bond in 2-Pyridylazirines.

The three-membered ring in 2-(2-pyridyl)azirine-2-carboxylic esters and thioesters can undergo selective cleavage of either the N-C2 bond under copper(II) catalysis or the C-C bond under the action of HCl to provide isomeric azirine ring expansion products of pyrazolo[1,5-]pyridine or imidazo[1,5-]pyridine series, respectively. Mild catalytic reaction conditions for the formation of pyrazolopyridines make it possible to obtain them directly from 4-bromoisoxazoles by a one-pot, three-stage procedure without isolating the intermediate 2-bromoazirines and 2-(2-pyridyl)azirines.

Divergent Diazo Approach toward Alkyl 5/4-Hydroxy-3-benzo[]indole-4/5-carboxylates.

A divergent diazo approach toward alkyl 5/4-hydroxy-3-benzo[]indole-4/5-carboxylates has been developed. The reaction of 1,3-diketones with alkyl 2-diazo-3-oxo-3-(2-azirin-2-yl)propanoates catalyzed by Co(acac) or Ni(acac) gives various alkyl 3-(1-pyrrol-2-yl)-2-diazo-3-oxopropanoate in good yields. The latter undergo Wolff rearrangement followed by the 6π-cyclization of transient ketene to form alkyl 5-hydroxy-3-benzo[]indole-4-carboxylates bearing various substituents in positions 1, 2, 7, and 8, as well as derivatives of methyl 4-hydroxy-6-thieno[2,3-]indole-5-carboxylates and methyl 5-hydroxy-7-benzo[]carbazole-6-carboxylate under thermolysis or Rh(OAc) catalysis.

[2 + 2] Cycloaddition/Retro-Electrocyclization/Decarboxylation Reaction Sequence: Access to 4-Aminopyridines from Methylideneisoxazolones and Ynamines.

4-(1-Aminoallylidene)isoxazol-5-ones were synthesized in good yields by the [2 + 2]cycloaddition-retro-electrocyclization reaction of 4-methylideneisoxazol-5(4)-ones with ynamines. The reaction mechanism and the absence of hetero-Diels-Alder cycloadducts were investigated by DFT calculations. 4-(1-Aminoallylidene)isoxazol-5-ones were found to be convenient substrates for the preparation of 4-aminopyridines under thermal metal-free conditions.

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.

Triethylamine-Promoted Oxidative Cyclodimerization of 2-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study.

An unprecedented oxidative cyclodimerization reaction of 2-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of ,-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule.

Gold vs Light: Chemodivergent Reactivity of Diazoesters toward 2-Azirine-2-carboxylic Acids.

An orthogonal reactivity of diazo compounds toward azirine-2-carboxylic acids, switching with the reaction conditions, is demonstrated. A gold-catalyzed reaction is N-selective and produces 1,3-oxazin-6-ones, whereas a blue light activation leads to O-H insertion products, azirine-2-carboxylic esters. The observed chemodivergence is explained by the metal-bound and metal-free carbenes exhibiting different electronic properties in these reactions.

Metal carbonyl mediated rearrangement of 5-(2-oxoalkyl)-1,2,4-oxadiazoles: synthesis of fully substituted pyrimidines.

Variously substituted ethyl 6-oxo-1,6-dihydropyrimidine-5-carboxylates can be easily prepared by a metal carbonyl mediated rearrangement of ethyl 3-oxo-2-(1,2,4-oxadiazol-5-yl)propanoates. The irradiation of a mixture of oxadiazoles and Fe(CO) in wet solvents with a 365 nm LED at room temperature for 2 h followed by heating at 80 °C for 2 h gives pyrimidines in up to 90% yield. This procedure enables the preparation of 6-oxo-1,6-dihydropyrimidine-5-carboxylates with various aryl substituents at the C2 and alkyl or aryl substituents at the C4 position.

5-Chloroisoxazoles: A Versatile Starting Material for the Preparation of Amides, Anhydrides, Esters, and Thioesters of 2-Azirine-2-carboxylic Acids.

Amides, anhydrides, esters, and thioesters of 2-azirine-2-carboxylic acids were prepared by a rapid procedure at room temperature involving FeCl-catalyzed isomerization of 5-chloroisoxazoles to 2-azirine-2-carbonyl chlorides, followed by reaction with N-, O-, or S-nucleophiles mediated by an -substituted pyridine. With readily available chloroisoxazoles and a nucleophile, 2-picoline can be used as an inexpensive base. When a high yield of the acylation product is important, the reagent 2-(trimethylsilyl)pyridine/ethyl chloroformate is more suitable for the acylation with 2-azirine-2-carbonyl chlorides.

Diazo Strategy for Intramolecular Azirine Ring Expansion: Rh(II)-Catalyzed Synthesis of 2-Hydroxy-3-oxo-2,3-dihydro-1-pyrrole-2-carboxylates.

A diazo strategy for the intramolecular azirine ring expansion was developed. Azirinyl-substituted diazodicarbonyl compounds, prepared from diazoacetylazirines, were converted in excellent yields to 2-hydroxy-3-oxo-2,3-dihydro-1-pyrrole-2-carboxylates under Rh catalysis in the presence of water. According to DFT calculations, the formation of only pyrrolinone derivatives and the absence of O-H insertion products of Rh carbene into water are due to the low Gibbs free energy of the transition state for the concerted opening of the azirine ring and recyclization to pyrrolone in intermediate Rh complexes.

Copper(II)-Catalyzed (3+2) Cycloaddition of 2-Azirines to Six-Membered Cyclic Enols as a Route to Pyrrolo[3,2-]quinolone, Chromeno[3,4-]pyrrole, and Naphtho[1,8-]indole Scaffolds.

A method for the [2+3] pyrroline annulation to the six-membered non-aromatic enols using 3-aryl-2-azirines as annulation agents is developed in the current study. The reaction proceeds as a formal (3+2) cycloaddition via the N1-C2 azirine bond cleavage and is catalyzed by both Cu(II) and Cu(I) compounds. The new annulation method can be applied to prepare pyrrolo[3,2-]quinoline, chromeno[3,4-]pyrrole, and naphtho[1,8-]indole derivatives in good to excellent yields from enols of the quinolin-2-one, 2-chromen-2-one, and 1-phenalen-1-one series.

Antiviral Activity of N,N-Disubstituted Uracil Derivatives against SARS-CoV-2 Variants of Concern.

Despite the widespread use of the COVID-19 vaccines, the search for effective antiviral drugs for the treatment of patients infected with SARS-CoV-2 is still relevant. Genetic variability leads to the continued circulation of new variants of concern (VOC). There is a significant decrease in the effectiveness of antibody-based therapy, which raises concerns about the development of new antiviral drugs with a high spectrum of activity against VOCs.

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.

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates.

A method has been developed for the preparation of 2-alkyl-6-aryl-, 2-aryl-6-aryl and 2,6-diaryl-5-aryl/hetaryl-substituted methyl 4-oxo-1,4-dihydropyridine-3-carboxylates by Mo(CO)-mediated ring expansion of methyl 2-(isoxazol-5-yl)-3-oxopropanoates. The high reactivity of 4-oxo-1,4-dihydropyridine-3-carboxylates synthesized provide easy access to 2,4,6-triaryl-substituted and 1,2,5,6-tetrasubstituted nicotinates.

Reaction of α-Diazopyrroles with Enamines: Synthesis of Pyrrolo[2,1-][1,2,4]triazines and α-(1,2,5-Triazapenta-1,3-dienyl)pyrroles.

α-Diazopyrroles selectively react with enamines at room temperature to give either (4+2)-cycloaddition-dehydroamination cascade products, pyrrolo[2,1-][1,2,4]triazines, or azo coupling products. The reaction was used for the synthesis of functionalized -fused heterocycles with new tetrahydrobenzo[]pyrrolo[2,1-][1,2,4]triazine and tetrahydro-6-cyclohepta[]pyrrolo[2,1-][1,2,4]triazine frameworks. Unstable azo compounds, 2-[(2-aminovinyl)diazenyl]pyrroles, were obtained from enamines of tetralone or acyclic ketones.

Azirine-triazole hybrids: selective synthesis of 5-(2-azirin-2-yl)-, 5-(1-pyrrol-2-yl)-1-1,2,3-triazoles and 2-(5-(2-azirin-2-yl)-1-1,2,3-triazol-1-yl)pyridines.

Azirine-triazole hybrids, 1--5-(3-aryl-2-azirin-2-yl)-1-1,2,3-triazoles, were selectively synthesized by reaction of 1-(3-aryl-2-azirin-2-yl)-2-(triphenylphosphoranylidene)ethanones with tosyl and ()-2-benzoylvinyl azides in high yields at rt. The reaction with 2-azidopyridine makes it possible to obtain azirine-triazole-pyridine hybrids, albeit in moderate yields, at 170 °C. The mechanism and selectivity of the reaction of α-carbonylphosphoranes with azides are discussed on the basis of DFT calculations.

One-Pot Synthesis of Multifunctionalized 1-Pyrrolines from 2-Alkyl-2-azirines and Diazocarbonyl Compounds.

A novel strategy for the synthesis of 1-pyrrolines based on formal [4 + 1] annulation of 2-alkyl-2-azirines with diazocarbonyl compounds has been developed. This one-pot approach includes the Rh(II)-catalyzed formation of 4-alkyl-2-azabuta-1,3-dienes, followed by the DBU-promoted cyclization, and features a good substrate tolerance. The 1-pyrrolines containing an ester group at the C3 were prepared in a three-step one-pot procedure starting from 5-alkoxyisoxazoles.

New Derivatives of 5-Substituted Uracils: Potential Agents with a Wide Spectrum of Biological Activity.

Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2'-deoxy-5-iodocytidine and 5-bromovinyl-2'-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV.

Synthesis of Imidazo[1,2-]pyridines via Near UV Light-Induced Cyclization of Azirinylpyridinium Salts.

An efficient one-pot synthesis of imidazo[1,2-]pyridines from 2-bromoazirines and pyridines has been developed. The construction of the bicyclic framework of imidazo[1,2-]pyridines occurs in two steps through the formation of (2-azirin-2-yl)pyridinium bromides followed by dehydrobrominative UV light-induced cyclization. The method can also be applied for the synthesis of imidazo[2,1-]isoquinolines.