Tertiary (2H-azirin-2-yl)ammonium salts were prepared from methyl 2-halo-3-aryl-2H-azirine-2-carboxylates and 1,4-diazabicyclo[2.2.2]octane in very good to excellent yields. Both iodide and bromide salts are stable enough in crystalline form to be stored in a freezer for up to several months. The structures of the obtained salts were confirmed by NMR spectroscopy and HRMS.

Quinazolinone derivatives are well-known anticancer agents; anticancer properties are also part of the broad spectrum of biological activity of coumarins. Conjugates containing quinazolin-4(3H)-one and coumarin fragments linked by polymethylene bridges of varying lengths were designed to improve properties of both parental compounds and create new anticancer or antibacterial agents. 3-{3-[(4-Methyl-2-oxo-2H-chromen-7-yl)oxy]propyl}quinazolin-4(3H)-one was synthesized as the base compound. It demonstrated moderate cytotoxicity against leukemia (K562 and HL60) and neuroblastoma (SH-SY5Y) cells in vitro, combined with relatively low acute, subacute, and chronic toxicity in vivo. Conjugates with various substituents and linkers were then synthesized to evaluate the structure-activity relationship. A study of the synthesized compounds on cell cultures showed that the introduction of a methyl substituent into the benzene ring of the coumarin fragment led to both an increase in cytotoxicity and expansion of its spectrum of action. Testing of the hybrids against Gram-positive and Gram-negative bacteria revealed that the introduction of halogens into the quinazoline fragment in the compounds or the elongation of the linker led to the emergence of pronounced antibacterial properties, which were most clearly manifested against Acinetobacter baumanii. The possibility of directing activity of quinazoline-4(3H)-one-coumarin hybrids by varying the substituents and the length of the linker was shown.

The Cs2CO3-induced condensation of 2-(diazoacetyl)-2H-azirines with aromatic aldehydes does not result in the formation of an azirinyl-substituted β-hydroxy-α-diazocarbonyl compound, but is accompanied by a tandem intramolecular cyclization involving the hydroxy group and the C=N bond of the azirine to form a bicyclic intermediate, a 4-diazo-2-oxa-7-azabicyclo[4.1.0]heptan-5-one derivative. The acid-catalyzed transformation of which leads to 2-aroyl-3-hydroxy-1H-pyrroles.

The azide group in azirine-2-carbonyl azides provides a unique electrophilic balance of the reaction sites, allowing these compounds to be used as all-carbon C3 synthons in the synthesis of N',N'-unsubstituted 5-aminopyrimidin-4-ones via a (3 + 3) cyclocondensation reaction with amidines. Strongly basic conditions alter the reactivity of the key intermediate 2,4,7-triazabicyclo[4.1.0]hept-2-en-5-one, resulting in a formal (4 + 3) cyclocondensation reaction to afford 3,7-dihydro-6H-1,3,5-triazepin-6-ones as the sole products.

Azirinyl ethynyl ketones, containing aryl/n-alkyl substituents at azirine C2/C3 and aryl/n-alkyl/2-thienyl substituents at the C≡C triple bond, undergo isomerization into 5-alkynyloxazoles under nucleophilic assistance in MeOH–K2CO3 media at room temperature, with the formation of 5-alkynyloxazoles in 20–84

1,3-Oxazines are important six-membered heterocycles demonstrating diverse biological activities and photochromic properties. Most of the known 1,3-oxazines are benzo-fused; however, in recent decades, numerous reports on the synthesis of monocyclic unsaturated 1,3-oxazine derivatives have appeared in the literature. New approaches toward these compounds, including inter- and intramolecular ring expansions, as well as various (5 + 1)-, (4 + 2)-, and (3 + 3)-annulations, have been discovered, opening access to 1,3-oxazines with unique substitution patterns. These methods are based on metal-catalyzed transformations, multicomponent and photoinduced reactions, etc. In this review, we discuss synthetic approaches to non-fused unsaturated 1,3-oxazine derivatives, mainly reported after 2000, with special attention to novel reactions and their mechanistic aspects. Herein, we will spotlight advances in the synthesis of 2H-, 4H-, and 6H-1,3-oxazines, 1,3-oxazinones and 1,3-oxazinediones with carbonyl group(s) at different positions.

2-Aminonicotinonitriles represent an important class of heterocycles with diverse biological activities. Herein, we report an unexpected photochemical transformation of azirine-2-carboxylic acids leading to the formation of 2-aminonicotinonitrile derivatives. Optimization of the reaction conditions enabled the synthesis of the target products in moderate yields. The structure of the obtained product was confirmed by NMR spectroscopy, HRMS, and single-crystal X-ray diffraction analysis.

2-Amino-2H-1,4-oxazines were synthesized from azirines, aroyl(diazo)acetonitriles, and secondary amines in a two-step sequence in generally good to excellent yields. Upon heating, cycloamino-substituted oxazines undergo stereoselective rearrangement into 2,3-fused pyrrolo[3,4-d]oxazoles through a retroelectrocyclization/1,6-prototropy/intramolecular 1,3-dipolar cycloaddition cascade. This transformation reveals a previously unknown mode of 2-azadiene reactivity and demonstrates, for the first time, the generation of azomethine ylides from 2-azadienes by prototropy.

The first representative of the aziridine-fused benzo[e][1,4]thiazine series was synthesized from methyl 2-bromo-2-phenyl-2H-azirine-2-carboxylate and benzo[d]thiazole in 74% yield. The reaction proceeds via the SN2′-SN2′-cascade to form the azirinylthiazolium salt followed by a water-induced thiazole ring expansion. The structure of the title compound was established based on 1H, 13C, 2D NMR spectroscopy and high-resolution mass spectrometry, and unambiguously confirmed by X-ray diffraction analysis.

A two-step method for the preparation of β-ethynylpyrroles from azirinyl ethynyl ketones by Wittig olefination, followed by FeCl2-catalyzed isomerization, has been developed. Azirines with various substitution patterns of the ring and the triple bond tolerate the reaction conditions of both steps, providing di-, tri-, and tetra-C-substituted β-ethynylpyrroles from fair-to-good yields.

We report a radical strategy for direct C2-alkylation of 2H-azirines via generation of elusive 2H-azirinyl radicals. These highly reactive intermediates are accessed under mild halogen-atom transfer conditions from readily available 2-haloazirines. The resulting cyclic radicals undergo regioselective Giese-type additions to electron-deficient alkenes, retaining the azirine ring. Mechanistic studies, including spin-trapping and DFT analysis, support a free radical pathway. The adducts undergo base-promoted ring expansion to yield 6-aminopyridines, underscoring this platform's synthetic utility.

The procedure for the generation of azirinyl-substituted nitrile oxides by the reaction of 2-(diazoacetyl)-2H-azirines with tert-butyl nitrite while preserving the azirine ring has been developed. The [3+2] cycloaddition of azirinyl-substituted nitrile oxides to terminal acetylenes produced azirinyl(isoxazolyl)ketones with various substituents in position 3 of azirine and position 5 of isoxazole fragments in a 51–91% yield at room temperature in DCM. DFT calculations and experimental data are consistent with the assumption that the formation of azirinyl-substituted nitrile oxides is accelerated by the acid catalyst. Cycloadducts of nitrile oxides with aryl/hetarylacetylenes and DMAD can be obtained by catalysis with boron trifluoride etherate, which significantly expands the scope of application of the reaction. Expansion of the azirine ring of the prepared cycloadducts allows obtaining a wide range of structurally diverse functionalized isoxazole-containing heterocyclic hybrids. LED light induces isomerization of the azirinecarbonyl moiety of the azirinyl(isoxazolyl)ketones, resulting in the formation of a set of 3,5’-biisoxazoles in a 40–71% yield, while the catalytic reaction of the azirine moiety with 1,3-diketones opens the way to pyrrole- and isoxazole-containing hybrids. 2-(Isoxazole-3-ylcarbonyl)-3-arylazirines were also easily isomerized to 3-(oxazol-5-yl)isoxazoles in methanol in the presence of excess potassium carbonate at room temperature.

A formal (4 + 1) cycloaddition of oxene occurs in the reaction of 2-azabuta-1,3-dienes with m-chloroperoxybenzoic acid under mild conditions to give 3-oxazolines. Mechanistically, the reaction is an extended Prilezhaev reaction involving the formation of previously unknown (1-azavinyl)oxiranes, followed by the acid-catalyzed ring expansion. This cycloaddition was used for the one-pot synthesis of densely substituted 3-oxazolines, inaccessible by other protocols, starting from the Cu(ii)- or Rh(ii)-catalyzed reaction of 2H-azirines with diazo compounds.

Transition metal-catalyzed and noncatalytic reactions of acrylic thioamides with N-sulfonyliminoiodinanes enabling the selective synthesis under mild conditions of a series of fully decorated S- and N,S-containing heterocycles are described. Fine-tuning of the thioamide structure allows selective preparation in good yields of ortho-fused thiophenes, 1,2-thiazines, and spiro-fused isothiazolines. A one-pot thermally induced rearrangement of sulfonylisothiazolines was discovered as a complementary route to thiophenes.

A high-yielding method for the synthesis of 3-arylbenzo[4,5]thieno[3,2-b]pyrroles has been developed via pyrrole ring annulation to the aromatic benzo[b]thiophene system, using 3-arylazirines as a N‒C=C synthon. The reaction is catalyzed by Ni(hfacac)2 and proceeds through the azirine ring opening across the N=C3 bond. Azirines with both electron-donating and electron-withdrawing C3-aryl substituents tolerate the reaction conditions. The reaction of the N-methylindole analog also provides the annulation product but in moderate yield. The described synthesis is the first example of a dealkoxycarbonylative annulation reaction, in which 2H-azirines act as the annulation reagent.

A two-step synthesis of fluorescent 2,3-dihydrobenzo[e]indole derivatives using only 1H-1,2,3-triazoles as starting materials was developed. At the first step of the synthesis, the 1-alkyl-1,2,3-triazole reacts with two 1-sulfonyl-1,2,3-triazole molecules via the domino transannulation/sulfonamidovinylation sequence under rhodium catalysis. The reaction involving two different 1-sulfonyltriazoles is accomplished in one pot. The further SEAr cyclization of the formed 4-aryl-5-(sulfonamidovinyl)pyrroles using Eaton's reagent provides 2,3-dihydrobenzo[e]indoles having a sulfonylimino-, hydroxy-, and primary amino groups at the C1, C2, and C5 positions, respectively.

S-Azirinyl xanthates were synthesized as novel 2H-azirine derivatives exhibiting dual reactivity toward free radicals. Carbon-, tin-, and silicon-centered radicals initiate a desulfurization/ring expansion cascade of these compounds to form thiazoles in fair to good yields. Radicals can react with azirinyl xanthates either at the nitrogen (stannyl radicals) or sulfur (alkyl and silyl radicals), transforming them into the thiazoles through the intermediate formation of either aziridinyl or thiaazabicyclopentyl radicals, respectively. Both transformations do not involve the degenerative radical transfer and are unprecedented for the radical chemistry of xanthates.

The synthesis of 2,4,5-trisubstituted imidazoles with a Weinreb amide, ester, keto or aldehyde group, as well as 2,5-diaryl substituted imidazoles by the reaction of amidines with azirines has been reported. The reaction mechanism explaining dependence of imidazole structure on substituent at the position 2 of the azirine is discussed based on experiment with 15N-labelled azirine and DFT calculations.

A synthetic method was developed for the preparation of O-pyridylamidoximes in good preparative yields (up to 99%) by a reaction of the corresponding amidoximes with pyridine/quinoline N-oxides in the presence of PyBroP as an activator. Substituents in the used arylamidoxime had little effect on the yield of the target products, whereas the N-oxide structure had the greatest effect. O-Pyridyl-substituted amidoximes undergo an unusual condensation with (chlorocarbonyl)sulfenyl chloride. This transformation provides access to previously unreported 1,2,4-thiadiazol-5(4H)-ones functionalized at the N4 atom of the heterocycle by a pyridine moiety. Structural analysis of the products, combined with DFT theoretical calculations, allowed us to propose a reaction mechanism involving a key acylpyridinium intermediate.

4-Selanylcarbonyl-substituted 2-azabuta-1,3-dienes, synthesized from Se-aryl 2H-azirine-2-carboselenoates and α-diazo esters, generate ketene-tethered 2-azaallyl radicals under UV light (365 nm) irradiation. These conjugated radical species, in the presence of catechol as a HAT donor, undergo practically barrierless 5-endo-trig cyclization to give 4-pyrrolin-3-ones in high yields. This synthetically valuable reaction, proceeding via an "unfavorable" anti-Baldwin cyclization, is the first example of an intramolecular transformation of azaallyl radicals.