Synthesis and properties of five-membered heterocycles containing two exocyclic conjugated double bonds

Heterocyclic compounds are undoubtedly among the most important objects of modern organic chemistry due to their wide application in medicine [1-4] and materials chemistry.[5-9] Heterocycles are widely present in nature, being key motifs in the structure of complex metabolites.[10-16] This certainly stimulates the continuation of research aimed at developing new synthetic approaches to nitrogen-containing heterocycles.

The research efforts led to the creation of novel types of heterocyclic compounds, vis., fused compounds,[17-20] heterocycle assemblies,[21-24] hybrids of two heterocycles connected by a linker [25][26] and non-aromatic heterocycles.[27-29] In the last decade, the interest of organic chemists in the synthesis of heterocycles containing two conjugated exocyclic bonds has increased. Efficient methods have been developed for the synthesis of such compounds containing 1,2,3-triazole,[30] imidazole,[21][31-34] pyrrole,[35-37] pyrazole,[23][38] thiazole,[39-43] indole,[27] [37][44-58] (benzo)thiophene,[59] (benzo)furan [28][35] [60-67] and selenazole [68] rings. Such molecules react with compounds containing double [29] [45] [69-72] and triple bonds,[73-75] naphthols,[76] active methylene compounds,[19][25] [38][77-82] azomethine ylides [83] and other zwitterionic compounds [21][84] and are the starting materials for the preparation of fused [19]^, [29][38][46][73][74] [85-87] and spiroheterocycles.[24][42] [45][70][71] [78-83] [88-96] Heterocycles with three exocyclic bonds have been reported.[97-101] The reviews by Belikov and Milovidova,[37] as well as Yurovskaya and co-workers [102] describe the synthesis and some properties of heterocycles containing conjugated double bonds. The first of the mentioned reviews[37] focuses on compounds containing a dicyanoacrylamide moiety, and the second one[102] highlights reactions catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO), and therefore do not cover the entire variety of compounds containing two conjugated double bonds.

This review provides the first generalization and systematization of the methods of synthesis and features of thermal and catalytic reactions of five-membered heterocycles with two exocyclic double bonds, mainly over the period 2016 – 2025.

Among the known five-membered heterocycles with two conjugated exocyclic bonds, the greatest number of publications relate to furan-2-ones containing an aryl(alkyl)idene moiety at position 3 of the ring. Such compounds are of interest due to their diverse biological activities such as antituberculotic,[103] antimalarial,[104] analgesic [105] and anti-inflammatory.[106] In addition, furan-2-ones are useful substrates for the synthesis of various oxacycles[107] and azacycles.[108-110] This Section provides information on the synthesis and properties of furan-2-ones containing either C=C or C=N bonds at position 3 of the ring.

Pent-4-ynoic acid 1 react with aldehydes 2 in the presence of 2-amino-3-picoline 3 as the base and Wilkinson’s complex 4 to give (E)-3-arylidene-3H-furan-2-ones 5 (Scheme 1).[111] The reaction pathway includes Rh-catalyzed cyclization of acid 1 to the corresponding lactone, which condenses with aldehydes 2 in the presence of picoline 3.

Scheme 1

When the reaction is carried out under the same conditions, but in the absence of picoline 3, it delivers only 5-methylenedihydrofuran-2-one.

Alkynes 6 and 7 undergo a catalytic formal carbonylation with carbon(II) monoxide at elevated pressures to yield teraconic anhydride 8 (Scheme 2).[112]

Scheme 2

An intramolecular exo-hydroarylation of 2-aryloxy-1,4-disilylbutenynes 9 via the ortho C – H bond activation using Pd(0) and acid catalysis furnishes 2,3-bis(silylmethylidene)-2,3-dihydrobenzofurans 10 (Scheme 3).[29]

Scheme 3

According to the authors, two silyl groups promote the reaction and play a key role in stabilizing the resulting product 10. As a result of cycloaddition to N-methylmaleimide 11, exo-dienes 10 are easily converted into endo-cycloadducts 12 (see Scheme 3). In addition, the developed one-pot protocol allows the use of unstable dienes 10 in situ in the reaction with pyrroledione 11.

The reaction between readily available cinnamic acids 13 and iodoacetylenes 14 gives rise to unstable iodo enol acrylates 15, which undergo 5-exo-trig-cyclization in situ in the presence of palladium acetate to give the target 3-arylidene-5-aryl(alkyl)-2(3H)-furanones 16 (Scheme 4).[60] In some cases, the reaction is rather prolonged and the yields of the target compounds 16 are low. It should be noted that this approach was used in the synthesis of the natural kinase inhibitor BE-23372M (16a). Two examples demonstrate the possibility of a one-pot synthesis of 2(3H)-furanones 16, which simplifies their isolation and reduces the reaction time.

Scheme 4

A three-component catalytic reaction of readily available alkyl, aryl, and hetaryl bromides or triflates 17, acetylenes 18, and carbon(II) monoxide is a general and efficient method for the synthesis of 5-aryl-3-alkyl(aryl)idenefuranones 16 (Scheme 5).[61] The versatility of this approach is supported by more than thirty examples of the synthesis of compounds 16 in good yields, including the kinase inhibitor BE-23372M (16a) (see Scheme 4).

Scheme 5

The catalytic reaction of arylpropargyl ethers 19 with nitrones 20 in the presence of gold and silver salts affords 3-alkylidenebenzofuran-2-ones 21 as a mixture of E/Z-isomers with the E-isomer predominating (E/Z = 2.7‒16 : 1) (Scheme 6).[84]

Scheme 6

The oxidation reaction pathway involves the formation of a gold carbene A (see Scheme 6).[84] After arylation of carbene A, the resulting gold enolate B reacts with a second nitrone molecule, converting into a complex intermediate C. The formation of a new C – C bond induces the formation of intermediate D, which then eliminates N-hydroxyaniline to give benzofuran-2-one 21a.

The gold-catalyzed oxidative cycloalkenylation of aryl propargyl ethers 19 with quinoline N-oxides 22 affords 3-alkylidenebenzofuran-2-ones 23 (Scheme 7).[22] Benzofuran-2-ones 24 were isolated as by-products of this reaction. The mechanism for the formation of benzofuran-2-ones 23 involves the initial formation of a gold α-oxocarbene that is attacked by a tethered arene to form a gold enolate that reacts with quinoline N-oxide to complete the olefination process. This reaction pathway is similar to that represented in Scheme 6.

Scheme 7

In solvents with low dielectric constant that do not have nucleophilic properties, alkyl derivatives of propenides 25 react with hydrogen halides (HCl or HBr) to give furans 26, which contain exocyclic C=C bonds in positions 2 and 3 (Scheme 8).[113]

Scheme 8

Hydrogen halide catalyzes the keto-enol tautomerism and the formation of enol A, which undergoes heterocyclization to intermediate B. Neutralization of the reaction mixture affords Z-alkylidene tetrahydrofurans 26. The authors assume that the stereoselectivity of the reaction is due to the steric factor, since unlike E-isomer of enol A, its Z-isomer is susceptible to further cyclization. In a follow-up study,[28] compounds 26 were obtained under mild basic catalysis conditions, though in lower yields.

Bromosilyloxyfuran 27 was used to obtain 3-(1-hydroxyalkyl)-2-silyloxyfurans 28 via halogen – metal exchange with n-butyllithium followed by exposure of the in situ generated 3-lithiated 2-triisopropyl silyloxyfuran to aldehydes (Scheme 9).[114]

Scheme 9

With the exception of p-nitrobenzaldehyde, all aliphatic and aromatic aldehydes used in the reaction gave high yields of carbinols 28. (E)-3-Alkylmethylidene- and (E)-3-(arylmethylidene)-2(3H)-furanones 29 were synthesized with high stereoselectivity by mesylation of 2-silyloxyfurans 28, followed by elimination of mesyltriisopropylsilyl moiety (see Scheme 9).

Yegorova and co-workers[115] showed the possibility of a microwave-assisted enamination of 5-arylfuran-2(3H)-ones 30 with dimethylformamide dimethyl acetal (DMF – DMA) (31) in toluene under elevated pressures. This reaction furnishes furanones 32 containing exocyclic C=O and C=C bonds (Scheme 10).

Scheme 10

According to the data of 1D NOESY experiments, compounds 32 have the E-configuration and are absolutely inactive to N-nucleophilic reagents. Furanones 32 were treated with Lawesson’s reagent in benzene, after which the resulting thioanalogues of furans 33 were reacted with arylamines containing electron-donating substituents (see Scheme 10).[64] As a result of transamination, furan-2(3H)-thiones 34 were obtained in high yields.

Husain et al.[116] showed that 3-arylidene-5-(4-methylphenyl)-2-(3Н)-furanons 16 are accessible from 3-(4-methylbenzoyl)propanoic acid 35 by the reaction with aromatic aldehydes 2 in the presence of triethylamine in acetic anhydride under modified Perkin reaction conditions (Scheme 11). Furanones 16b,c showed significant anti-inflammatory and analgesic activities.

Scheme 11

5-Alkylfuran-2(3Н)-ones 36 and 4-alkyldihydrofuran-2(3Н)-ones 37 can be condensed with 5-substituted furan-2-carbaldehydes 38 under base catalysis conditions to give butenolides 39 and butanolides 40, respectively (Scheme 12).[26]

Scheme 12

The reactivity of furanones 36 is higher than that of dihydrofuranones 37 due to the formation of an intermediate conjugated anion A, so that the reaction runs under milder conditions.

Shubin et al.[66] used the reaction of active methylene compounds with aldehydes to introduce a C=C bond into furan-3-one molecules. In particular, it was shown that 4,6-dihydroxy-7-methylbenzofuran-3(2H)-one 41 undergoes base-catalyzed crotonic condensation with substituted benzaldehydes 2 to yield aurones 42, including an analogue of natural 7-methylaureusidin isolated from Cyperus capitatus extract (compound 42a) (Scheme 13).

Scheme 13

The aldol condensation of lactone 36a with benzaldehyde 2a catalyzed by the ionic liquid EAPA is an environmentally friendly protocol for the synthesis of 3-arylidenefuranone 43, but the authors did not report the yield of the product (Scheme 14).[117] It should be noted that both reagents can be obtained from renewable raw materials. Lactone 36a is a product of the dehydration of levulinic acid, which can be derived from both cellulose [118] and hemicellulose;[119] benzaldehyde is produced by photocatalyzed selective oxidation of a model compound, lignin β-1.[120][121]

Scheme 14

2-Hydroxy-4-oxobut-2-enoic acids 44 react with 2-aminothiophenes 45 in ethanol at 60°C to give 2-(thiophen-2-yl)amino-4-oxobut-2-enoic acids 46, which undergo intramolecular cyclization in the presence of propionic anhydride (Scheme 15).[25] The 3-(thiophen-2-yl)amino-3H-furan-2-ones 47 obtained by cyclization were reacted with nitriles to afford compounds for testing for antitumour activity (see Section 3.2, Scheme 24).

Scheme 15

Annulation reactions have found wide application in the synthesis of various heterocyclic compounds due to their efficiency in constructing complex cyclic structures.[122-124] Chen et al.[125] suggested that allylamines 49 as C,N-synthons can undergo [3 + 2] or [3 + 4] cycloaddition with benzofuranazadienes 48 in a basic medium (Scheme 16).

Scheme 16

In search for the optimal reaction conditions, the authors varied the reagent ratio, the type of solvent and used different bases (organic and inorganic). It was found that spiranes 50 are formed mainly in high yields and with diastereoselectivity > 20 : 1 when carrying out the reaction of benzofuranazadienes 48 with allylamines 49 in the presence of cesium carbonate in DCE at room temperature.

According to the proposed mechanism (see Scheme 16), allylamine 49 is converted into intermediate product A when treated with cesium carbonate. Then, the nucleophilic attack of the latter on the molecule of azadiene 48 gives adduct B, which is further converted into intermediate C via the [3 + 2] cycloaddition pathway. In turn, intermediate C, in the presence of cesium hydrogen carbonate, forms spirocyclic product 50. According to the authors, the developed approach to spiranes 50 is consistent with the principles of ‘green’ chemistry, since it is implemented without the use of transition metals that are toxic to living cells.

2-Oxopyrroles are five-membered lactams. They exhibit a variety of biological activities,[126] including antimicrobial[127] and antimalarial,[128] and are found in a variety of natural compounds,[129] examples of which include the antitumour alkaloid Jatropha[130] and the platelet aggregation inhibitor PI-091 (Ref. [131]) (Fig. 1).

Fig. 1

Examples of natural pyrrolones

This Section provides data on the synthesis of properties of pyrroles containing conjugated exocyclic bonds.[35][69][126-128][132]

Three-component condensation of terminal alkynes 51 with carbodiimides 52 and malononitrile 53a in the presence of CuI, DBU, and tetra-n-butylphosphonium acetate (TBPAc) in anhydrous acetonitrile under optimized conditions gives rise to pyrroles 54 in good yields (Scheme 17).⁶⁹ Various alkynes 51 (alkyl-, aryl-, and heteroarylalkynes) can be used in this reaction. Carbodiimides 52 can be symmetrical and unsymmetrical, with aryl or alkyl substituents.

Scheme 17

The authors proposed a mechanism for the formation of pyrrole 54a (Scheme 18). In the first step, copper(I) iodide reacts with phenylacetylene 51a, thus activating the terminal C‒H bond. The abstraction of the terminal proton with DBU generates copper acetylide A, which attacks the electrophilic carbon of carbodiimide B in the presence of TBPAc to afford phenylpropionimidamide C. Apparently, DBU promotes the removal of CuI from the amidine moiety of intermediate C to give complex D. After this, the conjugate base of malononitrile E reacts with its triple bond and then intermediate F, the amino group of which is involved in nucleophilic addition to the nitrile carbon by intramolecular exocyclization, is converted to intermediate G. Tautomerization of the latter yields the target product 54a.

Scheme 18

In order to determine the possibility of using the above method in the Diels – Alder reaction, the reaction of diene 54a with alkynes and alkenes was explored.⁶⁹ It was shown that diene 54a reacts smoothly with ethoxyethene in the presence of Cu(OTf)₂ in dichloromethane to give bicyclic heterocycle 55 in 72% yield (Scheme 19).

Scheme 19

Unlike alkenes, diene 54a reacts with dimethyl acetylenedicarboxylate (DMAD) to give a complex mixture that could not be separated. Thus, the studied cycloaddition of pyrroles 54 containing two exocyclic bonds to dienophiles has limited application in organic synthesis.

In order to obtain pyrrolidones, Rao et al.¹³³ carried out the microwave-assisted condensation of 4-oxo-4-phenylbutanoic acids 33 with benzylamines 56 and obtained the target compounds 57 in good yields (Scheme 20). Interestingly, in 1986, Saeed ¹³⁴ assigned structure 58 to the products of this reaction.

Scheme 20

Rao et al.¹³³ carefully revised these data ¹³⁴ and confirmed the structure of the resulting compounds 57 based on the data of IR, ¹H, ¹³C NMR and mass spectra. It was shown that the reaction of acids 33 with amines 56 can afford the target products 57 also on heating at 140°C for 2 hours, but the reaction rate is higher under microwave irradiation.

The oxygen atom in butenolides 21 can be easily replaced by a nitrogen atom by reaction with a 30% ammonia solution in the presence of glacial acetic acid in boiling methanol ⁶² or by purging dry ammonia through solutions of butenolides 21 in anhydrous ethanol (Scheme 21, reaction a).¹³² Both pyrrolones 59 (Ar¹ = Ph, 3,4-(MeO)₂C₆H₃ , Ar² = Ph) and the starting butenolides 21 demonstrated efficient cis-trans photoisomerization, comparable to the behaviour of auto-fluorescent proteins (AFP).⁶² Remarkably, the configuration was determines using structure-adapted NMR measurements and their interpretation in view of theoretical calculations. Thus, a strategy was developed to enable rapid identification of photoisomerization features in AFP chromophore analogues.

Scheme 21

1-Benzyl-2(3Н)-pyrrolones 60 were obtained from the appropriate butenolides 21 and benzylamine in yields from moderate ¹³² to quantitative (see Scheme 21, reaction b).¹³³ Among pyrrolones 59, 60, compounds exhibiting antibacterial or fungicidal activity were identified.¹³²

Butenolides 21 react with substituted anilines in glacial acetic acid in a similar manner to give 1-aryl-2(3H)-pyrrolones 61 in low yields (see Scheme 21, reaction c).⁶³ All 1-arylpyrrolones 61 were tested for their potential antiviral activity using hepatitis C virus (HCV) replication and cytostatic assays. Compounds 61 (Ar² = 4-EtO₂CC₆H₄ , Ph and R = 2-Br, 4-Me) exhibited the highest antiviral activity.⁶³

Silaichev et al.¹³⁵ studied the reaction of 3,3-diamino­acrylonitriles 62 with dimethyl acetylenedicarboxylate (DMAD) (63a) and showed that the reaction pathway depends on the structure of substrate 62 (Scheme 22).

Scheme 22

Thus, DMAD 63a reacts with acrylonitriles 62 containing an N,N-disubstituted amidine moiety to give 1-NH-5-aminopyrroles 64. On the other hand, using acrylonitriles 62 containing a monosubstituted amidine group, 1-substituted 5-amino-2-oxopyrrol-3(2H)ylidenes 65 are formed. In both cases, pyrroles containing two conjugated exocyclic C=O and C=C bonds are produced in high yields. A significant drawback of this method is the low availability of the starting acetylenes.

Aroyl(heteroaroyl)pyruvic acid esters 66 provide a more accessible alternative to disubstituted acetylenes and can be used to prepare pyrrolones 67 and 68 bearing variously substituted 2-oxoethylidene moiety (Scheme 23).¹³⁶

Scheme 23

Rogova et al.²⁵ showed that (thiophen-2-yl)imino-3H-furan-3-ones 39 react with acetonitrile derivatives 53 to give thiophenylaminopyrroles 69 containing a system of two conjugated exocyclic C=O and C=C bonds (Scheme 24, reaction а).

Scheme 24

Heating of compounds 69 in acetic acid at 120°C induces their intramolecular cyclization to give fused pyrrolones 70 in high yields (see Scheme 24, reaction b). The results of in vitro tests of compounds 69a and 70a showed their high anti-proliferative activity and low cytotoxicity towards normal cells in a mouse lung metastatic melanoma model.²⁵

A one-pot protocol for the synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidines 70 was developed, based on a cascade reaction of acids 44 with various Gewald’s aminothiophenes 45 (see Scheme 24, reaction c).⁸⁰ This method represents a new synthetic approach to the preparation of fused pyrroles. The thieno[3,2-e]pyrrolo[1,2-a]pyrimidine core of compounds 70 is an important scaffold of new poly(ADP-ribose) polymerase (PARP) inhibitors, which play an important role in the development of new drug candidates.

The similar reaction of thiophene-3-carbonitriles 71 with acetonitriles 53 under milder conditions affords 2-amino-1-(thiophen-2-yl)dihydropyrroles 72, which, without further purification, were cyclized to pyrrolo[1,2-a]thieno[3,2-e]­pyrimidines 73 in boiling glacial acetic acid (Scheme 25).¹⁹ Compounds 73 are accessible through a one-pot protocol from acids 44 and thiophene-3-carbonitrile 74.

Scheme 25

In vivo experiments with melanoma-bearing mice demonstrated the high potential of compound 73a (R¹ = Ph, R² = CN) in the treatment of melanoma and showed significant suppression of tumour growth on the 15th day after the start of therapy.¹⁹

The oxindole ring is one of the key scaffolds in many alkaloids and highly active biologically active compounds. Among them, 3-alkylideneoxindoles can be distinguished, which are important targets for the synthesis of compounds of interest in medicinal chemistry and are present in many natural compounds.¹³⁶ This Section includes data on the synthesis and properties of indole derivatives containing conjugated exocyclic bonds.

In 2010, Millemaggi and Taylor ¹³⁷ published a review of classical methods for the synthesis of 3-alkylideneoxindoles developed before 2010. Many of them are still in use. The review includes data on the synthesis of 3-alkylidene-2-oxindoles from: (a) aryl alkynes using carbonylating annulation; (b) aryl propionamides, including arene-alkyne cyclization; (c) 1-benzylisatins with various active methylene compounds via the Knoevenagel reaction; (d ) benzofurandiones and triphenylphosphine derivatives, as well as methods based on the Heck/Suzuki – Miyaura reactions and the use of an approach involving reactions of activated aryls, as well as arene – alkyl cyclizations.

Considering the high synthetic potential of 3-alkylidene­oxindoles, the search for methods for their synthesis is currently ongoing. In particular, Chen et al.⁴⁴ developed an effective approach to 3-alkylideneoxindoles using a tandem Knoevenagel/deacetylation reaction. Thus, the reaction of 2-oxindoles 75 with acetyl ketones 76 in the presence of InCl₃ catalyst and acids affords the target products 77, mainly in high yields (Scheme 26).

Scheme 26

As an alternative to 1,3-dicarbonyl compounds 76, the authors propose using more accessible aldehydes and ketones 78 to obtain 3-alkylideneoxindoles 77 (Scheme 27).

Scheme 27

With the aim of obtaining novel effective antidiabetic agents, Mukhliss et al.¹³⁸ carried out a reaction of sulfonylpiperidin-4-ylindol-2-one 79 with substituted benzaldehydes 2 in ethanol in the presence of triethylamine to obtain 3-arylidene oxindoles 80 (Scheme 28).

Scheme 28

Unfortunately, the article does not provide data on the melting points and yields of the resulting compounds. 3-Arylideneoxindoles 80 were tested for their α-glucosidase and α-amylase inhibitory activities. Compared with the standard inhibitor acarbose, which has an IC₅₀ value of 100.30 ± 0.20 μM for α-amylase and 9.80 ± 0.20 μM for α-glucosidase, all compounds 80 showed complete inhibition of α-amylase and α-glucosidase. 3-Arylideneoxindole 80a (R = 2,4,6-(OH)₃) is the most potent compound in this series with an IC₅₀ value of 0.30 ± 0.05 μM for α-amylase and 0.40 ± 0.05 μM for α-glucosidase, which is significantly superior to the standard values. The structure-activity relationship (SAR) was established based on the change in the position of the R substituents in the arylidene moiety. The most effective drug interactions were studied by molecular docking.

It is known that VEGF (vascular endothelial growth factor, a signalling protein produced by cells to stimulate the growth of new vessels in the vascular system) and its receptors are hyperactivated in many types of cancer tumours and are considered promising targets for the administration of antitumour agents.¹³⁹ In order to find new VEGFK-2 inhibitors, Aboshouk et al.¹⁴⁰ carried out a study aimed at the synthesis of modified 2-oxoindolin-3-ylidenes containing an urea moiety. The target compounds were obtained in two steps. Addition of the corresponding 1-(acetylphenyl)-3-phenylurea 82 to isatins 81 in ethanol containing Et₂NH, followed by acidic dehydration (AcOH/HCl) of the intermediates 83 gave the target 2-oxoindolin-3-ylidenes 84 in high yields (Scheme 29).

Scheme 29

The authors note the presence of promising antiproliferative properties (according to MTT assay data) in most of the synthesized compounds 84 against colon, breast and pancreatic cancer cell lines. Compound 84a (R¹ = H, R² = 4-NHCONHPh, 87.2% inhibition) is the most promising anti-VEGFR-2 agent. Its activity is similar to that of Sunitinib (an antitumour agent that inhibits multiple kinases involved in tumour growth processes) (89.4% inhibition) at a concentration of 10 μM.

The discovered oxidative transformation of furans 85 into indole derivatives 86 in the presence of bases served as the basis for the development by Uchuskin and co-workers ²⁷ of a new and effective approach to 2-alkylideneoxindoles (Scheme 30). The driving force of the second step of the process is apparently the formation of a strong hydrogen bond, similar to that observed previously ³⁰ for the synthesis of 1,2,3-triazoles containing two exocyclic double bonds.

Scheme 30

Ueda et al.¹⁴¹ developed a method for the synthesis of 3-benzylidenindol-5-ones based on the construction of a pyrrolone ring to the benzene ring in N-cinnamoyl anilines 87 by palladium-catalyzed intramolecular alkenylation in the presence of silver trifluoroacetate as an oxidant (Scheme 31). This reaction can be used to synthesize NH-, N-aryl-, and N-alkyloxindoles 88, which opens an access to structurally diverse oxindoles with two exocyclic C=O and C=C bonds from readily available starting materials.

Scheme 31

In the case where R³ ¹ R⁴, compounds 88 are formed as a mixture of isomers with the E-isomer predominating (Scheme 32). The authors proposed a mechanism for the formation of each isomer.

Scheme 32

C – H-Activation of aniline 87a with palladium to form intermediate A, followed by syn-insertion of the olefin and β-hydride elimination affords Z-oxindole 88a. The E-isomer is formed from the palladium π-complex C with subsequent nucleophilic attack of the arene and elimination of β-H.

In order to synthesize tricyclic fused heterocycles, Vyalyh et al.¹⁴² used the reaction between 2-methylindoles 89 with lithium diisopropylamide (LDA) to generate indole-2,3-dienolates 90 (Scheme 33). Since the resulting compounds 90 were not stable enough to be isolated, they were used in situ to obtain carbolines 91 and thiopyranindoles 92 via reactions with nitriles ¹⁴² and carbon disulfide,⁴⁶ respectively.

Scheme 33

Knoevenagel condensation of isatins 93 and malononitrile 53a in the presence of triethylamine gives rise to another type of 3-alkylidene-2-oxoindoles 94 (Scheme 34).⁴⁵ The authors did not identify these compounds, but used them in situ in reactions with allenes 95 and amines 96 to obtain spirocyclic indolones 97. The mixture of Z/E-isomers can be separated into individual isomers by column chromatography on silica gel.

Scheme 34

The development of a strategy for the synthesis of spirooxindoles is well advanced due to their wide application in medicine.^143, 144 Traditional synthetic approaches to these compounds include transition metal (Mn, Fe, Ni, Cu, Zn, Ag, Au and Pd) catalysis ¹⁴⁵ and the use of a ‘green’ synthesis strategy.^146, 147

Spirooxindoles contain, in addition to the indole unit, a spirocyclic moiety. They are part of some natural compounds ^148, 149 and exhibit a wide range of biological activities (Fig. 2).^{149 – 152}

Fig. 2

Examples of biologically active spirooxindoles

The absolute configuration and the nature of the substituents in the spirocycle have been shown to significantly affect the biological activity of spirooxindoles. Advances in stereoselective and asymmetric synthesis of spirooxindoles have led to the discovery of new biologically active natural compounds such as horsfilin, kerulescin, and spirotryprostatins A and B (see Fig. 2).^148, 149 Synthetic analogues, chiral spiropyrrolidinyl- and spiropiperidinyl oxindoles containing a nitrogen atom located near the spiro-quaternary stereocenter, have antitumour, anticancer, and antimalarial activities.^{150 – 152} These promising biological data have stimulated the development of new stereoselective methods for the synthesis of spiropyrrolidinyl oxindoles.

One such study concerns the synthesis of enantio-enriched gem-difluoromethylated spiro-pyrrolidinyl- and spiro-piperidinyl oxindoles.¹⁵³ Diastereoselective nucleophilic addition of PhSCF₂SiMe₃ to chiral N-tert-butylsulfinyl- ketimines 98 obtained from isatins was a key step in the study and opened the way to diastereomeric adducts 99 (Scheme 35).

Scheme 35

Removal of the chiral sulfinyl group followed by structural modification delivered chiral gem-difluoromethylenated spiro-pyrrolidinyl- and spiro-piperidinyloxindoles 100.

Parida et al.⁷⁰ studied the aza-Michael reaction of N-Boc-aza-derivatives of isatin 101 with γ-hydroxyenones 102 in the presence of various catalysts and found that the quinine-derived bifunctional squaramide catalyst 103 performed best in the organocatalytic asymmetric synthesis of spirooxindoles 104 (Scheme 36). Compounds 104 were obtained using the optimized protocol with good diastereoselectivity and high enantioselectivity.

Scheme 36

In order to develop an enantioselective approach to indolone derivatives, Xue et al.¹⁵⁴ carried out a Cu(II)-catalyzed aza-Friedel – Crafts reaction of N-Boc derivatives of azaisatin 101 with indoles 105 using chiral O – N – N tridentate ligands derived from BINOL (1,1'-bi-2-naphthol) and proline. As a result, chiral 3-indolyl-3-aminooxindoles 106 were obtained in high yields and with high enantiomeric excess (ee) under mild conditions in the presence of ligand L1 (Scheme 37).

Scheme 37

Duan et al.⁷⁶ showed that it is possible to use naphthalene derivatives 107 instead of indole derivatives ¹⁵⁴ in the aza-Friedel – Crafts reaction (Scheme 38). Here, H₈-BINOL-derived chiral biarylphosphoric acid (CPA) was employed as a catalyst. The possibility of using a wide range of isatin-derived ketenimines 101 in this reaction for the synthesis of a series of chiral 3-amino-2-oxindoles 108 in good yields and with high optical purity was also demonstrated.

Scheme 38

Asymmetric addition of organometallic reagents to imines is an effective strategy for the design of chiral polysubstituted amines.^155, 156 In line with such studies, Zhang and co-workers ¹⁵⁷ developed the Pd(II)/Pyrox-catalyzed enantioselective addition of arylboronic acids to 3-ketimino oxindoles 109, delivering chiral 3-amino-2-oxindoles 110 with a quaternary stereocenter in high yields and with good enantioselectivity (Scheme 39).

Scheme 39

This reaction tolerates 3-ketimino oxindoles 109 with various substituents in the benzene ring and substituted arylboronic acids. The proposed asymmetric arylation of 3-ketimino oxindoles 109 represents an effective catalytic method for the preparation of chiral 3-aryl-3-amino-2-oxindoles and is the first example of Pd(II)-catalyzed addition of arylboronic acids to exocyclic ketimines.

β-Fluoramine is an interesting scaffold that plays an important role in pharmaceutical chemistry and is found in many biologically active substances, including drug candidates. β-Fluoro substitution can lower the pK_a value of amines, which improves many pharmacological properties.¹⁵⁸ In this context, effective methods of catalytic asymmetric synthesis of chiral β-fluoroamines are very attractive. One of the direct approaches to β-fluoroamines is the asymmetric Mannich reaction of α-fluoroketones. Therefore, the development of new methods for obtaining chiral fluoroamines is an important challenge in organic synthesis.

To advance this area, Zhao et al.¹⁵⁹ developed a method for the catalyzed enantioselective Mannich reaction of isatin-derived N-Boc-ketimines 101 with α-fluoroindanones 111 in the presence of a quinine-containing phase transfer catalyst (Scheme 40). As a result, various 3-substituted 3-amino-2-oxindoles 112 containing a fluorine atom and vicinal tetrasubstituted stereocentres were synthesized in good yields and with high diastereoselectivity. The above studies are the first example of an organocatalytic, dia- and stereoselective Mannich reaction of ketenimines with fluoroindanones.

Scheme 40

Yoshida et al.¹⁶⁰ reported the first example of asymmetric synthesis of 2-aminocyanoacetic esters with vicinal tetrasubstituted carbon centres using chiral halonium salts 14a – c as catalysts. The Mannich reaction involved isatin-based N-Boc-ketimines 101 and cyanoacetic esters 113 (Scheme 41).

Scheme 41

Optimization of the reaction conditions included varying catalysts 114a – d, solvent, and temperature. It was shown that the use of bromonium salt 114a is optimal for achieving high enantioselectivity, while iodonium salt 114b provides higher diastereoselectivity of the process. Carrying out the reaction in non-polar solvents improved the yields of the reaction products, and the optimal temperature is –40°C. The use of a fivefold excess of cyanoacetic esters 113 is necessary to achieve high yields of compounds 115 and higher enantioselectivity of the reaction. A study of the effect of substituents at position 1 of the indolone ring showed that products 115 with higher enantioselectivity are formed from sterically less hindered N-substituted substrates 101 (R = Me, Bn). The authors report that studies of the reaction pathway and the possible application of compounds 115 are ongoing.

Another type of spirocyclic compounds bearing an indolone ring was synthesized by Huang et al.,⁸⁵ who developed two methods for the substrate-controlled regiodivergent annulation of 2,3-dioxopyrrolidines 116 with 3-alkylideneoxindoles 117 and 118 (Scheme 42).

Scheme 42

Spirofused indoline-3,4'-isoindoles 119 and indolylchro­menopyrrolones 120 were obtained in high yields and with high stereoselectivities. The authors proposed mechanisms for both annulation reactions. It is assumed that [3 + 3] annulation involves conjugate Michael addition followed by intramolecular aldol cyclization, whereas [4 + 2] annulation proceeds via conjugate Michael addition followed by oxa-Michael cyclization.

Patil et al.¹⁶¹ synthesized a number of spirooxindoles 122 via [4 + 2] cycloaddition of isatylidene malononitrile 94 and α,β-unsaturated ketones 121 using L-proline as an organocatalyst (Scheme 43).

Scheme 43

In order to optimize the synthesis procedure, the authors tested various amines (pyrrolidine, piperidine, morpholine, 2-amino-N-(4-chlorophenyl)propanamide and an ionic liquid based thereon) as a catalyst, and also varied the catalyst loading. The use of 20 mol.% L-proline is optimal for achieving high yields of spiranes 122 and a short reaction time. When comparing the reaction rates of substrates with electron-withdrawing and electron-donating substituents, it was noted that the reaction rate is higher for compounds with electron-withdrawing groups.

The authors propose that initially, L-proline reacts with ketone 121 to form an imminium ion, which is converted to an enamine that acts as a 1,3-diene (see Scheme 43). Isatilydene malononitrile 94 acts as a dienophile in the [4 + 2] cycloaddition, forming the [4 + 2] adduct B. Subsequent hydrolysis of adduct C delivers spirocyclohexanone oxindoles 122 and regenerates L-proline for the next catalytic cycle.

An efficient synthetic approach to spiro(indoline-3,3'-pyrazolo[1,2-a]indazoles) 124 using the [3 + 2] N,N-cyclo­addition strategy for isatilydene malononitriles 94 and 1,2-dihydro-3H-indazol-3-one 123 under mild conditions has been developed (Scheme 44).¹⁶² A number of organic bases (DMAP, pyridine, DBU, DABCO, triethylamine) were tested as reaction catalysts in various solvents at ambient and elevated temperatures and it was found that the optimal conditions for the synthesis of spiranes 124 includes the use of triethylamine as a base, dichloromethane as a solvent, and carrying out the reaction at room temperature.

Scheme 44

Kumar et al.¹⁶² proposed that 1,2-dihydro-3H-indazol-3-one 123 can readily tautomerize to isomer 123', which reacts with indolone 94 according to the Michael reaction pathway. Subsequent cyclization and isomerization lead to rearrangement of the π-bonds and formation of three new C – N bonds of spirocyclic indolone 124 (Scheme 44).

Compounds 124 were evaluated for cytotoxicity against various cancer cell lines, including MCF-7 (breast cancer), A549 (lung cancer), Colo-205 (colon cancer) and A2780 (ovarian cancer).¹⁶² It should be noted that compound 124a (R¹ = All, R² = Me) showed the highest apoptotic activity, exhibiting the lowest IC₅₀ values among all four cancer cell lines. In addition, the observed biological activity was confirmed by molecular docking studies, suggesting that these compounds may interact with relevant cellular targets, potentially accounting for their cytotoxic effects.

Yavari et al.¹⁶³ described a cascade reaction between two equivalents of isatylidene malononitriles 94 and benzylamines 125 to afford dispirocyclopentene oxindoles 126 with high diastereoselectivity (dr ³ 19 : 1) (Scheme 45).

Scheme 45

Molecules of 126 comprise four chiral centres, including two vicinal spiro-quaternary chiral centres. The structures of compounds 126 were confirmed by X-ray diffraction analysis.

The authors proposed a reaction pathway for the formation of spiranes 126, which probably begins with the reaction of isatylidene malononitrile 94 with benzylamine 125 to give an intermediate product A, which reacts with a second molecule of 94 and then undergoes intramolecular cyclization to form aziridinium ylide C. Aziridinium ylide C subsequently undergoes ring opening and elimination reaction to afford dispirocyclopentene D. Attack of the alcohol molecule on the cyano group of intermediate D initiates a second cyclization reaction, which delivers the target dispiroindoline-cyclopentapyrimidinindolines 126.

It should be noted that the unique structural features of bi-spirooxindoles impart significant conformational rigidity, which often leads to increased biological activity of various biomolecules. According to recent findings, they can be uses as acetylcholinesterase inhibitors, which represents a promising therapeutic strategy for the treatment of Alzheimer’s disease.^164, 165

Isatin-derived trifluoromethyl-substituted alkyl acrylates 127 undergo an intermolecular [3 + 2] cycloaddition to azomethine ylides 128.¹⁶⁶ Unusual highly substituted pyrroledines 129 bearing adjacent quaternary all-carbon stereocentres, one of which being spirocyclic and another containing a trifluoromethyl group, were obtained in good yields and with high stereoselectivity (ee 80 – 99%, dr > 20 : 1) (Scheme 46).

Scheme 46

The authors used copper salts (Cu(OTf)₂ , Cu(CH₃CN)₄PF₆ , CuI and Cu(OAc)₂) as catalysts, six different ligands, various bases and also varied a solvent to optimize reaction conditions. Maximum yields, the highest diastereoselectivities and enantioselectivities were achieved when using Cu(CH₃CN)₄PF₆ , a chiral ligand 2-(1-(dimethylamino)ethyl)-1-(diphenyl­phosphino)ferrocene (L), Cs₂CO₃ as a base and МТВЕ as a solvent. The authors scaled up the reaction and reacted the resulting spiranes 129 with phenylboronic acid and Boc₂O under Suzuki – Miyaura conditions thereby demonstrating the synthetic potential of these compounds.¹⁶⁶

Liu and co-workers ¹⁶⁷ reported the asymmetric catalytic aza-Michael-initiated ring-closure of methylene indolinones 130 with N-tosyloxycarbamates 131 (Scheme 47).

Scheme 47

The use of chiral nickel complex catalyst L/Ni(OTf)₂ with good functional tolerability and wide versatility in this reaction under ambient conditions enabled the synthesis of spiro-aziridine oxindoles 132 in good yields (up to 99%) and with high stereoselectivity (up to 97% ee, > 19 : 1 dr) under mild conditions. The effect of substituents in the benzene ring of the ligand was studied, and the optimal reaction conditions were searched for by varying various metal triflates, various bases and solvents. All experiments were carried out in a nitrogen atmosphere at 0°C. The optimal conditions include the use of the L/Ni(OTf)₂/diisopropylamine catalytic system and dichloromethane as a solvent.

Karade and co-workers ¹⁶⁸ presented a new efficient method for the synthesis of 3-aryloxindoles from 3-arylideneindolin-2-ones. (Diacetoxyiodo)benzene initiates a skeletal rearrangement involving 1,2-aryl migration to position 3 of the ring. Ligand exchange between (diacetoxyiodo)benzene and methanol affords the trivalent iodine compound PhI(OMe)₂ (Scheme 48).

Scheme 48

The reaction begins with electrophilic activation of 3-arylideneindolin-2-one 133 by PhI(OMe)₂ leading to a stabilized benzyl carbocation A, which is trapped with methanol and converted to adduct B. Migration of the aryl substituent then occurs, facilitated by elimination of iodobenzene. This generates an intermediate oxonium ion C, which undergoes nucleophilic attack by the second molecule of methanol to give 3-(dimethoxymethyl)-3-arylindolin-2-ones 134.

This effective method provides an access to oxindoles with a quaternized C3 atom of the oxindole ring under mild conditions and demonstrates broad substrate tolerability, allowing the preparation of various 3-aryloxindoles in good yields.

Benzylidene indoline-2-thiones 135 react with DMAD 63a and benzynes 136 generated in situ from the appropriate 2-diazonio benzenecarboxylate hydrochlorides to form tetracyclic compounds 137 and 138 (Scheme 49).¹⁶⁹

Scheme 49

Subsequently, the number of dienophiles was expanded by using 2,5-diones 139, which made it possible to obtain tetracyclic compounds 140 (Ref. 74)^­ (see Scheme 49). The use of only highly electrophilic dienophiles narrows the applicability of this reaction. That could be the reason why there are no data on the use of indole thiones in other types of pericyclic reactions, e.g., in [4 + 3] cycloaddition.

It should be noted that benzylideneindoline-2-thiones 135 are unstable and exist as dimers 135А (Scheme 50).

Scheme 50

Jiang et al.⁸⁶ drew attention to donor-acceptor cyclopropanes 141, which are widely used for the preparation of complex cyclic and acyclic compounds. It was shown that cyclopropanes 141 can be suitable partners for Yb(OTf)₃-catalyzed formal [4 + 3] cycloaddition to benzylideneindolin-2-thiones 135, yielding thiepino[2,3-b]indoles 142 (see Scheme 50).

Thiazolidinones functionalized at position 5 of the ring exhibit a variety of biological activities, vis., antifungal,¹⁷⁰ neuroleptic,¹⁷¹ antidiabetic,¹⁷² anti-inflammatory ¹⁷³ and antitumour activities.¹⁷⁴ The search for new biologically active substances among compounds of this class is ongoing.

In the search for novel inhibitors of cancer cell division, Izmest’ev et al.¹⁷⁵ reacted isatins 93 with imidazothiazolotriazines 143 under aldol-croton condensation basic conditions and obtained two series of regioisomeric compounds, imidazo- [4,5-e]thiazolo[3,2-b][1,2,4]triazines 144 and imidazo[4,5-e]­thiazolo[2,3-c][1,2,4]triazines 145 (Scheme 51). Compound 145a (R¹ = Prⁱ, R² = Ph, R³ = Et) showed significant cytostatic activity against most of the cell lines tested.¹⁷⁵

Scheme 51

In order to synthesize new urease inhibitors,¹⁷⁶ Elbastawesy et al.¹⁷⁷ designed and obtained hybrids of well-known biologically active objects, quinoline-2-one and thiazolidinone, connected by a hydrazone linker. Refluxing a mixture of equimolar amounts of thiosemicarbazides 146 and DEAD 63b in DMF in the presence of triethylamine affords thiazolidin-4-ones 147 in high yields (Scheme 52).

Scheme 52

It is noted that all the synthesized target compounds 147 showed different degrees of urease inhibitory activity in the IC₅₀ range of 0.46 – 27.1 μM, which is higher than similar values for thiourea, which was chosen as a standard (IC₅₀ = 21.9 ± 0.89 μM). Compounds 147a – c (R¹ = Me, R² = Ph (147a), R¹ = Cl, R² = Ph (147b), R¹ = Br, R² = Ph (147c)) demonstrated outstanding urease inhibitory potential (IC₅₀ 0.92 ± 0.17, 0.74 ± 0.14 and 0.46 ± 0.04 μM, respectively). The binding interactions of compounds 147 were confirmed by molecular docking studies. The most active compounds showed complete overlap and a binding mode close to the standard.

Hydrazone 4-thiazolidinones 150 were obtained by the sequential reaction of thiosemicarbazide 148, 3-acyl-4-hydroxypyran-2-ones 149 and dialkyl acetylenedicarboxylates 63 using a new binary ionic liquid [LPC][MimS], [L-prolinium chloride][1-methylimidazolium-3-sulfonate], as a catalyst (Scheme 53).¹⁷⁸

Scheme 53

The reaction occurs under mild and solvent-free conditions. The binary ionic liquid melts at near room temperature and can be considered as a solution of HCl in a 1 : 1 mixture of two zwitterionic compounds. It appears to activate carbonyl compounds 149 either by conversion to a proline-based imine or as an acid catalyst. It should be noted that [LPC][MimS] is stable in air and in the presence of moisture and can be reused repeatedly without any noticeable loss in its catalytic activity. Some of the resulting compounds 150 exhibited pronounced antibacterial activity.

Condensation of thioureas 151, including their cyclic analogues, with acetylenedicarboxylic acid esters (63a,b) gives rise to a variety of functionalized thiazolidin-4-ones and their analogues with heterocyclic rings 152 (Scheme 54).¹⁷⁹

Scheme 54

The reaction is highly selective and leads to the formation of a five-membered thiazole ring rather than a six-membered triazine ring, which is demonstrated by comparison with the literature data ¹⁸⁰ regarding the spin – spin coupling constants between the carbonyl carbon atom (C4=O) and the vinyl hydrogen atom (=CH). The authors ¹⁷⁹ note that the bulky cyclohexyl substituent in the starting thiosemicarbazide 151C reduces the nucleophilicity of the corresponding nitrogen atom, resulting in intramolecular N-acylation at the N2 atom to give thiazolidin-4-one 152C (R³ = Cy). The reaction of 1,4-diphenylthiosemicarbazide with DMAD 63a is non-selective and affords two regioisomeric products 152C (R³ = Ph) and 152C' in equal amounts (according to ¹H NMR). The isomers were separated by fractional crystallization from methanol.

Gagarin et al.³⁹ synthesized penta-2,4-dienecarbo­thioamides 153 and reacted them with acetylenes 63 (Scheme 55). The key step of the process is 1,6-electrocyclization of 1-azahexatriene A to give pyridothiazoles 154 containing C=C and C=O bonds.

Scheme 55

Berseneva et al.¹⁸¹ found that active methylene 2-carbamoylthioamides 155 react with DMAD 63a in ethanol to furnish 2-methylidene-1,3-thiazolidin-4-ones 156 (Scheme 56, reaction a).

Scheme 56

Obydennov et al.¹⁸² demonstrated the possibility of using compounds 156 in the synthesis of double bond-linked bicyclic heterocycles 157 (see Scheme 56, reaction b). A screening for fungicidal activity revealed compounds with high antifungal potency. The authors subsequently published a review devoted to the synthesis of bicyclic compounds linked by an exocyclic double bond.¹⁸³

2-Phenylthiazolin-5-one 159, generated in situ from thiohippuric acid 158, was condensed with various aldehydes (Scheme 57).¹⁸⁴

Scheme 57

The reaction is catalyzed by basic lead acetate and runs equally successfully with both aliphatic and aromatic aldehydes. This version of the classical Erlenmeyer synthesis of azlactones under mild conditions is apparently possible due to the more pronounced aromaticity of the intermediate anionic thioazlactones 160, which are converted to alcohols 161 when treated with aldehydes. Dehydration of compounds 161 gives 4-alkyl(aryl)ydenetiazolin-5-ones 162 in good yields.

In contrast to sulfur-containing heterocyclic compounds, the chemistry of selenazoles is poorly represented in the literature.^{68, 185 – 187} However, these compounds exhibit antibacterial, antitumour ¹⁸⁷ and pesticidal activities,⁶⁸ which attracts interest in studying their properties.

Attanasi et al.¹⁸⁵ reported the synthesis of 2-selenazolin-4-ones 166 by the reaction of 1,3-butadienes 163 with selenoureas 164 in methanol at 0°C. It was noted that the resulting compounds 166 are predominantly in the form of hydrazones (Scheme 58).

Scheme 58

According to the authors, the reaction involves nucleophilic addition of the selenium atom of selenoureas 164 to the terminal carbon atom of the heterodiene moiety. Subsequent intramolecular nucleophilic attack of the imide NH nitrogen on the carboxylate carbon of Michael adduct 165 and elimination of the alcohol molecule leads to the formation of the selenazoline ring. Tautomeric selenazolinones 166' were isolated in low yields by fractional crystallization of mixtures of compounds 166/166' from a MeOH/Et₂O mixture.

Taking into account the successful use of acetylenes in a variety of chemical reactions, Ramazani et al.¹⁸⁶ studied the reaction of acetylenedicarboxylates 63 with selenourea 167 (Scheme 59).

Scheme 59

The authors believe that compounds 168 are formed via an initial Michael addition of selenourea 167 to the triple bond of acetylenes 63 to form adducts A, followed by intramolecular proton transfer from the amidine group to the C=C bond to give adducts B. Subsequent reaction of the imine nitrogen atom with the carbonyl group yields intermediates C. Intramolecular proton transfer in intermediate C affords 2-amino-4-oxo-1,3-selenazoles 168 in moderate yields.

In order to search for new fungicides, Galochkin et al.⁶⁸ designed and proposed a synthetic approach to fused compounds containing hexahydroimidazo[4,5-d ]imidazole and -selenazole moieties. Four representatives of a new heterocyclic system, 3,3a-dihydro-1H-imidazo[4',5':4,5]imidazo[2,1-b][1,3]- selenazoles (imidazo-imidazoselenazoles) 170 were obtained for the first time, based on the reaction of bicyclic selenoureas 169 with DEAD 63b (Scheme 60).

Scheme 60

Selenazoles 170 were obtained under mild conditions (rt, 1 – 2 h), but at R = H, the reaction mixture requires heating under reflux. The structure of compounds 170 was established using two-dimensional NMR spectroscopy, ¹³C GATED NMR spectra and high-resolution mass spectra.

Pyrazole and its derivatives are used in pharmacy due to their broad spectrum of their biological activity.¹⁸⁸ For example, edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one) is a drug with the trade name Radicut and is used to treat amyotrophic lateral sclerosis.¹⁸⁹

In order to expand the range of practical applications of pyrazoles, Rabbani et al.²³ carried out a three-step synthesis of pyrazoles 176, including diazotization of aromatic amines 171, azo coupling of diazonium salts 172 with 2-hydroxybenz­aldehydes 173 to afford aza compounds 174, and their subsequent condensation with edaravone 175 in the presence of DABCO (Scheme 61).

Scheme 61

Condensation involves the aldehyde group of aza compounds 174 and the active methylene group of edaravone 175. Among the resulting compounds 176, those with antibacterial activity against Gram-positive and Gram-negative bacteria were identified (176a (R¹ = 4-Me, R² = MeO), 176b (R¹ = 4-Et, R² = MeO), 176c (R¹ = R² = H)).

Boulos et al.³⁸ reacted pyrazolone 177 with phosphonate 178 in the presence of sodium ethoxide to give pyrazole 179 (Scheme 62). Pyrazolone 180 was isolated as a by-product of this reaction.

Scheme 62

Burgart et al.¹⁹⁰ proposed several ways for obtaining pyrazoles containing conjugated C=N – OH and C=O bonds. It was found that sequential treatment of esters 181 with sodium nitrite in acetic acid and subsequent heterocyclization of the intermediate hydroxyimines 182 with hydrazines delivers the target 4-hydroxyiminopyrazol-3-ones 184 in low yields (18 – 24%) (Scheme 63, reaction a).

Scheme 63

The use of another approach, including nitrosation of preliminary obtained pyrazol-5-oles 183 with sodium nitrite in acetic acid, allowed the yield of target compounds 184 to be increased to 85% (see Scheme 63, reaction b). In addition, the authors developed a one-pot procedure for obtaining pyrazolones 184 from esters 181 and hydrazines in acetic acid, followed by treatment of the reaction mixture with sodium nitrite (see Scheme 63, reaction c). Under these conditions, pyrazolones 184 are formed in 56 – 62% yields, which makes this method the most attractive for their synthesis, since it allows to exclude the step of isolation of pyrazolones 183.

Imidazoles occupy a special place in heterocyclic chemistry due to their diverse chemical and pharmacological properties.^{191 – 197} Compounds containing the imidazole ring exhibit a wide range of pharmacological activity, including antitumour,¹⁹³ antiepileptic,¹⁹⁴ antituberculotic,¹⁹⁵ antibacterial ¹⁹⁶ and antifungal.¹⁹⁷ A number of well-known antitumour drugs, such as dacarbazine, nilotinib, ponatinib, bendamustine hydrochloride, contain an imidazole ring in their structure.¹⁹² Imidazole derivatives are promising fluorophores for organic light-emitting diodes, chemo- and biosensors.¹⁹⁸ Therefore, the synthesis of new imidazole-based molecules is relevant.

Baranov et al.¹⁹⁹ studied the reaction of azidomethylacryl­amide 185 with triphenylphosphine, carboxylic acid anhydrides and acyl chlorides (Scheme 64). In the reaction with acyl chlorides, acrylamide 186 was preliminarily isolated, whereas in the case of using acid anhydrides, the reaction was carried out in a one-pot fashion. The yields of products 187 are low (17 – 45%), except for compound 187a (R = Me, 61%). In the final step, to obtain the desired analogues of the GFP (Green Fluorescent Protein) chromophore, the authors ¹⁹⁹ used standard conditions for phenol demethylation (BBr₃ in DCM). The experimental data obtained make it possible to introduce various substituents into the imidazole ring, as well as to obtain imidazolones unsubstituted at position 3 of the ring.

Scheme 64

Imidophosphazene 188 and unstable imides 189 derived in situ therefrom, which cyclize to imidazol-4-ones 190, were used to synthesize imidazoles containing two conjugated exocyclic C=C and C=O bonds (Scheme 65).³⁴ Formamido­acetals 191 were used for subsequent condensation. It was noted that the use of molecular sieves improved the yields of target compounds 192 by 15 – 20%.

Scheme 65

The number of imidazoles containing exocyclic C=C and C=O bonds can be increased by modifying the substituents at the ring and at the C=C bond. In particular, the reaction of benzylidene imidazolone esters 193 with ammonia and methylamine gives amides 194, which were subjected to oxidation with SeO₂ (Scheme 66).²⁰⁰ The authors found that, along with the oxidation of the methyl group, further oxidation and intramolecular condensation occur constructing the pyrazinone ring on the imidazole ring to form bicycles 195; however, the yields of the products are low.

Scheme 66

Baranov and co-workers ²⁰¹ utilized the synthetic potential of 4-arylidenethioimidazolones to obtain imidazole-containing spirocycles. Research in this direction is particularly relevant, since it is part of a broader area — the creation of heterocyclic non-planar compounds.²⁰²

Taking into account their previous findings,²⁰³ the authors ²⁰¹ reacted aldehydes 196 with thioxoimidazolinone 197 to obtain imidazolones 198, which were methylated and converted the resulting compounds 199 into spiro[imidazole-4,3'-quinolin]­ones 200 (Scheme 67). This transformation occurs due to a [1,5]-hydride shift and subsequent cyclization catalyzed by scandium triflate.

Scheme 67

Kuleshov et al.⁸⁹ studied the cycloaddition of 4-arylidene-1H-imidazol-5(4H)-ones 201 to N-benzylazomethine methylide, using N-benzyl-1-methoxy-(trimethylsilyl)methylamine 202 as a precursor, in the presence of a catalytic amount of trifluoroacetic acid with the aim of synthesizing spirocyclic compounds 203 (Scheme 68).

Scheme 68

It was found that the reaction proceeds diastereoselectively yielding 1,3,7-triazaspiro[4.4]non-1-en-4-ones 203 as an individual diastereomer. A study of the effect of substituents on the course of the reaction showed that the aryl substituent has the greatest effect. In the presence of electron-donating substituents, the reaction proceeds more slowly and requires the use of an excess of the precursor of azomethine methylide 202. The developed synthesis method can be successfully used to create small libraries of spiro-imidazolinepyrrolidines for screening their biological activity.

Interest in 1,2,3-triazoles has increased rapidly since the discovery in 2002 by Meldal ²⁰⁴ and Sharpless ²⁰⁵ of the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction, which is an extremely simple and effective synthetic approach to this class of compounds. In a series of synthesized 1,2,3-triazoles, compounds exhibiting diverse pharmacological activity ^{205 – 213} have been identified (antitumour,^205, 206 antiviral,^207, 209 antifungal,^210, 211 antimicrobial,²¹² antidiabetic ²¹³). 1,2,3-Triazoles have also found application in materials chemistry.^214, 215 Despite the enormous interest in 1,2,3-triazoles, the synthesis of their derivatives containing exocyclic bonds is represented by only one report.

Bakulev and co-workers ³⁰ showed that the reactions of 2-cyanoacetamidines 204 with sulfonyl azides proceed in two different routes to give 1-substituted 5-amino-1,2,3-triazoles 205 or 4-methylene-1H-1,2,3-triazole-5(4H)-imines 206 (Scheme 69).

Scheme 69

In the absence of base, the only products are 5-amino-1,2,3-triazoles 205. The presence of 1.2 equiv. sodium ethoxide or DBU changes the direction of the reaction towards the formation of triazoles 206. The authors developed methods for the selective and efficient synthesis of triazoles 205 and 206, including a one-pot synthesis from sodium azide and sulfonyl chlorides without isolation of sulfonyl azides. The formation of compounds 206 with two exocyclic bonds was explained by the presence of two strong hydrogen bonds in these molecules, N∙∙∙H and O∙∙∙H, which stabilize this unusual structure.

The plausible mechanism for the formation of compounds 206 is shown in Scheme 70.

Scheme 70

Apparently, the triazenide anion I1, resulting from the addition of mesyl azide to carbanion A, is a common intermediate for routes a and b leading to products 205 and 206. The proton addition to the negatively charged mesylamino group with subsequent conversion of triazene I1 to triazene I4 (route b) and the formation of triazoline I2 from triazene I1 (route a) are competitive reactions.^216, 217 Elimination of mesylamine from triazene I4 furnishes diazoimine I5, which cyclizes to triazole 205. The authors suggest that triazoline I2 is easily converted to aromatic triazole I3 in a basic medium, which is consistent with the formation of stable 5-amino-1-aryl-1,2,3-triazole-4-carbonitriles in reactions of malonodinitrile with aryl azides.²¹⁸ In turn, triazole I3, bearing an electron-withdrawing mesyl substituent at position 1, undergoes either a Dimroth-type or a double Cornforth rearrangement to give triazole I8. The final step of the rearrangement involves a 1,5-sigmatropic shift, leading to the target product 206.

The data presented in this review indicate a rapidly growing interest of organic chemists in methods for synthesizing five-membered heterocycles containing conjugated exocyclic double bonds. Over the past 10 years, effective approaches have been developed to such compounds based on furan, pyrrole, pyrazole, indole, 1,2,3-triazole, thiazole, aurone, imidazole, and selenazole scaffolds. The trend of recent years, especially 2025, is the study of the chemical and biological properties of heterocycles with conjugated exocyclic C=C and C=N bonds, and the development of new synthetic methods for obtaining these compounds.

The possibility of modifying the C=C bond of such compounds by annulation with non-aromatic five-membered heterocycles, using iodonium salts, and also with more complex objects to afford various spirocyclic compounds was demonstrated. Also, as a result of research in this area, enantioselective asymmetric methods for the synthesis of indolones with a quaternary stereocenter were developed. It is among such substances that compounds with antitumour, pesticide and other types of biological activity have been identified. It should be especially noted that in the first five months of 2025, 26 articles were published on the chemistry of heterocycles with two exocyclic bonds, exceeding the number of publications for any previous year. This is additional evidence of the prospects for further research in the field of synthesis, chemical and biological properties of heterocycles containing conjugated exocyclic bonds. We believe that the publication of this review will lead to a further increase in the interest of researchers in compounds containing conjugated exocyclic double bonds and, as a consequence, to the emergence of new scientific data and discovering practically useful properties of heterocyclic compounds.

This review was financially supported by the Russian Science Foundation (Project No. 24-23-00395).

Ac — acyl,

AFP — auto-fluorescent proteins,

All — allyl,

BINOL — 1,1'-bi-2-naphthol,

Boc — tert-butoxycarbonyl,

Bn — benzyl,

CPA — chiral biarylphosphoric acid,

Cy — cyclohexyl,

CuAAC — Cu(I)-catalyzed azide – alkyne cycloaddition,

DABCO — 1,4-diazabicyclo[2.2.2]octane,

DBU — 1,8-diazabicyclo[5.4.0]undec-7-ene,

DCC — 1,3-dicyclohexylcarbodiimide,

DCE — 1,2-dichloroethane,

DCM — dichloromethane,

DEAD — diethyl acetylenedicarboxylate,

DIPEA — N,N-diisopropylethylamine,

DMF – DMA — dimethylformamide dimethyl acetal,

DMAD — dimethyl acetylenedicarboxylate,

DMAP — 4-dimethylaminopyridine,

EAPA — 2-hydroxyethane-1-ammonium propionate,

Fu — furyl,

GFP — green fluorescent protein,

HCV — hepatitis C virus,

LDA — lithium diisopropylamide,

m-CPBA — meta-chloroperbenzoic acid,

MTBE — methyl tert-butyl ether,

MTT assay — a colorimetric test for assessing cell metabolic activity,

MW — microwave radiation,

Naph — naphthyl,

NOESY — Nuclear Overhauser Effect Spectroscopy,

Pd(TFA)₂ — palladium(II) trifluoroacetate,

Pd₂(dba)₃ — dipalladium(0) tris(dibenzylideneacetone),

Py — pyridinyl,

TBAF — tetra-n-butylammonium fluoride,

TBPAc — tetra-n-butylphosphonium acetate,

TBS — tert-butyldimethylsilyl,

TCAA — trichloroacetic acid,

TES — triethylsilyl,

Tf — trifluoromethanesulfonyl (triflyl),

TFA — trifluoroacetate,

TFAA — trifluoroacetic acid,

Th — thienyl,

TIPS — triisopropylsilyl,

Ts — p-toluenesulfonyl,

VEGF — vascular endothelial growth factor,

VEGFR-2 — vascular endothelial growth factor receptor 2.