Fused-Linked and Spiro-Linked N-Containing Heterocycles

Abstract

Fused and spiro nitrogen-containing heterocycles play an important role as structural motifs in numerous biologically active natural products and pharmaceuticals. The review summarizes various approaches to the synthesis of three-, four-, five-, and six-membered fused and spiro heterocycles with one or two nitrogen atoms. The assembling of the titled compounds via cycloaddition, oxidative cyclization, intramolecular ring closure, and insertion of sextet intermediates—carbenes and nitrenes—is examined on a vast number of examples. Many of the reactions proceed with high regio-, stereo-, or diastereoselectivity and in excellent, up to quantitative, yield, which is of principal importance for the synthesis of chiral drug-like compounds. For most unusual and hardly predictable transformations, the mechanisms are given or referred to.

1. Introduction

Nitrogen-containing heterocyclic compounds are an important structural motif in a significant number of natural compounds and pharmaceuticals [1]. Most biologically active molecules (more than 80%) contain heterocyclic rings in their structure, with nitrogen-containing rings being the most common type [2]. This is due to their chemical stability, ability to be functionalized, and ability to form hydrogen bonds during biological processes [1,2,3,4,5,6]. More than half of all pharmaceuticals contain nitrogen-based heterocyclic structures [1,2,7,8]. This review discusses recent advances in the synthesis of fused- and spiro-linked N-heterocyclic systems (fused heterocycles, or having one common bond for any pair of adjacent rings, and spiro heterocycles, or having one common atom belonging to both rings), containing aziridine, azetidine, pyrrolidine, imidazoline, and pyrazoline heterocyclic motifs, and focuses on the academic publications that have been released in the last five years. The synthesis of compounds containing aziridine moieties has been extensively documented in scientific publications. These compounds possess great potential for the synthesis, and various methods have been developed over time to create molecules that incorporate these three-membered functional groups, which are spiro- or fused with four- to seven-membered heterocyclic rings. From a pharmaceutical standpoint, aziridines are of significant interest due to their promising biological activity [9,10]. Azetidines are a class of four-membered ring compounds that contain nitrogen and are widely used in medicinal chemistry [11,12]. They impart structural rigidity to the molecules, making them capable of unique chemical modifications. Incorporating rigid structures into drug design can lead to the development of more promising pharmaceuticals. While the incorporation of azetidine rings into complex molecules is desirable, there are limited and reliable methods available for synthesizing these highly strained rings [9,13,14]. Pyrrolidines are a group of nitrogen-containing cyclic compounds that have been extensively utilized in medicine to develop drugs for treating human illnesses. Pyrrolidines are of great importance due to their capacity to thoroughly explore the potential for drug development, which is made possible by the sp³ hybridization and 3D coverage provided by the non-planar structure of the pyrrolidine ring, a phenomenon known as “pseudorotation” [15]. A substantial number of these compounds have been identified through pharmaceutical research, and they demonstrate a high degree of specificity for various diseases. The presence of the pyrrolidine ring and its derivatives, such as pyrrolysine and pyrrolidinones, as well as imidazolines and pyrazolines [16,17], has been shown to contribute to this specificity [15,18]. Spiro- and fused-linked compounds are found in a variety of natural products and have a rigid spatial structure that makes them useful as ligands in asymmetric synthesis and catalysis [19]. However, there is no one-size-fits-all approach to the synthesis of these compounds, and selecting proper reactivity and compatibility of functional groups is a major challenge. From the viewpoint of stereoselectivity, the presence of a quaternary and often chiral spiro center is apparently the most critical concern [19]. Spiro- and fused-linked compounds that incorporate a fluorophore group and exhibit photoresponsive fluorescence are of particular significance as versatile detectors, innovative ligand systems, laser dyes, and electroluminescent devices. They also draw attention in the realm of macromolecular compounds [20]. This review aims to discuss the latest developments in the synthesis of a diverse range of fused and spiro-heterocyclic systems.

2. Fused- and Spiro-Linked 3-, 4-, and 5-Membered Nitrogen Heterocycles

2.1. Fused Aziridines and Diaziridines

Two principal routes to construct aziridines, including fused aziridines 3, are nitrene 2 insertion into the C=C bond of alkenes 1 or insertion of carbene (generated, e.g., by dediazotation of diazoalkanes 5) into the C=N bond of imines 4 (Figure 1). Both reactions are [2 + 1]-cycloaddition processes (Figure 1).

Another route to polycyclic fused aziridines containing the 1-azabicyclo[4.1.0]hept-3-ene motif (8 or 10) with a bridgehead nitrogen atom is an intermolecular aza-Diels–Alder reaction of 1,3-dienes 6 with 2H-azirines 7. The reaction may be either intermolecular (Figure 2a) [21,22] or intramolecular (Figure 2b) [23].

An interesting Rh-catalyzed [4 + 1 + 1] sequential annulation was proposed recently for assembling highly fused aziridines 13 in up to 89% yield (Figure 3) [24].

A one-pot sequential transformation via decarboxylative Mannich reaction and oxidative C−H amination was shown to afford the products with fused aziridine and 1,2,3-oxathiazinane rings 17 with excellent diastereoselectivity (Figure 4) [25].

Similarly proceeds the reaction of benzo[e][1,2,3]oxathiazine 2,2-dioxides 14 in Figure 4 with α-azidostyrenes 18, leading, after denitrogenation and hydrolysis of the intermediate iminium Cu(II) complex, to 17 (Figure 5) [26]. The same product is formed by the reaction of benzo[e][1,2,3]oxathiazine 2,2-dioxide with the sulfur ylide formed in situ by the action of a base on its precursor, salt [PhC(O)CH₂SR₂]⁺ Br⁻ [27]. The synthetic utility of this chemistry was demonstrated by gram-scale operation and further product derivatizations. Compounds can be used as an actin polymerization inducer [27].

A related process of phosphonium salt-catalyzed annulation of α-halogenated ketones and cyclic N-sulfonyl ketimines (saccharine derivatives) 19 via the C=N bond led to the products 21 of the Mannich reaction under mild conditions in up to quantitative yield and enantioselectivity [28,29]. Another group of researchers has shown that the structure of the products 22 of condensation of cyclic N-sulfonyl ketimines (saccharine derivatives) 19 with acetophenones 20 depends on the conditions, as shown in Figure 6 [30].

Fused aziridines are also formed by [2 + 1] cycloaddition of sulfur ylides RC(O)–CH=SR₂ to saccharin-derived ketimines [31]; the reaction proceeds diastereoselectively in up to 94% yield. The one-pot three-component reaction of isatines 23, α-amino acids 24, and 2H-azirines 25 results in the formation of 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles 26 in high yields. The reaction occurs under mild conditions, tolerates a wide range of substrates, is regio- and diastereoselective, proceeds via the intermediate azomethine ylides generated in situ, and allows the construction of an unprecedented framework 26 (Figure 7) [32].

Using the procedure proposed earlier by the authors of [33], (1R,5S)-6-azabicyclo [3.2.0]hept-3-en-7-one 27 (a fused β-lactam, see next section) was converted into fused N-tosyl aziridine 29 via the ring opening of intermediate 28 and cyclization under the action of Chloramine-T (Figure 8) [33].

First, the product 29 of (1R,2R,3R,5S) configuration was formed, which was further converted to the trans-derivative of (1R,2R,3S,5S) configuration. Similar transformations were demonstrated for the isomeric nonfused β-lactam, 2-azabicyclo[2.2.1]hept-5-en-3-one [33]. Later, the same group of authors summarized in review [34] the results of the investigation of fused oxiranes and aziridines, focusing on regio and enantioselective ring-opening synthetic techniques for these compounds. Various N-containing polyheterocycles 31, containing a fused aziridine motif, can be synthesized from simple pyrroles 30 by irradiation using fluorinated ethylene propylene flow reactor technology, as shown in Figure 9 [35]. Their miscellaneous transformations to compound 32–39 have also been considered.

The aziridine ring opening in 2-oxazolidinone-fused aziridines was used for the regio- and stereoselective synthesis of L-kijanosides, which are highly functionalized and hardly accessible natural deoxysugars [36]. The same group proposed the aziridine ring opening by the fluoride anion in 2-oxazolidinone-fused aziridines as a general approach to optically active, primary, secondary, and tertiary organofluorides with the skeleton of arabinose, which were precursors of various fluorinated amino acids [37]. Fused aziridines are capable of the ring opening. Thus, compounds 42 containing the aziridine ring fused with imidazole, pyrazine, or quinoxaline rings are shown to be able to give stable triplet biradicals upon irradiation in the solid state, which form azomethine ylides (Figure 10) [38].

1,2,3-Triazoles, readily available and stable, can be found in equilibrium with their ring-opened isomers, diazo compounds. These opened forms can be captured by various metal catalysts to produce corresponding metal carbenoid products by expelling nitrogen [39]. Rh-catalyzed aziridine ring expansion of aziridines fused with 1,3-oxazinan-2-one 43 and having the bridgehead nitrogen atom was shown to furnish dehydropiperazines 46 by the reaction with N-sulfonyl-1,2,3-triazoles 44 [40]. The reaction is highly diastereoselective, allowing us to overcome the problem of preparing stereopure piperazines as pharmaceutically important products. The ring expansion proceeds via a pseudo-1,4-sigmatropic rearrangement of an aziridinium ylide species 45, (Figure 11). However, two years later, the same group re-examined their own results and showed that [3,9]-bicyclic aziridine formation competes with the supposed reaction course, and the final products are 9-membered heterocycles 47 with the aziridine and 3-(organsulfonyl)-6,7,8,9-tetrahydro-1,3,6-oxadiazonin-2(3H)-one rings [40], as shown in Figure 11, demonstrating how noncovalent interactions and restricted bond rotation in the aziridinium ylide intermediate 45 can unexpectedly change the reaction pathway.

Diaziridines have been known for more than 50 years, being first prepared by the reaction of cyclohexanone oxime O-sulfonic acid with ammonia. Here, we will mention only a few of the more recent publications; for earlier works, the reader can be referred to the reviews [41,42]. Thus, diamines of the norbornane or norbornene structure 48 react with p-chlorobenzaldehyde 49 in the presence of NBS as the oxidant to give a mixture of fused diaziridine 50 and pyrimidine products 51 in moderate overall yields, the former being the predominant one (Figure 12) [43]. The structure of the fused diaziridine 50 was proved by X-ray analysis.

The two nitrogen atoms in diaziridines in Figure 12 belong to the fused pyrrole and diaziridine heterocycles. Another type of fused diaziridine 53 can be prepared from cyclic secondary amines 52 and either arenesulfonamides in the presence of oxidant NBS or with bromamine-T and a catalytic amount of trifluoroacetic acid (Figure 13) [44]. Note that fused diaziridines of this type are hardly accessible by most of the existing methods.

Note that fused diaziridines 53 of the type shown in Figure 13 are hardly accessible by most of the existing methods. One of the methods that allow us to synthesize them was published very recently [45]. It is based on the reaction of homoallylic diazirines 54 with various radicals leading selectively to pyrrolines 57 via the addition to the C=C bond with subsequent ring expansion (intermediates 55–56) or fused diaziridines 60 via the addition to the N=N bond (intermediates 58–59) and hydrogen atom transfer (Figure 14).

2.2. Spiro Aziridines and Diaziridines

Spiro aziridines are represented in the literature mainly by the oxindole derivatives, which will be considered below separately. In 2017, a reaction of aziridination of cyclic enones 61 was proposed, affording new spiroaziridines 62–63 with a strained aziridine motif. The reaction is highly diastereoselective, scalable, proceeds under mild conditions, and tolerates a broad scope of substrates (Figure 15) [46]. A preliminary biological study of the products showed promising in vitro antibacterial activity against different pathogens.

The assembling of alkaloids possessing an unprecedented 1,5-diazaspiro[2.4]heptane fragment 67 with a spiro NH aziridine moiety and a 7-vinyl group by the thermal reaction of vinyl azides with tethered alkenes was reported [47]. Vinyl azides 64 are in situ converted to 2H-azirines 65, which act as enophiles for intramolecular imino-ene addition to the C=C bond (Figure 16). The reaction is highly cis-stereoselective and stereospecific. However, in the course of further studies, it was found that the process is extremely sensitive to the substituents at nitrogen, which strongly affect the diastereoselectivity (cis/trans ratio (Figure 16)). This effect is most prominent for prenyl (3-methylbut-2-en-1-yl) vinyl azides, varying from 100/0 to 1.5/1 [48].

The 1,3-dipolar cycloaddition of ninhydrin 68 and α-amino acids 69 was shown to give spirocyclic heterocycles containing 3-azabicyclo[3.1.0]hexane and 2H-indene-1,3-dione motifs 70 [49]. The reaction proceeds stereoselectively under mild conditions with the formation of 3-azabicyclo[3.1.0]hexane-2,2′-indenes (at room temperature) (Figure 17). The antitumor activity of some products against the cervical carcinoma cell line was evaluated in vitro.

The authors of [50] disclosed an efficient diastereoselective synthesis of N-alkyl spiroaziridines by addition of primary amines to α,β-unsaturated ketones in the oxidative system I₂/^tBuOOH, similar to the reaction in Figure 15. Strange enough (maybe out of ignorance), the authors stated that ‘synthesis of spiroaziridines 74 has not been well explored so far’. N-Tosylimines TsN=CHAr 72 react with bicyclo[1.1.0]butyl sulfoxide 71 lithiated in situ to afford an intermediate 73, which is cross-coupled with an aryl triflate through C-C σ-bond aminopalladation with concomitant aziridine 74 formation (Figure 18) [51].

In the last decade, a group of Indian chemists has published a whole series of papers on oxindoles with spiro-connected aziridine and oxindole rings [52,53,54,55,56,57,58,59,60,61]. Thus, based on the aza-Corey−Chaykovsky reaction of isatin-derived N-tert-butanesulfinyl ketimines 75 with sulfur ylides 76, they elaborated a general strategy for the synthesis of chiral spiro-aziridine oxindoles 77 with excellent selectivity (dr ≥ 98:2), also applicable to the synthesis of chiral 3-substituted spiro-aziridine oxindoles with high, up to 98:2, (2S,3S) over (2S,3R) selectivity (Figure 19) [52]. The ^tBuS(O) protecting group can be easily removed under mild conditions to afford product 78 (reaction a).

The N-sulfinyl azirine 77 in Figure 19 was oxidized to the corresponding N-sulfonyl azirine 79 with m-CPBA (m-chloroperbenzoic acid) and introduced in the reaction with indole to give, after the spiro-aziridine ring opening, unsymmetrical 3,3′-bis-indoles 80 (reaction b) [53]. The aziridine ring can be opened also by tetrabutylammonium fluoride to produce product 81 (reaction c) [54]. Other reactions of spiro-aziridine ring opening with various N-, O-, and S-nucleophiles as well as further transformations were studied [52,53,54,55,56,57,58,59,60,61]. The aziridine ring 79 in the sulfonyl derivatives in Figure 19 can not only be opened by different reagents but also undergo ring expansion to the 3-pyrrolyl ring by the action of allylsilanes in the presence of Lewis or Brønsted acids or allylmagnesium bromide [61]. Compound 79 can also be converted to the product with spiro-joined oxindole and 2-iminothiazolidine rings 82 (Figure 20) [62], or [2,3-b]-fused pyrrolyl rings [63,64]. A review summarizing some results of the last decade on epoxidation and aziridination of oxindole derivatives was published in 2020 [65].

As an alternative to aza-Corey−Chaykovsky reaction with ketimines in Figure 19, the Corey–Chaykovsky reaction of epoxidation of isatins was proposed, followed by the action of NH₄OH and sulfonyl chlorides on the formed epoxide and, after the treatment with a base, affording the same N-sulfonyl derivatives of the spiro-aziridinated oxindoles as in Figure 19 [66]. Concluding this section, three works should be mentioned in which spirooxindole 2H-azirines 85, rather than aziridines, were synthesized. The interest in 2H-azirines is due to their high ring strain and, hence, high reactivity as both nucleophiles and electrophiles, and in view of their presence in numerous natural compounds. In an earlier work [67], the Neber reaction was used to synthesize the target compounds. Later on, a modification was employed, affording the same spirooxindole 2H-azirines 85 ([68] and references therein) (Figure 21). Note that the work [67], in which (DHQD)₂PHAL, hydroquinidine 1,4-phthalazinediyl diether, was used as a chiral catalyst, was the first enantioselective Neber reaction of O-sulfonyl ketoxime 84 and allowed the synthesis of spirocyclic oxindoles with the azirine motif 86 in good to excellent yields and with up to a 92:8 enantiomeric ratio.

2.3. Fused Azetidines and Diazetidines

Although fused azetidines are important heterocycles appearing in many antibiotics (penicillin, ampicillin, gelsemoxonine, calydaphninone, etc.), they are far from being thoroughly investigated. As highly strained compounds, they are highly promising candidates for ring-opening and ring expansion reactions, and, as such, have been reviewed [69]. Principal methods for the synthesis of fused azetidines are depicted in Figure 22. They include four-membered ring closure promoted by elimination of an easily removable group X from the CH₂X substituent (in 87) vicinal to the nitrogen atom in cyclic precursors (88) (e.g., reaction a), or, vice versa, generation of carbene, e.g., by dediazotation, and ring closure by its insertion into the N–H or C–H bond (90 from 89) (reaction b). For the examples of these and other types of fused and spiro-joined azetidines in earlier works, the reader can be referred to review [70].

Another example of the azetidine ring closure is presented by the intramolecular Mitsunobu reaction (Figure 23) [71].

4-Allenyl β-lactams 93 (already containing the azetidine ring in the molecule) can be fused with a pyrroline or tetrahydrofurane ring 94 via Au-catalyzed cyclization (Figure 24), as described in a review [72]. Other types of cyclizations resulting in an azetidinone ring fused with different 5- and 7-membered O-heterocycles are also reported.

The Lewis bases-catalyzed cycloaddition of allenoates CH₂=C=CH–CO₂R 96 to cyclic ketimines 95 under mild conditions (r.t., toluene) was developed [73]. Remarkably, the reaction proceeds either as [2 + 2] or [3 + 2] cycloaddition, depending on the catalyst, as shown in Figure 25. With DABCO (1,4-diazabicyclo[2.2.2]octane) as the catalyst and PPh₃ the corresponding sultam-fused azetidines 97 are exclusively formed, whereas the triarylphosphine-catalyzed reactions give only dihydropyrroles 98 in the regiospecific manner, with the ester group in the α-position to nitrogen.

The use of organocatalytic protocols for the synthesis of enantiopure fused azetidines is limited. An example of chiral N-heterocyclic carbene (NHC)-catalyzed assembling of fused azetidines 102 and 106 is shown in Figure 26a [74]. Very recently, a chiral phosphoric acid (CPA)-catalyzed three-component reaction of anilines 103, aldehydes 104, and β-lactams 105 was reported (Figure 26b) [75].

Fused azetidinones 110 with a nitrogen atom belonging to both rings can be designed by insertion of a carbene at the β-position to nitrogen into the C–H bond at the β’-position to the same nitrogen atom, as shown, for example, in Figure 27 [76].

A large number of fused azetidines of the same type 113, have been prepared via intermolecular aza Paternò–Büchi reaction by photoinduced Ir-catalyzed [2 + 2]-cycloaddition of the excited alkenes 111 to imines 112, affording the 113 with the endocyclic nitrogen atom (Figure 28) [77] (see also [78]).

Another bicyclic heterocycle 116, with fused N-protected azetidine isoxazole rings, substituted 7-Boc-2-oxa-3,7-diazabicyclo[3.2.0]hept-3-enes, was synthesized by [3 + 2]-cycloaddition of N-Boc azetidines 114 with imidoyl chlorides 115 in up to 91% yield and dr > 97:3 (Figure 29) [79] (Boc = tert-butoxycarbonyl protecting group, ^tBuOC(O)−).

The visible-light-induced dearomatization of indole-tethered O-methyl oximes 117 proceeds via triplet diradicals, which undergo intramolecular cyclization followed by [2 + 2] cycloaddition to give heavily condensed indoline-fused azetidines 121 as the kinetically controlled products shown in Figure 30, in up to quantitative yield [80]. Alternatively, 1,5-hydrogen atom transfer can occur to the thermodynamically controlled products.

1,2-Fused indoloazetidines 124 were obtained by the Rh-catalyzed cyclization of 1-azido-2-[(cyclopropylidene)methyl]benzenes 122 (Figure 31). The mechanism includes dediazotation with the formation of nitrene 123, which is intramolecularly inserted into the C_sp2–C_sp3 bond of the cyclopropylidene moiety [81].

A large number of aziridine- and azetidine-fused bicyclic iminosugars were reported in the last decade and are described in the review [82]. A regiodivergent approach to fused 2- and 3-alkylideneazetines (127 and 128) was designed using the reaction of cycloaddition of intermediate 2- or 3-vinylazetines (126) to maleimide. The products of the elaborated three-step sequence (α-lithation, electrophilic addition, and [4 + 2] cycloaddition to maleimide) are formed in good yields and regio- and stereoselectivities (Figure 32) [83].

Not only fused azetidines but also fused 1- and 2-azetines are known, that is, four-membered N-heterocycles with the nitrogen atom only in the azetine motif or belonging to both fused rings, and with the C=C or C=N bond in the azetine ring. The works in this field published since 2018 have been summarized in a review [13]. Note that non-fused fluorinated 2-azetines 131 undergo original [2 + 2] photodimerization, resulting in the formation of bis-fused azetidines 132–133 in good to excellent yields (Figure 33) [84].

2.4. Spiro-Fused Azetidines

In the review [85], applications of pyrrolidine- and fused-pyrrolidine mimetics of piperazine and homopiperazine, including a number of fused azetidine derivatives, are discussed. A large series of spiro[3.3]heptanes containing an azetidine ring spiro-fused with cyclobutane, oxetane, thietane, or another azetidine ring (azaspiro[3.3]heptanes) with a nitrogen atom in either position was synthesized as potentially useful synthetic building blocks for drug design [86,87], and their molecular and conformational structure was discussed. The review [88] provides the reader with an up-to-date overview of the application of small rings, in particular, spiro and fused three- and four-membered rings, including azetidines, in medicinal chemistry. In the review [89], a comprehensive description of the biosyntheses of the azetidine-containing natural products, including those with fused and spiro-fused azetidine moieties, is described. A few examples of 2,5-diazaspiro[3.4]octanes with N-Boc-protected azetidine nitrogen were obtained by condensation of N-Boc-azetidine-3-one with N-benzylbut-3-yn-1-amine elaborated for a streamlined synthesis of C(sp³)-rich N-heterospirocycles via visible-light-mediated Ir-photocatalyzed reactions [90]. A new spirocyclization reaction for the synthesis of azetidine spirocycles was developed [91] and called ‘an elegant synthetic avenue’ to these compounds (135, 137) (Figure 34) [92]. An azabicyclo[2.1.1]hexane intermediate formed as a single diastereomer, is converted to the final product. The studied reactions reveal the potential of the strain-release-driven spirocyclization strategy for rapidly assembling complex sp³-rich scaffolds.

The strategy using the inherent strain energy of a cyclic fragment [93,94] was applied to the synthesis of azetidine-containing spirocycles [91,95,96] based on transformations of the strained heterocycle azabicyclo-[1.1.0]butane, which is known for more than half a century but is experiencing a renaissance in the last decade [97,98]. Cyclic β-keto phosphonates 138 react with N-nosyl-O-(2-bromoethyl)hydroxylamine 139, generated in situ from formaldehyde and nosylamide, affording 1,3-aminoalcohols 140, which are converted into the spirocyclic 141 and bispirocyclic azetidines 142 via the Mitsunobu reaction (Figure 35) [99,100].

Much fewer works are known in which the products contain a fused diazetidine fragment, that is, a four-membered ring with two nitrogen atoms in different positions with respect to each other and to the fused rings. The review of 2019 [101] summarizes synthetic studies of 1,2-diazetidines and 1,2-diazetines (including fused and spiro-fused ones) since 1980. For example, 1,2-dicarbalkoxy-3-alkylidene diazetidines 143 enter [2 + 2] cycloaddition with tetracyanoethylene 144 to give spiro-fused diazetidines 146 (Figure 36) [102].

A large series of fused 1,2-diazetidines 149 with one nitrogen atom common for the two fused rings was obtained by the [3 + 1] cycloaddition reaction of (3,4-dihydroisoquinolin-2-ium-2-yl)amides 148 with aryl isocyanides 147 (Figure 37) [103].

The reaction of N-methyl-1,2,4-triazoline-3,5-dione 150 with acenaphthylene 151 expectedly leads to the formation of [2 + 2] diazetidine 154, as shown in Figure 38 [85]. However, unexpectedly, the 2:1 adducts 156 and 157, also containing the diazetidine motif, are formed, presumably, by trapping a relatively stable intermediate biradical 155 in Figure 38 by the initial reagent, N-methyl-1,2,4-triazoline-3,5-dione 150 [104]. A similar diazetidine is formed by the reaction of indene with N-phenyl-1,2,4-triazoline-3,5-dione.

Two Pd⁰-catalyzed C(sp³)-H reactions proceeding via [105] or resulting in the formation of [106] fused azetidines are presented in Figure 39. The former reaction leads to benzazetidines 159 as unstable intermediates that rearrange to benzoxazines 160 through 4π electrocyclic ring-opening and 6π electrocyclization. The second one proceeds as 1,4-Pd migration, followed by intramolecular Heck coupling, allowing to obtain, among a variety of substituted bicyclo[4,2,0]octene-fused azetidines 162. The mechanistic studies point to a rate-limiting C(sp³)−H activation step.

A Pd(II)-catalyzed γ-C–H amination of cyclic alkyl amines 163 by oxidative addition/reductive elimination was reported to result in the diastereoselective formation of enantiopure highly fused azetidines 165 [107]. The reaction tolerates a range of functional groups. The mechanism involves an intermediate octahedral aminoalkyl Pd(IV) complex. Nucleophilic attack of the tosylate at the carbon atom bearing the Pd(IV) group forms the C–OTs bond, which in turn is displaced by the proximal amino group to form the final azetidine (Figure 40).

A large series of spiro-, fused-, and spiro-fused-azetidines 168 was synthesized by copper-catalyzed reaction of photocycloadditions of non-conjugated imines 166 and alkenes 167 [108]. The excitation occurs via metal-to-ligand charge-transfer to achieve [2 + 2] cycloaddition by selective alkene activation (Figure 41).

2.5. Fused 5-Membered Heterocycles

Cyclopropanes fused with lactam and pyrrolidine moieties are important pharmacophoric units in various pharmaceuticals, including ciproximide, boceprevir, amitifadine, and trovafloxacin [109]. Recently, authors of work [109] have developed a biocatalytic method using iron biocomplexes, such as myoglobin, for the asymmetric synthesis of these compounds. The method involves the use of mutational landscape analysis and iterative site-saturation mutagenesis of sperm whale myoglobin to create a cyclization reaction of allyldiazoacetamide derivatives 169 into the corresponding bicyclic lactams 170 with high yields and enantioselectivities up to 99% [109] (Figure 42):

The reaction covers a wide range of substrates. Substrates containing methyl, methoxy, and ethyl groups at the nitrogen atom yield bicyclic products with high or quantitative yields (90–99%) and excellent enantioselectivity (>99% ee) [109]. In this case, 3-azabicyclo[3.1.0]hexan-2-one 170 is formed [109]. The formation of 2-azabicyclo[3.1.0]hexan-3-one 170 was demonstrated in the presence of Pd(OAc)₂ via intramolecular asymmetric hydrocyclopropanylation of the corresponding alkynes [110].

Allyldiazoacetamides 169 with an unprotected secondary amide group are difficult substrates for transition metal-catalyzed cyclopropanation reactions due to the catalyst poisoning via coordination with the metal and competition with carbene insertion into the amide N-H bond. Under these conditions, the reaction yields 31% of the product with more than 99% enantioselectivity. Diazoacetamides 169 containing non-activated olefin groups and aryl substituents yield products in 23–99% yields but with high enantioselectivity (90–99%). It is worth noting that substrates with substituents in the para, meta, or ortho-positions to the nitrogen atom of the phenyl group yield cyclopropyl-γ-lactams 170 with good to excellent yields (71–99%) and good to excellent enantioselectivity (90–99% ee) [109].

These biocatalytic transformations have also been realized in whole cells, allowing the implementation of enzymatic cyclization to form chiral cyclopropane-γ-lactams 170 and β-cyclopropylamines 170, as well as cyclopropane-fused pyrrolidines 170. These compounds are valuable building blocks and synthons in medicinal chemistry and natural product synthesis [109].

The reaction for the formation of condensed pyrrolidine β-lactones 173 in the presence of NHC is known [111] (Figure 43):

Nitrogen-containing bicyclic β-lactone products 173 have been obtained in good yields and excellent stereoselectivity. The reaction is an efficient method for synthesizing target structures [111].

The main step of the reaction is the addition of a nitrogen nucleophile 174 to an acylazolium cation 175, which is catalytically generated by NHC [111] (Figure 44):

Both β-aryl and β-alkyl enals can participate in the reaction, yielding products 173 with acceptable yields and good enantiomeric ratios. The use of the products 173 for obtaining pharmacologically active derivatives can be achieved under mild conditions [111].

Recently, a method for the synthesis of a new polycyclic system 178 was demonstrated based on the 1,3-dipolar cycloaddition of unstabilized N-methylazomethyne ylide 177 with 2-R-3,5-dinitropyridine 176. These compounds can be considered as potential nitric oxide donors having other types of biological activity due to their pyrrolidine and tetrahydropyridine fragments [112,113] (Figure 45):

The products were obtained through reactions with unstabilized azomethine ylides 177, which were synthesized in situ from N-methylglycine and paraformaldehyde [112,113]. Compounds 178 with heterocyclic aromatic moieties were isolated, specifically those with C=C–NO₂. In contrast to 2-unsubstituted 176, the C=N fragment in these compounds is not involved in the reaction with the azomethine ylide 177, representing the first synthesis of 178. The compounds 178 with a hydrogenated pyrrolo[3,4-c]pyridine core have high antibacterial, anticancer, and cognitive-promoting potential for biological activity [112].

Recently, the synthesis of bicyclic fused pyrrolidines 181 through [3 + 2]-cycloaddition of an unstabilized azomethine ylide 180 with endocyclic electron-deficient alkenes 179 has been demonstrated. The products 181 are important in medicinal chemistry, as they include sulfonyl, trifluoromethyl- and fluorine-substituted derivatives, and oxygen-containing five- and six-membered heterocycles, which play a significant role in drug development and agrochemistry [114] (Figure 46):

Under acidic conditions (using TFA and CH₂Cl₂), the ylide precursor 180 forms a protonated intermediate 182 that eliminates MeOTMS ether (TMS = trimethylsilyl) to give the corresponding azomethine ylide 184. This azomethine 184 then reacts with the electron-deficient alkene 179 through a [3 + 2] cycloaddition reaction to form the bicyclic pyrrolidine. In the presence of LiF, the reaction proceeds via a concerted pathway. Elimination of trimethylsilyl fluoride (TMSF) and LiOMe from 183 gives the azomethine 184, which reacts with the alkene 179 [114] (Figure 47).

Some examples of chlorins have been synthesized similarly by the reaction of 5-(4-methoxycarbonylphenyl)-10,15,20-tris(pentafluorophenyl)porphyrin with azomethine ylide obtained from sarcosine and paraformaldehyde, followed by the hydrolysis of the ester group to obtain chlorin functionalized with benzoic acid. The reactions make it possible to obtain a number of N-functionalized chlorins in which the heterocyclic rings contain a condensed pyrroline fragment. The compounds can be used as photosensitizers in photodynamic therapy (PDT) of cancer and photodynamic inactivation (PDI) of microorganisms [115,116].

The same group of researchers [117], using acetylenes 186 as a starting material, demonstrated several examples of [2 + 2] and [2 + 3] cycloadditions of unstabilized azomethine ylides 180 and silyl enol ethers 185. They obtained derivatives 187 containing polysubstituted cyclobutyl fragments in good yields with excellent diastereoselectivity [117,118] (Figure 48):

The synthesis of azasteroids is an important task in organic chemistry. Recently, new isoxazole derivatives 189–190 have been synthesized, which can be used as substrates for producing dehydroepiandrosterone derivatives [119] (Figure 49):

The key stage in this process is a multistep cycloaddition reaction proceeding under high pressure between an enol ether, nitroalkene, and different types of dipolarophiles. The reactions are regioselective, forming a mixture of two diastereomers through azinate intermediates 188. Most often, only one of these isomers is isolated in pure form. If the dipolarophile has electron acceptor groups (like CO₂Me or CN), the yield of the product is higher than with the electron-rich alkenes. After the cycloaddition, the formed semi-products (azonites) 189–190 are reduced to produce the desired steroid products [119].

Recently [120], a new, atom-economic, and highly stereospecific synthetic method for alkylating arenes and heteroarenes using the Friedel-Crafts reaction without the use of metal catalysts has been demonstrated. The reaction takes place in the presence of an aminium radical cation salt (Magic Blue), which opens the aziridine ring 191 through an S_N2-type reaction in activated aziridines, followed by further alkylation with arenes or heteroarenes to produce 2,2-diaryl ethylamines. The reaction has been found to be useful in the synthesis of fused pyrrolidines 192–193. When activated aziridines 191 are reacted under these conditions with 1,3-dimethylindole or benzofuran, they undergo Domino Ring Opening Cyclization reaction (DROC), leading to the formation of various nitrogen-containing compounds with high potential for biological activity. Reaction of aziridines with 1,3-dimethylindole yields the corresponding 192. The reaction with benzofuran yields the corresponding 193 as a mixture of diastereomers with the overall yield of 46% [120,121,122] (Figure 50).

The synthesis of fused pyrrolidines was also achieved through a copper-catalyzed [3 + 2] cycloaddition reaction between 2-aryl aziridines 194 and cyclic silyl dienol ethers 195. It was found that the reaction proceeded at 60 °C in the presence of Cu(OTf)₂ as a catalyst and K₂CO₃ as an additive in a mixture of DCM and EtOH. Under optimized conditions, the method proved to be a versatile approach to the synthesis of bicyclic pyrrolidines 196 [123,124] (Figure 51):

2-Aryl-substituted aziridines 194, with both electron-donating and electron-withdrawing substituents on the benzene ring, showed good to excellent yields and high diastereoselectivity. The reaction was successfully scaled up to the gram-scale level.

The impact of substituents at the C2–C6 positions on the silyldienol 195 substrate also demonstrated the relative flexibility of the process, with hydroindolones 196 being obtained in yields ranging from 40% to 83% with excellent exo-selectivity [123].

Recently, a novel approach for the synthesis of stereochemically enriched pyrrolidine- and benzo-fused sultams 200 has been developed. The method involves coupling of the previously unknown (o-fluoroaryl)sulfonyl aziridines 197 with 2-hydroxymethylpyrrolidines 198 through a series of steps, including aziridine ring opening and intramolecular nucleophilic aromatic substitution [125] (Figure 52):

This approach enables the reaction of various amino alcohols 198 to afford products with high chemo- and regioselectivity. It was found that the concentration of the solvent, the duration of the reaction, and the temperature were crucial factors. The opening of the aziridine ring and the S_NAr reaction occur through sequential intra- and intermolecular pathways. Increasing the reaction time and temperature was found to increase the yield of the reaction. It is important to note that the intramolecular ring-opening of the aziridine occurs at relatively high concentrations, while the subsequent intramolecular S_NAr reaction requires lower concentrations. Additionally, it is worth mentioning that while the opening of the aziridine ring can occur at room temperature, the reaction took five days to complete, whereas the use of MW activation allowed the reaction to be completed in just 30 min. Attempts to improve the reaction outcome by testing bases, such as CsF, K₂CO₃, K₃PO₄, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and NaH, revealed that Cs₂CO₃ was the most effective. The use of both (R)- and (S)-prolinol as the amino alcohol 198 allowed the synthesis of a series of 6,10,5-fused tricyclic systems 200 with chiral center [125]. Recent advances in MW-assisted synthesis of heterocycles are described in the review [126].

A novel approach to the assembling of CF₃-substituted pyrrolidinedione-fused pyrrolidines 203 has been devised. The method involves a three-component, decarboxylative cycloaddition of unstabilized N-unsubstituted azomethine ylides with readily available trifluoroketones 202 [127] (Figure 53):

Under optimized conditions, a series of chemical reactions were conducted involving a variety of amino acids 201, 2-trifluoroacetophenones 202, and maleimides 203 with the aim of synthesizing a range of trifluoromethyl pyrrolidines 204. These compounds featured diverse substituents, and the yields of the products 204 varied within 55–77% and dr = 3–7:1. During the formation of the trifluoromethylated pyrrolidine-fused bicycles 204, it was established that azomethine ylides could adopt either a W- or a U-configuration. By utilizing structurally rigid maleimides 203, cycloaddition reactions resulted in the formation of only two diastereomers, which occurred through suprafacial reaction between W- or U-ylides 205 and maleimides 203. The ratio of the diastereomers 204 was determined by NOE-2DNMR [127] (Figure 54):

Benzo[b]thiophene 1,1-dioxides 207 also undergo asymmetric 1,3-dipolar cycloaddition with azomethine 206 ylides as dipolarophiles. This approach, in the presence of Cu(I)-based catalysts and bisphosphine ligands, allows for the stereoselective synthesis of chiral tricyclic pyrrolidines fused to 208, with four stereogenic centers [128] (Figure 55):

The products were obtained in good to excellent yields (up to 99%), with excellent diastereoselectivity and enantioselectivity (up to >25:1 dr and 99% ee). Several imino esters 206 and glycine derivatives were tested in the reaction, with varying ether groups (Me, Et, Bz, ^tBu). The substituent at the carboxylic group of 206 did not significantly affect the reaction. The corresponding chiral pyrrolidine-fused derivatives 208 of benzo[b]thiophene 1,1-dioxide 207 were obtained in high yields (90–94%) with excellent enantioselectivity (98–99% ee) using imino-^tBu-ether 206, resulting in a notable improvement in diastereoselectivity. For imino-^tBu-ethers 206 containing both electron-withdrawing and electron-donating or electron-neutral substituents on the phenyl ring, cyclization occurred in high yields (85–99%) with good to excellent diastereoselectivity (8:1 to >25:1) and excellent enantioselectivity (93–99% ee). Sterically hindered o-Cl, o-Br, o-Me, and 1-naphthyl-substituted iminoesters 206 also gave products, although the enantioselectivity was slightly lower. Cycloaddition also occurred with heteroaryl-substituted azomethine ylides 206 derived from 2-thienyl and 2-furyl derivatives 208 with 88% ee and 99%, respectively [128].

The synthesis of 212 in good yields through one-pot, three-component reactions with isatins 210, α-amino acids 211, and cyclopropenes 209 has been reported recently [129] (Figure 56):

The reaction of equivalent amounts of methyl 2,3-diphenylcycloprop-2-enecarboxylic acid 211, N-methyl substituted isatin 210, and a small excess (25%) of L-proline 211 was studied as a model process. The best results were obtained by refluxing the mixture of the reagents in methanol for 4 h, which ensured a high yield (85%) and good diastereoselectivity. When cyclopropenes 209 with methyl substituents on the double bond or tetrasubstituted cyclopropenes 209 were used, cycloadditions did not yield the corresponding products. The presence of a substituent on the nitrogen atom of isatine leads to the formation of one diastereomer with yields of 48–85%. It should be noted that not only N-substituted or unsubstituted α-amino acids 211 but also the dipeptide Gly-Gly were used as amine components for the generation of azomethyne ylides. The anticancer activity of some of the obtained compounds was tested against the human leukemia cell line K562 [129].

A series of chiral benzosulfamidate-fused pyrrolidines 215 was synthesized using the Mannich/aza-Michael cascade reaction involving cyclic N-sulfimines 214. The method is based on the reaction of cis-δ-formyl-α,β-unsaturated ketones 213 with cyclic N-sulfimines 214, with TMS ether used as a catalyst [130] (Figure 57):

The reaction proceeds most effectively from the point of view of stereocontrol at −40 °C. The use of various solvents showed that the reaction medium has a significant effect on the conversion and stereoselectivity of the reaction. The best results were obtained with EtOAc and Et₂O. Overall, the reactions of all substrates in Et₂O afforded the corresponding benzosulfamidate-fused pyrrolidines 215 in good yields (71–96%) with good to excellent diastereo- and enantioselectivity (10:1–30:1 dr, 82–93% ee). The nature of the substituents on the aromatic ring had only a minor effect on the yields and stereoselectivity, with both electron-donating and electron-withdrawing substituents giving good results. Meta-substituents generally resulted in a higher reactivity and enantioselectivity than para-substituents. The approach allows the preparation of pyrrolidine derivatives, including those of pharmaceutical value [130].

The involvement of 2- and 3-alkylideneazetines 217 in the reaction with N-substituted maleimides allows the formation of unsaturated condensed tricyclic structures 220 with a pyrrolidine fragment, with high yields and regio- and stereoselectivity, through [4 + 2] cycloaddition [83,131] (Figure 58):

The reaction proceeds through the α-lithiation of vinyl azetidines 217 in the presence of s-BuLi, accompanied by β-elimination. When excess s-BuLi is present, a main azetinyl lithium intermediate 218 is formed, which reacts with an appropriate electrophile, such as H₂O or TMSCl. The resulting diene 219 undergoes a [4 + 2]-cycloaddition reaction with electron-deficient dienophiles, forming condensed products 220 with high stereocontrol (up to 97:3 dr). This reaction allows the creation of several stereocenters, and, using in situ generated trans-2-butenyl lithium 218 and N-phenylmaleimide as the starting reagent, the products containing four consecutive stereocenters can be formed with excellent diastereomeric ratios and yields up to 96%. Substrates with bulky substituents also yield the expected products with good yields and stereoselectivity [83].

The synthesis of fused pyrrolidines 223 through the reaction of Michael addition products (semi-products were synthesized from α,α-dicyanoolefins and β-nitrostyrenes) has been elaborated. The resulting polycyclic fused pyrrolidines 223, with three adjacent stereocenters, were obtained in high yields and with excellent diastereo- and enantioselectivity. The C(CN)₂ group in 221 was oxidized using potassium permanganate in a mixture of acetone and water as a solvent at room temperature. The ketone 222 was reduced with zinc in acetic acid, resulting in a single stereoisomer in moderate yield and good enantioselectivity [132] (Figure 59):

Pyrazoline derivatives exhibit a wide range of biological and pharmaceutical activities, including antitumor, antibacterial, antifungal, antiviral, and anticancer activity. These nitrogen-containing five-membered heterocyclic compounds are well-known and have important applications in medicine. Various methods have been developed for the synthesis of pyrazolines, including the MW-assisted method, which offers several advantages, such as increased reaction rates [133]. Conventional heating of the reaction mixture to the temperature of boiling of acetic acid gives significantly lower yields [134]. An example of this synthesis is the preparation of new fused pyrazolines 227 by condensation of 224 with substituted benzaldehydes 225 under MW irradiation. The reactions yield chalcones 226, which further react with phenylhydrazine to form 227. Several of the obtained pyrazoline derivatives 227 show significant antibacterial activity, making them promising candidates for future drug development [133,135] (Figure 60):

The reaction of N-arylnitrilimines 228 prepared from trifluoroacetonitrile with levoglucosenone 230 proceeds through a [3 + 2] cycloaddition process, resulting in the formation of the corresponding fused pyrazolines 231. In contrast to the similar reaction with non-fluorinated analogs, such as C(Ph),N(Ph)-nitrilimines 228, the reaction with fluorinated derivatives, C(CF₃), N(Ar), leads to the formation of stable pyrazolines in a chemo- and stereoselective manner, to produce the exo-isomer as a single product resulting from the [3 + 2] cycloaddition process. In all cases, the only products were tricyclic pyrazolines 231, with yields ranging from satisfactory to good (47–88%). It is worth noting that, unlike non-fluorinated analogs, there was no spontaneous oxidation to trifluoromethyl-substituted pyrazolines 231 [136,137] (Figure 61):

A similar 1,3-dipolar cycloaddition reaction of nitrilimines 232 derived from hydrazonoyl chlorides was investigated [138,139] (Figure 62):

The process occurs under microwave radiation in the presence of N-phenyl- and N-methylmaleimides, as well as norbornene with specific substituents. The products exhibit exceptional optical characteristics, including fluorescence, positive solvatochromism, unique behavior in protic solvents like alcohols and water, and environmental sensitivity. Furthermore, these compounds 234–235 possess valuable features, such as intense green solid-state emission, making them ideal candidates for the development and synthesis of novel solid-state organic light-emitting materials. It is worth noting that the simultaneous demonstration of high fluorescence both in solutions and in solid form is a rare occurrence for both pyrazolines and other classes of organic fluorophores [138].

The environmentally friendly synthesis of imidazolidines 238 is achieved through a step-by-step process that involves the stereospecific opening of a ring and the addition of a C-H bond using aziridines 237 and secondary cyclic amines 236 under the influence of visible light in the presence of indazoloquinoline photoredox catalysts. The resulting fused imidazolines 238 exhibit high enantiomeric purity [140] (Figure 63):

Fused chiral pyrazolines 240 have also been synthesized by the reactions of hydrazine hydrate and 239 with moderate to good diastereoselectivity (up to 9.2:1 dr) and excellent enantioselectivity (up to 99% ee). The products 240 are tricyclic systems containing isoindoline, pyrrolidine, and pyrazoline moieties [141] (Figure 64):

2.6. Spiro-5-Membered Heterocycles

The reaction of isatin azomethine ylides with maleimides under asymmetric conditions in the presence of Cinchona alkaloid-based squaramide organocatalyst was studied [142] (Figure 65):

The reaction allows for the efficient synthesis of chiral pyrrolidine-fused spirooxindoles 244 in good yields (up to 89%) with excellent diastereo- and enantioselectivity (up to >20:1 dr, >99% ee). The approach allows the enantioselective assembly of synthetically and pharmaceutically important pyrrolidine-fused spirooxindoles 244 containing a pyrrolidine-2,5-dione moiety that contains four adjacent stereogenic centers, including one quaternary chiral center. As shown in Figure 65, the reaction proceeds in the presence of an organocatalyst together with 4A MS in CH₂Cl₂. Acidic additives significantly affect the enantioselectivity. In addition, under the action of stearic acid, isatin 241 condenses with the amine 242 to form the corresponding imine. The imine is then transformed into a 1,3-dipole via a 1,2-proton shift. Then, under the influence of Cinchona alkaloid catalysts and through multiple hydrogen bonds, the dipole undergoes a [3 + 2] 1,3-dipolar cycloaddition reaction [142]. A similar 1,3-dipolar [3 + 2]-cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and maleimides occurs in the presence of phase-transfer catalysts, allowing the synthesis of a large set of trifluoromethylspiro-fused [succinimide-pyrrolidineoxindoles] in good yields (69–96%) and with excellent diastereoselectivity (>99:1dr for most cases). Unlike the previous work, a pre-prepared CF₃-containing imine is introduced into the reaction with the maleimide [143]. Similar spiro-pyrolidinones are the basis for the synthesis of derivatives exhibiting insecticidal activity [144].

Chiral spirocyclic pyrrolidines can be synthesized by the use of CuBF₄ in an asymmetric 1,3-dipolar cycloaddition reaction between azomethine ylides and various heteroatom-containing azetidines with exocyclic alkenyl groups. By adjusting the ligand and maintaining the catalysis conditions, the exo- or endo-adducts can be obtained. Using a ligand with an oxazolidine moiety yields exo-products, while a pyrazoline ligand results in the endocyclic products. A wide range of functionalized spirocyclic pyrrolidine azetidines has been successfully synthesized with high yields (up to 99%) and excellent enantioselectivities (up to 99% ee) [145] (Figure 66):

The development of techniques for producing spirocyclic structures is crucial for creating analogs of natural biologically active substances and alkaloids. For instance, spirooxindole-pyrrolidine derivatives exhibit a broad spectrum of biological activity found in a diverse family of alkaloids and natural products. Among these compounds are Alstonisine, Horsfiline, Coerulescine, and Elacomine. For instance, spirotryptostatins A and B, isolated from Aspergillus fumigatus, completely halt the transition from the G2 phase to the M phase in mammalian tsFT210 cells [146]. Synthetic derivatives of these natural substances are often more potent and specific than their natural counterparts. For example, the spirooxindole-pyrrolidine derivative MI-77301, which inhibits murine double minute 2 (MDM2), is currently undergoing phase I clinical trials [146]. The synthesis of spirooxindole-pyrrolidines can be achieved through a one-pot process involving the reaction between aziridine and 3-ylideneoxindole 248. This reaction is highly efficient, with yields reaching 95% and diastereoselectivity exceeding 20:1 (Figure 67):

The synthesis of spirooxindole is a single-step process that involves the thermolysis of aziridine 249 to generate a 1,3-dipole. 1,3-Dipole then undergoes a 1,3-dipolar cycloaddition with 3-ylideneoxindole 248 as the dipolarophile, resulting in the formation of the target spirocycle 250. This approach not only expands the range of applications for aziridines 249 but also provides an alternative method for producing pharmacologically significant spirooxindole-pyrrolidines 250 [146]. Additionally, Lewis acids can be employed to activate aziridines 249 for the cycloaddition process. For instance, in the presence of Sc(OTf)₃, a [3 + 2]-annulation reaction between certain exo-glycals and aziridines has been successfully performed. Exo-glycals derived from D-ribose, D-galactose, and uridine have also been demonstrated to produce spiroheterocycles containing a pyrrolidine moiety with high efficiency when the reaction is carried out at −20 °C in dry DCM [147]. Some variations in a similar process are described in [64]. A novel approach to synthesizing spiro-1,3-benzothiazinoxindoles involved a unique rearrangement of cyclic ketimines derived from saccharin (SDCI) and 3-chlorooxindoles [148] or oxindoles and nitroalkenes [149,150,151]. The use of oxindoles in organic synthesis is described in the reviews [152,153,154].

The reaction of aziridines 252 and alkynyl alcohols or amides 251 under mild conditions in the presence of Au(I) catalyst and Lewis acids was studied. The reaction produces spiro nitrogen-containing heterocycles 253 with high stereoselectivity [155] (Figure 68):

Upon optimizing the conditions, it was found that the reaction proceeded smoothly when the alkyne 251 was slowly added to the reaction mixture in the presence of Ph₃PAuNTf₂. Six different Lewis acids have been tested, showing Yb(OTf)₃ to be most effective. It yielded the desired product in nearly quantitative yield as a single diastereomer. The effect of substituents in the starting aziridines 252 has also been studied. For substrates 251 with para-substituents, the reaction yielded the target products in yields ranging from 72% to 99%. Substituents such as fluorine, chlorine, and bromine, as well as electron-withdrawing groups such as NO₂ and CF₃ and electron-donating groups such as methyl and methoxy, did not affect the reaction yield. Ortho and meta substituents also did not affect the reaction, leading to excellent yields of the corresponding products. A substrate 251 containing a 2-naphthyl group was found to be suitable for this reaction. In this case, both 2,2-dimethyl ether- and N-methylsulfonyl-substituted aziridines 252 gave the products with high yields. Fluorinated alkynyl alcohols 251 could also produce the desired product 253 with an acceptable yield. All reactions proceeded in one hour without changing the diastereoselectivity [155].

Another example is a multistep assembly of spiro-pyrrolidines. The process involves the reaction of cyclic carboxylic aldehydes 264 (Mannich reaction). The reaction enables the synthesis of spirocyclic aminolactones 257, which can be further transformed into pharmaceutically important spiro[4.6]cyclic 3-aminopyrrolidines 260. 3-Aminopyrrolidines 260 serve as crucial building blocks for drug development and the synthesis of organocatalysts [156] (Figure 69):

The synthesis of the spirocyclic compound begins with the reaction between cycloheptanecarbaldehyde 254 and an imine 255 with equivalent amounts of the reactants. The reaction takes place in the presence of an organocatalyst and CF₃CO₂H (80 mol%). Subsequently, a reduction occurs in the presence of NaBH₄, resulting in the formation of a lactone 257. The resulting product is then placed in toluene and subjected to heating for 12 h in the presence of 2-hydroxypyridine, which acts as a bifunctional catalyst. The reduction in spirolactone with LiAlH₄ leads to the formation of the diol 258 in 79% yield. Further treatment with equivalent amounts of mesyl chloride directly results in the formation of the aziridine mesylate 259. After the replacement of the mesylate by benzylamine and the subsequent intramolecular aziridine ring opening, 3-aminopyrrolidine 260 was synthesized in 69% yield in two steps by performing the reaction in 2,2,2-trifluoroethanol without any additional base other than benzylamine [156]. The use of different catalysts in the synthesis of spiroheterocycles is described in the review [157].

Recently, a novel approach to the synthesis of β-spirocyclic pyrrolidines 264 from N-allylsulfonamides 261, halogenating agents, and exocyclic olefins 263 has been unveiled [158]. The presence of a side halomethyl group in the product 264 allows a variety of chemical transformations to be performed. Moreover, as demonstrated in this study, the method can be employed to produce spirocyclic derivatives 264 of pharmaceuticals, including celecoxib, valdecoxib, and methazolamide derivatives. The synthesis is conducted in a flow reactor on a scale of tens of grams, utilizing high-power light-emitting diodes, minimizing the potential risks associated with handling N-halogen intermediates [158] (Figure 70):

The work [159] shows a method for synthesizing spirocyclic imidazoloquinolines 269 from readily available 2-(methylsulfanyl)imidazolones 268 with various substituents in the benzylidene fragment with good yields [159] (Figure 71):

The reaction proceeds as a [1,5]-hydride shift from the NMe of the 267 group initiated by coordination of Sc(OTf)₃ with the imidazolone oxygen of the 271 atom and followed by cyclization. The products contain the SMe group, which allows modification of these compounds [159] (Figure 72).

The synthesis of similar compounds via cycloaddition of quinoline ylides with arylideneimidazole-4-ones is demonstrated in the work [160].

An efficient method for the construction of fluorovinylspiro[imidazole-indene] derivatives 274 in the presence of Rh(III) catalyst was proposed via C−H functionalization of 2H-imidazoles 272 with difluoromethylene alkynes 273 [161]. The reaction is a simple method for the formation of fluorine-containing substituents incorporated into a complex heterocyclic framework bearing several stereocenters (Figure 73):

The reaction occurs similarly with acetylenes 273 with nonfluorinated substituents [162].

In [163], the first example of a [3 + 2] cycloaddition reaction of donor/donor diazo derivatives 275 with alkenes was reported, resulting in a series of (spiro)pyrazolines 276 or 277 (Figure 74):

Methods for obtaining donor/donor diazo derivatives from N-tosylhydrazones 275 for introduction into [3 + 2] cycloaddition reactions, according to the authors of the paper [163], were not available before this study. The applicability limits of [3 + 2] cycloaddition reactions between various N-tosylhydrazones 275 and alkenes for the synthesis of (spiro)pyrazolines were shown. Both EWG-substituted and EDG-substituted N-tosylhydrazones readily react, providing functionalized spiropyrazolines. The reaction also involves heteroaromatic cyclic ketones 6,7-dihydro-4-benzothiophenone, BOC-protected 1,5,6,7-tetrahydro-4H-indol-4-one and 7,8-dihydroquinolin-5(6H)-one, 4-chromanone and 2-methyl-1-tetralone. N-tosylhydrazones 275 synthesized from 1-indanone, 1-acenaphthenone and benzocycloheptanone also give reaction products.

First, the N-tosylhydrazone 275 formed as a result of the condensation reaction between the ketone and 4-tosylhydrazide is introduced into the reaction mixture. After deprotonation, it gives the corresponding N-tosylhydrazone anion 278. Under the action of DBU and visible light (456 nm), homolytic cleavage of the N–S bond occurs. Next, donor/donor diazo species 279 are formed in situ, which then undergo [3 + 2]-cycloaddition with the alkene to give the desired spiropyrazoline 277 [163] (Figure 75):

Some examples of the use of hydrazones and diazo compounds in the synthesis of spiro-pyrazolines are presented in the works [164,165,166].

The reaction of 1H-pyrrole-2,3-diones 281 with phenylurea has been studied, followed by cyclization in the presence of sodium methoxide, leading to the formation of a 1,3,6-triazaspiro[4.4]nonane 284 structure with various functional groups [167] (Figure 76):

Compound 281 reacts with phenylurea at a 1:1 molar ratio by reflux in dry toluene for 5–10 min (until the color of the substrate disappears). The reaction results in the addition of the primary amino group of phenylurea, forming 282. Sodium methoxide is used in a two-fold excess, as one equivalent is consumed for the formation of enolate, while the remaining equivalent deprotonates the NH group, forming an amide anion 283. The latter undergoes intramolecular cyclization, forming a new amide bond and closing the five-membered ring, resulting in spiro compounds 284 [167]. Pyrrazoline spirocyclic fragments are found in natural alkaloids [168] and drugs [169].

One of the interesting examples of the synthesis of fused-linked or spiro-linked products from the same reagents, depending on the conditions, is presented in the works [170,171].

The reaction of camphene 286 with triflamide 285 and further treatment of the formed bromoamidine with Cs₂CO₃ gave the product of rearrangement, solvent (MeCN) interception, and fused camphane and quinazoline rings 287 [170,171]. This was the first synthesis of the product with fused quinazoline and terpene fragments. Replacement of the base by Cs₂CO₃ and carrying out the reaction in one-pot fashion allowed us to obtain the fused quinazoline products in up to 85% yield (Figure 77).

An unexpected result was obtained when using a three-fold excess of camphene 286 and NBS with respect to sulfonamide. Spirocyclic unrearranged imidazoline products (major, up to 70%) and rearranged fused azetidine products (minor, up to 27%) were isolated (Figure 78) [170]:

The difference in the reaction course in Figure 77 and Figure 78 is due to the different structure of the cation formed by electrophilic bromination: in the former case, the bromine atom is coordinated to Cs⁺, and the carbocation suffers skeletal rearrangement. In the latter case, the rearrangement of the formed bromonium ion is a side process leading to a minor azetidine product due to the attack of sulfonamide on the rearranged cation [170].

3. Conclusions

To summarize, the synthesis of fused- and spiro-linked N-heterocyclic systems is a rather non-trivial and creative task. The reviews on the chemistry of heterocycles, published earlier [13,34,41,65,72,82,101,126,152,153,154,157], also address the issues of synthesis and properties of some fused and spiro-heterocyclic systems. However, these reviews focus on specific compound classes of substrates or methods.

The synthesis of aziridines is based on nitrene insertion into the C=C bond or insertion of carbene into the C=N bond. Decarboxylative Mannich reaction and oxidative C−H amination are used for the synthesis of polycyclic aziridines. One approach to the synthesis of spiro-aziridines is the use of methylidene derivatives. The intra- and intermolecular Mitsunobu reactions provide an approach to the fused and spirocyclic azetidines, respectively. Acetylenic compounds are much less studied than alkenes or azomethines for the synthesis of the small fused and spiro N-heterocycles. The main starting materials for the synthesis of condensed pyrrolidines include enals, α-amino ketones, azomethyne ylides, aziridines, oxindoles, imines, β-nitrostyrenes, and hydrazonoyl derivatives of pyrazolines. The synthesis of spiropyrrolidines relies on the use of aziridines, oxindoles, imines, and enamides as reactants. These compounds are found in various important biological substances, such as physostigmine (also known as ezerine), a cholinesterase inhibitor. Asenapine, used in the treatment of bipolar disorder and schizophrenia, and other antiviral medications that inhibit hepatitis C virus proteases, are also included. Additionally, spirooxindole pyrrolidines like Horsifilin and Coerulescine are used as analgesics and local anesthetics. This gives an impetus to develop the design of structurally interesting and potentially biologically active new compounds based on these substrates. Of great importance is the selectivity of the reactions. Ideally, the products should be formed not only in high yield but also with high diastereo- or/and enantioselectivity.

An important trend in the chemistry of 3- and 4-membered heterocycles in the near future will be the application of biosynthetic techniques. The technology of reaction activation by visible light (blue LED) is also largely used for the synthesis of the compounds under consideration. The strategy of harnessing the inherent strain energy within the cyclic fragment for the synthesis of heterocyclic elements based on transformations of small heterocycles remains relevant and is experiencing a revival. In recent years, there have been no new methods discovered for the synthesis of small heterocyclic compounds with two nitrogen atoms. This task remains relevant, as diazetidines and diazeridines could become important building blocks for introducing two nitrogen atoms into larger heterocyclic compounds.

Significant progress has been made in the chemistry of five-membered rings, as this fragment is commonly found in natural products and drugs. Therefore, much time has been dedicated to studying methods for constructing or incorporating a pyrrhodine ring in these compounds.

The main goal of the present review was not so much to show a huge variety of fused and spiro structures, which is clearly evident from the figures above, but rather to provide the reader with a guiding line for further synthetic studies in the field.