Efficient Approaches to the Design of Six-Membered Polyazacyclic Compounds—Part 1: Aromatic Frameworks

Abstract

This review summarises the possible applications and basic methodologies for the synthesis of six-membered polyazo heterocycles, namely, diazines, triazines, and tetrazines. The time period covered by the analysed works ranges from the beginning of the 20th century to the present day. This period was chosen because it was during this time that synthetic chemistry, as defined by physicochemical research methods, became capable of solving such complex problems as efficiently as possible. The first part of the review describes the applications of polyazo heterocyclic compounds, whose frameworks are found in the composition of drugs, dyes, and functional molecules for materials chemistry, as well as in a wide variety of natural compounds and their synthetic analogues. The review also systematises the methods for assembling six-membered aromatic polyazo heterocycles, including intramolecular and sequential cyclisation, which determine the possible structural and functional diversity based on the presence and arrangement of nitrogen atoms and the position of the corresponding substituents.

1. Introduction

Nitrogen is one of the essential elements which, being a part of natural compounds, provides functional diversity. A special place among nitrogen-containing compounds is occupied by polyazo heterocycles, which can undoubtedly be called an indispensable attribute of life. Such heterocycles provide oxygen transport in organisms (e.g., chlorophyll and hemoglobin) and transfer hereditary information (e.g., the nitrogenous bases of DNA and RNA), which makes reproduction and evolution of life possible.

A close look at natural molecules with azaheterocyclic scaffolds (apart from the aforementioned compounds, these include vast libraries of alkaloids that regulate activity of virtually all types of organism), drugs, dyes, and advanced materials reveals that such systems are mainly represented by polyazo annulated heterocycles. In addition to their use in drug development and advanced technology materials, N-heterocyclic compounds are also in demand in synthetic chemistry due to their reactivity. Therefore, it is not surprising that the development of modern approaches to the synthesis of polyazo annulated heterocycles is an urgent task for the global synthetic community.

The chemistry of polyazocyclic compounds has recently been the subject of active development. The synthesis of diazine, triazine, and tetrazine derivatives allows the discovery of new drugs and preparation of high-energy systems. Nitrogen-containing heterocycles are important because they often form the basis of many pharmaceutically and agrochemically active compounds. The search for new materials with high energy density is being conducted among hybrid compounds, i.e., substances that incorporate different nitrogen-containing heterocycles. Researchers believe that combining different heterocycles into one molecule endows it with new, useful properties. Polyazo heterocyclic compounds constitute an important area of organic chemistry. Nitrogen heterocycles have been found to mimic various endogenous metabolites and natural products, emphasising their key role in the development of modern drugs. They have diverse applications and are predominantly used as pharmaceuticals, corrosion inhibitors, polymers, agrochemicals, dyes, and developers. Their catalytic behaviour makes these compounds notable precursors in the synthesis of various important organic compounds.

The present literature review summarises works that describe polyazo compounds based on six-membered aromatic heterocycles and their applications and methods of preparation. Given the diversity and volume of existing literature data, the proposed systematisation seems to be the most effective method of presentation.

2. Application of Six-Membered Polyazocyclic Compounds

2.1. Diazines

Diazines are six-membered heterocyclic compounds containing two nitrogen atoms: pyridazines, pyrimidines, and pyrazines (Figure 1). This section summarises the literature data on their applications and methods of preparation. The diverse biological activities of diazines are well documented in research papers and reviews [1,2,3,4,5,6,7].

Due to their wide range of biological properties, including antiviral [8,9], antifungal [10], antimicrobial [11,12,13,14,15], anticancer [16], antitubercular [17], anti-inflammatory [18], antibacterial [19,20,21], antidiabetic [22], and others [23,24,25], pyridazine analogues have long been of interest for both medicine and agriculture [26,27,28,29].

The pyridazine structural motif is a popular pharmacophore and is found in some drugs, such as the fourth-generation cephalosporin antibiotic Cefozopran and the psychotropic drug Minaprin. Optivar (azelastine hydrochloride) is indicated for the treatment of itchy eyes associated with allergic conjunctivitis [30]. Aprésolien (hydralazine) and its analogue Cadralazine are antihypertensive vasodilators [31]. Digihydralazine^® is used to treat hypertension [32] (Figure 2).

Pyridazine core is also met in several herbicides, including Credazine, Pyridafol, and Pyridate. It is incorporated in metal complex ligands that can be applied as active electrocatalysts for proton reduction [33,34,35]. The electrochemical and photophysical properties of new organic light-emitting diodes containing the pyridazine acceptor part have been studied [36]. [1,2,5]-Thiadiazolo [3,4-d]pyridazines are used as internal acceptors for sensitisers [37]. Pyridazine scaffold is of great importance in optoelectronics because of its highly fluorescent properties, and it can be employed as sensors, biosensors, electroluminescent materials, lasers, and semiconductor devices [38,39,40,41,42].

Some pyrimidine analogues exhibit a variety of properties, including antiviral [43], antibacterial [44,45,46], anticancer [47], antidiabetic [48], antiparasitic [49], anticonvulsant [50], and others [51]. They also act as antidepressants [52] and analgesics [53].

The best-known drug containing a pyrimidine fragment is Acyclovir [54,55], which was the first effective antiviral agent to be discovered. Valacyclovir, which is also available on the market under the brand name Vitrax, was derived from Acyclovir [56]. Rosuvastatin (Crestor) is a fourth-generation hypolipidaemic drug that inhibits cholesterol synthesis [57]. Allopurinol (Zyloprim) is mainly used to treat hyperuricaemia (elevated uric acid levels in the blood) and its complications [58]. Risperidone is effective in therapy of Alzheimer’s disease and substance abuse disorders [59]. Pyrrolopyrimidines are efficient antitumour drugs. For instance, Ruxolitinib is indicated for the treatment of myelofibrosis [60], Ribociclib is recommended against breast cancer [61], and Pemetrexed is used in therapy of non-small cell lung cancer [62,63]. Tubercidin inhibits the growth of certain bacterial strains [64]. Toyocamycin is a well-known antitumour antibiotic [65,66] that is active against L1210 leukaemia, P338 leukaemia, and Lewis lung carcinoma. It has also been tested in clinical trials for use against colon cancer, gallbladder cancer, and acute myelogenous leukaemia in humans [67] (Figure 3).

Pyrimidines are used as building blocks for aromatic [68] and partially aromatic compounds [69,70], in biorthogonal reactions [71], as flavouring agents [72], luminescent materials [73], and in combination with metal ions for design of highly structured molecular architectures [74]. Pyrimidine-based oligomers were investigated for their optical absorption and emission properties and for utilisation as a pH indicator [75]. Photoreactive surfaces were prepared by attaching pyrimidine molecules to planar gold substrates to form films [76]. It was shown that a series of carbene systems of palladium ligands was effective in the activation of methane and in the Mizoroki–Heck reaction [77].

Pyrazines are known to exhibit antitumour [78], antibiotic, anticonvulsant, antitubercular, and other activities [6,79,80,81,82,83,84]. They also possess antimicrobial and anti-inflammatory properties [85].

Pyrazine derivatives are pharmacologically active. Pyrazinamide is a well-known antitubercular agent [86]. Glipizide and Sitagliptin (Januvia) are efficient against diabetes [87], and Amiloride is used as a diuretic [88]. Bortezomib and Oltipraz are indicated for therapy of cancer [89]. Sildenafil (Viagra) is used to treat erectile dysfunction, pulmonary arterial hypertension, and other diseases [90]. Studies on the efficacy of this drug in Alzheimer’s disease are also known [91]. Doxazosin (Cardura) is a non-selective alpha-1-adrenergic antagonist (alpha-adrenoblocker) employed in the therapy of arterial hypertension and benign prostatic hypertrophy [92]. Levofloxacin (Levaquin) is the antibiotic against bacterial infections [93]. It was also approved for the management of H. pylori-associated out-of-hospital pneumonia [94]. Ciprofloxacin is a broad-spectrum antimicrobial agent belonging to the fluoroquinolone group of antimicrobials [95,96]. Ketoconazole (Nizoral) is primarily employed in the treatment of fungal skin infections [97]. Trazodone is a drug efficient against depressive and anxiety disorders [98] and it is also used in the treatment of insomnia [99]. Aripiprazole (Abilify) is an atypical antipsychotic medication that can be employed for the treatment of Tourette’s syndrome [100]. Hydroxyzine (Atarax) reduces central nervous system activity and is used as a sedative [101,102]. Zopiclone is a non-benzodiazepine sleep-inducing pharmaceutical agent used for the short-term treatment of insomnia [103]. Meclizine (Bonine) is used to treat vestibular disorders [104]. Some of these drugs are depicted in Figure 4.

Pyrazines are used in agriculture as insecticides [105]. Some pyrazine derivatives are employed as flavouring and colouring agents in food products [106]. Additionally, quinoxaline compounds were appraised for utilisation as bulk heterojunction solar cells [107] and characterised as functionalised p-conjugated dendrimers with electronic applications [108]. Moreover, different types of polypyrazine derivatives are also used in the polymer industry as conjugated polymers [109] and semiconductors [110]. n-Type polymeric semiconductors based on dithienylpyrazindiimide were reported [111]. The polyimides constructed from a pyrazine moiety and cured at a low temperature find application in the modern microelectronics [112]. The fused ring pyrazine core impacts the thermal, electronic, and optical properties, as well as the thin film morphology, of organic field-effect transistors [113]. The utilisation of pyrimidine and pyrazine bridges as a design strategy was demonstrated to enhance the performance of thermally activated organic light-emitting diodes with delayed fluorescence [114,115].

2.2. Triazines

Triazines represent an important class of six-membered aromatic heterocycles comprising three nitrogen atoms. There are three types of triazine regioisomers (Figure 5). 1,2,4-Triazines, also known as a-triazines, are an asymmetric subset of triazines. Among the three classes of triazines, 1,2,4-triazines are the most studied.

Biological activity of the compounds bearing a triazine structural motif is surveyed in reviews [116,117]. For instance, a series of 1,3,5-triazine derivatives exhibit antiviral activity that is higher than that of moroxidine hydrochloride [118]. The 1,2,4-triazine ring is frequently met in many natural or synthetic biologically active compounds with a wide variety of pharmacological properties. They are especially active as antitumour [119] and anti-AIDS agents [120], CRF receptor antagonists [121], antimicrobials, and anti-inflammatories [122]. A range of synthetic analogues of 1,2,3-triazine have been shown to possess biological activities, including antitumour [123], antimicrobial [124,125], antiviral [126], analgesic [127], anti-inflammatory [128], antihistamine [129], antiangiogenic [130], and antifungal [131].

A plethora of drugs are based on triazine moieties. For example, Altretamine, an antitumour agent, is employed in the management of persistent or recurrent ovarian cancer [132,133,134,135]. Oteracil is a chemotherapeutic agent, which is used in combination with other pharmaceuticals for the treatment of advanced gastric cancer [136] and nasopharyngeal cancer [137]. Tretamine is an antitumour medicine that is utilised in the therapy for retinoblastoma [138]. Lamotrigine (Lamictal) is an antiepileptic drug to combat certain types of epilepsy and type I bipolar disorder [139]. Tirapazamine, also known as SR-4233, is an experimental anticancer drug [140], Azaribine is an antiviral agent [141], and Remdesivir (whose framework is pyrrolo[2,1-f][1,2,4]triazine) is an antiviral medicine [142] (Figure 6).

1,3,5-Triazines also play a prominent role in fluorescent chemosensor applications [143]. These compounds and their nitrogen-containing heterocyclic derivatives have key structural features with a wide range of photovoltaic characteristics and find application as UV absorbers, fluorescent probes, and phosphorescent organic light-emitting diodes [144,145,146]. Triazines are used as herbicides and pesticides, including atrazine, simazine, and cyanazine [147].

2.3. Tetrazines

Tetrazines represent an important and sought-after class of N-heterocycles that find applications in various fields of human activity among the three possible isomers (Figure 7).

Tetrazines are utilised as synthons in the synthesis of various alkaloids. For instance, lycorine possesses analgesic, antipyretic, and anti-inflammatory properties. The alkaloid hippadine exhibits cytotoxic activity against a number of tumour cells, whilst epibatidine is a potent analgesic [148]. 1,2,3,4-Tetrazines have anticancer and antimicrobial properties [149,150,151].

The antitumour drug mitozolomide was synthesised on the basis of imidazotetrazine. Further development of this pharmaceutical product was discontinued during phase II clinical trials, as the recommended dose proved was found to be too toxic, causing severe thrombocytopenia. Temozolomide proved to be less effective but less toxic than mitozolomide. It is currently marketed under the trade name Temodal (Temodar and Temomedac) and is used against malignant melanoma, mycosis fungoides, and brain tumours [152,153,154,155] (Figure 8).

In addition to their biological applications, tetrazines and their 3,6-disubstituted derivatives are of great interest to the field of coordination chemistry. They are characterised by unusual transfer of electron density and charge and the ability to coordinate metal centres through multiple mechanisms [156]. As an electron-deficient 4π-component, they participate in Diels–Alder reverse electron-transfer reactions [157]. Tetrazines are employed in the synthesis of energetic materials with a high nitrogen content [158,159]. Tetrazino-tetrazine-1,3,6,8-tetraoxide is considered to be one of the most potent energetic materials that has been synthesised to date [160]. Tetrazines conjugated to tetrazole are versatile bifunctional building blocks for the synthesis of linear oligoheterocycles [161]. Tetrazines linked to pyridine open access to substituted pyridazines, which are known for their high ability to coordinate metals [162]. Tetrazine-based metal–organic frameworks find applications in small molecule adsorption, sensing, and in the detection of organic functional molecules [163]. Tetrazines are utilised for the development of chromophoric nucleosides to produce coloured uridines ranging from purple to orange and red [164].

3. Synthesis of Six-Membered Polyazocyclic Compounds

The methods for assembly of six-member polyazo aromatic systems, namely, diazines, triazines, and tetrazins, as well as structures containing pyrrole condensed frameworks, starting with diazine structures, will be successively considered. Literature analysis shows that the main strategies for design of the above systems are (1) catalysis of transition metal complexes, both in the presence of specially introduced ligands and in the ligand-free version; (2) direct synthesis of polyazotic aromatic heterocycles, carried out in the presence of (i) strong organic bases, (ii) organocatalysts, under the influence of (iii) microwave or ultrasonic radiation, as well as (iv) electrochemically. Considering the significant role of pyrrolo-fused in pharmaceutical and material science, some methods for their production were considered. It should be noted that, in this part of the review, we will only discuss six-membered polynitrogen systems having aromaticity.

3.1. Synthesis of Diazine Derivatives

3.1.1. Synthesis of Pyridazine Derivatives

To date, a plethora of syntheses of chemically and pharmacologically valuable pyridazines have been developed. A variety of synthetic methodologies for the construction of pyridazine systems [165,166,167], including pyrrolopyridazines [168], were comprehensively documented in the literature. The pioneering data were obtained by Curtius [169] using the reaction of diethyl-1,2-diacetylsuccinate with hydrazine hydrate as an example. Consequently, an in-depth investigation of this reaction was initiated. The majority of general methods for the synthesis of pyridazines involves the condensation of 1,4-dicarbonyl compounds 2 with hydrazine 1 and its derivatives (Scheme 1) [170,171,172,173,174].

One of the general methods for the preparation of pyridazines has been known since 1972; the work of Meresz et al. [175] described the Diels–Alder reaction using 1,2,4,5-tetrazines as dienes and alkynes [176,177,178]. In a similar manner, 1,2,3-triazines were found to react with 1-propynylamines under neutral conditions [179]. Scheme 2 shows the general method for the synthesis of pyridazine derivatives 4 from tetrazines 3 via the Diels–Alder reaction.

Other methods for the synthesis of pyridazines include annelation of aldehyde hydrazones with α,β-unsaturated nitriles [180,181]; alkoxyallenes with 1,2-diaza-1,3-dienes [182]; ketene with N,S-acetals and N-tosylhydrazones [183]; cyclopropene derivatives with hydrazones [184]; catalytic three-component one-step annelation [185,186]; and multistep synthesis using the Diaz–Wittig reaction [187]. The cyclisation of alkynones 5 with indium(III) triflate-activated hydrazine afforded substituted pyrazines 6 (Scheme 3). When substrates containing a benzoyl or tosyl group were used as R², this group was removed to form 4-substituted products [188].

Under microwave irradiation, dibenzyl 7 reacted with cyanoacetohydrazide to give 3-oxo-5,6-diphenyl-2,3-dihydro-pyridazine-4-carbonitrile 8 (Scheme 4). The microwave irradiation method gave better yield and needs short reaction time [189].

Pyridazines can be obtained by the recyclisation involving either the compression [190] or expansion of the diazepinone cycle [191]. Pyrrolopyridazine derivatives were first obtained by Flitsch and Krämer in 1968–1969; pyrrolo [1,2-b]pyridazines were synthesised from 1-aminopyrrol and its derivatives [192,193]. The synthesis of pyrrolo[1,2-b]pyridazine derivatives was reported in 1977 by Kuhla and Lombardino [194]. Pyridazines containing a pyrrole backbone are synthesised in a multistep manner [195]. The first step includes the functionalisation of the pyrrole backbone 7 at the nitrogen atom and then to the second position of the pyrrole ring 8. After that, pyrrolo[1,2-b]pyridazines 10 were readily obtained via a domino-coupling–isomerisation–condensation reaction between 9 and the corresponding (hetero)arylpropargyl alcohols (Scheme 5) [196].

3.1.2. Synthesis of Pyrimidine Derivatives

A number of reviews are devoted to the synthesis of pyrimidines [197,198]. For instance, the work by Pino-González surveys catalytic methods of preparation [199]. Pyrimidines are generally formed via a three-component reaction between aldehydes, ketones, and various amidines [200,201,202,203,204,205]. The use of a catalyst in the reaction allows the synthesis of substituted pyrimidines without organic solvents [206]. This section deals with other methods for the synthesis of pyrimidines.

Pyrimidines 12 were obtained under microwave irradiation of a mixture of 11, formamide, and phosphorus oxychloride (Scheme 6). The one-pot microwave-assisted synthetic protocol is high-yielding, ecofriendly, and eliminates intermediate workups [207].

Rostovskii [208] studied a novel photolysis of α-azidocinnamates, leading to the key intermediate 2H-azirines, which underwent the dimerisation ring-expansion cascade to produce fully substituted pyrimidines. For dimerisation involving 2H-azirine via a Pd/Ag cocatalysed intermolecular self-assembly, a wide variety of unsymmetrical tetra-arylsubstituted pyrimidines efficiently give a wide variety of moderate yields [209].

Pyrimidines 14 were synthesised by the reacylisation of indoles 13. The reaction was carried in LiHMDS under mild conditions (Scheme 7a). The same reaction was applicable to 1H-pyrroles 15 (Scheme 7b), which, in the presence of PIFA as an oxidising agent, gave compounds 16 [210].

The electro-oxidative formal [3+3] annulation of 1,3,5-triazinane 17 with enamines 18 affording polysubstituted 1,2-dihydropyrimidines 19 was implemented (Scheme 8) [211]. It was noted that the reaction was carried out under mild conditions without transition metal compounds to give the target products in excellent yields.

In regard to pyrrolo[1,2-a]pyrimidines, methods for the preparation of these compounds can be categorised into three groups: syntheses starting with the preliminary formation of the pyrimidine part of the bicyclic system; syntheses starting with the preliminary formation of the pyrrole part; and syntheses from acyclic reagents only. A limited number of functional group transformations, such as esterification and nitrile hydrolysis, were documented for derivatives of the completely unsaturated pyrrolo[1,2-a]pyrimidine core. However, the reactions described for pyrrolo[1,2-c]pyrimidines fall into three main types: electrophilic attack, addition reactions, and cycle opening processes. It was disclosed [212] that the cyclocondensation of 20 with tosylmethylisocyanide followed by desulfonylation of 2-tosylpyrrolo[1,2-c]pyrimidines 21 with sodium amalgam afforded pyrrolo[1,2-c]pyrimidines 22 (Scheme 9).

A series of pyrrolo[1,2-a]pyrimidines 25 containing 1,3-indanedione skeleton (Scheme 10) was obtained by bicyclisation from triethylammonium thiolates 23, methyl iodide, and 24 [213]. The unique property of this method is a simple procedure without using any metal catalysts or acid/base additives.

A wide range of asymmetrically tetrasubstituted fused pyrrolo[1,2-a]pyrimidines 28 was obtained from NH-pyrroles 26 and diketones 27 and Scheme 11 shows the synthesis [214].

3.1.3. Synthesis of Pyrazine Derivatives

There are many methods for the synthesis of pyrazine and its derivatives [215], some of which are among the oldest. Examples include the works of Staedel-Rügheimer [216], Gutknecht [114,217], and Gastaldi [218], which are still in use today.

The reaction of α-iminocarbenoids 29 with 2H-azirines 30 delivered asymmetrically substituted pyrazines 31 in good to high yields (Scheme 12a). The authors suggest that the reaction begins with the initial formation of the metallocarbene complex of 29 with 30 to give ylide 29A, which is isomerised to 1,4-diazahexatriene 29B (Scheme 12b). Further, 1,2-dihydropyrazine formed by electrocyclisation is rapidly converted to 1,4-dihydropyrazine 29C, in which spontaneous cleavage of MeOH occurs to afford pyrazine 31. This mechanism is consistent with the observed regiochemistry of pyrazines [219].

Pyrazines can be synthesised via the dehydrogenating coupling of alcohols and amines catalysed by Ru [220], Ir [221], Co [222], Mg [223], and Pd [83] complexes. The reaction of alkynes 32 with diamine 33 under the action of divalent cobalt bromide led to a wide range of substituted pyrazines 34 (Scheme 13) [224].

The same reaction can proceed with DABCO as a catalyst, which activates sulphur to give the target products in more than 50% yields [225]. Also, a catalyst-free approach to the synthesis of pyrazine derivatives from sulfoxonium ylides and o-phenylenediamines with the participation of elemental sulphur was developed [226].

Pyrrolopyrazine derivatives have been studied for several decades [227,228]. They can be synthesised in various ways: from functionalised pyrazines or pyrroles and via a three-component reaction from acyclic compounds. Pyrrolo[1,2-a]pyrazines are also obtained by different methods, including the Pictet–Spengler reaction of isotryptamine and 2-(pyrrol-1-yl)ethanamine with trifluoromethylated carbonyl compounds and 2-perfluoroalkyl-substituted cyclic imines [229]; catalytic and thermal cycloisomerisations of propargyl-containing heterocycles [230]; and domino reaction of 2-pyrrolcarbaldehyde with vinylazides [231]. In addition, N-allylenylpyrrole-2-carbaldehydes [232,233] and N-propargylamino(pyrrolyl)enones [234] were employed as the starting compounds for the construction of such structures.

The reaction of N-propargylpyrrol-2-carbaldehyde 35 with various amines led to pyrrolo[1,2-a]pyrazines 36 (Scheme 14) [235].

A one-pot, three-component reaction between 2-methylene cyanoazaheterocycles 37, aldehyde 38, and acetylcyanide 39 afforded pyrrolo[1,2-a]pyrazine 40 (Scheme 15). The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methylene-cyano aza-heterocycles, followed by [4+1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement [236].

3.2. Synthesis of Triazine Derivatives

The widespread use of triazines makes the development of efficient methods for their synthesis an important task. Methods for the preparation of 1,3,5-, 1,2,4-, and 1,2,3-triazines are described in detail below. Among the triazines described above, 1,2,3-triazines are the least studied because their ring system is considered the least stable, and their syntheses are limited.

3.2.1. Synthesis of 1,3,5-Triazine Derivatives

The synthesis of 1,3,5-triazine compounds was first reported by A. Pinner in 1890 [237]. In the syntheses of 1,3,5-triazines, triamines or polyamines were used as nucleophiles, while the substrates included aldehydes and their derivatives [238].

In 2002, Díaz-Ortiz et al. synthesised symmetrically substituted 1,3,5-triazines (30–84% yields) via the solvent-free cyclisation of nitrile reaction using Lewis acids on silicon oxide as catalysts under microwave radiation [239]. Later, this research team implemented the reaction of dicyandiamide with aromatic/aliphatic/heterocyclic nitriles under microwave irradiation in the presence of a base for 10–15 min to furnish 2,4-diamino-6-1,3,5-triazines in 52–92% yields [240]. Triazines 43 were also obtained in high yields by microwave irradiation-assisted reaction of primary aldehydes 41, which were treated with iodine in ammonia water to give the intermediate nitriles, which were subjected to [2+3] cycloaddition with dicyandiamide 42 without isolation (Scheme 16) [241].

Acid chlorides or anhydrides 44 reacted with stoichiometric amounts of zinc dimethylimidodicarbonimidate zinc 45 to form 4,6-dimethoxy-1,3,5-triazines 46 in high yields (Scheme 17) [242].

The CuI-catalysed reaction of 1,1-dibromoalkenes 47 and biguanides 48 gave rise to the substituted 2,4-diamino-1,3,5-triazines 49 (Scheme 18). The reaction tolerated alkyl-, heteroaryl-, or aryl-substituted 1,1-dibromoalkenes to afford the products in moderate to good yields [243].

The reactions of 1,2,3,5-tetrazine 50 with amidines 51 led to the formation of substituted 4,6-diphenethyl-1,3,5-triazine 52 (Scheme 19). All amidines examined, including aryl-, heteroaryl-, and alkyl amidines 51, smoothly react with tetrazine 50 at ambient temperature to provide the 1,3,5-triazines 53 in uniformly high yields [157].

3.2.2. Synthesis of 1,2,4-Triazine Derivatives

Several reviews were devoted to the synthesis of 1,2,4-triazines [244,245]. For instance, 1,2,4-triazine derivatives 55 were prepared via simple and efficient [4+2] annulation reactions of imidohydrazides 54 with ketones, aldehydes, alkynes, secondary alcohols, and alkenes (Scheme 20) [246].

The reaction of oxazolone 56 with phenylhydrazine in the presence of acetic acid and sodium acetate delivered 1,2,4-triazine 57. The lactam form 57 is thermodynamically more stable than the enolic form 58 (Scheme 21) [247].

Pyrrolotriazine 62 was synthesised from 3-iodo-1H-pyrrole-2-carbaldehyde 59, which was converted to pyrrole-2-carbonitrile 60 (Scheme 22). Electrophilic N-amination of compound 60 followed by cyclisation of the formed N-aminopyrrole 61 with triethylorthoformate gave pyrrolo[2,1-f][1,2,4]triazine 62 [248].

Pyrrolo[2,1-f][1,2,4]triazin-4-amine 64 was prepared by a two-step reaction from pyrrole 63 (Scheme 23) [249]. 64 is an important regulatory starting material in the production of the antiviral drug Remdesivir. This method is suitable for obtaining 64 in kilogram quantities.

3.2.3. Synthesis of 1,2,3-Triazine Derivatives

It was found that (Z)-4-aryl-2,4-diazido-2-alkenoates 65 underwent cyclisation under slightly alkaline conditions without transition metals or strong acids to furnish esters of 6-aryl-1,2,3-triazine-4-carboxylic acid 66 (Scheme 24) [250].

The [5+1] cycloaddition reaction of vinyl diazo compounds 67 with tert-butyl nitrites was employed for the directed synthesis of 1,2,3-triazine-1-oxides 68, which then underwent further functionalisation (Scheme 25) [251].

3.3. Synthesis of 1,2,3,4-Tetrazine Derivatives

1,2,4,5-tetrazine (s-tetrazine) is of particular interest due to its enhanced stability. The literature review revealed that 1,2,3,4- and 1,2,3,5-tetrazines have not been sufficiently investigated, and there are only a few examples of their synthesis. A selection of examples will be illustrated below.

3.3.1. Synthesis of 1,2,3,4-Tetrazine Derivatives

The development of the experimental and theoretical chemistry of 1,2,3,4-tetrazines is comprehensively covered in the review [252]. The first compound with four neighbouring nitrogen atoms in a six-membered ring was obtained in 1972 by Nelsen and Fibiger in less than 5% yield [253].

The oxidation of 1-amino-5-phenyl-1,2,3-triazolo[4,5-d]-1,2,3-triazole 69 with lead tetraacetate afforded 1,2,3,4-tetrazine 70 (Scheme 26) [254].

The conversion of diazocyclopentadienes 71 into arylazo-diazocyclopentadienes 72 was documented [255]. Such products can spontaneously transform into 2-aryltetrazines 73 via reversible electrocyclisation (Scheme 27a). The same reaction can proceed with MeLi and subsequent TsN₃-associated diazoperoxide transfer to give stable products 75 (Scheme 27b).

Another approach to the formation of the 1,2,3,4-tetrazine ring 77 is shown in Scheme 28. This approach is based on the azidation of compound 76, followed by the intramolecular cyclisation of the azide group with the pyrimidinone nitrogen atom [256].

3.3.2. Synthesis of 1,2,3,5-Tetrazine Derivatives

1,2,3,5-Tetrazines are mainly obtained by the reactions of pyrazoles or triazoles with amines [157,257]. For instance, cycloaddition of aryl-N-sulfinylamines 79 to substituted triazolimides 78 gave rise to tetrasubstituted-1,2,3,5-tetrazines 80 (Scheme 29) [258].

Substituted 1,2,3,5-tetrazine 83 was prepared by a similar reaction from 1,2,3-triazole 81 and ((4-nitrophenyl)imino)-14-sulfanone 82 (Scheme 30) [259].

The synthesis can be started with the condensation of 1,2-benzisoxazole-3-hydrazine 85 with the α-diketones 84 to provide the bishydrazones 86 in near quantitative yield. A subsequent (CAN)-mediated oxidation followed by an acid promoted ring-closure reaction generated the zwitterionic N1,N2-substituted 1,2,3-triazolium intermediates 87. Conversion to the dihydro-1,2,3,5-tetrazine system 88 was accomplished through a 1,3-dipolar cycloaddition-triggered rearrangement cascade (Scheme 31).

3.3.3. Synthesis of 1,2,4,5-Tetrazine Derivatives

The most studied of the tetrazine derivatives is 1,2,4,5-tetrazine, which is the subject of several reviews [260,261]. Most publications are devoted to the synthesis of both symmetric and asymmetric 3,6-disubstituted s-tetrazines, which are assembled by classical methods via the reactions of nitriles or carbaldehydes with hydrazine [262,263]. Pinner’s synthesis plays an important role in s-tetrazine chemistry. The dihydro-s-tetrazines synthesis involves the reaction of aromatic nitrile 89 with hydrazine 90, followed by the addition of a second nitrile molecule to give dihydro-s-tetrazines 91, which are further oxidised to s-tetrazines 92 (Scheme 32) [264].

Devaraj et al. [265] reported a one-pot synthesis of s-tetrazines 95 from aliphatic nitriles 93, 94, and hydrazine using metal (Ni and Zn) triphthalates as catalysts (Scheme 33). Zinc salts gave higher yields for less active nitriles such as those that were sterically hindered or affected by electron-donating groups. On the other hand, more reactive nitriles benefited from the use of nickel salts.

The work of Ott’s team [266] is of great importance for the synthesis of s-tetrazines. This group developed a facile method for the preparation of these compounds involving the treatment of triaminoguanidine monohydrochloride 96 with 2,4-pentanedione to deliver 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2-dihydro-1,2,4,5-tetrazine 97 in 80–85% yield, followed by oxidation of 97 with nitric oxide to 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine 98 (Scheme 34).

Disubstituted asymmetric aryl- or alkyltetrazines 100 were synthesised by a solid-phase method using readily available nitriles 99 [267] as the starting materials (Scheme 35). This synthetic route was compatible with different solid-phase resins and linkers and did not require metal catalysts or high temperatures.

The synthesis of 1,2,4,5-tetrazine derivatives 102 conjugated via a 1,4-phenylene linker to the 4H-1,2,4-triazole ring 101 (Scheme 36) [268] was described. This approach leads to the desired products in satisfactory yields, regardless of the nature of the substituents attached to the terminal rings, as well as the type of groups on the triazole nitrogen atom.

Neunhoeffer’s group has published works describing the synthesis of pyrrolo[1,2-b][1,2,4,5]tetrazine derivatives 106. These were obtained by cyclisation of hydrazidine hydrochloride 103 with 2,5-dimethoxy-2,5-dihydrofuran 104 and maleic anhydride 105 (Scheme 37). The aromatisation of the dihydro derivatives can be achieved through oxidation with manganese dioxide or through hydrogen halide abstraction under the action of triethylamine. Analogous cyclisation of hydrazines with 2-formylbenzoic acid gave similar products 106 [269,270,271].

Previously, we reported on the interaction of N-allylenylpyrrol-2-carbaldehydes 107 with hydrazine hydrate and substituted hydrazines, which resulted in the assembly of complex pyrrolopyrazinotetrazine ensembles 108 via the formation of aminopyrrolopyrazinium salts 109 (Scheme 38). The syntheses of similar annulated tetrazines were also described in this work [272].

4. Conclusions

The review systematises and analyses the possible applications and methods for the synthesis of polyazo six-membered aromatic cyclic frameworks. Despite the large number of examples available in the literature, it is shown that the assembly of such structures usually begins with the interaction of aldehydes, ketones, amines, and/or with molecules containing double or triple bonds with N-nucleophiles and is carried out via sequential or intramolecular cyclisation, as well as through the recycling of some nitrogen-containing heterocycles. Each of the described techniques has certain advantages and shortcomings. The latter include the fact that many reactions under consideration require expensive catalysts, long reaction times, are carried out in several stages, etc. Therefore, it is not surprising that the development of more efficient approaches to the synthesis of polyazo heterocycles is an urgent task in modern organic chemistry. Although the list of sources is not exhaustive, the analysis performed indicates that the majority of diazines, triazines, and tetrazines exist in the form of aromatic structures. At the same time, methodologies for the creation of frameworks lacking aromaticity and containing saturated and/or partially saturated polyazo heterocycles are also known. These methodologies will be discussed in the next part of the review.