Advances in the chemistry of 1,2,3,4-tetrazines

The chemistry of 1,2,3,4-tetrazines is a relatively new area of the heterocyclic chemistry, which has been successfully developing in recent decades. Biologically active representatives, in particular, a new class of nitric oxide (NO) donors, have been found among these compounds. However, the primary feature responsible for high interest in these derivatives is that the four nitrogen atoms linked to one another account for the high energy content of molecules, which is important for the development of explosives and components of solid composite propellants. The 1,2,3,4-tetrazine skeleton serves as an attractive base for the design of these molecules. In addition, 1,2,3,4-tetrazines are of considerable interest for theoretical chemistry in relation to the issue of heterocycle aromaticity.

The review considers derivatives of non-annulated 1,2,3,4-tetrazine (1)^* and its annulated analogues, including completely unsaturated and partly reduced compounds. 1,2,3,4-Tetrazine N-oxides are also considered. This publication continues the previous review ¹ covering the period of 1994 – 2003 and includes publications up to the beginning of 2023. New methods of synthesis, reactivity, and physicochemical characteristics of 1,2,3,4-tetrazines are discussed.

Structure 1

1,2,3,4-Tetrazines are the subjects of some chapters in the periodic edition Comprehensive Heterocyclic Chemistry III (2008) and Comprehensive Heterocyclic Chemistry IV (2021).^2, 3 Energetic 1,2,3,4-tetrazines are considered in a special part of a monograph.⁴ The synthesis of 1,2,3,4-tetrazine N-oxides is discussed in reviews,^5 – 8 in a survey paper ⁹ devoted to fused heterocyclic energetic compounds and covering publications of 2012 – 2019, and in a review.¹⁰

* Completely unsaturated non-annulated 1,2,3,4-tetrazine 1 has not been synthesized to date.

The synthesis of 1,2,3,6-tetrahydro-1,2,3,4-tetrazines 2 includes the [4+2]-cycloaddition reaction of azodicarboxylic acid derivatives (3) with 1,2-diazabuta-1,3-dienes 4, which are generated in situ from α-halohydrazones 5 under the action of bases (Scheme 1).^{11, 12} The reaction gives products in good yields (40 – 99%), it is easily scalable and makes it possible to vary substituents in the target tetrazines over wide limits.

Scheme 1

The method of synthesis of 1,2,3,4-tetrahydro-1,2,3,4-tetrazine 6 differs by the fact that 1,2-diazabuta-1,3-diene 7 is generated from hydrazone 8 on treatment with triphenylphosphine at room temperature (rt) (Scheme 2).¹³ The intermediate tetrazine 9 isomerizes during the reaction to give product 6.

Scheme 2

A new synthetic route to 1,2,3,4-tetrazines 10 is based on the [3+3]-cycloaddition of azides 11 to azaoxyallylic intermediates 12, which are generated in situ from the corresponding α-halohydroxamides 13 under the action of potassium carbonate in hexafluoroisopropyl alcohol (Scheme 3).¹⁴ Compounds 10 represent a new type of 1,2,3,4-tetrazines with an alkoxy substituent at the tetrazine nitrogen atom. The reaction proceeds under mild conditions and gives products containing pharmacophore groups and fragments of natural compounds such as vitamin E, cholesterol, lithocholic acid, celecoxib and zidovudine (AZT). The catalytic hydrogenation of tetrazine 10a [R¹ = R² = Me, R³ = Bn, R⁴ = (CH₂)₂N(Me)Ts, where Ts is p-toluenesulfonyl (tosyl)] is accompanied by cleavage of the N – O bond yieldng tetrazine 14.

Scheme 3

One more approach to the formation of a tetrazine ring was demonstrated in relation to the synthesis of tetrazine 15. The synthesis is based on the intramolecular reaction of the azide group with the pyrimidinone nitrogen atom in azide derivative 16. Compound 16 is prepared by the reaction of the corresponding chloro derivative with NaN₃ (Scheme 4).¹⁵

Scheme 4

A series of substituted 5-aryl-3-methylpyrazolotetrazines 18 were synthesized by cyclization of diazo compounds obtained by diazotization of arylazopyrazoles 17 with sodium nitrite in a mixture of sulfuric and acetic acids followed by treatment of the intermediate diazonium salts with sodium acetate (Scheme 5).¹⁶ Compounds 18 are fairly stable: their melting points (T_m) vary from 145 to 228 °C, depending on the nature of substituents in the benzene ring. Note that tetrazines of this type do not always exist in the cyclic form, some of them occur in the tetrazine ⇋ azo(diazo) compound equilibrium.¹

Scheme 5

Heteroannulated tetrazine perchlorates 19 and 20 were obtained by diazotization of aminopyrazole 21 and aminothiophene 22 (Scheme 6). The cyclic structure of the tetrazinium salt 19 was confirmed by X-ray diffraction analysis.¹⁷

Scheme 6

Diazonium salts 23 prepared by diazotization of the corresponding amines may exist in equilibrium with the closed-ring tetrazinium form 24 (Scheme 7). The position of equilibrium depends on the nature of the substituent R. In the case where R = Ph, the compound exists in the open form, while in the presence of electron-donating alkyl substituents, there is equilibrium in which the closed-ring form prevails (for example, for R = Me the tautomer ratio 23 : 24 is 3 : 7 according to NMR spectroscopy data).¹ In 2018, it was shown that the electron-donating substituents in the benzene ring (such as a dimethylamino group) completely shift the equilibrium towards closed-ring isomer 25. Compound 26 also exists as the cyclic form.¹⁸

Scheme 7

New substituted pyrazolobenzotetrazin-3-ones 27 were synthesized in good yields ^{19 – 21} using a previously developed procedure,²² based on the diazotization of 1-(2-aminophenyl)­pyrazol-3-ones 28 (Scheme 8). Tetrazines 27 are also fairly stable (T_m = 143 – 238 °C, depending on the substituents in the benzene ring).

Scheme 8

Tetrazine 29 with T_m = 138 °C (dec.) with fused to two nitrotriazole rings was formed in a high yield when diamine 30 was allowed to react with tert-butyl hypochlorite (Scheme 9).²³ O-Mesitylenesulfonylhydroxylamine was used for amination of bis-triazole 31.

Scheme 9

A similar synthetic route was utilized to prepare tetrazine 32 with two dinitropyrazole rings fused to the tetrazine ring (Scheme 10).²⁴ The amination of bis-pyrazole 33 with O-tosylhydroxylamine (in the presence of 1,8-diazabicyclo-[5.4.0]­undec-7-ene, DBU) or with hydroxylamine-O-sulfonic acid resulted in the formation of diamine 34, which was then oxidized into tetrazine 32 by the reaction with tert-butyl hypochlorite in MeCN. This tetrazine proved to be thermally stable: T_m = 205 °C, the onset decomposition temperature (T_onset) amounted to 233 °C.

Scheme 10

The oxidation of aminated bis-imidazole 35 with tert-butyl hypochlorite involved not only N=N bond formation, but was also accompanied by nucleophilic substitution of the nitro group in position 5 substituted with the chloride ion. This gave thermally stable dichloro derivative 36 (T_m = 215 °C) (Scheme 11).²⁵ When this compound reacted with NaN₃ in a mixture of MeCN and H₂O, the chlorine atoms was easily replaced with azido groups, thus yielding tetrazine 37, which started to decompose at temperatures above >111 °C.

Scheme 11

The first completely unsaturated annulated tetrazine 38 was synthesized for the first time by Ohsawa and co-workers* in 1988. The key step of the synthesis was expansion of the 1,2,3-triazole ring in compound 39 via the oxidation with lead tetraacetate (LTA) (Scheme 12).¹ Tetrazine 38 proved to have low thermal stability and slowly decomposed at room temperature. Subsequently this class of compounds was not investigated.

Scheme 12

* T.Kaihoh, T.Itoh, K.Yamaguchi, A.Ohsawa. J. Chem. Soc., Chem. Commun., 1608 (1988); https://doi.org/10.1039/C39880001608

Benzoannulated tetrazine 1-oxides were considered in our previous review,¹ and no studies devoted to compounds of this class have appeared since 2004.

The first non-annulated 1,2,3,4-tetrazine 1-oxide 40 was obtained from 1-(benzyloxy)-1,2,3-triazole 41 (Scheme 13) in three steps.²⁶ Initially, this triazole was aminated with O-tosyl hydroxylamine, then the resulting tosylate 42 was oxidized with MnO₂ to give salt 43. The reaction mechanism is apparently similar to the mechanism of formation of tetrazine 38 (see Scheme 12) and includes a ring expansion step. The Pd/C-catalyzed reduction of salt 43 with hydrogen furnished tetrazine 1-oxide 40, which was characterized by electron impact mass spectrum and by ¹H and ¹³C NMR spectra. The thermal stability of this tetrazine was not studied.

Scheme 13

The general approach to the formation of 1,2,3,4-tetrazine 1,3-dioxide (TDO) ring is based on the intramolecular reaction of the tert-butyl-NNO-azoxy group with oxodiazonium ion [R–N=N=O]⁺ followed by elimination of the tert-butyl cation (Scheme 14). The existence of the oxodiazonium ion as an intermediate species was confirmed by experiments in which this species was intramolecularly trapped by the benzene ring to give cinnoline N-oxide derivatives.²⁷

Scheme 14

Methods for TDO synthesis differ from one another by the way of generation of oxodiazonium ions. The first tetrazine 1,3-dioxides were prepared by the nitration method (Scheme 15), which consists in the reaction of primary nitramines, usually generated in situ, with nitrating agents (NO₂BF₄, N₂O₅).¹ Recently, nitronium sulfates were used as nitrating agents.²⁸

Scheme 15

In recent years, new methods for the generation of oxodiazonium ion have been developed. The acetylation method includes the intermediate formation of O-acetylated nitramines, which dissociate in acid media, giving rise to the [R–N=N=O]⁺ ion (Scheme 16).^{29, 30} Nitramine is usually formed in situ. This method is suitable for the preparation of annulated 1,2,3,4-tetrazine 1,3-dioxides. The starting compounds used in these reactions are aromatic and heteroaromatic compounds (benzenes, 1,2,5-oxadiazoles, 1,2,3-triazoles, 1,2,3,4-tetrazine 1,3-dioxide) containing amino- and tert-butyl-NNO-azoxy groups in neighbouring positions (see Sections 2.3.3.2, 2.3.3.3).

Scheme 16

One more method for the generation of the oxodiazonium ion, O-alkylation method, includes the reaction of O-alkylated nitramines with boron trifluoride etherate or with acids (Scheme 17). This method is suitable for the synthesis of both annulated ³¹ and non-annulated tetrazine 1,3-dioxides (see Section 2.3.3.1.1).

Scheme 17

The approach to the synthesis of non-annulated TDOs from aliphatic precursors is based on the intramolecular reaction of alkenes containing a tert-butyl-NNO-azoxy group and an O-alkylated N-(nitro)amino group in neighbouring positions (Scheme 18). The cyclization is induced by boron trifluoride etherate. The plausible reaction mechanism is shown above in Scheme 17. Non-annulated TDOs 44a and 45a,b were obtained from azoxyalkenes 46a and 47a,b, respectively.^32, 33 The azoxyalkenes, in turn, were prepared by reacting bis(tert-butyl-NNO-azoxy)acetonitrile (48) with alkanethiols and subsequent nitration and O-alkylation of the intermediate N-nitroimines 49a,b. The oxidation of compounds 46a,b afforded sulfones 47a,b. The best yields of TDOs were attained when sulfones with electron-withdrawing alkylsulfonyl substituents were used. The relatively low yield of product 44a (20%) can be attributed to the fact that in this case, the intermediate oxodiazonium cation is fairly unstable and easily eliminates N₂O to give a vinyl cation stabilized by a methanethiol group. The alkylsulfonyl groups at the C(5) atom in TDOs 45a,b are readily substituted with ammonia to give product 50. The replacement of the methanethiol group by ammonia in compound 44a also affords TDO 50, but in a lower yield (18 – 20%).

Scheme 18

The reaction of 5-amino-6-(tert-butyl-NNO-azoxy)tetrazine 1,3-dioxide 50 with an excess of NO₂BF₄ in MeCN gives rise to 5-amino-6-nitro derivative 51 in 45% yield [T_m = 195 – 200 °C (dec.)]³⁴ and TDO 52 in 30% yield [T_m = 110 – 112 °C (dec.)] (Scheme 19).³⁵ Apparently, product 51 is formed by the electrophilic substitution mechanism of the tert-butyl-NNO-azoxy group by the nitro group (path a), while compound 52 is produced by the electrophilic substitutive N-nitration (path b).

Scheme 19

An alternative approach to the synthesis of non-annulated TDOs is benzene ring opening in benzo-1,2,3,4-tetrazine 1,3-dioxides (BTDOs), which can be accomplished in two ways.

The first one is thermolysis of polyazido-substituted BTDOs. The latter were synthesized from 6,8-dibromo-5,7-dinitro-BTDO 53, which was obtained by nitration of 6,8-dibromo-BTDO (Scheme 20). The reaction of compound 53 with NaN₃ led to tri- and tetra-azido-BTDOs (54 and 55) depending on the reaction conditions.³⁶ Heating of a toluene solution of triazidonitro-BTDO 54 at 100 °C for a few minutes resulted in benzene ring opening to give non-annulated TDO 56 [T_m = 165 – 167 °C (dec.)]. 5,6-Dicyanotetrazine dioxide 57 [T_m = 110 – 130 °C (dec.)] was obtained by heating tetraazido-BTDO 55 in toluene at 80 °C for 1.5 h.

Scheme 20

The second way for benzene ring opening is ozonolysis of BTDOs containing electron-donating substituents.³⁷ Ozonolysis of dimethoxy derivatives 58 and 59 in CH₂Cl₂ with subsequent treatment of the primary ozonides with AcCl in MeOH resulted in 5,6-di(methoxycarbonyl)tetrazine dioxide 60 (T_m = 93 – 96 °C, decomposition temperature (T_dec) > 190 °C) as the major product (Scheme 21). Compounds 61 [T_m = 156 – 158 °C (dec.)] and 62 were formed in these reactions in lower amounts.

Scheme 21

Unsubstituted benzotetrazine 1,3-dioxide and some nitro- and bromo-substituted BTDOs are prepared by closure of a TDO ring in benzenes containing amino- and tert-butyl-NNO-azoxy groups in neighbouring positions (Scheme 22). The cyclization is accomplished via the nitration or acetylation method (most often, the intermediate nitramines are not isolated) (see Scheme 15 and 16) or by the O-alkylation method (see Scheme 17). The benzo derivatives thus formed can be introduced into electrophilic substitution reactions. In relation to nitration and bromination, it was shown ³⁸ that in terms of the ease of these reactions, the positions in the benzene ring vary as follows: 5 ~ 7 > 8 > 6. The successive use of cyclization and nitration reactions made it possible to develop a one-pot method for the synthesis of 5,7-dinitro-BTDO from 2-(tert-butyl-NNO-azoxy)aniline (45% yield).³⁹

Scheme 22

The brominated and nitro-substituted BTDOs easily undergo nucleophilic substitution reactions, in which the tetrazine ring remains intact (see Scheme 22). In relation to the reactions of mono- and di-bromo-substituted BTDOs with the methoxide anion, it was shown ⁴⁰ that in terms of the ease of nucleophilic substitution, positions in the benzene ring are arranged as 6 > 8 > 7 > 5.

The unusual nucleophilic substitution with 1,2,3-triazole resulted in the discovery of a ‘billiard’ reaction for this series of compounds. In order to prepare BTDOs annulated with tetraazapentalene systems, an attempt was made to synthesize a derivative containing triazole moiety in position 5. However, the reaction of compound 63 with sodium azide did not give the expected 6-azido-5-triazolyl derivative 64, but instead furnished an isomer with the inverted positions of substituents, namely, 5-azido-6-triazolyl-BTDO 65 (Scheme 23).⁴¹

Scheme 23

The formation of product 65 can be explained in the following way (Scheme 24). In the first step, the triazole anion attacks BTDO 63 at position 6 to give the anionic σ-complex A. This is followed by elimination of azide anion to give intermediate 66. However, the reaction does not stop at this stage: now the azide ion itself acts as a nucleophile and attacks position 5 of intermediate 66 to form anionic σ-complex B, and the subsequent elimination of the nitrite anion leads to BTDO 65.

Scheme 24

This unusual cascade of nucleophilic substitution reactions in which a nucleofuge turns into a nucleophile can be called a ‘billiard’ reaction. To our knowledge, such cascades of reactions have not been observed earlier among benzene derivatives.

A similar ‘billiard’ process occurs when BTDO 67 reacts with 1,2,3-triazole in the presence of a base; this gives a mixture of isomers 68 and 69 (Scheme 25).⁴¹ The azido group migrates from position 8 to position 7 during the reaction.

Scheme 25

One more example of the ‘billiard’ process is the conversion of BTDO 70 to compound 71 via the reaction with 1,2,3-triazole in the presence of a base (Scheme 26).⁴¹ In this case, the benzenethiol group migrates from position 6 to position 7. Similarly to the azido group in the above examples, the benzene-thiol group acts as a nucleofuge in the first step and as a nucleophile in the second step.

Scheme 26

Tetrazinobenzotetrazine 1,3,7,9-tetraoxides (TBTTOs) 72a,b were synthesized by simultaneous or successive closure of two TDO rings (Scheme 27).⁴² In the former case, chloroaniline 73 was converted to phenylenediamine 74 by treatment with NH₃ at 250 atm. Cyclization of 74 by the nitration method under the action of N₂O₅ in CH₂Cl₂ resulted in the closure of both tetrazine rings and formation of TBTTOs 72a and 72b in a nearly 1 : 1 ratio. In the latter case, chloroaniline 73 was first cyclized on treatment with N₂O₅ to give BTDO 75, and then the chlorine atom was substituted with an amino group via the reaction with ammonia. Tetrazine ring closure in amino derivative 76 induced by the reaction with N₂O₅ in CH₂Cl₂ gave TBTTOs 72a and 72b in a ratio close to 1 : 2. The nitration of compound 76 with one equivalent of NO₂BF₄ afforded nitramine 77, which was cyclized by the phosphorylation method by treatment with P₄O₁₀ in MeCN to give unsubstituted TBTTO 72a without an impurity of nitro derivative 72b. The bromination of compound 76 yielded benzotetrazine dioxide 78, which was converted to TBTTO 79 by treatment with an excess of N₂O₅ in MeCN.

Scheme 27

TBTTOs start to decompose without melting at 140 – 160 °C. It was found that these compounds, including the unsubstituted compound 72a, were highly sensitive to hydrolysis. This is, most likely, due to the ease of formation of the thermodynamically stable anionic σ-complex, in which the negative charge is distributed over both TDO rings, via an attack by a nucleophile on position 10.

Structure of anionic σ-complexes

An attempt to replace the bromine atom in 5-bromo derivative 79 with nucleophiles was unsuccessful, probably due to the fact that nucleophiles attack position 10 much more easily than position 5.

The initial compounds used for the preparation of benzotetrazine dioxides annulated with tetraazapentalenes (T-BTDOs) represent BTDOs that contain azide and 1,2,3-triazole groups in neighbouring positions.

T-BTDO 80 with a tetraazapentalene system fused at the C(5) – C(6) bond was prepared from 5-azido-6-(1,2,3-triazol-2-yl)benzotetrazine dioxide 81 (Scheme 28).⁴³ This precursor was obtained using two successive nucleophilic aromatic substitution reactions. First, 6-bromo-5-nitro-BTDO 82, obtained by nitration of 6-bromo-BTDO 83, was treated with 1,2,3-triazole in DMF in the presence of Na₂CO₃ to replace the bromine atom in position 6 with a 1,2,3-triazole moiety. Then the nitro group in position 5 was replaced with an azido group via the reaction of BTDO 84 with sodium azide in DMF.

Scheme 28

Heating of benzotetrazine dioxide 81 without a solvent at 140 °C for 8 h resulted in the formation of T-BTDO 80 in 67% yield.⁴³ The structure of this product was confirmed by its oxidation with trifluoroperoxyacetic acid (CF₃CO₃H) giving 5-nitro-6-(triazol-2-yl)-BTDO 84.

According to differential thermal analysis (DTA) at a heating rate of 10 °C min^–1, T-BTDO 80 decomposes without melting: the decomposition starts at 245 °C, while the onset of intense decomposition is observed at 280 °C.

A similar synthetic approach was used to obtain T-BTDOs 85 and 86 with a tetraazapentalene system fused at the C(6)–C(7) bond.⁴⁴ The reaction of 6,7-dibromo-BTDO 87 with 1,2,3-tri­azole in the presence of a base resulted in the replacement of a bromine atom in position 6 giving rise to (triazol-2-yl)-BTDO 88 in 77% yield (Scheme 29). Triazol-1-yl-substituted isomer 89 was isolated upon this reaction in only 5% yield. Meanwhile, a good yield of this isomer was attained upon the cycloaddition of acetylene to the azido group in BTDO 90, which was obtained by reaction of compound 87 with NaN₃. The bromine atom in position 7 of the triazole-substituted BTDOs 89 and 88 is readily replaced with the azido group when these compounds are allowed to react with NaN₃; the reactions afford products 91 and 92, respectively. Heating of these BTDOs without a solvent at 140 °C furnishes compounds 85 and 86, respectively. The structure of T-BTDO 86 was confirmed by its oxidation to afford 7-nitro-(6-triazol-2-yl)benzotetrazine dioxide 93 (see Scheme 29).

Scheme 29

The results of DTA (heating rate of 10 °C min^–1) demonstrated that T-BTDOs 85 and 86 start to decompose without melting. For compound 85, the decomposition starts at 210 °C, while the onset of intense decomposition is observed at 250 °C; for isomer 86, these values are 215 and 235 °C, respectively. These compounds are somewhat less stable than T-BTDO 80, in which annulation occurs at the C(5) – C(6) bond.

Benzotetrazine dioxides 94 and 95 with a tetraazapentalene system attached at the C(7) – C(8) bond were synthesized as described in Scheme 30.⁴⁵ In the reaction of 8-bromo-7-nitro-BTDO 96 with 1,2,3-triazole in the presence of Na₂CO₃, bromine atom was rapidly displaced to give isomers 97 and 98 in 3 : 5 ratio. The mixture was easily separated by extraction with benzene in which the major isomer 98 is virtually insoluble. Despite the fact that position 8 in benzo-1,2,3,4-tetrazine 1,3-dioxides is activated towards nucleophilic substitution reactions to a higher extent than position 7, the triazole ring is not a good leaving group, and, hence, the nitro group at position 7 is substituted when BTDOs 97 and 98 react with NaN₃; this results in the formation of products 99 and 100, respectively. Heating of these compounds without a solvent at 140 °C affords T-BTDOs 94 (95% yield) and 95 (96% yield).

Scheme 30

The results of DTA (heating rate of 10 °C min^–1) showed that compounds 94 and 95 decompose without melting. For T-BTDO 94, the temperatures of the onset of decomposition and the onset of the intense decomposition are 220 and 245 °C, respectively. For compound 95, these values are 220 and 235 °C, respectively. In terms of stability, these derivatives resemble compounds 85 and 86 and are somewhat inferior to T-BTDO 80.

The starting compounds used to prepare benzo-1,2,3,4-tetrazine 1,3-dioxides annulated with a furoxan ring (F-BTDO) are BTDOs in which the azido and nitro groups are located in the neighbouring positions. These precursors were synthesized from appropriate BTDOs via electrophilic and/or nucleophilic substitution reactions.

6-Azido-5-nitro-BTDO 101 was obtained in 82% yield by nitration of 6-azido derivative 102 with one equivalent of HNO₃ in H₂SO₄ (Scheme 31). The nitration occurs almost exclusively at position 5. Compound 101 was also prepared by substitution of bromine in 6-bromo-5-nitro-BTDO 103 with an azide group on treatment with sodium azide (85% yield). The formation of the furoxan ring took place when BTDO 101 was heated without a solvent at 100 °C or in AcOH at 90 °C. The ¹H and ¹³C NMR spectra recorded at 297 K demonstrated that F-BTDO 104 exists as a 1 : 1 equilibrium mixture of isomers 104a and 104b (T_m = 204 °C) (83% total yield).⁴⁶

Scheme 31

Benzotetrazine dioxide 105 was synthesized by nitration of 6,7-dibromo derivative 106 at position 5 followed by treatment with sodium azide (Scheme 32). The azido group replaced only the bromine atom at position 6. The cyclization of BTDO 105 proceeded under somewhat more rigorous conditions than in the previous case, namely, on heating without a solvent at 120 – 125 °C. The resulting bromo-substituted F-BTDO 107 (T_m = 95 – 105 °C) was also an equilibrium mixture of two isomers (66% total yield), but in this case, isomer 107a predominated (the 107a : 107b ratio was 9 : 1).

Scheme 32

For the synthesis of F-BTDO 108 with a furoxan ring fused at the C(7) – C(8) bond, the bromine atom in 8-bromo-7-nitro-BTDO 109 was substituted with an azido group, and then 8-azido-7-nitro-BTDO 110 was kept in AcOH at 118 °C (Scheme 33). These conditions are somewhat more rigorous than those required to obtain F-BTDO 104 with fusion at the C(5) – C(6) bond. Product 108 proved to be less thermally stable than F-BTDO 104: it melted without decomposition at 74 – 76 °C and started to decompose at temperatures above 90 °C. The low thermal stability is likely to be responsible for the low yield (30%).⁴⁷ The cause for the low stability of this compound is apparently in the easy interaction of the furoxan ring with the N-oxide oxygen atom of the tetrazine ring.

Scheme 33

An attempt to obtain F-BTDO 111 according to Scheme 34 did not meet with success. The reaction of 5,7-dibromo derivative 112 with NaN₃ gave 7-azido-5-bromo-BTDO 113 as the major product. The minor isomer, 5-azido-7-bromo-BTDO, was formed in a yield of only 12%. The nitration of compound 113 involved position 8 and gave benzotetrazine dioxide 114; heating of this product under various conditions yielded only resinification products. The cyclization is probably hampered by the steric strain in the cyclic transition state and also by low thermal stability of F-BTDOs of this type.

Scheme 34

The attempted preparation of F-BTDO 115 by Scheme 35 also failed. 6-Azido-7-nitro-BTDO 116 is easily formed when the bromine atom in compound 117 is replaced with an azido group. However, heating of BTDO 116 under various conditions gave only resinification products. Probably, this is due to high reactivity of F-BTDO 115, which is susceptible to intermolecular reactions due to the quinoid structure.

Scheme 35

Heating of 6,8-diazido-5,7-dinitro-BTDO 118, obtained by the reaction of compound 119 with sodium azide, gave only products of resinification (Scheme 36). The target F-BTDO 120 with two furoxan rings was not formed under these conditions.

Scheme 36

Furazanotetrazine 4,6-dioxide (FTDO) 121 was synthesized for the first time by the nitration method from aminofurazan 122 without isolation of intermediate nitramine 123.⁴⁸ Later, an improved two-step method was developed; the method included the preparation of nitramine 123 by the nitration of aminofurazan 122 with 70% HNO₃ and the subsequent cyclization by the acetylation method (Scheme 37).^29, 30 This approach can also be used to prepare FTDO in one step, but the yield of the product is lower in this case.

Scheme 37

At room temperature, FTDO 121 is stable to the action of water, but at 80 °C, it is completely hydrolyzed within 2 h to yield triazolofurazan 124 (Scheme 38).⁴⁹ A probable mechanism of hydrolysis starts with the attack by water on the N(3) atom of the tetrazine ring.

Scheme 38

Aminofuroxan 125 served as the starting compound for the synthesis of a number of tetrazine dioxides annulated with 1,2,3-triazole and 1,2,3-triazole 1-oxide rings. Compound 125 was synthesized from furazan 122 in three step, which included furazan ring opening to give the sodium salt of cyanoxime 126, which was then converted to amidoxime 127, and the subsequent cyclization gave furoxan 125 (Scheme 39).⁵⁰ 1,2,3-Triazole 1-oxides 128a – d were obtained by reacting this furoxan with aliphatic amines.⁵¹ The reduction of compounds 128a,c,d to 1,2,3-triazoles 129a,c,d followed by the reaction with the HNO₃ – H₂SO₄ – Ac₂O system afforded triazolotetrazine dioxides 130a,c,d.⁵² The cyclization of 1,2,3-triazole 1-oxides 128a – c induced by the same system of reagents afforded TDO 131a – c fused with triazole 1-oxides.

Scheme 39

The tert-butyl group is readily removed from the nitrogen atom of triazole 128d in an acid medium to give hydroxytriazole 132 (Scheme 40).⁵² The treatment of this product with the HNO₃ – H₂SO₄ – Ac₂O system resulted in the formation of 1-hydroxytriazolo-TDO 133 in 62% yield. Compound 133 was also prepared in one step without isolation of intermediate triazole 132, but the product yield was somewhat lower in this case (45%).

Scheme 40

The alkylation of TDO 133 and its Ag salt 134 with various reagents (diazomethane, diazoacetone, bromoacetone, α-bromacetophenone, methyl iodide, methyl vinyl ketone or tert-butyl alcohol in acid medium) resulted in the synthesis of a number of new triazolo-1,2,3,4-tetrazine 1,3-dioxide derivatives (Scheme 41). The reaction of TDO 133 with diazo compounds and the reactions of salt 134 with halo derivatives afford, most often, O-alkylated compounds 135 – 137.⁵³ The reaction of TDO 133 with methyl vinyl ketone and with tert-butyl alcohol in acid medium is directed towards the nitrogen atom of the triazole ring and gives N(3' )-substituted products 138 and 139, respectively.^52, 53

Scheme 41

Three methods have been developed to remove the hydroxyl group from hydroxytriazolo-TDO 133 and prepare triazole derivative 140 in high yields (77 – 94%): (a) reduction of 1-hydroxytriazolo-TDO 133 by treatment with PCl₃ in acetonitrile; (b) reduction of 1-methoxytriazolo-TDO 135 with Na₂S₂O₄; and (c) reaction of 1-alkoxytriazolo-TDOs 135 – 137 with Et₃N in methanol (Scheme 42). The mechanism of the latter non-classical reduction includes, most likely, elimination of the active proton to give the corresponding aldehyde, which was isolated in one case. The tetrazine ring remains intact in these reactions.⁵⁴

Scheme 42

Methylation of triazolo-TDO 140 with diazomethane afforded isomers 141, 130a, and 142 in 41 : 33 : 26 ratio in a total yield of 34% (Scheme 43). Isomer 141 was formed as the major methylation product. In the case where Ag salt 143 was methylated with methyl iodide in acetonitrile, three isomers were also formed (83% total yield), but 130a was the major product (the 141, 130a and 142 isomer ratio was 30 : 56 : 14). In both reactions, the thermodynamically less stable isomer 142 was formed in the lowest amount.

Scheme 43

The above-described approach is unsuitable for the synthesis of aryl-substituted triazolo-TDOs. For the synthesis of these compounds, an alternative route was developed, in which (tert-butyl-NNO-azoxy)acetonitrile (144) containing an active methylene unit served as the key compound (Scheme 44). This nitrile was prepared by reductive amination of cyanoxime sodium salt 126.⁵⁵ 1-Aryltriazoles 145a,b were obtained by the reaction of nitrile 144 with aryl azides in the presence of a base. The cyclization of these triazoles to aryl-substituted triazolo-TDO 146a,b was induced by the HNO₃ – H₂SO₄ – Ac₂O system.⁵⁶

Scheme 44

For the synthesis of 2-phenyltriazolo-TDO 147, nitrile 144 was reacted with phenyldiazonium chloride; this gave hydrazone 148, which was converted to amidoxime 149 upon the reaction with hydroxylamine (Scheme 45). On heating at 150 °C in dimethylformamide in the presence of sodium acetate, amidoxime 149 cyclized to triazole 150, which was then treated with the HNO₃ – H₂SO₄ – Ac₂O system to give 2-phenyltriazolo-TDO 147.⁵⁶

Scheme 45

Amidoxime 151, containing a 2-azidophenyl group, was produced similarly to amidoxime 149 (see Scheme 45); however, ring closure to give 1,2,3-triazole by the heating in dimethylformamide failed. Therefore, this amidoxime was converted to oxadiazole 152 and further to triazole 153 by the reaction with a base (Boulton – Katritsky rearrangement). This was followed by elimination of the formyl group in methanol in the presence of methanesulfonic acid (Scheme 46). 2-Azido­phenyltriazolo-TDO 154 was synthesized by the reaction of triazole 153 with the HNO₃ – H₂SO₄ – Ac₂O system.⁵⁷

Scheme 46

The nitration of triazolo-TDO 154 with concentrated HNO₃ at room temperature furnished mononitrated product 155,⁵⁷ while the reaction at 40 °C led to doubly nitrated derivative 156 (Scheme 47).⁵⁸

Scheme 47

When triazolo-TDO 154 was heated in 1,2-dichlorobenzene at 170 °C for 2.5 h, ring closure took place to give isomeric tetraazapentalenes 157 (T_dec > 183 °C) and 158 in 5.3 : 1 ratio in a total yield of 75% (Scheme 48).⁵⁷ The cyclization of nitro derivative 155 under the same conditions proceeded in 30 min and afforded isomers 159 (T_dec > 191 °C) and 160 in 1.1 : 1 ratio (91% total yield).

Scheme 48

Dinitro derivative 156 cyclized on heating in toluene at 110 °C (Scheme 49).⁵⁸ The azido group mainly reacted with the neighbouring nitro group, thus giving furoxan 161 (T_dec > 190 °C) in 68% yield. The isomeric tetraazapentalenes 162 and 163 were produced in 5% yield each. Markedly higher yields of tetraazapentalene 162 were attained when tetraazapentalenes 157 or 159 were nitrated with a mixture of nitric and sulfuric acids: 63 and 54%, respectively.⁵⁷

Scheme 49

According to differential scanning calorimetry (DSC) data (10 °C min^–1 heating rate), the onset decomposition temperature of tetraazapentalene 162 is 234 °C; this is much higher than that of isomer 163, which starts to decompose at 158 °C.

The reaction of 2-amino-3-(tert-butyl-NNO-azoxy)pyridine (164) with an excess of N₂O₅ in dichloromethane resulted in the formation of pyrido-TDO 165 and its nitro derivative 166 in 1 : 2 ratio (Scheme 50).⁵⁹

Scheme 50

The isomeric pyrido-TDO 167 was synthesized from pyridine 168 using nitronium tetrafluoroborate as a tetrazine ring closure reagent (Scheme 51). The use of N₂O₅ proved inefficient in this case.

Scheme 51

Tetrazinotetrazine 1,3,6,8-tetraoxide (TTTO) 169 was synthesized in 22% yield from TDO 50 using the HNO₃ – H₂SO₄ – Ac₂O system of reagents (Scheme 52).³³ This compound was fairly thermally stable, but it was completely hydrolyzed in 50% aqueous EtOH at 20 °C in 2 h to be converted to triazolo-TDO 140. The mechanism of hydrolysis appears to be the same as for FTDO 121 (see Scheme 38), starting with the attack by a water molecule on the N(3) atom of the tetrazine ring.

Scheme 52

According to DSC data, for compound 169, the decomposition onset temperature amounts to 158 °C at a heating rate of 5 °C min^–1 and to 165 °C at a heating rate of 10 °C min^–1. The peak of the decomposition temperature is 183 °C at a heating rate of 10 °C min^–1.