Reactions of o-Quinone Methides with Halogenated 1H-Azoles: Access to Benzo[e]azolo[1,3]oxazines

Abstract

A simple route to the series of azolo-condensed benzo[e][1,3]oxazines such as 9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines, 9H-benzo[e]pyrazolo[5,1-b][1,3]oxazines, and 5H-benzo[e]imidazo[2,1-b][1,3]oxazines has been developed. The reaction proceeds through formation of an ortho-quinone methide intermediate followed by aza-Michael addition of the halogenoazoles to the o-quinone methide and intramolecular nucleophilic substitution.

Key words

quinone methide - 1H-azoles - cascade reactions - aza-Michael­ reaction - benzo[e]azolo[1,3]oxazines

Condensed systems based on 1H-azoles attached with another heterocycle at the C–N bond are attracting the high attention of researchers. The principal reason for this interest is the high biological activity of some heteroannulated 1H-azoles such as [1,5]-fused 1,2,4-triazoles and pyrazoles, as well as [1,2]-fused imidazoles (Figure [1]). Among the biologically relevant 1,2,4-triazoles, there are cytokine TNF-α and IL-6 inhibitors,[1] the ligands of benzodiazepine receptors,[2] modulators of γ-secretase,[3] compounds effective against hepatitis B virus,[4] and compounds exhibiting anticonvulsant[5] and antihypertensive activities.[6] One of the most attractive classes of antituberculosis compounds is [1,2]-annulated imidazoles, such as (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (Pretomanid, PA-824) and its analogues.[7] Furthermore, imidazo[2,1-b][1,3,4]thiadiazoles exhibit anticancer[8] and antihyperlipidemic activity.[9] Some of the heteroannulated pyrazoles possess antitubercular,[10] anti-inflammatory[­11] and other types of activities.[12]

Figure 1 Selected examples of biologically active condensed 1H-azoles

On the other hand, there is an ongoing need to establish new synthetic methodologies for the construction of different heterocycles, which are important for the development of the theoretical chemistry of heterocycles and for drug discovery.[13] The most preferable tools towards the achievement of this goal seem to be cascade (or domino) reactions due to the benefits of their use.[14]

The cascade aza-Michael intramolecular nucleophilic substitution or addition reactions seem to be a useful sequence to produce nitrogen-containing heterocycles with high step economy. o-Quinone methides (o-QMs) can be efficiently used in these reactions as Michael acceptors.[15] At the same time, in spite of numerous reports on aza-Michael reactions of o-QMs in biological systems,[16] they are seldom used for the construction of heterocycles.

As part of our current studies on the development of new routes to heterocyclic systems from o-QMs,[15e] [f] [g] [h] [i] [j] ^, [17] we focused our attention on the reaction of o-QMs with halogen-1H-azoles. In the case of presence of good leaving group such as halogen, near nucleophilic nitrogen atom azoles may be considered as 1,2-ambiphiles.[18] Reactions of this type of azoles with o-QMs as 1,4-ambiphiles[15d] ^, [17a] [b] [c] lead to different benzo[e]azolo[1,3]oxazines (Scheme [1]).

Scheme 1 Retrosynthetic analysis of benzo[e]azolo[1,3]oxazine unit

It was found that condensation of 3,5-dibromo-1,2,4-triazole (1) with a series of o-QM precursors 2 by heating equimolar quantities of the starting materials in DMF in the presence of K₂CO₃ gave benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines 3 in good yields (Table [1]). o-QMs were generated from o-hydroxybenzyl alcohols 2a–c, Mannich base 2d, and quaternary ammonium salts 2e–l,n derived from phenols. The reactions were performed in DMF under reflux for completely thermal decomposition of the o-QM precursors. Products can be easily purified from impurities by single recrystallization, chromatographic purification is not usually required. The reaction was performed with comparable yields on several different scales (up to 20 mmol). It should be noted that none of the products of the o-QM oligomerization, which are obtained in the usual pyrolytic methods[19] were detected. In the case of esters 2i and 2n low yields of the products 3i (24%) and 3n (39%) were caused by partial hydrolysis of the ester group (Table [1], entries 9,14). The sterically hindered triazolobenzoxazines 3a,k,l were obtained in good yields, indicating that steric hindrance had no obvious influence on the efficiency of this method (entries 1,11,12). We could not obtain product 3m from the methiodide of 2-[(dimethylamino)methyl]-4-nitrophenol. Nevertheless, in the reaction with more reactive precursor of o-QM 2m, the corresponding triazolobenzoxazine 3m was obtained in 64% yield (entry 13). In order to broaden the scope of the present method, this protocol was attempted using bis-Mannich base 2o derived from hydroquinone. As a result, novel heterocyclic system 3o was prepared in 72% yield (entry 15). Besides, 3-chloro-1,2,4-triazole can be also involved in this reaction instead of 3,5-dibromo-1,2,4-triazole (1) (entry 16).

In the absence of a base, the reaction can be stopped at the stage of 2-(1H-1,2,4-triazol-1-ylmethyl)phenols 4a,b (Scheme [2]). It is interesting to note that the generation of o-QM from Mannich base 2p took place at milder conditions (in ethanol under reflux), which can be explained by increased conjugation in this intermediate.

Scheme 2 Synthesis of 2-(1H-1,2,4-triazol-1-ylmethyl)phenols 4a,b. Reagents and conditions: 1 (2.9 mmol) and o-QM precursor 2 (2.9 mmol) were refluxed in DMF (10 mL, for 2c) or EtOH (10 mL, for 2p) for 2 h.

The mechanism of the reaction is believed to involve the formation of the o-QM intermediate A, which is generated in situ from the corresponding precursor 2. Subsequent aza-Michael addition of the o-QM with 1 and intramolecular nucleophilic substitution via formation of the Meisenheimer­-type complex B affords the expected benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines 3 (Scheme [3]). The driving force of the reaction is the resulting rearomatization of the benzene ring and the entropy factor, favoring intramolecular versus intermolecular nucleophilic addition-elimination reactions in the 1,2,4-triazole moiety. During the reaction only a small concentration of o-QM is produced, which prevents its oligomerization and leds to good yields of the products of N-hydroxybenzylation. K₂CO₃ is required to facilitate the o-QM generation and subsequent cyclization to the benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine ring system. It should be noted that the alkylation of 3,5-dibromo-1,2,4-triazole (1) with o-QM precursors may give rise to two isomeric triazolobenzoxazines 3 and 5. However, in all cases, the alkylation occurs at N¹⁽²⁾ rather than N⁴, reflecting the higher nucleophilicity of N–N systems (α-effect).[20]

Table 1 Scope and Yields of the Synthesis of Compounds 3 ^a

Entry	o-QM precursor	Product	Entry	o-QM precursor	Product
1			9
2			10
3			11
4			12
5			13b
6			14
7			15c
8			16d

^a Reaction conditions: 1 (2.9 mmol), o-QM precursor 2 (2.9 mmol), and K₂CO₃ (8.7 mmol) were refluxed in DMF (10 mL) for 4 h.

^b Reaction was carried out in mixture of MeCN and H₂O (2:1) at 80 °C without K₂CO₃.

^c Two equivalents of 3,5-dibromo-1,2,4-triazole (1) were used.

^d 3-Chloro-1,2,4-triazole was used instead of 3,5-dibromo-1,2,4-triazole (1).

The generation of the o-QM under reaction conditions from Mannich base 2d was indirectly confirmed by its trapping with N-vinyl-2-pyrrolidone with formation of the corresponding Diels–Alder cycloadduct 6 in 72% yield (Scheme [4]). However, a stepwise reaction route without formation of o-QM intermediate via nucleophilic substitution of leaving group by triazole moiety and ring closure could not be completely rejected.

Scheme 3 Proposed mechanism for the formation of benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines 3

Scheme 4 Trapping of o-quinone methide generated from Mannich base 2d. Reagents and conditions: N-Vinyl-2-pyrrolidone (4.3 mmol) and o-QM precursor 2d (3.8 mmol) were refluxed in DMF (10 mL) for 12 h.

Scheme 5 Synthesis of compound 3q. Reagents and conditions: 1 (5 mmol) and o-QM precursor 2q (2.5 mmol) were refluxed in DMF (10 mL) for 5 h.

The reaction of 1 and 4-chloro-2,6-bis(hydroxymethyl)phenol (2q) due to the tandem generation of the o-QM gives benzoxazine 3q containing two 1,2,4-triazole moieties (Scheme [5]). The reaction is a domino-process that includes five steps: two dehydration reactions, two Michael-type additions, and one nucleophilic substitution reaction. It was difficult to stop the reaction at the stage of the formation of the corresponding 1,2,4-triazol-1-ylmethylphenol even in the absence of a base. The formation of the product 3q indicates a greater rate of 1,4-addition rather than intramolecular nucleophilic substitution.

Magnetic nonequivalence of the 1,2,4-triazole carbon atoms in the compounds 4a,b and also 3q (8 signals for 4a and 10 signals both for 4b and 3q in the aromatic region of ¹³C NMR spectra) indicates that the alkylation occurred at the N¹⁽²⁾ atom of the 1,2,4-triazole ring rather than N⁴. The same regioselectivity was observed in reactions of 1 with p-hydroxybenzyl alcohols 7 as precursors of p-quinone methides C, which allow to prepare the 4-[(1,2,4-triazol-1-yl)methyl]phenols 8a–c in good yields (Scheme [6]).

Scheme 6 Reactions of p-hydroxybenzyl alcohols with 3,5-dibromo-1,2,4-triazole 1. Reagents and conditions: 1 (2.9 mmol) and p-QM precursor 7 (2.9 mmol) were refluxed in DMF (10 mL) for 4 h.

We have also applied the developed method to the synthesis of 9H-benzo[e]pyrazolo[5,1-b][1,3]oxazines 10a–d from salicylic alcohols 2r–u and 3,4,5-tribromopyrazole (9a) and 3,5-dibromo-4-nitropyrazole (9b) (Table [2]). In the case of 9b, the presence of a base is not required because the nitro group in the pyrazole moiety significantly increases the reactivity to nucleophilic substitution and the ability of the bromine atoms to be eliminated.

Table 2 Scope of the Benzo[e]pyrazolo[5,1-b][1,3]oxazine Formation

Entry	o-QM precursor	Product
1a
2a
3b
4b

^a Reaction conditions: 9a (2.5 mmol), o-QM precursor 2r or 2s (2.5 mmol), and K₂CO₃ (7.5 mmol) were refluxed in DMF (10 mL) for 5 h.

^b Reaction conditions: 9b (2.5 mmol) and o-QM precursor 2t or 2u (2.5 mmol) were refluxed in DMF (10 mL) for 5 h.

The reaction of ammoniomethylphenolate 2m and 2-bromo-1H-imidazole-4,5-dicarbonitrile (11a) or dimethyl 2-bromo-1H-imidazole-4,5-dicarboxylate (11b) in aqueous acetonitrile leads to 5H-benzo[e]imidazo[2,1-b][1,3]oxazines 12a,b in 47% and 57% yield, respectively (Scheme [7]). At the same time, reactions of salicylic alcohols with 2-bromo-, 2-chloro-, 2-(methylthio)-1H-benzo[d]imidazoles or 2-bromo-4,5-diphenyl-1H-imidazole require harsh conditions both for efficient generation of o-QM intermediates and for successful further cyclization.[15i] [j] It should be noted that the reaction of the imidazoles 11a,b with other precursors of the o-QMs (salicylic alcohols, phenolic Mannich bases, quaternary salts) in refluxing aqueous acetonitrile did not proceed, and in boiling DMF a complex mixture of unidentified products was obtained.

Scheme 7 Synthesis of benzo[e]imidazo[2,1-b][1,3]oxazines 12. Reagents and conditions: 11a or 11b (1.2 mmol) and o-QM precursor 2m (1.2 mmol) were refluxed in H₂O (1.5 mL) and MeCN (3 mL) for 4 h.

The IR spectra of compounds 3a–q, 10b–d, and 12a,b show the absence of stretching vibration bands for an O–H bond, which supports the cyclic structure of the compounds obtained. The methylene signals in ¹H NMR spectra shift downfield due to the electron-withdrawing azole group and appear as singlets in the region of 5.21–5.64 ppm. In the ¹³C NMR spectra, the signals of the methylene carbon atoms appear at 44.6–47.0 ppm. The IR spectra of compounds 4a,b show a broad absorption band in the range 3400–3200 cm^–1 corresponding to the stretching vibration of a hydroxyl group associated with hydrogen bonding and singlets at δ = 9.10 and 9.21 in the ¹H NMR spectra were assigned to OH protons. In the case of compounds 8a–c, absorption of the phenolic hydroxyl groups was observed as strongly broadened diffuse bands with several maxima in the region of 3000–3500 cm^–1. The number of protons that were directly linked to ¹³C atoms, inferred from DEPT spectra, was in accordance with the presented structures.

In conclusion, a useful method for the synthesis of 9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines, 9H-benzo[e]pyrazolo[5,1-b][1,3]oxazines, and 5H-benzo[e]imidazo[2,1-b][1,3]oxazines based on cascade aza-Michael and intramolecular nucleophilic substitution reactions was developed. Their synthesis by the suggested procedure does not require an excess of any reagents, includes the use of available reagents, simple workup procedure, scalability, and good functional group tolerance. The Michael-type addition reaction of o-QMs and azoles is advantageous due to its higher regioselectivity compared to alkylation reactions using alkyl halides or alkyl sulfates. Besides, due to the presence of the bromine atoms some of the prepared products may be valuable intermediates for obtaining aryl-substituted­ azolobenzoxazines by C–C cross-coupling methods.[21]

Melting points were determined by capillary method on a SRS OptiMelt MPA100 apparatus and are uncorrected. FTIR-spectra were taken on a Shimadzu FTIR-8400S spectrophotometer as KBr pellets. ¹H and ¹³C NMR spectra (including DEPT-135 experiments) were recorded on a Jeol JNM-ECX 400 spectrometer (400 and 100 MHz, respectively) in DMSO-d ₆ or CDCl₃ solutions, relative to residual solvent signal [CHCl₃ δ = 7.26 ppm (¹H), CDCl₃ δ = 77.0 ppm (¹³C); DMSO-d ₆ δ = 2.50 ppm (¹H), δ = 39.5 ppm (¹³C)]. Chemical shifts and coupling constants were recorded in units of parts per million and hertz, respectively. Mass spectra were recorded on a Finnigan Trace DSQ chromato mass spectrometer with direct introduction of the sample into the ion source (EI, 70 eV, mass-selective detector). Elemental analyses were carried out on a Euro Vector EA-3000 automatic CHNS analyzer.

The reported o-QM precursors were prepared according to literature procedures.[17d] [e] [f] ^, [22] 4-Nitro-2-[(triethylammonio)methyl]phenolate (2m) was prepared from 2-(chloromethyl)-4-nitrophenol and triethylamine.[22e]

Benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazines 3; General Procedure

3,5-Dibromo-1,2,4-triazole (1; 658 mg, 2.9 mmol) or 3-chloro-1,2,4-triazole (300 mg, 2.9 mmol), o-quinone methide precursor 2 (2.9 mmol), and K₂CO₃ (1.2 g, 8.7 mmol) were refluxed for 4 h in DMF (10 mL). After completion of the reaction, the mixture was cooled, and poured into H₂O (30 mL). The precipitate formed was collected by filtration, washed with H₂O, dried, and recrystallized.

2′-Bromospiro[adamantane-2,9′-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine] (3a)

Yield: 658 mg (61%); colorless crystals; mp 214–216 °C (DMF).

IR (KBr): 2978, 2916, 2884, 1524, 1489, 1466, 1447, 1269, 1219, 1188, 1177, 1095, 1038, 972, 825, 748 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.90 (d, J = 7.8 Hz, 1 H, Ar), 7.42–7.49 (m, 2 H, Ar), 7.32–7.36 (m, 1 H, Ar), 2.49–2.54 (m, 4 Н, Ad), 2.01–2.05 (m, 2 H, Ad), 1.80–1.87 (m, 4 H, Ad), 1.64–1.69 (m, 4 H, Ad).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.0 (C), 152.2 (C), 135.5 (C), 130.0 (CH), 129.6 (C), 127.9 (CH), 126.0 (CH), 118.5 (CH), 69.2 (C-2, Ad), 37.9 (CH₂, Ad), 35.1 (2 × CH, Ad), 35.0 (2 × CH₂, Ad), 33.4 (2 × CH₂, Ad), 26.7 (CH, Ad), 26.5 (CH, Ad).

MS (EI): m/z (%) = 371 (24, [M]⁺), 354 (5, [M – OH]⁺), 316 (7), 292 (90, [M – Br]⁺), 250 (13), 226 (57, [M – C₂BrN₃]⁺), 196 (32), 183 (37), 172 (37), 165 (60), 152 (62), 131 (57), 128 (49), 115 (78), 107 (52), 103 (42), 91 (98), 79 (83), 77 (100).

Anal. Calcd for C₁₈H₁₈BrN₃O: C, 58.08; H, 4.87; N, 11.29. Found: C, 58.14; H, 4.93; N, 11.24.

2-Bromo-9-phenyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3b)

Yield: 638 mg (67%); colorless crystals; mp 219–221 °C (EtOH).

IR (KBr): 1593, 1543, 1514, 1483, 1454, 1285, 1196, 1173, 1146, 1099, 988, 908, 833, 812, 756, 737, 694 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.35–7.40 (m, 4 H, Ar), 7.30 (d, J = 8.7 Hz, 1 H, Ar), 7.16–7.25 (m, 3 H, Ar), 7.06 (d, J = 7.8 Hz, 1 H, Ar), 6.41 (s, 1 H, H-9).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.6 (C), 147.3 (C), 139.0 (C), 138.7 (C), 130.1 (CH), 129.4 (CH), 129.3 (2 × CH), 128.7 (CH), 128.0 (2 × CH), 125.8 (CH), 119.1 (C), 117.6 (CH), 61.3 (CH).

Anal. Calcd for C₁₅H₁₀BrN₃O: C, 54.90; H, 3.07; N, 12.80. Found: C, 54.98; H, 3.07; N, 12.80.

2-Bromo-5-methoxy-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3c)

Yield: 581 mg (71%); colorless crystals; mp 240–242 °C (DMF).

IR (KBr): 2841, 1595, 1557, 1522, 1489, 1441, 1341, 1327, 1296, 1275, 1182, 1152, 1082, 953, 885, 785 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆ at 80 °C): δ = 7.19 (t, J = 8.0 Hz, 1 H, Ar), 7.08 (d, J = 8.0 Hz, 1 H, Ar), 6.89 (d, J = 7.6 Hz, 1 H, Ar), 5.28 (s, 2 H, CH₂), 3.86 (s, 3 H, CH₃O).

¹³C NMR (100 MHz, DMSO-d ₆ at 80 °C): δ = 154.0 (C), 148.3 (C), 137.8 (C), 137.2 (C), 126.1 (CH), 119.1 (CH), 117.0 (C), 113.1 (CH), 56.9 (CH₃O), 46.2 (CH₂).

Anal. Calcd for C₁₀H₈BrN₃O₂: C, 42.58; H, 2.86; N, 14.90. Found: C, 42.68; H, 2.77; N, 14.82.

2-Bromo-5,7-di-tert-butyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3d)

Yield: 497 mg (47%); colorless crystals; mp 145–146 °C (MeOH).

IR (KBr): 2967, 2905, 2870 (C–H t-C₄H₉), 1609, 1564, 1524, 1479, 1460, 1443, 1364, 1294, 1242, 1215, 1198, 1165, 1146, 1117, 986, 874, 800, 718 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36 (d, J = 2.3 Hz, 1 H, Ar), 7.04 (d, J = 2.3 Hz, 1 H, Ar), 5.27 (s, 2 H, CH₂), 1.44 (s, 9 H, t-C₄H₉), 1.31 (s, 9 H, t-C₄H₉).

¹³C NMR (100 MHz, CDCl₃): δ = 153.7 (C), 148.2 (C), 144.6 (C), 138.4 (C), 138.3 (C), 124.7 (CH), 121.8 (CH), 113.9 (C), 46.5 (CH₂), 35.4 [C(CH₃)₃], 34.8 [C(CH₃)₃], 31.4 [C(CH₃)₃], 30.1 [C(CH₃)₃].

Anal. Calcd for C₁₇H₂₂BrN₃O: C, 56.05; H, 6.09; N, 11.54. Found: C, 56.11; H, 6.02; N, 11.61.

2-Bromo-6,7-dimethyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3e)

Yield: 666 mg (82%); colorless crystals; mp 240–241 °C (EtOH–DMF, 4:1).

IR (KBr): 2970, 2943, 2920, 2893, 2858, 1593, 1558, 1520, 1458, 1416, 1292, 1265, 1234, 1200, 1177, 1146, 1076, 1003, 987, 887, 717 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.11 (s, 1 H, Ar), 7.08 (s, 1 H, Ar), 5.21 (s, 2 H, CH₂), 2.21 (s, 3 H, CH₃), 2.18 (s, 3 H, CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.1 (C), 145.7 (C), 138.5 (C), 137.1 (C), 134.1 (C), 128.4 (CH), 117.8 (CH), 112.7 (C), 45.9 (CH₂N), 19.6 (CH₃), 19.1 (CH₃).

Anal. Calcd for C₁₁H₁₀BrN₃O: C, 47.16; H, 3.60; N, 15.00. Found: C, 47.21; H, 3.62; N, 14.91.

2-Bromo-7-tert-butyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3f)

Yield: 688 mg (77%); colorless crystals; mp 146–148 °C (i-PrOH).

IR (KBr): 3055, 2962, 2905, 2870, 1597, 1558, 1520, 1504, 1423, 1366, 1288, 1219, 1204, 1184, 1157, 1122, 1099, 987, 876, 837, 798, 741, 717 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.41 (dd, J = 8.2, 2.3 Hz, 1 H, H-6), 7.39 (d, J = 2.3 Hz, 1 H, H-8), 7.20 (d, J = 8.2 Hz, 1 H, H-5), 5.28 (s, 2 H, CH₂), 1.26 (s, 9 H, t-C₄H₉).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.0 (C), 148.5 (C), 145.7 (C), 137.1 (C), 126.9 (CH), 124.8 (CH), 116.9 (CH), 115.4 (C), 46.4 (CH₂N), 34.8 [C(CH₃)₃], 31.6 [C(CH₃)₃].

Anal. Calcd for C₁₃H₁₄BrN₃O: C, 50.67; H, 4.58; N, 13.64. Found: C, 50.73; H, 4.64; N, 13.58.

2-Bromo-7-benzyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3g)

Yield: 685 mg (69%); colorless crystals; mp 185–186 °C (EtOH).

IR (KBr): 3024, 2905, 1601, 1562, 1520, 1497, 1462, 1431, 1404, 1288, 1258, 1200, 1150, 1111, 987, 895, 845, 764, 721, 694 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.13–7.28 (m, 8 H, Ar), 5.24 (s, 2 H, CH₂N), 3.91 (s, 2 H, CH ₂Ph).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.9 (C), 146.2 (C), 141.3 (C), 139.2 (C), 137.1 (C), 130.2 (CH), 129.2 (2 × CH), 129.1 (2 × CH), 128.0 (CH), 126.7 (CH), 117.4 (CH), 116.0 (C), 46.2 (CH₂N), 40.7 (CH₂).

Anal. Calcd for C₁₆H₁₂BrN₃O: C, 56.16; H, 3.53; N, 12.28. Found: C, 56.22; H, 3.48; N, 12.33.

7-(Adamantan-1-yl)-2-bromo-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3h)

Yield: 896 mg (80%); colorless crystals; mp 206−208 °C (EtOH).

IR (KBr): 3053, 2926, 2899, 2845, 1599, 1560, 1526, 1503, 1449, 1423, 1290, 1258, 1211, 1115, 989, 889, 829, 808, 799, 737, 714 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.35–7.38 (m, 2 H, H-6, 8), 7.20 (d, J = 8.2 Hz, 1 H, H-5), 5.27 (s, 2 H, CH₂), 2.03 (br s, 3 H, СH, Ad), 1.80–1.83 (m, 6 H, СH₂, Ad), 1.66–1.73 (m, 6 H, СH₂, Ad).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 154.0 (C), 148.7 (C), 145.7 (C), 137.1 (C), 126.4 (CH), 124.5 (CH), 116.9 (CH), 115.4 (C), 46.4 (CH₂N), 43.1 (3 × CH₂, Ad), 36.6 (3 × CH₂, Ad), 36.1 (C, Ad), 28.8 (3 × CH, Ad).

Anal. Calcd for C₁₉H₂₀BrN₃O: C, 59.08; H, 5.22; N, 10.88. Found: C, 59.16; H, 5.26; N, 10.82.

Methyl 2-Bromo-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine-7-carboxylate (3i)

Yield: 216 mg (24%); colorless crystals; mp 251–253 °C (EtOAc).

IR (KBr): 3043, 2955, 1717, 1597, 1558, 1524, 1497, 1439, 1300, 1277, 1250, 1195, 1177, 1126, 991, 914, 768 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.03 (d, J = 1.8 Hz, 1 H, H-8), 7.93 (dd, J = 8.7, 1.8 Hz, 1 H, H-6), 7.42 (d, J = 8.7 Hz, 1 H, H-5), 5.35 (s, 2 H, CH₂), 3.84 (s, 3 H, CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.6 (C), 153.6 (C), 151.2 (C), 137.2 (C), 130.9 (CH), 129.9 (CH), 127.0 (C), 117.9 (CH), 117.1 (C), 52.9 (CH₃), 46.2 (CH₂N).

Anal. Calcd for C₁₁H₈BrN₃O₃: C, 42.60; H, 2.60; N, 13.55. Found: C, 42.70; H, 2.55; N, 13.59.

2-Bromo-7-methoxy-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3j)

Yield: 589 mg (72%); colorless crystals; mp 214–216 °C (EtOH).

IR (KBr): 2993, 2939, 2839, 1597, 1562, 1520, 1497, 1435, 1292, 1265, 1234, 1196, 1038, 879, 802, 717 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.22 (dd, J = 6.4, 3.2 Hz, 1 H, H-6), 6.92–6.96 (m, 2 H, H-5, 8), 5.28 (s, 2 H, CH₂), 3.75 (s, 3 H, CH₃O).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 156.8 (C), 154.0 (C), 141.6 (C), 137.1 (C), 118.4 (CH), 116.9 (C), 115.8 (CH), 112.2 (CH), 56.2 (CH₃), 46.3 (CH₂N).

Anal. Calcd for C₁₀H₈BrN₃O₂: C, 42.58; H, 2.86; N, 14.90. Found: C, 42.64; H, 2.80; N, 14.87.

5-(Adamantan-1-yl)-2-bromo-7-methyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3k)

Yield: 975 mg (84%); colorless crystals; mp 241−242 °C (EtOH–DMF, 4:1).

IR (KBr): 2916, 2847, 1609, 1558, 1547, 1462, 1427, 1265, 1200, 1150, 1130, 852, 710 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.06 (s, 1 H, Ar), 7.00 (s, 1 H, Ar), 5.25 (s, 2 H, CH₂), 2.26 (s, 3 H, CH₃), 2.04 (br s, 9 H, СН₂, Ad, СН, Ad), 1.73 (br s, 6 H, СН₂, Ad).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.6 (C), 145.0 (C), 137.8 (C), 137.3 (C), 134.7 (C), 127.9 (CH), 126.2 (CH), 116.2 (C), 46.2 (CH₂N), 40.9 (3 × CH₂, Ad), 37.1 (C, Ad), 36.8 (3 × CH₂, Ad), 28.8 (3 × CH, Ad), 21.1 (CH₃).

Anal. Calcd for C₂₀H₂₂BrN₃O: C, 60.01; H, 5.54; N, 10.50. Found: C, 59.92; H, 5.60; N, 10.60.

5-(Adamantan-2-yl)-2-bromo-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3l)

Yield: 884 mg (79%); colorless crystals; mp 228–229 °C (EtOH).

IR (KBr): 2905, 2847, 1558, 1518, 1472, 1443, 1408, 1287, 1250, 1215, 1169, 988, 885, 781, 768, 716 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.47 (d, J = 7.3 Hz, 1 H, Ar), 7.19–7.26 (m, 2 H, Ar), 5.29 (s, 2 H, CH₂), 3.25 (s, 1 H, Ad), 2.26 (s, 2 H, Ad), 1.82–1.97 (m, 8 H, Ad), 1.72 (s, 2 H, Ad), 1.59 (d, J = 12.4 Hz, 2 H, Ad).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.9 (C), 146.2 (C), 137.1 (C), 133.6 (C), 128.2 (CH), 125.7 (CH), 125.2 (CH), 116.0 (C), 46.1 (CH₂N), 43.6 (CH₂, Ad), 39.9 (2 × CH₂, Ad), 37.8 (CH₂, Ad), 32.8 (2 × CH₂, Ad), 31.3 (2 × CH, Ad), 27.9 (CH, Ad), 27.4 (CH, Ad).

Anal. Calcd for C₁₉H₂₀BrN₃O: C, 59.08; H, 5.22; N, 10.88. Found: C, 59.15; H, 5.16; N, 10.93.

2-Bromo-7-nitro-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3m)

Yield: 551 mg (64%); light-yellow crystals; mp 236–238 °C (EtOH–MeCN, 1:2).

IR (KBr): 1597, 1557, 1518, 1479, 1404, 1346, 1287, 1217, 1184, 1150, 1084, 930, 893, 839, 820, 748, 716, 656 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.40 (d, J = 2.8 Hz, 1 H, H-8), 8.23 (dd, J = 2.8, 9.2 Hz, 1 H, H-6), 7.54 (d, J = 9.2 Hz, 1 H, H-5), 5.38 (s, 3 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.3 (C), 152.3 (C), 144.6 (C), 137.3 (C), 125.4 (CH), 124.5 (CH), 118.8 (CH), 118.3 (C), 46.4 (CH₂).

Anal. Calcd for C₉H₅BrN₄O₃: C, 36.39; H, 1.70; N, 18.86. Found: C, 36.44; H, 1.78; N, 19.79.

Ethyl 8-Bromo-2-methyl-3,11-dihydro[1,2,4]triazolo[5′,1′:2,3][1,3]oxazino[5,6-e]indole-1-carboxylate (3n)

Yield: 427 mg (39%); white crystals; mp 269–270 °C (DMF).

IR (KBr): 3300–3100, 2978, 2932, 1701, 1570, 1520, 1477, 1435, 1385, 1288, 1215, 1200, 1150, 1092, 1057, 1030, 991, 802, 783 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.09 (br s, 1 H, NH), 7.36 (d, J = 8.7 Hz, 1 H, Ar), 7.04 (d, J = 8.7 Hz, 1 H, Ar), 5.64 (s, 2 H, CH₂), 4.24 (q, J = 7.1 Hz, 2 H, CH ₂CH₃), 2.57 (s, 3 H, CH₃), 1.32 (t, J = 7.1 Hz, 3 H, CH₂CH ₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.1 (C=O), 153.5 (C), 146.3 (C), 143.2 (C), 137.1 (C), 132.7 (C), 123.2 (C), 112.9 (CH), 112.5 (CH), 106.7 (C), 105.3 (C), 60.1 (CH₂), 47.0 (CH₂), 15.3 (CH₃), 14.8 (CH₃).

Anal. Calcd for C₁₅H₁₃BrN₄O₃: C, 47.76; H, 3.47; N, 14.85. Found: C, 47.84; H, 3.55; N, 14.81.

2,9-Dibromo-6,13-dihydrobis[1,2,4]triazolo[5,1-b:5,1-b′]benzo[1,2-e:4,5-e′]bis[1,3]oxazine (3o)

The title compound was synthesized by the general procedure using 2 equiv of 1; yield: 890 mg (72%); colorless crystals; mp >350 °C (DMF, dec.).

IR (KBr): 3063, 2935, 1562, 1528, 1501, 1440, 1404, 1327, 1300, 1281, 1242, 1196, 1161, 1134, 987, 914, 887, 729, 717 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆ at 140 °C): δ = 7.39 (s, 2 H, Ar), 5.35 (s, 4 H, 2 × CH₂).

¹³C NMR (100 MHz, DMSO-d ₆ at 145 °C): δ = 154.1 (2 C), 154.1 (2 C) 137.4 (2 C), 117.9 (2 × CH), 116.4 (2 C), 46.3 (2 × CH₂).

Anal. Calcd for C₁₂H₆Br₂N₆O₂: C, 33.83; H, 1.42; N, 19.73. Found: C, 33.88; H, 1.51; N, 19.68.

5-(Adamantan-1-yl)-7-methyl-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3p)

The title compound was synthesized by the general procedure using 3-chloro-1,2,4-triazole; yield: 652 mg (70%); colorless crystals; mp 197–199 °C (EtOH).

IR (KBr): 3109, 2916, 2847, 1612, 1558, 1547, 1462, 1427, 1265, 1242, 1200, 1150, 1130, 868, 856 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.81 (s, 1 H, H-2), 7.01 (s, 1 H) and 7.05 (s, 1 H) (H-6, 8), 5.30 (s, 2 H, CH₂), 2.26 (s, 3 H, CH₃), 2.06 (br s, 9 H, СН Ad, СН₂, Ad), 1.73 (br s, 6 H, СН₂, Ad).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.5 (C), 149.5 (CH-2), 145.4 (C), 137.8 (C), 134.3 (C), 127.8 (CH), 126.2 (CH), 116.3 (C), 46.0 (CH₂N), 40.8 (3 × CH₂, Ad), 37.1 (C, Ad), 36.8 (3 × CH₂, Ad), 28.8 (3 × CH, Ad), 21.0 (CH₃).

MS (EI): m/z (%) = 321 (100, [M]⁺), 320 (22, [M – H]⁺), 278 (8), 264 (62), 236 (17), 228 (15), 221 (7), 200 (11), 165 (16).

Anal. Calcd for C₂₀H₂₃N₃O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.80; H, 7.17; N, 13.01.

2-Bromo-7-chloro-5-[(3,5-dibromo-1H-1,2,4-triazol-1-yl)methyl]-9H-benzo[e][1,2,4]triazolo[5,1-b][1,3]oxazine (3q)

3,5-Dibromo-1,2,4-triazole (1; 1.134 g, 5.0 mmol) and 4-chloro-2,6-bis(hydroxymethyl)phenol (2q; 472 mg, 2.5 mmol) were refluxed for 5 h in DMF (10 mL). After completion of the reaction, the mixture was cooled and poured into H₂O (30 mL). The precipitate formed was collected by filtration, washed with H₂O, dried, and recrystallized; yield: 722 mg (55%); colorless crystals; mp 258–260 °C (DMF).

IR (KBr): 2924, 1601, 1555, 1520, 1470, 1431, 1292, 1261, 1180, 1150, 1065, 987, 864 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.58 (d, J = 2.3 Hz 1 H, Ar), 7.50 (d, J = 2.3 Hz, 1 H, Ar), 5.47 (s, 2 H, CH₂), 5.29 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.2 (C), 145.0 (C), 140.3 (C), 137.2 (C), 132.2 (C), 130.6 (CH), 129.2 (C), 128.4 (CH), 124.9 (C), 119.0 (C), 48.0 (CH₂), 46.1 (CH₂).

MS for ⁷⁹Br, ³⁵Cl (EI): m/z (%) = 522 (2, [M]⁺), 443 (2, [M – Br]⁺), 364 (1, [M – 2 Br]⁺), 298 (7, [M – C₂Br₂N₃]⁺), 218 (5), 177 (5), 156 (21), 153 (23, [C₈H₆ClO]⁺), 137 (20), 128 (30), 125 (58), 102 (73), 89 (100), 80 (65).

Anal. Calcd for C₁₂H₆Br₃ClN₆O: C, 27.43; H, 1.15; N, 16.00. Found: C, 27.51; H, 1.09; N, 16.09.

2-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-6-methoxyphenol (4a)

3,5-Dibromo-1,2,4-triazole (1; 658 mg, 2.9 mmol) and salicylic alcohol 2c (447 mg, 2.9 mmol) were refluxed for 2 h in DMF (10 mL). After completion of the reaction, the mixture was cooled and poured into H₂O (30 mL). The precipitate formed was collected by filtration, washed with H₂O, dried, and recrystallized from EtOH; yield: 585 mg (60%); colorless crystals; mp 149–150 °C.

IR (KBr): 3500–3000 (O–H), 1612, 1593, 1553, 1520, 1485, 1468, 1433, 1364, 1290, 1267, 1231, 1184, 1069, 1005, 916, 837, 777, 760, 721, 704 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.09 (s, 1 H, OH), 6.91 (dd, J = 8.2, 1.2 Hz, 1 H, Ar), 6.73 (t, J = 7.9 Hz, 1 H, Ar), 6.57 (d, J = 7.6 Hz, 1 H, Ar), 5.26 (s, 2 H, CH₂), 3.75 (s, 6 H, 2 × CH₃O).

¹H NMR (400 MHz, CD₃CN): δ = 6.91 (dd, J = 8.0, 1.4 Hz, 1 H, Ar), 6.89 (br s, 1 H, OH), 6.79 (t, J = 8.0 Hz, 1 H, Ar), 6.66 (dd, J = 7.8, 1.4 Hz, 1 H, Ar), 5.27 (s, 2 H, CH₂), 3.82 (s, 6 H, 2 × CH₃O).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 148.0 (C), 144.8 (C), 139.6 (C), 131.7 (C), 121.5 (C, CH), 119.5 (CH), 112.4 (CH), 56.4 (2 × CH₃), 49.2 (CH₂).

¹³C NMR (100 MHz, CD₃CN): δ = 147.2 (C), 144.2 (C), 139.4 (C), 130.5 (C), 121.4 (CH), 120.3 (C), 119.7 (CH), 111.7 (CH), 55.9 (2 × CH₃), 48.7 (CH₂).

Anal. Calcd for C₁₀H₉Br₂N₃O₂: C, 33.09; H, 2.50; N, 11.58. Found: C, 32.95; H, 2.41; N, 11.45.

5-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-6-hydroxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (4b)

3,5-Dibromo-1,2,4-triazole (1; 658 mg, 2.9 mmol) and Mannich base 2p (752 mg, 2.9 mmol) were refluxed for 2 h in EtOH (10 mL). Product was isolated analogously to compound 4a; yield: 475 mg (59%); colorless crystals; mp 199−200 °C (EtOH).

IR (KBr): 3309, 3240, 1643, 1582, 1539, 1512, 1454, 1427, 1369, 1346, 1300, 1261, 1204, 1084, 1045, 930, 810, 775 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.46 (s, 1 H, NH), 9.21 (s, 1 H, OH), 7.52 (s, 1 Н, NHCO), 7.22 (d, J = 8.7 Hz, 1 H, Ar), 6.78 (d, J = 8.7 Hz, 1 H, Ar), 5.48 (s, 2 H, CH₂N), 3.45 (td, J = 6.9, 2.3 Hz, 2 H, CH₂), 3.01 (t, J = 6.9 Hz, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.3 (C=O), 150.4 (C), 139.4 (C), 132.5 (C), 131.3 (C), 128.8 (C), 125.7 (C), 117.1 (C), 115.0 (CH), 114.5 (CH), 110.3 (C), 46.0 (CH₂), 41.5 (CH₂), 22.8 (CH₂).

Anal. Calcd for C₁₄H₁₁Br₂N₅O₂: C, 38.12; H, 2.51; N, 15.88. Found: C, 38.05; H, 2.46; N, 15.92.

1-(6,8-Di-tert-butylchroman-2-yl)pyrrolidin-2-one (6)

Mannich base 2d (1 g, 3.8 mmol) and N-vinyl-2-pyrrolidone (0.5 mL, 0.48 g, 4.3 mmol) in DMF (10 ml) were refluxed for 12 h. After completion of the reaction, the solution was cooled and poured into H₂O (30 mL). The precipitate formed was collected by filtration, washed with H₂O, dried, and recrystallized from MeOH; yield: 0.9 g (72%); colorless crystals; mp 134–135 °C.

IR (KBr): 2955, 2924, 2872 (C–H t-Bu), 1701 (C=O), 1476, 1458, 1449, 1423, 1362, 1321, 1288, 1221, 1200, 1167, 1125, 1098, 1045, 1003 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.16 (d, J = 2.3 Hz, 1 H, Ar), 6.93 (d, J = 2.3 Hz, 1 H, Ar), 5.87 (dd, J = 11.0, 2.3 Hz, 1 H, CHNO), 3.58–3.64 (m, 1 H), 3.46–3.52 (m, 1 H), 3.07 (ddd, J = 16.5, 12.4, 6.4 Hz, 1 H), 2.85 (ddd, J = 16.5, 5.5, 2.3 Hz, 1 H), 2.49 (t, J = 8.2 Hz, 2 H), 2.05–2.17 (m, 3 H), 1.96–2.01 (m, 1 H), 1.36 (s, 9 H, t-C₄H₉), 1.29 (s, 9 H, t-C₄H9).

¹³C NMR (100 MHz, CDCl₃): δ = 175.6 (C=O), 150.8 (C–O), 142.5 (C), 137.0 (C), 123.9 (CH), 122.1 (CH), 120.2 (C), 78.0 (CHNO), 42.7 (CH₂), 35.1 (C), 34.3 (C), 31.7 [C(CH₃)₃] , 30.0 [C(CH₃)₃] , 25.9 (CH₂), 25.5 (CH₂), 18.5 (CH₂).

MS (EI): m/z (%) = 329 (55, [M]⁺), 314 (11, [M – CH₃]⁺), 244 (65, [M – C₄H₇NO]⁺), 229 (100, [M – CH₃ – C₄H₇NO]⁺), 203 (47, [M – C₆H₉NO – CH₃]⁺), 187 (45), 98 (32), 57 (12, [Me₃C]⁺).

Anal. Calcd for C₂₁H₃₁NO₂: C₂₁H₃₁NO₂. Found: С, 76.48; Н, 9.59; N, 4.13.

4-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]phenols 8; General Procedure

3,5-Dibromo-1,2,4-triazole (1; 658 mg, 2.9 mmol) and p-quinone methide precursor 7 (2.9 mmol) were refluxed for 4 h in DMF (10 mL). Products were isolated analogously to compound 4a.

4-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-2-ethoxyphenol (8a)

Yield: 864 mg (79%); colorless crystals; mp 125–127 °C (EtOH).

IR (KBr): 3500–3000 (OH), 2980, 1603, 1530, 1454, 1435, 1414, 1393, 1352, 1271, 1223, 1161, 1126, 1069, 1036 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.04 (s, 1 H, OH), 6.85 (d, J = 1.6 Hz, 1 H, H-3), 6.73 (d, J = 8.0 Hz, 1 H, H-5), 6.63 (dd, J = 8.0, 1.6 Hz, 1 H, H-6), 5.22 (s, 2 H, CH₂N), 3.95 (q, J = 7.2 Hz, 2 H, CH ₂CH₃), 1.28 (t, J = 7.2 Hz, 3 H, CH₂CH ₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 147.5 (C), 147.2 (C), 139.8 (C), 131.0 (C), 125.7 (C), 121.2 (CH), 116.2 (CH), 114.1 (CH), 64.4 (CH₂), 53.5 (CH₂), 15.2 (CH₃).

MS for ⁷⁹Br (EI): m/z (%) = 375 (14, [M]⁺), 151 (100, [M – C₂Br₂N₃]⁺), 123 (90, [M – C₂Br₂N₃ – C₂H₄]⁺), 122 (26).

Anal. Calcd for C₁₁H₁₁Br₂N₃O₂: C, 35.04; H, 2.94; N, 11.14. Found: C, 34.95; H, 2.88; N, 11.19.

4-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-2,6-dimethoxyphenol (8b)

Yield: 707 mg (62%); colorless crystals; mp 154−156 °C (EtOH).

IR (KBr): 3500–3100 (OH), 3011, 2967, 2940, 2841, 1616, 1591, 1520, 1458, 1431, 1375, 1356, 1329, 1263, 1244, 1223, 1190, 1159, 1117, 1076, 1042, 827, 770 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.51 (br s, 1 H, OH), 6.55 (s, 2 H, H-3, 5), 5.23 (s, 2 H, CH₂), 3.70 (s, 6 H, 2 × CH₃O).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 148.6 (2 C), 139.8 (C), 136.3 (C), 131.1 (C), 124.8 (C), 106.3 (2 × CH), 56.6 (2 × CH₃), 53.8 (CH₂).

MS for ⁷⁹Br (EI): m/z (%) = 391 (14, [M]⁺), 167 (100, [M – C₂Br₂N₃]⁺).

Anal. Calcd for C₁₁H₁₁Br₂N₃O₃: C, 33.62; H, 2.82; N, 10.69. Found: C, 33.71; H, 2.76; N, 10.75.

4-[(3,5-Dibromo-1H-1,2,4-triazol-1-yl)methyl]-2,6-dimethylphenol (8c)

Yield: 838 mg (80%); colorless crystals; mp 185–186 °C (EtOH).

IR (KBr): 3500–3200 (O–H), 16.3, 1489, 1452, 1427, 1383, 1354, 1337, 1312, 1273, 1211, 1155, 1069, 962, 876, 768 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.36 (s, 1 H, OH), 6.82 (s, 2 H, H-3, 5), 5.16 (s, 2 H, CH₂), 2.11 (s, 6 H, 2 × CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 153.9 (C), 139.8 (C), 130.8 (C), 128.5 (2 × CH), 125.3 (2 C), 125.1 (C), 53.3 (CH₂), 17.1 (2 × CH₃).

MS for ⁷⁹Br (EI): m/z (%) = 359 (10, [M]⁺), 135 (100, [M – C₂Br₂N₃]⁺), 91 (15).

Anal. Calcd for C₁₁H₁₁Br₂N₃O: C, 36.59; H, 3.07; N, 11.64. Found: C, 36.62; H, 3.00; N, 11.71.

9H-Benzo[e]pyrazolo[5,1-b][1,3]oxazines 10; General Procedure

3,4,5-Tribromopyrazole (9a; 762 mg, 2.5 mmol) or 3,5-dibromo-4-nitropyrazole (9b; 677 mg, 2.5 mmol), o-quinone methide precursor 2 (2.5 mmol) and K₂CO₃ (only for 9a, 1.035 g, 7.5 mmol) were refluxed for 4 h in DMF (10 mL). Product was isolated analogously to compound 4a.

(2,3-Dibromo-7-methoxy-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazin-5-yl)methanol (10a)

Yield: 634 mg (65%); colorless crystals; mp 229–230 °C (MeOH–DMF, 3:1).

IR (KBr): 3500–3300, 2931, 2870, 2839, 1624, 1609, 1570, 1531, 1481, 1435, 1389, 1358, 1234, 1188, 1142, 1084, 1045, 1022, 891, 856, 737 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 6.98 (s, 1 H, Ar), 6.79 (s, 1 H, Ar), 5.36 (br s, 1 H, OH), 5.21 (s, 2 H, CH₂), 4.58 (s, 2 H, CH ₂OH), 3.72 (s, 3 H, CH₃O).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 156.2, 145.7, 138.1, 132.1, 127.1, 116.5, 113.6, 110.0, 76.0 (C-3), 57.4, 56.0, 46.7 (СH₂N).

MS for ⁷⁹Br (EI): m/z (%) = 388 (22, [M]⁺), 309 (5, [M – Br]⁺), 164 (20), 149 (37), 121 (94), 107 (27), 91 (38, [C₇H₇]⁺), 77 (100).

Anal. Calcd for C₁₂H₁₀Br₂N₂O₃: С, 36.95; Н, 2.58; N, 7.18. Found: 37.01; Н, 2.52; N, 7.09.

7-(1-Adamantyl)-2,3,5-tribromo-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazine (10b)

Yield: 719 mg (53%); colorless crystals; mp 212–214 °C (MeOH–DMF, 3:1).

IR (KBr): 2924, 2901, 2847, 1566, 1528, 1470, 1450, 1385, 1358, 1315, 1269, 1223, 1130, 1011, 895, 868 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 1.8 Hz, 1 H, Ar), 7.11 (d, J = 1.8 Hz, 1 H, Ar), 5.25 (s, 2 H, CH₂), 2.11 (br s, 3 H, CH, Ad), 1.71–1.86 (m, 12 Н, СН₂, Ad).

¹³C NMR (100 MHz, CDCl₃): δ = 149.6, 145.6, 142.3, 130.5, 128.5, 122.9, 115.8, 110.9, 77.4 (C-3), 46.9 (CH₂N), 43.1, 36.5, 36.2, 28.8.

Anal. Calcd for C₂₀H₁₉Br₃N₂O: С, 44.23; Н, 3.53; N, 5.16. Found: С, 44.12; Н, 3.55; N, 5.06.

2-Bromo-3-nitro-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazine (10c)

Yield: 592 mg (80%); colorless crystals; mp 228–230 °C (DMF).

IR (KBr): 1593, 1562, 1528, 1489, 1454, 1416, 1400, 1354, 1339, 1273, 1246, 1223, 1173, 1107, 1061, 918, 849, 833, 760 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.36–7.44 (m, 3 H, Ar), 7.30 (dd, J = 7.8, 1.4 Hz, 1 H, Ar), 5.30 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 146.6 (C), 145.5 (C), 130.2 (CH), 128.4 (CH), 126.5 (CH), 123.0 (C), 117.3 (CH), 116.4 (C-3), 116.0 (C), 46.3 (CH₂N).

Anal. Calcd for C₁₀H₆BrN₃O₃: С, 40.57; Н, 2.04; N, 14.19. Found: С, 40.63; Н, 1.99; N, 14.03.

2,7-Dibromo-3-nitro-9H-benzo[e]pyrazolo[5,1-b][1,3]oxazine (10d)

Yield: 703 mg (75%); light-yellow crystals; mp 244–246 °C (DMF).

IR (KBr): 3055, 1593, 1562, 1528, 1501, 1477, 1420, 1400, 1350, 1250, 1173, 1115, 1065, 918, 833 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.67 (d, J = 2.3 Hz, 1 Н, H-8), 7.58 (dd, J = 8.7, 2.3 Hz, 1 H, H-6), 7.34 (d, J = 8.7 Hz, 1 H, H-5), 5.27 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 146.0 (C), 145.1 (C), 132.8 (CH), 130.9 (CH), 123.1 (C), 119.5 (CH), 118.6 (C), 118.0 (C), 116.5 (C-3), 46.1 (CH₂N).

MS for ⁷⁹Br (EI): m/z (%) = 373 (32, [M]⁺), 343 (4, [M – NO]⁺), 294 (2, [M – Br]⁺), 210 (50), 184 (25), 156 (18, [C₆H₅Br]⁺), 131 (32), 113 (58), 89 (38), 77 (100, [C₆H₅]⁺).

Anal. Calcd for C₁₀H₅Br₂N₃O₃: С, 32.03; Н, 1.34; N, 11.21. Found: С, 31.92; Н, 1.28; N, 11.19.

7-Nitro-5H-benzo[e]imidazo[2,1-b][1,3]oxazines 12; General Procedure

Imidazole 11a or 11b (1.2 mmol) and o-quinone methide precursor 2m (303 mg, 2.5 mmol) were refluxed for 4 h in a mixture of H₂O (1.5 mL) and MeCN (3 mL). Product was isolated analogously to compound 4a.

7-Nitro-5H-benzo[e]imidazo[2,1-b][1,3]oxazine-2,3-dicarbonitrile (12a)

Yield: 151 mg (47%); yellow crystals; mp 258–260 °C (MeCN–H₂O, 2:1, dec.).

IR (KBr): 3074, 3047, 2928, 2233 (C≡N), 1597, 1547, 1535 (NO₂), 1504, 1481, 1350 (NO₂), 1319, 1304, 1273, 1223, 1188, 1130, 1092, 930, 868, 852, 748, 706 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.46 (d, J = 2.7 Hz, 1 H, H-6), 8.25 (dd, J = 9.2, 2.7 Hz, 1 H, H-8), 7.57 (d, J = 9.2 Hz, 1 H, H-9), 5.48 (s, 2 H, CH₂).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 151.8 (C), 147.8 (C), 144.9 (C), 125.7 (CH), 124.2 (CH), 118.7 (CH), 118.3 (C), 116.5 (C), 112.6 (C), 108.8 (CN), 108.6 (CN), 44.6 (CH₂).

Anal. Calcd for C₁₂H₅N₅O₃: C, 53.94; H, 1.89; N, 26.21. Found: C, 53.88; H, 1.83; N, 26.13.

Dimethyl 7-Nitro-5H-benzo[e]imidazo[2,1-b][1,3]oxazine-2,3-dicarboxylate (12b)

Yield: 228 mg (57%); light-yellow crystals; mp 227–229 °C (MeCN–H₂O, 2:1, dec.).

IR (KBr): 3047, 1751 (C=O), 1713 (C=O), 1555, 1543 (NO₂), 1501, 1485, 1342 (NO₂), 1304, 1261, 1219, 1165, 1088, 1068, 899, 806, 748 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.43 (d, J = 2.5 Hz, 1 H, H-6), 8.20 (dd, J = 9.0, 2.5 Hz, 1 H, H-8), 7.48 (d, J = 9.0 Hz, 1 H, H-9), 5.47 (s, 2 H, CH₂), 3.82 (s, 3 H, CH₃), 3.78 (s, 3 H, CH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 163.2 (C=O), 159.4 (C=O), 152.3 (C), 146.8 (C), 144.4 (C), 134.1 (C), 125.3 (CH), 124.4 (CH), 119.5 (C), 118.3 (CH), 117.7 (C), 52.8 (2 × CH₃), 45.2 (CH₂).

Anal. Calcd for C₁₄H₁₁N₃O₇: C, 50.46; H, 3.33; N, 12.61. Found: C, 50.41; H, 3.28; N, 12.72.

Acknowledgment

This publication was supported by the Ministry of Education and Science of the Russian Federation (Agreement No. 02.a03.21.0008) and by the Grant Council of the President of the Russian Federation (State Program for support of young Russian scientists, grant MD-5833.2016.3).

• References

• 1 Hu J, Wang Y, Wei X, Wu X, Chen G, Cao G, Shen X, Zhang X, Tang Q, Liang G, Li X. Eur. J. Med. Chem. 2013; 64: 292
• 2 Catarzi D, Cecchi L, Colotta V, Filacchioni G, Varano F, Martini C, Giusti L, Lucacchini A. J. Med. Chem. 1995; 38: 2196
• 3 Gijsen HJ, Mercken M. Int. J. Alzheimers Dis. 2012; 295207
• 4 Yu W, Goddard C, Clearfield E, Mills C, Xiao T, Guo H, Morrey JD, Motter NE, Zhao K, Block TM, Cuconati A, Xu X. J. Med. Chem. 2011; 54: 5660
• 5a Deng X.-Q, Quan L.-N, Song M.-X, Wie C.-X, Quan Z.-S. Eur. J. Med. Chem. 2011; 46: 2955
• 5b Guan L.-P, Quan Z.-S. Mini-Rev. Med. Chem. 2016; 16: 323
• 6 Liu K.-C, Hu M.-K. Arch. Pharm. (Weinheim) 1986; 319: 188
• 7a Patterson S, Wyllie S, Norval S, Stojanovski L, Simeons FR. C, Auer JL, Osuna-Cabello M, Read KD, Fairlamb AH. eLife 2016; 5: e09744
• 7b Thompson AM, O’Connor PD, Blaser A, Yardley V, Maes L, Gupta S, Launay D, Martin D, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA. J. Med. Chem. 2016; 59: 2530
• 7c Palmer BD, Sutherland HS, Blaser A, Kmentova I, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA, Thompson AM. J. Med. Chem. 2015; 58: 3036
• 8 Noolvi MN, Patel HM, Kamboj S, Kaur A, Mann V. Eur. J. Med. Chem. 2012; 56: 56
• 9 Patel HM, Noolvi MN, Goyal A, Thippeswamy BC. Eur. J. Med. Chem. 2013; 65: 119
• 10 Thomson AM, Blaser A, Anderson RF, Shinde SS, Franzblau SG, Ma Z, Denny WA, Palmer BD. J. Med. Chem. 2009; 52: 637
• 11a Ranatunge RR, Garvey DS, Janero DR, Letts LG, Martino AM, Murty MG, Richardson SK, Young DV, Zemetseva IS. Bioorg. Med. Chem. 2004; 12: 1357
• 11b Asano T, Yamazaki H, Kasahara C, Kubota H, Kontani T, Harayama Y, Ohno K, Mizuhara H, Yokomoto M, Misumi K, Kinoshita T, Ohta M, Takeuchi M. J. Med. Chem. 2012; 55: 7772
• 12 Liu J.-J, Zhao M.-Y, Zhang X, Zhao X, Zhu H.-L. Mini-Rev. Med. Chem. 2013; 13: 1957
• 13a Cabrele C, Reiser O. J. Org. Chem. 2016; 81: 10109
• 13b Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi O. Org. Biomol. Chem. 2016; 14: 6611
• 14a Tietze LF, Brasche G, Gericke K. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2006
• 14b Ho T.-L. Tandem Organic Reactions . Wiley; New York: 1992
• 14c Nicolaou KC, Edmonds DJ, Bulger PG. Angew. Chem. Int. Ed. 2006; 45: 7134
• 15a Balasubramanian K, Selvaraj S. Synthesis 1977; 767
• 15b Arct J, Jakubska E, Olszewska G. Synthesis 1977; 314
• 15c Arct J, Jakubska E, Olszewska G. Synth. Commun. 1978; 8: 143
• 15d Samarakoon TB, Hur MY, Kurtz RD, Hanson PR. Org. Lett. 2010; 12: 2182
• 15e Osyanin VA, Nakushnov VYu, Osipov DV, Klimochkin YuN. Chem. Heterocycl. Compd. 2010; 46: 1027
• 15f Osyanin VA, Osipov DV, Klimochkin YuN. Chem. Heterocycl. Compd. 2010; 46: 377
• 15g Osyanin VA, Nakushnov VYu, Klimochkin YuN. Chem. Heterocycl. Compd. 2011; 47: 755
• 15h Osyanin VA, Klimochkin YuN. Chem. Heterocycl. Compd. 2009; 45: 833
• 15i Sidorina NE, Osyanin VA. Chem. Heterocycl. Compd. 2005; 41: 1201
• 15j Sidorina NE, Osyanin VA. Chem. Heterocycl. Compd. 2007; 43: 1065
• 16a Wang P, Song Y, Zhang L, He H, Zhou X. Curr. Med. Chem. 2005; 12: 2893
• 16b Freccero M. Mini-Rev. Org. Chem. 2004; 1: 403
• 16c Rokita SE. Reversible Alkylation of DNA by Quinone Methides. In Quinone Methides. Rokita SE. Wiley; Hoboken: 2009
• 17a Osyanin VA, Osipov DV, Demidov MR, Klimochkin YuN. J. Org. Chem. 2014; 79: 1192
• 17b Osyanin VA, Lukashenko AV, Osipov DV, Klimochkin YuN. Chem. Heterocycl. Compd. 2015; 50: 1528
• 17c Lukashenko AV, Osyanin VA, Osipov DV, Klimochkin YuN. Chem. Heterocycl. Compd. 2016; 52: 711
• 17d Osyanin VA, Ivleva EA, Klimochkin YuN. Synth. Commun. 2012; 42: 1832
• 17e Osyanin VA, Osipov DV, Klimochkin YuN. Tetrahedron 2012; 68: 5612
• 17f Osipov DV, Osyanin VA, Klimochkin YuN. Russ. J. Org. Chem. 2013; 49: 398
• 18 Babaev EV. Chem. Heterocycl. Compd. 1993; 29: 796
• 19a Osyanin VA, Popova YuV, Klimochkin YuN. Russ. J. Org. Chem. 2011; 47: 958
• 19b Osyanin VA, Popova YuV, Klimochkin YuN. Russ. J. Org. Chem. 2010; 46: 302
• 20a Ball C, Dean DK, Lorthioir O, Page LW, Smith CL, Watson SP. Tetrahedron Lett. 2010; 51: 3907
• 20b Bulger PG, Cottrell IF, Cowden CJ, Davies AJ, Dolling U.-H. Tetrahedron Lett. 2000; 41: 1297
• 21a Díaz-Ortiz A, Prieto P, de Cózar A, Cebrián C, Moreno A, de la Hoz A. Aust. J. Chem. 2009; 62: 1600
• 21b Wille S, Hein M, Miethchen R. Tetrahedron 2007; 62: 3301
• 22a Tally JJ, Evans IA. J. Org. Chem. 1984; 49: 5267
• 22b Liang D, Wang M, Bekturhun B, Xiong B, Liu Q. Adv. Synth. Catal. 2010; 352: 1593
• 22c Choi YL, Lim HS, Lim HJ, Heo J.-N. Org. Lett. 2012; 14: 5102
• 22d Belostotskaya IS, Vol’eva VB, Komissarova NL, Dekaprilevich MO, Khrustalev VN, Karmilov AYu, Ershov VV. Russ. Chem. Bull. 1997; 46: 1272
• 22e Fanghänel E, Böckelmann J, Grossman N, Pfeifer D. J. Prakt. Chem. 1986; 328: 724
• 22f Caldwell WT, Thompson TR. J. Am. Chem. Soc. 1939; 61: 765
• 22g Hampton PD, Bencze Z, Tong W, Daitch CE. J. Org. Chem. 1994; 59: 4838