Next Article in Journal
Methyl 6-Benzyl-3-Hydroxy-3,6-Dimethyl-1,2-Dioxane-4-Carboxylate
Previous Article in Journal
4-(Tris(4-methyl-1H-pyrazol-1-yl)methyl)aniline
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molbank
Volume 2024
Issue 2
10.3390/M1824
molbank-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Communication

(Hetero)Arene Ring-Fused [1,2,4]Triazines

by
Mahshid Teymouri
1,
Anna Pietrzak
2 and
Paulina Bartos
1,*
1
Faculty of Chemistry, University of Lodz, Tamka 12, 91-403 Łódź, Poland
2
Faculty of Chemistry, Lodz University of Technology, 90-924 Łódź, Poland
*
Author to whom correspondence should be addressed.
Molbank 2024, 2024(2), M1824; https://doi.org/10.3390/M1824
Submission received: 26 April 2024 / Revised: 9 May 2024 / Accepted: 14 May 2024 / Published: 20 May 2024
(This article belongs to the Section Organic Synthesis and Biosynthesis)
Browse Figures
Versions Notes

Abstract

:
Synthetic access to a five (hetero)arene ring-fused 3-phenyl[1,2,4]triazines is described. The resulting compounds were characterized via 1H and 13C NMR, IR, UV–vis spectroscopy and HRMS. The structure of 3-phenyl[1,2,4]triazino[5,6-c]quinoline was unambiguously confirmed by single crystal XRD.

1. Introduction

[1,2,4]Triazine and its derivatives represent an important class of nitrogen heterocycles that exhibit many biological activities, e.g., antitumor [1,2], antibacterial [3,4], anti-inflammatory [5] and antiviral activities [3,6] (Figure 1). Moreover, [1,2,4]triazines are also often used in materials chemistry for a wide range of organic optoelectronic applications, such as strong electron acceptor units for n-type semiconductors [7,8] or dye-sensitized solar cells [9].
In spite of the broad application of [1,2,4]triazine derivatives, there are surprisingly few investigations of their (hetero)arene ring-fused derivatives [10,11,12,13,14], and existing reports are mostly outdated. There has been no systematic investigation of the synthetic access and study of their electronic properties. Thus, analytical data, XRD structures and UV–vis spectroscopic data are often limited.
In this work we present synthetic access to a group of five [1,2,4]triazines 1a–1e with a fused (hetero)arene ring system at the e edge (Figure 2) and study the effect of ring fusion on their properties.

2. Results and Discussion

Analysis of the literature data indicates that there are several synthetic methods suitable for the construction of ring-fused [1,2,4]triazines, including reductive cyclization of nitrophenylhydrazides [11,14,15,16], reductive deoxygenation of triazine N-oxides [12], photochemical oxidation of dihydro[1,2,4]triazines [10], reaction of N-aminobezamidine hydrochlorides with aryl ortho-quinone [17,18], one-pot three-step reaction of N-tosyl hydrazones and aziridines [19] and reaction of cyclic triazole with hydrazones [20].
In this work, two methods were used to synthesize a series of (hetero)arene ring-fused [1,2,4]triazines 1 (Figure 3). Method A involved reductive cyclization of nitroarylhydrazides 2 [15,16] obtained from ortho-nitro hydroxyarenes 3 through aromatic nucleophilic substitution with benzhydrazide [21,22]. In Method B, appropriate ortho-quinones 4 reacted with benzamidrazone [23] to yield desired triazines 1.
The requisite 3-phenyl[1,2,4]triazines 1a and 1b were synthesized by the cyclization reaction of hydrazides 2 under reductive conditions, as shown in Scheme 1. Triazines 1a and 1b were obtained in 80–84% and 50–55% yields, respectively. Appropriate hydrazides 2 were prepared in an aromatic nucleophilic substitution of triflate 5a [24] or chlorides 6a–6b [25] with benzhydrazide in DMSO. The use of triflate 5a gave hydrazide 2a in a 90% yield, and the utilization of chloride 6a allowed to obtain hydrazide 2a in a 69% yield. In the case of the reaction of 4-chloro-3-nitroquinoline (6b) with benzhydrazide, the desired hydrazide 2b was formed in a 93% yield. Triflate 5a was synthesized by the reaction of 3a with triflic anhydride [26] in the presence of Et3N in CH2Cl2 in a 91% yield. Chlorides 6a and 6b were obtained from appropriate ortho-nitrohydroxyarenes 3 according to the literature procedures [27,28,29] in 72% and 75% yields, respectively.
3-Phenyl[1,2,4]triazines 1c–1e were obtained according to the literature procedure [30] from appropriate ortho-quinones 4c–4e and benzamidrazone 7 (Scheme 2). Benzamidrazone was prepared from benzonitrile and hydrazine hydrate [10]. Thus, the 3-phenylphenanthro[9,10-e][1,2,4]triazine (1c) was obtained in a 86% yield, and 3-phenylpyreno[9,10-e][1,2,4]triazine (1d) and 9-phenyl-3a,10b-dihydroacenaphtho[1,2-e][1,2,4]triazine (1e) were obtained in 73% and 43% yields, respectively. Attempted synthesis of triazines 1c–1e via an alternative procedure [17] involving three-component condensation of ortho-quinones, acid hydrazide and ammonium acetate in the presence of sodium bisulphate adsorbed on silica as a catalyst did not provide the expected products.
Among the final [1,2,4]triazines obtained, 1a–1c and 1e are known in the literature, while triazine 1d is a new compound. The yields of the obtained products were much higher than those previously reported in the literature [10,12,17,20,23], with the exception of 1e, which was obtained with a slightly lower yield than in the patent report [18]. All compounds obtained were fully characterized using 1H and 13C NMR, IR, UV–vis spectroscopy and HRMS techniques.
The molecular structure of 1b was confirmed with the single-crystal X-ray diffraction analysis of an orange needle-shaped monoclinic crystal characterized by a P21/n space group. The asymmetric unit contained one molecule of 1b adopting a nearly planar conformation. The phenyl ring was twisted relative to the core plane by 3.3°. The dimensions of triazine fragment were similar to those found in 11-methyl-3-phenyl-11H-[1,2,4]-triazino[6,5-a]carbazole [31]. Results are shown in Figure 4, and full data are provided in the Supplementary Materials.
The nearly planar conformation of the [1,2,4]triazine phenyl ring at the C3 position made the ortho-protons sensitive to changes in the electronic structure of the triazine caused by ring fusion. This, in turn, facilitated recording the alteration in electronic properties using the 1H NMR technique. The analysis of 1H NMR spectra of 1 revealed that the values of chemical shifts of ortho-protons of the C3 phenyl group (indicated in red) increased upon ring expansion from naphthalene, through phenanthrene to the pyrene ring appended to 3-phenyl-1,2,4-triazine (Figure 5). The fusion of quinoline or acenaphthylene with [1,2,4]triazine has little effect on values of chemical shifts of ortho-protons.
To assess the effect of the fusion of (hetero)arene rings on electronic properties, triazines 1 were analyzed using UV–vis spectroscopy, and the results are shown in Figure 6. Data analysis revealed that triazines 1 in CH2Cl2 solutions exhibit typical strong absorption in the UV region and lower intensity absorption bands in the visible range up to 500 nm, related to n–π* transitions. Analysis of a series of triazines 1a–1e indicated that the size of the rings had some, albeit modest, effects on the electronic absorption energy of the molecules, and that ring expansion caused hypsochromic shift of the lowest energy absorption maxima.

3. Materials and Methods

3.1. General Information

Commercially available reagents and solvents were used as obtained. NMR spectra were obtained at 600 MHz (1H), 151 MHz (13C) in CDCl3 and referenced to the solvent (δ = 7.26 ppm for 1H and δ = 77.16 ppm for 13C) or in DMSO-d6 and referenced to the solvent (δ = 2.50 ppm for 1H and δ = 39.52 ppm for 13C). A Nexus FT-IR Thermo Nilolet IR spectrometer was used to record IR spectra (KBr tablets). A Jasco V770 spectrophotometer (Jasco, Oklahoma City, OK, USA) was used to detect UV spectra in CH2Cl2. Uncorrected melting points were established using a Stuart SMP30 Advanced Digital Melting Point Apparatus. High-resolution mass spectrometry (HRMS) measurements were carried out utilizing a Bruker SYNAPT G2-Si High-Definition Mass Spectrometer equipped with an ESI or APCI source and a quantitative time-of-flight (QuanTof) mass analyzer. An inert atmosphere (Ar gas) was used for reactions, while reaction workups were conducted in air. Oil baths were used to provide heat for processes that required high temperatures. Volatiles were evaporated under reduced pressure. The progress of reaction mixtures and column eluents were monitored by TLC using aluminum-backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F254 or, where stated, Merck Al2O3 F254 neutral). For chromatographic separation, silica gel 60 (70−230 μm) was used in column chromatography.

3.2. General Procedure for the Synthesis of Triazines 1a–1b—Method A

To the solution of compound 2 (1.73 mmol) in warm acetic acid (10 mL), tin powder (4.0 eq, 812 mg, 6.92 mmol) was added in one portion and the mixture was stirred at room temperature for 1 h and then for 30 min at 65 °C. After cooling, it was poured into water (100 mL), filtered through Cellite®, which was well washed with AcOEt, and the resulting yellow-orange filtrate was extracted with AcOEt (3×). Water (100 mL) was added to the combined extracts, and while stirring, solid NaHCO3 was added in portions until complete neutralization of AcOH. The organic layer was separated, dried (Na2SO4), and the solvent was removed, leaving a brown-red solid. The residue was dissolved in a CH2Cl2/MeOH mixture (1:1, 10 mL) and solid NaIO4 (1.4 eq, 2.4 mmol, 510.0 mg) was added in one portion. The mixture was stirred for 30 min, filtered, the solid was washed with CH2Cl2, and the filtrate was evaporated. The resulting residue was passed through a SiO2 plug (20% CH2Cl2/pet. ether), the solvent was evaporated, and product 1 was recrystallized (EtOH).
  • 3-Phenylnaphtho[2,1-e][1,2,4]triazine (1a). 360–378 mg (80–84% yield) as a yellow solid: mp 135–140 °C; 1H NMR (600 MHz, CDCl3) δ 9.50 (d, J = 8.1 Hz, 1H), 8.77 (dt, J1 = 8.4 Hz, J2 = 2.3 Hz, 2H), 8.19 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.89–7.83 (m, 2H), 7.83–7.78 (m, 1H), 7.65–7.51 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.4, 144.9, 143.1, 138.3, 135.7, 132.8, 131.5, 130.2, 129.4, 129.4, 129.0, 128.6, 125.8, 124.0; IR (KBr) ν 1599, 1518, 1434, 1384, 1276, 1219, 1160, 1048, 927, 849, 738, 689, 544 cm−1; UV (CH2Cl2) λmax (log ε) 295 (4.65), 358 (3.68), 373 (3.69), 388 (3.62 sh), 466 (2.41) nm; HRMS (ESI) [M + H]+ m/z calcd for C17H12N3: 258.1031; found: 258.1029. Anal. Calcd for C17H11N3: C, 79.36; H, 4.31; N, 16.33. Found: C, 79.15; H, 4.27; N, 16.44.
  • 3-Phenyl-[1,2,4]triazino[5,6-c]quinoline (1b). 227–248 mg (50–55% yield) as orange needles: mp 204–205 °C; 1H NMR (600 MHz, CDCl3) δ 9.56 (s, 1H), 9.36 (dd, J1 = 8.0 Hz, J2 = 1.3 Hz, 1H), 8.74 (dd, J1 = 6.7 Hz, J2 =3.0 Hz, 2H), 8.26 (d, J = 8.1 Hz, 1H), 7.97–7.93 (m, 1H), 7.92–7.87 (m, 1H), 7.63–7.53 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 162.7, 154.8, 145.8, 144.6, 134.8, 134.6, 132.2, 132.0, 130.3, 129.9, 129.2, 128.7, 123.2, 121.7; IR (KBr) ν 1607, 1509, 1419, 1376, 1271, 1120, 1004, 931, 853, 766, 688, 563 cm−1; UV (CH2Cl2) λmax (log ε) 296 (4.72), 360 (3.83), 378 (3.88), 432 (2.60) nm; HRMS (ESI) [M + H]+ m/z calcd for C16H11N4: 259.0984; found: 259.0988. Anal. Calcd for C16H10N4: C, 74.40; H, 3.90; N, 21.69. Found: C, 74.53; H, 3.92; N, 21.80.

3.3. General Procedure for Synthesis of Triazines 1c–1e—Method B

Into the ice-cooled solution of stirred benzonitrile (100 mmol, 10.3 g) in dry MeOH (5.0 mL), dry gaseous HCl was bubbled until the substrate was finished. The mixture was refrigerated overnight and then poured into Et2O (100 mL). Colorless crystals were collected and washed with Et2O (2 × 30 mL). Saturated aqueous NaHCO3 was added to the solution of obtained crystals in DCM (20 mL) until neutralization. The organic layer was separated and the aqueous phase was extracted with DCM (50 mL). The combined organic phases were dried over Na2SO4 and evaporated to dryness.
To an ice-cooled stirred solution of the product from the previous step (3.1 g, 22.8 mmol) in iPrOH (30 mL) hydrazine hydrate (1.0 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred for 1 h under gradual warming up to room temperature, and then at room temperature overnight. After the evaporation of volatiles, the residue was treated with Et2O (50 mL) and cooled in ice. Crystals of benzamidrazone 7 formed, were filtered off, dried in vacuo, and immediately used in the next step.
A suspension of an appropriate ortho-quinone 4 (1 mmol) in dry methanol (5 mL) was added to a solution of benzamidrazone 7 (1.5 mmol) in dry methanol under an argon atmosphere and stirred at room temperature. After 30 min, the precipitate was filtered off, washed with methanol, and recrystallized (EtOH) to give the pure product 1.
  • 3-Phenylphenanthro[9,10-e][1,2,4]triazine (1c). 266 mg (86% yield) as a yellow powder: mp 175–180 °C; 1H NMR (600 MHz, CDCl3) δ 9.41 (d, J = 7.8 Hz, 1H), 9.29 (d, J = 7.9 Hz, 1H), 8.87–8.79 (m, 2H), 8.48 (d, J = 8.0 Hz, 2H), 7.85–7.73 (m, 3H), 7.70 (t, J = 7.5 Hz, 1H), 7.66–7.57 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.3, 144.8, 143.0, 135.8, 133.9, 132.4, 131.5, 131.0, 130.7, 129.0, 128.7, 128.5, 128.2, 128.1, 127.7, 126.6, 124.9, 123.1, 123.1; IR (KBr) ν 1607, 1508, 1448, 1408, 1369, 1279, 1167, 1080, 960, 870, 758, 690, 541, 431 cm−1; UV (CH2Cl2) λmax (log ε) 261 (4.72), 289 (4.45), 303 (4.43), 316 (4.30 sh), 431 (2.70) nm; HRMS (ESI) [M + H]+ m/z calcd for C21H14N3: 308.1188; found: 308.1191. Anal. Calcd for C21H13N3: C, 82.06; H, 4.26; N, 13.67. Found: C, 82.16; H, 4.26; N, 13.49.
  • 3-Phenylpyreno[9,10-e][1,2,4]triazine (1d). 242 mg (73% yield) as a yellow solid: mp 246–247 °C; 1H NMR (600 MHz, CDCl3) δ 9.58 (dd, J1 = 7.6 Hz, J2 = 0.9 Hz, 1H), 9.48 (dd, J1 = 7.6 Hz, J2 = 0.9 Hz, 1H), 8.89 (dt, J1 = 8.4 Hz, J2 = 2.1 Hz, 2H), 8.28 (dd, J1 = 19.3 Hz, J2 = 7.6 Hz, 2H), 8.10 (t, J = 7.7 Hz, 1H), 8.04 (t, J = 7.6 Hz, 1H), 7.98 (q, J = 8.9 Hz, 2H), 7.70–7.58 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.6, 145.7, 144.0, 135.8, 131.6, 131.4, 131.3, 131.1, 129.4, 129.1, 128.6, 127.7, 127.5, 127.3, 127.3, 127.2, 126.9, 126.8, 125.2, 124.6, 122.6; IR (KBr) ν 3049, 1625, 1492, 1444, 1364, 1294, 1228, 1175, 1053, 928, 831, 769, 697 cm−1; UV (CH2Cl2) λmax (log ε) 240 (4.81), 287 (4.62), 333 (4.37), 348 (4.38), 407 (3.77), 428 (3.75) nm; HRMS (ESI) [M + H]+ m/z calcd for C23H14N3: 332.1188; found: 332.1186. Anal. Calcd for C23H13N3: C, 82.86; H, 4.54; N, 12.60. Found: C, 82.82; H, 4.27; N, 12.85.
  • 9-Phenylacenaphtho[1,2-e][1,2,4]triazine (1e). 121 mg (43% yield) as a yellow solid; 1H NMR (600 MHz, CDCl3) δ 8.74–8.68 (m, 2H), 8.53–8.47 (m, 2H), 8.22 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.86 (dt, J = 8.2, 7.2 Hz, 2H), 7.62–7.54 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.5, 157.7, 155.1, 136.0, 134.3, 132.3, 131.4, 130.2, 130.1, 130.0, 129.5, 129.1, 128.9, 128.8, 128.5, 125.2, 123.6; IR (KBr) ν 1617, 1565, 1528, 1479, 1382, 1353, 1207, 1159, 1110, 1028, 831, 775, 705; UV (CH2Cl2) λmax (log ε) 318 (4.66), 347 (4.08 sh), 451 (1.47) nm; HRMS (ESI) [M + H]+ m/z calcd for C19H12N3: 282.1031; found: 282.1033. Anal. Calcd for C19H11N3: C, 81.12; H, 3.94; N, 14.94. Found: C, 81.07; H, 3.89; N, 14.93.

3.4. General Procedure for the Synthesis of Hydrazides 2

  • N′-(2-Nitronaphthalen-1-yl)benzohydrazide (2a). A mixture of compound 5 or 6 (2.0 mmol) and benzhydrazide (1 eq, 2.0 mmol) in DMSO (8 mL) was stirred at 65 °C under an argon atmosphere overnight. The mixture was cooled and poured into water (50 mL). The resulting yellow solid was filtered, washed with water, and dried. The crude product was purified by silica column chromatography (50% DCM/pet. ether) and recrystallized (EtOH) to give 553 mg (90% yield) of 2a from 5a, and 424 mg (69% yield) of 2a from 6a. Yellow solid: mp 195–200 °C; 1H NMR (600 MHz, DMSO–d6) δ 11.03 (s, 1H), 9.32 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 9.1 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (151 MHz, DMSO-d6) δ 166.7, 142.8, 135.8, 134.7, 132.0, 131.9, 129.5, 128.5, 127.3, 126.5, 125.8, 125.0, 121.4, 120.6; IR (KBr) ν 3260, 1648, 1578, 1515, 1457, 1393, 1303, 1211, 1140, 1092, 1025, 903, 812, 761, 689 cm−1; HRMS (ESI) [M − H]− m/z calcd for C17H12N3O3: 306.0879; found: 306.0884. Anal. Calcd for C17H13N3O3: C, 66.44; H, 4.26; N, 13.67. Found: C, 66.30; H, 4.42; N, 13.52.
  • N’-(3-Nitroquinolin-4-yl)benzohydrazide (2b). 573 mg (93% yield) of 2b from 6b. Yellow solid: mp 228–229 °C; 1H NMR (600 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.86 (s, 1H), 8.06–7.97 (m, 2H), 7.84 (d, J = 7.6 Hz, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (151 MHz, DMSO-d6) δ 168.0, 166.2, 142.4, 138.4, 133.5, 133.1, 131.0, 130.5, 129.0, 128.9, 128.2, 127.9, 127.7, 126.1, 119.7; IR (KBr) ν 3100, 3007, 2944, 2796, 1987, 1687, 1595, 1526, 1348, 1265, 1077, 1023, 880, 840, 754, 690, 608, 532, 445 cm−1; HRMS (ESI) [M + H]+ m/z calcd for C16H13N4O3: 309.0988; found: 309.0991. Anal. Calcd for (C16H12N4O3)2H2O: C, 60.57; H, 4.13; N, 17.66. Found: C, 56.69; H, 3.88; N, 16.60.

Supplementary Materials

The following data are available online: additional synthetic details, 1H-NMR, 13C-NMR (Figures S1–S7), crystal data and refinement parameters for 1b (Table S1, Figure S8), UV–Vis spectra (Figures S9–S13) and references [26,27,28,32,33,34,35,36].

Author Contributions

Conceptualization, P.B.; methodology and analysis, M.T., A.P. and P.B.; writing—original draft preparation, P.B.; writing—review and editing, M.T., A.P. and P.B. All authors have read and agreed to the published version of this manuscript.

Funding

This work was financially supported by the National Science Centre Poland (2017/25/B/ST5/02851).

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

Piotr Kaszyński is gratefully acknowledged for his advice, scientific discussions, and consultations pertaining to the concerned work.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Yurttaş, L.; Demirayak, Ş.; Ilgin, S.; Atli, Ö. In Vitro Antitumor Activity Evaluation of Some 1,2,4-Triazine Derivatives Bearing Piperazine Amide Moiety against Breast Cancer Cells. Bioorganic Med. Chem. 2014, 22, 6313–6323. [Google Scholar] [CrossRef] [PubMed]
  2. Cascioferro, S.; Parrino, B.; Spanò, V.; Carbone, A.; Montalbano, A.; Barraja, P.; Diana, P.; Cirrincione, G. An Overview on the Recent Developments of 1,2,4-Triazine Derivatives as Anticancer Compounds. Eur. J. Med. Chem. 2017, 142, 328–375. [Google Scholar] [PubMed]
  3. Sztanke, K.; Pasternak, K.; Rajtar, B.; Sztanke, M.; Majek, M.; Polz-Dacewicz, M. Identification of Antibacterial and Antiviral Activities of Novel Fused 1,2,4-Triazine Esters. Bioorganic Med. Chem. 2007, 15, 5480–5486. [Google Scholar] [CrossRef]
  4. Arshad, M.; Bhat, A.R.; Hoi, K.K.; Choi, I.; Athar, F. Synthesis, Characterization and Antibacterial Screening of Some Novel 1,2,4-Triazine Derivatives. Chin. Chem. Lett. 2017, 28, 1559–1565. [Google Scholar]
  5. Khoshneviszadeh, M.; Ghahremani, M.H.; Foroumadi, A.; Miri, R.; Firuzi, O.; Madadkar-Sobhani, A.; Edraki, N.; Parsa, M.; Shafiee, A. Design, Synthesis and Biological Evaluation of Novel Anti-Cytokine 1,2,4-Triazine Derivatives. Bioorganic Med. Chem. 2013, 21, 6708–6717. [Google Scholar] [CrossRef] [PubMed]
  6. Rusinov, V.L.; Egorov, I.N.; Chupakhin, O.N.; Belanov, E.F.; Bormotov, N.I.; Serova, O.A. The Search for New Drugs: Synthesis and Antiviral Activity of 1,2,4-Triazine Derivatives. Pharm. Chem. J. 2012, 45, 655–659. [Google Scholar] [CrossRef]
  7. Branowska, D.; Olender, E.; Wysocki, W.; Karczmarzyk, Z.; Bancerz, I.; Ledwon, P.; Lapkowski, M.; Mirosław, B.; Urbańczyk-Lipkowska, Z.; Kalicki, P. Synthesis and Electrochemical Characterization of Oligothiophenes with 1,2,4-Triazine and 5,5′-Bi-1,2,4-Triazine as Strong Electron Acceptor Units. Electrochim. Acta 2016, 214, 19–30. [Google Scholar] [CrossRef]
  8. Maggiore, A.; Tan, X.; Brosseau, A.; Danos, A.; Miomandre, F.; Monkman, A.P.; Audebert, P.; Clavier, G. Novel D-A Chromophores with Condensed 1,2,4-Triazine System Simultaneously Display Thermally Activated Delayed Fluorescence and Crystallization-Induced Phosphorescence. Phys. Chem. Chem. Phys. 2022, 24, 17770–17781. [Google Scholar] [PubMed]
  9. Sakr, M.A.; Kana, M.T.A. 1,2,4-Triazine-Based Materials: Spectroscopic Investigation, DFT, NBO, and TD-DFT Calculations as Well As Dye-Sensitized Solar Cells Applications. J. Fluoresc. 2022, 32, 2053–2063. [Google Scholar] [CrossRef]
  10. Nagy, J.; Nyitrai, J.; Kolonits, P.; Lempert, K.; Gergely, A.; Párkányi, L.; Kálmán, A. Photochemistry of N-Heterocycles. Part 1. Synthesis and Photochemistry of Some 2,5-Dihydro-1,2,4-Triazines. X-ray Molecular Structure of 1-(4-Methyl-3,5,6-Triphenyl-1,4,5,6-Tetrahydro-1,2,4-Triazin-6-Yl)Ethanol. J. Chem. Soc. Perkin Trans. 1988, 12, 3267–3274. [Google Scholar] [CrossRef]
  11. Wright, G.C.; Gray, J.E.; Yu, C.N. Synthesis and Antifungal Properties of 3-Substituted Os-Triazino[5,6-c]Quinolines. J. Med. Chem. 1974, 17, 244–246. [Google Scholar] [CrossRef]
  12. Bennett, G.B.; Mason, R.B.; Alden, L.J.; Roach, J.B. Synthesis and Antiinflammatory Activity of Trisubstituted Pyrimidines and Triazines. J. Med. Chem. 1978, 486, 623–628. [Google Scholar] [CrossRef] [PubMed]
  13. Hajpal, I.; Berenyi, E. Synthesis of As-Triazono[5,6-b]Quinoline, a New Heterocyclic Ring System. J. Heterocycl. Chem. 1982, 19, 313–315. [Google Scholar] [CrossRef]
  14. Berényi, E.; Benkó, P.; Pallos, L. Synthesis of As-Triazno[5,6-c]Quinolines and Its Derivatives. Acta Chim. Acad. Sci. Hung. 1976, 90, 399–404. [Google Scholar]
  15. Berezin, A.A.; Zissimou, G.; Constantinides, C.P.; Beldjoudi, Y.; Rawson, J.M.; Koutentis, P.A. Route to Benzo- and Pyrido-Fused 1,2,4-Triazinyl Radicals via N′-(Het)Aryl-N′-[2-Nitro(Het)Aryl]Hydrazides. J. Org. Chem. 2014, 79, 314–327. [Google Scholar] [CrossRef]
  16. Azizian, J.; Krimi, A.R. Synthesis of Trisubstituted 1,2,4-Triazines in Presence of NaHSO4/SiO2. Asian J. Chem. 2011, 23, 980–982. [Google Scholar]
  17. Linsong, C.; Xiangdong, Z.; Yexin, Z.; Hua, C. Polycyclic Aromatic Hydrocarbon Aza-Naphthalene Derivative, Synthesis Method and Electronic Device Thereof. CN111548350A, 16 April 2020. [Google Scholar]
  18. Crespin, L.; Biancalana, L.; Morack, T.; Blakemore, D.C.; Ley, S.V. One-Pot Acid-Catalyzed Ring-Opening/Cyclization/Oxidation of Aziridines with N-Tosylhydrazones: Access to 1,2,4-Triazines. Org. Lett. 2017, 19, 1084–1087. [Google Scholar] [CrossRef]
  19. Meng, J.; Wen, M.; Zhang, S.; Pan, P.; Yu, X.; Deng, W.P. Unexpected O-H Insertion of Rhodium-Azavinylcarbenes with N-Acylhydrazones: Divergent Synthesis of 3,6-Disubstituted- and 3,5,6-Trisubstituted-1,2,4-Triazines. J. Org. Chem. 2017, 82, 1676–1687. [Google Scholar] [CrossRef]
  20. Constantinides, C.P.; Obijalska, E.; Kaszyński, P. Access to 1,4-Dihydrobenzo[e][1,2,4]Triazin-4-Yl Derivatives. Org. Lett. 2016, 18, 916–919. [Google Scholar] [CrossRef]
  21. Abramovitch, R.A.; Schofield, K. Polyazabicyclic Compounds. Part I. Preliminary Experiments on the Bischler and the Bamberger Synthesis of Benzo-1:2:4-Triazines. J. Chem. Soc. 1955, 1955, 2326–2336. [Google Scholar] [CrossRef]
  22. Reich, M.F.; Fabio, P.F.; Lee, V.J.; Kuck, N.A.; Testa, R.T. Pyrido[3,4-e]-1,2,4-Triazines and Related Heterocycles as Potential Antifungal Agents. J. Med. Chem. 1989, 32, 2474–2485. [Google Scholar] [CrossRef]
  23. Fort, E.H.; Scott, L.T. Gas-Phase Diels-Alder Cycloaddition of Benzyne to an Aromatic Hydrocarbon Bay Region: Groundwork for the Selective Solvent-Free Growth of Armchair Carbon Nanotubes. Tetrahedron Lett. 2011, 52, 2051–2053. [Google Scholar] [CrossRef]
  24. Pomikło, D.; Pietrzak, A.; Kishi, R.; Kaszyński, P. Bi-Blatter Diradicals: Convenient Access to Regioisomers with Tunable Electronic and Magnetic Properties. Mater. Chem. Front. 2023, 7, 4928–4943. [Google Scholar] [CrossRef]
  25. Bodzioch, A.; Pomikło, D.; Celeda, M.; Pietrzak, A.; Kaszyński, P. 3-Substituted Benzo[e][1,2,4]Triazines: Synthesis and Electronic Effects of the C(3) Substituent. J. Org. Chem. 2019, 84, 6377–6394. [Google Scholar] [CrossRef]
  26. Liu, M.; Li, X.L.; Chen, D.C.; Xie, Z.; Cai, X.; Xie, G.; Liu, K.; Tang, J.; Su, S.J.; Cao, Y. Study of Configuration Differentia and Highly Efficient, Deep-Blue, Organic Light-Emitting Diodes Based on Novel Naphtho[1,2-d]Imidazole Derivatives. Adv. Funct. Mater. 2015, 25, 5190–5198. [Google Scholar] [CrossRef]
  27. Kokatla, H.P.; Yoo, E.; Salunke, D.B.; Sil, D.; Ng, C.F.; Balakrishna, R.; Malladi, S.S.; Fox, L.M.; David, S.A. Toll-like Receptor-8 Agonistic Activities in C2, C4, and C8 Modified Thiazolo[4,5-c]Quinolines. Org. Biomol. Chem. 2013, 11, 1179–1198. [Google Scholar] [CrossRef] [PubMed]
  28. Shukla, N.M.; Kimbrell, M.R.; Malladi, S.S.; David, S.A. Regioisomerism-Dependent TLR7 Agonism and Antagonism in an Imidazoquinoline. Bioorganic Med. Chem. Lett. 2009, 19, 2211–2214. [Google Scholar] [CrossRef]
  29. Van Galen, P.J.; Nissen, P.; van Wijngaarden, I.; Ijzerman, A.P.; Soudijn, W. 1H-Imidazo [4,5-c] Quinolin-4-Amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202–1206. [Google Scholar] [CrossRef] [PubMed]
  30. Al-Awadi, H.; Ibrahim, M.R.; Al-Awadi, N.A.; Ibrahim, Y.A. Gas-Phase Thermolysis of Condensed-1,2,4-Triazines: Interesting Routes toward Heterocyclic Ring Systems. Tetrahedron 2007, 63, 12948–12953. [Google Scholar] [CrossRef]
  31. Szamweber, P.; Pietrzak, A.; Zissimou, G.A.; Kaszyński, P. Toward N-Peri-Annulated Planar Blatter Radical through Aza-Pschorr and Photocyclization. J. Org. Chem. 2023, 88, 17197–17205. [Google Scholar] [CrossRef]
  32. Hodson, H.H.; Walke, J. The Diazotisation of Aromatic Nitro-Amines, Etc. 382. The Diamtisation of Aromatic Nitro-Amines and the Prevention. J. Am. Chem. Soc. 1933, 1620, 1620–1621. [Google Scholar] [CrossRef]
  33. Rigaku Oxford Diffraction. CrysAlis CCD, CrysAlis RED, CrysAlisPro; Version 1.171.40.84a; Rigaku Oxford Diffraction: Abingdon, UK, 2020. [Google Scholar]
  34. Sheldrick, G.M. SHELXT—Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr. Sect. A 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  35. Hübschle, C.B.; Sheldrick, G.M.; Dittrich, B. ShelXle: A Qt Graphical User Interface for SHELXL. J. Appl. Crystallogr. 2011, 44, 1281–1284. [Google Scholar] [CrossRef] [PubMed]
  36. Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71, 3–8. [Google Scholar] [CrossRef]
Molbank 2024 m1824 g001
Figure 1. Chemical structure of [1,2,4]triazine and properties of its derivatives.
Figure 1. Chemical structure of [1,2,4]triazine and properties of its derivatives.
Molbank 2024 m1824 g001
Molbank 2024 m1824 g002
Figure 2. Structure of π-extended [1,2,4]triazines 1a–1e.
Figure 2. Structure of π-extended [1,2,4]triazines 1a–1e.
Molbank 2024 m1824 g002
Molbank 2024 m1824 g003
Figure 3. Two synthetic strategies towards [1,2,4]triazines 1 applied herein.
Figure 3. Two synthetic strategies towards [1,2,4]triazines 1 applied herein.
Molbank 2024 m1824 g003
Molbank 2024 m1824 sch001
Scheme 1. Synthesis of triazines 1a–b. Reagents and conditions: (i) triflic anhydride, Et3N, DCM, 0 °C, 3 h, 91% yield; (ii) for obtaining 6a; (a) (NH4)2CO3, NH3aq, 120 °C, overnight, 82% yield; (b) NaNO2, H2SO4 aq, CuCl, HCl, 88% yield (6a); (iii) for obtaining 6b; POCl3, PCl5, 110 °C, overnight, 75% yield (6b); (iv) benzhydrazide, DMSO, 65 °C, overnight; 2a: 90% yield (from 5a), 69% yield (from 6a); 2b: 93% yield (from 6b); (v) (a) Sn, AcOH, 50 °C for 1 h and then 30 min at 65 °C, (b) NaIO4, DCM/MeOH (1:1), rt, 30 min, 80–84% yield (1a), 50–55% yield (1b).
Scheme 1. Synthesis of triazines 1a–b. Reagents and conditions: (i) triflic anhydride, Et3N, DCM, 0 °C, 3 h, 91% yield; (ii) for obtaining 6a; (a) (NH4)2CO3, NH3aq, 120 °C, overnight, 82% yield; (b) NaNO2, H2SO4 aq, CuCl, HCl, 88% yield (6a); (iii) for obtaining 6b; POCl3, PCl5, 110 °C, overnight, 75% yield (6b); (iv) benzhydrazide, DMSO, 65 °C, overnight; 2a: 90% yield (from 5a), 69% yield (from 6a); 2b: 93% yield (from 6b); (v) (a) Sn, AcOH, 50 °C for 1 h and then 30 min at 65 °C, (b) NaIO4, DCM/MeOH (1:1), rt, 30 min, 80–84% yield (1a), 50–55% yield (1b).
Molbank 2024 m1824 sch001
Molbank 2024 m1824 sch002
Scheme 2. Synthesis of triazines 1c–e. Reagents and conditions: (i) MeOH, rt, 30 min, 86% yield (1c), 73% yield (1d), 43% yield (1e).
Scheme 2. Synthesis of triazines 1c–e. Reagents and conditions: (i) MeOH, rt, 30 min, 86% yield (1c), 73% yield (1d), 43% yield (1e).
Molbank 2024 m1824 sch002
Molbank 2024 m1824 g004
Figure 4. Left: molecular structure of 1b. Atomic displacement parameters are drawn at 50% probability level. Right: partial crystal packing of 1b. Only the main component of disordered structure is shown for clarity.
Figure 4. Left: molecular structure of 1b. Atomic displacement parameters are drawn at 50% probability level. Right: partial crystal packing of 1b. Only the main component of disordered structure is shown for clarity.
Molbank 2024 m1824 g004
Molbank 2024 m1824 g005
Figure 5. 1H NMR spectra of triazines 1a–1e with indications, in red, of changes in chemical shifts of ortho-protons of the C3 phenyl group.
Figure 5. 1H NMR spectra of triazines 1a–1e with indications, in red, of changes in chemical shifts of ortho-protons of the C3 phenyl group.
Molbank 2024 m1824 g005
Molbank 2024 m1824 g006
Figure 6. Electronic absorption spectra of triazines 1a–1e recorded in CH2Cl2. a Lowest energy absorption bands.
Figure 6. Electronic absorption spectra of triazines 1a–1e recorded in CH2Cl2. a Lowest energy absorption bands.
Molbank 2024 m1824 g006
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Teymouri, M.; Pietrzak, A.; Bartos, P. (Hetero)Arene Ring-Fused [1,2,4]Triazines. Molbank 2024, 2024, M1824. https://doi.org/10.3390/M1824

AMA Style

Teymouri M, Pietrzak A, Bartos P. (Hetero)Arene Ring-Fused [1,2,4]Triazines. Molbank. 2024; 2024(2):M1824. https://doi.org/10.3390/M1824

Chicago/Turabian Style

Teymouri, Mahshid, Anna Pietrzak, and Paulina Bartos. 2024. "(Hetero)Arene Ring-Fused [1,2,4]Triazines" Molbank 2024, no. 2: M1824. https://doi.org/10.3390/M1824

APA Style

Teymouri, M., Pietrzak, A., & Bartos, P. (2024). (Hetero)Arene Ring-Fused [1,2,4]Triazines. Molbank, 2024(2), M1824. https://doi.org/10.3390/M1824

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop