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

: Synthetic access to a five (hetero)arene ring-fused 3-phenyl[1,2,4]triazines is described. The resulting compounds were characterized via 1 H and 13 C 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


Introduction
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.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few investigations of their (hetero)arene ring-fused derivatives [10][11][12][13][14], and existing reports are mostly outdated.There has been no systematic investigation of the synthetic access and study of their electronic properties.Thus, analytical data, XRD structures and UV-vis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.[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], antiinflammatory [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few investigations of their (hetero)arene ring-fused derivatives [10][11][12][13][14], and existing reports are mostly outdated.There has been no systematic investigation of the synthetic access and study of their electronic properties.Thus, analytical data, XRD structures and UV-vis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.

Introduction
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.
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 1 H NMR technique.The analysis of 1 H 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 Scheme 2. Synthesis of triazines 1c-e.Reagents and conditions: (i) MeOH, rt, 30 min, 86% yield (1c), 73% yield (1d), 43% yield (1e).
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 1 H and 13 C 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 P2 1 /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.
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 1 H and 13 C 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 1 H NMR technique.The analysis of 1 H 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 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 1 H NMR technique.The analysis of 1 H 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.
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.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 CH 2 Cl 2 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.
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.

General Information
Commercially available reagents and solvents were used as obtained.NMR spectra were obtained at 600 MHz ( 1 H), 151 MHz ( 13 C) in CDCl 3 and referenced to the solvent (δ = 7.26 ppm for 1 H and δ = 77.16ppm for 13 C) or in DMSO-d 6 and referenced to the solvent (δ = 2.50 ppm for 1 H and δ = 39.52 ppm for 13 C).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 CH 2 Cl 2 .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 Al 2 O 3 F254 neutral).For chromatographic separation, silica gel 60 (70−230 µm) was used in column chromatography.

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 NaHCO 3 was added in portions until complete neutralization of AcOH.The organic layer was separated, dried (Na 2 SO 4 ), and the solvent was removed, leaving a brown-red solid.The residue was dissolved in a CH 2 Cl 2 /MeOH mixture (1:1, 10 mL) and solid NaIO 4 (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 CH 2 Cl 2 , and the filtrate was evaporated.The resulting residue was passed through a SiO 2 plug (20% CH 2 Cl 2 /pet.ether), the solvent was evaporated, and product 1 was recrystallized (EtOH).

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 Et 2 O (100 mL).Colorless crystals were collected and washed with Et 2 O (2 × 30 mL).Saturated aqueous NaHCO 3 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 Na 2 SO 4 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 Et 2 O (50 mL) and cooled in ice.Crystals of benzamidrazone 7 formed, were filtered off, dried in vacuo, and immediately used in the next step.

Figure 4 .
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 .
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 .
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 5 . 1 H
Figure 5. 1 H 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 . 1 H
Figure 5. 1 H 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 .
Figure 5. 1 H NMR spectra of triazines 1a-1e with indications, in red, of changes in chemical shifts of ortho-protons of the C3 phenyl group.