Expedient synthesis of 1,2,4-triazinyl substituted benzo[ c ]coumarins via double oxidation strategy

Herein, we report a convenient one-pot synthesis of 1,2,4-triazinyl derivatives of benzocoumarins. The proposed approach consists of the nucleo-philic addition of tetrahydrobenzo annulated dimethoxycoumarin to 1,2,4-triazines followed by double oxidation of both dihydrotriazine and tetra-hydrobenzo groups with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The nucleophilic addition of the dimethoxycoumarin to 1,2,4-tria-zines was carried out in the presence of three-fold excess of methanesul-fonic acid in DCM at room temperature. It takes place between positions 8 and 5 of coumarin and 1,2,4-triazine, respectively. The double oxidation step was carried out with 3.6 equivalent of DDQ. Selective oxidation of dihy-drotriazine moiety, without affecting the tetrahydrobenzo fragment, was achieved using 1.2 equivalent of tetrachlorobenzoquinone (TCQ). The differences in the oxidation with TCQ and DDQ appear to be related to the higher oxidative potential of DDQ in contrast to TCQ. The advantages of the method are the elimination of the use of transition metals, the availability of starting materials, and the simplicity of the procedure. The proposed approach provides a two-step one-pot protocol for the synthesis of triazinyl benzocouma-rins, precursors for the preparation of push-pull pyridinyl chromophore.

nucleophilic substitution of hydrogen quinone oxidation push-pull chromophore
In the literature, the synthesis of azinyl-coumarin or benzocoumarin derivatives is reported by multistep reactions sequences, involving construction of azaheterocyclic ring (Scheme 1, a) [16] or pyrone core (Scheme 1, b) [17] from corresponding precursors or transition metal (TM)-catalyzed cross-coupling reactions between prefunctionalized precursors (Scheme 1, c) [14].Nucleophilic substitution of hydrogen (SN H ) [18] in nitrogen-containing heterocycles represents a powerful tool for the construction of a novel C-C bond, conforming to the requirements of "green" chemistry and PASE (pot, atom, step economy) approaches.The advantages of this approach are the avoidance of TM catalysts and the so-called "chlorine technologies", mild reaction conditions, which, in turn, leads to a decrease in the number of steps and an increase in the overall yield of the desired product.SN H reactions often proceed as the addition of a nucleophile to an electrophilic azine with the formation of a σ Н -adduct, which can subsequently be oxidized in the presence of an external oxidizing agent (air oxygen [19], 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) [20][21][22][23], K3[Fe(CN)6] [24-26], MnO2 [22,27]) to a product of nucleophilic substitution of hydrogen.
Earlier, we proposed a convenient synthetic approach to push-pull 8-pyridinylcoumarin chromophores (Scheme 1, d) by using a sequence of reactions of nucleophilic substitution of hydrogen and Boger pyridine synthesis in the series of 3,6-diaryl-substituted 1,2,4-triazines and 5,7-dimethoxycoumarins [20,28].Thus, at the first step, coumarin was added to the triazine core with the formation of a 1,4-dihydrotriazine derivative, which then easily underwent aromatization under the action of the external oxidant such as DDQ with the formation of SN H product in high yield, which then transformed to pyridine derivative with 2,5-norbornadiene.In order to study the scope and limitations of this SN H approach, we adopted synthetic protocol of the oxidative cross-coupling of 1,3-dimethoxy-7,8,9,10-tetrahydro-6H-benzo[c]coumarin 1 with 3,6-substituted triazines 2. In the present work, we report the double aromatization of both the dihydrotriazine and tetrahydrobenzene moieties (Scheme 1, e).This double aromatization strategy allowed us to extend the opportunities of SN H reactions in triazines providing stringboard access to 1,2,4-triazinyl substituted benzo[c]coumarins.

Experimental
1 H NMR (400 MHz) and 13 C NMR (101 MHz) spectra were recorded on a Bruker DRX-400 Avance spectrometer with DMSO-d6 or CDCl3 as a solvent at ambient temperature.Chemical shifts are reported in ppm and coupling constants are given in Hz.Data for 1 H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; m, multiplet; br s, broad signal), coupling constant (Hz), integration.High resolution mass spectra were recorded on an Agilent UHPLC/MS Accurate-Mass Q-TOF 1290/6545.Thin layer chromatography (TLC) was performed on silica gel coated glass slide (Merck, Silica gel G for TLC).Aluminium oxide 90 (70-230 mesh, Merck) was used for column chromatography.All solvents were dried and distilled before use.Commercially available substrates were freshly distilled before the reaction.Solvents, reagents and chemicals were purchased from Aldrich, Fluka, Merck, SRL, Spectrochem and Process Chemicals.All reactions involving moisture sensitive reactants were carried out using oven dried glassware.
After completion of the reaction, the reaction mixture was washed with a saturated Na2CO3 solution.The organic layer was separated, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure.The residue was recrystallized from benzene to give pure adduct 3a.White precipitate.Yield 449 mg (91%).

General method for synthesis of compounds 5
To a solution of coumarin 1 (260 mg, 1 mmol) and corresponding triazine 2a-i (1 mmol) in DCM (6 ml) was added MeSO3H (288 mg, 3 mmol).The resulting solution was left for 3 h.After completion of the reaction, the reaction mixture was washed with a saturated Na2CO3 solution.The organic layer was separated, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give adduct 3, which then was dissolved in DCE (10 ml).Then, DDQ (3.6 mmol, 817 mg) was added, and the mixture was refluxed for 6 h.The resulting mixture was purified using flash chromatography (Al2O3/ethyl acetate).The solvent was removed under reduced pressure, and the residue was recrystallized from butanol-1 to give pure 5.

Results and Discussion
We started our research with the reaction of dimethoxycoumarin 1 with 3,6-diphenyl-1,2,4-triazine 2a, which was carried out in the presence of three-fold excess of methanesulfonic acid (MsOH) in DCM at room temperature, yielding dihydrotriazine 3a in high yield (Scheme 2), in accordance with the previously described procedure [2o].Aromatization of the adduct 3a with 1.5 equivalent of DDQ (Table 1, entry 1) [20] provided a complex mixture of products.We hypothesized that, in contrast to our previous work [20,28], DDQ not only oxidizes 1,4-dihydrotriazine core to give expected product of the nucleophilic substitution of hydrogen 4a, but also aromatizes tetrahydrobenzene moiety yielding 5a and 6a, which is confirmed by the literature data [29,30].
In addition, we also demonstrated that using even fourfold excess of TCQ (Table 1, entry 4) instead of DDQ as the oxidizing agent in the same oxidation process led to aromatization of dihydrotriazine moiety with excellent chemoselectivity to give SN H product (Scheme 5).
After quick reoptimization of the reaction conditions, we found that the use of 1.2 eq.TCQ in DCE at 70 °C (Table 1, entry 5) could allow the formation of 4a in best yield.One can assume that the differences in the oxidation with TCQ and DDQ are related to the higher oxidative potential of DDQ in contrast to TCQ (0.51 vs. 0.01 volts [31]).
Scheme 2 Synthesis of adduct 3a.Scheme 3 Formation of the complex mixture of products during the oxidation of adduct 3a with 1.5 equivalents of DDQ.Air or oxygen bubbling through the reaction mixture did not produce desired products (Table 1, entries 6 and 7, respectively), and only the starting material was isolated from the reaction mixture.
Formation of compound 5a was proven by 1 H and 13 C NMR spectroscopy data.In particular, multipletes of protons of the methylene groups were not observed in the 3.5-1.5 ppm region.In addition, signals of sp 3 -hybridized carbons of the tetrahydrobenzene ring were also absent in the high field of 13 C NMR spectrum.
It is well known that 1,2,4-triazines are readily accessible and cheap building block for construction of pyridine derivatives, which are used as functional materials [33].At the same time, the annulation of an additional benzene cycle to the coumarin framework often improves the photophysical characteristics: it leads to a bathochromic shift of the absorption and emission maxima and can also increase the fluorescence quantum yield [34,35].Thus, the obtained products may be considered as precursors for pyridyl-coumarin conjugate chromophores.Further transformations and detailed photophysical studies are in progress and will be published later.

Conclusion
We proposed a new protocol of the synthesis of triazinylbenzo[c]coumarin derivatives by means of simultaneous oxidation dihydrotriazine and tetrahydrobenzene frameworks under the action of DDQ as an oxidant.In contrast to DDQ, oxidation in the presence of TCQ exclusively provided the SN H products.The obtained products could serve as precursors for push-pull pyridyl-coumarin conjugate chromophores for potential applications in material science.

• Supplementary materials
This manuscript contains supplementary materials, which are available on the corresponding online page.

Table 1
Optimization of the oxidation reaction conditions a .
dStarting material was isolated.