MnO₂-Mediated Oxidative Cyclization of “Formal” Schiff’s Bases: Easy Access to Diverse Naphthofuro-Annulated Triazines

Abstract

A different type of MnO₂-induced oxidative cyclization of dihydrotriazines has been developed. These dihydrotriazines are considered as a “formal” Schiff’s base. This method provided easy access to naphthofuro-fused triazine via the C-C/C-O oxidative coupling reaction. The reaction sequence comprised the nucleophilic addition of 2-naphthol or phenol to 1,2,4-triazine, followed by oxidative cyclization. The scope and limitations of this novel coupling reaction have been investigated. Further application of the synthesized compound has been demonstrated by synthesizing carbazole-substituted benzofuro-fused triazines. The scalability of the reaction was demonstrated at a 40 mmol load. The mechanistic study strongly suggests that this reaction proceeds through the formation of an O-coordinated manganese complex.

1. Introduction

In organic synthesis, C−H functionalization in the presence of transition metal catalysts has become one of the fundamental methods, and has had a massive impact on synthetic organic chemistry, medicinal chemistry, and material science [1,2,3,4,5,6,7,8]. In this context, cross dehydrogenative coupling (CDC) reactions have gained much interest in the last decade [9,10,11,12,13,14,15] among all types of C-H functionalization/activation reactions. This type of coupling reaction allows the construction of a C-C bond or C-X bond directly from C-H-containing substrates in the presence of an oxidant via the formal removal of a H₂ molecule. In addition, these methods avoid the prefunctionalization of starting materials, which makes the synthetic routes straightforward and more efficient. For CDC reactions, various transition metals such as Pd, Cu, Ag, Rh, and Ru have been extensively studied due to their high efficiency. However, the exploration of manganese catalysis in CDC reactions is in high demand due to its low price, ready availability, sustainability, nontoxicity, and environmentally friendly properties [16]. Simple manganese salts were sensibly employed in the CDC reaction due to their ability to undergo the reaction in a radical way.

Benzofuro-fused N-heterocycles are considered as common structural motifs in biologically active compounds, drug candidates and fluorescence materials (Figure 1). For example, benzofuro [2,3-b]pyridine, in particular Elbfluorene I, and its derivatives are important cyclin-dependent kinase inhibitors [17,18,19,20], the benzofuro [3,2-d]pyrimidine derivative Amuvatinib II is a multitarget tyrosine kinase inhibitor [21,22,23,24], and benzofuro[2,3-b]pyrazine III was designed as a deep-blue fluorescent emitter [25].

Considering the importance of this moiety, several methods have been developed for developing benzofuro-fused N-heterocycles such as pyridine, pyrimidine and pyrazine derivatives. The first synthetic approach comprises the annulation of the heterocyclic ring to a benzofuran core (Scheme 1a) [26,27,28,29,30,31,32,33,34]. Alternatively, other approaches include the intramolecular cyclization (C-C bond formation) of arylhetaryl ethers [35,36,37,38,39,40] (Scheme 1b) or the intramolecular cyclization (C-O bond formation) of 2-hetaryl-substituted phenol derivatives [41,42,43,44,45,46,47] (Scheme 1c), as well as the intermolecular tandem C-C/C-O cross-coupling reaction of prefunctionalized substrate [48,49,50] to form a furan ring fused between the benzene and mono/diazine ring. However, these approaches usually require multistep synthesis, harsh reaction conditions, and the use of transition metal catalysts or special reagents and conditions.

On the other hand, it is worth mentioning that information about the synthetic and applied data of benzofuro-fused triazines is lacking in the literature. To date, only a few studies have investigated the synthesis of benzofurotriazine derivatives. In 1988, Eid et al. reported the synthesis of naphthofuro[2,3-e][1,2,4]triazine in a 33% overall yield via the annulation of the triazine core to naphthofuran-1,2-dione [51]. The reaction was carried out in four steps. Later, Seitz and Richter reported that the intramolecular [4+2]-cycloaddition of 2-(tetrazinyloxy)benzonitrile led to the formation of benzofuro[3,2-e][1,2,4]triazine derivatives [52]. Neunhoeffer et al. synthesized benzofuro[2,3-e][1,2,4]triazine at 26% yield using the tandem S_N^H-S_N^ipso reaction of resorcinol and 1,2,4-triazine with a good leaving group [53]. Unfortunately, these methods represent the only examples of benzofurotriazine derivatives, and provide poor yields of the desired products. At the same time, 1,2,4-triazines represent readily accessible and cheap building blocks for the construction of pyridine [54,55,56,57,58,59,60,61,62], pyrimidine [63,64] or pyrazine [59,65,66] cores via the sequence of Diels-Alder/retro-Diels-Alder reactions.

In a continuation of our research on CDC reactions in triazines [54,67] and diazines [68], herein, we are pleased to report an unusual synthesis of benzofuro-fused 1,2,4-triazines via the sequence of C-C/C-O CDC reactions of 1,2,4-triazines with 2-naphthols or phenols (Scheme 1d). The reaction proceeded through the formation of 1,4-dihydrotriazine, followed by oxidative cyclization.

2. Results and Discussion

Based on retrosynthetic analysis of benzofurotriazine (Scheme 1d), we assume that 5,6-unsubstituted triazine and α-unsubstituted phenol are the best building blocks for the construction of the desired molecule through a sequence of C-C/C-O cross-coupling reactions. Earlier, our [67,69,70] and other [70,71] research groups demonstrated that 5,6-unsubstituted 1,2,4-triazines may be used in a two-step CDC reaction with various aromatic C-nucleophiles via the formation of 1,4-dihydrotriazine derivatives as intermediates, followed by aromatization to bi(het)aryl products. As mentioned above, the prefunctionalized azine is required for C-O cross-coupling reaction [53]. On the other hand, it is well known that the phenolic Schiff’s bases readily undergoes intramolecular oxidative cyclization in the presence of various oxidizing agents, in particular, hypervalent iodine compounds [72,73,74,75], lead(IV) acetate [76,77,78], or manganese salts such as Mn(OAc)₃^.2H₂O [78,79] and MnO₂ [80]. We hypothesized that 1,4-dihydrotriazines containing 2-hydroxyaryl moiety can be considered as a “formal” phenolic Schiff’s base (Scheme 2).

Based on this hypothesis, we have focused our attention on the oxidative cyclization of dihydrotriazines easily obtainable from triazine and naphthol. For example, the reaction of readily available 3-methylthio-1,2,4-triazine 1a and naphthol 2a yields dihydrotriazine 3aa (Scheme 3), which was used for the initial screening of the optimal conditions. Using standard oxidizing agent, such as phenyliodonine(III) diacetate, phenyliodonine(III) bis(trifluoroacetate) or Pb(OAc)₄, for the oxidative cyclization of the phenolic Schiff’s base, only a complex mixture was isolated from the reaction. Surprisingly, when using MnO₂ for the oxidation of the “formal” Schiff’s base 3aa, the desired oxidative coupling product naphthofurotriazine 4aa was formed in one step. At the same time, the side product 5aa was also observed in the reaction (Scheme 3). After comprehensive screening (Please see Supporting Information for details, Section S6), we found that the vigorous stirring (1500 rpm) of 3aa in CHCl₃ at 50 °C in the presence of 3 equiv. of γ-MnO₂ [81] provided the naphthofurotriazine 4aa in an almost quantitative yield after 3 h (

Table 1. Optimization of the reaction conditions ¹.

Entry	Conditions	4aa (%) b	5aa (%) b
1	Using 3 equiv. of γ-MnO2	>99	trace
2	HNO3@γ-MnO2 instead of γ-MnO2	75	trace
3	Mn(OAc)2.4H2O instead of γ-MnO2	-	-
4	MnCl2 instead of γ-MnO2	-	-
5	Mn(acac)2 instead of γ-MnO2	-	-
6	Mn(OAc)3.2H2O instead of γ-MnO2	29	5
7	Ag2O instead of γ-MnO2	60	-
8	DTBP instead of γ-MnO2	35	15
9	DDQ instead of γ-MnO2	39	43
10	p-Chloranil instead of γ-MnO2	-	89
11	HFIP instead of CHCl3	89	trace
12	EtOH instead of CHCl3	66	trace
13	DCE instead of CHCl3	85	trace
14	Benzene instead of CHCl3	90	trace
15	Performed at 60 °C	94	4
16	Performed at 25 °C	91	3
17	Using 2 equiv. of γ-MnO2	85	3
18	Using 5 equiv. of γ-MnO2	90	6

¹ Conditions: 3aa (0.2 mmol), solvent (4 mL), 3 h. ^{b 1}H NMR yield using 1,3,5-trimethoxybenzene as an internal standard.

, entry 1). Besides γ-MnO₂, other manganese salts such as Mn(OAc)₃^.2H₂O, Mn(OAc)₂.4H₂O and MnCl₂, Mn(acac)₂ were not so effective for this reaction, or provided 4aa in very poor yields (Table 1, entries 3-6), except MnO₂ impregnated with nitric acid [82], which afforded 4aa in a good yield (Table 1, entry 2). One may assume that Mn(OAc)₃ has low oxidative potential in organic media [83] compared to MnO₂. Other alternative oxidants such as Ag₂O, DTBP and DDQ led to low yields (Table 1, entries 7-9), and p-chloranil exclusively provided compound 5aa in a high yield (Table 1, entry 10). The use of other solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), EtOH, DCE or benzene clearly gave worse results (Table 1, entries 11-14). By increasing the temperature, the yield of 4aa was decreased (Table 1, entry 15). In contrast, lower conversion was observed at room temperature (Table 1, entry 16). Carrying out the reaction in the presence of a decreased amount of MnO₂ (Table 1, entry 17) had negative effects on the efficiency of the reaction. In contrast, using 5 equiv. of MnO₂ increased the yield of the side product 5aa (Table 1, entry 18). At the same time, all attempts were unsuccessful to cyclize 5aa to 4aa.

In order to study the applicability of the proposed oxidative coupling reaction, we synthesized a series of starting dihydrotriazines 3. It was observed that our earlier proposed method [54] of the nucleophilic addition of 5,7-dimethoxycoumarins to 1,2,4-triazines with some modifications allowed us to prepare a series of compounds 3 using a variety of 3-S-substituted 1,2,4-triazines 1 and 2-naphthols 2 (Scheme 4). In all cases, the reaction proceeded with high regioselectivity to give compounds 3 in good to high yields. When methoxy- or hydroxy-substituted 2-naphthols 2b-e were involved in the reaction with 1,2,4-triazine, the best yields were achieved in the presence of BF₃^.OEt₂ under refluxed conditions in methanol.

With the optimized reaction conditions and a set of dihydrotriazines 3 in hand, we then examined the applicability and scope of this MnO₂-induced oxidative cyclization reaction of dihydrotriazines 3. At first, the scope of the reaction was studied with respect to different S-substituents in the dihydrotriazine core, and the results are summarized in Scheme 5. The naphthofuro-fused triazine 4aa was isolated in a 95% yield under optimal reaction conditions after recrystallization from MeCN. Other 3-alkylthio-substituted triazine derivatives 3ba-3da and 3fa also underwent oxidative cyclization, producing only the desired cyclic product 4 in good to high yields. Moreover, 3-(but-2-yn-1-yl)- and 3-allylthio derivatives 3ea and 3ga smoothly transformed to 4ea and 4ga in 70% and 78% yields, respectively. However, in the case of phenylthio-substituted derivative 3ha, a 5:1 mixture of 4ha and 5ha was isolated. Next, an investigation of this coupling reaction on 3-methylthiotriazine adducts 3ab-3ag showed that the naphthyl ring substituted with various functional groups at different positions afforded the corresponding products with good to excellent yields. For example, bromo-, hydroxy-, methoxy- and cyano-substituted adducts 3ab-3ag underwent oxidative cyclization with high regioselectivity to give only naphthofuro[3,2-e]triazine derivatives 4 in up to 91% yields (Scheme 5).

Encouraged by these results, we then investigated the oxidative cyclization reaction of triazine not bearing S-substituents (Scheme 6). In particular, 3-phenyl and 3-(4-methoxyphenyl) (PMP) derivatives 3ia and 3ja prepared under standard conditions (MsOH, AcOH) underwent MnO₂-induced oxidative cyclization to afford cyclic products 4ia and 4ja, respectively, as minor products with up to 28% yield. In contrast, 3-methyltriazine 1k smoothly reacted with 2-naphthol 2a in AcOH without the addition of MsOH, leading to the corresponding adduct 3la, which was oxidized in the presence of MnO₂ to generate the desired 4la as a major product in a 48% overall yield. Similar to triazine 1k, 3-benzyltriazine 1l was also involved in the same cascade reaction to give the mixture of 4ka and 5ka in a ratio of 1:1. In addition, we were pleased to find that the oxidative cyclization of 3ma bearing the N-morpholinyl group in a triazine core produced the respective oxidative product 4ma in a 75% yield. Actually, the adduct 3ma was synthesized in situ by the interaction between triazine 1m and 2-naphthol 2a in the presence of BF₃^.OEt₂ under reflux in methanol.

Further, we explored the reactivity of p-substituted phenols in these sequence reactions. Unfortunately, all attempts to prepare the starting materials (3) under standard conditions (MsOH, AcOH, rt) failed, and only starting materials 1 and 2 were isolated from the reactions. However, we found that the use of trifluoroacetic acid (TFA) as the activator and medium at room temperature could allow the formation of unstable compounds 3ah and 3ai by the nucleophilic addition of phenol to the triazine core. These two compounds (3ah and 3ai) underwent the oxidative cyclization reaction, giving benzofuro[3,2-e]triazine 4 in lower to moderate yields. At the same time, biaryl by-products 5ah and 5ai were also isolated.

For further assessing the synthetic utility of the method, we performed the addition and coupling reaction sequence again at the gram scale. Thus, under slightly optimized conditions, we synthesized compound 4ad from triazine 1a and naphthol 2d at 40 mmol loading in an 85% yield via two steps (Scheme 4).

The thiomethyl group is a versatile moiety for coupling reactions. In triazines, the thiomethyl group may be easily substituted with aryl boronic acids [84,85] or trialkyl(aryl)stannanes [86] using Liebeskind–Srogl coupling [87]. To demonstrate the synthetic potential of benzofuro-annulated triazines, we performed the substitution of the thiomethyl group with an aryl substituent. The reaction of triazine 4aa with 4-carbazolyl-phenylboronic acid 6 provided the corresponding coupling product 7 in a 73% yield (Scheme 7a).

Furthermore, a thiomethyl group can easily be oxidized with mCPBA to afford the methylsulfonyl group, which can be substituted with various nucleophiles [88,89,90]. Treatment of the synthesized compound 4aa with mCPBA gave the corresponding sulfonyl derivative 8 at an 85% yield. After that, we successfully synthesized carbazole-substituted naphthofuro-fused 1,2,4-triazine 9 via the subsequent replacement of the sulfonyl group in 8 with carbazole in the presence of sodium hydride (Scheme 7b). It is worth mentioning that these types of carbazole-substituted triazine derivatives have potential uses in biological fields [91,92] and OLED applications [93].

To gain some mechanistic insights into this oxidative cyclization, we first carried out several control experiments. When (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) or butylated hydroxytoluene (BHT) was added to the oxidative cyclization of 3aa under the standard reaction conditions (Scheme 8a), the desired product 4aa was obtained in a yield up 81%, suggesting that radicals may not be involved in the catalytic cycle, in contrast to the earlier published cyclization of the Schiff’s base in the presence of Mn salt [78,79]. The slight decrease in yield is probably due to the deactivation of manganese oxide under the reducing action of TEMPO and BHT. In addition, a high yield of 4aa was achieved, even when performing the reaction under a N₂ atmosphere, demonstrating that aerobic oxygen is not the oxidizing agent in this transformation (Scheme 8a).

Subsequently, in order to get some information about possible reaction intermediates, we carried out the oxidative cyclization of 3aa under various conditions. After several trials, we managed to isolate one of the possible intermediates, 4aa′, in the presence of MnO₂ impregnated with nitric acid [82] in CH₂Cl₂ at room temperature (Scheme 8b). The structure of the intermediate 4aa′ was supported by NMR and HRMS data. The ¹H NMR spectrum comprises two dihydrotriazine proton doublets at 5.69 and 5.66 ppm with an SSCC (spin–spin coupling constant) of 10.8 Hz. Another intermediate 4aa′′ was detected by ¹H NMR analysis (Please see Supporting Information for details, Section S6) in the crystallized reaction mixture when the reaction was carried out in the presence of a twofold excess of MnO₂ (Scheme 8c). We ascribed the structure of dihydrotriazine to this compound since a single proton resonance at the sp³ carbon is observed in the ¹H NMR spectrum.

After summarizing these preliminary mechanistic studies, a plausible reaction mechanism of the oxidative cyclization has been postulated (Scheme 9). The reaction may proceed through two different pathways: path a and path b. In path a, the reaction starts with the formation of an O-coordinated complex A, which agrees well with the oxidation of alcohol to aldehyde in the presence of MnO₂ [94]. Then, complex A undergoes intramolecular nucleophilic addition to generate an intermediate 4aa′ with the elimination of Mn(II) species detected by an EPR experiment (Please see Supporting Information for details, Section S6). Then, the quick tautomerization of 4aa′ leads to the intermediate 4aa′′, which is aromatized with the second equivalent of MnO_2, as well as with 1,4-dihydropyridine [95,96,97,98] or 1,4-dihydrotriazine [71,99], to give the final product 4aa. On the other hand, if we consider path b, at the first step, MnO₂ may coordinate with the nitrogen atom of the triazine core, leading to N-coordinated complex B, which is also aromatized with the formation of biaryl product 5aa. Thus, the formation of the final product depends on the position of the initial coordination of the manganese dioxide, through which the reaction can proceed through the regular aromatization of dihydrotriazine (path A) or through the path of oxidative cyclization (path A).

In order to rationalize the regioselectivity of pathways of the products’ formation (4 vs. 5) we have performed a series of DFT calculations of the electron density of HOMO and HOMO-1 in the compounds 3aa, 3fa, 3ha and 3ia (Figure 2). The results show that the electron density on the oxygen atom of the hydroxyl group is comparable with the one on the nitrogen of the triazine core in compounds 3aa and 3ha. However, the larger energy gap between HOMO and HOMO-1 of 3aa compared with the energy gap in 3ha increased the regioselectivity of the formation of O-coordinated manganese ester. In the case of compound 3ia, the localization of the orbitals on the triazine N2 nitrogen (HOMO-1) was higher than those on the phenol oxygen (HOMO). So, the reaction proceeds partially via the aromatization of dihydrotriazine, rather than through oxidative cyclization. As follows from Figure 2, the important role of the alkylthio group is that it reduces the electron density at the nitrogen atom of dihydrotriazine, which leads to a reaction at the phenolic oxygen atom. Therefore, these results suggest that MnO₂ may coordinate with either oxygen or nitrogen atoms, depending on the delocalization of the electron density of HOMO and HOMO-1 on the corresponding oxygen or nitrogen atom, and the energy gap between these orbitals.

3. Materials and Methods

General Information: All commercially available chemicals were used without further purifications. ¹H NMR (400 MHz) and ¹³C NMR (101 MHz) spectra were registered on a Bruker DRX-400 Avance spectrometer with DMSO-d₆ or CDCl₃ as the solvent at ambient temperature. Chemical shifts are reported in ppm, and coupling constants are given in Hz. Data for ¹H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sex, sextet; m, multiplet; br s, broad signal), integration and coupling constant (Hz). High-resolution mass spectra were recorded on an Agilent UHPLC/MS Accurate-Mass Q-TOF 1290/6545. EPR spectra were obtained using a Bruker Elexsys E500 CW-EPR spectrometer (modulation amplitude was set as 0.3 mT). The simulation of the EPR spectra was performed using the package EasySpin 5.2 software [100]. Molecular geometry optimization and the calculation of energies of molecules were carried out in the gas phase using the B3LYP DFT functional [101] with a 6-311 + G (d, p) basis set [102] according to [103] in Gaussian09 [104]. The plots of electron densities of molecular orbitals were obtained using the GaussView 6.0 software [105]. X-ray analysis for compound 5fa was executed on an Xcalibur 3 diffractometer (MoKα radiation, graphite monochromator, 295(2) K, φ- and ω-scanning with a step of 1°). Thin-layer chromatography (TLC) was performed on a silica gel-coated glass slide (Merck, Silica gel G for TLC). Column chromatography was carried out on silica gel (60 Å, 0.035−0.070 mm). Images of ¹H and ¹³C NMR spectra are provided on pages S26–S81 of the Supplementary Materials.

3.1. Synthesis of S-substituted 3-thio-1,2,4-triazines 1a-f

S-substituted 3-thio-1,2,4-triazines 1a-f were prepared from the corresponding salt of S-substituted isothiosemicarbazide (2 mmol) and glyoxal solution according to the following procedure [106].

A solution of 40% glyoxal (8 mmol, 1160 mg) and NaHCO₃ (5 mmol, 420 mg) in ice water (40 mL) was added to a solution of S-substituted isothiosemicarbazide hydrogen iodide (2 mmol) dissolved in ice water (40 mL). The reaction mixture was stirred for 15 min; during that time, the evolution of gas (CO₂) was observed. The reaction mixture was left in the fridge overnight and the aqueous solution was extracted with chloroform. The combined organic layer was washed with 10% oxalic acid, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to obtain oil or a solid triazine compound.

3.1.1. Synthesis of 3-(phenylthio)-1,2,4-triazine 1h

Compound 1h was prepared via the oxidation of 1a with mCPBA using a modified procedure [107] followed by the treatment of compound 1a′ with thiophenol.

mCPBA (11.6 g, 77%, 52 mmol) and anhydrous Na₂SO₄ (4.0 g) were successively added to DCM (60 mL); the mixture was stirred for 15 min and then filtered and the filter cake was washed with 10 mL of DCM to obtain a clear dichloromethane solution of mCPBA. A dichloromethane solution of 3-methylthio-1,2,4-triazine 1a (3.0 g, 23.6 mmol) was added to this dichloromethane solution of mCPBA at −10 °C with stirring. The reaction mixture was allowed to heat to ambient temperature and then stirred for an additional 3 h. Dichloromethane was evaporated under reduced pressure to obtain a dry mixture of 3-(methylsulfonyl)-1,2,4-triazine 1a′ and m-chlorobenzoic acid. The mixture was dissolved in pyridine (40 mL) and thiophenol (5.3 mL, 5.72 g, 52 mmol) was added after. After 24 h the mixture was evaporated in vacuo, and the residue was treated with a mixture of dichloromethane and aqueous NaHCO₃. The organic layer was evaporated, yielding pure compound 1h.

3.1.2. Synthesis of 3-phenyl- and 3-(4-methoxyphenyl)-1,2,4-triazines 1i and 1j

Compounds 1i and 1j were prepared according to the published procedure [108]. The spectroscopic data for compound 1i are in agreement with the literature [109].

3.1.3. Synthesis of 3-methyl- and 3-benzyl-1,2,4-triazine 1k and 1l

Compounds 1k and 1l were prepared according to the known procedure [110]. The spectroscopic data of compounds 1k are in agreement with the published data [110].

3.1.4. Synthesis of 4-(1,2,4-triazin-3-yl)morpholine 1m

Compound 1m was prepared according to the published procedure [111].

3.2. General Procedure for the Synthesis of Dihydrotriazines 3

3.2.1. Method A

To a stirred solution of triazine 1a-j (1 mmol, 1 equiv.) and 2-naphthol 2a,f,g (1 mmol, 1 equiv.) in acetic acid (4 mL), we added a methanesulfonic acid (195 μL, 3 mmol, 3 equiv.). The resulting mixture was stirred at room temperature for 1-5 h. The progress of the reaction was monitored using TLC. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), neutralized with aq. NaHCO₃ solution and extracted with AcOEt (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography or recrystallization from the corresponding solvent to afford product 3.

3.2.2. Method B

To a stirred solution of triazine 1a (1 mmol, 1 equiv.) and 2-naphthol 2b-e (1 mmol, 1 equiv.) in methanol (4 mL) we added BF₃^.OEt₂ (985 μL, 8 mmol, 8 equiv.) and the resulting mixture was refluxed for 5 h. After cooling the methanol was evaporated under reduced pressure, and the residue was dissolved in AcOEt (10 mL) and washed with 5% aq. NaHCO₃ solution (50 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The crude product was recrystallized from MeCN to obtain the product 3ab-3ae.

3.3. General Procedure for the Synthesis of Naphthofuro-Fused Triazines 4

To a stirred solution of 3 (0.2 mmol, 1 equiv.) in CHCl₃ (3 mL), MnO₂ (52 mg, 0.6 mmol, 3 equiv.) was added in one portion. The resulting mixture was stirred at 50 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature; the MnO₂ was filtered and the filter cake was washed with CHCl₃ (3 × 10 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel or recrystallization to afford the pure product 4.

3.3.1. 10-(Methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4aa

Pale yellow needles after recrystallization from MeCN. Yield 51 mg, 95%; m.p. 185–187 °C. ¹H NMR (CDCl₃): 8.78–8.66 (m, 1H, H-1), 8.20–8.06 (m, 1H, H-5), 7.97–7.86 (m, 1H, H-4), 7.76–7.52 (m, 3H, H-2, H-3, H-6), 2.79 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 169.8, 160.0, 158.6, 143.7, 137.0, 130.5, 129.6, 129.2, 128.7, 126.7, 124.7, 112.7, 112.6, 14.8. Anal. Calcd. For C₁₄H₉N₃OS: C, 62.91; H, 3.39; N, 15.72%; found: C, 62.96; H, 3.47; N, 15.79%.

3.3.2. 10-(Ethylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ba

Pale yellow needles after recrystallization from MeCN. Yield 47 mg, 84%; m.p. 141–143 °C. ¹H NMR (CDCl₃): 8.97–8.88 (m, 1H, H-1), 8.28–8.21 (m, 1H, H-5), 8.06–7.99 (m, 1H, H-4), 7.87–7.75 (m, 2H, H-2, H-6), 7.70–7.62 (m, 1H, H-3), 3.44 (q, 2H, J = 7.3 Hz, SCH₂), 1.56 (t, 3H, J = 7.3 Hz, CH₃); ¹³C NMR (CDCl₃): 169.6, 160.1, 158.7, 143.9, 137.0, 130.6, 129.6, 129.3, 128.9, 126.8, 124.8, 112.9, 112.7, 26.1, 14.4. Anal. Calcd. For C₁₅H₁₁N₃OS: C, 64.04; H, 3.94; N, 14.94%; found: C, 64.12; H, 3.99; N, 14.85%.

3.3.3. 10-(Butylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ca

Pale yellow needles after recrystallization from MeCN. Yield 53 mg, 85%; m.p. 121–123 °C. ¹H NMR (CDCl₃): 8.83–8.75 (m, 1H, H-1), 8.20–8.12 (m, 1H, H-5), 7.99–7.92 (m, 1H, H-4), 7.79–7.55 (m, 3H, H-2, H-3, H-6), 3.45–3.33 (m, 2H, SCH₂), 1.96–1.83 (m, 2H, SCH₂CH₂), 1.68–1.53 (m, 2H, SCH₂CH₂CH₂), 1.08–0.97 (m, 3H, CH₃); ¹³C NMR (CDCl₃): 169.8, 160.1, 158.7, 143.9, 137.1, 130.6, 129.6, 129.4, 128.9, 126.8, 124.9, 113.0, 112.8, 31.4, 31.3, 22.3, 13.9. Anal. Calcd. For C₁₇H₁₅N₃OS: C, 66.00; H, 4.89; N, 13.58%; found: C, 66.09; H, 4.82; N, 13.50%.

3.3.4. 10-((Cyclobutylmethyl)thio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4da

Yellow needles after recrystallization from MeCN. Yield 57 mg, 89%; m.p. 154–156 °C. ¹H NMR (CDCl₃): 8.81–8.76 (m, 1H, H-1), 8.17 (d, 1H, J = 9.0 Hz, H-5), 7.98–7.93 (m, 1H, H-4), 7.78–7.72 (m, 1H, H-2), 7.70 (d, 1H, J = 9.0 Hz, H-6), 7.63–7.57 (m, 1H, H-3), 3.53–3.44 (m, 2H, SCH₂), 2.90–2.80 (m, 1H, CH-1′), 2.29–2.18 (m, 2H, CH₂-3′), 1.98–1.83 (m, 4H, CH₂-2′, CH₂-4′); ¹³C NMR (CDCl₃): 169.7, 160.0, 158.7, 143.8, 137.0, 130.6, 129.6, 129.3, 128.8, 126.7, 124.8, 112.8, 112.7, 37.9, 34.7, 28.0, 18.2. Anal. Calcd. For C₁₈H₁₅N₃OS: C, 67.27; H, 4.70; N, 13.07%; found: C, 67.35; H, 4.78; N, 13.12%.

3.3.5. 10-(But-2-yn-1-ylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ea

Brown powder after purification by chromatography on silica gel using n-hexane-ethyl acetate (10:1). Yield 45 mg, 70%; m.p. 163–165 °C. ¹H NMR (CDCl₃): 8.88–8.83 (m, 1H, H-1), 8.22 (d, 1H, J = 9.0 Hz, H-5), 8.02–7.97 (m, 1H, H-4), 7.82–7.77 (m, 1H, H-2), 7.74 (d, 1H, J = 9.0 Hz, H-6), 7.67–7.61 (m, 1H, H-3), 4.15 (q, 2H, J = 2.5 Hz, SCH₂), 1.84 (t, 3H, J = 2.5 Hz, CH₃); ¹³C NMR (CDCl₃): 168.4, 160.1, 158.8, 143.9, 137.3, 130.6, 129.8, 129.8, 128.9, 126.9, 124.9, 112.9, 112.7, 79.5, 73.7, 21.0, 3.9. Anal. Calcd. For C₁₇H₁₁N₃OS: C, 66.87; H, 3.63; N, 13.76%; found: C, 66.80; H, 3.60; N, 13.86%.

3.3.6. 10-(Benzylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4fa

Yellow needles after recrystallization from MeCN. Yield 63 mg, 90%; m.p. 161–163 °C. ¹H NMR (CDCl₃): 8.82–8.73 (m, 1H, H-1), 8.17 (d, 1H, J = 9.1 Hz, H-5), 7.97–7.93 (m, 1H, H-4), 7.78–7.72 (m, 1H, H-3), 7.70 (d, 1H, J = 9.1 Hz, H-6), 7.26–7.56 (m, 3H, H-2, Ph), 7.38–7.32 (m, 2H, Ph), 7.30–7.25 (m, 1H, Ph), 4.66 (m, 1H, SCH₂); ¹³C NMR (CDCl₃): 169.0, 160.2, 158.8, 143.9, 137.2, 137.1, 130.6, 129.7, 129.4, 129.4, 128.9, 128.7, 127.6, 126.8, 124.9, 112.9, 112.7, 36.1. Anal. Calcd. For C₂₀H₁₃N₃OS: C, 69.95; H, 3.82; N, 12.24%; found: C, 69.85; H, 3.76; N, 12.20%.

3.3.7. 10-(Allylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ga

Pale yellow powder after recrystallization from MeCN. Yield 46 mg, 78%; m.p. 126–128 °C. ¹H NMR (CDCl₃): 8.83–8.74 (m, 1H, H-1), 8.17 (d, 1H, J = 9.1 Hz, H-5), 7.99–7.93 (m, 1H, H-4), 7.78–7.72 (m, 1H, H-3), 7.70 (d, 1H, J = 9.1 Hz, H-6), 7.64–7.57 (m, 1H, H-2), 6.13 (ddt, 1H, ³J = 6.9 Hz, ³J(cis) = 10.0 Hz, ³J(trans) = 17.0 Hz, CH-2′), 5.47 (dd, 1H, ³J(trans) = 16.9 Hz, J = 1.2 Hz, CH-3a′), 5.22 (d, 1H, ³J(cis) = 10.0 Hz, CH-3b′), 4.06 (d, 2H, ³J = 6.9 Hz, SCH₂); ¹³C NMR (CDCl₃): 168.9, 160.1, 158.7, 143.8, 137.1, 133.1, 130.6, 129.7, 129.3, 128.8, 126.8, 124.8, 118.7, 112.9, 112.7, 34.5. Anal. Calcd. For C₁₆H₉N₃OS: C, 65.97; H, 3.11; N, 14.42%; found: C, 65.90; H, 3.18; N, 14.50%.

A mixture of 4ha and 5ha was separated by silica gel chromatography using n-hexane-ethyl acetate (17:1) to isolate 4ha and n-hexane-ethyl acetate (10:1) to give 5ha.

3.3.8. 10-(Phenylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ha

Yellow powder. Yield 46 mg, 70%; m.p. 196–198 °C. ¹H NMR (CDCl₃): 8.58–8.53 (m, 1H, H-1), 8.22–8.17 (m, 1H, H-5), 8.00–7.95 (m, 1H, H-4), 7.83–7.77 (m, 2H, Ph), 7.75–7.67 (m, 2H, H-3, H-6), 7.64–7.58 (m, 1H, H-2), 7.56–7.50 (m, 3H, Ph); ¹³C NMR (CDCl₃): 170.0, 160.3, 158.8, 144.0, 137.2, 135.8, 130.6, 129.7, 129.6, 129.5, 129.3, 129.2, 128.8, 126.8, 124.8, 113.0, 112.7. Anal. Calcd. For C₁₉H₁₁N₃OS: C, 69.29; H, 3.37; N, 12.76%; found: C, 69.20; H, 3.45; N, 12.70%.

3.3.9. 1-(3-(Phenylthio)-1,2,4-triazin-5-yl)naphthalen-2-ol 5ha

Yellow powder. Yield 9 mg, 14%; m.p. 149–151 °C. ¹H NMR (CDCl₃): 11.01 (s, 1H, OH), 9.51 (s, 1H, H-6′), 8.09–8.03 (m, 1H, H-8), 7.84 (d, 1H, J = 9.0 Hz, H-4), 7.82–7.76 (m, 1H, H-5), 7.75–7.67 (m, 2H, Ph), 7.59–7.51 (m, 4H, Ph, H-7), 7.44–7.37 (m, 1H, H-6), 7.07 (d, 1H, J = 9.0 Hz, H-3); ¹³C NMR (CDCl₃): 172.3, 160.8, 155.7, 146.2, 136.2, 136.0, 130.8 (2C), 130.3, 129.5, 129.2, 128.7, 126.9, 124.7, 123.2, 119.7, 108.9. Anal. Calcd. For C₁₉H₁₃N₃OS: C, 68.86; H, 3.95; N, 12.68%; found: C, 68.77; H, 3.90; N, 12.60%.

A mixture of 4ia and 5ia was separated by chromatography using n-hexane-ethyl acetate (15:1) to give 4ia and n-hexane-ethyl acetate (8:1) to give 5ia.

3.3.10. 10-Phenylnaphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ia

Pale yellow solid. Yield 12 mg, 21%, m.p. 189–191 °C. Rf = 0.54 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 9.09–8.99 (m, 1H, H-1), 8.75–8.64 (m, 2H, Ph), 8.24–8.14 (m, 1H, H-5), 8.03–7.94 (m, 1H, H-4), 7.86–7.73 (m, 2H, H-2, H-6), 7.66–7.52 (m, 4H, H-3, Ph); ¹³C NMR (CDCl₃): 161.5, 160.8, 158.5, 143.9, 136.7, 135.7, 131.2, 130.7, 129.6, 129.3, 129.1, 129.0, 128.5, 126.7, 124.9, 113.7, 112.8. Anal. Calcd. For C₁₉H₁₁N₃O: C, 76.76; H, 3.73; N, 14.13%; found: C, 76.83; H, 3.70; N, 14.19%.

3.3.11. 1-(3-Phenyl-1,2,4-triazin-5-yl)naphthalen-2-ol 5ia

Yellow solid. Yield 31 mg, 52%, m.p. 204–206 °C. Rf = 0.39 (ethyl acetate:hexane, 1:1). ¹H NMR (DMSO-d₆): 12.45–12.16 (br s, 1H, OH), 9.77 (s, 1H, H-6′), 8.56–8.47 (m, 2H, Ph), 8.21–8.11 (m, 1H, H-8), 7.95 (d, 1H, J = 9.0 Hz, H-4), 7.90–7.83 (m, 1H, H-5), 7.67–7.55 (m, 4H, H-6, Ph), 7.49–7.42 (m, 1H, H-7), 7.28 (d, 1H, J = 9.0 Hz, H-3); ¹³C NMR (DMSO-d₆): 161.3, 160.3, 155.9, 148.3, 135.8, 134.2, 132.4, 131.0, 129.6, 129.3 (2C), 128.7, 128.4, 124.7, 123.1, 119.6, 109.4. Anal. Calcd. For C₁₉H₁₃N₃O: C, 76.24; H, 4.38; N, 14.04%; found: C, 76.32; H, 4.45; N, 14.12%.

A mixture of 4ja and 5ja was separated by silica gel chromatography using n-hexane-ethyl acetate (17:1) to isolate 4ja and n-hexane-ethyl acetate (7:1) to give 5ja.

3.3.12. 10-(4-Methoxyphenyl)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ja

Pale yellow solid. Yield 18 mg, 28%; m.p. 205–207 °C. Rf = 0.53 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 9.05–8.99 (m, 1H, H-1), 8,64 (d, 2H, J = 8.8 Hz, Ph), 8.19 (d, 1H, J = 9.0 Hz, H-5), 8.02–7.94 (m, 1H, H-4), 7.85–7.78 (m, 1H, H-3), 7.76 (d, 1H, J = 9.0 Hz, H-6), 7.66–7.58 (m, 1H, H-2), 7.08 (d, 2H, J = 8.8 Hz, Ph), 3.93 (s, 3H, OCH₃); ¹³C NMR (CDCl₃): 162.3, 161.4, 160.6, 158.4, 143.9, 136.5, 130.7, 130.1, 129.5, 129.3, 129.1, 128.3, 126.7, 124.9, 114.3, 113.7, 112.8, 55.6. Anal. Calcd. For C₂₀H₁₃N₃O₂: C, 73.38; H, 4.00; N, 12.84%; found: C, 73.30; H, 3.92; N, 12.94%.

3.3.13. 1-(3-(4-Methoxyphenyl)-1,2,4-triazin-5-yl)naphthalen-2-ol 5ja

Yellow solid. Yield 31 mg, 47%; m.p. 178–180 °C. Rf = 0.41 (ethyl acetate:hexane, 1:1). ¹H NMR (DMSO-d₆): 12.33–12.08 (br s, 1H, OH), 9.59 (s, 1H, H-6′), 8.38 (d, 2H, J = 8.7 Hz, Ph), 8.09–8.01 (m, 1H, H-8), 7.87–7.81 (m, 1H, H-4), 7.80–7.72 (m, 1H, H-5), 7.54–7.45 (m, 1H, H-7 or H-6), 7.39–7.30 (m, 1H, H-6 or H-7), 7.22–7.13 (m, 1H, H-3), 7.03–6.95 (d, 2H, J = 8.7 Hz, Ph), 3.83 (s, 3H, OCH₃); ¹³C NMR (DMSO-d₆): 162.5, 156.8, 154.1, 151.0, 135.1, 132.6, 132.2, 131.6, 129.1, 128.4, 128.0, 127.8, 127.6, 123.4, 123.1, 118.1, 113.9, 55.7. Anal. Calcd. For C₂₀H₁₅N₃O₂: C, 72.94; H, 4.59; N, 12.76%; found: C, 72.83; H, 4.65; N, 12.70%.

3.3.14. 6-Methoxy-10-(methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ab

Yellow powder after recrystallization from MeCN. Yield 48 mg, 80%; m.p. 183–185 °C. ¹H NMR (CDCl₃): 8.55–8.51 (m, 1H, H-4 or H-1), 7.71–7.66 (m, 1H, H-1 or H-4), 7.55–7.50 (m, 1H, H-3 or H-2), 7.79–7.50 (m, 1H, H-2 or H-3), 7.32 (s, 1H, H-5), 4.13 (s, 3H, OCH₃), 2.78 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 169.9, 159.9, 149.9, 145.0, 143.3, 131.2, 127.6, 126.9, 126.8, 124.3, 123.6, 114.1, 113.3, 56.5, 14.8. Anal. Calcd. For C₁₅H₁₁N₃O₂S: C, 60.59; H, 3.73; N, 14.13%; found: C, 60.67; H, 3.65; N, 14.04%.

3.3.15. 2-Methoxy-10-(methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ac

Yellow powder after recrystallization from MeCN. Yield 50 mg, 84%; m.p. 219–221 °C. ¹H NMR (CDCl₃): 8.22–8.19 (m, 1H, H-1), 8.14–8.10 (m, 1H, H-4), 7.88 (d, 1H, J = 8.9 Hz, H-4), 7.57 (d, 1H, J = 8.9 Hz, H-3), 7.27–7.22 (m, 1H, H-3), 4.06 (s, 3H, OCH₃), 2.81 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 169.6, 161.0, 160.2, 159.4, 144.1, 136.8, 131.0, 125.7, 118.8, 112.0, 109.8, 104.2, 96.3, 55.8, 14.8. Anal. Calcd. For C₁₅H₁₁N₃O₂S: C, 60.59; H, 3.73; N, 14.13%; found: C, 60.50; H, 3.66; N, 14.10%.

3.3.16. 10-(Methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazin-2-ol 4ad

According to the general procedure, in the mixture of CHCl₃:EtOH (4:1) as solvent, 4ad was obtained as yellow powder after recrystallization from EtOH. Yield 38 mg, 68%; m.p. 282–284 °C. ¹H NMR (DMSO-d₆): 10.61 (s, 1H, OH), 8.30 (d, 1H, J = 8.9 Hz, H-6), 8.03–7.97 (m, 2H, H-1, H-4), 7.70 (d, 1H, J = 8.9 Hz, H-4), 7.57 (d, 1H, J = 8.9 Hz, H-3), 7.19–7.14 (m, 1H, H-3), 2.76 (s, 3H, SCH₃); ¹³C NMR (DMSO-d₆): 168.0, 159.9, 159.1, 159.1, 144.0, 137.4, 131.6, 130.2, 124.4, 118.4, 110.5, 108.9, 106.5, 14.1. Anal. Calcd. For C₁₄H₉N₃O₂S: C, 59.35; H, 3.20; N, 14.83%; found: C, 59.25; H, 3.15; N, 14.75%.

3.3.17. 3-Methoxy-10-(methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ae

Yellow powder after recrystallization from MeCN. Yield 49 mg, 82%; m.p. 214–216 °C. ¹H NMR (CDCl₃): 8.83 (d, 1H, J = 8.9 Hz, H-1), 8.13 (d, 1H, J = 9.0 Hz, H-5), 7.74 (d, 1H, J = 9.0 Hz, H-6), 7.47 (dd, 1H, J = 8.9 Hz, J = 2.5 Hz, H-2), 7.33 (d, 1H, J = 2.5 Hz, H-4), 3.98 (s, 3H, OCH₃), 2.83 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 169.7, 160.2, 158.3, 157.6, 143.9, 135.9, 132.2, 126.3, 123.8, 121.7, 113.1 (2C), 108.2, 55.6, 14.9. Anal. Calcd. For C₁₅H₁₁N₃O₂S: C, 60.59; H, 3.73; N, 14.13%; found: C, 60.65; H, 3.82; N, 14.10%.

3.3.18. 3-Bromo-10-(methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4af

Yellow powder after recrystallization from toluene. Yield 53 mg, 75%; m.p. 244–246 °C. ¹H NMR (CDCl₃): 8.86 (d, 1H, J = 8.7 Hz, H-1), 8.23 (d, 1H, J = 1.8 Hz, H-4), 8.19 (d, 1H, J = 9.1 Hz, H-5), 7.92 (dd, 1H, J = 8.7 Hz, J = 1.8 Hz, H-2), 7.85 (d, 1H, J = 9.1 Hz, H-6), 2.85 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 170.2 160.3, 158.7, 143.6, 136.0, 133.0, 132.0, 131.5, 127.5, 126.6, 120.8, 114.1, 113.2, 14.9. Anal. Calcd. For C₁₄H₈BrN₃OS: C, 48.57; H, 2.33; N, 12.14%; found: C, 48.50; H, 2.26; N, 12.06%.

3.3.19. 10-(Methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine-3-carbonitrile 4ag

Yellow solid after recrystallization from MeCN. Yield 54 mg, 91%; m.p. 283–285 °C. ¹H NMR (CDCl₃): 9.09 (d, 1H, J = 8.5 Hz, H-1), 8.44 (d, 1H, J = 1.5 Hz, H-4) 8.33 (d, 1H, J = 9.1 Hz, H-5), 7.99 (dd, 1H, J = 8.5 Hz, J = 1.5 Hz, H-2), 7.96 (d, 1H, J = 9.1 Hz, H-6), 2.85 (s, 3H, SCH₃); ¹³C NMR (CDCl₃): 170.7, 160.4, 159.8, 143.3, 136.8, 134.9, 130.9, 130.6, 129.9, 126.3, 118.6, 115.1, 113.4, 110.7, 14.9. Anal. Calcd. For C₁₅H₈N₄OS: C, 61.63; H, 2.76; N, 19.17%; found: C, 61.72; H, 2.86; N, 19.22%.

3.3.20. Synthesis of 10-alkyl naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazines 4ka and 4la

To a stirred solution of corresponding triazine 1k or 1l (1 mmol, 1 equiv.) in acetic acid (4 mL), 2-naphthol 2a (144 mg, 1 mmol, 1 equiv.) was added. Then the mixture was stirred at room temperature for 5 h, concentrated under reduced pressure, dissolved in CHCl₃ (10 mL) and washed with saturated aq. NaHCO₃ solution (10 mL). The organic layer was dried over anhydrous Na₂SO₄ and filtered. To the organic phase, MnO₂ (261 mg, 3.0 mmol, 3 equiv.) was added in one portion and the mixture was stirred at 50 °C for 3 h. The reaction mixture was then cooled to room temperature. MnO₂ was filtered and washed with CHCl₃ (3 × 10 mL). The combined organic phase was concentrated under reduced pressure to give a mixture of 4 and 5, which was separated by chromatography on silica gel using a mixture of n-hexane-ethyl acetate as the eluent.

A mixture of 4ka and 5ka was separated by chromatography on silica gel using n-hexane-ethyl acetate (25:1) to isolate 4ka and n-hexane-ethyl acetate (8:1) to give 5ka.

3.3.21. 10-Methylnaphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ka

Yellow solid. Yield 113 mg, 48%; m.p. 190–192 °C. Rf = 0.46 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 8.98–8.92 (m, 1H, H-1), 8.24–8.17 (m, 1H, H-5), 8.04–7.98 (m, 1H, H-4), 7.84–7.72 (m, 2H, H-2, H-6), 7.68–7.59 (m, 1H, H-3), 3.08 (s, 3H, CH₃); ¹³C NMR (CDCl₃): 164.4, 160.6, 158.4, 144.0, 136.7, 130.7, 129.5, 129.3, 129.0, 126.7, 124.9, 113.4, 112.8, 23.9. Anal. Calcd. For C₁₄H₉N₃O: C, 71.48; H, 3.86; N, 17.86%; found: C, 71.39; H, 3.93; N, 17.92%.

3.3.22. 1-(3-Methyl-1,2,4-triazin-5-yl)naphthalen-2-ol 5ka

Pale yellow solid. Yield 45 mg, 19%; m.p. 168–170 °C. Rf = 0.25 (ethyl acetate:hexane 1:1). ¹H NMR (DMSO-d₆): 10.46 (s, 1H, OH), 9.44 (s, 1H, H-6′), 8.01–7.96 (m, 1H, H-4), 7.92–7.85 (m, 1H, H-8 or H-5), 7.73–7.67 (m, 1H, H-5 or H-8), 7.45–7.29 (m, 3H, H-3, H-6, H-7), 2.85 (s, 3H, CH₃); ¹³C NMR (DMSO-d₆): 166.2, 156.4, 153.8, 150.2, 132.3, 132.1, 128.3, 127.9, 127.4, 123.3, 123.2, 118.1, 113.8, 23.6. Anal. Calcd. For C₁₄H₁₁N₃O: C, 70.87; H, 4.67; N, 17.71%; found: C, 70.77; H, 4.72; N, 17.80%.

A mixture of 4la and 5la was separated by chromatography on silica gel using n-hexane-ethyl acetate (17:1) to give 4la, and n-hexane-ethyl acetate (10:1) to give 5la.

3.3.23. 10-Benzylnaphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4la

Pale yellow solid. Yield 109 mg, 35%; m.p. 226–228 °C. Rf = 0.57 (ethyl acetate:hexane, 1:1). ¹H NMR (DMSO-d₆): 8.89–8.82 (m, 1H, H-1), 8.49 (d, 1H, J = 9.0 Hz H-5), 8.25–8.20 (m, 1H, H-4), 8.06 (d, 1H, J = 9.0 Hz H-6), 7.93–7.87 (m, 1H, H-3 or H-2), 7.74–7.69 (m, 1H, H-2 or H-3), 7.49–7.44 (m, 2H, Ph), 7.37–7.32 (m, 2H, Ph), 7.27–7.22 (m, 1H, Ph), 4.62 (s, 2H, CH₂); ¹³C NMR (DMSO-d₆): 165.0, 160.2, 158.0, 143.9, 138.1, 137.0, 130.2, 129.5 (2C), 129.0 (2C), 128.3 (2C), 128.1, 126.4 (2C), 123.7, 112.9, 112.5, 42.7. Anal. Calcd. For C₂₀H₁₃N₃O: C, 77.16; H, 4.21; N, 13.50%; found: C, 77.25; H, 4.30; N, 13.57%.

3.3.24. 1-(3-Methyl-1,2,4-triazin-5-yl)naphthalen-2-ol 5la

Pale yellow solid. Yield 110 mg, 35%; m.p. 155–157 °C. Rf = 0.34 (ethyl acetate:hexane, 1:1). ¹H NMR (DMSO-d₆): 10.55 (s, 1H, OH), 9.49 (s, 1H, H-6′), 8.01–7.94 (m, 1H, H-4), 7.90–7.84 (m, 1H, H-8 or H-5), 7.63–7.55 (m, 1H, H-5 or H-8), 7.43–7.22 (m, 8H, H-3, H-6, H-7, Ph), 4.47 (s, 2H, CH₂); ¹³C NMR (DMSO-d₆): 167.9, 156.7, 154.0, 150.6, 137.7, 132.6, 132.0, 129.2, 128.5, 128.3, 128.0, 127.3, 126.6, 123.4, 123.1, 118.0, 113.5, 43.0. Anal. Calcd. For C₂₀H₁₅N₃O: C, 76.66; H, 4.83; N, 13.41%; found: C, 76.75; H, 4.74; N, 13.48%.

3.3.25. 10-Morpholinonaphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4ma

To a stirred solution of 4-(1,2,4-triazin-3-yl)morpholine 1m (1 mmol, 1 equiv.) and 2-naphthol 2a (1 mmol, 1 equiv.) in methanol (4 mL) BF₃^.OEt₂ (370 μL, 3 mmol, 3 equiv.) was added dropwise, and the resulting mixture was refluxed for 3 h. After cooling to room temperature the methanol was evaporated under reduced pressure, and the residue was dissolved in CHCl₃ (10 mL) and washed with aq. NaHCO₃. Then, the organic layer was dried over Na₂SO₄ and filtered. To the resulting solution MnO₂ (261 mg, 3 mmol, 3 equiv.) was added in one portion and the mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled to room temperature. MnO₂ was filtered and washed with CHCl₃ (3 × 10 mL). The combined organic phase was concentrated under reduced pressure, and the residue was crystallized from MeCN to afford pure 4ma. Yellow powder. Yield 225 mg, 75%; m.p. 230–232 °C. ¹H NMR (CDCl₃): 8.87–8.82 (m, 1H, H-1), 8.19 (d, 1H, J = 9.1 Hz, H-5), 8.02–7.96 (m, 1H, H-4), 7.80–7.73 (m, 1H, H-3), 7.70 (d, 1H, J = 9.1 Hz, H-6), 7.65–7.58 (m, 1H, H-2), 4.07–4.00 (m, 4H, morpholine), 3.95–3.88 (m, 4H, morpholine); ¹³C NMR (CDCl₃): 161.1, 158.9, 157.7, 144.2, 136.0, 130.5, 129.3, 129.3, 129.2, 126.3, 124.6, 113.5, 113.0, 67.0, 45.1. Anal. Calcd. For C₁₇H₁₄N₄O₂: C, 66.66; H, 4.61; N, 18.29%; found: C, 66.75; H, 4.54; N, 18.36%.

3.3.26. Synthesis of Benzofuro-Fused Triazines 4ah and 4ai

To a solution of triazine 1a (127 mg, 1 mmol) in TFA (4 mL), a corresponding phenol 2h or 2i (1 mmol) was added, and the resulting mixture was stirred at room temperature for 24 h. The completion of the reaction was monitored by TLC. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CHCl₃ (10 mL) and washed with 5% aq. NaHCO₃. The organic layer was dried over Na₂SO₄ and filtered. MnO₂ (52 mg, 0.6 mmol, 3 equiv.) was added to the resulting solution in one portion and the mixture was stirred at 50 °C for 3 h, cooled to room temperature, and MnO₂ was filtered and the filter cake washed with CHCl₃ (3 × 10 mL). The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford the pure product, using n-hexane-ethyl acetate (80:1) to afford 4ah or 4ai and n-hexane-ethyl acetate (40:1) to give 5ah or 5ai.

3.3.27. 6,8-Di-tert-butyl-3-(methylthio)benzofuro[3,2-e][1,2,4]triazine 4ah

Yellow powder. Yield 167 mg, 51%; m.p. 105–107 °C. Rf = 0.67 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 8.08 (d, 1H, J = 1.8 Hz H-5), 7.78 (d, 1H, J = 1.8 Hz, H-7), 2.79 (s, 3H, SCH₃), 1.57 (s, 9H, C(CH₃)₃), 1.41 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): 169.1, 160.7, 155.8, 148.6, 144.2, 136.1, 130.3, 118.8, 118.0, 35.4, 35.0, 31.7, 29.8, 14.8. Anal. Calcd. For C₁₈H₂₃N₃OS: C, 65.62; H, 7.04; N, 12.75%; found: C, 65.72; H, 7.10; N, 12.82%.

3.3.28. 2,4-Di-tert-butyl-6-(3-(methylthio)-1,2,4-triazin-5-yl)phenol 5ah

Pale yellow powder. Yield 67 mg, 20%; m.p. 113–115 °C. Rf = 0.64 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 12.73 (s, 1H, OH), 9.50 (s, 1H, H-6′), 7.69 (d, 1H, J = 2.3 Hz, H-5), 7.57 (d, 1H, J = 2.3 Hz, H-3), 2.75 (s, 3H, SCH₃), 1.46 (s, 9H, C(CH₃)₃), 1.35 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): 170.1, 160.0, 156.0, 141.8, 141.6, 139.0, 130.9, 121.2, 113.0, 35.5, 34.6, 31.5, 29.5, 14.1. Anal. Calcd. For C₁₈H₂₅N₃OS: C, 65.22; H, 7.60; N, 12.68%; found: C, 65.31; H, 7.51; N, 12.74%.

3.3.29. 6-(tert-Butyl)-3-(methylthio)benzofuro[3,2-e][1,2,4]triazine 4ai

Yellow powder. Yield 30 mg, 11%; m.p. 136–138 °C. Rf = 0.64 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 8.23 (d, 1H, J = 1.8 Hz, H-5), 7.88 (dd, 1H, J = 1.8 Hz, J = 8.9 Hz, H-7), 7.61 (d, 1H, J = 8.9 Hz, H-8), 2.78 (s, 3H, SCH₃), 1.42 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): 169.3, 161.0, 157.2, 149.0, 144.1, 133.5, 120.6, 118.5, 112.8, 35.3, 31.6, 14.8. Anal. Calcd. For C₁₄H₁₅N₃OS: C, 61.52; H, 5.53; N, 15.37%; found: C, 61.59; H, 5.44; N, 15.30%.

3.3.30. 4-(tert-Butyl)-2-(3-(methylthio)-1,2,4-triazin-5-yl)phenol 5ai

Yellow powder. Yield 120 mg, 43%; m.p. 123–125 °C. Rf = 0.59 (ethyl acetate:hexane, 1:1). ¹H NMR (CDCl₃): 11.97 (s, 1H, OH), 9.49 (s, 1H, H-6′), 7.80 (d, 1H, J = 2.0 Hz, H-3), 7.53 (dd, 1H, J = 2.0 Hz, J = 8.8 Hz, H-5), 6.99 (d, 1H, J = 8.8 Hz, H-8), 2.71 (s, 3H, SCH₃), 1.34 (s, 9H, C(CH₃)₃); ¹³C NMR (CDCl₃): 170.6, 160.3, 155.3, 142.9, 141.2, 133.5, 123.2, 119.1, 113.2, 34.4, 31.4, 14.0. Anal. Calcd. For C₁₄H₁₇N₃OS: C, 61.06; H, 6.22; N, 15.26%; found: C, 61.13; H, 6.29; N, 15.16%.

3.3.31. 40 mmol Scaled Synthesis of 3ad

To a stirred solution of triazine 1a (5.10 g, 40 mmol, 1 equiv.) and 2,7-dihydroxynaphthalene 2d (6.40 g, 40 mmol, 1 equiv.) in methanol (40 mL), BF₃.OEt₂ (40 mL, 320 mmol, 8 equiv.) was added dropwise and the resulting mixture was refluxed for 8 h. After cooling the methanol was evaporated under reduced pressure, and then the residue was treated with AcOEt (30 mL) and stirred for 15 min. The precipitate formed was filtered and washed with AcOEt (10 mL). The precipitate was suspended in AcOEt and the resulting mixture was washed with aq. NaHCO₃ solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure to give 3ad. The 3ad was dissolved in a mixture of CHCl₃:EtOH (4:1, 300 mL). To the resulting solution, MnO₂ (10.44 g, 120 mmol, 3 equiv.) was added in one portion. The resulting mixture was stirred at 50 °C for 6 h. The completion of the reaction was monitored by TLC. The reaction mixture was then cooled to room temperature, and the MnO₂ was filtered and washed with CHCl₃ (3 × 50 mL). The combined organic phase was concentrated under reduced pressure. The residue was recrystallized in EtOH to give pure 4ad (9.62 g, 85% in two steps).

3.4. Further Modifications of Compound 4aa

3.4.1. 10-(4-(Carbazol-9-yl)phenyl)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 7

To a solution of 10-(methylthio)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 4aa (100 mg, 1 equiv.) in dry THF (5 mL), we added CuTC (249 mg, 3.5 equiv), Pd[PPh₃]₄ (43 mg, 10 mol%) and (4-(9H-carbazol-9-yl)phenyl)boronic acid (322 mg, 3 equiv.). Then, the reaction mixture was stirred at reflux for 32 h. The progress of the reaction was monitored by TLC. After completion, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using n-hexane-ethyl acetate (10:1→5:1) to give a pure product 7 as yellow powder. Yield 126 mg, 73%; m.p. 280–282 °C. ¹H NMR (CDCl₃): 9.22–9.18 (m, 1H, H-1), 9.01–8.97 (m, 2H, H-2′′), 8.34–8.29 (m, 1H, H-5), 8.20–8.16 (m, 2H, H-1′), 8.11–8.08 (m, 1H, H-4), 7.94–7.82 (m 4H, H-2, H-6, H-3′′), 7.74–7.70 (m, 1H, H-3), 7.60-7.57 (m, 2H, H-4′), 7.48–7.43 (m, 2H, H-3′ or H-2′), 7.36-7.31 (m, 2H, H-2′ or H-3′); ¹³C NMR (CDCl₃): 161.1, 161.0, 158.8, 144.3, 140.7, 140.5, 137.1, 134.5, 130.9, 130.2, 129.8, 129.6, 129.2, 127.2, 126.9, 126.3, 125.1, 123.8, 120.6, 120.5, 113.8, 112.9, 110.1. Anal. Calcd. For C₃₁H₁₈N₄O: C, 80.50; H, 3.92; N, 12.11%; found: C, 80.31; H, 4.07; N, 11.96%.

3.4.2. 10-(Methylsulfonyl)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 8

mCPBA (427 mg, ≤77%, 2.2 equiv.) was dissolved in dry DCM (5 mL), Na₂SO₄ (2.0 g) was added to the resulting solution and the mixture was stirred for 10 min. Na₂SO₄ was filtered and washed with DCM (3 × 5 mL). The obtained solution of mCPBA was added dropwise to a solution of 4aa (133 mg, 0.5 mmol) in DCM (4 mL) at 0 °C. Then the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with an aqueous solution of NaHCO₃, washed with water and dried over Na₂SO_4, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using n-hexane-chloroform (2:1) as eluent to give pure 8 as a yellow powder. Yield 127 mg, 85%; m.p. 248–251 °C. ¹H NMR (CDCl₃): 9.07–9.04 (m, 1H, H-1), 8.43–8.39 (m, 1H, H-5), 8.11–8.08 (m, 1H, H-4), 7.93–7.88 (m, 2H, H-2, H-6), 7.76–7.72 (m, 1H, H-3), 7.65–7.58 (m, 1H, H-2), 3.66 (s, 2H, SO₂CH₃); ¹³C NMR (CDCl₃): 163.8, 161.6, 160.4, 145.3, 139.5, 131.0, 130.7, 129.7, 128.7, 127.8, 125.5, 113.0, 112.6, 40.6. Anal. Calcd. For C₁₄H₉N₃O₃S: C, 56.18; H, 3.03; N, 14.04%; found: C, 56.05; H, 3.20; N, 13.96%.

3.4.3. 10-(Carbazol-9-yl)naphtho[1′,2′:4,5]furo[3,2-e][1,2,4]triazine 9

To a solution of carbazole (106 mg, 1.9 equiv.) in dry DMF (3 mL), we added NaH (60% suspension in mineral oil, 19 mg, 1.4 equiv.) and the mixture was stirred for 10 min. Then methylsulfonyl derivative 8 (100 mg, 0.33 mmol) was added to the resulting solution and the mixture was heated at 70 °C for 12 h. After completion of the reaction, the mixture was diluted with water (15 mL), and the forming precipitate was filtered and washed with water and ethanol and purified by flash chromatography using n-hexane:chloroform (2:1) as the eluent to give pure 9 as a yellow powder. Yield 71 mg, 55%; m.p. 250–253 °C. ¹H NMR (HMPA d-18): 9.02–8.98 (m, 1H, H-1), 8.95-8.90 (d, J = 9.1 Hz, 1H, H-5), 8.85–8.78 (m, 2H, H-1′), 8.58–8.54 (m, 1H, H-4), 8.51–8.46 (m, 2H, H-4′), 8.42 (d, J = 9.1 Hz, 1H, H-6), 8.15–8.09 (m, 1H, H-3 and H-2), 7.89–7.82 (m, 1H, H-2 and H-3), 7.68–7.61 (m, 2H, H-3′ or H-2′), 7.50–7.43 (m, 2H, H-2′ or H-3′); ¹³C NMR (HMPAd-18): 160.2, 159.8, 157.9, 144.5, 139.4, 139.3, 131.5, 130.9, 130.6, 128.9, 127.3, 127.1, 126.0, 124.0, 122.9, 121.0, 115.1, 113.8, 113.2. Anal. Calcd. For C₂₅H₁₄N₄O: C, 77.71; H, 3.65; N, 14.50%; found: C, 77.90; H, 2.81; N, 14.29%.

4. Conclusions

In summary, we have developed an unusual MnO₂-induced oxidative cyclization in adducts of phenols and triazines. This method provides easy two-step access to benzofuro-fused triazine via the nucleophilic addition of the 2-naphthol to 1,2,4-triazine, followed by oxidative cyclization. The scope and limitations of this novel reaction have been investigated. Further application of the synthesized compound has been demonstrated by synthesizing carbazole-substituted benzofuro-fused triazines. The mechanistic study has revealed that the process proceeds through the formation of an O-coordinated Mn complex. We believe that the present methodology will open a new door to synthesizing important building blocks of α-sulfonylamino ketones.