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

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.


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 H 2 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.

Scheme 2. Retrosynthetic analyses of benzofurotriazine scaffold.
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 Scheme 2. Retrosynthetic analyses of benzofurotriazine scaffold.
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 MnO 2 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 CHCl 3 at 50 • C in the presence of 3 equiv. of γ-MnO 2 [81] provided the naphthofurotriazine 4aa in an almost quantitative yield after 3 h (  [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]  pling 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, 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][12][13][14]. By increasing the temperature, the yield of 4aa was decreased ( Using 2 equiv. of γ-MnO 2 85 3 18 Using 5 equiv. of γ-MnO 2 90 6 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 BF 3 . OEt 2 under refluxed conditions in methanol.
posed 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 3allylthio 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). With the optimized reaction conditions and a set of dihydrotriazines 3 in hand, we then examined the applicability and scope of this MnO 2 -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-(4methoxyphenyl) (PMP) derivatives 3ia and 3ja prepared under standard conditions (MsOH, AcOH) underwent MnO 2 -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 MnO 2 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 BF 3 . OEt 2 under reflux in methanol. 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 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-carbazolylphenylboronic 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). 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 N 2 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 1 H 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 1 H 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 sp 3 carbon is observed in the 1 H 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 MnO2, 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). 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 MnO 2 impregnated with nitric acid [82] in CH 2 Cl 2 at room temperature (Scheme 8b). The structure of the intermediate 4aa was supported by NMR and HRMS data. The 1 H 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 1 H 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 MnO 2 (Scheme 8c). We ascribed the structure of dihydrotriazine to this compound since a single proton resonance at the sp 3 carbon is observed in the 1 H 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 MnO 2 [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, MnO 2 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. 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 MnO 2 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.

Materials and Methods
General Information: All commercially available chemicals were used without further purifications. 1 H NMR (400 MHz) and 13 C 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 1 H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, Figure 2. Localizations of electron density on nitrogen and oxygen atoms for compounds 3aa, 3fa, 3ha, and 3ia.

Materials and Methods
General Information: All commercially available chemicals were used without further purifications. 1 H NMR (400 MHz) and 13 C NMR (101 MHz) spectra were registered on a Bruker DRX-400 Avance spectrometer with DMSO-d 6 or CDCl 3 as the 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; 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, ϕand 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 1 H and 13 C NMR spectra are provided on pages S26-S81 of the Supplementary Materials.
A solution of 40% glyoxal (8 mmol, 1160 mg) and NaHCO 3 (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 (CO 2 ) 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 Na 2 SO 4 , filtered, and concentrated in vacuo to obtain oil or a solid triazine compound.

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 Na 2 SO 4 (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 NaHCO 3 . The organic layer was evaporated, yielding pure compound 1h.

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].

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. NaHCO 3 solution and extracted with AcOEt (3 × 10 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography or recrystallization from the corresponding solvent to afford product 3.

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 BF 3 . OEt 2 (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. NaHCO 3 solution (50 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure. The crude product was recrystallized from MeCN to obtain the product 3ab-3ae.

General Procedure for the Synthesis of Naphthofuro-Fused Triazines 4
To a stirred solution of 3 (0.2 mmol, 1 equiv.) in CHCl 3 (3 mL), MnO 2 (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 MnO 2 was filtered and the filter cake was washed with CHCl 3 (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. [1 ,2 :4,5]furo [3,2-  A mixture of 4ha and 5ha was separated by silica gel chromatography using n-hexaneethyl acetate (17:1) to isolate 4ha and n-hexane-ethyl acetate (10:1) to give 5ha.  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 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. A mixture of 4ja and 5ja was separated by silica gel chromatography using n-hexaneethyl acetate (17:1) to isolate 4ja and n-hexane-ethyl acetate (7:1) to give 5ja.  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 CHCl 3 (10 mL) and washed with saturated aq. NaHCO 3 solution (10 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered. To the organic phase, MnO 2 (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. MnO 2 was filtered and washed with CHCl 3 (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.

10-(Methylthio)naphtho
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. [1 ,2 :4,5]furo [3,2- A mixture of 4la and 5la was separated by chromatography on silica gel using nhexane-ethyl acetate (17:1) to give 4la, and n-hexane-ethyl acetate (10:1) to give 5la. 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) BF 3 . OEt 2 (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 CHCl 3 (10 mL) and washed with aq. NaHCO 3 . Then, the organic layer was dried over Na 2 SO 4 and filtered. To the resulting solution MnO 2 (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. MnO 2 was filtered and washed with CHCl 3 (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. 1  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 CHCl 3 (10 mL) and washed with 5% aq. NaHCO 3 . The organic layer was dried over Na 2 SO 4 and filtered. MnO 2 (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 MnO 2 was filtered and the filter cake washed with CHCl 3 (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

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), BF 3 .OEt 2 (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. NaHCO 3 solution. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure to give 3ad. The 3ad was dissolved in a mixture of CHCl 3 :EtOH (4:1, 300 mL). To the resulting solution, MnO 2 (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 MnO 2 was filtered and washed with CHCl 3 (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).

Conclusions
In summary, we have developed an unusual MnO 2 -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.