Heterogeneously Catalyzed Domino Synthesis of 3-Indolylquinones Involving Direct Oxidative C–C Coupling of Hydroquinones and Indoles

Abstract

A domino synthesis of 3-indolylquinones was achieved successfully via direct oxidative C–C coupling of hydroquinones with indoles over Ag₂O and Fe₃O₄/povidone–phosphotungstic acid (PVP–PWA) catalysts using H₂O₂ in tetrahydrofuran at room temperature. Ag₂O catalyzed the in situ oxidation of hydroquinone and 3-indolylhydroquinone intermediates, whereas ferrite solid acid, Fe₃O₄/PVP–PWA, with a 1:4:1 ratio of Fe₃O₄, PVP, and PWA, catalyzed the activation of quinones. The efficiency of this catalytic domino approach was established by a broad scope of substrates involving a variety of hydroquinones and quinones to give high yields (81–97%) of 3-indolylquinones. Fe₃O₄/PVP–PWA was separated magnetically, whereas simple filtration could separate Ag₂O, both of which could be recycled several times without losing their activities.

Introduction

3-Indolylquinones are core structures of highly significant biologically active natural products called “asterriquinones”, which are found in fungal species like Aspergillus terreus, Chaetomium sp., and Pseudomassaria sp.¹⁻⁵ Asterriquinones are emerging as potential pharmacophores due to their wide range of biological activities, including inhibition of human immunodeficiency virus reverse transcriptase;⁶⁻⁸ these also act as antitumor agents to promote apoptotic cell death.^9,10 Among these, demethylasterriquinone B1, an orally active insulin mimetic with excellent antidiabetic activity, exhibits nonprotein behavior (Figure 1).¹¹ 3-Indolylquinone represents a pharmacophore for protein–protein interactions and thus should be antagonistic toward bis-indolylquinones in asterriquinones. 3-Indolylquinone could be used in the total synthesis of asterriquinones and also as reagents to probe the biological activity of indolylquinones.

Figure 1.

Structures of some biologically active asterriquinone derivatives.

3-Indolylquinones were first synthesized by Möhlau et al. in 1911, who obtained a red product from the reaction of benzoquinone and indole; however, this product was not isolated.¹² Further, in 1951 Bu’Lock reinvestigated and isolated 3-indolylquinones in a very low yield.¹³ Thereafter, high-yield synthesis of 3-indolylquinones was achieved using excess quinone in presence of a clay catalyst,¹⁴ InBr₃,¹⁵ and Bi(OTf)₂¹⁶ under mild reaction conditions. Similarly, various efforts have been made by Park and co-workers with mineral acids, Zn(OTf)_2, and mercury reagents along with Pd(II)/Cu(OAc)₂.¹⁷⁻¹⁹ Synthesis of 3-indolylquinones was also attempted by ultrasound activation using molecular iodine as a catalyst²⁰ and using nano iron hydroxide²¹ and also through catalyst-free-water-promoted reactions.²² The cheap external oxidant DDQ with Ag₂CO₃ on celite was explored to avoid excess use of costly quinone substrates to oxidize the intermediate under intensive conditions in tetrahydrofuran (THF) under reflux for a long reaction time.^23,24 Nevertheless, these protocols suffered serious environmental problems, like cumbersome workup to separate the byproducts, such as hydroquinones, and loss of reusability and recyclability of the catalysts. Hence, we developed a novel catalytic system for oxidation of hydroquinone followed by C–C bond formation, resulting in efficient synthesis of 3-indolylquinones. Our approach is unique in that it eliminates the use of excessive quinone, which produces hydroquinone that necessitates separation from the crude (Scheme 1).

Scheme 1. General Reaction Scheme for the Synthesis of 3-Indolylquinone.

In this article, we envisioned the direct oxidative C–C coupling of hydroquinones and indoles at room temperature (RT) over recyclable Ag₂O and Fe₃O₄/povidone–phosphotungstic acid (PVP–PWA) (141) catalysts. The catalyst Fe₃O₄/PVP–PWA (141) has been recently reported by us for the synthesis of 2-cyanoacrylamides.²⁵ Characterization details, such as data from transmission electron microscopy, ammonia temperature-programmed desorption (TPD), and Brunauer–Emmett–Teller (BET) surface area measurements are provided in the Supporting Information (Tables S1 and S2 and Figure S1). Although Ag₂O and m-CPBA have been reported for the oxidation of hydroquinones and phenols to benzoquinones, respectively,^26,27 surprisingly, none of them have yet been explored for the synthesis of 3-indolylquinones. Hence, in situ production of quinones from hydroquinones over Ag₂O was considered for the synthesis of 3-indolylquinones (Scheme 2). Subsequent activation of quinones without isolation was achieved with the solid acid catalyst Fe₃O₄/PVP–PWA (141) for addition to indoles.

Scheme 2. Single-Pot Direct Synthesis of 3-Indolylquinones from Hydroquinones.

Results and Discussion

Study of Oxidizing Agents and Catalysts

As the first step of our strategy involves in situ oxidation of hydroquinones to quinones, the study of different oxidants and catalysts was mandatory, and the results are presented in Table 1.

Table 1. Screening of Oxidants for the Synthesis of 3-Indolylquinone.

entry	oxidant	catalyst	yieldab, %
1	air		NR
2	oxygen		NR
3	H2O2		NR
4	H2O2	MoO3	10a
5	H2O2	WO3	15a
6	H2O2	Fe3O4/PVP–PWA	10a
7		Ag2O	30a/40b
8	air	Ag2O	25a/45b
9	oxygen	Ag2O	27a/41b
10	H2O2	Ag2O	94a
11	H2O2	AgNO3	35a
12	DDQ		41a/55b
13	KBrO3		10a/30b
14	K4FeCN6		NR
15	oxone		NR

^aReactions were performed with 1:1 2-methylhydroquinone/2-methylindole, 0.1 g Fe₃O₄/PVP–PWA (141), 3 mmol oxidant, 10 mL of THF, and 20 mol % catalyst in 1 atm air/oxygen at RT for 2 h. NR, no reaction; isolated yield of 3-indolylquinone after column chromatography. Bold values represent maximum product yield under optimized reaction conditions.

^bThe product 3-indolylhydroquinone is formed.

Initially, air, oxygen, and H₂O₂ were used for the oxidation of hydroquinone (1a) without any catalyst, but no products were obtained, implying that not only the oxidant but also a suitable catalyst was needed for the oxidation (Table 1, entries 1–3). Therefore, MoO₃ and WO₃ were evaluated as oxidation catalysts in presence of H₂O₂, which gave 10 and 15% yields, respectively (Table 1, entries 4 and 5). Fe₃O₄/PVP–PWA (141) was also evaluated as a catalyst for this oxidation due to the presence of WO₃, but only a 10% yield was obtained, similar to that obtained with pure WO₃ (Table 1, entries 5 and 6). Although a well-known oxidation catalyst, Ag₂O when used alone yielded only 30% 3-indolylquinone (3a) and 40% 3-indolylhydroquinone (4). This is due to the fact that reduced Ag could not be reoxidized to Ag₂O (Table 1, entry 7). Surprisingly, Ag₂O in presence of air and oxygen as oxidants also showed poor performances, with yields of 3a (about 25 and 27%, respectively) and 4 (45 and 41%, respectively) similar to those obtained in absence of an oxidant (Table 1, entries 8 and 9). When Ag₂O was combined with H₂O_2, the product yield increased to 94%. H₂O₂ when used as an oxidant with AgNO₃ as a catalyst gave only a 35% yield of 3a (Table 1, entries 10 and 11). Thus, Ag₂O in the presence of H₂O₂ served as the best catalyst for the oxidation of 1a and 3-indolylhydroquinone (4) during the synthesis of 3a. Various other oxidants, like DDQ and KBrO₃, gave product yields of 41 and 10%, with 55 and 30% of 4, respectively (Table 1, entries 12 and 13). Interestingly, K₄FeCN₆ and oxone did not furnish any products (Table 1, entries 14 and 15).

Optimization of Acid Catalysts

Having established the first oxidation step catalyzed by Ag₂O to give quinone, we then screened several solid acid catalysts for the synthesis of 3-indolylquinones, and the results are summarized in Table 2.

Table 2. Catalyst Screening for the Synthesis of 3-Indolylquinones from Hydroquinone.

entry	catalyst	yieldsa, %
1		00/86c
2	PVP	00/73c
3	Fe3O4	00/81c
4	Amberlyst-15	12/67c
5	PWA	75/9c
6	PVP–PWA	83
7	PVP–phosphomolybdic acid (PMA)	72/10c
8	PVP–silicotungstic acid (STA)	65/20c
9	Fe3O4/PVP–PWA (131)	75/6c
10	Fe3O4/PVP–PWA (141)	94
11	Fe3O4/PVP–PWA (181)	42/32c
12	Fe3O4/PVP–PWA (141)	95b
13	Fe3O4/PVP–PWA (141)	97a,d

^aReactions were performed with 1:1 2-methylhydroquinone/2-methylindole, 0.1 g Fe₃O₄/PVP–PWA (141), 20 mol % Ag₂O, 1.5 [quinone]/3 [hydroquinone] mmol H₂O₂, and 10 mL of THF at RT for 5 h; isolated yields of 3a after column chromatography. Bold values represent maximum product yield under optimized reaction conditions.

^bReflux condition.

^cByproduct 2-methylbenzoquinone was obtained (5).

^d2-Methylbenzoquinone was used as the reactant.

A control reaction of 2-methylhydroquinone (1a) with 2-methylindole (2a) in the presence of Ag₂O and H₂O₂ furnished 5a in 86% yield, without the formation of 3a (Table 2, entry 1).

PVP and Fe₃O₄ did not produce 3a, and only 5a was produced (Table 2, entries 2 and 3). To accomplish C–C coupling of the oxidation product quinone (5a) with indole (2a), several acid catalysts were screened. Initially, commercially available Amberlyst-15 gave only 12% of 3a, with 67% of 5a (Table 2, entry 4). The yield of 3a increased to 71% with PWA which clearly indicated that strong acid sites were necessary to catalyze the C–C coupling of 1a and 2a (Table 2, entry 5). PVP–PWA showed the highest yield of 3a, of 83%, as compared with other heteropoly acids, such as PMA and STA, on PVP (Table 2, entries 6–8).

A triple composite of PVP–PWA with Fe₃O₄, designated as Fe₃O₄/PVP–PWA, which was previously reported by our group as the best solid acid catalyst,²⁴ with varying mole ratios of Fe₃O_4, PVP, and PWA in this work exhibited different levels of activity; for example, a 1:3:1 composition gave the product in 75% yield, whereas a 1:4:1 composition enhanced the yield of 3a to 94% (Table 2, entries 9 and 10). With a further increase in PVP, the yields of 3a and 5a markedly reduced to 42 and 32% (Table 2, entry 11). This could be attributed to the masking of acid sites by a higher concentration of PVP. At a higher temperature (under reflux) the yield of 3a remained almost same as that at RT (Table 2, entry 12). 5a when used as a substrate yielded 97% of 3a, which clearly confirmed the high reactivity of quinones under our standard reaction conditions (Table 2, entry 13). Thus, Fe₃O₄/PVP–PWA (141) was chosen as the best catalyst for further studies on the synthesis of 3-indolylquinones.

Solvent Screening

Table 3 illustrates the results of screening solvents for the synthesis of 3-indolylquinone (3a) by reacting 1a and 2-methylindole 2a over a combination of Fe₃O₄/PVP–PWA (141) and Ag₂O in H₂O₂ at RT.

Table 3. Screening of Solvents for the Synthesis of 3-Indolylquinone from Hydroquinone.

entry	solvent	yieldsa,b,c, %	time, h
1	nil	9a/15c	10
2	water	12a/67c	15
3	MeOH	45a/10b/20c	7
4	1,4-dioxane	10a	9
5	DCM	18a	8
6	acetonitrile (ACN)	68a/24c	8
7	THF	93a	2

^aReactions were performed with 1:1 2-methylhydroquinone/2-methylindole, 0.1 g Fe₃O₄/PVP–PWA (141), 20 mol % Ag₂O, 3 mmol H₂O₂, and 10 mL of solvent at RT; isolated yield of the 3-indolylquinone after column chromatography. Bold values represent maximum product yield under optimized reaction conditions.

^bThe byproduct is 4-methoxy-hydroquinone (6).

^cThe byproduct 2-methylbenzoquinone was formed.

A control experiment without any solvent gave a very poor yield of <10% of 3a even after a reaction time of 10 h, due to lack of a homogeneous reaction phase (Table 3, entry 1). With water as a solvent, 3a was obtained in 12% yield even after a prolonged reaction time, with oxidation product 5a (67%; Table 3, entry 2) being present in majority. A highly polar and protic solvent like methanol gave the desired C–C coupling product 3a in 45% yield, but etherification was also observed to give 4-methoxy-hydroquinone (6) (10%), along with 20% of 5a (Table 3, entry 3). 1,4-Dioxane and DCM gave only 10 and 18% yields, respectively, after 8–9 h (Table 3, entries 4 and 5), whereas ACN as a solvent enhanced the yield of the desired product to 68%, with 24% of 5a (Table 3, entry 6). The maximum yield of 3a achieved was 93%, when THF was used as a solvent, in a very short reaction time of about 2 h (Table 3, entry 7). Hence, THF was identified as the most suitable solvent for the synthesis of 3-indolylquinones under optimized reaction conditions.

Effect of Catalyst Amount

As the availability of active sites varied with a variation in the catalyst amount, the latter had a considerable effect on product yields, and the results are presented in Table 4.

Table 4. Effect of Catalysts Concentration in the Synthesis of 3-Indolylquinone.

entry	catalyst	yieldsa,b,c, %
Fe3O4/PVP–PWA (141), g
1	0.025	60/21c
2	0.05	82/6c
3	0.1	94
4	0.15	94
Ag2O, mol %
5	5	23b
6	10	45b
7	15	70b
8	20	95b
9	40	95b

^aReactions were performed with 1:1 2-methylhydroquinone/2-methylindole, 10 mL of THF, 20 mol % Ag₂O, and 3 mmol H₂O₂ at RT for 5 h; isolated yields of 3-indolylquinone after column chromatography. Bold values represent maximum product yield under optimized reaction conditions.

^bFe₃O₄/PVP–PWA (141) (0.1 g).

^cThe byproduct 2-methyl benzoquinone is formed.

Initially, the amount of Fe₃O₄/PVP–PWA (141) was varied from 0.025 to 0.150 g by keeping Ag₂O at a constant concentration of 20 mol %. It was observed that the yield of the desired product, 3a, was also enhanced. At 0.025 g, the catalyst produced only 60% of 3a, with 21% of 5a (Table 4, entry 1). The yield of product 3a increased up to 82% on doubling the catalyst amount, but still, 6% of 5a was observed (Table 4, entry 2). On further increasing the catalyst amount to 0.1 g, 94% of the desired product, 3a, was obtained, without the formation of the intermediate. Above 0.1 g, no effect of catalyst amount on the product yield was observed (Table 4, entry 4). Keeping Fe₃O₄/PVP–PWA (141) at an optimum value of 0.1 g, an increase in Ag₂O led to an ascending trend in the yield of 3a. Ag₂O at 5 mol % gave the lowest yield of 23%, whereas an excellent yield of up to 95% was observed with 20 mol % of the catalyst. Further increasing the Ag₂O concentration to 40 mol % did not enhance the product yield (Table 4, entries 5–9); thus, 20 mol % Ag₂O was most optimal for oxidation of hydroquinone to 3-indolylquinone.

Substrate Scope

The excellent performance of the catalyst system with Ag₂O and Fe₃O₄/PVP–PWA (141) in the single-pot synthesis of 3-indolylquinones encouraged us to elaborate their applications for a broad substrate scope involving a variety of hydroquinones and quinones with various indoles at RT. As shown in Table 5, excellent yields of 3-indolylquinones (3a–n) of up to 96% were obtained upon reacting 1,4-naphthoquinone with various indoles having electron-donating groups, as in the case of 1-methyl, 2-methyl, and 1-methyl-2-phenyl indoles. However, the activity shown by 1H-indole was lower even after a prolonged reaction time of 5 h (Table 5, entries 3b–e). Electron-donating groups present on the phenyl ring of indoles also helped elevate the product yields (Table 5, entries 3f–g).

Table 5. Substrate Scope for Direct Oxidative Synthesis of 3-Indolylquinones from Hydroquinones Using Ag₂O/H₂O₂ and Fe₃O₄/PVP–PWA (141)^a.

^aReactions were performed with 1:1 hydroquinone/indole, 0.1 g Fe₃O₄/PVP–PWA (141), 20 mol % Ag₂O, 3 mmol H₂O₂, and 10 mL of THF at RT for 2–5 h; isolated yields after column chromatography.

1,4-Benzoquinones smoothly reacted with 2-methyl and 1-methyl indole to give 93 and 97% yields of the corresponding products; however, indole provided only a moderate yield (81%) (Table 5, entries 3h–k and 3a). 2,5-Dichloroquinones also reacted efficiently with indoles, giving high product yields of 89–95% (Table 5, entries 3l–n). Thus, the suitability of our approach for single-pot synthesis of 3-indolylquinones starting from hydroquinones and involving oxidative C–C coupling over Ag₂O-Fe₃O₄/PVP–PWA (141) could be successfully demonstrated.

The conventional synthesis of 3-indolylquinones from indoles and quinones was also evaluated with our Ag₂O/H₂O₂ and Fe₃O₄/PVP–PWA (141) catalyst system in THF at RT. Table 6 shows that 2-methylindole (2a) reacted actively with 1,4-naphthoquinone and benzoquinone to produce excellent yields of the products of up to 97 and 94% (Table 6, entries 3d and 3h). Similarly, 1-methyl-2-phenyl indole with benzoquinone also provided a high yield of 91% (Table 6, entry 3i). 2-Methylbenzoquinone treated with 1H- and 2-methyl-indole gave 83 and 89% yields of the products, respectively (Table 6, entries 3j and 3a). 2,5-Dichlorobenzoquinone also provided 95–97% yields of the products with various indoles (Table 6, entries 3l and 3m).

Table 6. Substrate Scope for Direct Coupling of Quinones and Indoles Using Ag₂O/H₂O₂ and Fe₃O₄/PVP–PWA (141)^a.

^aReactions were performed with 1:1 quinone/indole, 0.1 g Fe₃O₄/PVP–PWA (141), 20 mol % Ag₂O, 1.5 mmol H₂O₂, and 10 mL of THF at RT for 2–5 h; isolated yield after column chromatography.

Reaction Pathway

The reaction pathway for the synthesis of 3-indolylquinone, as proposed in Figure 2, commences with the in situ oxidation of hydroquinone (A) to quinone (B) over a Ag₂O catalyst. This is followed by the activation of quinone, which forms a C–C bond with indoles over Fe₃O₄/PVP–PWA (141) to give 3-indolylhydroquinone (C), and the catalyst Fe₃O₄/PVP–PWA (141) is regenerated for the next cycle. Finally, 3-indolylhydroquinone further oxidized to 3-indolylquinone (D) by Ag₂O regenerated by H₂O₂.

Figure 2.

Proposed reaction pathway for the direct oxidative synthesis of 3-indolylquinone.

Recycle Study

The magnetic nature of catalyst Fe₃O₄/PVP–PWA (141) allowed its retention in the flask, whereas simple filtration of the reaction crude could offer easy recovery of Ag₂O (Figure 3). Following this procedure, several catalyst-recycling experiments were performed for both 2-methylhydroquinone and 2-methylbenzoquinone substrates separately with 2-methylindole under our standard reaction conditions to give 3-indolylquinones in 95 and 97% yields, respectively. After repeating the reactions for four times with the reused catalysts, only marginal decreases in the yields, up to 91 and 92%, respectively, were observed for both substrates (Figure 4). The absence of “W”, “Fe”, and “Ag” in the ICP-OES study in the filtrate after the last recycle run also confirmed the stability of both the catalysts under our standard reaction conditions. Thus, catalysts Fe₃O₄/PVP–PWA (141) and Ag₂O could be efficiently recycled, which also established the stability of the catalyst system.

Figure 3.

Schematic presentation of the separation of catalysts in the recycling experiment.

Figure 4.

Recycling experiments for the synthesis of 3-indolylquinones. Reactions were performed with 1:1 2MeHQ/2MeBQ–2Me-indole ( mmol), 0.1 g Fe₃O₄/PVP–PWA (141), 20 mol % Ag₂O, 1.5/3 mmol H₂O₂, and 10 mL of THF at RT for 2 h; isolated yield of the 3-indolylquinones after column chromatography.

Stability of the Catalyst Fe₃O₄/PVP–PWA (141)

The stability of the Fe₃O₄/PVP–PWA (141) catalyst was also confirmed by studying the Fourier transform infrared (FT-IR) spectra of fresh and used catalyst samples. Characteristic peaks of Keggin ions were distinctly observed at 1078, 976, 893, and 808 cm^–1 for the fresh Fe₃O₄/PVP–PWA (141) sample in Figure 5, corresponding to the terminal oxygen of P–O, W=O, the corner-sharing oxygen of W–Ob–W, and the edge-sharing oxygen of W–Oc–W, respectively (Figure 5A). All of these peaks were also observed at nearly the same position in the recovered catalyst sample after reaction (Figure 5B), which confirmed the retention of PWA in the catalyst, Fe₃O₄/PVP–PWA (141), after reaction even under oxidation conditions.

Figure 5.

FT-IR study of (A) fresh and (B) recovered Fe₃O₄/PVP–PWA (141) catalyst.

Conclusions

We newly developed an efficient catalytic system combining Ag₂O in H₂O₂ and Fe₃O₄/PVP–PWA for the domino synthesis of 3-indolylquinones in high-to-excellent yields (81–97%). Various oxidizing agents and catalysts were screened for oxidation, but Ag₂O in H₂O₂ was able to oxidize both hydroquinones and 3-indolylhydroquinones over a very short reaction time. Among the different Fe₃O₄/PVP–PWA catalytic systems prepared with varying mole ratios of Fe₃O₄, PVP, and PWA, the Fe₃O₄/PVP–PWA (141) catalytic system showed rapid activation of the quinones. FT-IR study also revealed the retention of the heteropoly acid structure in the catalyst Fe₃O₄/PVP–PWA (141) after reaction, which confirmed the stability of the catalyst under H₂O₂. The applicability of our catalyst system was proven for a broad substrate scope with various hydroquinones and benzoquinones with indoles under the standard reaction conditions. Recycling experiments proved that both the catalysts, Ag₂O and Fe₃O₄/PVP–PWA (141), were efficiently recycled at least up to four times for hydroquinone and benzoquinone without any loss of activity.

Experimental Section

Materials and General Methods

All reactions were carried out in a flame-dried glass apparatus under an open atmosphere using analytical reagent-grade dried solvents procured from Aldrich, Alfa Aser, Thomas Baker, etc. Heteropoly acids were purchased from Thomas Baker, and thin-layer chromatography (TLC) plates were purchased from Loba. The products were separated using 100–200 mesh silica for column chromatography, with 5% ethyl acetate in petroleum ether as the mobile phase; characterized by ¹H NMR, using DMSO-d₆ or CDCl₃ (0.01% TMS) as the solvent, on a 200 MHz frequency Bruker instrument; and compared with authentic samples reported in the literature. FT-IR spectroscopy was performed on a PerkinElmer frontier instrument in the ATR (PIKE make) mode at RT.

General Procedure for the Synthesis of the Catalyst Fe₃O₄/PVP–PWA

Fe₃O₄/PVP–PWA was synthesized with varying ratios of Fe₃O₄, PVP, and PWA, 1:4:1, 1:3:1, and 1:8:1, as required and designated as Fe₃O₄/PVP–PWA (131), Fe₃O₄/PVP–PWA (141), or Fe₃O₄/PVP–PWA (181).

PVP (0.333/0.444/0.888 g, 3/4/8 mmol) was taken in a 250 mL round-bottom flask as per requirement. Thereafter, the solution of PWA (2.880 g, 1 mmol) in 30 mL of distilled water was added dropwise with stirring using an addition funnel for 15 min. Simultaneously, Fe₃O₄ (0.231 g, 1 mmol) was added and the mixture was stirred for 12 h at RT; a brown precipitate was obtained. Water was removed from the mixture on a rotavapor for 2 h at 80 °C. Finally, the brown powdered catalyst was obtained in 95% yield, which was then dried at 100 °C for 6 h.

Experimental Procedure for the Synthesis of Quinones Using Ag₂O

Some quinones were synthesized from hydroquinones using the reported procedure, with slight modifications.²⁵ To a mixture of hydroquinone (1 mmol), Ag₂O (0.2 mmol), and THF (5 mL) stirred for 5 min was added dropwise a solution of 30% aq. H₂O₂ (2.5 mmol) in THF (5 mL) under stirring for 10 min at RT. Then, the mixture was continuously stirred for 1–2 h at RT, and progress of the reaction was monitored by TLC. Subsequently, the reaction mixture was diluted with water (15 mL) and then extracted with diethyl ether (2 × 25 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over Na₂SO₄. The solvents were evaporated under reduced pressure, affording quinones in up to 90% yield.

General Procedure for the Synthesis of 3-Indolylquinones from Hydroquinone and Benzoquinones

Catalyst Fe₃O₄/PVP–PWA (0.1 g) was added to a solution of benzoquinone or hydroquinone (1 mmol) and indole (1 mmol) in a 25 mL round-bottom flask containing 5 mL of THF. The solution was then stirred and Ag₂O (0.2 mmol) was added to the mixture. Finally, 30% aq. H₂O₂ (1.5 mmol for benzoquinone and 3 mmol for hydroquinone) in 5 mL of THF was added dropwise to the mixture using an addition funnel over 15 min (the THF/H₂O₂ with Ag₂O used here was completely safe and nonexplosive because the ratio of THF/H₂O₂ was 46:1 and the reaction was carried out at RT, 25 °C). Thereafter, the reaction mixture was stirred again, and progress of the reaction was monitored using TLC. After completion of the reaction, catalyst Fe₃O₄/PVP–PWA separated using a magnet and the solution was filtered to separate the Ag₂O. After evaporation of THF, the crude was further extracted with ethyl acetate and washed with 30 mL of water to remove excess H₂O₂. Finally, the compounds were separated by column chromatography.

Spectroscopic Data of all Compounds

All products were confirmed using ¹H NMR.^15−19,23 However, ¹³C NMR spectra of compounds 3a, 3b, 3f, 3h, 3j, 3k, 3m, and 3n were not clearly distinguishable.

2-(1H-Indol-3-yl)naphthalene-1,4-dione (3b, Table 5)

Solid, reddish brown; ¹H NMR (200 MHz, DMSO-d₆): δ 12.04 (br s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.98–8.13 (m, 2H), 7.84–7.93 (m, 3H), 7.50–7.57 (m, 1H), 7.20–7.29 (m, 3H) ppm.

2-(1-Methyl-1H-indol-3-yl)naphthalene-1,4-dione (3c, Table 5)

Solid, brown; ¹H NMR (200 MHz, chloroform-d): δ 8.11–8.20 (m, 3H), 7.99–8.04 (m, 1H), 7.71–7.79 (m, 2H), 7.45 (s, 1H), 7.40–7.44 (m, 1H), 7.29–7.38 (m, 2H), 3.90 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆): δ 178.0, 176.7, 143.2, 139.3, 138.8, 137.5, 135.4, 133.2, 126.9, 120.9, 120.4, 119.6, 119.3, 117.5, 110.9, 104.1, 13.2 ppm.

2-(2-Methyl-1H-indol-3-yl)naphthalene-1,4-dione (3d, Tables 5 and 6)

Solid, violet; ¹H NMR (200 MHz, chloroform-d): δ 8.35 (br s, 1H), 8.11–8.26 (m, 2H), 7.73–7.85 (m, 2H), 7.50–7.61 (m, 1H), 7.27–7.39 (m, 1H), 7.09–7.25 (m, 3H), 2.49 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆): δ 184.4, 184.1, 144.2, 138.3, 135.5, 133.9, 133.7, 133.4, 132.5, 131.8, 127.4, 126.5, 125.3, 121.2, 119.9, 119.1, 111.0, 106.2, 13.4 ppm.

2-(1-Methyl-2-phenyl-1H-indol-3-yl)naphthalene-1,4-dione (3e, Table 5)

Solid, blue; ¹H NMR (200 MHz, chloroform-d): δ 8.07 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.60–7.78 (m, 3H), 7.32–7.48 (m, 7H), 7.29 (d, J = 1.5 Hz, 1H), 7.25 (d, J = 1.3 Hz, 1H), 6.96 (s, 1H), 3.73 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆): δ 184.0, 183.6, 144.4, 141.5, 137.2, 135.1, 134.0, 133.9, 132.3, 131.6, 130.9, 130.4, 128.6, 126.5, 126.3, 125.3, 122.4, 120.8, 119.7, 110.6, 107.4, 31.2 ppm.

2-(5-Bromo-1H-indol-3-yl) naphthalene-1,4-dione (3f, Table 5)

Solid, reddish brown; ¹H NMR (200 MHz, DMSO-d₆): δ 12.15 (br s, 1H), 8.22–8.04 (m, 5H), 7.32–7.52 (m, 3H), 7.21 (s, 1 H) ppm.

2-(5-Methoxy-1H-indol-3-yl)naphthalene-1,4-dione (3g, Table 5)

Solid, reddish brown; ¹H NMR (200 MHz, DMSO-d₆): δ 11.92 (br s, 1H), 9.30 (s, 1H), 8.01–8.06 (m, 4H), 7.21 (s, 1H), 7.30 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 6.65 (s, 1H), 3.82 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆): δ 185.0, 184.0, 155.0, 142.1, 133.9, 133.4, 133.0, 132.4, 131.6, 127.1, 126.4, 125.7, 125.1, 113.2, 112.0, 107.2, 102.5, 55.4 ppm.

2-(2-Methyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3h, Tables 5 and 6)

Solid, blue; ¹H NMR (200 MHz, DMSO-d₆): δ 11.61 (br s, 1H), 7.25–7.43 (m, 2H), 6.87–7.12 (m, 4H), 6.75 (br s, 1H), 2.36 (s, 3H) ppm.

2-(1-Methyl-2-phenyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3i, Tables 5 and 6)

Solid, violet; ¹H NMR (200 MHz, DMSO-d₆): δ 7.35–7.69 (m, 7H), 7.07–7.35 (m, 2H), 6.70–6.91 (m, 2H), 6.64 (s, 1H), 3.69 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆): δ 187.2, 186.0, 142.2, 141.3, 137.1, 136.9, 136.3, 132.7, 130.9, 130.4, 128.5, 126.3, 122.5, 120.8, 119.4, 110.6, 106.9, 31.1 ppm.

2-(1H-Indol-3-yl)-5-methylcyclohexa-2,5-diene-1,4-dione (3j, Tables 5 and 6)

Solid, black; ¹H NMR (200 MHz, DMSO-d₆): δ 9.19 (s, 1H), 7.74–7.89 (m, 1H), 7.39–7.50 (m, 2H), 7.24–7.36 (m, 2H), 7.09–7.18 (m, 1H), 6.84 (d, J = 8.2 Hz, 1H), 2.19 (s, 3 H) ppm.

2-Methyl-5-(2-methyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3a, Tables 5 and 6)

Solid, blue; ¹H NMR (200 MHz, DMSO-d₆): δ 11.58 (br s, 1H), 7.26–7.40 (m, 2H), 6.95–7.12 (m, 2H), 6.83 (s, 1H), 6.74 (s, 1H), 2.36 (s, 3H), 2.03 (s, 3H) ppm.

2-Methyl-5-(1-methyl-2-phenyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3k, Table 5)

Solid, violet; ¹H NMR (200 MHz, DMSO-d₆): δ 7.37–7.75 (m, 7H), 7.04–7.36 (m, 2H), 6.64 (d, J = 6.1 Hz, 1H), 6.52 (s, 1H), 3.69 (s, 3H), 1.96–1.85 (d, 3H) ppm.

2,5-Dichloro-3-(2-methyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3l, Tables 5 and 6)

Solid, violet; ¹H NMR (200 MHz, DMSO-d₆): δ 11.55 (s, 1H), 7.56 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.91–7.08 (m, 2H), 2.26 (s, 3H) ppm. ¹³C NMR (50 MHz, DMSO-d₆) δ 178.0, 176.7, 143.2, 139.3, 138.8, 137.5, 135.4, 133.2, 126.9, 120.9, 120.4, 119.6, 119.3, 117.5, 110.9, 104.1, 13.2 ppm.

2,5-Dichloro-3-(1-methyl-2-phenyl-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3m, Tables 5 and 6)

Solid, violet; ¹H NMR (200 MHz, DMSO-d₆): δ 7.57–7.65 (m, 1H), 7.54 (s, 1H), 7.36–7.48 (m, 6H), 7.24–7.30 (m, 1H), 7.10–7.20 (m, 1H), 3.77 (s, 3H) ppm.

2,5-Dichloro-3-(5-methoxy-1H-indol-3-yl)cyclohexa-2,5-diene-1,4-dione (3n, Table 5)

Solid, violet; ¹H NMR (200 MHz, DMSO-d₆): δ 11.77 (br s, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.50–7.56 (m, 1H), 7.32–7.42 (m, 1H), 6.80–6.95 (m, 2H), 3.72 (s, 3H) ppm.

Glossary

ABBREVIATIONS

PWA

phosphotungstic acid

PMA

phosphomolybdic acid

STA

silicotungstic acid

PVP

polyvinylpyrrolidone

TLC

thin-layer chromatography

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00201.

• Further experimental procedures for the synthesis of quinones, ammonia TPD study, and BET surface area measurements (PDF)

The authors declare no competing financial interest.