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Heterogeneously Catalyzed Domino Synthesis of 3‑Indolylquinones Involving Direct Oxidative C−C Coupling of Hydroquinones and Indoles Sumit B. Kamble,† Praneet P. Vyas,‡ Radha V. Jayaram,‡ and Chandrashekhar V. Rode*,† †
Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pune 411008, India Department of Chemistry, Institute of Chemical Technology, Mumbai 400019, India
‡
S Supporting Information *
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.
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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). 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
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. 3Indolylquinone could be used in the total synthesis of asterriquinones and also as reagents to probe the biological activity of indolylquinones. 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 © 2017 American Chemical Society
Received: February 21, 2017 Accepted: May 3, 2017 Published: May 23, 2017 2238
DOI: 10.1021/acsomega.7b00201 ACS Omega 2017, 2, 2238−2247
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Article
Figure 1. Structures of some biologically active asterriquinone derivatives.
Scheme 1. General Reaction Scheme for the Synthesis of 3-Indolylquinone
Scheme 2. Single-Pot Direct Synthesis of 3-Indolylquinones from Hydroquinones
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.
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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% 3indolylhydroquinone (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
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. 2239
DOI: 10.1021/acsomega.7b00201 ACS Omega 2017, 2, 2238−2247
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Table 1. Screening of Oxidants for the Synthesis of 3-Indolylquinone
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
oxidant
yieldab, %
catalyst
air oxygen H2O2 H2O2 H2O2 H2O2
NR NR NR 10a 15a 10a 30a/40b 25a/45b 27a/41b 94a 35a 41a/55b 10a/30b NR NR
MoO3 WO3 Fe3O4/PVP−PWA Ag2O Ag2O Ag2O Ag2O AgNO3
air oxygen H2O2 H2O2 DDQ KBrO3 K4FeCN6 oxone
a
Reactions 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.
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 H2O2, 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 3indolylhydroquinone (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 3indolylquinones, and the results are summarized in Table 2. A control reaction of 2-methylhydroquinone (1a) with 2methylindole (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 Fe3O4, PVP, and PWA in this work exhibited different levels
Table 2. Catalyst Screening for the Synthesis of 3Indolylquinones from Hydroquinone
entry 1 2 3 4 5 6 7 8 9 10 11 12 13
catalyst
yieldsa, %
PVP Fe3O4 Amberlyst-15 PWA PVP−PWA PVP−phosphomolybdic acid (PMA) PVP−silicotungstic acid (STA) Fe3O4/PVP−PWA (131) Fe3O4/PVP−PWA (141) Fe3O4/PVP−PWA (181) Fe3O4/PVP−PWA (141) Fe3O4/PVP−PWA (141)
00/86c 00/73c 00/81c 12/67c 75/9c 83 72/10c 65/20c 75/6c 94 42/32c 95b 97a,d
a
Reactions were performed with 1:1 2-methylhydroquinone/2methylindole, 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.
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 2240
DOI: 10.1021/acsomega.7b00201 ACS Omega 2017, 2, 2238−2247
ACS Omega
Article
Table 3. Screening of Solvents for the Synthesis of 3-Indolylquinone from Hydroquinone
entry
solvent
yieldsa,b,c, %
time, h
1 2 3 4 5 6 7
nil water MeOH 1,4-dioxane DCM acetonitrile (ACN) THF
9a/15c 12a/67c 45a/10b/20c 10a 18a 68a/24c 93a
10 15 7 9 8 8 2
a Reactions 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.
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. A control experiment without any solvent gave a very poor yield of
