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Cite this: DOI: 10.1039/c5cc00623f Received 24th January 2015, Accepted 1st April 2015

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Organocatalyzed benzannulation for the construction of diverse anthraquinones and tetracenediones† Krishna Bahadur Somai Magar, Likai Xia and Yong Rok Lee*

DOI: 10.1039/c5cc00623f www.rsc.org/chemcomm

An efficient one-pot synthesis of anthraquinones and tetracenediones was achieved via L-proline catalyzed [4+2] cycloaddition of in situ generated azadiene from a,b-unsaturated aldehydes and 1,4-naphthoquinones or 1,4-anthracenedione in good to excellent yield. This protocol constitutes an unprecedented tandem benzannulation that allows one-pot construction of diverse anthraquinones and tetracenediones in the presence of organocatalysts. This methodology was applied successfully to the synthesis of naturally occurring molecules and photochemically interesting phenanthrenequinone derivatives.

Anthraquinones are important compounds with many applications in pharmaceutical and materials chemistry.1 Molecules bearing an anthraquinone skeleton are distributed widely as natural products in bacteria, fungi, lichens, higher plants, pigments, vitamins, and enzymes.2 They exhibit a wide range of biological activities, such as anti-tumor, anti-cancer, antibacterial, antitrypanosomal, antineoplastic, and anti-HIV activities.3 Furthermore, anthraquinone derivatives are used as dyes for coloring natural and synthetic fibers, such as cotton, silk, wool, polyamide, and polyester.4 They have also been used as powerful photo-oxidants that absorb UV-A radiation and as a protein cleaver upon photoirradiation.5 Tetracenedione derivatives are also found in natural products6 and have been used as important building blocks for the synthesis of organic electronic devices7 and organic semiconductors.8 The importance and usefulness of anthraquinone and tetracenedione derivatives have led to the development of several synthetic approaches.9,10 The representative approaches for anthraquinone derivatives are based on Friedel–Crafts reactions of phthalic anhydride with several substituted benzenes,9a oxidation of anthracenes or hydroxyl anthracenes,9h reaction of chromium(0) alkynyl carbenes and isobenzofuran,9e thermal or Lewis acid catalyzed Diels–Alder reactions followed by aromatization,9b,g,i

School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea. E-mail: [email protected]; Fax: +82-53-810-4631; Tel: +82-53-810-2529 † Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc00623f

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ZnI2-catalyzed Diels–Alder reaction/oxidation/Friedel–Crafts cyclization,9j the cyclization of polyketides,9c,d and Cu-catalyzed intramolecular cyclization of enynes.9f The general synthetic methods for tetracenedione derivatives include aromatization of isobenzofuran from o-dicarbonylbenzenes,10c reduction of 1,4-naphthoquinone followed by cyclization with o-phthalaldehyde,10b and an intramolecular dehydro Diels–Alder approach.10a Despite their merits, many existing synthetic approaches have several shortcomings, such as multiple reaction steps, harsh reaction conditions, expensive catalysts, and low product yields due to side reactions. Although many synthetic methods have been described, there is still a demand for a general and facile synthetic method that can efficiently provide a range of anthraquinone and tetracenedione derivatives using mild catalysts. The development of a new and efficient methodology for the synthesis of anthraquinone and tetracenedione derivatives has attracted considerable interest. Among these, L-proline is a viable alternative, and may be a promising catalyst for the synthesis of anthraquinone derivatives because of its high tolerance to air and moisture, low-cost, easy availability, sustainability, non-toxicity, and high catalytic activity.11 More significantly, L-proline bearing a bifunctional group of a Brønsted acid and base is quite effective in a range of catalytic reactions.12 To date, there have been no reports on the synthesis of anthraquinone and tetracenedione derivatives by the L-proline catalyzed benzannulation reaction of 1,4-naphthoquinones or 1,4anthracenedione with a variety of a,b-unsaturated aldehydes. This paper describes a novel and efficient synthesis of anthraquinone and tetracenedione derivatives by L-proline catalyzed benzannulation between 1,4-naphthoquinones or 1,4-anthracenedione and a,b-unsaturated aldehydes through domino formal diene formation–[4+2] cycloaddition–oxidation (Scheme 1). To determine the feasibility of the strategy and optimize the reaction conditions for the synthesis of anthraquinones, L-prolinecatalyzed reactions between 1,4-naphthoquinone (1a) and 3-methyl2-butenal (2a) were attempted in several solvents and additives at 50 1C. The results are summarized in Table 1. When the reaction of 1a with 2a was carried out in the presence of 20 mol% of L-proline

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Scheme 1 Scheme 2 Table 1

Optimization of the reaction conditionsa

Entry Catalyst (mol%)

Additive (mol%)

Solvent

Time Yieldb (h) (%)

L-Proline

None Acetic acid (10) Pivalic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (30) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10) Benzoic acid (10)

Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene CH2Cl2 MeCN THF PhF Benzene DMF

24 20 20 5 15 15 15 10 10 10 10 5 10 48 10 10 20 20 20 10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 a c

Proposed mechanism for the formation of 3a.

(20) (20) L-Proline (20) L-Proline (20) L-Asparagine (20) L-Aspartic acid (20) L-Histidine (20) Diethylamine (20) Pyrrolidine (20) Pyrrolidine (20) Piperidine (20) L-Proline (10) None L-Proline (20) L-Proline (20) L-Proline (20) L-Proline (20) L-Proline (20) L-Proline (20) L-Proline (20) L-Proline

38 42 45 78 15 12 10 48 45 51 48 58 n.r.c n.r.c,d 56 62 52 47 32 50

Reaction conditions: 1a (1.0 mmol) and 2a (1.6 mmol). b Isolated yield. n.r. = no reaction. d Reaction was conducted at room temperature.

for 24 h, compound 3a was produced in 38% yield, which is a natural product known as tectoquinone isolated from the roots of Pentas micrantha (Table 1, entry 1).13 The reactions were examined further in the presence of some additives, such as acetic acid, pivalic acid, and benzoic acid (Table 1, entries 2–4). Interestingly, with the addition of 10 mol% benzoic acid, 3a was isolated in a shorter reaction time (5 h) and higher yield (78%) (entry 4). Benzoic acid may play a role in the formation of 3a assisting proton transfer and activating the carbonyl group to produce the product in a much shorter time and a higher yield.14 The presence of other amino acids, such as L-asparagine, L-aspartic acid, and L-histidine, also produced the desired product 3a in 10–15% yield (entries 5–7). The use of other secondary amines such as diethylamine, pyrrolidine, and piperidine was also successful and gave 3a in 45–51% yield (entries 8–11). On the other hand, when the reaction was conducted in the presence of a reduced L-proline loading of 10 mol%, the yield was decreased to 58% (entry 12). Reactions with only 10 mol% benzoic acid in the absence of L-proline (entry 13) or at room temperature (entry 14) gave no products. With different solvents, such as CH2Cl2, CH3CN, THF, PhF, benzene, and DMF, the desired product 3a

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was obtained in lower yield (entries 15–20). The structure of compound 3a was determined by a comparison with the spectral data of the reported compound.13 The 1H NMR spectrum of 3a showed a characteristic methyl peak on the benzene ring at d = 2.45 ppm as a singlet, whereas a methyl carbon peak was observed in the 13C NMR spectrum at d = 21.8 ppm. The formation of product 3a was assumed to be initiated by an L-proline-catalyzed in situ generated azadiene intermediate (5a) from 3-methyl-2-butenal (2a) via initial iminium ion formation (4) followed by deprotonation (Scheme 2). The diene intermediate 5a would undergo [4+2] cycloaddition with 1,4-naphthoquinone (1a) to give intermediate 6, which undergoes elimination to furnish intermediate 7 and generates L-proline as a recycled catalyst. Finally, the oxidation of 7 would lead to desired product 3a. To extend the utility and generality of these benzannulation reactions, further reactions between several 1,4-naphthoquinones 1a–1e and a variety of a,b-unsaturated aldehydes 2a–2f were attempted under the optimized conditions (Table 2). The reactions between 1a and crotonaldehyde (2b), trans-2-pentenal (2c), or trans-2-hexenal (2d) in the presence of 20 mol% of L-proline in toluene at 50 1C for 5 h afforded the desired products 3b–3d in 60–75% yield. The reactions of 1,4-naphthoquinone 1b and 1c bearing the electron donating group at the 5-position on the benzene ring, such as a hydroxyl or a methoxy group with a,bunsaturated aldehydes, were also successful. The treatment of 1b or 1c with crotonaldehyde (2b) provided the desired products 3e and 3f in 80 and 83% yields, respectively. Importantly, with 1d bearing hydroxy groups at the 5 and 8 positions on the benzene ring, the yields of the products were increased. For example, the reactions of 1d with 2a–2d provided the desired products 3g–3j in 82–94% yield. Similarly, the treatment of 1e with 3-methyl-2-butenal (2a), Table 2

Examples for the synthesis of a variety of 9,10-anthraquinonesa

a Isolated yields. side product.

b

Compound 3a was also produced in 23% yield as a

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Table 3

Regioselective synthesis of various anthraquinonesa

a The ratio of regioisomers was determined by 1H NMR. b 3-Methyl-2butenal (2a) was used. c (E)-2-Methyl-2-butenal (2f) was used. d In the presence of pyrrolidine (20 mol%) and benzoic acid (10 mol%). e In the presence of pyrrolidine (20 mol%) and benzoic acid (30 mol%).

crotonaldehyde (2b), and trans-2-pentenal (2c) afforded products 3k, 3l, and 3m in 93, 88 and 91% yields, respectively. As an expansion of this protocol, disubstituted anthraquinone 3n was also prepared from the reaction of 1a with 2-bromo-3-methylbut-2-enal (2g) for 12 h in 47% yield along with the formation of 3a (23%). After the successful synthesis of a variety of 9,10-anthraquinone derivatives, the scope of this protocol was extended to the regioselective preparation of various anthraquinone derivatives (Table 3). A reaction of 1a with citral (2e) in toluene at 50 1C for 5 h gave two products 3o and 3o0 in 67% yield as a 95 : 5 mixture of regioisomers. The structure of 3o was confirmed by a comparison with the spectral data of a naturally occurring authentic compound that had been isolated from the roots of Sesamum indicum.15 The other regioisomer 3o0 was determined by an analysis of its spectral data. The 1 H NMR spectrum of 3o0 showed a methyl peak on the benzene ring at 2.42 ppm as a singlet and one methylene peak on the prenyl group at 3.94 ppm as a doublet. The formation of these two regioisomers could be explained by two possible diene intermediate formation methods obtained through the reaction of citral and L-proline, as shown in Fig. 1. Using 1d, compounds 3p and 3p 0 were produced in increased yield (85%) as an 87 : 13 mixture of regioisomers. The reactions of 1b and 1c bearing electron-donating groups, such as OH and OMe with 3-methyl-2-butenal (2a), were also tried, but the products showed different regiochemistry (Table 3). For example, the reaction of 1b with 3-methyl-2-butanal (2a) gave a 77 : 23 mixture of regioisomers 3q and 3q0 in 77% yield. On the other hand, when 1c was treated with 3-methyl-2-butenal (2a), a 20 : 80 mixture of regioisomers 3r and 3r 0 was obtained in 91% yield. The predominant outcome of 3q to 3q0 may be explained by intramolecular hydrogen bonding to facilitate the regiochemically controlled product 3q (Fig. 2). In the case of 3r and 3r 0 , electron donation

Fig. 1

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Two possible pathways for 3o and 3o 0 .

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Fig. 2

Possible explanation for the regioselectivity of 3q and 3r 0 .

from the methoxy group to C-4 carbonyl would render the C-1 carbonyl group more electron deficient, which gives the dominant regiochemical control product 3r 0 . The structures of the regioisomers, 3q to 3q 0 or 3r and 3r0 , were confirmed by a comparison with the data of the authentic compounds.16,17 The signals of one aromatic proton at C-5 for compounds 3q and 3r showed upfield shifts (3q: 7.97 ppm and 3r: 7.86 ppm) with respect to those of compounds 3q0 and 3r0 (3q0 : 7.98 ppm and 3r0 : 7.90 ppm). On the other hand, the reaction of 1b with (E)-2-methyl2-butenal (2f) provided products 3q and 3q0 in 66% yield with a 15 : 85 ratio of regioisomers, whereas the treatment of 1c with 2f afforded 3r and 3r0 in 77% yield with the reverse isomer ratio of 74 : 26. This suggests that these reactions proceed through domino formal diene formation–[4+2] cycloaddition–oxidation. With trans2-pentenal (2c), the regioselectivity increased to a 5 : 95 mixture of the regioisomers (3s and 3s0 ) in 85% yield. It is worth noting that the outcome of regioselectivity would be changed in the presence of pyrrolidine (without bearing carboxylic acid). In the case of 1b, the ratio of 3q to 3q0 was increased to 95 : 5 (pyrrolidine: 20 mol%, benzoic acid: 10 mol%) and 97 : 3 (pyrrolidine: 20 mol%, benzoic acid: 30 mol%), probably due to the absence of intermolecular hydrogen bonding. On the other hand, in the case of 1c, the ratio of 3r to 3r0 was decreased to 30 : 70 without the intermolecular H-bonding. With the additional loading of benzoic acid up to 30 mol%, the ratio of 3r to 3r0 was increased to 13 : 87, probably due to the H-bonding interaction between benzoic acid and 1c. In order to explain the inherent regioselectivity, the LUMO orbital coefficients of 1a and 1c were calculated. The difference in the magnitude of the LUMO coefficients (C-2, 0.192; C-3, 0.217) of the dienophile 1c predicts the formation of regioisomer 3r0 as a major product, which is in agreement with the experimental result (Fig. S1, ESI†). To further demonstrate the versatility of this reaction, the reactions of 1,4-anthracenedione that would lead to the formation of tetracenedione derivatives were examined (Table 4). The reactions of 1,4-anthracenedione (1f) with 3-methyl-2-butenal (2a), crotonaldehyde (2b), trans-2-pentenal (2c), or trans-2-hexenal (2d) provided the expected products 4a–4d in 60–86% yield. The treatment of 1f with citral (2e) provided products 4e and 4e0 as a 96 : 4 mixture of regioisomers in 74% yield. The reactions of 1,2-naphthoquinone were also successful (Scheme 3). The reaction of 1,2-naphthoquinone (8) with 2a provided the desired phenanthrenequinone 9a (53%), whereas the reaction with 2b afforded 9b in 57% yield. The structure of

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Table 4 Application for the synthesis of tetracenediones bearing an anthraquinone moietya

Science, and Technology (2012M3A7B4049675). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF2014R1A2A1A11052391).

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Notes and references

a

The ratio of regioisomers was determined by 1H NMR.

Scheme 3

Scheme 4

9a was confirmed by comparison with spectral data of the reported compound.18 Considering the general applicability of the benzannulation reaction employing 1,4-naphthoquinones, 1,4-anthracenedione, and 1,2-naphthoquinone, the possibility of the synthesis of anthraquinones using 1,4-benzoquinone (10) was tested. The reaction of 1,4-benzoquinoe (10) with 2a at 90 1C for 8 h afforded two inseparable regioisomers 3t and 3t 0 as a 50 : 50 mixture in 62% yield. The 1H NMR spectra of 3t and 3t 0 were so similar that the two compounds could not be distinguished by their 1H NMR spectra. On the other hand, two isomers could be differentiated by the two carbonyl peaks (3t: 183.1 ppm, 3t 0 : 183.5 and 182.7 ppm) in their 13C NMR spectra. With 2b, the desired product 3b was produced in 41% yield (Scheme 4). In summary, this study developed an efficient and convenient one-pot synthesis of anthraquinones and tetracenediones from the benzannulation reaction of various 1,4-naphthoquinones or 1,4-anthracenediones with a,b-unsaturated aldehydes using an inexpensive, non-toxic and readily available catalyst, L-proline. This benzannulation process allows the synthesis of various functionalized 9,10-anthraquinones and tetracenediones, which should find a wide range of applications in the synthesis of natural products, dyes and pharmaceuticals. Using this methodology, phenanthrenequinone derivatives were also synthesized. As an application of this methodology, 9,10-anthraquinones were also obtained using 1,4-benzoquinoe as the starting material. This research was supported by the Nano Material Technology Development Program through the Korean National Research Foundation (NRF) funded by the Korean Ministry of Education,

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Organocatalyzed benzannulation for the construction of diverse anthraquinones and tetracenediones.

An efficient one-pot synthesis of anthraquinones and tetracenediones was achieved via L-proline catalyzed [4+2] cycloaddition of in situ generated aza...
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