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Article

Synthesis of Anthraquinones by Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of a 1,2-Bis(propiolyl)benzene Derivative with Alkynes

by
Takahiro Sawano
,
Yuko Toyoshima
and
Ryo Takeuchi
*
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5258, Japan
*
Author to whom correspondence should be addressed.
Inorganics 2019, 7(11), 138; https://doi.org/10.3390/inorganics7110138
Submission received: 4 October 2019 / Revised: 5 November 2019 / Accepted: 11 November 2019 / Published: 18 November 2019
(This article belongs to the Special Issue Iridium Complexes)
Browse Figures
Versions Notes

Abstract

:
[2 + 2 + 2] cycloaddition of a 1,2-bis(propiolyl)benzene derivative with terminal and internal alkynes takes place in the presence of [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene) combined with bis(diphenylphosphino)ethane (DPPE) to give anthraquinones in 42% to 93% yields with a simple experimental procedure. A fluorenone derivative can also be synthesized by iridium-catalyzed [2 + 2 + 2] cycloaddition of a benzene-linked ketodiyne with an internal alkyne to give a 94% yield.

Graphical Abstract

1. Introduction

Anthraquinones and their derivatives are important structures found in natural products and bioactive compounds and show a broad range of bioactivities including anti-tumor [1,2], cytotoxic [3], anti-cancer [4,5,6], anti-bacterial [7,8], laxative [9], anti-arthritic [10], anti-fungal [11], anti-platelet [12,13], and neuroprotective effects [14]. Moreover, anthraquinones have been widely used as catalysts for producing hydrogen peroxide [15], dyes for fibers [16,17] and cells [18], a digestion catalyst for wood [19], and chemical sensors [20]. Thus, the development of synthetic methods for the formation of multi-substituted anthraquinones is an important research topic, and several synthtic methods including the oxidation of anthracene [21,22], the Friedel-Crafts reaction of phthalic anhydride [23], and the Diels-Alder reaction of naphthoquinones followed by aromatization [24] have been developed.
Transition metal-catalyzed [2 + 2 + 2] cycloaddition represents a powerful and atom-economical method to access a variety of complex aromatic carbocycles and heterocycles in short steps [25,26,27,28,29,30]. From 1,2-bis(propiolyl)benzene derivatives and alkynes, [2 + 2 + 2] cyclization has realized the synthesis of anthraquinones. After the success of stoichiometric reactions with a large amount of highly toxic Ni(CO)4 [31] and isolated naphthoquinone-fused rhodacyclopentadiene [32], catalytic reactions were realized by the use of Ni(PPh3)2(CO)2 [33], CpCo(CO)2 [34], and RhCl(PPh3)3 [35]. However, the reaction systems require high reaction temperatures, and the yields of the desired anthraquinones are moderate. Yamamoto and co-workers elegantly demonstrated that Cp*RuCl(cod) (cod = 1,5-cyclooctadiene) can catalyze the [2 + 2 + 2] cycloaddition of 1,2-bis(propiolyl)benzene derivatives with terminal alkynes and methyl-substituted internal alkynes under mild reaction conditions in high yields [36,37,38,39,40]. On the other hand, the rhodium-catalyzed reaction reported by Tanaka realized [2 + 2 + 2] cycloaddition with aryl-substituted diynes to give anthraquinones in high yields [41]. Despite this progress with methods for the synthesis of anthraquinones, few highly atom-economical methods are available, and, thus, novel methods to efficiently obtain anthraquinones are still desired. Our laboratory has developed an iridium-catalyzed [2 + 2 + 2] cycloaddition of diynes with alkynes, nitriles, and isocyanate to provide a variety of aromatic carbocycles and heterocycles [42,43,44,45,46,47,48,49,50]. In the course of our ongoing investigation into iridium-catalyzed [2 + 2 + 2] cycloaddition, we found that an iridium/bisphosphine catalytic system catalyzed the [2 + 2 + 2] cycloaddition of 1,2-bis(propiolyl)benzene derivatives to provide anthraquinones bearing a variety of substituents in an atom-economical manner.

2. Results and Discussion

The reaction of 1,2-bis(propiolyl)benzene derivative 1 with three equivalents of 1-hexyne (2a) in the presence of 2 mol % of [Ir(cod)Cl]2 in toluene under reflux for 20 h gave the anthraquinone 3a in 20% yield (entry 1, Table 1). The phosphine ligand was found to improve the yield of anthraquinone 3a. With a monophosphine ligand, PPh3, the cyclized product was obtained in a moderate yield (Yield 64%, entry 2). Sufficient yield was achieved with the use of 1,2-bis(diphenylphosphino)ethane (DPPE) as a ligand to give 83% yield of anthraquinone 3a (entry 3), while other representative bidentate phosphine ligands such as 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), and 1,1′-bis(diphenylphosphino)ferrocene (DPPF) were ineffective at achieving a high yield (Yield 22% to 45%, entries 4 to 6).
The Ir/dppe complex demonstrates high activity for [2 + 2 + 2] cycloaddition with various kinds of terminal alkynes to provide anthraquinone derivatives 3b–i in good to high yields (Table 2). Cyclized products were obtained in high yields with 1-octyne and 1-decyne, respectively (Yields 92 and 93%, 3b and 3c). A chloride group can be tolerated under the reaction conditions (Yield 73%, 3d). As well as aliphatic alkynes, the aromatic alkyne can also be used in the reaction (Yield 77%, 3e). The present iridium-catalyzed [2 + 2 + 2] cyclization can introduce a sterically hindered functional group such as a trimethylsilyl group to give the corresponding cyclized product in a moderate yield (Yield 42%, 3f). Terminal alkynes with primary, secondary, and tertiary alcohols are also good substrates for this [2 + 2 + 2] cyclization (Yields 75–85%, 3g–3i).
Unfortunately, the optimized reaction conditions in Table 2 resulted in a diminished yield for the cyclization with internal alkyne 2j, likely due to the formation of the dimer or oligomer of 1 as byproducts (Yield 36%, entry 1, Table 3). Our examination of the reaction conditions found that halogenated solvent was more suitable for the reaction than toluene. With dichloroethane (DCE) as a solvent, 62% of the cyclized product 3j was obtained (entry 2). The yield was slightly improved in dichloromethane (DCM) under reflux to give 3j in a 72% yield (entry 3).
The results obtained for the iridium-catalyzed [2 + 2 + 2] cycloaddition of 1,2-bis(propiolyl)benzene derivative with internal alkynes are summarized in Table 4. In refluxing DCM, [2 + 2 + 2] cycloaddition with several internal alkynes proceeded to form tetra-substituted anthraquinones in good yields (Yield 72–86%, 3j–3l).
As shown in Scheme 1, a gram-scale reaction of 1 with 2a also proceeded smoothly. The yield was comparable as in the 0.5 mmol scale.
Based on our previous results [45,46,48,49], we envision that the catalytic reaction is initiated by the coordination of diyne 1 to the iridium(I) complex. Oxidative addition of diyne 1 to an iridium(I) complex forms iridacyclopentadiene [51,52,53,54]. Reaction of alkyne 2 with the iridacyclopentadiene gives anthraquinone 3 and regenerates the iridium(I) complex.
Fluorenones, which have structures similar to those of anthraquinones, are also a fascinating class of compounds due to their wide range of bioactivities [55,56,57,58], and photochemical [59,60,61,62] and electronic natures [63,64,65]. Fortunately, the [2 + 2 + 2] cyclization of benzene-linked ketodyne 4 with alkyne 2j in the presence of [Ir(cod)Cl]2 (2 mol %), DPPE (4 mol %) in DCM under reflux for 24 h afforded the fluorenone 5j in a 43% yield (entry 1, Table 5). The proper choice of the ligand was found to be essential for the formation of fluorenone 5j in a good yield. While PPh3, 2,2′-bis(diphenylphosphino)biphenyl (BIPHEP), and DPPF were ineffective at catalyzing the formation of fluorenone 5j (Yield 28% to 63%, entries 2 to 4), excellent yield was realized with the use of 1,2-bis[bis(pentafluorophenyl)phosphino]ethane (F-DPPE) (Yield 94%, entry 5).

3. Materials and Methods

3.1. General Methods and Materials

All anaerobic and moisture-sensitive manipulations were carried out with standard Schlenk techniques under pre-dried argon. 1H and 13C NMR spectra were measured on JEOL ECX 500II spectrometers (500 MHz for 1H, 125 MHz for 13C) (JEOL Ltd., Tokyo, Japan). Chemical shifts are reported in δ (ppm) referenced to the tetramethylsilane (δ 0.00) for 1H NMR and the residual peaks of CDCl3 (δ 77.00) for 13C NMR. The following abbreviations are used: s: singlet, d: doublet, t: triplet, q: quartet, sext: sextet, m: multiplet, br: broad. High-resolution mass spectra were obtained with a JEOL Mstation JMS-700 (JEOL Ltd., Tokyo, Japan). IR spectra were measured on a JASCO FTIR-4100A spectrometer (JASCO Corporation, Tokyo, Japan). The products were purified by column chromatography on 63–210 mesh silica gel (Silica Gel 60N) (Kanto Chemical Co., Inc., Tokyo, Japan). All solvents were dried and distilled before use by the usual procedures. [Ir(cod)Cl]2 was prepared as described in the literature [66]. Alkynes 2a (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), 2b (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), 2c (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 2d (Sigma-Aldrich Co. LLC., St. Louis, USA), 2e (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 2f (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 2g (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 2h (Sigma-Aldrich Co. LLC., St. Louis, USA), 2i (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 2j (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), 2l (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan), 1,2-bis(diphenylphosphino)ethane (DPPE) (Kanto Chemical Co., Inc., Tokyo, Japan), and 1,2-bis[bis(pentafluorophenyl)phosphino]ethane (F-DPPE) (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan) were purchased and used as received. 2-(1-Hexyn-1-yl)benzaldehyde and 1,4-dimethoxybut-2-yne (2k) were prepared by analogy to the reported procedure [67,68].

3.2. Preparation of Anthraquinone 1

To a solution of magnesium (1.632 g, 67.15 mmol) in tetrahydrofuran (THF) (120 mL) was added bromoethane (8.17 g, 75.0 mmol) dropwise at room temperature, and the mixture was stirred for 2 h. At the same temperature, 1-hexyne (5.400 g, 65.74 mmol) was added. After being stirred at 50 °C for 1 h, the reaction mixture was stirred at room temperature for 2 h. In addition, o-phthalaldehyde (4.039 g, 30.11 mmol) was added to the reaction mixture. After the mixture was stirred for 18 h, sat. NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated on a rotary evaporator. The residue was subjected to column chromatography (silica gel, hexane/ethyl acetate = 8/2) to give compound S1 (8.647 g, 28.98 mmol, 96% yield, Scheme 2).
S1: Yellow oil, Yield 96%, 8.647 g, 1H NMR (500 MHz, CDCl3, a mixture of two diastereomers) δ 0.91 (t, J = 7.3 Hz, 6H), 0.92 (t, J = 7.5 Hz, 6H), 1.37–1.49 (m, 8H), 1.49–1.62 (m, 8H), 2.25–2.35 (m, 8H), 3.33 (d, J = 4.5 Hz, 2H), 3.70 (d, J = 5.5 Hz, 2H), 5.80–5.86 (m, 2H), 5.96–6.02 (m, 2H), 7.31–7.35 (m, 2H), 7.35–7.40 (m, 2H), 7.59–7.65 (m, 2H), 7.79–7.86 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.5, 18.5, 22.0, 30.52, 30.55, 62.0, 63.4, 78.7, 79.1, 88.1, 88.6, 127.8, 128.7, 128.9, 138.3, 138.7, IR (neat, cm−1) 3338, 2958, 2931, 2870, 2280, 2232, 1604, 1456, 1433, 1328, 1280, 1253, 1203, 1133, 1050, 998, 807, 758, High Resolution Mass Spectrometer (HRMS) (EI+) m/z [M]+ calculated (calcd) for C20H26O2 298.1933, found 298.1933.
To a solution of MnO2 (28.79 g, 331.1 mmol) in DCM (120 mL), S1 (4.945 g, 16.57 mmol) was added at room temperature. After being stirred for 18 h, the reaction mixture was filtered through a pad of Celite and subjected to column chromatography (silica gel, hexane/ethyl acetate = 8/2) to give 1,1′-(1,2-phenylene)bis(hept-2-yn-1-one) (1) (4.553 g, 15.48 mmol, 93% yield, Scheme 3).
1: Yellow oil, Yield 93%, 4.553 g, 1H NMR (500 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz, 6H), 1.45 (sext, J = 7.5 Hz, 4H), 1.55–1.64 (m, 4H), 2.43 (t, J = 7.3 Hz, 4H), 7.56–7.62 (m, 2H), 7.76–7.81 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.4, 18.9, 22.0, 29.6, 80.7, 97.9, 129.4, 131.6, 139.2, 179.4, IR (neat, cm−1) 3275, 3065, 2959, 2872, 2206, 1647, 1572, 1465, 1324, 1264, 915, 778, 724, HRMS (EI+) m/z [M]+ calcd for C20H22O2 294.1620, found 294.1619.

3.3. Preparation of Fluorenone 4

To a solution of magnesium (390.5 mg, 16.07 mmol) in THF (35 mL) bromoethane (2.059 g, 18.89 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 h. At the same temperature, 1-hexyne (1.409 g, 17.16 mmol) was added. After the mixture was stirred for 3 h, 2-(1-hexyn-1-yl)benzaldehyde (1.853 g, 9.947 mmol) was added, and the reaction mixture was stirred for 18 h. The mixture was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated on a rotary evaporator. The residue was subjected to column chromatography (silica gel, hexane/ethyl acetate = 95/5) to give compound S2 (2.489 g, 9.273 mmol, 93% yield, Scheme 4).
S2: Yellow oil, Yield 93%, 2.489 g, 1H NMR (500 MHz, CDCl3) δ 0.91 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 1.37–1.47 (m, 2H), 1.47–1.57 (m, 4H), 1.57–1.66 (m, 2H), 2.27 (td, J = 7.3, 1.8 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 2.66 (d, J = 5.0 Hz, 1H), 5.83 (dt, J = 5.5, 2.0 Hz, 1H), 7.23 (td, J = 7.5, 1.3 Hz, 1H), 7.31 (td, J = 7.5, 1.0 Hz, 1H), 7.40 (dd, J = 7.5, 1.5 Hz, 1H), 7.64–7.69 (m, 1H), 13C NMR (125 MHz, CDCl3) δ 13.57, 13.60, 18.5, 19.3, 21.9, 22.0, 30.6, 30.7, 63.5, 77.9, 79.2, 87.4, 96.1, 122.1, 126.5, 127.9, 128.0, 132.4, 142.7, IR (neat, cm−1) 3421, 2958, 2934, 2871, 2226, 1708, 1465, 1379, 1328, 1134, 1005, 758, 630, HRMS (EI+) m/z [M]+ calcd for C19H24O 268.1827, found 268.1827.
To a solution of MnO2 (7.960 g, 91.56 mmol) in DCM (26 mL) S2 (1.233 g, 4.595 mmol) was added at room temperature. After being stirred for 24 h, the reaction mixture was filtered through a pad of Celite and subjected to column chromatography (silica gel, hexane/ethyl acetate = 7/3) to give 4 (1.177 g, 4.418 mmol, 96% yield, Scheme 5).
4: Orange oil, Yield 96%, 1.177 g, 1H NMR (500 MHz, CDCl3) δ 0.945 (t, J = 7.5 Hz, 3H), 0.953 (t, J = 7.5 Hz, 3H), 1.42–1.56 (m, 4H), 1.58–1.67 (m, 4H), 2.46 (t, J = 6.5 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.44 (td, J = 7.5, 1.2 Hz, 1H), 7.50 (dd, J = 7.5, 1.3 Hz, 1H), 8.04 (dd, J = 8.0, 1.3 Hz, 1H), 13C NMR (125 MHz, CDCl3) δ 13.5, 13.6, 19.0, 19.6, 22.0, 29.8, 30.6, 79.2, 80.7, 96.5, 96.8, 123.6, 127.0, 131.5, 132.0, 134.5, 138.4, 177.9, IR (neat, cm−1) 3062, 2959, 2871, 2207, 1651, 1593, 1561, 1478, 1466, 1272, 1242, 909, 756, HRMS (EI+) m/z [M]+ calcd for C19H22O 266.1671, found 266.1670.

3.4. General Procedure for the Reaction of 1,2-Bis(propiolyl)benzene Derivative 1 with Alkyne 2

Representative Procedure for the Reaction of 1,2-Bis(propiolyl)benzene Derivative 1 with Alkyne 2a (Table 1 and Table 2).
To a solution of [Ir(cod)Cl]2 (6.7 mg, 0.010 mmol) and DPPE (8.0 mg, 0.020 mmol) in toluene (1.0 mL), 1-hexyne (125.7 mg, 1.530 mmol) and a solution of 1 (148.1 mg, 0.5031 mmol) in toluene (1.5 mL) were added. The mixture was stirred under reflux for 20 h. After removal of the solvent on a rotary evaporator, the residue was subjected to column chromatography (silica gel, hexane/EtOAc = 99/1) to give compound 1,2,4-tributylanthracene-9,10-dione (3a) (157.8 mg, 0.4191 mmol, 83% yield, Scheme 6).
A procedure for the Gram-Scale Synthesis of Anthraquinone 3a from 1,2-Bis(propiolyl)benzene Derivative 1 and Alkyne 2a.
To a solution of [Ir(cod)Cl]2 (45.6 mg, 0.068 mmol) and DPPE (53.8 mg, 0.135 mmol) in toluene (6.8 mL), 1-hexyne (0.838 g, 10.2 mmol) and a solution of 1 (1.019 g, 3.46 mmol) in toluene (10.1 mL) were added, and the mixture was stirred under reflux for 20 h. After removal of the solvent on a rotary evaporator, the residue was subjected to column chromatography (silica gel, hexane/EtOAc = 99/1) to give compound 1,2,4-tributylanthracene-9,10-dione (3a) (1.032 g, 2.740 mmol, 79% yield, Scheme 7).

3.5. Characterization of 3a–3l

1,2,4-Tributylanthracene-9,10-dione (3a, Scheme 8). Brown solid, mp 42.0–43.0 °C, Yield 83%, 157.8 mg, 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 6H), 1.02 (t, J = 6.8 Hz, 3H), 1.40–1.53 (m, 4H), 1.52–1.70 (m, 8H), 2.68–2.72 (m, 2H), 3.02–3.18 (m, 4H), 7.32 (s, 1H), 7.65–7.73 (m, 2H), 8.07–8.15 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.9, 14.0, 14.1, 22.9, 23.1, 23.5, 29.9, 33.0, 33.1, 33.4, 33.5, 35.7, 126.1, 126.3, 131.1, 133.0, 133.1, 133.9, 134.3, 135.0, 138.2, 142.5, 144.0, 148.4, 185.9, 187.1, IR (KBr, cm−1) 2956, 2927, 2869, 1665, 1590, 1536, 1456, 1320, 1288, 1262, 1102, 1020, 898, 802, 726, HRMS (EI+) m/z [M]+ calcd for C26H32O2 376.2402, found 376.2401.
1,4-Dibutyl-2-hexylanthracene-9,10-dione (3b, Scheme 9). Yellow solid, mp 41.0–41.5 °C, 188.0 mg, Yield 92%, 1H NMR (500 MHz, CDCl3) δ 0.91 (t, J = 6.8 Hz, 3H), 0.98 (t, J = 7.0 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H), 1.29–1.38 (m, 4H), 1.38–1.45 (m, 2H), 1.45–1.68 (m, 2H), 1.53–1.68 (m, 8H), 2.67–2.76 (m, 2H), 3.03–3.17 (m, 4H), 7.32 (s, 1H), 7.68 (t, J = 3.8 Hz, 1H), 7.70 (t, J = 4.0 Hz, 1H), 8.07–8.15 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 14.0, 14.1, 22.6, 23.1, 23.5, 29.5, 29.9, 31.3, 31.6, 33.1, 33.3, 33.4, 35.7, 126.1, 126.3, 131.1, 133.0, 133.1, 133.9, 134.4, 135.0, 138.3, 142.5, 144.0, 148.4, 185.9, 187.1, IR (KBr, cm−1) 2959, 2927, 2854, 1668, 1595, 1539, 1462, 1320, 1288, 1265, 727; HRMS (EI+) m/z [M]+ calcd for C28H36O2 404.2715, found 404.2722.
1,4-Dibutyl-2-octylanthracene-9,10-dione (3c, Scheme 10). Brown solid, mp 39.5–39.8 °C, 200.0 mg, Yield 93%, 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H), 1.21–1.38 (m, 8H), 1.38–1.45 (m, 2H), 1.45–1.53 (m, 2H), 1.53–1.69 (m, 8H), 2.68–2.75 (m, 2H), 3.01–3.17 (m, 4H), 7.32 (s, 1H), 7.68 (t, J = 3.8 Hz, 1H), 7.70 (t, J = 3.8 Hz, 1H), 8.08–8.14 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 14.0, 14.1, 22.7, 23.1, 23.5, 29.2, 29.4, 29.8, 29.9, 31.3, 31.8, 33.1, 33.3, 33.4, 35.7, 126.1, 126.3, 131.1, 133.0, 133.1, 133.9, 134.4, 135.0, 138.3, 142.5, 144.0, 148.4, 185.9, 187.1, IR (KBr, cm−1) 3460, 2964, 2925, 2856, 1668, 1595, 1540, 1461, 1324, 1288, 1262, 996, 904, 728, HRMS (EI+) m/z [M]+ calcd for C30H40O2 432.3028, found 432.3024.
1,4-Dibutyl-2-(3-chloropropyl) anthracene-9,10-dione (3d, Scheme 11). Yellow oil, 144.4 mg, Yield 73%, 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H), 1.49 (sext, J = 6.8 Hz, 2H), 1.53–1.70 (m, 6H), 2.05–2.14 (m, 2H), 2.92 (t, J = 7.3 Hz, 2H), 3.05–3.17 (m, 4H), 3.63 (t, J = 6.3 Hz, 2H), 7.35 (s, 1H), 7.69 (t, J = 3.8 Hz, 1H), 7.71 (t, J = 4.0 Hz, 1H), 8.08–8.16 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 14.0, 14.1, 23.1, 23.4, 29.9, 30.3, 33.2, 33.4, 33.7, 35.6, 44.4, 126.1, 126.3, 131.5, 133.1, 133.2, 134.1, 134.3, 134.9, 138.3, 142.6, 144.2, 146.2, 185.9, 186.9, IR (neat, cm−1) 2956, 2934, 2860, 1669, 1595, 1541, 1456, 1392, 1331, 1287, 1251, 997, 904, 798, 727, 653, HRMS (EI+) m/z [M]+ calcd for C25H29O235Cl 396.1856, found 396.1863.
1,4-Dibutyl-2-phenylanthracene-9,10-dione (3e, Scheme 12). Yellow oil, 152.6 mg, Yield 77%, 1H NMR (500 MHz, CDCl3) δ 0.75 (t, J = 7.5 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 1.24 (sext, J = 7.1 Hz, 2H), 1.39–1.54 (m, 4H), 1.62–1.72 (m, 2H), 3.01–3.09 (m, 2H), 3.12–3.20 (m, 2H), 7.29 (d, J = 7.0 Hz, 2H), 7.36 (s, 1H), 7.38–7.48 (m, 3H), 7.71 (t, J = 3.8 Hz, 1H), 7.73 (t, J = 3.8 Hz, 1H), 8.11–8.19 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.7, 14.0, 23.0, 23.1, 30.8, 33.2, 33.4, 35.6, 126.2, 126.4, 127.5, 128.1, 128.8, 132.4, 133.2, 133.3, 133.8, 134.3, 135.0, 138.6, 141.0, 142.6, 143.7, 149.1, 186.0, 186.7, IR (neat, cm−1) 3059, 3022, 2958, 2931, 2862, 1672, 1595, 1535, 1458, 1324, 1256, 1018, 886, 723, 703, HRMS (EI+) m/z [M]+ calcd for C28H28O2 396.2089, found 396.2087.
1,4-Dibutyl-2-(trimethylsilyl) anthracene-9,10-dione (3f, Scheme 13). Brown oil, 83.0 mg, Yield 42%, 1H NMR (500 MHz, CDCl3) δ 0.41 (s, 9H), 1.00 (t, J = 7.3 Hz, 6H), 1.44–1.60 (m, 6H), 1.61–1.70 (m, 2H), 3.10–3.17 (m, 2H), 3.32 (br, 2H), 7.64 (s, 1H), 7.68–7.75 (m, 2H), 8.10–8.17 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 0.7, 14.0, 14.1, 23.1, 23.5, 33.5, 34.5, 35.7, 35.8, 126.1, 126.4, 132.2, 133.1, 133.3, 133.7, 134.2, 135.0, 142.7, 143.8, 148.1, 150.8, 186.5, 186.9, IR (neat, cm−1) 2960, 2934, 2866, 1669, 1595, 1457, 1312, 1287, 1255, 1103, 959, 887, 883, 841, 800, 727, 659, HRMS (EI+) m/z [M]+ C25H32O2Si calcd for 392.2172, found 392.2172.
1,4-Dibutyl-2-(hydroxymethyl) anthracene-9,10-dione (3g, Scheme 14). Yellow solid, mp 123.5–124.0 °C, 134.3 mg, Yield 76%, 1H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.5 Hz, 3H), 1.01 (t, J = 6.5 Hz, 3H), 1.43–1.53 (m, 2H), 1.53–1.70 (m, 6H), 1.94 (t, J = 5.3 Hz, 1H), 3.00–3.12 (m, 2H), 3.12–3.21 (m, 2H), 4.89 (d, J = 5.5 Hz, 2H), 7.66–7.74 (m, 3H), 8.08–8.15 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.96, 14.05, 23.1, 23.4, 29.5, 32.7, 33.4, 35.8, 62.3, 126.2, 126.4, 132.1, 133.2, 133.3, 133.5, 134.3, 134.9, 135.5, 141.9, 144.6, 145.1, 185.9, 186.7, IR (KBr, cm−1) 3371, 3320, 2956, 2927, 2859, 1666, 1591, 1469, 1319, 1287, 1259, 1046, 981, 907, 730, HRMS (EI+) m/z [M]+ calcd for C23H26O3 350.1882, found 350.1882.
1,4-Dibutyl-2-(1-hydroxyethyl) anthracene-9,10-dione (3h, Scheme 15). Brown oil, 156.4 mg, Yield 85%, 1H NMR (500 MHz, CDCl3) δ 0.98 (t, J = 7.0 Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H), 1.42–1.60 (m, 8H), 1.60–1.71 (m, 3H), 2.00 (s, 1H), 2.78–2.92 (m, 1H), 3.16 (t, J = 8.0 Hz, 2H), 3.20–3.31 (m, 1H), 5.35 (q, J = 5.8 Hz, 1H), 7.69 (t, J = 3.5 Hz, 1H), 7.70 (t, J = 3.8 Hz, 1H), 7.80 (s, 1H), 8.06–8.13 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.96, 14.05, 23.1, 23.4, 25.3, 29.2, 33.4, 33.5, 35.9, 65.7, 126.1, 126.3, 132.1, 133.17, 133.24, 133.8, 134.0, 134.2, 135.0, 140.4, 144.8, 150.6, 185.9, 186.9, IR (neat, cm−1) 3453, 3073, 2957, 2862, 1672, 1594, 1542, 1462, 1291, 1123, 1062, 908, 759, 727, HRMS (EI+) m/z [M]+ calcd for C24H28O3 364.2038, found 364.2044.
1,4-Dibutyl-2-(2-hydroxypropan-2-yl) anthracene-9,10-dione (3i, Scheme 16). Brown solid, mp 77.5–78.2 °C, 140.3 mg, Yield 75%, 1H NMR (500 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H), 1.39–1.59 (m, 6H), 1.59–1.68 (m, 2H), 1.75 (s, 6H), 1.94 (s, 1H), 3.08–3.16 (m, 2H), 3.54 (br, 2H), 7.66–7.73 (m, 2H), 7.75 (s, 1H), 8.05–8.12 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 13.9, 14.0, 23.1, 23.6, 30.3, 31.9, 33.6, 35.4, 36.0, 74.0, 125.9, 126.3, 132.4, 133.0, 133.3, 134.1, 134.2, 135.5, 135.6, 143.6, 143.7, 151.8, 186.0, 187.8, IR (KBr, cm−1) 3372, 2956, 2931, 2872, 1666, 1592, 1462, 1316, 1291, 1142, 728, HRMS (EI+) m/z [M]+ calcd for C25H30O3 378.2195, found 378.2196.
1,4-Dibutyl-2,3-diethylanthracene-9,10-dione (3j, Scheme 17). Yellow oil, 134.6 mg, Yield 72%, 1H NMR (500 MHz, CDCl3) δ 1.02 (t, J = 7.3 Hz, 6H), 1.22 (t, J = 7.3 Hz, 6H), 1.50–1.69 (m, 8H), 2.82 (q, J = 7.5 Hz, 4H), 3.11 (br, 4H), 7.63–7.69 (m, 2H), 8.02–8.09 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 14.0, 15.3, 22.5, 23.5, 30.1, 33.6, 125.9, 132.2, 132.8, 135.1, 142.4, 147.9, 187.3, IR (neat, cm−1) 3316, 3065, 2961, 2934, 2870, 1669, 1595, 1536, 1458, 1401, 1377, 1328, 1287, 1265, 1102, 1055, 907, 797, 730, HRMS (EI+) m/z [M]+ calcd for C26H32O2 376.2402, found 376.2401.
1,4-Dibutyl-2,3-bis(methoxymethyl)anthracene-9,10-dione (3k, Scheme 18). Yellow solid, mp 86.2–86.5 °C, 167.5 mg, Yield 82%, 1H NMR (500 MHz, CDCl3) δ 1.03 (t, J = 7.3 Hz, 6H), 1.53–1.70 (m, 8H), 3.18 (br, 4H), 3.52 (s, 6H), 4.58 (s, 4H), 7.65–7.72 (m, 2H), 8.03–8.10 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 14.0, 23.5, 30.1, 33.7, 59.0, 67.8, 126.1, 133.1, 134.1, 134.9, 142.6, 144.1, 186.8, IR (KBr, cm−1) 2953, 2927, 2870, 2807, 1670, 1593, 1462, 1320, 1288, 1191, 1097, 947, HRMS (EI+) m/z [M]+ calcd for C26H32O4 408.2301, found 408.2300.
1,4-Dibutyl-2,3-bis(hydroxymethyl)anthracene-9,10-dione (3l, Scheme 19). Yellow solid, mp 153.2–154.0 °C, 162.8 mg, Yield 86%, 1H NMR (500 MHz, CDCl3) δ 1.02 (t, J = 7.0 Hz, 6H), 1.52–1.72 (m, 8H), 2.96 (s, 2H), 3.15 (br, 4H), 4.95 (s, 4H), 7.66–7.73 (m, 2H), 8.02–8.08 (m, 2H), 13C NMR (125 MHz, CDCl3) δ 14.0, 23.3, 30.4, 34.1, 58.9, 126.1, 133.2, 134.2, 134.9, 143.2, 145.0, 186.8, IR (neat, cm−1) 3233, 2952, 2923, 2869, 1670, 1593, 1468, 1318, 1290, 1260, 1007, 907, 729, HRMS (EI+) m/z [M]+ calcd for C24H28O4 380.1988, found 380.1988.

3.6. Procedure for the Reaction of Diyne 4 with Alkyne 2j

To a solution of [Ir(cod)Cl]2 (6.7 mg, 0.010 mmol) and F-DPPE (15.2 mg, 0.0200 mmol) in DCM (1.0 mL), 3-hexyne (125.9 mg, 1.530 mmol) and a solution of diyne (133.5 mg, 0.5012 mmol) in DCM (1.5 mL) were added. The mixture was stirred under reflux for 24 h. After removal of the solvent on a rotary evaporator, the residue was subjected to column chromatography (silica gel, hexane/EtOAc = 99.5/0.5) to give compound 1,4-dibutyl-2,3-diethyl-9H-fluoren-9-one (5j) (164.1 mg, 0.4708 mmol, 94% yield, Scheme 20).
1,4-Dibutyl-2,3-diethyl-9H-fluoren-9-one (5j, Scheme 21). Yellow oil, 164.1 mg, Yield 94%, 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.8 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H), 1.45–1.66 (m, 8H), 2.67 (q, J = 7.5 Hz, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.84–2.92 (m, 2H), 3.00–3.14 (m, 2H), 7.22 (t, J = 7.0 Hz, 1H), 7.43 (td, J = 7.5, 1.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.0 Hz, 1H), 13C NMR (125 MHz, CDCl3) δ 14.0, 15.5, 15.6, 21.4, 22.3, 23.3, 23.5, 27.3, 29.1, 32.2, 33.3, 122.8, 123.5, 127.7, 129.3, 134.1, 135.4, 135.5, 140.7, 141.5, 142.2, 144.3, 147.8, 195.1, IR (neat, cm−1) 2963, 2876, 1704, 1606, 1564, 1464, 1261, 1098, 1058, 1026, 800, HRMS (EI+) m/z [M]+ calcd for C25H32O 348.2453, found 348.2453.

4. Conclusions

In summary, we have developed an efficient and convenient method for the synthesis of anthraquinones ranging from a 42% yield to a 93% yield through an iridium/dppe complex-catalyzed [2 + 2 + 2] cycloaddition of a 1,2-bis(propiolyl)benzene derivative with a broad range of terminal and internal alkynes. The use of dichloromethane as a solvent is important for the success of [2 + 2 + 2] cyclization with internal alkynes to lead to the desired anthraquinones in 72–86% yields. Furthermore, the synthesis of the fluorenone was also achieved by [2 + 2 + 2] cyclization with the iridium/F-dppe catalytic system to give a 94% yield.

Author Contributions

Conceptualization, R.T. Methodology, Y.T. Investigation, Y.T. and T.S. Writing-Original Draft Preparation, T.S. Writing-Review & Editing, T.S. and R.T. Visualization, T.S. Supervision, R.T. Project Administration, R.T. Funding Acquisition, R.T.

Funding

Grant-in-Aid for Scientific Research (KAKENHI) (No. 17K05867) from JSPS supported this work.

Acknowledgments

This work was partly supported by Grant-in-Aid for Scientific Research (KAKENHI) (No. 19K23636) from JSPS.

Conflicts of Interest

The authors declare no conflict of interest.

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Inorganics 07 00138 sch001 550
Scheme 1. Gram-scale synthesis of anthraquinone 3a.
Scheme 1. Gram-scale synthesis of anthraquinone 3a.
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Scheme 2. Synthesis of S1.
Scheme 2. Synthesis of S1.
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Inorganics 07 00138 sch003 550
Scheme 3. Synthesis of 1.
Scheme 3. Synthesis of 1.
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Inorganics 07 00138 sch004 550
Scheme 4. Synthesis of S2.
Scheme 4. Synthesis of S2.
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Scheme 5. Synthesis of 4.
Scheme 5. Synthesis of 4.
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Inorganics 07 00138 sch006 550
Scheme 6. Synthetic procedure for 3a.
Scheme 6. Synthetic procedure for 3a.
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Scheme 7. Gram-scale synthesis of 3a.
Scheme 7. Gram-scale synthesis of 3a.
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Scheme 8. Characterization of 3a.
Scheme 8. Characterization of 3a.
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Scheme 9. Characterization of 3b.
Scheme 9. Characterization of 3b.
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Scheme 10. Characterization of 3c.
Scheme 10. Characterization of 3c.
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Scheme 11. Characterization of 3d.
Scheme 11. Characterization of 3d.
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Scheme 12. Characterization of 3e.
Scheme 12. Characterization of 3e.
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Scheme 13. Characterization of 3f.
Scheme 13. Characterization of 3f.
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Scheme 14. Characterization of 3g.
Scheme 14. Characterization of 3g.
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Scheme 15. Characterization of 3h.
Scheme 15. Characterization of 3h.
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Scheme 16. Characterization of 3i.
Scheme 16. Characterization of 3i.
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Scheme 17. Characterization of 3j.
Scheme 17. Characterization of 3j.
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Scheme 18. Characterization of 3k.
Scheme 18. Characterization of 3k.
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Scheme 19. Characterization of 3l.
Scheme 19. Characterization of 3l.
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Scheme 20. Synthetic procedure for 5j.
Scheme 20. Synthetic procedure for 5j.
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Scheme 21. Characterization of 5j.
Scheme 21. Characterization of 5j.
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Table
Table 1. Ligand effects a.
Table 1. Ligand effects a.
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EntryLigand (mol %)Yield of 3a (%) b
1none20
2PPh3 (8)64
3DPPE (4)83
4DPPP (4)40
5DPPB (4)45
6DPPF (4)22
a Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), [Ir(cod)Cl]2 (0.1 mmol), ligand, toluene (2.5 mL), under reflux for 20 h. b Isolated yield.
Table
Table 2. Synthesis of anthraquinones with terminal alkynes a.
Table 2. Synthesis of anthraquinones with terminal alkynes a.
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Inorganics 07 00138 i003 Inorganics 07 00138 i004 Inorganics 07 00138 i005
Inorganics 07 00138 i006 Inorganics 07 00138 i007 Inorganics 07 00138 i008
Inorganics 07 00138 i009 Inorganics 07 00138 i010
a Reaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), [Ir(cod)Cl]2 (0.1 mmol), DPPE (0.2 mmol), toluene (2.5 mL) under reflux for 20 h. Yields are isolated yields.
Table
Table 3. The [2 + 2 + 2] cycloaddition of 1 with internal alkyne 2j a.
Table 3. The [2 + 2 + 2] cycloaddition of 1 with internal alkyne 2j a.
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EntryReaction ConditionsYield of 3j (%) b
1Toluene, reflux36
2DCE, reflux62
3DCM, reflux72
a Reaction conditions: 1 (0.5 mmol), 2j (1.5 mmol), [Ir(cod)Cl]2 (0.1 mmol), DPPE (0.2 mmol), solvent (2.5 mL) under reflux for 24 h. b Isolated yield.
Table
Table 4. Synthesis of tetra-substituted anthraquinones a.
Table 4. Synthesis of tetra-substituted anthraquinones a.
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Inorganics 07 00138 i013 Inorganics 07 00138 i014 Inorganics 07 00138 i015
a1 (0.5 mmol), 2 (1.5 mmol), [Ir(cod)Cl]2 (0.1 mmol), DPPE (0.2 mmol), DCM (2.5 mL) under reflux for 24 h. Yields are isolated yields.
Table
Table 5. Synthesis of fluorenone from diyne 4 and alkyne 2j a.
Table 5. Synthesis of fluorenone from diyne 4 and alkyne 2j a.
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EntryLigand (mol %)Yield of 5j (%) b
1DPPE (4)43
2PPh3 (8)45
3BIPHEP (4)63
4DPPF (4)28
5F-DPPE (4)94
a Reaction conditions: 4 (0.5 mmol), 2j (1.5 mmol), [Ir(cod)Cl]2 (0.1 mmol), ligand, DCM (2.5 mL) under reflux for 24 h. b Isolated yield.

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MDPI and ACS Style

Sawano, T.; Toyoshima, Y.; Takeuchi, R. Synthesis of Anthraquinones by Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of a 1,2-Bis(propiolyl)benzene Derivative with Alkynes. Inorganics 2019, 7, 138. https://doi.org/10.3390/inorganics7110138

AMA Style

Sawano T, Toyoshima Y, Takeuchi R. Synthesis of Anthraquinones by Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of a 1,2-Bis(propiolyl)benzene Derivative with Alkynes. Inorganics. 2019; 7(11):138. https://doi.org/10.3390/inorganics7110138

Chicago/Turabian Style

Sawano, Takahiro, Yuko Toyoshima, and Ryo Takeuchi. 2019. "Synthesis of Anthraquinones by Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of a 1,2-Bis(propiolyl)benzene Derivative with Alkynes" Inorganics 7, no. 11: 138. https://doi.org/10.3390/inorganics7110138

APA Style

Sawano, T., Toyoshima, Y., & Takeuchi, R. (2019). Synthesis of Anthraquinones by Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of a 1,2-Bis(propiolyl)benzene Derivative with Alkynes. Inorganics, 7(11), 138. https://doi.org/10.3390/inorganics7110138

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