Synthesis of 1,8-dioxo-octahydroxanthenes and bis(indolyl)methanes catalyzed by [Et₃NH][H₂PO₄] as a cheap and mild acidic ionic liquid

1 Introduction

Ionic liquids (ILs) are very attractive and environmentally acceptable solvents because they have very low vapor pressure and are stable in a wide temperature range (Wasserscheid and Keim, 2000). Therefore, they can be used as environmentally benign solvents for a number of chemical processes, such as separations (Huddleston et al., 1998), reactions (Sheldon, 2001), homogeneous two-phase catalyses (Holbrey and Seddon, 1999), and extractions (Esser et al., 2004). The current emphasis on novel reaction media is motivated by the need for efficient methods for replacing of toxic or hazardous solvents and catalysts. The use of ionic liquids as novel reaction media may offer a convenient solution to both the solvent emission and the catalyst recycling problem (Gmouh et al., 2003). Another promising class of new media is molten salts which can be used instead of ionic liquids. Molten salts are generally thermally stable and chemically resistant.

Indole and xanthene derivatives are parent compounds generally of a large number of naturally occurring, as well as synthetic derivatives, and occupy a prominent position in medicinal chemistry. Many procedures are disclosed to synthesize bis-indolyl carbonyl compounds (Sonar et al., 2009; Kundu et al., 2010) and xanthenediones (Karthikeyana and Pandurangana, 2009; Dabiri et al., 2008). In spite of potential utility of these methods, many of them involve expensive reagents, strong acidic conditions, long reaction times, low yields, use of excess of reagents/catalysts, and use of toxic organic solvents. Therefore, to avoid these disadvantages, the discovery of a new and efficient catalyst with high catalytic activity, short reaction time and simple work-up for the preparation of bis-indolyl methanes and xanthenediones under mild and practical conditions is of prime interest. The aim of this study is to utilize the [Et₃NH][H₂PO₄] in molten state as a very efficient mild acidic ionic liquid catalyst for the synthesis of bis-indolyl methanes and 1,8-dioxo-octahydroxanthene derivatives (Scheme 1).

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Scheme 1

[Et₃NH][H₂PO₄]-catalyzed synthesis of bis(indolyl)methanes and 1,8-dioxo-octahydroxanthenes.

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2 Materials and methods

All compounds are known and were identified by comparison of their spectral data and physical properties with those of the authentic samples. ¹H NMR and ¹³C NMR spectra were recorded on a BRUKER DRX-500 AVANCE NMR spectrometer. All chemicals were purchased from Merck chemical company and used without further purification. [Et₃NH][H₂PO₄] was prepared according to a literature method (Wang et al., 2006).

2.2

2.2 Spectral data for selected bis(indolyl)methanes

2.2.1

2.2.1 Bis(3-indolyl)phenylmethane (Table 1, entry 1)

¹H NMR (CDCl₃, 500 MHz): δ (ppm) 5.93 (s, 1H, CH), 6.67 (s, 2H), 7.05 (t, J = 7.3 Hz, 2H, arom), 7.21 (t, J = 7.3 Hz, 2H, arom), 7.25 (t, J = 7.2 Hz, 1H, arom), 7.29–7.33 (m, 2H, arom), 7.37–7.40 (m, 4H, arom), 7.43 (d, J = 7.9 Hz, 2H, arom), 7.88 (s, br, 2H, NH). ¹³C NMR: δ (ppm) 40.6, 111.4, 119.7, 120.2, 120.4, 122.4, 124.1, 126.6, 127.5, 128.6, 129.2, 137.1, and 144.4.

Table 1 Synthesis of bis(indolyl)methanes in molten [Et₃NH][H₂PO₄].

Entry	R	Product	Time (min)	Yield (%)
1	C6H5		10	97
2	4-Cl-C6H4		5	84
3	4-NO2-C6H4		5	87
4	4-Br-C6H4		10	97
5	4-CH3-C6H4		30	95
6	3-NO2-C6H4		5	93
7	2-Cl-C6H4		5	96
8	4-OCH3-C6H4		10	98

2.2.2

2.2.2 Bis(3-indolyl)-(p-chlorophenyl)methane (Table 1, entry 2)

¹H NMR (CDCl₃, 500 MHz): δ (ppm) 5.09 (s, 1H, CH), 6.66 (s, 2H), 7.06 (t, J = 7.4 Hz, 2H, arom), 7.22 (t, J = 7.6 Hz, 2H, arom), 7.27–7.32 (m, 4H, arom), 7.40 (t, J = 7.7 Hz, 4H, arom), 7.92 (s, br, 2H, NH). ¹³C NMR: δ (ppm) 40.1, 111.5, 119.6, 119.8, 120.3, 122.5, 124.0, 127.3, 128.8, 130.5, 132.2, 137.1, and 142.9.

2.2.3

2.2.3 Bis(3-indolyl)-p-nitrophenylmethane (Table 1, entry 3)

¹H NMR (CDCl₃, 500 MHz): δ (ppm) 5.92 (s, 1H, CH), 6.63 (s, 2H), 6.91 (t, J = 7.3 Hz, 2H, arom), 7.08 (t, J = 7.3 Hz, 2H, arom), 7.25 (d, J = 7.9 Hz, 2H, arom), 7.32 (d, J = 8.1 Hz, 2H, arom), 7.44 (d, J = 8.6 Hz, 2H, arom), 8.04 (d, J = 8.6 Hz, 2H, arom), 9.31 (s, br, 2H, NH). ¹³C NMR: δ (ppm) 40.5, 111.8, 117.8, 119.4, 119.7, 122.1, 123.8, 124.4, 127.0, 129.9, 137.3, 146.7, and 152.8.

2.4

2.4 Spectral data for selected 1,8-dioxo-octahydroxanthenes

2.4.1

2.4.1 3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-phenyl-2H-xanthene-1,8(5H, 9H)-dione (Table 2, entry 1)

¹H NMR (CDCl₃, 500 MHz): δ (ppm) 1.03 (s, 6H), 1.14 (s, 6H), 2.33–2.51 (m, 8H, 4CH₂), 4.79 (s, 1H, CH), 7.13 (d, J = 7.8 Hz, 2H, arom), 7.20 (t, J = 7.2 Hz, 1H, arom), 7.28–7.31 (m, 2H, arom). ¹³C NMR: δ (ppm) 27.1, 29.0, 31.5, 31.8, 40.5, 51.0, 115.6, 126.1, 127.7, 128.2, 142.0, 163.2, and 196.1.

Table 2 Synthesis of 1,8-dioxo-octahydroxanthenes in molten [Et₃NH][H₂PO₄].

Entry	R	Product	Time (min)	Yield (%)
1	C6H5		5	96
2	4-Cl-C6H4		20	95
3	3-NO2-C6H4		5	86
4	4-NO2-C6H4		5	86
5	4-CH3-C6H4		30	84
6	2-Cl-C6H4		5	95
7	4-OCH3-C6H4		15	86
8	2-OH-C6H4		10	90
9	4-OH-C6H4		10	92
10	4-Br-C6H4		5	94

2.4.2

2.4.2 9-(4-Chlorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H, 9H)-dione (Table 2, entry 2)

¹H NMR (CDCl₃, 500 MHz): δ (ppm) 0.99 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3), 2.25–2.50 (m, 8H, 4CH₂), 4.66 (s, 1H), 7.26–7.43 (m, 4H, arom). ¹³C NMR: δ (ppm) 27.3, 29.2, 31.5, 32.2, 40.9, 50.7, 115.3, 128.2, 129.8, 132.0, 143.8, 162.4, and 196.3.

3 Results and discussion

We first studied a reaction between benzaldehyde (1 mmol) and indole (2 mmol) by screening the reaction conditions. In order to determine the optimum conditions, we examined the influence of the reaction temperature, the reaction time, and the amounts of (Et₃NH)(H₂PO₄). The best result was obtained with 0.4 g of [Et₃NH][H₂PO₄] at 100 °C.

After optimizing the conditions, we next examined the generality of these conditions to other substrates using several aromatic aldehydes. The results are summarized in Table 1. The results showed that the reaction proceeds very efficiently in all cases.

Encouraged by these results, we used same conditions for the synthesis of 1,8-dioxo-octahydroxanthenes (Scheme 1). We optimized amount of [Et₃NH][H₂PO₄] for condensation reaction of 5,5-dimethyl-1,3-cyclohexanedione 4 and benzaldehyde at 100 °C. The best result was obtained with a 0.4 g of [Et₃NH][H₂PO₄].

To investigate the versatility of the catalyst, the reaction of 5,5-dimethyl-1,3-cyclohexanedione 4 was carried out with various aromatic aldehydes in molten [Et₃NH][H₂PO₄] at 100 °C, which also afforded 1,8-dioxo-octahydroxanthene derivatives 5 in good to excellent yields. The results are given in Table 2.

Here also the aromatic aldehydes containing both electron-donating and electron withdrawing groups afforded the products with high yields. Work-up procedure was so simple and including addition of water at the end of the reaction, filtration, and finally recrystallizing the products from ethanol.

Comparison of the time, and yield of our method for the synthesis of bis(indolyl)methanes and 1,8-dioxo-octahydroxanthenes with the literature are indicated in Tables 3 and 4. As it is evident from the results, [Et₃NH][H₂PO₄] was found to be effective catalyst for the synthesis of bis(indolyl)methanes and 1,8-dioxo-octahydroxanthenes.

4 Conclusion

In summary, a mild Brønsted-acidic task-specific ionic liquid such as [Et₃NH][H₂PO₄] was found to be efficient catalyst for synthesis of 1,8-dioxo-octahydroxanthenes and bis(indolyl)methanes. The merit of this methodology is that it is simple, mild, and efficient and the used ionic liquid is cheaper than conventional ionic liquids. Therefore, we believe that the work reported here would have potential application in green chemistry.