Organic Chemistry International

Volume 2013 (2013), Article ID 978397, 5 pages

http://dx.doi.org/10.1155/2013/978397

Research Article

Novel ZrOCl₂·8H₂O-Catalysed One-Pot Multicomponent Synthesis of 9,10-Dihydro-8H-benzo[a]xanthen-11(12H)-one Derivatives

Mohammad Reza Poor Heravi, Mahsa Ahmadinejad, Bakhshali Masoumi, and Kamelia Nejati

Department of Chemistry, Payame Noor University, Tehran 19395-4697, Iran

Received 30 April 2013; Revised 18 July 2013; Accepted 1 August 2013

Academic Editor: Dipakranjan Mal

Copyright © 2013 Mohammad Reza Poor Heravi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

A simple and efficient protocol for the synthesis of highly substituted xanthenes is developed through the condensation of β-naphthol, aldehydes, and cyclic 5,5-dimethylcyclohexane-1,3-dione with zirconium oxychloride octahydrate as a catalyst via multicomponent condensation strategy. The present method gives good to excellent yields of substituted 9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one derivatives.

1. Introduction

Xanthenes and benzoxanthenes are biologically important drug intermediates. They are cited as active oxygen hetero-cycles possessing antibacterial. Research on xanthenes, especially benzoxanthenes, has emerged in organic synthesis due to their wide range of biological and therapeutic properties like antiviral [1], antibacterial [2], and anti-inflammatory activities [3], as well as in photodynamic therapy [4] and as antagonists of the paralyzing action of zoxazolamine [5]. Xanthenes are also available from natural sources. Popularly known, Santalin pigments have been isolated from a number of plant species [6]. Furthermore, due to their useful spectroscopic properties, they are used as dyes [7], in laser technologies [8], and in fluorescent materials for visualization of biomolecules [9]. Many procedures are disclosed to synthesize xanthenes and benzoxanthenes like cyclodehydrations [10], trapping of benzynes by phenols [11], alkylations of hetero atoms [12], and cyclocondensations between 2-hydroxy aromatic aldehydes and 2-tetralone [13]. Benzaldehydes and acetophenones bearing tethered carbonyl chains underwent the intermolecular phenyl-carbonyl coupling reactions in the presence of samarium diiodide and hexamethylphosphoramide to afford xanthenes [14]. In addition, 14H-dibenzo[a,j]xanthenes and related products are prepared by reaction of β-naphthol with form amide [15], 1-hydroxy methyl-naphthalen-2-ol [16], and carbon monoxide [17].

Initially, we investigated the condensation reaction of β-naphthol, benzaldehyde, and 5,5-dimethylcyclohexane-1,3-dione using different Lewis acids catalysts and conditions such as La(OTf)₃, ZnCl₂, AlCl₃, and Sr(OTf)₃ [18]. However, many of these reagents or catalysts are expensive, harmful, and difficult to handle especially on a large scale.

2. Experimental

2.1. Materials and Instruments

All reagents were purchased from Merck. Aldehydes were distilled before use. Melting points were determined using a Linkman HF591 heating stage, used in conjunction with a TC92 controller, and re-uncorrected. NMR spectra were recorded using either a Brucker DRX500 machine at room temperature. ¹H, ¹³C NMR, and ¹⁹F NMR spectra were measured using DMSO- as solvent. CHN analyses were performed on Exeter Analytical Inc. Model C-400 CHN Analyzer. Mass spectra were obtained using a Micromass LCT machine in ES or EI mode. Infrared spectra were measured on a Perkin Elmer Paragon 100 FT-IR spectrometer. All the reactions were monitored by TLC using 0.25 mm silica gel plates (Merck 60F₂₅₄) UV indicator.

2.2. Typical Procedure for Synthesis of 99,9-Dimethyl-12-phenyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4a)

A mixture of β-naphthol (1.0 mmol), benzaldehyde (1.1 mmol), and 5,5-dimethylcyclohexane-1,3-dione was added to zirconium oxychloride octahydrate (0.2 mmol) in ethanol (2 mL). The mixture was stirred at room temperature for the given times (Table 2). The progress of the reaction was monitored by TLC. After completion of the reaction water was added and the product was extracted with ethyl acetate (3 × 10 mL). The organic layer was dried (MgSO₄) and evaporated, and the crude product was purified by column chromatography by using ethyl acetate and hexane (7 : 3) to provide the pure product. The filtrate was concentrated under reduced pressure and dried at 100°C to recover the catalyst for subsequent use.

2.3. Selected Spectra

9,9-Dimethyl-12-phenyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4a). White crystals mp 202-203°C; yield: 97%; FT-IR (KBr, cm⁻¹) 3062, 3023, 2953, 1647, 1550, 1443, 1367, 1234; ¹H NMR (CDCl₃  δ ppm): 1.1 (3H, s, CH₃), 1.26 (3H, s, CH₃), 2.23 (2H, dd, ¹J = 4.0 Hz, ²J = 17.0 Hz), 2.57 (2H, dd, ¹J = 2.5 Hz, ²J = 17.5 Hz), 5.67 (1H, s, CH), 7.04 (1H, t, J = 7.5 Hz, Ar–H), 7.13 (2H, t, Ar–H), 7.35–7.40 (5H, m, Ar–H), 778 (2H, t, Ar–H), 7.99 (1H, d, Ar–H). ¹³C NMR (CDCl₃  δ ppm): 26.1, 28.3, 28.7, 31.2, 33.7, 40.4, 49.9, 113.2, 116.0, 116.6, 122.6, 123.8, 125.2, 125.9, 127.2, 127.2, 127.3, 127.3, 127.8, 130.4, 130.4, 143.7, 146.7, 162.8, 195.9; (EI) found: M⁺, 354.1632, C₂₅H₂₂O₂ requires M⁺, 354.1611; LRMS m/z (EI): 354 (M⁺, 70%), 277 (M-C₆H₅, 65%); elemental analysis: found (%): C, 84.87; H, 6.31. Calcd for C₂₅H₂₂O₂: C, 84.72; H, 6.26.

12-(4-Fluorophenyl)-9,9-dimethyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4i). White crystals mp 196-197°C, yield: 97%; FT-IR (KBr, cm⁻¹) 3053, 3028, 2953, 1640, 1583, 1435, 1373, 1228; ¹H NMR (CDCl₃  δ ppm): 1.18 (3H, s, CH₃), 1.33 (3H, s, CH₃), 2.31 (2H, dd, ¹J = 3.5 Hz, ²J = 17.5 Hz), 2.64 (2H, dd, ¹J = 2.5 Hz, ²J = 17.5 Hz), 5.23 (1H, s, CH), 7.32 (1H, t, J = 8.0 Hz, Ar–H), 7.52 (2H, t, Ar–H), 7.62–7.76 (5H, m, Ar–H), 8.14 (2H, t, J = 8.0 Hz, Ar–H); ¹³C NMR (CDCl₃  δ ppm): 26.1, 28.3, 28.7, 31.2, 33.7, 40.4, 49.9, 113.2, 116.0, 116.6, 122.6, 123.8, 125.2, 125.9, 127.2, 127.2, 127.3 (d,  = 14.98 Hz, C-3), 127.8 (d,  = 250.32 Hz, C-4), 130.4, 130.4, 143.7, 146.7, 162.8, 195.9; ¹⁹F NMR (CDCl₃  δ ppm): −64.19; (EI) found: M⁺, 372.2103, C₂₅H₂₁FO₂ requires M⁺, 372.1503; LRMS m/z (EI): 372 (M⁺, 45%), 277 (M-(4-FC₆H₅), 75%); elemental analysis: found (%): C, 80.71; H, 5.72. Calcd for C₂₅H₂₁FO₂: C, 80.62; H, 5.68.

12-(2-Fluorophenyl)-9,9-dimethyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4j) . White crystals mp 231-232°C; yield: 95%. FT-IR (KBr, cm⁻¹) 3073, 3056, 2906, 1662, 1534, 1423, 1372, 1230, cm⁻¹; ¹H NMR (CDCl₃  δ ppm): 1.18 (3H, s, CH₃), 1.29 (3H, s, CH₃), 2.11 (2H, dd, ¹J = 3.0 Hz, ²J = 18.0 Hz), 2.31 (2H, dd, ¹J = 2.5 Hz, ²J = 17.5 Hz), 5.06 (1H, s, CH), 7.08 (1H, t, J = 8.0 Hz, Ar–H), 7.32 (2H, t, Ar–H), 7.59–7.83 (5H, m, Ar–H), 8.14 (2H, t, J = 8.0 Hz, Ar–H); ¹³C NMR (CDCl₃  δ ppm): 25.4, 27.8, 29.1, 30.2, 35.3, 42.2, 48.2, 112.7, 115.2, 117.4, 121.7, 124.2, 125.8, 126.6, 127.8, 127.9, 129.5 (d,  = 14.95 Hz, C-3), 130.2 (d,  = 251.76 Hz, C-2), 131.8, 136.5, 140.5, 148.5, 161.9, 193.6; ¹⁹F NMR (CDCl₃  δ ppm): −73.23; (EI) found: M⁺, 372.3110, C₂₅H₂₁FO₂ requires M⁺, 372.1503; LRMS m/z (EI): 372 (M⁺, 35%), 277 (M-(2-FC₆H₅), 84%); elemental analysis: found (%): C, 80.71; H, 5.72. Calcd for C₂₅H₂₁FO₂: C, 80.62; H, 5.68.

9,9-Dimethyl-12-(4-(trifluoromethyl)phenyl)-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4k). White crystals mp 227-228°C; yield: 97%.; FT-IR (KBr, cm⁻¹) 3098, 3043, 2923, 1673, 1555, 1465, 1343, 1223, cm⁻¹. ¹H NMR (CDCl₃  δ ppm): 1.31 (3H, s, CH₃), 1.52 (3H, s, CH₃), 2.27 (2H, dd, ¹J = 2.5 Hz, ²J = 16.0 Hz), 2.43 (2H, dd, ¹J = 2.5 Hz, ²J = 17.0 Hz), 5.43 (1H, s, CH), 7.20 (1H, t, J = 7.5 Hz, Ar–H), 7.43 (2H, t, Ar–H), 7.59–7.83 (5H, m, Ar–H), 8.14 (2H, t, J = 8.0 Hz, Ar–H); ¹³C NMR (CDCl₃  δ ppm): 25.1, 28.3, 29.5, 32.9, 34.4, 46.3, 49.1, 110.9, 116.1, 119.2, 123.4, 124.7, 125.2, 126.1, 127.2, 127.3, 128.3, 130.2, 131.8, 133.3, 135.35 (q,  = 251.9 Hz, CF₃), 136.5, 140.5, 148.5, 161.9, 193.6; ¹⁹F NMR (CDCl₃  δ ppm): −112.32; (EI) found: M⁺, 422.2130, C₂₆H₂₁F₃O₂ requires M⁺, 422.1523; LRMS m/z (EI): 422 (M⁺, 25%), 277 (M-(4-CF₃C₆H₅), 72%); elemental analysis: found (%): C, 80.05; H, 5.23. Calcd for C₂₆H₂₁F₃O₂: C, 73.92; H, 5.01.

12-([1,1 ′-Biphenyl]-4-yl)-9,9-dimethyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4l). White crystals mp 214-215°C; yield: 91%; FT-IR (KBr, cm⁻¹) 3086, 3039, 2909, 1680, 1543, 1436, 1352, 1231, cm⁻¹; ¹H NMR (CDCl₃  δ ppm): 1.27 (3H, s, CH₃), 1.39 (3H, s, CH₃), 2.10 (2H, dd, ¹J = 3.0 Hz, ²J = 17.5 Hz), 2.28 (2H, dd, ¹J = 3.0 Hz, ²J = 17.5 Hz), 5.08 (1H, s, CH), 7.11 (3H, m, Ar–H), 7.42 (2H, t, Ar–H), 7.21 (2H, t, J = 7.5 Hz, Ar–H), 7.42 (1H, t, Ar–H), 7.59–7.83 (5H, m, Ar–H), 8.14 (2H, t, J = 7.5 Hz, Ar–H); ¹³C NMR (CDCl₃  δ ppm): 23.7, 24.9, 27.9, 31.3, 32.4, 41.3, 43.4, 110.7, 113.3, 116.6, 120.3, 121.3, 121.9, 122.4, 123.5, 125.3, 126.8, 129.1, 129.9, 130.2, 130.0, 131.4, 132.0, 133.8, 134.2, 135.6, 141.6, 145.6, 146.7, 168.5, 192.1; (EI) found: M⁺, 430.2109, C₃₁H₂₆O₂ requires M⁺, 422.1523; LRMS m/z (EI): 430 (M⁺, 15%), 277 (M-(C₆H₅C₆H₄), 63%); elemental analysis: found (%): C, 86.32; H, 5.98. Calcd for C₃₁H₂₆O₂: C, 86.48; H, 6.09.

12-(Furan-2-yl)-9,9-dimethyl-9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one (4o). White crystals mp 245-246°C; yield: 97%; FT-IR (KBr, cm⁻¹) 3060, 3046, 2943, 1672, 1539, 1482, 1362, 1231, cm⁻¹; ¹H NMR (CDCl₃  δ ppm): 1.24 (3H, s, CH₃), 1.35 (3H, s, CH₃), 2.36 (2H, dd, ¹J = 2.5 Hz, ²J = 17.5 Hz), 2.42 (2H, dd, ¹J = 2.5 Hz, ²J = 17.5 Hz), 5.26 (1H, s, CH), 7.21 (1H, t, J = 7.0 Hz, Furyl–H), 7.33 (1H, t, J = 7.5 Hz, Furyl–H), 7.42 (1H, t, J = 7.0 Hz, Furyl–H), 7.5. ¹³C NMR (CDCl₃  δ ppm): 23.2, 24.4, 28.8, 29.6, 32.5, 40.2, 46.2, 114.9, 116.2, 119.4, 121.7, 124.2, 125.8, 126.6, 127.8, 127.9, 129.5, 131.8, 136.5, 140.5, 148.5, 161.9, 193.6; (EI) found: M⁺, 344.1911, C₂₃H₂₀O₃ requires M⁺, 344.1421; LRMS m/z (EI): 344 (M⁺, 34%), 267 (M-(Furyl), 48%); elemental analysis: found (%): C, 80.33; H, 5.63, 5.98. Calcd for C₂₃H₂₀O₃: C, 80.21; H, 5.85.

3. Results and Discussion

In continuation of our efforts towards the development of novel methodologies under green chemical approaches herein we report a mild, efficient, and facile one-pot synthesis of multisubstituted xanthen derivatives for the first time by the multicomponent reaction of β-naphthol, benzaldehyde, and 5,5-dimethylcyclohexane-1,3-dione using zirconium oxychloride octahydrate as a Lewis acid catalyst (Scheme 1). The side reactions were not observed in our work. However, the corresponding of (4a–j) were the major products, when ZrOCl₂·8H₂O was employed as the catalyst, hence, showing good chemoselectivity.

Scheme 1

In order to determine the most appropriate choice of catalyst and solvent system for this ZrOCl₂·8H₂O catalyzed synthesis of substituted xanthenes, we examined the above reaction in several catalyst amounts and solvents (Table 1). The results indicate that different solvents affected the efficiency of the reaction. Acetonitrile, nitromethane, and chloroform catalyst afforded low yields (Table 1, entries 3–5), while when water and tetrahydrofuran with were used as solvents, no products were detected (Table 1, entries 1 and 2). The use of solvents such as DMF, dichloromethane, and [bmim]BF₄ could improve the yields (Table 1, entries 6–8). In particular, the reaction could be carried out under solvent-free condition and gave moderate yield (Table 1, entry 9); finally, when ethanol under reflux with 20 mol% catalyst was used, the yield increased to 92% better than any other solvents examined here. The catalytic activity of the recycled ZrOCl₂·8H₂O was also examined. ZrOCl₂·8H₂O could be reused five times for the reaction without noticeable loss of activity (Table 1, entry 11).

Table 1: Screening of the catalyst and solvent for the reaction of -naphthol, benzaldehyde, and 5,5-dimethylcyclohexane-1,3-dione catalyzed by ZrOCl₂·8H₂Oa.

Entry
Catalyst (mol%)
Solvent/condition
Time (h)
Yieldb (%)

1
20
Water/80°C
10
—

2
20
THF/Reflux
10
—

3
20
CH₃CN/Reflux
10
<10

4
20
CH₃NO₂/Reflux
10
15

5
20
CHCl₃/Reflux
10
15

6
20
DMF/80°C
10
55

7
20
CH₂Cl₂/Reflux
10
65

8
20
(bmim) BF₄/Reflux
5
75

9
20
None/80°C
10
20

10
20
CH₃CH₂OH/rt
4
85

11
20
/Reflux
1
92, 93, 92, 92, 91

12
10
CH₃CH₂OH/Reflux
10
80

12
30
CH₃CH₂OH/Reflux
4
92

10
none
CH₃CH₂OH/Reflux
10
Nil

Reaction conditions: -naphthol (1.0 mmol), benzaldehyde (1.0 mmol), and 5,5-dimethylcyclohexane-1,3-dione (1.1 mmol), zirconium oxychloride catalyst.

bIsolated yield.

cCatalyst was reused five times.

Table 2: Synthesis of xanthenes in the presence of ZrOCl₂·8H₂O.

Entry
R
Product
Time (h)
Yielda (%)

1
C₆H₅
4a
1
92

2
p-CH₃C₆H₄
4b
2
85

3
3-CH₃-4-CH₃-C₆H₃
4c
3
82

4
p-CH₃OC₆H₄
4d
2
85

5
p-ClC₆H₄
4e
1
95

6
p-NO₂C₆H₄
4f
1
96

7
o-NO₂C₆H₄
4g
1
90

8
p-ClC₆H₄
4h
1
95

9
p-FC₆H₄
4i
0.5
97

10
o-FC₆H₄
4j
0.5
95

11
p-CF₃C₆H₄
4k
0.5
97

12
p-(C₆H₅)C₆H₄
4l
1
91

13
CH₃CH₂
4m
4
75

14
2-Thiophene
4n
5
80

15
2-Furan
4o
5
82

Isolated yield.

In order to determine the scope of this reaction, we have synthesized differently substituted xanthenes by varying differently substituted aldehydes including both electron-donating and electron-withdrawing groups. It is observed that the reaction gave good yields of products with faster reaction rate when the aldehyde bearing electron-withdrawing group is used compared to the aldehydes with electron-donating groups. The corresponding results are tabulated in Table 2.

On the basis of the above results, this process was then extended to heterocyclic and aliphatic aldehydes. Propionaldehyde, thiophene-2-carbaldehyde, and furan-2-carbaldehyde afforded the corresponding products (4 m, 4n, 4o) in 75%, 80%, and 82% yields, respectively (Table 2, entries 13–15). Compared with aromatic aldehydes, heterocyclic or aliphatic aldehydes afforded relatively lower yields of the corresponding 4 (Table 2).

A tentative mechanism for the formation of derivatives 4 is proposed in Scheme 2. By referring to the literature [19], we supposed that the reaction may proceed via the ortho-quinone methides intermediate 5, which was formed by the nucleophilic addition of β-naphthol to aldehyde with ZrOCl₂·8H₂O. Subsequent substitution of the oxygen atom, which was coordinated by zirconium oxychloride, with 5,5-dimethylcyclohexane-1,3-dione 1 afforded 6. Then compounds 6 eliminated one molecule of H₂O and afforded title product 4. All the products were characterized by ¹H, ¹³C NMR, IR, and mass spectra and compared with authentic samples.

Scheme 2: Proposed mechanism for the condensation reaction of aldehydes, β-naphthol, and 5,5-dimethylcyclohexane-1,3-dione.

4. Conclusion

We have developed a one-pot multicomponent reaction for the synthesis of 9,10-dihydro-8H-benzo[a]xanthen-11(12H)-one derivatives catalyzed by zirconium oxychloide in excellent yields. This method includes the use of recyclable catalyst, mild reaction conditions, easy work-up, good chemoselectivity, high yields, and cleaner reaction profiles.

Acknowledgment

The authors are grateful to the Payame Noor University (PNU), Tehran, Iran, for financial support.

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