Organic Chemistry International

Organic Chemistry International / 2013 / Article

Research Article | Open Access

Volume 2013 |Article ID 978397 | https://doi.org/10.1155/2013/978397

Mohammad Reza Poor Heravi, Mahsa Ahmadinejad, Bakhshali Masoumi, Kamelia Nejati, "Novel ZrOCl2·8H2O-Catalysed One-Pot Multicomponent Synthesis of 9,10-Dihydro-8H-benzo[a]xanthen-11(12H)-one Derivatives", Organic Chemistry International, vol. 2013, Article ID 978397, 5 pages, 2013. https://doi.org/10.1155/2013/978397

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

Academic Editor: Dipakranjan Mal
Received30 Apr 2013
Revised18 Jul 2013
Accepted01 Aug 2013
Published10 Sep 2013

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.

978397.sch.001

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).


EntryCatalyst (mol%)Solvent/conditionTime (h)Yieldb (%)

120Water/80°C10
220THF/Reflux10
320CH3CN/Reflux10<10
420CH3NO2/Reflux1015
520CHCl3/Reflux1015
620DMF/80°C1055
720CH2Cl2/Reflux1065
820(bmim) BF4/Reflux575
920None/80°C1020
1020CH3CH2OH/rt485
11 20 /Reflux192, 93, 92, 92, 91
1210CH3CH2OH/Reflux1080
1230CH3CH2OH/Reflux492
10noneCH3CH2OH/Reflux10Nil

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.

EntryRProductTime (h)Yielda (%)

1C6H54a192
2p-CH3C6H44b285
33-CH3-4-CH3-C6H34c382
4p-CH3OC6H44d285
5p-ClC6H44e195
6p-NO2C6H44f196
7o-NO2C6H44g190
8p-ClC6H44h195
9p-FC6H44i0.597
10o-FC6H44j0.595
11p-CF3C6H44k0.597
12p-(C6H5)C6H44l191
13CH3CH24m475
142-Thiophene4n580
152-Furan4o582

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.

978397.sch.002

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.

References

  1. R. W. Lambert, J. A. Martin, J. H. Merrett, K. E. B. Parkes, and G. J. Thomas, PCT International Application W0 9706178, Chemical Abstract 126, 212377y. 1997.
  2. T. Hideo, Jpn Tokkyo Koho JP 56005480, Chemical Abstract, 95, 95, 1981.
  3. J. P. Poupelin, G. Saint-Rut, O. Foussard-Blanpin, G. Narcisse, G. Uchida-Ernouf, and R. Lacroix, “Synthesis and antiinflammatory properties of bis (2-hydroxy-1-naphthyl)methane derivatives I,” European Journal of Medicinal Chemistry, vol. 13, pp. 67–71, 1978. View at: Google Scholar
  4. R. M. Ion, Progr. Catal., vol. 2, p. 55, 1997.
  5. G. Saint-Ruf, A. De, and H. T. Hieu, Bull. Chim. Ther, vol. 7, p. 83, 1972.
  6. B. Ravindranath and T. R. Seshadri, “Structural studies on santalin permethyl ether,” Phytochemistry, vol. 12, no. 11, pp. 2781–2788, 1973. View at: Google Scholar
  7. A. Banerjee and A. K. Mukherjee, “Chemical aspects of santalin as a histological stain,” Stain Technology, vol. 56, no. 2, pp. 83–85, 1981. View at: Google Scholar
  8. O. Sirkeeioglu, N. Talinli, and A. Akar, Journal of Chemical Research, p. 502, 1995.
  9. C. G. Knight and T. Stephens, “Xanthene-dye-labelled phosphatidylethanolamines as probes of interfacial pH. Studies in phospholipid vesicles,” Biochemical Journal, vol. 258, no. 3, pp. 683–689, 1989. View at: Google Scholar
  10. A. Bekaert, J. Andrieux, and M. Plat, “New total synthesis of bikaverin,” Tetrahedron Letters, vol. 33, no. 20, pp. 2805–2806, 1992. View at: Publisher Site | Google Scholar
  11. D. W. Knight and P. B. Little, “The first high-yielding benzyne cyclisation using a phenolic nucleophile: a new route to xanthenes,” Synlett, no. 10, pp. 1141–1143, 1998. View at: Google Scholar
  12. R. Vazquez, M. C. de la Fuente, L. Castedo, and D. DomInguez, “A short synthesis of (±)-clavizepine,” Synlett, vol. 1994, no. 6, pp. 433–434, 1994. View at: Google Scholar
  13. A. Jha and J. Beal, “Convenient synthesis of 12H-benzo[a]xanthenes from 2-tetralone,” Tetrahedron Letters, vol. 45, no. 49, pp. 8999–9001, 2004. View at: Publisher Site | Google Scholar
  14. C. -W. Kuo and J. -M. Fang, “Synthesis of xanthenes, indanes, and tetrahydronaphthalenes via intramolecular phenyl–carbonyl coupling reactionss,” Synthetic Communications, vol. 31, no. 6, pp. 877–892, 2001. View at: Google Scholar
  15. P. Papini and R. Cimmarusti, “The action of formamide and formanilide on naphthols and on barbituric acid,” Gazzetta Chimica Italiana, vol. 77, pp. 142–147, 1947. View at: Google Scholar
  16. R. N. Sen and R. N. Sarkar, “The condensation of primary alcohols with resorcinol and other hydroxy aromatic compounds,” Journal of the American Chemical Society, vol. 49, no. 47, pp. 1079–1091, 1925. View at: Google Scholar
  17. K. Ota and T. Kito, “An improved synthesis of dibenzoxanthene,” Bulletin of the Chemical Society of Japan, vol. 49, no. 4, pp. 1167–1168, 1976. View at: Google Scholar
  18. J. Li, W. Tang, L. Lu, and W. Su, “Strontium triflate catalyzed one-pot condensation of β-naphthol, aldehydes and cyclic 1,3-dicarbonyl compounds,” Tetrahedron Letters, vol. 49, no. 50, pp. 7117–7120, 2008. View at: Google Scholar
  19. S. H. Mashraqui, M. B. Paul, H. D. Mistry, S. Ghadigaonkar, and A. Meetsma, “A three-component reaction of phenol, aldehyde, and active methylene substrate under Lewis acid catalysis: successful trapping of o-quinone methide to afford benzopyran systems,” Chemistry Letters, vol. 33, no. 8, pp. 1058–1059, 2004. View at: Publisher Site | Google Scholar

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.


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