PEG–SO₃H catalyzed, environmentally benign synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes under solvent-free conditions

Abstract

A highly efficient, eco-friendly and high yielding procedure for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes has been developed through one-pot condensation reaction of β-naphthol with various aromatic aldehydes in the presence of a catalytic amount of sulfonated polyethylene glycol 6000 (PEG–SO₃H) as a stable, recyclable and bio-degradable polymeric catalyst under solvent-free conditions. This protocol was found to be applicable to obtain a diverse range of dibenzoxanthene derivatives in 82–98% isolated yields and the catalyst was recycled for four cycles.

---

Introduction

Xanthenes belong to an important class of oxygen heterocycles that are known to possess diverse pharmacological activities such as antibacterial,^1,2 anti-proliferative,³ anti-inflammatory,⁴ and antiviral activities.⁵ They have also been employed as excellent fluorescent dyes,⁶ pH-sensitive fluorescent materials for the visualization of biomolecules,⁷ photosensitizers in photodynamic therapy for the treatment of tumor cells,⁸ and in laser technology.⁹ Due to the unique biological profiles of xanthenes, there has been growing interest in the development of a number of efficient synthetic protocols for the preparation of these molecules. The most widely used approach to synthesize xanthenes involves one-pot thermal reaction of β-naphthol with various aromatic aldehydes in the presence of a number of catalysts such as pTSA,¹⁰ silica sulfuric acid,¹¹ BF₃·SiO₂,¹² ionic liquids,^13,14 amberlyst-15,¹⁵ LiBr,¹⁶ cyanuric chloride,¹⁷ K₅CoW₁₂O₄₀·3H₂O,¹⁸ HClO₄–SiO₂,¹⁹ sulfamic acid,²⁰ P₂O₅ or InCl₃,²¹ [MIMPS]HSO₄,²² and Sr(OTf)₂,²³etc. Although these methods are effective, they suffer from some disadvantages such as longer reaction times, use of expensive catalysts, low yields of products, necessity of excess reagents, use of volatile and hazardous organic solvents and requirement of harsh reaction conditions. Consequently, the development of more convenient, economical and eco-friendly methodology for the synthesis of xanthenes is highly desired.

Recently, a significant attention has been focused on designing environmentally benign synthetic strategies²⁴ for the construction of various interesting molecules with unique structural diversity in a one-pot operation. The green processes generally involve the use of efficient, cost-effective and biodegradable catalysts, non-toxic and non-inflammable media such as water, ionic liquids, supercritical fluids and the reactions under solvent-free conditions. To this end, the polymer-supported catalysts have gained considerable importance because of their low cost, high efficiency, easy work-up, and recyclability.²⁵ Among these, sulfuric acid-modified polyethylene glycol 6000 (PEG–SO₃H) has emerged as a cheap, acidic, non-volatile, non-corrosive, recyclable and versatile catalyst for several organic reactions including ring opening of epoxides,²⁶ synthesis of bis(indolyl-/pyrazolyl)methanes,²⁷ Beckmann rearrangement and dehydration of oximes.²⁸ In addition, PEG–SO₃H is a homogeneous catalyst, soluble in a number of solvents including water, thereby eliminating the problems associated with heterogeneous catalysts such as lower reactivity, extended reaction times and sometimes, toxicity. According to the literature, mainly the acidic catalysts have been successful in affording the title compounds in better yields. Thus, we envisaged that the catalytic use of PEG–SO₃H could lead to an efficient method for the synthesis of dibenzoxanthene derivatives. Hence, in the context of our ongoing work on the development of environmentally benign methods for the synthesis of biologically important heterocycles^29,30 and owing to the medicinal importance of the xanthene scaffold, we report herein a facile, convenient and green one-pot methodology for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes by reacting β-naphthol with various aromatic aldehydes in the presence of PEG–SO₃H as an efficient and biodegradable polymeric catalyst under solvent-free conditions (Scheme 1).

Scheme 1 PEG–SO₃H catalyzed synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes.

Results and discussion

In the search of a novel and efficient acidic catalyst for one-pot synthesis of dibenzoxanthenes, a model reaction was carried out by using β-naphthol and p-chlorobenzaldehyde as substrates in the presence of 1 mol% Eu(OTf)₃ at 125 °C under solvent-free conditions for 3 hours. To our delight, the product, 14-(4-chlorophenyl)-14H-dibenzo[a,j]-xanthene (3b) was obtained as a white solid in 84% yield after the purification by column chromatography. However, when the reaction was performed with p-tolualdehyde under same reaction conditions, the yield of the corresponding product (3j) decreased to 50% (Table 1, entry 1). Increasing the load of the catalyst or the reaction time did not bring any significant improvement in the yield of the desired product (Table 1, entries 2–4). Therefore, the search of other acidic catalysts begun and we came across a polymeric catalyst, PEG–SO₃H, which was known to be highly acidic due to the presence of two sulfonated groups at the terminal ends. To examine the catalytic ability of PEG–SO₃H in the synthesis of dibenzoxanthenes, a one-pot condensation cyclization reaction of β-naphthol with p-tolualdehyde was carried out in the presence of 10 mol% catalyst under solvent-free conditions at 125 °C. Surprisingly, the reaction was complete within 10 minutes and the desired product, 14-(4-methylphenyl)-14H-dibenzo[a,j]xanthene (3j) was obtained in 96% yield (Table 1, entry 5) after workup and chromatographic purification over a silica gel column. Interestingly, when the reaction was performed in the absence of PEG–SO₃H under same reaction conditions, it did not produce the desired product even after 24 hours (Table 1, entry 6), demonstrating the catalytic role of PEG–SO₃H in the synthesis of desired xanthene derivative (3j). Encouraged by these results and to optimize the reaction conditions, the effect of load of the catalyst on the reaction rate was studied. It was observed that the 1 mol% of PEG–SO₃H was as effective as higher loads of the catalyst to efficiently catalyze the reaction (Table 1, entries 5, 7 and 8) and hence, the optimal reaction conditions for the model reaction were found to be 1 mol% PEG–SO₃H at 125 °C for 10 minutes.

Table 1 Optimization of the reaction conditions for the synthesis of 14-(4-methylphenyl)-14H-dibenzo[a,j]xanthene (3j)

Entry	Catalysts	Catalyst load (mol%)	Time/min	Yields^a (%)
a Isolated yields; b No product formation.
1	Eu(OTf)3	1	180	50
2	Eu(OTf)3	5	180	52
3	Eu(OTf)3	10	180	53
4	Eu(OTf)3	10	600	64
5	PEG–SO3H	10	10	96
6	PEG–SO3H	0	1440
7	PEG–SO3H	5	10	96
8	PEG–SO3H	1	10	95

---

Under the optimized reaction conditions, the scope and limitations of this synthetic protocol were investigated by treating β-naphthol with a wide range of aromatic aldehydes to afford the corresponding 14-aryl-14H-dibenzo[a,j]xanthenes (3a–n) in good to excellent yields in the presence of 1 mol% PEG–SO₃H for 10 minutes (Table 2).

Table 2 PEG–SO₃H catalyzed synthesis of 14-aryl-14H-dibenzo[a,j]-xanthenes via one-pot condensation reaction of β-naphthol (2 moles) with aromatic aldehydes (1 mole)^a

Entry	Aldehydes	Product	Yields^b (%)
a All reactions were carried out under solvent-free conditions at 125 °C and products were characterized by ^1H NMR, ^13C NMR, IR and mass spectrometry; b Isolated yields after column chromatography.
1	Benzaldehyde	3a	96
2	p-Chlorobenzaldehyde	3b	97
3	o-Chlorobenzaldehyde	3c	95
4	m-Chlorobenzaldehyde	3d	96
5	p-Bromobenzaldehyde	3e	97
6	p-Fluorobenzaldehyde	3f	97
7	m-Fluorobenzaldehyde	3g	96
8	p-Nitrobenzaldehyde	3h	98
9	α,α,α-Trifluoro-p-tolualdehyde	3i	98
10	p-Tolualdehyde	3j	95
11	p-Anisaldehyde	3k	86
12	p-tert-Butylbenzaldehyde	3l	92
13	β-Naphthaldehyde	3m	84
14	2-Fluorenecarboxaldehyde	3n	82

---

The aromatic aldehydes with both electron-withdrawing and electron-donating substituents such as halogens, CF₃, NO₂, CH₃, C(CH₃)₃ reacted smoothly to afford the corresponding products (3a–j and 3l) in high yields (Table 2, entries 1–10 and 12). The aromatic aldehydes bearing strong electron-withdrawing groups such as NO₂ and CF₃ afforded the target products (3h and 3i) in almost quantitative (98%) yields (Table 2, entries 8 and 9) while the aldehydes carrying halogens such as Cl, Br and F at the para-position of the aromatic ring reacted at the same rates to produce the corresponding dibenzoxanthenes (3b, 3e and 3f) in 97% isolated yields (Table 2, entries 2, 5 and 6). On the other hand, the yields of the products were slightly varied with respect to the positions of the halogen substituents viz. o-, m- or p- in the aromatic aldehydes (Table 2, entries 2–4, 6 and 7). However, the aromatic aldehydes having either a strong electron-donating substituent such as p-OCH₃ or bulky groups provided the lower yields of products (Table 2, entries 11, 13 and 14) when compared to the aromatic aldehydes containing either electron-withdrawing or moderate electron-donating substituents.

Furthermore, a comparative evaluation of the catalytic efficiency of PEG–SO₃H for the synthesis of 14-(4-methylphenyl)-14H-dibenzo[a,j]xanthene (3j) with other reported catalysts was studied (Table 3). Though, PEG–SO₃H displayed relatively comparable reactivity to the catalysts, HClO₄·SiO₂ and [MIMPS]HSO₄ (Table 3, entries 6 and 10), but it can be considered as an efficient, economical and biodegradable catalyst for the synthesis of various dibenzoxanthene analogues.

Table 3 Comparison of catalytic efficiency of PEG–SO₃H with different catalysts for the preparation of 14-(4-methylphenyl)-14H-dibenzo[a,j]xanthene (3j)

Entry	Catalysts	Catalyst load (mol%)	Time/min	Temp/°C	Yield (%)^Ref
a Present work.
1	pTSA	2	180	125	92^10
2	[TEBSA]HSO4	15	10	120	84^13
3	LiBr	15	65	130	82^16
4	Cyanuric acid	20	35	110	92^17
5	K5CoW12O40·3H2O	1	120	125	96^18
6	HClO4·SiO2	1	8	125	92^19
7	Sulfamic acid	10	660	125	92^20
8	P2O5	20	55	80	84^21
9	InCl3	30	65	80	76^21
10	[MIMPS]HSO4	5	9	100	91^22
11	PEG–SO3H	1	10	125	95^a

---

Additionally, we also investigated the recyclability of PEG–SO₃H for four consecutive cycles (fresh + 3 cycles) for the synthesis of 14-phenyl-14H-dibenzo[a,j]xanthene (3a). β-Naphthol was heated with benzaldehyde in the presence of 1 mol% catalyst at 125 °C for 10 minutes. After completion of the reaction, PEG–SO₃H was extracted with water and reused after the evaporation of aqueous layer under reduced pressure. The above sequence was repeated three times to produce product (3a) in good yields without significant loss in catalytic activity of PEG–SO₃H (Table 4).

Table 4 Recyclability of the PEG–SO₃H for the one-pot condensation reaction of β-naphthol with benzaldehyde at 125 °C under solvent-free conditions

Entry	Recovery	Time/min	Yields^a (%)
a Isolated yields for 14-phenyl-14H-dibenzo[a,j]xanthene (3a) after each cycle.
1	0	10	96
2	1	10	95
3	2	10	93
4	3	10	93

---

Conclusions

In summary, PEG–SO₃H has been successfully applied as an efficient and environmentally benign polymeric catalyst for the synthesis of a series of 14-aryl-14H-dibenzo[a,j]xanthenes through one-pot condensation–cyclization reaction of β-naphthol with various aromatic aldehydes under solvent-free conditions at 125 °C. This synthetic protocol offers several advantages including short reaction times, solvent-free conditions, recyclability of the catalyst and high isolated yields of the products.

Experimental

All the chemicals were purchased from Sigma-Aldrich and used without further purification. The progress of the reactions was monitored by thin layer chromatography (TLC) using silica gel 60 F₂₅₄ (pre-coated aluminium sheets) from Merck. ¹H NMR and ¹³C NMR spectra were obtained in CDCl₃ on a Jeol ECX 400 MHz NMR spectrometer by using TMS as an internal standard. Chemical shifts are expressed in parts per million (ppm) and coupling constants (J) are reported in Hertz (Hz). Infrared spectra were recorded on a Perkin Elmer IR spectrometer and absorption maxima (υ_max) are given in cm⁻¹. Mass spectra were recorded on a Thermo Finnigan LCQ Advantage max ion trap mass spectrometer. The melting points were determined in open capillary tubes on Buchi M-560 melting point apparatus and are uncorrected.

The catalyst, PEG–SO₃H, was prepared by reacting PEG-6000 with chlorosulfonic acid in CH₂Cl₂ at 0 °C to 25 °C according to the literature procedure.³²

General procedure for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes (3a–n)

A mixture of β-naphthol (2 mmol), aromatic aldehyde (1 mmol) and PEG–SO₃H (0.01 mmol) was heated at 125 °C in a preheated oil bath for 10 minutes. After the completion of the reaction, the mixture was cooled to room temperature and the residue was washed with water to remove the catalyst. The crude product was dissolved in ethyl acetate (20 mL) and the solution was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the desired product was purified by column chromatography over silica gel (60–120 mesh size) using 1–2% ethyl acetate in heptane as an eluent. The catalyst (PEG–SO₃H) was successfully recovered after evaporation of water under reduced pressure which can be reused.

The physical and spectral data of known compounds (3a–k and 3m) were found to be in agreement with the reported data^16,31 while the characterization data of newly synthesized products (3l and 3n) are given below.

14-(4-t-Butylphenyl)-14H-dibenzo[a,j]xanthene (3l; entry 12)

White solid, mp 303 °C; yield 92%. IR (CHCl₃): ν 2961, 1592, 1513, 1431, 1399, 1249, 1240, 960, 826, 801, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.40 (d, J = 8.05 Hz, 2H, ArH), 7.83–7.76 (m, 4H, ArH), 7.59–7.55 (m, 2H, ArH), 7.47 (d, J = 8.79 Hz, 2H, ArH), 7.42–7.38 (m, 4H, ArH), 7.12 (d, J = 8.05 Hz, 2H, ArH), 6.46 (s, 1H, CH), 1.12 (s, 9H, 3CH₃) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 148.82, 141.77, 131.49, 130.98, 128.70, 128.62, 127.67, 126.65, 125.34, 124.12, 122.78, 117.99, 117.63, 37.34, 34.18, 31.15 ppm; ESI-MS: m/z = 415 [M + H]⁺; anal. calcd for C₃₁H₂₆O: C, 89.82; H, 6.32%. Found: C, 90.01; H, 6.25%.

14-(9H-fluoren-2-yl)-14H-dibenzo[a,j]xanthene (3n; entry 14)

White solid, mp 255 °C; yield 82%. IR (CHCl₃): ν 3056, 1592, 1515, 1457, 1431, 1400, 1251, 1241, 1080, 963, 813, 742, 664 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 8.44 (d, J = 8.05 Hz, 2H, ArH), 7.82–7.78 (m, 4H, ArH), 7.64–7.56 (m, 6H, ArH), 7.50 (d, J = 8.79 Hz, 2H, ArH), 7.41–7.36 (m, 2H, ArH), 7.22–7.15 (m, 3H, ArH), 6.55 (s, 1H, CH), 3.66 (s, 2H, CH₂) ppm; ¹³C NMR (100 MHz, CDCl₃): δ 148.61, 143.71, 143.65, 143.15, 141.08, 140.03, 131.40, 131.02, 128.77, 128.74, 126.80, 126.71, 126.40, 126.28, 124.87, 124.68, 124.19, 122.67, 119.50, 119.40, 117.98, 117.41, 38.10, 36.64 ppm; ESI-MS: m/z = 447 [M + H]⁺; anal. calcd for C₃₄H₂₂O·0.4H₂O: C, 90.00; H, 5.06%. Found: C, 90.02; H, 4.80%.

Acknowledgements

This work is supported by University of Delhi, India, under the scheme to strengthen R&D Doctoral Research Programme. We are thankful to Central Instrumentation Facility, University of Delhi, India, for providing NMR spectra. Davinder Prasad is grateful to CSIR, New Delhi, India, for providing Senior Research Fellowship.

References

1. H. Wang, L. Lu, S. Zhu, Y. Li and W. Cai, Curr. Microbiol., 2006, 52, 1.
2. S. Limsuwan, E. N. Trip, T. R. H. M. Kouwen, S. Piersma, A. Hiranrat, W. Mahabusarakam, S. P. Voravuthikunchai, J. M. V. Dijl and O. Kayser, Phytomedicine, 2009, 16, 645.
3. A. Kumar, S. Sharma, R. A. Maurya and J. Sarkar, J. Comb. Chem., 2010, 12, 20.
4. H. N. Hafez, M. I. Hegab, I. S. Ahmed-Farag and A. B. A. El-Gazzar, Bioorg. Med. Chem. Lett., 2008, 18, 4538.
5. J. M. Jamison, K. Krabill, A. Hatwalker, E. Jamison and C. Tsai, Cell Biol. Int. Rep., 1990, 14, 1075.
6. B. B. Bhowmik and P. Ganguly, Spectrochim. Acta, Part A, 2005, 61, 1997.
7. A. M. El-Brashy, M. E. Metwally and F. A. El-Sepai, Farmaco, 2004, 59, 809.
8. R. M. Ion, A. Planner, K. Wiktorowicz and D. Frackowiak, Acta Biochim. Pol., 1998, 45, 833.
9. E. Klimtchuk, M. A. J. Rodgers and D. C. Neckers, J. Phys. Chem., 1992, 96, 9817.
10. A. R. Khosropour, M. M. Khodaei and H. Moghannian, Synlett, 2005, 955.
11. H. R. Shaterian, M. Ghashang and A. Hassankhani, Dyes Pigm., 2008, 76, 564.
12. B. B. F. Mirjalili, A. Bamoniri and A. Akbari, Tetrahedron Lett., 2008, 49, 6454.
13. A. R. Hajipour, Y. Ghayeb, N. Sheikhan and A. E. Ruoho, Synlett, 2010, 741.
14. S. Kantevari, M. V. Chary, A. P. R. Das, S. V. N. Vuppalapati and N. Lingaiah, Catal. Commun., 2008, 9, 1575.
15. S. Ko and C. F. Yao, Tetrahedron Lett., 2006, 47, 8827.
16. A. Saini, S. Kumar and J. S. Sandhu, Synlett, 2006, 1928.
17. M. A. Bigdeli, M. M. Heravi and G. H. Mahdavinia, Catal. Commun., 2007, 8, 1595.
18. L. Nagarapu, S. Kantevari, V. C. Mahankhali and S. Apuri, Catal. Commun., 2007, 8, 1173.
19. M. A. Bigdeli, M. M. Heravi and G. H. Mahdavinia, J. Mol. Catal. A: Chem., 2007, 275, 25.
20. B. Rajitha, B. S. Kumar, Y. T. Reddy, P. N. Reddy and N. Sreenivasulu, Tetrahedron Lett., 2005, 46, 8691.
21. R. Kumar, G. C. Nandi, R. K. Verma and M. S. Singh, Tetrahedron Lett., 2010, 51, 442.
22. K. Gong, D. Fong, H. L. Wang, X. L. Zhou and Z. L. Liu, Dyes Pigm., 2009, 80, 30.
23. J. Li, W. Tang, L. Lu and W. Su, Tetrahedron Lett., 2008, 49, 7117.
24. S. L. Y. Tang, R. L. Smith and M. Poliakoff, Green Chem., 2005, 7, 761.
25. M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003, 103, 3401.
26. A. R. Kiasat and M. F. Mehrjardi, Catal. Commun., 2008, 9, 1497.
27. A. Hasaninejad, M. Shekouhy, A. Zare, S. M. S. H. Ghattali and N. J. Golzar, J. Iran. Chem. Soc., 2011, 8, 411.
28. X. C. Wang, L. Li, Z. J. Quan, H. P. Gong, H. L. Ye and X. F. Cao, Chin. Chem. Lett., 2009, 20, 651.
29. B. P. Mathew and M. Nath, J. Heterocycl. Chem., 2009, 46, 1003.
30. B. P. Mathew, A. Kumar, S. Sharma, P. K. Shukla and M. Nath, Eur. J. Med. Chem., 2010, 45, 1502.
31. R. J. Sarma and J. B. Baruah, Dyes Pigm., 2005, 64, 91.
32. A. Hasaninejad, A. Zare, M. Shekouhy and J. Ameri-Rad, Green Chem., 2011, 13, 958.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c1cy00407g

---