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A greener synthesis of 1,8-dioxo-octahydroxanthene derivatives under ultrasound
Tetrahedron Letters 53 (2012) 6923–6926
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
A greener synthesis of 1,8-dioxo-octahydroxanthene derivatives under ultrasound Naveen Mulakayala a, G. Pavan Kumar b, D. Rambabu a, Madhu Aeluri a, M. V. Basaveswara Rao c,⇑, Manojit Pal a,⇑ a
Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, India Department of Chemistry, Acharya Nagarjuna University, Guntur 522510, A.P., India c Department of Chemistry, Krishna University, Machilipatnam 521001, A.P., India b
a r t i c l e
i n f o
Article history: Received 12 July 2012 Revised 3 October 2012 Accepted 5 October 2012 Available online 12 October 2012 Keywords: 1,8-Dioxo-octahydroxanthene One pot synthesis Ceric ammonium nitrate (CAN) Ultrasound
a b s t r a c t The ceric ammonium nitrate (CAN) has been identified as an efficient and eco-friendly catalyst for the one pot and virtually three-component reaction of 5,5-dimethyl-1,3-cyclohexanedione with various aldehydes in 2-propanol. Under ultrasound irradiation, the reaction proceeded smoothly at a faster rate at 50 °C affording a variety of 9-alkyl/aryl/heteroaryl substituted 3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones in good to excellent yields. A probable mechanism for this CAN-mediated synthesis of 1,8-dioxo-octahydroxanthene derivatives is presented. Overall, the methodology provides advantages such as low cost, high yields of products and simple operational procedures and is free from the use of harmful chlorinated solvents. Ó 2012 Elsevier Ltd. All rights reserved.
Xanthene derivatives have attracted considerable interest in both pharmaceutical and medicinal chemistry because of their numerous pharmacological properties such as antibacterial, antiviral, anti-inflammatory, or anticancer activities.1–3 Furthermore, in addition to their use as valuable synthetic precursors for many organic compounds4 and dyes5 xanthene derivatives have also found use in laser technologies6 and fluorescent materials for visualization of biomolecules.7 There are several reports available in the literature for the preparation of various xanthene derivatives. One of the commonly used method for the synthesis of xanthene derivatives however involves the condensation of aldehydes with 1,3-cyclohexanedione or 5,5dimethyl-1,3-cyclohexanedione. This reaction can be carried out in the presence of protonic acids8 or a range of Lewis acids such as InCl34H2O,9,10 FeCl38H2O,11 NaHSO4,12 and tetrabutylammonium hydrogen sulfate (TBAHS),13 or heterogeneous catalysts, such as Dowex-50W,14 NaHSO4SiO2,15 silica sulfuric acid,16 polyaniline p-toluenesulfonate,17 PPA–SiO2,18 TiO2/SO4,19 Amberlyst-15,20 SbCl3/SiO2,21 Fe3+-montmorillonite,22 or iodine.3 Among the other catalysts used include trimethylsilyl chloride,23 p-dodecylbenzenesulfonic acid,24,25 triethylbenzylammonium chloride,26 or NH2SO3H/SDS.27 Additionally, the above condensation reaction can also be carried out in ionic liquid28 or ethylene glycol.29 While many of these methods are effective for the preparation of target
⇑ Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581. E-mail address: [email protected] (M. Pal). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.10.024
compounds some of them however suffer from disadvantages, such as low yields,17,18 prolonged reaction time,9,15,24–26 harsh reaction conditions,8 and the requirement of excess catalysts22 or special apparatus.24 More importantly, many of them are either not eco-friendly or cause environmental pollution. During the last three decades ultrasound mediated reactions have emerged as efficient and attractive methodologies in organic synthesis.30–32 Compared with traditional methods, these reactions are more convenient and advantageous. Thus, various organic reactions can be carried out under ultrasound irradiation within shorter reaction time and mild conditions affording high yields of desired products.33,34 The ceric(IV)ammonium nitrate [(NH4)2Ce(NO3)6 or CAN] has emerged as a useful catalyst for the construction of various carbon–carbon and carbon–heteroatom bonds.35 Several advantages such as its excellent solubility in water, eco-friendly nature, easy handling, cost-effectiveness, high reactivity, and easy work-up procedures made CAN as an effective catalyst in organic synthesis. Moreover, CAN is able to catalyze various organic transformations not only based on its electron transfer capacity but also with its role as a Brønsted acid.36 We anticipated that the use of CAN under ultrasound would be beneficial for the development of a new method toward the synthesis of 1,8-dioxo-octahydroxanthene derivatives. Herein, we report a highly efficient synthesis of 9-alkyl/aryl/heteroaryl substituted 3,3,6,6tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones from aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione in 2propanol under ultrasound irradiation in the presence of CAN (Scheme 1).
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N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926
O 2
+ O 1
O
alkyl aryl hetaryl CHO 2
Ceric(IV) ammonium nitrate 2-propanol, 50 oC
alkyl aryl hetaryl
O
O 3
Scheme 1. Ultrasound assisted one pot synthesis of 1,8-dioxo-octahydroxanthene derivatives using CAN as a catalyst.
Initially, we choose to investigate the CAN-catalyzed condensation of 5,5-dimethyl-1,3-cyclohexanedione (1) with benzaldehyde (2a) in 2-propanol under ultrasound (SONOREX SUPER RK 510H model with ultrasonic peak output: 640 W) to establish the optimized reaction conditions. We preferred 2-propanol over other solvents because of its well known and frequent use in industry and easy recoverability. Thus, the virtual three-component reaction of 1 (2.0 mmol) and 2a (1.0 mmol) was carried out by changing various reaction parameters and the results are summarized in Table 1. While the reaction proceeded in the absence of CAN the yield of product 3a however was only 34% (entry 1, Table 1). A dramatic increase in yield and decrease in reaction time was observed when 5 mol % of CAN was used as catalyst (entry 2, Table 1). We were delighted with this observation which prompted us to investigate the reaction further. While the reaction time was not shortened with the use of higher quantity of catalyst (entries 3–4, Table 1) the absence of ultrasound however decreased the product yield significantly (entry 5, Table 1) indicating the key role played by both catalyst and ultrasound in the present reaction. The reaction was usually carried out using ultrasound at the frequency of 40 kHz maintaining the temperature at 50 °C. A decrease in frequency reduced the product yield with the increase in reaction time (entry 6, Table 1). The decrease in reaction temperature also increased the duration of the reaction with the decrease in product yield (entries 7 and 8, Table 1). Overall, the use of CAN under ultrasound at the frequency of 40 kHz at 50 °C was found to be the optimum reaction conditions to obtain the best yield of product. Having the optimized reaction conditions in hand we then examined the generality and scope of the present ultrasound assisted reaction using CAN as a catalyst. Accordingly, a wide range of aldehydes (2) including aliphatic, aromatic, and heteroaromatic class were employed in this reaction the results of which are presented in Table 2.37 The reaction proceeded well in all these cases affording the desired 1,8-dioxo-octahydroxanthene derivatives (3) in good to excellent yields. All the products isolated were purified by simple crystallization as the use of column chromatography was not required. Additionally, the solvent 2-propanol used for performing the reaction was recovered easily after completion of the reaction via simple filtration followed by distillation and then reused. Nevertheless, the reaction showed good functional group tolerance for example, substituents like Cl, Br, OH, NO2, and OMe present on the aryl ring of the aldehyde were well tolerated (entries 2–6, Table 2). The aldehydes containing more than one substituents or bulky aromatic ring for example, naphthaldehyde (entries 7–9, Table 2) were also well tolerated providing excellent yields of the corresponding products. The use of isobutyraldehyde (entry 10, Table 2) or heteroaryl aldehydes for example, thiophene2-carbaldehyde, picolinaldehyde, or furan-2-carbaldehyde (entries 11–13, Table 2) was examined and found to be equally effective. We have demonstrated that a variety of 1,8-dioxo-octahydroxanthene derivatives (3) can be synthesized in high yields by using CAN as a catalyst under ultrasound irradiation. To the best of our knowledge only two reports were previously available on the ultrasound assisted synthesis of this class of compounds for example, describing the synthesis (i) promoted by a room temperature
Table 1 The effect of reaction conditions on the reaction of 1 and 2a under ultrasonic irradiationa
CHO
O
O
Ph
O
Catalyst
2
+
Solvent
O 1
O
2a
3a
Entry
Mol % of CAN
Frequency (kHz)
Temp (°C)
Time (min)
Yield (%)
1 2 3 4 5 6 7 8
0 5 10 15 5 5 5 5
40 40 40 40 — 25 40 40
50 50 50 50 50 50 30 rt
60 35 35 35 35 120 150 180
34 98 92 90 35b 75 55 22c
a The reactions were carried out using 5,5-dimethyl-1,3-cyclohexanedione 1 (2 mmol); benzaldehyde 2a (1 mmol) in 2-propanol (2 mL). b The reaction was performed in the absence of ultrasound. c Stirring at room temperature.
ionic liquid at ambient conditions38 and (ii) catalyzed by p-dodecylbenzenesulfonic acid in aqueous media.25 However, the yields of the several products isolated were not particularly high in the first case and the duration of the reaction was relatively longer in the second case. Nevertheless, the present method could be complementary to these previously reported methods especially where the use of ionic liquid or p-dodecylbenzenesulfonic acid is not compatible to the reactants employed or products formed. Moreover, the solvent used in the present reaction that is, 2-propanol is a common solvent used in industry and easily recoverable. It is also popular in pharmaceutical applications presumably due to the low toxicity caused by the residues obtained after evaporation. The methodology therefore has advantages over those that involve the use of chlorinated or other harmful organic solvents or a mixture of them. A probable mechanism for the present CAN-mediated synthesis of 1,8-dioxo-octahydroxanthene derivatives (3) is proposed (Scheme 2) which is expected to proceed via several steps such as (i) aldol-type condensation between 1,3-cyclohexanedione (1) and aldehyde (2) followed by (ii) Michael type addition of 1 with the resulting intermediate25 A leading to B, and (iii) subsequent intramolecular Michael addition involving the hydroxyl group and enone moiety of B to afford the compound 3. It is known that the condensation reaction of 1 and 2 proceeds via in situ generation of the intermediate B which has been isolated and characterized on several occasions earlier. Presumably, the interaction of CAN (due to its inherent Brønsted acidity) with the carbonyl oxygen of the reacting 1,3-cyclohexanedione (1) facilitated the aldol as well as the subsequent Michael addition step leading to the intermediate B. A further activation of the carbonyl oxygen of B by CAN39 favored the intramolecular cyclization leading to the product 3. Nevertheless, the results presented in Table 1 clearly
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N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926 Table 2 Ultrasound assisted synthesis of 1,8-dioxo-octahydroxanthene derivatives (3) using CAN as catalyst (Scheme 1).a alkyl
O 2 O
2
1
Entry Aldehyde (2)
Time (min) Producta (3)
OH O
CHO
O
50
O
O
3
Time (min) Producta (3)
Yieldb (%)
OH
O
O 8
CAN 2-propanol 50 oC
CHO
Entry Aldehyde (2)
aryl hetaryl
O
alkyl aryl + hetaryl
Table 2 (continued)
91
O
3h
Yieldb (%)
CHO
CHO O
O
35
1
O 98
O
55
9
94
O
O
3a
3i
Cl
CHO
O
O
CHO 40
2
O
O
60
10
90
O
93
3j
Cl
O
S
3b Br
CHO
CHO
11
S
O
O
60
93
O 3
40
Br
O
O
3k 95
N O
12
3c CHO
O
CHO
93
HO
O
3l OH
OH
50
O
O
O
90 13
O CHO
50
O
O
91
O
3e OCH 3
6
OCH 3
45
CHO
O
O
95
O
3f CHO
H3 CO
OH
7
OCH 3
55
HO O
O
O
3g
60
O 89
3m
NO2
NO 2
CHO
O
O
O
3d
5
O
55
OH
4
N
94
a All the reactions were carried out using 5,5-dimethyl-1,3-cyclohexanedione 1 (2 mmol), aldehyde 2 (1 mmol) and CAN (5 mol %) in 2-propanol (2 mL) under ultrasound. b Isolated yield.
suggested that the CAN-mediated reaction was accelerated in the presence of ultrasound leading to the increased yield of product (entry 2 vs 5, Table 1). Perhaps, the activation of 1,3-cyclohexanedione (1) was facilitated by the ultrasound cavitation in the first step.40 Thus sonolysis of the O–H bond of enolic form of 1 accelerated the first step. Additionally, the intramolecular cyclization of B followed by removal of water molecule may also have been accelerated by ultrasound. In conclusion, we have demonstrated that ceric ammonium nitrate (CAN) can be utilized as an efficient catalyst for the development of a general and high yielding method for the greener synthesis of 1,8-dioxo-octahydroxanthenes. The reaction involved condensation of 5,5-dimethyl-1,3-cyclohexanedione with various aldehydes in the presence of CAN under ultrasound irradiation. The reaction was performed in 2-propanol, a commonly used solvent in industry and is easily recoverable. A variety of compounds for example, 9-alkyl/aryl/heteroaryl substituted 3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones were
6926
N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926
O
O
O
RCHO
+
O
R
O
O
A
CeIV
Ce IV O
R
[Ce IV]
2
1
Ce IV R
O
1 [Ce IV]
OH
OH B
3 O
OH2
Scheme 2. Proposed reaction mechanism for the CAN-mediated reaction of 1,3-cyclohexanedione (1) with aldehyde (2) under ultrasound irradiation.
prepared in good to excellent yields by using this methodology. A probable mechanism of the reaction is presented. Due to the ecofriendly nature, low cost, simple purification, and high yields of products the present methodology could become complementary to the previously reported methods and may find wide usage in generating a diversity based library of molecules related to 1,8-dioxo-octahydroxanthenes. Acknowledgment The authors sincerely thank the management of the Institute of Life Sciences for continuous support and encouragement. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 10.024. References and notes 1. Jonathan, R. D.; Srinivas, K. R.; Glen, E. B. Eur. J. Med. Chem. 1988, 23, 111. 2. (a) Robak, J.; Gryglewski, R. J. Pol. J. Pharmacol. 1996, 48, 555; (b) Wang, H. K.; Lee, S. L.; Morris-Natschke, K. H. Med. Res. Rev. 1997, 17, 367; (c) Rukavishnikov, A. V.; Smith, M. P.; Birrell, G. B.; Keana, J. F. W.; Griffith, O. H. Tetrahedron Lett. 1998, 39, 6637. 3. Mulakayala, N.; Murthy, P. V. N. S.; Rambabu, D.; Aeluri, M.; Adepu, R.; Krishna, G. R.; Reddy, C. M.; Prasad, K. R. S.; Chaitanya, M.; Kumar, C. S.; Rao, M. V. B.; Pal, M. Bioorg. Med. Chem. Lett. 2012, 22, 2186. 4. Shchekotikhin, Y. M.; Nikolaeva, T. G. Chem. Heterocycl. Compd. 2006, 42, 28. 5. Hilderbrand, S. A.; Weissleder, R. Tetrahedron Lett. 2007, 48, 4383. 6. (a) Pohlers, G.; Scaiano, J. C. Chem. Mater. 1997, 9, 3222; (b) Knight, C. G.; Stephens, T. Biochem. J. 1989, 258, 683. 7. (a) Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D. M. Bioorg. Med. Chem. 2010, 18, 1456; (b) Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, J. Cancer J. Clin 2005, 55, 74. 8. Darviche, F.; Balalaie, S.; Chadegani, F.; Salehi, P. Synth. Commun. 2007, 37, 1059. 9. Fan, X.; Hu, X.; Zhang, X.; Wang, J. Can. J. Chem. 2005, 83, 16. 10. Girijesh, K. V.; Keshav, R.; Rajiv, K. V.; Pratibha, D.; Singh, M. S. Tetrahedron 2011, 67, 3698. 11. Fan, X.-S.; Li, Y.-Z.; Zhang, X.-Y.; Hu, X.-Y.; Wang, J.-J. Chin. J. Org. Chem. 2005, 25, 1482. 12. Ma, J.-J.; Li, J.-C.; Tang, R.-X.; Zhou, X.; Wu, Q.-H.; Wang, C.; Zhang, M.-M.; Li, Q. Chin. J. Org. Chem. 2007, 27, 640. 13. Karade, H. N.; Sathe, M.; Kaushik, M. P. ARKIVOC 2007, xiii, 252.
14. Shakibaei, G. I.; Mirzaei, P.; Bazgir, A. Appl. Catal. 2007, 325, 188. 15. Das, B.; Thirupathi, P.; Reddy, K. R.; Ravikanth, B.; Nagarapu, L. Catal. Commun. 2007, 8, 535. 16. Seyyedhamzeh, M.; Mirzaei, P.; Bazgir, A. Dyes Pigm. 2008, 76, 836. 17. John, A.; Yadav, P. J. P.; Palaniappan, S. J. Mol. Catal. A: Chem. 2006, 248, 121. 18. Kantevari, S.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53. 19. Jin, T.-S.; Zhang, J.-S.; Wang, A.-Q.; Li, T.-S. Synth. Commun. 2005, 35, 2339. 20. Das, B.; Thirupathi, P.; Mahender, I.; Reddy, V. S.; Rao, Y. K. J. Mol. Catal. A: Chem. 2006, 247, 233. 21. Zhang, Z.-H.; Liu, Y.-H. Catal. Commun. 2008, 9, 1715. 22. Song, G.; Wang, B.; Luo, H.; Yang, L. Catal. Commun. 2007, 8, 673. 23. Kantevari, S.; Bantu, R.; Nagarapu, L. ARKIVOC 2006, xvi, 136. 24. Jin, T.-S.; Zhang, J.-S.; Xiao, J.-C.; Wang, A.-Q.; Li, T.-S. Synlett 2004, 866. 25. Jin, T.-S.; Zhang, J.-S.; Xiao, J.-C.; Wang, A.-Q.; Li, T.-S. Ultrason. Sonochem. 2006, 13, 220. 26. Shi, D.-Q.; Zhuang, Q.-Y.; Chen, J.; Wang, X.-S.; Tu, S.-J.; Hu, H.-W. Chin. J. Org. Chem. 2003, 23, 694. 27. Jin, T.-S.; Zhang, J.-S.; Wang, A.-Q.; Zhang, F.-S. Chin. J. Org. Chem. 2005, 25, 335. 28. Ma, J.-J.; Zhou, X.; Zhang, X.-H.; Wang, C.; Wang, Z.; Li, J.-C.; Li, Q. Aust. J. Chem. 2007, 60, 146. 29. Tu, S.-J.; Zhou, J.-F.; Lu, Z.-S.; Deng, X.; Shi, D.-Q.; Wang, S.-H. Synth. Commun. 2002, 32, 3063. 30. Luche, J. L. Synthetic Organic Sonochemistry; Plenum Press: New York, 1998. 31. Li, J. T.; Han, J. F.; Yang, J. H.; Li, T. S. Ultrason. Sonochem. 2003, 10, 119. 32. Mcnulty, J.; Steere, J. A.; Wolf, S. Tetrahedron Lett. 1998, 39, 8013. 33. Li, J. T.; Wang, S. X.; Chen, G. F.; Li, T. S. Curr. Org. Synth. 2005, 2, 415. 34. Ratoarinoro, N.; Wilhelm, A. M.; Berlan, J.; Delmas, H. Chem. Eng. J. 1992, 50, 27. 35. (a) Itoh, K.; Akira Horiuchi, C. Tetrahedron 2004, 60, 1671; (b) Han, B.; Jia, X.-D.; Jin, X.-L.; Zhou, Y.-L.; Yang, L.; Liu, Z.-L.; Yu, W. Tetrahedron Lett. 2006, 47, 3545. 36. (a) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862; (b) Sridharan, V.; Menendez, J. C. Org. Lett. 2008, 10, 4303; (c) Chang, M.-Y.; Wu, T.-C.; Lin, C.-Y.; Hung, C.-Y. Tetrahedron Lett. 2006, 47, 8347. 37. General procedure for the preparation of 3a–l: To a solution of 5,5-dimethyl-1,3cyclohexanedione (1, 2 mmol) and aldehyde (2, 1 mmol) in 2-propanol (2 mL) was added ceric ammonium nitrate (5 mol %) and the mixture was irradiated in a water bath of ultrasound (40 kHz) continuously at 50 °C till the completion of the reaction (monitored by TLC). The temperature of the water bath was maintained at 50 °C by adding additional cold water whenever necessary and was examined by using a thermometer at a regular interval. After completion of the reaction the mixture was filtered and the residue was washed with 2propanol (2 2 mL). The filtrates were collected, combined, and concentrated. The residue was purified by recrystallization from EtOH to give the desired products (3). All the products prepared (3a–m) were known compounds and characterized by NMR, IR, and MS spectra. The data generated were compared with that reported in the literature. 38. Venkatesan, K.; Pujari, S. S.; Lahoti, R. J.; Srinivasan, K. V. Ultrason. Sonochem. 2008, 15, 548. 39. (a) Tapaswi, P. K.; Mukhopadhyay, C. ARKIVOC 2011, x, 287; (b) Durgadas, S.; Chatare, V. K.; Mukkanti, K.; Pal, S. Lett. Org. Chem. 2010, 7, 306. 40. The ultrasound cavitation can induce shear forces and the jets produced near the surface of the vessel and catalyst may activate the reactant, see: Sudha, S.; Pasha, M. A. Ultrason. Sonochem. 2012, 19, 994.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
A greener synthesis of 1,8-dioxo-octahydroxanthene derivatives under ultrasound Naveen Mulakayala a, G. Pavan Kumar b, D. Rambabu a, Madhu Aeluri a, M. V. Basaveswara Rao c,⇑, Manojit Pal a,⇑ a
Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, India Department of Chemistry, Acharya Nagarjuna University, Guntur 522510, A.P., India c Department of Chemistry, Krishna University, Machilipatnam 521001, A.P., India b
a r t i c l e
i n f o
Article history: Received 12 July 2012 Revised 3 October 2012 Accepted 5 October 2012 Available online 12 October 2012 Keywords: 1,8-Dioxo-octahydroxanthene One pot synthesis Ceric ammonium nitrate (CAN) Ultrasound
a b s t r a c t The ceric ammonium nitrate (CAN) has been identified as an efficient and eco-friendly catalyst for the one pot and virtually three-component reaction of 5,5-dimethyl-1,3-cyclohexanedione with various aldehydes in 2-propanol. Under ultrasound irradiation, the reaction proceeded smoothly at a faster rate at 50 °C affording a variety of 9-alkyl/aryl/heteroaryl substituted 3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones in good to excellent yields. A probable mechanism for this CAN-mediated synthesis of 1,8-dioxo-octahydroxanthene derivatives is presented. Overall, the methodology provides advantages such as low cost, high yields of products and simple operational procedures and is free from the use of harmful chlorinated solvents. Ó 2012 Elsevier Ltd. All rights reserved.
Xanthene derivatives have attracted considerable interest in both pharmaceutical and medicinal chemistry because of their numerous pharmacological properties such as antibacterial, antiviral, anti-inflammatory, or anticancer activities.1–3 Furthermore, in addition to their use as valuable synthetic precursors for many organic compounds4 and dyes5 xanthene derivatives have also found use in laser technologies6 and fluorescent materials for visualization of biomolecules.7 There are several reports available in the literature for the preparation of various xanthene derivatives. One of the commonly used method for the synthesis of xanthene derivatives however involves the condensation of aldehydes with 1,3-cyclohexanedione or 5,5dimethyl-1,3-cyclohexanedione. This reaction can be carried out in the presence of protonic acids8 or a range of Lewis acids such as InCl34H2O,9,10 FeCl38H2O,11 NaHSO4,12 and tetrabutylammonium hydrogen sulfate (TBAHS),13 or heterogeneous catalysts, such as Dowex-50W,14 NaHSO4SiO2,15 silica sulfuric acid,16 polyaniline p-toluenesulfonate,17 PPA–SiO2,18 TiO2/SO4,19 Amberlyst-15,20 SbCl3/SiO2,21 Fe3+-montmorillonite,22 or iodine.3 Among the other catalysts used include trimethylsilyl chloride,23 p-dodecylbenzenesulfonic acid,24,25 triethylbenzylammonium chloride,26 or NH2SO3H/SDS.27 Additionally, the above condensation reaction can also be carried out in ionic liquid28 or ethylene glycol.29 While many of these methods are effective for the preparation of target
⇑ Corresponding authors. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581. E-mail address: [email protected] (M. Pal). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.10.024
compounds some of them however suffer from disadvantages, such as low yields,17,18 prolonged reaction time,9,15,24–26 harsh reaction conditions,8 and the requirement of excess catalysts22 or special apparatus.24 More importantly, many of them are either not eco-friendly or cause environmental pollution. During the last three decades ultrasound mediated reactions have emerged as efficient and attractive methodologies in organic synthesis.30–32 Compared with traditional methods, these reactions are more convenient and advantageous. Thus, various organic reactions can be carried out under ultrasound irradiation within shorter reaction time and mild conditions affording high yields of desired products.33,34 The ceric(IV)ammonium nitrate [(NH4)2Ce(NO3)6 or CAN] has emerged as a useful catalyst for the construction of various carbon–carbon and carbon–heteroatom bonds.35 Several advantages such as its excellent solubility in water, eco-friendly nature, easy handling, cost-effectiveness, high reactivity, and easy work-up procedures made CAN as an effective catalyst in organic synthesis. Moreover, CAN is able to catalyze various organic transformations not only based on its electron transfer capacity but also with its role as a Brønsted acid.36 We anticipated that the use of CAN under ultrasound would be beneficial for the development of a new method toward the synthesis of 1,8-dioxo-octahydroxanthene derivatives. Herein, we report a highly efficient synthesis of 9-alkyl/aryl/heteroaryl substituted 3,3,6,6tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones from aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione in 2propanol under ultrasound irradiation in the presence of CAN (Scheme 1).
6924
N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926
O 2
+ O 1
O
alkyl aryl hetaryl CHO 2
Ceric(IV) ammonium nitrate 2-propanol, 50 oC
alkyl aryl hetaryl
O
O 3
Scheme 1. Ultrasound assisted one pot synthesis of 1,8-dioxo-octahydroxanthene derivatives using CAN as a catalyst.
Initially, we choose to investigate the CAN-catalyzed condensation of 5,5-dimethyl-1,3-cyclohexanedione (1) with benzaldehyde (2a) in 2-propanol under ultrasound (SONOREX SUPER RK 510H model with ultrasonic peak output: 640 W) to establish the optimized reaction conditions. We preferred 2-propanol over other solvents because of its well known and frequent use in industry and easy recoverability. Thus, the virtual three-component reaction of 1 (2.0 mmol) and 2a (1.0 mmol) was carried out by changing various reaction parameters and the results are summarized in Table 1. While the reaction proceeded in the absence of CAN the yield of product 3a however was only 34% (entry 1, Table 1). A dramatic increase in yield and decrease in reaction time was observed when 5 mol % of CAN was used as catalyst (entry 2, Table 1). We were delighted with this observation which prompted us to investigate the reaction further. While the reaction time was not shortened with the use of higher quantity of catalyst (entries 3–4, Table 1) the absence of ultrasound however decreased the product yield significantly (entry 5, Table 1) indicating the key role played by both catalyst and ultrasound in the present reaction. The reaction was usually carried out using ultrasound at the frequency of 40 kHz maintaining the temperature at 50 °C. A decrease in frequency reduced the product yield with the increase in reaction time (entry 6, Table 1). The decrease in reaction temperature also increased the duration of the reaction with the decrease in product yield (entries 7 and 8, Table 1). Overall, the use of CAN under ultrasound at the frequency of 40 kHz at 50 °C was found to be the optimum reaction conditions to obtain the best yield of product. Having the optimized reaction conditions in hand we then examined the generality and scope of the present ultrasound assisted reaction using CAN as a catalyst. Accordingly, a wide range of aldehydes (2) including aliphatic, aromatic, and heteroaromatic class were employed in this reaction the results of which are presented in Table 2.37 The reaction proceeded well in all these cases affording the desired 1,8-dioxo-octahydroxanthene derivatives (3) in good to excellent yields. All the products isolated were purified by simple crystallization as the use of column chromatography was not required. Additionally, the solvent 2-propanol used for performing the reaction was recovered easily after completion of the reaction via simple filtration followed by distillation and then reused. Nevertheless, the reaction showed good functional group tolerance for example, substituents like Cl, Br, OH, NO2, and OMe present on the aryl ring of the aldehyde were well tolerated (entries 2–6, Table 2). The aldehydes containing more than one substituents or bulky aromatic ring for example, naphthaldehyde (entries 7–9, Table 2) were also well tolerated providing excellent yields of the corresponding products. The use of isobutyraldehyde (entry 10, Table 2) or heteroaryl aldehydes for example, thiophene2-carbaldehyde, picolinaldehyde, or furan-2-carbaldehyde (entries 11–13, Table 2) was examined and found to be equally effective. We have demonstrated that a variety of 1,8-dioxo-octahydroxanthene derivatives (3) can be synthesized in high yields by using CAN as a catalyst under ultrasound irradiation. To the best of our knowledge only two reports were previously available on the ultrasound assisted synthesis of this class of compounds for example, describing the synthesis (i) promoted by a room temperature
Table 1 The effect of reaction conditions on the reaction of 1 and 2a under ultrasonic irradiationa
CHO
O
O
Ph
O
Catalyst
2
+
Solvent
O 1
O
2a
3a
Entry
Mol % of CAN
Frequency (kHz)
Temp (°C)
Time (min)
Yield (%)
1 2 3 4 5 6 7 8
0 5 10 15 5 5 5 5
40 40 40 40 — 25 40 40
50 50 50 50 50 50 30 rt
60 35 35 35 35 120 150 180
34 98 92 90 35b 75 55 22c
a The reactions were carried out using 5,5-dimethyl-1,3-cyclohexanedione 1 (2 mmol); benzaldehyde 2a (1 mmol) in 2-propanol (2 mL). b The reaction was performed in the absence of ultrasound. c Stirring at room temperature.
ionic liquid at ambient conditions38 and (ii) catalyzed by p-dodecylbenzenesulfonic acid in aqueous media.25 However, the yields of the several products isolated were not particularly high in the first case and the duration of the reaction was relatively longer in the second case. Nevertheless, the present method could be complementary to these previously reported methods especially where the use of ionic liquid or p-dodecylbenzenesulfonic acid is not compatible to the reactants employed or products formed. Moreover, the solvent used in the present reaction that is, 2-propanol is a common solvent used in industry and easily recoverable. It is also popular in pharmaceutical applications presumably due to the low toxicity caused by the residues obtained after evaporation. The methodology therefore has advantages over those that involve the use of chlorinated or other harmful organic solvents or a mixture of them. A probable mechanism for the present CAN-mediated synthesis of 1,8-dioxo-octahydroxanthene derivatives (3) is proposed (Scheme 2) which is expected to proceed via several steps such as (i) aldol-type condensation between 1,3-cyclohexanedione (1) and aldehyde (2) followed by (ii) Michael type addition of 1 with the resulting intermediate25 A leading to B, and (iii) subsequent intramolecular Michael addition involving the hydroxyl group and enone moiety of B to afford the compound 3. It is known that the condensation reaction of 1 and 2 proceeds via in situ generation of the intermediate B which has been isolated and characterized on several occasions earlier. Presumably, the interaction of CAN (due to its inherent Brønsted acidity) with the carbonyl oxygen of the reacting 1,3-cyclohexanedione (1) facilitated the aldol as well as the subsequent Michael addition step leading to the intermediate B. A further activation of the carbonyl oxygen of B by CAN39 favored the intramolecular cyclization leading to the product 3. Nevertheless, the results presented in Table 1 clearly
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N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926 Table 2 Ultrasound assisted synthesis of 1,8-dioxo-octahydroxanthene derivatives (3) using CAN as catalyst (Scheme 1).a alkyl
O 2 O
2
1
Entry Aldehyde (2)
Time (min) Producta (3)
OH O
CHO
O
50
O
O
3
Time (min) Producta (3)
Yieldb (%)
OH
O
O 8
CAN 2-propanol 50 oC
CHO
Entry Aldehyde (2)
aryl hetaryl
O
alkyl aryl + hetaryl
Table 2 (continued)
91
O
3h
Yieldb (%)
CHO
CHO O
O
35
1
O 98
O
55
9
94
O
O
3a
3i
Cl
CHO
O
O
CHO 40
2
O
O
60
10
90
O
93
3j
Cl
O
S
3b Br
CHO
CHO
11
S
O
O
60
93
O 3
40
Br
O
O
3k 95
N O
12
3c CHO
O
CHO
93
HO
O
3l OH
OH
50
O
O
O
90 13
O CHO
50
O
O
91
O
3e OCH 3
6
OCH 3
45
CHO
O
O
95
O
3f CHO
H3 CO
OH
7
OCH 3
55
HO O
O
O
3g
60
O 89
3m
NO2
NO 2
CHO
O
O
O
3d
5
O
55
OH
4
N
94
a All the reactions were carried out using 5,5-dimethyl-1,3-cyclohexanedione 1 (2 mmol), aldehyde 2 (1 mmol) and CAN (5 mol %) in 2-propanol (2 mL) under ultrasound. b Isolated yield.
suggested that the CAN-mediated reaction was accelerated in the presence of ultrasound leading to the increased yield of product (entry 2 vs 5, Table 1). Perhaps, the activation of 1,3-cyclohexanedione (1) was facilitated by the ultrasound cavitation in the first step.40 Thus sonolysis of the O–H bond of enolic form of 1 accelerated the first step. Additionally, the intramolecular cyclization of B followed by removal of water molecule may also have been accelerated by ultrasound. In conclusion, we have demonstrated that ceric ammonium nitrate (CAN) can be utilized as an efficient catalyst for the development of a general and high yielding method for the greener synthesis of 1,8-dioxo-octahydroxanthenes. The reaction involved condensation of 5,5-dimethyl-1,3-cyclohexanedione with various aldehydes in the presence of CAN under ultrasound irradiation. The reaction was performed in 2-propanol, a commonly used solvent in industry and is easily recoverable. A variety of compounds for example, 9-alkyl/aryl/heteroaryl substituted 3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-diones were
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N. Mulakayala et al. / Tetrahedron Letters 53 (2012) 6923–6926
O
O
O
RCHO
+
O
R
O
O
A
CeIV
Ce IV O
R
[Ce IV]
2
1
Ce IV R
O
1 [Ce IV]
OH
OH B
3 O
OH2
Scheme 2. Proposed reaction mechanism for the CAN-mediated reaction of 1,3-cyclohexanedione (1) with aldehyde (2) under ultrasound irradiation.
prepared in good to excellent yields by using this methodology. A probable mechanism of the reaction is presented. Due to the ecofriendly nature, low cost, simple purification, and high yields of products the present methodology could become complementary to the previously reported methods and may find wide usage in generating a diversity based library of molecules related to 1,8-dioxo-octahydroxanthenes. Acknowledgment The authors sincerely thank the management of the Institute of Life Sciences for continuous support and encouragement. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 10.024. References and notes 1. Jonathan, R. D.; Srinivas, K. R.; Glen, E. B. Eur. J. Med. Chem. 1988, 23, 111. 2. (a) Robak, J.; Gryglewski, R. J. Pol. J. Pharmacol. 1996, 48, 555; (b) Wang, H. K.; Lee, S. L.; Morris-Natschke, K. H. Med. Res. Rev. 1997, 17, 367; (c) Rukavishnikov, A. V.; Smith, M. P.; Birrell, G. B.; Keana, J. F. W.; Griffith, O. H. Tetrahedron Lett. 1998, 39, 6637. 3. Mulakayala, N.; Murthy, P. V. N. S.; Rambabu, D.; Aeluri, M.; Adepu, R.; Krishna, G. R.; Reddy, C. M.; Prasad, K. R. S.; Chaitanya, M.; Kumar, C. S.; Rao, M. V. B.; Pal, M. Bioorg. Med. Chem. Lett. 2012, 22, 2186. 4. Shchekotikhin, Y. M.; Nikolaeva, T. G. Chem. Heterocycl. Compd. 2006, 42, 28. 5. Hilderbrand, S. A.; Weissleder, R. Tetrahedron Lett. 2007, 48, 4383. 6. (a) Pohlers, G.; Scaiano, J. C. Chem. Mater. 1997, 9, 3222; (b) Knight, C. G.; Stephens, T. Biochem. J. 1989, 258, 683. 7. (a) Giri, R.; Goodell, J. R.; Xing, C.; Benoit, A.; Kaur, H.; Hiasa, H.; Ferguson, D. M. Bioorg. Med. Chem. 2010, 18, 1456; (b) Parkin, D. M.; Bray, F.; Ferlay, J.; Pisani, J. Cancer J. Clin 2005, 55, 74. 8. Darviche, F.; Balalaie, S.; Chadegani, F.; Salehi, P. Synth. Commun. 2007, 37, 1059. 9. Fan, X.; Hu, X.; Zhang, X.; Wang, J. Can. J. Chem. 2005, 83, 16. 10. Girijesh, K. V.; Keshav, R.; Rajiv, K. V.; Pratibha, D.; Singh, M. S. Tetrahedron 2011, 67, 3698. 11. Fan, X.-S.; Li, Y.-Z.; Zhang, X.-Y.; Hu, X.-Y.; Wang, J.-J. Chin. J. Org. Chem. 2005, 25, 1482. 12. Ma, J.-J.; Li, J.-C.; Tang, R.-X.; Zhou, X.; Wu, Q.-H.; Wang, C.; Zhang, M.-M.; Li, Q. Chin. J. Org. Chem. 2007, 27, 640. 13. Karade, H. N.; Sathe, M.; Kaushik, M. P. ARKIVOC 2007, xiii, 252.
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