D.M. Pore

D.S. Gaikwad

K.A. Undale

T.S. Shaikh

Comptes Rendus Chimie

C. R. Chimie 13 (2010) 1429–1432Preliminary communication/CommunicationA green protocol for catalyst-free synthesis of 1-oxo-hexahydroxanthenesin aqueous mediumD.M. Pore *, T.S. Shaikh, K.A. Undale, D.S. GaikwadDepartment of Chemistry, Shivaji University, Kolhapur 416 004, IndiaA R T I C L E I N F OArticle history:Received 10 April 2010Accepted after revision 22 June 2010Available online 7 August 2010Keywords:OctahydroxantheneHexahydroxantheneSalicylaldehydeWaterCyclohexane-1,3-dioneDimedoneA B S T R A C TAn efficient and eco-friendly synthesis of 1-oxo-hexahydroxanthenes has beenexpediently accomplished by a reaction of salicylaldehyde with cyclohexane-1,3-dioneor dimedone in water as universal solvent at reflux condition without a catalyst. Excellentyields of the products, operational simplicity, simple work-up and catalyst-free synthesisare attractive features of this green protocol. 2010 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.Contents lists available at ScienceDirectComptes Rendus Chimiewww.sciencedi rec t .com1. IntroductionDeveloping a simple, eco-friendly as well as economicreaction protocol for the synthesis of organic transforma-tions is an attractive area of research in both academic andpharmaceutical R and D [1]. Hence the challenging task ofachieving ‘efficiency’ in all aspects of chemical production,advocated by green chemistry can be realized by innova-tive research which comprehensively addresses the issuesof atom economy, economy and avoidance of auxiliarychemicals [2]. By keeping these ideas in mind andparaphrasing the concept reported by Sheldon ‘‘the bestsolvent is no solvent’’ [3] and by Maggi ‘‘the best catalyst isno catalyst’’ [4], we can state that the greener protocol isone which involves no catalyst and no solvent or use ofwater as a universal solvent.Xanthenes are frequently occurring motifs in a numberof natural products [5], and have been used as versatilesynthons due to the inherent reactivity of the inbuilt pyranring [6] Most of the natural schweinfurthins [7] (diversonoland blennolide C, Fig. 1) are potent and selective inhibitors* Corresponding author.E-mail address: p_dattaprasad@rediffmail.com (D.M. Pore).1631-0748/$ – see front matter  2010 Académie des sciences. Published by Edoi:10.1016/j.crci.2010.06.015of cell growth as measured by the National CancerInstitute’s 60-cell line screen [8]. Xanthenes are knownfor their utility as leuco-dyes [9], pH-sensitive fluorescentmaterials for the visualization of biomolecules [10] and inlaser technologies [11] due to their useful spectroscopicproperties. Octahydroxanthene derivatives containing astructural unit of benzopyrans can be used as antispasm[12] and fluorescent fuel [13]. These multifarious applica-tions of xanthenediones have stimulated both the devel-opment of environmentally benign methods for theirsynthesis as well as their derivatives.In contrast to the widely studied 1,8-dioxo-octahy-droxanthene derivatives [12,13], relatively few papersdescribe the chemistry of 1-oxo-hexahydroxanthenes [14–17]. Synthetic routes to 1-oxo-hexahydroxanthenes gen-erally involve prolonged heating in acid-catalyzed reac-tions of salicylaldehyde with 1,3-diketone. The classicalmethods involve catalysts viz 2,4,6-trichloro-1,3,5-triazine(TCT) [14], KF/ Al2O3 [15], CeCl3.7H2O [16] and triethyl-benzylammonium chloride (TEBA as a cationic surfactant)[17]. Therefore an environmentally benign protocol forsynthesis of 1-oxo-hexahydroxanthenes is highly desir-able. In view of this, we are working on the synthesis of 1-oxo-hexahydroxanthenes using an eco-friendly syntheticstrategy. Hence we report our findings.lsevier Masson SAS. All rights reserved.Fig. 1. Important xanthene derivatives.D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–143214302. Results and discussionEPZ-10, a clay catalyst commercially available fromContract Chemicals, England (www.contract-chemicals.-com.), which is prepared by supporting ZnCl2 on clay, isknown to contain predominantly strong Lewis acid sites aswell as weak Bronsted acid sites [18]. Recently, we havereported synthesis of 1,8-dioxo-octahydroxanthenes inaqueous medium using EPZ-10 (10 mol %) as an ecofriendlycatalyst under reflux conditions [19]. This spurned us toinvestigate the capability of EPZ-10 to act as catalyst forthe synthesis of 1-oxo-hexahydroxanthene. Initially thereaction of salicylaldehyde (1, R’ = H) and dimedone (2,R = Me) [1:2] was carried using EPZ-10 (10 mol %) inaqueous medium at reflux conditions and corresponding1-oxo-hexahydroxanthene (3) (Scheme 1) was obtained in92% yield in 3 h. In order to investigate the role of EPZ-10,the above reaction was performed in the absence of thecatalyst and gratifyingly 1-oxo-hexahydroxanthene wasachieved in 90% yield. After this success, we focused ourattention towards catalyst-free synthesis of 1-oxo-hex-ahydroxanthene in aqueous medium.Using the catalyst-free condition, both electron-rich aswell as electron-deficient salicylaldehydes reacted effec-tively with 1,3-dicarbonyl compounds in aqueous medi-um. (Table 1) Both dimedone and cyclohexane-1,3-dionereacted smoothly with substituted salicylaldehydes suchScheme 1. Catalyst-free synthesis oas 5-chloro-, 3-methoxy-, 5-bromo, 4 and 5-hydroxy, 3,5-dichloro and 3,5-dibromo derivatives to produce thecorresponding 1-oxo-hexahydroxanthene in high yields(Table 1, entries a–o).In recent years, water has been demonstrated as anideal medium for many organic transformations even ifstarting materials and products appear to be insoluble [20].Many organic reactions such as Claisen rearrangement,aldol condensation, benzoin condensation, and Diels–Alder cycloaddition exhibit rate enhancement in water[21].In this reaction water (e = 78.6) helps in the easyconversion of the keto form to enol form of the compound(2) which is useful for Knoevenagel condensation fol-lowed by subsequent Michael addition and dehydrationaffords product (3). A plausible mechanism is depicted inScheme 2.3. ConclusionIn conclusion, we have developed practical and eco-friendly method for the efficient synthesis of 1-oxo-hexahydroxanthenes by a condensation of salicylaldehydeand dimedone/cyclohexane-1,3-dione. The use of water asa solvent, simple work-up procedure and no need ofcatalyst make it an eco-friendly as well as an economicalalternative to earlier reported approaches.4. ExperimentalVarious substituted salicylaldehydes (Sigma-Aldrich),1,3-diketones viz cyclohexane-1,3-dione (Alfa Aesar) anddimedone (Thomas Baker) were used as received. Meltingpoints were determined and are uncorrected. IR spectrawere recorded on Perkin-Elmer [FT-IR-783] spectropho-tometer. NMR spectra were recorded on Bruker AC-300(300 MHz for 1H NMR and 75 MHz for 13C NMR)spectrometer in DMSO-d6 or CDCl3 using TMS as aninternal standard and d values are expressed in ppm. Massspectra (LCMS) were recorded on Shimadzu LCMS 2010,mass spectrometer.4.1. General procedure for catalyst-free synthesis of 1-oxo-hexahydroxanthenesA suspension of an salicylaldehyde (1 mmol) anddimedone/cyclohexane-1,3-dione (2 mmol) in waterf 1-oxo-hexahydroxanthenes.Table 1Catalyst-free synthesis of 1-oxo- hexahydroxanthenes.Entry Product (3) Time (h) Yield (%)a,b M.P Obs.(Lit oC)[TD$INLINE]R R'OOR'R' R'OHOa R = H; R’ = CH3 3.5 90 204 (206) [14]b R = 5-Cl ; R’ = CH3 5.0 88 235 (238) [14]c R = 3-OMe; R’ = CH3 4.5 85 231 (230) [14]d R = 5-Br ; R’ = CH3 5.0 86 251 (253) [14]e R = 5-OH; R’ = CH3 4.0 93 217 (————)f R = 4-OH; R’ = CH3 4.0 95 232 (————)g R = 3,5 Cl; R’ = CH3 4.5 87 231 (235) [14]h R = H; R’ = H 3.5 88 242 (244) [14]i R = 3,5 Cl; R’ = CH3 4.0 85 252 (254) [14]k R = 5-NO2; R’ = H 5.0 87 243 (245) [14]l R = 3,5-Br; R’ = H 5.0 89 254 (255) [14]m R = 5-OH; R’ = H 4.5 89 227 (————)n R = 4-OH; R’ = H 4.5 91 240 (————)[TD$INLINE]OHOR'R'R'OOR'Ro R = H; R’ = H 4.5 84 215 (216) [14]Yields refer to pure isolated products. All products are racemic mixtures.D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–1432 1431(5 mL) were stirred at reflux condition and the progress ofthe reaction was monitored by TLC. After completion of thereaction, the resulting solid products were collected byfiltration and were recrystallized from 95% ethanol. Theseproducts were characterized by usual spectral techniques.(i.e. IR, 1H and 13C NMR, LCMS).4.2. Spectral data of unknown compounds:Compound (3 e); mp. 217 oC, IR (KBr): 3110, 2958, 2926,1589, 1468, 1382, 1230, 1192, 1034, 820 cm-1; 1H NMR(300 MHz, DMSO-d6): d 10.29 (bs, 1H), 9.07 (s, 1H), 6.74 (d,1H, J=8.7 Hz), 6.45 (dd, 1H, J=8.7 Hz and J=2.7 Hz), 6.37 (d,1H, J=2.7 Hz), 4.95 (s, 1H), 1.96-2.49 (m, 8H), 1.01 (s, 3H),0.95 (s, 3H), 0.88 (s, 6H); 13CMR: 26.64, 29.69, 32.01, 41.21,50.90, 99.98, 110.38, 114.10, 114.37, 116.39, 116.78,126.72, 143.12, 154.10, 165.40, 195.54, 196.12; LCMS:m/z 382.Compound (3 f); mp. 232 oC IR (KBr): 3308, 3196, 2955,2927, 1621, 1457, 1382, 1274, 1145, 1034, 845 cm-1; 1HNMR (300 MHz, DMSO-d6): d 10.25 (bs, 1H), 9.37 (s, 1H),6.72 (d, 1H, J=8.4 Hz), 6.39 (dd, 1H, J=8.4 Hz and J=1.5 Hz),6.29 (d, 1H, J=1.5 Hz), 4.90 (s, 1H), 1.96-2.48 (m, 8H), 1.01(s, 3H), 0.95 (s, 3H), 0.86 (s, 6H); 13CMR: 26.67, 28.17,29.64, 32.03, 50.90, 99.88, 102.28, 111.60, 112.21, 116.34,129.22, 150.48, 156.54, 165.07, 195.27, 196.27; LCMS: m/z382.Compound (3 m); mp. 227 oC IR (KBr): 3346,2948, 2918, 1622, 1598, 1450, 1379, 1299, 1196, 1002,920 cm-1; 1H NMR (300 MHz, DMSO-d6): d 10.39 (bs,1H), 9.08 (s, 1H), 6.75 (d, 1H, J=8.7 Hz), 6.46 (dd, 1H,J=8.7 Hz and J=2.7 Hz), 6.39 (d, 1H, J=2.7 Hz), 4.98 (s, 1H),1.67-2.48 (m, 12H); 13CMR: 20.77, 20.86, 26.12, 27.81,37.14, 99.99, 111.57, 114.12, 114.40, 116.33,119.72, 126.82, 143.09, 154.09, 167.30, 196.36; LCMS:m/z 326.Compound (3 n); mp. 240 oC, IR (KBr): 3339, 3190,2954, 1624, 1589, 1456, 1378, 1231, 1189, 1139, 987 cm-1;1H NMR (300 MHz, DMSO-d6): d 10.35 (bs, 1H), 9.38 (s,1H), 6.74 (d, 1H, J=8.1 Hz), 6.39 (dd, 1H, J=8.1 Hz andJ=2.1 Hz), 6.29 (d, 1H, J=2.1 Hz), 4.92 (s, 1H), 1.65-2.21 (m,12H); 13CMR: 20.75, 20.85, 25.21, 27.73, 37.13, 99.98,102.19, 112.27, 112.80, 116.45, 120.00, 129.26, 150.55,156.55, 166.96, 196.54; LCMS: m/z 326.Scheme 2. A mechanism for formation of 1-oxo-hexahydroxanthene influenced by water.D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–14321432AcknowledgementsAuthors DMP and KAU thank UGC, New Delhi forfinancial assistance [F.2-3/2007(Policy/SR)] and for theResearch Fellowship, respectively.References[1] (a) Organic Reactions in Water: Principles, Strategies and Applications,ed. U. M. Lindstr̈om, Blackwell publishing, Oxford, UK 2007.(b) L. Weber, Drug Discov. Today 7 (2002) 143;(c) C. Hulme, V. Gore, Curr. Med. Chem 10 (2003) 51;(d) A. Dömling, Chem. Rev 106 (2006) 17;(e) I. Kanizsai, S. Gyäónfalvi, Z. Szadonyi, R. Sillanpää, F. Fülöp, GreenChem 9 (2007) 357.[2] (a) P.T. Anastas, J.C. Warner, Green Chemistry. Theory and Practice,Oxford University Press, Oxford, UK, 1998;(b) P.T. Anastas, T. Williamson, Green Chemistry. Frontiers in benignchemical synthesis and process, Oxford University Press, Oxford, UK,1998.[3] R.A. Sheldon, J. Mol. Catal. A 107 (1996) 75.[4] R. Maggi, F. Bigi, S. 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A green protocol for catalyst-free synthesis of 1-oxo-hexahydroxanthenes in aqueous medium

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A green protocol for catalyst-free synthesis of 1-oxo-hexahydroxanthenes in aqueous medium

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