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

Article abstract of DOI:10.1016/j.crci.2010.06.015

An efficient and eco-friendly synthesis of 1-oxo-hexahydroxanthenes has been expediently accomplished by a reaction of salicylaldehyde with cyclohexane-1,3-dione or dimedone in water as universal solvent at reflux condition without a catalyst. Excellent yields of the products, operational simplicity, simple work-up and catalyst-free synthesis are attractive features of this green protocol.

Full text of DOI:10.1016/j.crci.2010.06.015

C. R. Chimie 13 (2010) 1429–1432
Contents lists available at ScienceDirect
Comptes Rendus Chimie
www.sciencedirect.com
Preliminary communication/Communication
A green protocol for catalyst-free synthesis of 1-oxo-hexahydroxanthenes
in aqueous medium
*
D.M. Pore , T.S. Shaikh, K.A. Undale, D.S. Gaikwad
Department of Chemistry, Shivaji University, Kolhapur 416 004, India
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and eco-friendly synthesis of 1-oxo-hexahydroxanthenes has been
expediently accomplished by a reaction of salicylaldehyde with cyclohexane-1,3-dione
or dimedone in water as universal solvent at reflux condition without a catalyst. Excellent
yields of the products, operational simplicity, simple work-up and catalyst-free synthesis
are attractive features of this green protocol.
Received 10 April 2010
Accepted after revision 22 June 2010
Available online 7 August 2010
Keywords:
ß 2010 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Octahydroxanthene
Hexahydroxanthene
Salicylaldehyde
Water
Cyclohexane-1,3-dione
Dimedone
1. Introduction
of cell growth as measured by the National Cancer
Institute’s 60-cell line screen [8]. Xanthenes are known
Developing a simple, eco-friendly as well as economic
reaction protocol for the synthesis of organic transforma-
tions is an attractive area of research in both academic and
pharmaceutical R and D [1]. Hence the challenging task of
achieving ‘efficiency’ in all aspects of chemical production,
advocated by green chemistry can be realized by innova-
tive research which comprehensively addresses the issues
of atom economy, economy and avoidance of auxiliary
chemicals [2]. By keeping these ideas in mind and
paraphrasing the concept reported by Sheldon ‘‘the best
solvent is no solvent’’ [3] and by Maggi ‘‘the best catalyst is
no catalyst’’ [4], we can state that the greener protocol is
one which involves no catalyst and no solvent or use of
water as a universal solvent.
for their utility as leuco-dyes [9], pH-sensitive fluorescent
materials for the visualization of biomolecules [10] and in
laser technologies [11] due to their useful spectroscopic
properties. Octahydroxanthene derivatives containing a
structural 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 their
synthesis as well as their derivatives.
In contrast to the widely studied 1,8-dioxo-octahy-
droxanthene derivatives [12,13], relatively few papers
describe 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 classical
methods 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 for
synthesis 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 synthetic
strategy. Hence we report our findings.
Xanthenes are frequently occurring motifs in a number
of natural products [5], and have been used as versatile
synthons due to the inherent reactivity of the inbuilt pyran
ring [6] Most of the natural schweinfurthins [7] (diversonol
and 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 ß 2010 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.crci.2010.06.015

1430
D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–1432
as 5-chloro-, 3-methoxy-, 5-bromo, 4 and 5-hydroxy, 3,5-
dichloro and 3,5-dibromo derivatives to produce the
corresponding 1-oxo-hexahydroxanthene in high yields
(Table 1, entries a–o).
In recent years, water has been demonstrated as an
ideal medium for many organic transformations even if
starting 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 easy
conversion of the keto form to enol form of the compound
(2) which is useful for Knoevenagel condensation fol-
lowed by subsequent Michael addition and dehydration
affords product (3). A plausible mechanism is depicted in
Scheme 2.
Fig. 1. Important xanthene derivatives.
3. Conclusion
2. Results and discussion
In conclusion, we have developed practical and eco-
friendly method for the efficient synthesis of 1-oxo-
hexahydroxanthenes by a condensation of salicylaldehyde
and dimedone/cyclohexane-1,3-dione. The use of water as
a solvent, simple work-up procedure and no need of
catalyst make it an eco-friendly as well as an economical
alternative to earlier reported approaches.
EPZ-10, a clay catalyst commercially available from
Contract Chemicals, England (www.contract-chemicals.-
com.), which is prepared by supporting ZnCl2 on clay, is
known to contain predominantly strong Lewis acid sites as
well as weak Bronsted acid sites [18]. Recently, we have
reported synthesis of 1,8-dioxo-octahydroxanthenes in
aqueous medium using EPZ-10 (10 mol %) as an ecofriendly
catalyst under reflux conditions [19]. This spurned us to
investigate the capability of EPZ-10 to act as catalyst for
the synthesis of 1-oxo-hexahydroxanthene. Initially the
reaction of salicylaldehyde (1, R’ = H) and dimedone (2,
R = Me) [1:2] was carried using EPZ-10 (10 mol %) in
aqueous medium at reflux conditions and corresponding
1-oxo-hexahydroxanthene (3) (Scheme 1) was obtained in
92% yield in 3 h. In order to investigate the role of EPZ-10,
the above reaction was performed in the absence of the
catalyst and gratifyingly 1-oxo-hexahydroxanthene was
achieved in 90% yield. After this success, we focused our
attention towards catalyst-free synthesis of 1-oxo-hex-
ahydroxanthene in aqueous medium.
4. Experimental
Various substituted salicylaldehydes (Sigma-Aldrich),
1,3-diketones viz cyclohexane-1,3-dione (Alfa Aesar) and
dimedone (Thomas Baker) were used as received. Melting
points were determined and are uncorrected. IR spectra
were 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 an
internal standard and
d values are expressed in ppm. Mass
spectra (LCMS) were recorded on Shimadzu LCMS 2010,
mass spectrometer.
Using the catalyst-free condition, both electron-rich as
well as electron-deficient salicylaldehydes reacted effec-
tively with 1,3-dicarbonyl compounds in aqueous medi-
um. (Table 1) Both dimedone and cyclohexane-1,3-dione
reacted smoothly with substituted salicylaldehydes such
4.1. General procedure for catalyst-free synthesis of 1-oxo-
hexahydroxanthenes
A suspension of an salicylaldehyde (1 mmol) and
dimedone/cyclohexane-1,3-dione (2 mmol) in water
Scheme 1. Catalyst-free synthesis of 1-oxo-hexahydroxanthenes.

D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–1432
1431
Table 1
Catalyst-free synthesis of 1-oxo- hexahydroxanthenes.
Entry
Product (3)
Time (h)
Yield (%)a,b
M.P Obs.(Lit oC)
[TD$LINE]
R'
R'
O
OH
O
R'
O
R'
R
a
b
c
R = H; R’ = CH3
3.5
5.0
4.5
5.0
4.0
4.0
4.5
3.5
4.0
5.0
5.0
4.5
4.5
90
88
85
86
93
95
87
88
85
87
89
89
91
204 (206) [14]
235 (238) [14]
231 (230) [14]
251 (253) [14]
217 (————)
232 (————)
231 (235) [14]
242 (244) [14]
252 (254) [14]
243 (245) [14]
254 (255) [14]
227 (————)
240 (————)
R = 5-Cl ; R’ = CH3
R = 3-OMe; R’ = CH3
R = 5-Br ; R’ = CH3
R = 5-OH; R’ = CH3
R = 4-OH; R’ = CH3
R = 3,5 Cl; R’ = CH3
R = H; R’ = H
d
e
f
g
h
i
R = 3,5 Cl; R’ = CH3
R = 5-NO2; R’ = H
R = 3,5-Br; R’ = H
R = 5-OH; R’ = H
R = 4-OH; R’ = H
k
l
m
n
[TD$LINE]
R'
R'
O
OH
O
R'
O
R'
R
o
R = H; R’ = H
4.5
84
215 (216) [14]
Yields refer to pure isolated products. All products are racemic mixtures.
(5 mL) were stirred at reflux condition and the progress of
the reaction was monitored by TLC. After completion of the
reaction, the resulting solid products were collected by
filtration and were recrystallized from 95% ethanol. These
products were characterized by usual spectral techniques.
(i.e. IR, 1H and 13C NMR, LCMS).
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/z
382.
Compound (3 m); mp. 227 oC IR (KBr): 3346,
2948, 2918, 1622, 1598, 1450, 1379, 1299, 1196, 1002,
4.2. Spectral data of unknown compounds:
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 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 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 and
J=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.
Compound (3 f); mp. 232 oC IR (KBr): 3308, 3196, 2955,
;
2927, 1621, 1457, 1382, 1274, 1145, 1034, 845 cm-1 1H
NMR (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),

1432
D.M. Pore et al. / C. R. Chimie 13 (2010) 1429–1432
Scheme 2. A mechanism for formation of 1-oxo-hexahydroxanthene influenced by water.
(b) G.A. Reynolds, S.A. Tuccio, O.G Peterson, Chem. Abstr 71 (1971)
81334c.
Acknowledgements
[10] R.C. Hunter, T. Beveridge, J. Appl. Environ. Microbiol 71 (2005)
2501.
[11] M. Ahmad, T.A. King, D.K Ko, B.H. Cha, J. Lee, J. Phys. D: Appl. Phys 35
(2002) 1473.
[12] W.S. Johnson, Angew. Chem. 88 (1976) 33; Angew. Chem., Int. Ed. Engl
15 (1976) 9.
Authors DMP and KAU thank UGC, New Delhi for
financial assistance [F.2-3/2007(Policy/SR)] and for the
Research Fellowship, respectively.
References
[13] R.B. Herbert, Nat. Prod. Rep 8 (1991) 185.
[14] P. Zhang, Y.D Yu, Z.H Zhang, Synth. Commun 38 (24) (2008)
4474.
[15] Y.L. Li, H. Chen, Z.S. Zeng, X.S. Wang, D.Q. Shi, S.J Tu, Chin. J. Org. Chem
25 (2005) 846.
[1] (a) Organic Reactions in Water: Principles, Strategies and Applications,
ed. U. M. Lindstr¨om, 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. Do¨mling, Chem. Rev 106 (2006) 17;
[16] S. Gowravaram, K. Arundhathi, K. Sudhakar, B.S. Sastry, J.S. Yadav,
Synth. Commun 38 (20) (2008) 3439.
[17] X.S. Wang, D.Q. Shi, Y.L. Li, H. Chen, X.Y. Wei, Z.M. Zong, Synth. Commun
35 (2005) 97.
(e) I. Kanizsai, S. Gya¨o´nfalvi, Z. Szadonyi, R. Sillanpa¨a¨, F. Fu¨lo¨p, Green
Chem 9 (2007) 357.
[18] S.J. Barlow, T.W. Bastock, J.H. Clark, S.R. Cullen, Tetrahedron Lett 34
(1993) 3339.
[2] (a) P.T. Anastas, J.C. Warner, Green Chemistry. Theory and Practice,
Oxford University Press, Oxford, UK, 1998;
[19] T. S. Shaikh, N. G. Patil, S. B. Dongare, U. V. Desai, D. M. Pore, Synth.
Commun. 40 (2010) 2215.
[20] (a) M.C. Pirrung, K.D. Sarma, Tetrahedron 61 (2005) 11456;
(b) H.C. Kolb, M.G. Finn, K.B. Sharpless, Angew. Chem., Int. Ed 40 (2001)
2004.
(b) P.T. Anastas, T. Williamson, Green Chemistry. Frontiers in benign
chemical 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. Carloni, A. Mazzacani, G. Sartori, Green Chemistry 3
(2001) 173.
[5] S. Hatakeyma, N. Ochi, H. Numata, S. Takano, J. Chem. Soc. Chem.
Commun (1988) 1202.
[6] G. Song, B. Wang, H. Luo, L. Yang, Catal. Commun 8 (2007) 673,
references cited therein.
[21] (a) C.-J. Li, Chem. Rev 93 (1993) 2023;
(b) A. Lubineau, Chem. Ind (1996) 123;
(c) F. Fringuelli, O. Piermatti, F. Pizzo, in : O. Attanasi, D. Spinelli (Eds.),
Targets in Heterocyclic Systems. Italian Society of Chemistry: Rome, l,
1997, pp. 57;
(d) P.A. Organic Synthesis in Water, Grieco Blackie Academic and
Professional: London (1998);
(e) A. Meijer, S. Otto, J.B.F.N. Engberts, J. Org. Chem 63 (1998) 8989,
and references cited therein.
[7] F. Lynen, Pure Appl. Chem 14 (1967) 137.
[8] E.M.C. Gerard, H. Sahin, A. Encinas, S. Brase, Synlett 17 (2008) 2702.
[9] (a) S.M.S.C. Menchen, J.Y.L. Benson, W. Lam, D. Zhen, B.B. Sun, S.H.
Rosenblum, M.U.S. Khan, Taing, Chem. Abstr 139 (2003) 54287f;