CeCl3·7H2O-catalyzed synthesis of 1-oxo-hexahydroxanthene derivatives in aqueous media

Article abstract of DOI:10.1080/00397910802154253

Cerium(III) chloride heptahydrate (CeCl3·7H2O) catalyzes the reaction of substituted salicylaldehydes with 1,3-cyclohexane dione or dimedone in aqueous medium at reflux temperature to afford the corresponding 1-oxo-1,2,3,4,9,10-hexahydroxanthene derivativ

Full text of DOI:10.1080/00397910802154253

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CeCl3·7H2O-Catalyzed Synthesis
of 1-Oxo-hexahydroxanthene
Derivatives in Aqueous Media
Gowravaram Sabitha a , K. Arundhathi a , K.
Sudhakar a , B. S. Sastry b & J. S. Yadav a
a Organic Division I, Indian Institute of Chemical
Technology, Hyderabad, India
b Univesity College of Pharmaceutical Sciences,
Andhra University, Vizag, India
Version of record first published: 29 Sep 2008
To cite this article: Gowravaram Sabitha, K. Arundhathi, K. Sudhakar, B. S. Sastry
& J. S. Yadav (2008): CeCl3·7H2O-Catalyzed Synthesis of 1-Oxo-hexahydroxanthene
Derivatives in Aqueous Media, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:20, 3439-3446
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Synthetic Communications1, 38: 3439–3446, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802154253
CeCl3ꢀ7H2O-Catalyzed Synthesis
of 1-Oxo-hexahydroxanthene Derivatives
in Aqueous Media
Gowravaram Sabitha,1 K. Arundhathi,1 K. Sudhakar,1 B. S. Sastry,2
and J. S. Yadav1
1Organic Division I, Indian Institute of Chemical Technology,
Hyderabad, India
2Univesity College of Pharmaceutical Sciences, Andhra University,
Vizag, India
Abstract: Cerium(III) chloride heptahydrate (CeCl3ꢀ7H2O) catalyzes the reaction
of substituted salicylaldehydes with 1,3-cyclohexane dione or dimedone
in aqueous medium at reflux temperature to afford the corresponding 1-oxo-1,2,
3,4,9,10-hexahydroxanthene derivatives4 0 in high yields.
Keywords: CeCl3ꢀ7H2O, 1, 3-cyclohexane dione, dimedone, hexahydroxanthenes,
salicylaldehyde
INTRODUCTION
Xanthone derivatives are parent compounds of a large number of naturally
occurring, as well as synthetic derivatives, and they occupy a prominent
position in medicinal chemistry.[1] A new hexahydroxanthene derivative,
vedelianin, has been extracted from the leaves of Macaranga vedeliana.[2]
Hexahydroxanthenes are not abundant in nature, but they are a key feature
in the schweinfurthins and some related natural products such as ugonstil-
bene, ugonin L, and cymobarbatol. The anticancer activity of the schwein-
furthins, together with the difficulties encountered in efforts at repeated
Received March 3, 2008.
Address correspondence to Gowravaram Sabitha, Organic Division I, Indian
Institute of Chemical Technology, Hyderabad 500 007, India. E-mail: gowravaramsr
@yahoo.com
3439

3440
G. Sabitha et al.
isolation, has drawn attention to their synthesis. The reports for the synth-
esis of hexahydroxanthene derivatives are rare.[3] Because of their biological
importance, there is still demand for the synthesis of hexahydroxanthenes
under mild conditions. In recent decades, chemists have begun investigating
the possibility of using water as a solvent for organic reactions, with sometimes
surprising and unforeseen results. The fact is that water is the cheapest, safest,
and most non toxic solvent in the world. Some organic transformations that
can be performed efficiently in aqueous solvent are the Diels–Alder reaction,
Claisen rearrangements,[4] aldol reactions,[5],[6] allylation reactions,[7–9] and
oxidations[10–12] and hydrogenations[13] of alkenes, to mention a few. Recently,
CeCl3ꢀ7H2 O has received attention as a cost-effective, nontoxic, readily avail-
able, and selective reagent for various organic transformations.[14] The mild
Lewis acidity associated with cerium(III) chloride enhances its use at levels
from stoichiometric to catalytic, and it is a powerful reagent for several organic
reactions.[15] To the best of our knowledge, the synthesis of hexahydroxanthene
derivatives has not reported using CeCl3ꢀ7H2O.
Therefore, we report a new synthesis of 1-oxo-hexahydroxanthene
derivatives using a catalytic amount of CeCl3ꢀ7H2O in aqueous medium.
Thus, refluxing a mixture of 1 eq of salicilaldehyde 1 with 2 eq of 1,3-
cyclohexane dione 2a in the presence of a catalytic amount of
CeCl3ꢀ7H2O in water afforded the corresponding hexahydroxanthene
3a in 90% yield after recrystallization from 95% EtOH.
Similarly, various substituted salicylaldehydes reacted smoothly with
cyclohexanedione, resulting in good yields of products. Dimedone also
reacted well with substituted salicylaldehydes, affording the correspond-
ing products in high yields, and the results are indicated in Table 1. The
crude products were purified by recrystallization from 95% EtOH. All the
products were characterized by IR, 1H NMR, and mass spectral analysis
and also by comparision with authentic samples.
In summary, we have demonstrated a simple, efficient, and practical
synthesis of 1-oxo-1,2,3,4,9,10-hexahydroxanthene derivatives using
CeCl3ꢀ7H2O as a catalyst in aqueous media. The use of inexpensive
and readily available CeCl3ꢀ7H2O makes this procedure simple, conveni-
ent, and practical. The advantages are easy work up with high yields,
cleaner reactions, short reaction times, and a nontoxic catalyst.

1-Oxo-hexahydroxanthene Derivatives
3441
Table 1. CeCl3ꢀ7H2O-catalyzed synthesis of 1-oxo-hexehydroxanthenesa,b
in aqueous media
Entry
R1
R2
R3
R4
Time (h)
Yield (%)
Mp(ꢁC)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
FOMe
Br
t-Butyl
H
H
H
Cl
Br
H
t-Butyl
t-Butyl
H
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
4
3
3
4
3
3
3
3
3
4
3
3
82
87
91
86
85
82
92
96
94
90
83
82
226
220
219
232
201
211
204
228
231
222
212
216
H
3j
3k
3l
OMe
Br
t-Butyl
H
t-Butyl
t-Butyl
aAll products were characterized by spectral data and compared with authentic
samples.
bIsolated pure products.
EXPERIMENTAL
Melting points were determined using a Buchi R-535 apparatus and are
uncorrected. All reactions were monitored by thin-layer chromato-
graphy (TLC) using silica-coated plates and visualization under UV
light. Light petroleum of the distillation range 60–80 ꢁC was used.
Yields refer to pure products isolated by recrystallization and spectro-
scopically (1H, IR) homogeneous material. 1H NMR spectra were
recorded on Varian FT 200-MHz (Gemini) and Bruker UXNMR FT
300-MHz (Avance) instruments in CDCl3. Chemical shift values were
reported in parts per million (d) relative to tetramethylsilane (TMS)
Scheme 1.

3442
G. Sabitha et al.
(d 0.0) as an internal standard. Mass spectra were recorded under elec-
tron impact at 70 eV on an LC-MSD (Agilent Technologies). EtOH
95% was used for recrystallization.
General Procedure
A mixture of 1 eq of substituted salicylaldehyde (1) and 2 eq of cyclohex-
ane1,3-dione or dimedone (2a or 2b) in the presence of ceriumtrichloride
heptahydrate in a small amount of water was stirred at 90 ꢁC for 1.5–5 h.
The crude product was collected by filtration, washed with water, dried,
and purified by recrystallization from 95% EtOH to give 1-oxo-1,2,3,
4,9,10-hexahydroxanthene derivatives (3) in high yields (see Table 1).
The structure of the products was confirmed by spectral data
(1H NMR, IR, mass).
Spectral Data
Compound 3a
Mp 226 ꢁC; IR (KBr): 3150, 2920, 2880, 1640, 1570, 1550, 1485, 1440.
;
1360, 1280, 1220, 1180, 1051, 991, 970, 905, 840 cmꢂ1 1H NMR
(300 MHz, CDCl3): 1.92–2.75 (m, 12H, 6CH2), 4.60 (s, 1H, CH),
6.98–7.05 (m, 3H, ArH), 7.01–7.20 (m, 1H, ArH), 10.81 (s, 1H, OH);
ESI MS: m=z 310 (Mþ).
Compound 3b
Mp 220 ꢁC; IR (KBr): 3110, 2989, 2884, 1675, 1642, 1580, 1481, 1376,
1219, 1210, 1186, 1072, 982, 810, 764 cmꢂ1; 1H NMR (300 MHz, CDCl3):
1.84–2.82 (m, 12H, 6CH2), 4.64 (s, 1H, CH), 6.94 (d, J ¼ 8.4 Hz, 1H,
ArH), 7.09 (d, J ¼ 2.4 Hz, 1H, ArH), 7.54 (dd, J ¼ 8.4 Hz, J ¼ 2.4 Hz,
1H, ArH), 10.56 (s, 1H, OH); ESI MS: m=z 367 (Mþ þ Na).
Compound 3c
Mp 219 ꢁC: IR (KBr): 3112, 2950, 2884, 1676, 1650, 1598, 1481, 1370,
1
1271, 1219, 1188, 1070, 982, 910, 820, 765 cmꢂ1; H NMR (200 MHz
CDCl3): 1.91–2.78 (m, 12H, 6CH2), 4.50 (s, 1H, CH), 6.93 (d, J ¼ 8.4 Hz,
Hz, 1H, ArH), 7.20 (d, J ¼ 2.4 Hz, 1H, ArH), 7.32 (dd, J ¼ 8.4 Hz,
J ¼ 2.4 Hz, 1H, ArH), 10.71 (s, 1H, OH); ESI MS: m=z (%) 389 (Mþ).

1-Oxo-hexahydroxanthene Derivatives
3443
Compound 3d
Mp 232 ꢁC: IR (KBr): 3220, 2956, 2884, 1672, 1650, 1598, 1482, 1370,
1271, 1219, 1198, 1070, 982, 910, 820, 765 cmꢂ1; 1H NMR (200 MHz,
CDCl3): 1.81–2.74 (m, 12H, 6CH2), 3.82 (s, 3H, OCH3), 4.50 (s, 1H,
CH), 6.80 (d, J ¼ 8.3 Hz, 3H, ArH), 11.81 (s, 1H, OH); ESI MS: m=z
340 (Mþ).
Compound 3e
Mp 201 ꢁC: IR (KBr): 3210, 2950, 2890, 1680, 1640, 1598, 1480, 1370, 1221,
;
1186, 1076, 984, 810, 760 cmꢂ1 1H NMR (300 MHz, CDCl3): 1.16
(s, 6H, 2CH3), 1.21 (s, 3H, CH3), 1.93–2.77 (m, 12H, 6CH2), 4.62 (s, 1H,
CH), 7.06–7.22 (m, 2H, ArH), 10.71 (s, 1H, OH); ESI MS: m=z 446
(Mþ þ 1).
Compound 3f
Mp 211 ꢁC: IR (KBr): 3110, 2942, 2890, 1670, 1636, 1598, 1456, 1370,
;
1210, 1185, 1078, 984, 810, 760 cmꢂ1 1H NMR (200 MHz, CDCl3):
1.18 (s, 12H, 4CH3), 1.22 (s, 6H, 2CH3), 1.92–2.78 (m, 12H, 6CH2),
4.68 (s, 1H, CH), 7.10–7.25 (m, 2H, ArH), 10.82 (s, 1H, OH); ESI MS:
m=z 443 (Mþ þ Na).
Compound 3g
Mp 204 ꢁC: IR (KBr): 3182, 2951, 2860, 1652, 1591, 1481, 1372, 1320,
1246, 1185, 1140, 1013, 985, 810, 756 cmꢂ1; 1H NMR (300 MHz, CDCl3):
1.01 (s, 3H, CH3), 1.04 (s, 6H, 2CH3), 1.12 (s, 3H, CH3), 1.96–2.72
(m, 8H, 4CH2), 4.62 (s, 1H, CH), 6.98–7.22 (m, 4H, ArH), 10.40 (s, 1H,
OH); ESI MS: m=z 366 (Mþ).
Compound 3h
Mp 228 ꢁC: IR (KBr): 3184, 2960, 2862, 1650, 1596, 1481, 1460, 1371,
1313, 1247, 1188, 1016, 985, 810, 755 cmꢂ1; 1H NMR (300 MHz, CDCl3):
0.98 (s, 3H, CH3), 1.06 (s, 6H, 2CH3), 1.13 (s, 3H, CH3), 1.94–2.56
(m, 8H, 4CH2), 4.63 (s, 1H, CH), 6.93 (d, J ¼ 8.8 Hz, 1H, ArH), 6.99
(d, J ¼ 2.4 Hz, 1H, ArH), 7.10 (dd, J ¼ 8.8 Hz, J ¼ 2.4 Hz, 1H, ArH),
10.41 (s, 1H, OH); ESI MS: m=z 400 (Mþ).

3444
G. Sabitha et al.
Compound 3i
Mp 231 ꢁC: IR (KBr): 3121, 2962, 2873, 1619, 1561, 1477, 1372, 1294,
1229, 1178, 1152, 1070, 1032, 886, 819 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): 0.99 (s, 3H, CH3), 1.04 (s, 6H, 2CH3), 1.11 (s, 3H, CH3),
1.98–2.60 (m, 8H, 4CH2), 4.61 (s, 1H, CH), 6.93 (d, J ¼ 8.4 Hz, 1H,
ArH), 7.12 (d, J ¼ 2.4 Hz, 1H, ArH), 7.19 (dd, J ¼ 8.4 Hz, J1 ¼ 2.4 Hz,
1H, ArH), 10.52 (s, 1H, OH); ESI MS: m=z (%) 446 (Mþ þ 1).
Compound 3j
Mp 222 ꢁC: IR (KBr): 3120, 2960, 2876, 1620, 1562, 1475, 1372, 1296,
1222, 1178, 1152, 1077, 1030, 888, 819 cmꢂ1; 1H NMR (300 MHz, CDCl3):
0.98 (s, 3H, CH3), 1.02 (s, 6H, 2CH3), 1.10 (s, 3H, CH3), 1.99–2.75 (m, 8H,
4CH2), 3.78 (s, 3H, O CH3), 4.64 (s, 1H, CH), 6.93 (d, J ¼ 8.4 Hz, 1H,
ArH), 7.13 (d, J ¼ 7.55 Hz, 2H, ArH), ESI MS: m=z 396 (Mþ).
Compound 3k
Mp 212 ꢁC: IR (KBr): 3122, 2982, 2874, 1620, 1560, 1450, 1372, 1295,
1
1220, 1176, 1152, 1070, 1032, 886, 820, 726 cmꢂ1; H NMR (300 MHz,
CDCl3): 0.99 (s, 3H, CH3), 1.06 (s, 6H, 2CH3), 1.12 (s, 9H, 3CH3),
1.16 (s, 3H, CH3), 1.96–2.62 (m, 8H, 4CH2), 4.60 (s, 1H, CH), 6.98–
7.23 (m, 2H, ArH), 10.52 (s, 1H, OH); ESI MS: m=z 502 (Mþ þ 1).
Compound 3l
Mp 216 ꢁC: IR (KBr): 3126, 2981, 2872, 1620, 1564, 1444, 1376, 1298,
1
1222, 1178, 1152, 1070, 1032, 889, 824, 726 cmꢂ1; H NMR (200 MHz,
CDCl3): 0.94 (s, 3H, CH3), 1.02 (s, 6H, 2CH3), 1.06 (s, 9H, 3CH3), 1.09
(s, 9H, 3CH3), 1.12 (s, 3H, CH3), 1.94–2.68 (m, 8H, 4CH2), 4.64 (s, 1H,
CH), 6.98–7.25 (m, 2H, ArH), 10.52 (s, 1H, OH); ESI MS: m=z 478 (Mþ).
ACKNOWLEDGMENT
K. S. thanks University Grants Commission, New Delhi, for the award of
a fellowship.
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