An efficient and convenient protocol for the synthesis of novel 12-aryl- or 12-alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives

Article abstract of DOI:10.1055/s-2007-990922

An efficient and direct procedure for the synthesis of novel 12-aryl- or 12-alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one derivatives has been described. The process employs a three-component condensation reaction in one-pot using 2-naphthol, aldehydes

Full text of DOI:10.1055/s-2007-990922

LETTER
3107
An Efficient and Convenient Protocol for the Synthesis of Novel 12-Aryl- or
12-Alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one Derivatives1
Synthesisof
Nov
i
el
T
etr
s
hydroben
w
zo[
a
]xanthen-11-o
a
ne
D
erivat
nives ath Das,* Keetha Laxminarayana, Maddeboina Krishnaiah, Yallamalla Srinivas
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 19 March 2007
antiviral11 and antibacterial activities,12 and are being uti-
lized as antagonists for paralyzing action of
zoxazolamine13 and in photodynamic therapy.14 Further-
more, these compounds can be employed as dyes,15 pH-
Abstract: An efficient and direct procedure for the synthesis of
novel 12-aryl- or 12-alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-
11-one derivatives has been described. The process employs a
three-component condensation reaction in one-pot using 2-naph-
thol, aldehydes and cyclic 1,3-dicarbonyl compounds in the pres- sensitive fluorescent materials for visualization of
biomolecules16 and in laser technologies.17 Thus, the syn-
ence of a catalytic amount of NaHSO4·SiO2 in 1,2-dichloroethane
under reflux.
thesis of a variety of xanthene heterocyclic molecules is
Key words: xanthene, three-component condensation reaction, 2-
naphthol, aldehydes, cyclic 1,3-dicarbonyl compounds,
NaHSO4·SiO2
desirable.
Recently we reported the reaction of 2-naphthol and alde-
hydes (2:1) to form dibenzoxanthenes18a and the conden-
sation of aldehydes, 2-naphthol and amides (1:1:1) to
form amidoalkyl naphthols.18b These reactions proceed
through the in situ formation of ortho-quinone methides.
Our goal was to develop a tandem process that would al-
low in situ trapping of the o-QM intermediate with carbon
nucleophiles other than phenols to provide a rapid access
to novel xanthene derivatives under simple reaction con-
ditions. Our expectation was found to be fulfilled when a
mixture of 2-naphthol, 4-chlorobenzaldehyde and dime-
done (5,5-dimethyl-1,3-cyclohexanedione) was heated in
dichloroethane under reflux for five hours using
NaHSO4·SiO2 as a heterogeneous catalyst to form the cor-
responding 12-aryl-8,9,10,12-tetrahydro-benzo[a]xan-
then-11-one derivative in high yield (91%, Scheme 1).
Multicomponent reactions play an important role in mod-
ern synthetic organic chemistry since they generally occur
in a single pot and exhibit a high atom-economy and se-
lectivity. They also deliver fewer byproducts compared to
classical stepwise synthetic routes. This reduces time and
saves energy and raw materials.2 Biginelli,3 Ugi4 and
Mannich5 reactions are some examples of multicompo-
nent reactions. Nevertheless, the development of new
multicomponent reactions is still in demand. In this con-
text, ortho-quinone methides (o-QMs) have been utilized
in many tandem processes.6 The condensation of phenols
with aldehydes under acid or base catalysis is believed to
proceed via ortho-quinone methide intermediates.7 These
intermediates mainly involve [4+2] cycloadditions with a
wide range of dienophiles.8 However, only a limited work
has appeared with carbon nucleophiles.9 It is difficult to
create proper reaction conditions compatible with the si-
multaneous generation of both the o-QM and the carbon
nucleophile and this seems to hamper the proper exploita-
tion of o-QMs in reactions with carbon nucleophiles in or-
ganic synthesis.6
Heterogeneous catalysts have gained much importance in
recent years due to economic and environmental bene-
fits.19 These catalysts make the synthetic processes clean,
safe, high yielding and inexpensive. In the present three-
component coupling reaction of 2-naphthol, 4-chloroben-
zaldehyde and dimedone, NaHSO4·SiO2, a simple hetero-
geneous solid acid, catalyzed the reaction efficiently. The
catalyst can be easily prepared from the readily available
ingredients, NaHSO4 and silica gel.20 The reaction condi-
tions using this catalyst are very mild and the experimen-
tal procedure is very simple.
Xanthenes and benzoxanthenes are important biologically
active heterocycles. They possess anti-inflammatory,10
CHO
O
O
NaHSO4⋅SiO2
OH
CH2Cl2 (reflux)
+
+
5 h
O
O
Cl
91%
Cl
Scheme 1
SYNLETT 2007, No. 20, pp 3107–3112
x
x
.x
x
.2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-990922; Art ID: D08207ST
© Georg Thieme Verlag Stuttgart · New York

3108
B. Das et al.
LETTER
Initially, we conducted the reaction of 2-naphthol, 4-chlo- tions using different solvents including dichloromethane,
robenzaldehyde and dimedone in the presence of various 1,2-dichloroethane, chloroform and acetonitrile. The de-
heterogeneous solid acid catalysts such as NaHSO4·SiO2, sired product 3b was obtained in 74%, 91%, 79% and
Amberlyst-15 and montmorillonite K-10 clay separately 22% yields, respectively. 1,2-Dichloroethane was thus
in 1,2-dichloroethane under reflux for five hours. The cor- found to be the solvent of choice. We also conducted the
responding xanthene derivative 3b (Table 1) was formed reaction without solvent but the product was formed in
in 91%, 53% and 69% yield. NaHSO4·SiO2 was thus se- low yield.
lected as the most effective catalyst to carry out this reac-
tion. We selected the solvent 1,2-dichloroethane after
examination of the same reaction under the similar condi-
a,21
Table 1 Preparation of 12-Aryl- or 12-Alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one Derivatives Using NaHSO4·SiO2
Entry
Aldehyde 1
1,3-Diketone 2
Product 3
Time (h)
4
Isolated yield (%)
87
a
O
CHO
O
O
O
O
b
5
91
O
CHO
Cl
O
O
Cl
O
c
7
6
71
86
CHO
NO2
O
O
O
NO2
d
O
CHO
NO2
O
O
O
NO2
O
e
6.5
74
83
O
CHO
Br
O
O
Br
f
6
O
CHO
O
O
CF3
O
CF3
Synlett 2007, No. 20, 3107–3112 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Tetrahydrobenzo[a]xanthen-11-one Derivatives
3109
Table 1 Preparation of 12-Aryl- or 12-Alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one Derivatives Using NaHSO4·SiO2a,21 (continued)
Entry
Aldehyde 1
1,3-Diketone 2
Product 3
Time (h)
6.5
Isolated yield (%)
78
g
CHO
O
O
O
O
OH
OH
O
h
6
72
86
78
O
CHO
O
O
OMe
CHO
OMe
O
i
6.5
O
OMe
O
O
OH
OMe
OH
O
j
5.5
O
CHO
Cl
O
O
Cl
Cl
Cl
O
k
7
73
O
CHO
O
O
l
6.8
6.6
7
71
72
75
O
CHO
O
O
O
O
O
O
O
m
n
O
CHO
O
O
CHO
O
Synlett 2007, No. 20, 3107–3112 © Thieme Stuttgart · New York

3110
B. Das et al.
LETTER
Table 1 Preparation of 12-Aryl- or 12-Alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one Derivatives Using NaHSO4·SiO2a,21 (continued)
Entry
Aldehyde 1
1,3-Diketone 2
Product 3
Time (h)
5.4
Isolated yield (%)
89
o
O
O
CHO
O
O
Cl
Cl
O
p
q
6.2
4.4
84
81
O
CHO
O
O
NO2
NO2
O
O
O
O
CHO
O
r
s
7
76
69
O
O
CHO
CHO
O
O
O
6.9
O
O
a The structures of the products were established from their spectral (1H and 13C NMR and MS) data.
We subsequently extended the above method (using phenols the reaction was not favorable under the present
NaHSO4·SiO2 as a catalyst and 1,2-dichloroethane as a reaction conditions.
solvent) with both aromatic and aliphatic aldehydes to
The plausible mechanism of the reaction is shown in
prepare a series of 12-aryl- or 12-alkyl-8,9,10,12-tetrahy-
Scheme 2. In 2-naphthol the electron density at the ben-
drobenzo[a]xanthen-11-one derivatives (Table 1). Vari-
zylic C-1 position (which is in conjugation with the aro-
ous aromatic aldehydes with electron-donating and
matic ring) is higher than that at the C-3 position. Thus the
electron-withdrawing substituents reacted successfully
regioselective formation of the ortho-quinone methide
from this compound involving the C-1 and C-2 positions
and gave the products in good to high yields. To demon-
strate the scope and limitations of the procedure, the reac-
is favored. In simple phenolic compounds and 1-naphthol
tions of ortho-substituted aromatic aldehydes such as 2-
(which are weaker nucleophiles compared to 2-naphthol)
the electron density at the ortho position of the hydroxyl
group is not sufficient for the reaction of these compounds
nitro-, 2-bromo- and 2,4-dichlorobenzaldehydes were
studied and the results are reported in Table 1. 2-Naph-
thaldehyde also underwent the conversion smoothly (en-
with the aldehydes leading to the formation of the corre-
try k). Aliphatic aldehydes also afforded the desired
sponding ortho-quinone methides.
products with equal ease (entries l–n). The conversion
In conclusion, we have developed a novel and highly effi-
was found to be less impressive with acyclic 1,3-dicarbo-
cient methodology for the synthesis of 12-aryl- or 12-
alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one deriv-
atives from aldehydes, 2-naphthol and cyclic 1,3-dicarbo-
nyl compounds such as 2,4-pentanedione, 1-phenyl-1,3-
butanedione and 1,3-diphenyl-1,3-propanedione as the
corresponding xanthene derivatives were formed in very
nyl compounds. The method is associated with the
poor yields (5–7%). Acyclic 1,3-dicarbonyl compounds
benefits derived from multicomponent reactions and the
formed the mixtures of products containing the desired
application of a heterogeneous catalyst. We feel that this
compounds in low concentrations. However, with other
economically viable procedure will find practical utility
for the one-pot synthesis of novel xanthenes.
Synlett 2007, No. 20, 3107–3112 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Tetrahydrobenzo[a]xanthen-11-one Derivatives
3111
..
OH
RCHO
+
O
O
OH
H+
CHR
O
O
R
O
H
O
O
OH
– H2O
R
R
O
O
Scheme 2
(10) Poupelin, J. P.; Saint-Ruf, G.; Foussard-Blanpin, O.;
Acknowledgment
Marcisse, G.; Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med.
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The authors thank CSIR, New Delhi for financial assistance.
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References and Notes
(1) Part 130 in the series ‘Studies on novel synthetic
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Y.; Miyazawa, T.; Kuwata, S. Synthesis 1998, 991.
(c) Ross, G. F.; Herdtweck, E.; Ugi, I. Tetrahedron 2002, 58,
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Ravindranath, N.; Das, B. Tetrahedron Lett. 2003, 44, 1465.
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2004, 60, 8357. (d) Das, B.; Ravinder Reddy, K.;
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(21) General Procedure for the Synthesis of 12-Aryl- or 12-
Alkyl-8,9,10,12-tetrahydrobenzo[a]xanthen-11-one
Derivatives: NaHSO4·SiO2 (100 mg) was added to a mixture
of 2-naphthol (1.0 mmol), aldehyde (1.0 mmol) and
dimedone (1.2 mmol) in DCE (5 mL). The mixture was
stirred at reflux conditions and the reaction was monitored
by TLC. After completion of the reaction, the mixture was
filtered. The filtrate was concentrated and the residue was
purified by column chromatography (silica gel, 3% EtOAc
in hexane) to afford the pure 12-aryl- or 12-alkyl-8,9,10,12-
Synlett 2007, No. 20, 3107–3112 © Thieme Stuttgart · New York

3112
B. Das et al.
LETTER
tetrahydrobenzo[a]xanthen-11-one derivative.
Spectral data of some representative products are given
below:
H) 5.59 (s, 1 H), 5.28 (s, 1 H), 3.86 (s, 3 H), 2.52 (s, 2 H),
2.30 (d, J = 12.0 Hz, 1 H), 2.22 (d, J = 12.0 Hz, 1 H), 1.13
(s, 3 H), 0.99 (s, 3 H). 13C NMR (50 MHz, CDCl3): d =
197.2, 164.6, 147.8, 146.2, 144.1, 137.4, 131.1, 128.8,
128.2, 127.0, 124.9, 124.2, 121.2, 118.0, 117.5, 114.6,
114.3, 110.9, 55.8, 50.5, 40.1, 34.2, 31.8, 29.7, 26.8. MS
(FAB): m/z = 401 [M + H]+·.
Compound 3b: 1H NMR (200 MHz, CDCl3): d = 7.86 (dd,
J = 2.0, 8.0 Hz, 1 H), 7.75 (dd, J = 2.0, 8.0 Hz, 2 H), 7.11–
7.46 (m, 7 H), 5.62 (s, 1 H), 2.63 (s, 2 H), 2.31 (d, J = 12.0
Hz, 1 H), 2.20 (d, J = 12.0 Hz, 1 H), 1.12 (s, 3 H), 0.91 (s, 3
H). 13C NMR (50 MHz, CDCl3): d = 196.8, 164.0, 147.8,
143.3, 132.0, 131.5, 131.3, 129.8, 129.1, 128.5, 128.4,
127.1, 125.0, 123.5, 117.1, 117.0, 113.9, 50.9, 41.4, 34.2,
32.2, 29.3, 27.1. MS (FAB): m/z = 389, 391 [M + H]+·.
Compound 3g: 1H NMR (200 MHz, CDCl3): d = 7.94 (dd,
J = 2.0, 8.0 Hz, 1 H), 7.72 (dd, J = 2.0, 8.0 Hz, 2 H), 7.32–
7.45 (m, 2 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.14 (d, J = 8.0 Hz,
2 H), 6.55 (d, J = 8.0 Hz, 2 H), 5.59 (s, 1 H), 5.47 (s, 1 H),
2.58 (s, 2 H), 2.32 (d, J = 12.0 Hz, 1 H), 2.23 (d, J = 12.0 Hz,
1 H), 1.12 (s, 3 H), 1.01 (s, 3 H). 13C NMR (50 MHz,
CDCl3): d = 197.6, 164.8, 154.6, 148.1, 137.5, 131.1, 129.9,
129.9, 129.1, 128.8, 127.2, 125.0, 124.6, 117.5, 117.0,
115.2, 114.9, 50.7, 40.4, 33.2, 31.8, 29.1, 26.9. MS (FAB):
m/z = 371 [M + H]+·.
Compound 3l: 1H NMR (200 MHz, CDCl3): d = 8.07 (d, J =
8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1
H), 7.49 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.12
(d, J = 8.0 Hz, 1 H), 4.69 (t, J = 7.0 Hz, 1 H), 2.50 (s, 2 H),
2.38 (d, J = 12.0 Hz, 1 H), 2.29 (d, J = 12.0 Hz, 1 H), 1.78–
1.89 (m, 2 H), 1.20 (s, 3 H), 1.12 (s, 3 H), 0.61 (t, J = 7.0 Hz,
3 H). 13C NMR (50 MHz, CDCl3): d = 197.9, 166.1, 148.8,
131.2, 131.0, 128.2, 128.1, 126.4, 124.2, 123.1, 117.8,
115.2, 111.5, 50.8, 41.1, 31.5, 29.2, 28.8, 27.3, 9.1. MS
(FAB): m/z = 307 [M + H]+·.
Compound 3o: 1H NMR (200 MHz, CDCl3): d = 7.85 (dd,
J = 2.0, 8.0 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 2 H), 7.06–7.48 (m,
7 H), 5.64 (s, 1 H), 2.63–2.85 (m, 2 H), 2.31–2.42 (m, 2 H),
1.92–2.11 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 197.0,
165.8, 147.8, 143.5, 132.0, 131.5, 131.2, 130.0, 129.1,
128.5, 128.4, 127.1, 125.0, 123.5, 117.0, 116.9, 115.1, 37.0,
34.1, 27.7, 20.3. MS (FAB): m/z = 361, 362 [M + H]+·.
Compound 3i: 1H NMR (200 MHz, CDCl3): d = 7.92 (dd,
J = 2.0, 8.0 Hz, 1 H), 7.74 (dt, J = 2.0, 8.0 Hz, 2 H), 7.42–
7.55 (m, 2 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 2.0 Hz,
1 H), 6.62 (d, J = 8.0 Hz, 1 H), 6.51 (dd, J = 2.0, 8.0 Hz, 1
Synlett 2007, No. 20, 3107–3112 © Thieme Stuttgart · New York

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