A new strategy for the synthesis of benzoxanthenes catalyzed by proline triflate in water

Article abstract of DOI:10.1016/j.tetlet.2010.02.149

Catalyzed by proline triflate, benzoxanthenes were obtained in good yields from the condensation of naphthols, aldehydes, and 1,3-dicarbonyl compounds in water. A possible mechanism of this reaction is proposed.

Full text of DOI:10.1016/j.tetlet.2010.02.149

Tetrahedron Letters 51 (2010) 2434–2437
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new strategy for the synthesis of benzoxanthenes catalyzed by proline
triflate in water
*
Jianjun Li, Lingmei Lu, Weike Su
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalyzed by proline triflate, benzoxanthenes were obtained in good yields from the condensation of
naphthols, aldehydes, and 1,3-dicarbonyl compounds in water. A possible mechanism of this reaction
is proposed.
Received 6 January 2010
Revised 20 February 2010
Accepted 24 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzoxanthenes
Proline triflate
Condensation reaction
Naphthol
Xanthenes are one of the most widely distributed classes of nat-
ural compounds. Most of these derivatives are biologically active,
such as possessing antiplasmodial1 and anti-inflammatory2 activi-
ties, and being utilized as antagonists for drug-resistant leukemia
lines.3 Besides, these heterocyclic molecules have been widely
used as dyes,4 pH-sensitive fluorescent materials5 as well as in la-
ser technologies.6 Therefore, the synthesis of various xanthene
derivatives is of great importance.
NaHSO4ÁSiO2. Singh12 and Khurana13 further explored p-toluenesul-
fonic acid as a catalyst for the synthesis of these compounds. Unfor-
tunately, the current methods have not been extended to the use of
simple
The above studies illustrated the electron density at the b-position of
the -naphthol is not sufficient for the formation of the correspond-
ing o-QMs under these acid catalysis conditions (Scheme 1). There-
fore, the synthesis of xanthene from -naphthol remains
a-naphthol to form the corresponding benzo[c]xanthenes 2.
a
a
a
Classical methods reported for the synthesis of xanthenes in-
clude: (1) annulation reaction of aryne with salicylates7 or salicyl-
aldehyde;8 (2) palladium-catalyzed cyclization of polycyclic
aryltriflate esters;9 (3) addition reaction of ortho-quinone methides
(o-QMs) with certain nucleophiles.10 In comparison with other
routes to synthesize xanthenes, the one that employs o-QMs has
long been believed to be the most efficient.
challenge. In continuation of our previous work on the synthesis of
benzoxanthenes,14 we were interested in developing an efficient
catalyst for the preparation of new benzo[c]xanthenes 2 starting
from a-naphthol.
Ammonium triflate has been used as a mild and efficient cata-
lyst in organic synthesis.15 Recently, ammonium triflate has shown
the prospect to be used as a substitute for conventional acidic
catalytic materials. We thus focused on the application of such
catalyst in catalyzing the one-pot condensation reaction of
Recently, Das et al.11 have synthesized benzo[a]xanthenes 1 from
b-naphthol, aldehydes, and 1,3-dicarbonyl compounds catalyzed by
OH
R
O
O
O
O
O
O
OH
R
O
O
O
CHR
RCHO
CHR
o-QMs
Scheme 1. Routes to synthesize benzoxanthenes by reaction of naphthol, aldehydes, and 1,3-dicarbonyl compounds.
O
Benzo[a]xanthenes 1
Benzo[c]xanthenes 2
* Corresponding author. Tel./fax: +86 (571) 88320752.
E-mail address: pharmlab@zjut.edu.cn (W. Su).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.149

J. Li et al. / Tetrahedron Letters 51 (2010) 2434–2437
2435
Table 3
R
O
OH
Reaction of
a
-naphthol 3, benzaldehyde 4, and 1,3-dicarbonyl compounds 5 catalyzed
O
+
Ammonium
triflates
by proline triflatea
+ RCHO
O
R2 R2
R2
R2
O
5
O
4
3
2
O
O
OH
Scheme 2. Reaction of
catalyzed by ammonium triflates.
a-naphthol, aldehyde, and 1,3-dicarbonyl compounds
R1
or
O
O
Proline Triflate
10 mol%
5a-5b
or
+ R1CHO
+
H2O, reflux
O
O
4
3
Table 1
5a, R2=CH3
5b, R2=H
R1
2
O
The condensation reaction catalyzed by proline triflatea
5c
O
OH
Entry
R1
Compounds 5
Product 2
Time (h)
Yieldb (%)
O
Proline
triflates
1
2
3
4
5
6
7
8
9
C6H5
p-ClC6H4
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5c
5c
2a
2b
2c
2d
2e
2f
2g
2h
2i
5.0
5.0
4.0
5.5
6.5
9.0
15.0
15.0
5.0
79
76
77
72
64
70
+
PhCHO
+
O
Ph
O
m-OCH3C6H4
m-NO2C6H4
PhCH@CH
2-Thiophene
CH3CH2
Cyclohexyl
C6H5
m-OHC6H4
C6H5
4a
5a
Temp (°C)
3
2a
Entry
Solvent
Time (h)
Yieldb (%)
<5, 70c
<5
78
68
80
71
1
2
3
4
5
6
7
8
CH3CH2OH
CH2Cl2
ClCH2CH2Cl
CH3CN
THF
DMF
Et2O
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
80
7.0
5.0
4.5
6.0
22
70
57
28
10
11
12
2j
2k
2l
4.5
5.0
5.0
7.0
<10
<10
36
10.0
7.0
m-OHC6H4
Reflux
80
a
All reactions were run with 3 (1.0 mmol), 4 (1.0 mmol), and 5 (1.0 mmol) in the
presence of proline triflate (0.1 mmol) in H2O (2 mL) at reflux temperature.
Isolated yields based on 3.
The major product obtained was 1,8-dioxo-dodecahydroxanthene 6g, which
was formed from the condensation of one aldehyde and two cyclic 1,3-dicarbonyl
compounds.
6.5, 5.0c
69, 79c
b
a
All reactions were run with the molar ratio of 3:4a:5a: proline triflate
= 1:1:1:0.1.
c
b
Isolated yields based on 3.
c
The reaction was carried out under reflux temperature.
Table 2
Table 4
The condensation reaction catalyzed by different catalystsa
Reaction for synthesizing benzo[a]xanthenesa
O
+
R1
O
Entry
Cat. (10 mol %)
Temp (°C)
Time (h)
Yieldb (%) 2a:6a:7a
Proline Triflate
10 mol%
OH
+ R1CHO
1
2
3
4
5
6
Proline triflate
DPAT
DCAT
Sr(OTf)2
Proline triflate
Proline triflate
Reflux
Reflux
Reflux
Reflux
0
5
5
5
5
22
15
79:5:3
45:12:9
35:10:12
NDc
25:9:9
23:12:9
H2O, reflux
O
5
O
1
8
4
Entry
R1
Compounds 5
Product 1
Time (h)
Yieldb (%)
rt
1
2
3
4
5
6
C6H5
p-ClC6H4
m-OCH3C6H4
2-Thiophene
m-OCH3C6H4
C6H5
5a
5a
5a
5a
5b
5c
1a
1b
1c
1d
1e
1f
3.0
3.0
2.5
4.0
3.0
3.0
85
82
88
79
84
83
a
All reactions were run with 3 (1.0 mmol), 4a (1.0 mmol), 5a (1.0 mmol), and
catalyst (0.1 mmol) in H2O (2 mL).
b
Isolated yields based on 3.
No desired product was detected.
c
a
All reactions were run with 8 (1.0 mmol), 4 (1.0 mmol), and 5 (1.0 mmol) in the
a
-naphthol 3, aldehyde 4, and 1,3-dicarbonyl compounds 5 so as to
presence of proline triflate (0.1 mmol) in H2O (2 mL) at reflux temperature.
prepare benzo[c]xanthene 2 (Scheme 2).
b
Isolated yields based on 8.
Initially, we investigated the condensation reaction of a-naph-
thol 3, benzaldehyde 4a, and 5,5-dimethylcyclohexane-1,3-dione
5a using 10 mol % of proline triflate in different solvents. It is
encouraging to find 2a could be isolated with this catalyst albeit
in low to moderate yields. The results are listed in Table 1. Tetra-
hydrofuran (THF) and N,N-dimethylformamide (DMF) afforded 2a
in not more than 10% yield (Table 1, entries 5 and 6), and other po-
lar solvents such as ethanol and acetonitrile proved inefficient,
either (Table 1, entries 1 and 4). Use of 1,2-dichloroethane and
dichloromethane afforded 2a in better yields (Table 1, entry 4).
However, the best results came from the use of water as a solvent
(Table 1, entry 8).
It should be mentioned that besides 2a, a noticeable amount of
6a16 and 7a was also obtained (Scheme 3). To minimize the forma-
tion of 6a and 7a, further optimization of the reaction by using dif-
ferent catalysts and reaction temperature was undertaken (Table
OH OH
OH
O
O
O
Triflates
+
+
+
PhCHO
+
O
Ph
O
O
Ph
O
Ph
O
major
4a
6a
5a
3
2a
7a
Scheme 3. The condensation reaction of aldehyde, a-naphthol, and 1,3-dicarbonyl compound.

2436
J. Li et al. / Tetrahedron Letters 51 (2010) 2434–2437
O
R1
O
O
O
R1
O
COOH
OTf
H
N
O
O
O
H2O
R1
-H2O
5a
5a
R1
9
O
OTf
OH
O
O
4
OH
13
6a
COOH
OH
N
NH2
OTf
R1
O
R1
O
R1
O
O
O
O
R1
10
COOH
H
R1
-H2O
HOOC
TfOH
3
N
O
O
O
OH
14
O
OH OH
R1
12
7a
2a
11
Scheme 4. Proposed mechanism for the condensation reaction of aldehydes,
a-naphthol, and 1,3-dicarbonyl compounds.
2). Other ammonium triflates such as diphenylammonium triflate
(DPAT) and dicyclohexylammonium triflate (DCAT) did not give
improved yields and selectivity (Table 2, entries 2 and 3). It should
be noted that Sr(OTf)2, which was effective for the synthesis of
benzo[a]xanthene,14 did not promote the reaction at all under
similar conditions (Table 2, entry 4). On the other hand, decreasing
temperature favored the formation of 6a and 7a. Therefore,
although better conditions were not found, it is reasonable to sup-
port that the proline triflate has higher activity and selectivity in
this condensation reaction (Table 2, entry 1). Control experiment
without proline triflate showed that only the starting materials
were recovered.
12 produced 7a. Title product 2a was obtained by loss of a mol-
ecule of H2O. Otherwise, the intermediate may react with 1,3-
dicarbonyl compound via a conjugate addition to form 4H-pyran
derivatives 6a. The latter pathway has been proved by the reac-
tion between aldehyde 4 and 1,3-dicarbonyl compound 5a, where
only 6a was obtained in the absence of
a-naphthol under the
same condition.
In summary, we have developed an efficient synthesis of
benzo[c]xanthene derivatives18 via a one-pot condensation of
a-
naphthol, aldehydes, and cyclic 1,3-dicarbonyl compounds in the
present of proline triflate. Further applications of proline triflate
on the extension of this protocol are ongoing in our laboratory.
To demonstrate the generality of this method, the scope of the
reaction was investigated under the optimized conditions
(10 mol % proline triflate in H2O at reflux temperature), and the re-
sults are summarized in Table 3.
Gratifyingly, all the aromatic aldehydes employed here gave
good yields of 2. As shown in Table 3, electron-neutral, -rich, and -
poor aromatic aldehydes were all compatible with this condition.
It could also be concluded that the reaction rate of aromatic alde-
hydes with electron-donating groups is faster than those with elec-
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20806073), Technology Projects of Zhejiang (No.
2008C11046), the Opening Foundation of Zhejiang Provincial Top
Key Pharmaceutical Discipline for financial support. We also thank
professor Xiaoxia Wang of Zhejiang Normal University for helpful
discussions.
tron-withdrawing groups. Furthermore, a,b-unsaturated aldehydes
and heteroaromatic aldehydes also afforded good yields (Table 3,
entries 5 and 6). However, the reaction failed with aliphatic alde-
hydes such as propionaldehyde and cyclohexanecarbaldehyde
(Table 3, entries 7 and 8). In these cases, 1,8-dioxo-dodecahydrox-
anthene 6g was the exclusive product.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.149.
On the basis of the above-mentioned results, this process was then
extended to other cyclic 1,3-dicarbonyl compounds, such as cyclo-
hexane-1,3-dione and cyclopentane-1,3-dione. As summarized in
Table 3, good yields of the corresponding tetrahydrobenzo[c]xan-
then-8-one derivatives and dihydrobenzo[h]cyclopenta[b]chromen-
8-one derivatives were obtained regardless of structural variations
in the cyclic 1,3-dicarbonyl compounds.
References and notes
1. Zelefack, F.; Guilet, D.; Fabre, N.; Bayet, C.; Chevalley, S.; Ngouela, S.; Lenta, B.
N.; Valentin, A.; Tsamo, E.; Dijoux-Franca, M. G. J. Nat. Prod. 2009, 72, 954.
2. Poupelin, J. P.; Saint-Ruf, G.; Foussard-Blanpin, O.; Narcisse, G.; Uchida-Ernouf,
G.; Lacroix, R. Eur. J. Med. Chem. 1978, 13, 67.
3. Nguyen, H. T.; Lallemand, M. C.; Boutefnouchet, S.; Michel, S.; Tillequin, F. J. Nat.
Prod. 2009, 72, 527.
Encouraged by this success, we attempted to synthesize
benzo[a]xanthenes 1 from b-naphthol, aldehydes and 1,3-dicar-
bonyl compounds under similar conditions (Table 4). Good yields
were obtained for all cases, all the aldehydes and 1,3-dicarbonyl
compounds gave the corresponding benzo[a]xanthenes as the ma-
jor products. By contrast, the reaction between phenol, aldehyde,
and 1,3-dicarbonyl compounds resulted in no target product under
the same reaction conditions.
With the above-mentioned results in hand, a plausible mech-
anism of this condensation reaction was proposed in Scheme 4.
The first step was the condensation of the aldehyde 4 with the
catalyst to form an iminium ion 9.17 Iminium ion was then at-
tacked by the 1,3-dicarbonyl compound to give intermediate 12.
4. (a) Peters, A. T.; Bide, M. J. Dyes Pigments 1985, 6, 349; (b) Banerjee, A.;
Mukherjee, A. K. Stain Technol. 1981, 56, 83.
5. (a) Liu, J.; Diwu, Z.; Leung, W. Y. Bioorg. Med. Chem. Lett. 2001, 11, 2903; (b)
Knight, C. G.; Stephens, T. Biochem. J. 1989, 258, 683.
6. (a) Ahmad, M.; King, T. A.; Ko, D. K.; Cha, B. H.; Lee, J. J. Phys. D: Appl. Phys. 2002,
35, 1473; (b) Sirkencioglu, O.; Talinli, N.; Akar, A. J. Chem. Res. Synop. 1995, 502.
7. Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583.
8. Okuma, K.; Nojima, A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009, 11, 169.
9. Wang, J. Q.; Harvey, R. G. Tetrahedron 2002, 58, 5927.
10. (a) Jha, A.; Beal, J. Tetrahedron Lett. 2004, 45, 8999; (b) Yoshida, H.; Wasahiko,
W.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049.
11. Das, B.; Laxminarayana, K.; Krishnaiah, M.; Srinivas, Y. Synlett 2007, 3107.
12. Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 65, 7129.
13. Khurana, J. M.; Magoo, D. Tetrahedron Lett. 2009, 50, 4777.
14. Li, J. J.; Tang, W. Y.; Lu, L. M.; Su, W. K. Tetrahedron Lett. 2008, 49, 7117.
15. (a) Wakatsugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41,
5249; (b) Funatomi, T.; Wakasugi, K.; Misaki, T.; Tanabe, Y. Green Chem. 2006,
8, 1022; (c) Ishihara, K.; Nakagawa, S.; Sakakura, A. J. Am. Chem. Soc. 2005, 127,
Subsequently, ortho C-alkylation of
a-naphthol with intermediate

J. Li et al. / Tetrahedron Letters 51 (2010) 2434–2437
2437
4168; (d) Iida, A.; Osada, J.; Nagase, R.; Misaki, T.; Tanabe, Y. Org. Lett. 2007, 9,
1859.
purified by flash chromatography (ethyl acetate/petroleum ether, 1:10) to
provide 10,10-dimethyl-7-phenyl-10,11-dihydro-7H-benzo[c]xanthen-8(9H)-
16. (a) Fang, D.; Gong, K.; Liu, Z. L. Catal. Lett. 2009, 127, 291; (b) Amalraj, J.;
Palamari, J. P. Y.; Srinivasan, P. Chem. J. Mol. Catal. A: Chem. 2006, 248, 121.
17. (a) Seebach, D.; Groselj, U.; Badine, D. M.; Schweizer, W. B.; Beck, A. K. Helv.
Chim. Acta 2008, 91, 1999; (b) Groselj, U.; Schweizer, W. B.; Ebert, M. O.;
Seebach, D. Helv. Chim. Acta 2009, 92, 1.
one 2a. White solid; mp: 155.7–156.9 °C. IR (KBr):
mmax = 2958, 2935, 1650,
1628, 1370, 1253, 807 cmÀ1 1H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 8.4 Hz,
.
1H), 7.77 (d, J = 8.4 Hz, 1H), 7.58–7.55 (m, 1H), 7.52–7.48 (m, 2H), 7.28 (d,
J = 7.6 Hz, 2H), 7.23–7.19 (m, 2H), 7.16–7.09 (m, 2H), 5.13 (s, 1H), 2.75 (d,
J = 17.2 Hz, 1H), 2.68 (d, J = 17.2 Hz, 1H), 2.32 (d, J = 16.0 Hz, 1H), 2.26 (d,
J = 16.0 Hz, 1H), 1.16 (s, 3H), 1.09 (s, 3H). 13C NMR (100 MHz, CDCl3) d = 197.0,
164.2, 145.8, 133.1, 128.4, 128.2 (CH Â 2), 127.7 (CH Â 2), 127.0 (CH Â 2),
126.4 (CH Â 3), 126.3, 124.6, 123.7, 121.0, 119.9, 113.6, 50.9, 41.5, 32.3, 29.2,
27.5. MS (ESI): m/z = 355 [M+1]+. HRMS-ESI: calcd for C25H23O2: 355.1698;
found: 355.1680.
18. Typical procedure for the preparation of compound 2a: To
a mixture of
a
-naphthol (1.0 mmol) 3, benzaldehyde (1.0 mmol) 4a, and 5,5-
dimethylcyclohexane-1,3-dione (1.0 mmol) 5a was added proline triflate
(0.1 mmol) in H2O (2 mL). The progress of the reaction was monitored by
TLC. The resulting mixture was extracted with ethyl acetate (3 Â 10 mL). The
organic layer was dried (Na2SO4) and evaporated, and the crude product was