An efficient synthesis of spiro[dibenzo[b,i]xanthene-13,3′-indoline]-pentaones and 5H-dibenzo[b,i]xanthene-tetraones

Article abstract of DOI:10.1016/j.tetlet.2008.06.077

Spiro[dibenzo[b,i]xanthene-13,3′-indoline]-pentaones and 5H-dibenzo[b,i]xanthene-tetraones are synthesized from the condensation of 2-hydroxynaphthalene-1,4-dione with isatins or aldehydes.

Full text of DOI:10.1016/j.tetlet.2008.06.077

Tetrahedron Letters 49 (2008) 5165–5168
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Tetrahedron Letters
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An efficient synthesis of spiro[dibenzo[b,i]xanthene-13,30-indoline]-pentaones
and 5H-dibenzo[b,i]xanthene-tetraones
*
Ayoob Bazgir , Zeinab Noroozi Tisseh, Peiman Mirzaei
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Spiro[dibenzo[b,i]xanthene-13,30-indoline]-pentaones and 5H-dibenzo[b,i]xanthene-tetraones are
synthesized from the condensation of 2-hydroxynaphthalene-1,4-dione with isatins or aldehydes.
Ó 2008 Published by Elsevier Ltd.
Article history:
Received 12 April 2008
Revised 10 June 2008
Accepted 18 June 2008
Available online 21 June 2008
Keywords:
Isatin
2-Hydroxynaphthalene-1,4-dione
Spiro[dibenzo[b,i]xanthene-13,30-indoline]-
pentaone
5H-Dibenzo[b,i]xanthene-tetraone
1. Introduction
activity highly.13,14 The spiro-oxindole system is the core structure
of some pharmacological agents and natural alkaloids.15–17 Simi-
Polyfunctionalized heterocyclic compounds play important
roles in the drug discovery process, and analysis of drugs in late
development or on the market shows that 68% of them are hetero-
cycles.1,2 Therefore, it is not surprising that research on the synthe-
sis of polyfunctionalized heterocyclic compounds has received
significant attention.
larly, xanthenes have been reported to possess diverse biological
and therapeutic properties such as antibacterial, antiviral, and
anti-inflammatory activities, as well as being used in photody-
namic therapy.18,19 Other useful applications of these heterocycles
are as dyes, fluorescent materials for visualization of biomolecules
and in laser technologies.20,21
The quinone moiety is involved in a wide variety of biochemical
processes including electron transport and oxidative phosphoryla-
tion.3 Various biological properties including enzyme inhibition,
antibacterial, antifungal, and anticancer activities have been re-
ported for quinones and quinone derivatives.4–7 The antitumor
activity of the quinone moiety has been studied thoroughly, and
it is known that they act as topoisomerase inhibitors via DNA-
intercalation.8,9 Quinone-annulated heterocycles are found in nat-
ure, and most of them exhibit interesting biological activities. The
chemistry of quinone-annulated heterocycles is dependent largely
on the substituent being either on the quinone or on adjacent
rings.10,11 These activities, combined with diverse chemical behav-
ior make quinones attractive targets in organic synthesis.
Considering the above reports, and as part of our program aimed
at developing new selective and environmentally friendly method-
ologies for the preparation of heterocyclic compounds,22–28
we undertook the synthesis of spiro[dibenzo[b,i]xanthene-
13,30-indoline]-pentaone derivatives through a cyclo-condensation
reaction employing water as the reaction medium.
Reaction of 2-hydroxynaphthalene-1,4-dione 1 and isatins 2a–f
in the presence of a catalytic amount of p-toluenesulfonic acid (p-
TSA) as an inexpensive and readily available catalyst proceeded
smoothly in water at reflux for 24 h to produce spiro[dibenzo[b,i]-
xanthene-13,30-indoline]-20,5,7,12,14-pentaones 3a–f in 75–82%
yields (Scheme 1). Without p-TSA, for long periods of time (60 h),
the yields of products were low (<30%).
The indole framework is common in a wide variety of pharma-
cologically and biologically active compounds.12 Furthermore, it
has been reported that sharing of the indole 3-carbon atom during
the formation of spiroindoline derivatives enhances the biological
It is thought that compounds 3 result from initial addition of
2-hydroxynaphthalene-1,4-dione 1 to the isatin 2 to yield interme-
diates 4, which react further with another molecule of 1. Finally,
cyclization afforded the corresponding products 3 (Scheme 2).
To further explore the potential of this protocol for spiro-
heterocycle synthesis, we investigated the reaction between nin-
hydrin 5 and 1, and obtained spiro[dibenzo[b,i]xanthene-13,20-
indene]-10,30,5,7,12,14-hexaone 6 in 62% yield (Scheme 3).
* Corresponding author. Tel.: +98 21 22401765; fax: +98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.06.077

5166
A. Bazgir et al. / Tetrahedron Letters 49 (2008) 5165–5168
NR
O
X
O
O
O
O
O
O
X
OH
p-TSA/24 h
O
+
2
H2O,
N
O
R
O
1
2a-f
3a-f
Product 3
R
X
Yield (%)
a
b
c
d
e
f
H
H
H
H
Br
NO2
Br
80
79
81
82
75
77
Me
PhCH2
H
H
Me
Scheme 1.
classical heating conditions. In refluxing solvents, after 48 h, the
yields of products were low (<40%). We found that the best results
were obtained under solvent-free conditions in the presence of p-
TSA at 80 °C. Several aromatic aldehydes reacted to give products
8a–f in 70–78% yields in 7 h (Scheme 4). When this reaction was
carried out with an aliphatic aldehyde such as propionaldehyde,
TLC and 1H NMR spectroscopy of the reaction mixture showed a
combination of starting materials and numerous products, the
yield of the expected product was very poor.
R
N
O
O
X
X
O
1
OH
O
H+
N
R
2
OH
4
O
Compounds 3, 6, and 8 are stable solids whose structures were
established by IR, 1H NMR spectroscopy, mass spectrometry and
H+, 1
-H2O
elemental analysis. The electronic absorption spectra of 10ꢀ5
M
solutions of 3a–f and 8a–f in DMSO were measured, Table 1. The
longest wavelength maximum absorption (kmax) of all the com-
pounds was located between 260 and 275 nm. Studies on the fluo-
rescent properties of these compounds were also carried out in
DMSO (Table 2).
In summary, we have described efficient and simple methods
for the preparation of spiro[dibenzo[b,i]xanthene-13,30-indoline]-
pentaones yand 5H-dibenzo[b,i]xanthene-tetraones via condensa-
tion reactions of 2-hydroxynaphthalene-1,4-dione with isatins or
aldehydes.
NR
X
-H2O
O
O
O
O
O
3
HO
OH
Scheme 2.
2. Typical procedure for the preparation of
Finally, the feasibility of employing aldehydes for the synthesis
of 5H-dibenzo[b,i]xanthene-tetraones was also investigated. When
aromatic aldehydes were used, the yields of the expected products
were low (<30%). In order to improve the yields of the 5H-
dibenzo[b,i]xanthene-ytetraones, we examined the reaction under
different conditions including refluxing in various solvents (MeOH,
EtOH, THF, CH3CN, EtOAc, and toluene) and also under solvent-free
spiro[dibenzo[b,i]xanthene-13,30-indoline]-pentaone (3a)
A mixture of 2-hydroxynaphthalene-1,4-dione (2 mmol), an
isatin (1 mmol) and p-TSA (0.1 g) in refluxing water (5 ml) was stir-
red for 24 h (the progress of the reaction was monitored by TLC).
After completion, the reaction mixture was filtered and the
obtained precipitate washed with water and recrystallized from
O
O
O
O
O
O
O
O
OH
H2O,
2
+
O
p-TSA/24 h
O
O
O
62%
1
5
6
Scheme 3.

A. Bazgir et al. / Tetrahedron Letters 49 (2008) 5165–5168
5167
O
O
O
Ar
O
O
OH
Solvent-free/80 oC
2
ArCHO
+
p-TSA/7 h
O
1
7a-f
O
8a-f
Product 8
Ar
Yield (%)
a
b
c
d
e
f
C6H5
74
76
75
70
71
78
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
2-Cl-C6H4
3-NO2-C6H4
Scheme 4.
402 (70), 76 (30).1H NMR (300 MHz, DMSO-d6): dH (ppm) 3.33 (3H,
s, CH3), 6.86–820 (12H, m, H–Ar). Anal. Calcd for C29H15NO6: C,
73.57; H, 3.19; N, 2.96. Found: C, 73.51; H, 3.15; N, 2.90.
Table 1
UV/visible data for compounds 3 and 8 in DMSO
Entry
Compound
kmax (nm)
e
(104 L molꢀ1 cmꢀ1
)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
8a
8b
8c
8d
8e
8f
265
267
268
260
264
270
274
272
270
271
275
268
6.55
7.15
7.91
7.46
6.84
7.35
7.25
6.89
6.94
7.11
7.45
6.97
3.2. 10-Benzylspiro[dibenzo[b,i]xanthene-13,30-indoline]-
pentaone (3c)
Red powder (81%); mp: 358 °C dec. IR (KBr) (m
max/cmꢀ1): 3013,
1724, 1672, 1610. MS (EI, 70 eV) m/z (%): 549 (M+, 50), 453 (100),
414 (30), 91 (80). 1H NMR (300 MHz, DMSO-d6): dH 5.10 and 5.30
(2H, AB system, J = 15.2 Hz, CH2), 6.74–8.33 (17H, m, H–Ar). Anal.
Calcd for C35H19NO6: C, 76.50; H, 3.48; N, 2.55. Found: C, 76.45; H,
3.42; N, 2.62.
10
11
12
3.3. 50-Bromo-10-methylspiro[dibenzo[b,i]xanthene-13,30-
indoline]-pentaone (3f)
Table 2
Fluorescence properties for compounds 3 and 8 in DMSO
Orange powder (77%); mp: 365 °C dec. IR (KBr) (m
max/cmꢀ1):
3015, 1716, 1605. MS (EI, 70 eV) m/z (%): 553 (M+, 81Br, 100), 551
(M+, 79Br, 100), 525 (26), 480 (30), 76 (40).1H NMR (300 MHz,
DMSO-d6): dH (ppm) 3.32 (3H, s, CH3), 7.03–8.18 (11H, m, H–Ar).
Anal. Calcd for C29H14BrNO6: C, 63.06; H, 2.55; N, 2.54. Found: C,
63.01; H, 2.60; N, 2.61.
Entry
Compound
kex (nm)
kem (nm)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
8a
8b
8c
8d
8e
8f
355
328
350
315
384
319
310
306
300
314
309
335
398
362
397
347
391
359
340
333
321
342
328
374
3.4. Spiro[dibenzo[b,i]xanthene-13,20-indene]-10,30,5,7,12,14-
hexaone (6)
10
11
12
Yellow powder (62%); mp: 230 °C dec. IR (KBr) (m
max/cmꢀ1):
3011, 1734, 1725, 1678, 1615. MS (EI, 70 eV) m/z (%): 472 (M+,
15), 444 (10), 290 (30), 104 (100). 1H NMR (300 MHz, DMSO-d6):
dH 7.26–8.08 (12H, m, H–Ar). Anal. Calcd for C29H12O7: C, 73.73;
H, 2.56. Found: C, 73.80; H, 2.60.
EtOH/H2O (1:3) to afford pure 3a. Orange powder (80%); mp:
350 °C dec. IR (KBr) (m
max/cmꢀ1): 3410, 3090, 1720, 1668, 1603.
MS (EI, 70 eV) m/z (%): 459 (M+, 80), 417 (100), 76 (70). 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 6.78–8.11 (12H, m, H–Ar), 10.84
(1H, s, NH). Anal. Calcd for C28H13NO6: C, 73.20; H, 2.85; N, 3.05.
Found: C, 73.25; H, 2.80; N, 3.12.
3.5. 13-Phenyl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-
tetraone (8a)
Red powder (74%); mp: 305–307 °C; IR (KBr) (m
max/cmꢀ1): 3035,
1660, 1569. MS (EI, 70 eV) m/z (%): 418 (M+, 57), 390 (90), 313
(100). 1H NMR (DMSO-d6): dH 5.09 (1H, s, CH), 7.16–8.08 (13H,
m, H–Ar). Anal. Calcd for C27H14O5: C, 77.51; H, 3.37. Found C,
77.64; H, 3.41.
Due to the very low solubilities of products 3, 6, and 8, we were
unable to obtain 13C NMR spectra for these products.
3. Selected data for products
3.1. 10-Methylspiro[dibenzo[b,i]xanthene-13,30-indoline]-
pentaone (3b)
3.6. 13-(4-Chlorophenyl)-5H-dibenzo[b,i]xanthene-
5,7,12,14(13H)-tetraone (8b)
m
max/cmꢀ1): 3064,
Orange powder (76%); mp: 330–332 °C; IR (KBr) (
3028, 1663, 1610. MS (EI, 70 eV) m/z (%): 452 (M+, 5), 424 (60),
m
max/cmꢀ1):
Red powder (79%); mp: 360 °C dec. IR (KBr) (
1714, 1674, 1602. MS (EI, 70 eV) m/z (%): 473 (M+, 100), 445 (40),

5168
A. Bazgir et al. / Tetrahedron Letters 49 (2008) 5165–5168
313 (100). 1H NMR (DMSO-d6): dH 5.10 (1H, s, CH), 7.26–8.07 (12H,
m, H–Ar). Anal. Calcd for C27H13ClO5: C, 71.61; H, 2.89. Found C,
71.56; H, 3.93.
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Chem. 2006, 12, 2483.
3.7. 13-p-Tolyl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-
tetraone (8d)
Brick-red powder (70%); mp: 304–307 °C; IR (KBr) (m
max/cmꢀ1):
3088, 1663, 1608. MS (EI, 70 eV) m/z (%): 432 (M+, 45), 404 (100),
313 (65). 1H NMR (DMSO-d6): dH 2.21 (3H, s, CH3), 5.09 (1H, s, CH),
7.07–8.12 (12H, m, H–Ar). Anal. Calcd for C28H16O5: C, 77.77; H,
3.73. Found C, 77.68; H, 3.66.
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44, 1009.
3.8. 13-(3-Nitrophenyl)-5H-dibenzo[b,i]xanthene-5,7,12,14
(13H)-tetraone (8f)
Orange powder (78%); mp: 340–342 °C; IR (KBr) (m
max/cmꢀ1):
3035, 1662, 1605. MS (EI, 70 eV) m/z (%): 463 (25), 418 (40), 313
(100). 1H NMR (DMSO-d6): dH 5.47 (1H, s, CH), 7.11–8.13 (12H,
m, H–Ar). Anal. Calcd for C27H13NO7: C, 69.98; H, 2.83; N, 3.02.
Found C, 69.91; H, 2.78; N, 3.09.
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
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