A clean synthesis of spiro[indoline-3,9′-xanthene]trione derivatives

Article abstract of DOI:10.1248/cpb.56.1328

A simple, clean and efficient method for the synthesis of spiro[indoline-3,9′-xanthene]trione derivatives and spiro[acenaphthene-l, 9′-xanthene]-l′,2,8′(2′H,5′H)-trione by condensation reaction of dimedone and isatins or acenaphthene in aqueous media is reported.

Full text of DOI:10.1248/cpb.56.1328

1328
Notes
Chem. Pharm. Bull. 56(9) 1328—1330 (2008)
Vol. 56, No. 9
A Clean Synthesis of Spiro[indoline-3,9ꢀ-xanthene]trione Derivatives
Somayeh AHADI, Hamid Reza KHAVASI, and Ayoob BAZGIR*
Department of Chemistry, Shahid Beheshti University; Tehran 1983963113, Iran.
Received April 5, 2008; accepted May 19, 2008; published online June 10, 2008
A simple, clean and efficient method for the synthesis of spiro[indoline-3,9ꢀ-xanthene]trione derivatives and
spiro[acenaphthene-1,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione by condensation reaction of dimedone and isatins or
acenaphthene in aqueous media is reported.
Key words isatin; spirooxindole; spiro[indoline-3,9ꢀ-xanthene]trione; spiro[acenaphthene-1,9ꢀ-xanthene]trione
Polyfunctionalized heterocyclic compounds play important found that water was a solvent of choice for the reaction and
roles in the drug discovery process, and analysis of drugs in the desired product was obtained in good yield in water
late development or on the market shows that 68% of them (Entry 4).
are heterocycles.1,2) Therefore; it is not surprising that re-
The general efficiency of this protocol was then studied for
search on the synthesis of heterocyclic compounds has re- the synthesis of a variety of spiro[indoline-3,9ꢀ-xanthene]tri-
ceived significant attention. one derivatives and the results are summarized in Table 2.
Indole fragment is featured widely in a wide variety of Various isatins (2a—g) reacted efficiently with dimedone 1
pharmacologically and biologically active compounds.3) Fur- to afford the desired spiro[indoline-3,9ꢀ-xanthene]triones
thermore, it has been reported that sharing of the indole 3- (3a—g) in good yields (Chart 1, Table 2). The results were
carbon atom in the formation of spiroindoline derivatives good in terms of yields and product purity in the presence of
highly enhances biological activity.4—6) The spirooxindole p-TSA, while without p-TSA and over a long period of time
system is the core structure of many pharmacological agents (48 h) the yields of products were low (ꢁ30%).
and natural alkaloids.7—10) For example, spirotryprostatins A
and B, two natural alkaloids isolated from the fermentation
broth of Aspergillus fumigatus, have been identified as two
novel inhibitors of microtubule assembly,8) and pteropodine
and isopteropodine have been shown to modulate the func-
tion of muscarinic serotonin receptors.10)
The compounds 3 apparently result from the initial addi-
Xanthene derivatives have been reported to possess diverse
biological and therapeutic properties such as antibacterial,
antiviral, and anti-inflammatory activities, as well as being
useful in photodynamic therapy.11,12) The other useful appli-
cations of these heterocycles are as dyes, fluorescent materi-
als for visualization of biomolecules, and in laser technolo-
gies.13,14)
Chart 1. Synthesis of Spiro[indoline-3,9ꢀ-xanthene]triones
As part of our program aimed at developing new selective
and environmentally-friendly methodologies for the prepara-
tion of heterocyclic compounds,15—21) we performed the
synthesis of spiro[indoline-3,9ꢀ-xanthene]triones through a
cyclo-condensation reaction employing water as the reaction
medium. In fact, as clearly stated by R. A. Sheldon, it is gen-
erally recognized that “the best solvent is no solvent and if a
solvent (diluent) is needed it should preferably be water.”22)
The use of water as the reaction medium represents a re-
markable benefit since this green solvent is highly polar and
therefore immiscible with most organic compounds; more-
over, the water soluble catalyst resides and operates in the
aqueous phase and separation of the organic materials is thus
easy.
Table 1. Solvent Effect on Reactiona)
Entry
Solvent
Yield (%)b)
Time (h)
1
2
3
4
5
6
EtOH (reflux)
MeOH (reflux)
CHCl3 (reflux)
H2O (reflux)
CH3CN (reflux)
PhCH3 (reflux)
60
52
Trace
75
47
Trace
24
24
24
24
24
24
a) Dimedone (2 mmol), isatine (1 mmol), p-TSA (0.1 g). b) Isolated yield.
Table 1. Synthesis of Spiro[indoline-3,9ꢀ-xanthene]triones 3
Product 3
X
R
Time (h)
Yield (%)
Results and Discussion
a
b
c
d
e
f
H
H
H
Br
Br
NO2
H
H
Me
Et
H
Me
H
24
30
30
24
24
24
39
75
67
63
70
68
78
65
To achieve suitable conditions for the synthesis of
spiro[indoline-3,9ꢀ-xanthene]triones, we tested the reaction
of dimedone 1 and isatin 2a as a simple model substrate in
different solvents in the presence of p-toluenesulfonic acid
(p-TSA) as an inexpensive and available catalyst in reflux
conditions (Chart 1). The results are shown in Table 1. It was
g
PhCH2
∗ To whom correspondence should be addressed. e-mail: a_bazgir@sbu.ac.ir
© 2008 Pharmaceutical Society of Japan

September 2008
1329
mass spectrometry and elemental analysis. The structure of
3b was confirmed by single crystal X-ray analysis (Fig. 1).25)
Conclusions
In summary, we have described a clean, efficient and simple
method for the preparation of spiro[indoline-3,9ꢀ-xanthene]tri-
one derivatives in a condensation reaction of dimedone and
isatins under reflux in water. Furthermore, a novel synthesis of
spiro[acenaphthene-1,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione
was reported.
Experimental
Apparatus Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. Mass spectra were recorded on a FINNI-
GAN-MAT 8430 mass spectrometer operating at an ionization potential of
70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1H-
and 13C-NMR spectra were recorded on a BRUKER DRX-300 AVANCE
spectrometer at 300.13 and 75.47 MHz, respectively. Elemental analyses
were performed using a Heracus CHN-O-Rapid analyzer.
Chart 2. Proposed Mechanism for the Synthesis of Spiro[indoline-3,9ꢀ-
xanthene]triones
Typical Procedure for the Preparation of 3ꢀ,3ꢀ,6ꢀ,6ꢀ-Tetramethyl-
3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-tri-
one (3a, C24H25NO4) A mixture of dimedone (2 mmol), isatin (1 mmol)
and p-TSA (0.1 g) in refluxing water (5 ml) was stirred for 24 h (The reac-
tion progress was monitored by TLC). After completion of the reaction, the
reaction mixture was filtered and the precipitate washed with water and
residue recrystallized from EtOH/H2O (1 : 3) to afford the pure product 3a.
White powder (75%); mp 305 °C (decomp.). IR (KBr) cmꢂ1: 3429, 3056,
1733, 1710. MS m/z: 391 (Mꢃ, 100), 346 (42), 307 (100). 1H-NMR
(CDCl3): dH (ppm) 0.91 (6H, s, 2CH3), 0.99 (6H, s, 2CH3), 2.01 and 2.16
(4H, AB system, Jꢄ12.1 Hz, 2CH2), 2.55 (4H, m, 2CH2), 6.72—7.04 (4H,
m, H-Ar), 10.29 (1H, s, NH). 13C-NMR (CDCl3): dC (ppm) 26.9, 28.3, 32.0,
40.6, 45.6, 50.9, 108.9, 113.3, 121.2, 122.6, 128.2, 134.4, 144.1, 164.03,
178.9, 195.6. Anal. Calcd for C24H25NO4: C, 73.64; H, 6.44; N, 3.58%.
Found: C, 73.69; H, 6.38; N, 3.51%.
Chart 3. Synthesis of Spiro[acenaphthene-1,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-
trione
1,3ꢀ,3ꢀ,6ꢀ,6ꢀ-Pentamethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-3,9ꢀ-
xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3b, C25H27NO4) White powder
(67%); mp 306 °C (decomp.). IR (KBr) cmꢂ1: 3051, 1733, 1703, 1597. MS
1
m/z: 405 (Mꢃ, 100), 377 (40), 321 (380). H-NMR (CDCl3): dH (ppm) 1.02
(6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.09 and 2.22 (4H, AB system,
Jꢄ15.1 Hz, 2CH2), 2.44 and 2.56 (4H, AB system, Jꢄ15.6 Hz, 2CH2), 3.33,
(3H, s, CH3), 6.81—7.25 (4H, m, H-Ar). 13C-NMR (CDCl3): dC (ppm) 26.7,
27.1, 29.1, 31.9, 41.2, 45.3, 50.9, 107.6, 113.7, 121.8, 121.9, 128.5, 133.0,
145.2, 163.5, 177.6, 195.3. Anal. Calcd for C25H27NO4: C, 74.05; H, 6.71;
N, 3.45%. Found: C, 72.99; H, 6.66; N, 3.39%.
1-Ethyl-3ꢀ,3ꢀ,6ꢀ,6ꢀ-tetramethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-
3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3c, C26H29NO4) White powder
(63%); mp 201 °C (decomp.). IR (KBr) cmꢂ1: 3007, 1724, 1702, 1609. MS
1
m/z: 419 (Mꢃ, 100), 376 (37), 298 (30). H-NMR (CDCl3): dH 1.01 (6H, s,
2CH3), 1.10 (6H, s, 2CH3), 1.40 (3H, t, Jꢄ6.8 Hz, CH3), 2.08 and 2.23 (4H,
AB system, Jꢄ15.7 Hz, 2CH2), 2.43 and 2.57 (4H, AB system, Jꢄ15.6 Hz,
2CH2), 3.85 (2H, t, Jꢄ6.7 Hz, CH2), 6.84—7.20 (4H, m, H-Ar). 13C-NMR
(CDCl3): dC (ppm) 11.8, 27.0, 29.1, 31.9, 35.0, 41.2, 45.4, 50.9, 107.8,
113.6, 121.6, 122.2, 128.4, 133.2, 144.3, 163.5, 177.0, 195.3. Anal. Calcd
for C26H29NO4: C, 74.44; H, 6.97; N, 3.34%. Found: C, 74.38; H, 6.91; N,
Fig. 1. X-Ray Crystal Structure of 3b
tion of dimedone 1 to the isatins 2 to yield intermediate 4, 3.41%.
5-Bromo-3ꢀ,3ꢀ,6ꢀ,6ꢀ-tetramethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-
which reacted further with another molecule of dimedone 1
(molar ratio of dimedone to isatins is 2 : 1) and followed by
cyclization afforded the corresponding spiro[indoline-3,9ꢀ-
xanthene]triones 3 (Chart 2).
3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3d, C24H24BrNO4) White pow-
der (70%); mp 290 °C (decomp.). IR (KBr) cmꢂ1: 3342, 2957, 1736, 1669,
1616. MS m/z: 471 (Mꢃꢃ2, 100), 469 (Mꢃ, 100), 426 (26), 387 (79), 359
1
(27). H-NMR (CDCl3): dH (ppm) 1.05 (6H, s, 2CH3), 1.12 (6H, s, 2CH3),
2.15 and 2.26 (4H, AB system, Jꢄ15.3 Hz, 2CH2), 2.47 and 2.55 (4H, AB
system, Jꢄ15.5 Hz, 2CH2), 6.70 (1H, d, Jꢄ5.2 Hz, H-Ar), 6.95 (1H, s, H-
Ar), 7.25 (1H, d, Jꢄ5.4 Hz, H-Ar), 8.20 (1H, s, NH). 13C-NMR (CDCl3): dC
(ppm) 27.5, 28.7, 32.0, 41.2, 45.8, 50.9, 110.9, 113.2, 114.2, 125.4, 131.2,
135.6, 141.7, 163.9, 178.4, 195.6. Anal. Calcd for C24H24BrNO4: C, 61.28;
H, 5.14; N, 2.98%. Found: C, 61.33; H, 5.19; N, 2.90%.
5-Bromo-1,3ꢀ,3ꢀ,6ꢀ,6ꢀ-pentamethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indo-
line-3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3e, C25H26BrNO4) White
powder (68%); mp 310 °C (decomp.). IR (KBr) cmꢂ1: 3064, 2866, 1727,
1674, 1608. MS m/z: 485 (Mꢃꢃ2, 100), 483 (Mꢃ, 100), 401 (20), 315 (30).
1H-NMR (CDCl3): dH 1.03 (6H, s, 2CH3), 1.09 (6H, s, 2CH3), 2.15 (4H, m,
2CH2), 2.49 (4H, m, 2CH2), 3.28 (3H, s, CH3), 6.70—7.32 (3H, m, H-Ar).
Finally, to further explore the potential of this protocol for
spiro-heterocyclic synthesis, we investigated the reaction in-
volving acenaphthene 5 and obtained 3ꢀ,3ꢀ,6ꢀ,6ꢀ-tetramethyl-
3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydro-2H-spiro[acenaphthene-1,9ꢀ-xan-
thene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione 6 in a 61% yield (Chart 3).
Previously, related acid-catalyzed condensation reactions of
indan-1,3-dione with acenaphthene have been reported by
Gieta et al.23,24)
Compounds 3a—g and 6 are stable solids whose structures
were established by IR, 1H- and 13C-NMR spectroscopy,

1330
Vol. 56, No. 9
13C-NMR (CDCl3): dC 26.77, 27.5, 28.7, 32.0, 41.1, 45.3, 50.9, 109.0,
113.1, 114.2, 125.1, 131.3, 134.9, 144.5, 163.9, 177.1, 195.5. Anal. Calcd
for C25H26BrNO4: C, 61.99; H, 5.41; N, 2.89%. Found: C, 61.92; H, 5.35; N,
2.82%.
Bioorg. Med. Chem., 14, 2409—2417 (2006).
8) Khafagy M. M., El-Wahas A. H. F. A., Eid F. A., El-Agrody A. M.,
Farmaco, 57, 715—722 (2002).
9) Ma J., Hecht S. M., Chem. Commun., 2004, 1190—1191 (2004).
10) Kang T. H., Matsumoto K., Murakami Y., Takayama H., Kitajima M.,
Aimi N., Watanabe H., Eur. J. Pharmacol., 444, 39—45 (2002).
11) Hideu T., Jpn. Tokkyo Koho JP 56005480 (1981) [Chem. Abstr., 95,
80922b].
3ꢀ,3ꢀ,6ꢀ,6ꢀ-Tetramethyl-5-nitro-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-
3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3f, C24H24N2O6) Yellow powder
(78%); mp 278 °C (decomp.). IR (KBr) cmꢂ1: 3359, 2957, 1742, 1661. MS
1
m/z: 436 (Mꢃ, 39), 419 (100), 389 (34). H-NMR (CDCl3): dH 1.07 (6H, s,
12) Lamberk R. W., Martin J. A., Merrett J. H., Parkes K. E. B., Thomas
G. J., PCT Int. Appl. WO 9706178 (1997) [Chem. Abstr., 126,
P212377y].
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14) Sekercioglu O., Tulinli N., Akar A., J. Chem. Res. (S), 1995, 502—506
(1995).
15) Dabiri M., Delbari A. S., Bazgir A., Synlett, 2007, 821—823 (2007).
16) Dabiri M., Delbari A. S., Bazgir A., Heterocycles, 71, 543—548
(2007).
17) Dabiri M., Arvin-Nezhad H., Khavasi H. R., Bazgir A., Tetrahedron,
63, 1770—1774 (2007).
18) Dabiri M., Azimi S. C., Arvin-Nezhad H., Bazgir A., Heterocycles, 75,
87—93 (2008).
19) Dabiri M., Arvin-Nezhad H., Khavasi H. R., Bazgir A., J. Heterocycl.
Chem., 44, 1009—1011 (2007).
20) Sayyafi M., Seyyedhamzeh M., Khavasi H. R., Bazgir A., Tetrahedron,
64, 2375—2378 (2008).
21) Bazgir A., Seyyedhamzeh M., Yasaei Z., Mirzaei P., Tetrahedron Lett.,
48, 8790—8794 (2007).
2CH3), 1.14 (6H, s, 2CH3), 2.18 and 2.29 (4H, AB system, Jꢄ15.9 Hz,
2CH2), 2.54 and 2.60 (4H, AB system, Jꢄ16.6 Hz, 2CH2), 6.87 (1H, d,
Jꢄ7.7 Hz, H-Ar), 7.80 (1H, s, H-Ar), 8.11 (1H, d, Jꢄ7.1 Hz, H-Ar), 8.85
(1H, s, NH). 13C-NMR (CDCl3): dC 27.6, 28.5, 32.1, 41.2, 45.6, 50.8, 109.2,
112.8, 113.1, 125.9, 134.4, 142.9, 148.8, 164.6, 173.9, 195.6. Anal. Calcd
for C24H24N2O6: C, 66.04; H, 5.54; N, 6.42%. Found: C, 65.98; H, 5.59; N,
6.37%.
1-Benzyl-3ꢀ,3ꢀ,6ꢀ,6ꢀ-tetramethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydrospiro[indoline-
3,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (3g, C31H31NO4) White powder
(65%); mp 258 °C (decomp.). IR (KBr) cmꢂ1: 3064, 2955, 1714, 1673. MS
m/z: 481 (Mꢃ, 100), 453 (100), 436 (40), 390 (80), 91 (98). 1H-NMR
(CDCl3): dH 1.03 (6H, s, 2CH3), 1.13 (6H, s, 2CH3), 2.14 and 2.29 (4H, AB
system, Jꢄ15.8 Hz, 2CH2), 2.46 and 2.59 (4H, AB system, Jꢄ15.9 Hz,
2CH2), 5.07 (2H, br s, CH2), 6.54—7.67 (9H, m, H-Ar). 13C-NMR (CDCl3):
d
C 26.8, 27.0, 29.2, 32.0, 41.3, 45.3, 50.9, 107.5, 109.1, 113.5, 121.9, 125.2,
127.3, 128.4, 128.6, 128.8, 132.2, 133.1, 145.3, 163.5, 197.2. Anal. Calcd
for C31H31NO4: C, 77.31; H, 6.49; N, 2.91%. Found: C, 77.36; H, 6.42; N,
2.96%.
Due to very low solubility, 13C-NMR spectra of product 6 are not re-
ported.
22) Sheldon R. A., J. Mol. Catal. A, 107, 75—83 (1996).
23) Gieta L., Vanags G., Latvijas PSR Zinatnu Akad. Vestis, 1958, 127—
132 (1958) [Chem. Abstr., 53, 11371d (1959)].
3ꢀ,3ꢀ,6ꢀ,6ꢀ-Tetramethyl-3ꢀ,4ꢀ,6ꢀ,7ꢀ-tetrahydro-2H-spiro[acenaphthene-
1,9ꢀ-xanthene]-1ꢀ,2,8ꢀ(2ꢀH,5ꢀH)-trione (6, C28H26O4) White powder
(61%); mp 295 °C (decomp.). IR (KBr) cmꢂ1: 2962, 1730, 1669, 1610. MS
m/z: 426 (Mꢃ, 37), 342 (100), 258 (50). 1H-NMR (DMSO-d6): dH 1.01 (6H,
s, 2CH3), 1.09 (6H, s, 2CH3), 1.62 (4H, br s, 2CH2), 2.53 (4H, br s, 2CH2),
7.15—7.99 (6H, m, H-Ar). Anal. Calcd for C28H26O4: C, 78.85; H, 6.14%.
Found: C, 78.80; H, 6.10%.
24) Stankevich E. I., Vanags G., Latvijas PSR Zinatnu Akad. Vestis, Kim.
Ser., 1963, 475—478 (1963) [Chem. Abstr., 59, 123309g (1963)].
25) X-Ray data for 3b: (C25H27NO4), Mꢄ405.48 g/mol, triclinic system,
¯
space group P1, aꢄ11.1462 (12), bꢄ11.9893 (16), cꢄ16.1294 (19) Å,
aꢄ94.154 (10), bꢄ90.004 (9)°, gꢄ90.195 (10), Vꢄ2149.8 (4) Å3,
Zꢄ4, Dcꢄ1.253 g·cmꢂ3, m(MoKa)ꢄ0.084 mmꢂ1, crystal dimension
of 0.50ꢅ0.40ꢅ0.25 mm. The structure was solved by using SHELXS.
The structure refinement and data reduction was carried out with
SHELXL of the X-Step32 suite of programs.26) The non-hydrogen
atoms were refined anisotropically by full matrix least-squares on F2
values to final R1ꢄ0.0932, wR2ꢄ0.1526 and Sꢄ1.567 with 551 pa-
rameters using 10440 independent reflection (q rangeꢄ1.70—29.29°).
Hydrogen atoms were located from expected geometry and were not
refined. Crystallographic data for 3b have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data can be
obtained, free of charge, on application to The Director, CCDC
679233, Union Road, Cambridge CB2 1EZ, U.K. Fax: ꢃ44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
Acknowledgements We gratefully acknowledge financial support from
the Research Council of Shahid Beheshti University.
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