A one-pot, three-component synthesis of spiro[indoline-isoxazolo[40,30:5,6] pyrido [2,3-d]pyrimidine]triones in water

Article abstract of DOI:10.1016/j.tet.2012.07.073

A one-pot, three-component condensation reaction of an isatin, isoxazole, and barbituric acid in water to give spirooxindoles in high yields, at 70°C temperature, using a catalytic amount of p-toluene sulfonic acid, is described.

Full text of DOI:10.1016/j.tet.2012.07.073

Tetrahedron 68 (2012) 8472e8479
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A one-pot, three-component synthesis of spiro[indoline-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]triones in water
*
Abbas Rahmati , Zahra Khalesi
Department of Chemistry, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot, three-component condensation reaction of an isatin, isoxazole, and barbituric acid in water to
give spirooxindoles in high yields, at 70 ꢀC temperature, using a catalytic amount of p-toluene sulfonic
acid, is described.
Received 8 February 2012
Received in revised form 21 June 2012
Accepted 23 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 31 July 2012
Keywords:
Spirooxindole
Isatin
1,4-Dihydropyridines
1. Introduction
heterocyclic compounds, which have multi-ring structures similar
to spiro[oxindole-30:4-dihydropyridines] 1 and spiro[oxindole-30:4-
Multi-component reactions (MCRs) are chemical trans-
formations in which three or more different starting materials react
to give a final product in a one-pot procedure. Such reactions are
one of the best tools in modern organic synthesis because they can
generate a product with most of the atoms incorporating from the
starting materials (this is important from as atom economic
standpoint).1 Also these reactions have received considerable at-
tention in synthetic chemistry for the production of a broad spec-
trum of organic molecules. In addition, water has emerged as
a versatile solvent for organic reactions in the last two decades
since it is readily available, inexpensive, environmentally benign,
neutral, and a natural solvent.2 For these reasons, water has been
used for MCRs as well.3 MCRs in water are of outstanding value in
organic synthesis and green chemistry.4
Spirooxindoles have received more attention due to the wide
range of useful pharmacological properties and biological activities,
such as antimicrobial,5 antitumoral,6 antibiotic agents,7 inhibitors
of human NK-1 receptor,8 CRTH2 receptor antagonist,9 and in-
hibitors of microtubule assembly.10 Also, in a large number of bio-
active naturally occurring alkaloids, such as horsfiline,11
spirotryprostatin A and spirotryprostatin B,10b,12 pseudotaberso-
nine,13 coerulescine,14 chitosenine,15 and alstonisine16 a spiroox-
indole ring is the main core of the structure.
pyrans] 2 (Fig. 1). Two parts of (I) and (II) in Fig. 1 may be as sub-
stituents and/or homocyclic and heterocyclic rings. Although in var-
ious three and four component reactions for the synthesis of
spirooxindoles annulated with dihydropyrimidine-containing com-
pounds some aminoheterocycles, such as aminouracils,17 amino-
pyrazoles18 and aminobenzthiazoles19 inthe presence ofvariousCeH
acids have been devised, there are no reports on the preparation of
spirooxindoles from aminoisoxazole rings. Therefore, it is useful to
introduce a new procedure for the synthesis of derivatives of these
compounds incorporating both isoxazole and pyrimidinone rings.
In continuation of our interest in the development of new and
efficient multi-component reactions for the preparation of het-
erocyclic compounds;20 herein we wish to report synthesis of spiro
[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones 6 via
a one-pot three-component condensation reaction. The reaction
was performed using barbituric acid 3 and an isatin 4a with an
aminoisoxazole 5 in water in the presence of para-toluene sulfonic
acid (p-TsOH) as a catalyst at 70 ꢀC (Scheme 1).
R
R
HN
HN
O
O
ΙΙ
ΙΙ
Ι
Ι
During the last years, there has been considerable interest into the
synthesis of spirooxindoles annulated in the 3-position with fused-
N
O
1
2
* Corresponding author. E-mail address: a.rahmati@sci.ui.ac.ir (A. Rahmati).
Fig. 1. Various structures of spirooxindoles.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.073

A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
8473
R
HN
O
O
R1
NH2
O
O
R2
X
O
p-TsOH
N
+
+
N
O
N
N
O
R2
R2
N
N
water
O
N
N
H
70 °C
X
3
H
6
R2
5
4
Scheme 1. Synthesis of spiro[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones 6.
2. Results and discussion
Table 2
Effects of various catalysts in synthesis of spiro[indoline-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]triones in watera
To optimize the conditions for the synthesis of spiro[indoline-
isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones, the simple
isatin 4a, barbituric acid 3a, and aminoisoxazole 5 were selected as
model reactants. Initially, different solvents in the presence and
absence of p-TsOH were utilized for investigation of its catalytic
effect (Table 1). The reactions were also performed under solvent
free conditions (Table 1, entry 12). The results indicated that solvent
free condition resulted in lower yields than some solvents and
among the different solvents; water was found to be the best sol-
vent at 70 ꢀC temperature (Table 1). The presence of the catalyst for
this transformation was also found to give higher yield. In another
experiment we examined the effect of salting out on the reaction
yield using a NaCl saturated solution (entry 2, Table 1). As can be
seen, there is no difference between the yields of reaction for the
two conditions (water solvent and NaCl saturated solution).
Entry
Catalyst
Amount (%)
Temperature (ꢀC)
Yieldb (%)
1
2
3
4
5
ZrCl4
Zr(acac)2
ZrOCl2
Sulfuric acid 88%
p-TsOH
40 mol
40 mol
40 mol
40 mol
40 mol
20 mol
20 mol
20 mol
20 mol
20 mol
10 mol
5 mol
70
70
70
70
70
90
70
60
40
25
70
70
70
70
70
83
44
29
55
88
88
88
80
67
49
61
58
50
46
41
3 mol
1 mol
d
a
Isatin (1 mmol), barbituric acid (1 mmol), 5-amino-3-methyl isoxazole (1 mmol)
in solvent (5 mL), 24 h.
b
Isolated yield.
Table 1
One-pot synthesis of spiro[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]
trione at different solventsa
The reaction was then repeated at various temperatures in water.
The results showed that the best yields of reaction were obtained at
70 ꢀC.
Entry
Solvent
Yieldb (%)
Solvent/catalystc
Yieldb (%)
1
2
3
4
5
6
7
8
Water
41
42
16
24
12
11
35
0
0
16
0
0
18
0
Water
61
61
25
48
27
21
59
12
0
15
16
12
32
0
To explore the scope and limitations of this reaction, we extended
it to various substituted isatins with 5-amino-3-methyl isoxazoles in
the presence of barbituric acid derivatives (Scheme 2). As indicated
in Table 3, the structural effects of these two types of compounds
were investigated. The reaction was found to proceed with electron-
withdrawing and electron-donating substituted isatins. Some
moderate increases in reaction yields were observed by increasing
the electron-withdrawing effect of substituents on isatins, (Table 3,
entries 1e4 also 6, 7). When 5-methoxy isatin was used the reaction
proceeded, but, the purification of product was proved difficult and
indeed we were unable to purify the final product. As indicated in
Table 3, when 1-acyl isatin was utilized there was no evidence for the
presence of an acyl group in the product because of hydrolysis (en-
tries 7, 14). Similarly to isatins the reaction yield also depends with
structure of the barbituric acid derivative (entries 4e6), this effect
was more pronounced compared to substituted isatins. When
alkylated barbituric acid 3b and thiobarbituric acid 3d were used the
results indicated that yields of products were better than when
unsubstituted derivatives 3a and 3c were used. The yields with
barbituric acids were better than with thiobarbituric acids, among
isatins that were treated with thiobarbituric acid only the reaction of
nitroisatin 4g00 give any product. On the other hand, a different trend
was observed for aminoisoxazoles. The examined aminoisoxazoles
were shown in Scheme 2. The reaction didn’t proceed with amino-
isoxazoles 5b00 and 5c00. As seen in Table 1, the structural effect of
aminoisoxazoles was more influential than that of the isatin and
barbituric acid derivatives.
Water/NaCl
Acetonitrile
Ethyl acetate
Methanold
Ethanol
Water/NaCl
Acetonitrile
Ethyl acetate
Methanold
Ethanol
Dioxane
DMSO
Dioxane
DMSO
9
DMF
DMF
10
11
12
13
14
THFd
THFd
Chloroformd
Toluene
Chloroformd
Toluene
Solvent-free
d
Solvent-free
Choline chloride RTIL
a
Isatin (1 mmol), barbituric acid (1 mmol), 5-amino-3-methyl isoxazole (1 mmol)
in solvent (5 mL), 24 h, 70 ꢀC.
b
Isolated yield.
In the presence of p-TsOH catalyst (10 mol %).
Reflux condition.
c
d
It is noteworthy that in some of the above solvents, such as
chloroform and toluene due to the low solubility of barbituric acid
the reaction yield was low and at the end of the reaction this
compound was recovered along with the product.
At the next step, in order to determine the best catalyst,
a numbers of Lewis and Bronsted acids (40 mol %) screened. The
employed catalysts were listed in Table 2. The experiments showed
that the highest yields were obtained using p-TsOH as catalyst. The
optimum catalyst loading was next investigated by studying the
reaction with different amounts of p-TsOH at 70 ꢀC. The best results
were obtained in the presence of 20 mol % of p-TsOH at 70 ꢀC
temperature in water. Results show that by reducing the amount of
catalyst from 20 mol % yields were decreased, while increasing the
amount of p-TsOH did not have any effect on the yield of reaction.
Another interesting feature of this reaction was revealed when
5-amino-3-methyl isoxazole 5a00 (2 equiv) and 1,3-dimethyl bar-
bituric acid 3a (2 equiv) were simultaneously added to 1,10-(pro-
pane-1,3-diyl)bis-isatins 4k0 (Scheme 3). The reaction proceeded as

8474
A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
O
O
O
O
O
O
O
O
O
N
N
N
N
HN
NH
HN NH
Barbituricacids
derivatives
O
3b
S
3d
S
3c
O
3a
O
O
O
O
H3CO
Cl
O
Br
O
O
O
O
O
N
N
N
H
N
N
H
H
H
H
/
/
4c
/
/
4d
/
4a
4b
4e
O
O
O
O
O
I
O2N
O
O
O
O
O
N
N
N
N
Isatins
N
H
H
H
O
/
/
/
4f
4h
4g
/
/
4j
4i
O
O
Br
O
N
O
N
N
N
N
O
O
O
N
O
O
O
O
O
O
O
Br
/
/
4l
N
O
4k
O
/
4m
NH2
O
O
Isoxazoles
H2N
O
H2N
N
N
5b//
N
5c//
5a//
Scheme 2. Various compounds of three groups applied in synthesis of products 6.
a pseudo five-component reaction and resulted in good yields of
1,10-(propane-1,3-diyl)spiro[indoline-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]triones. IR, 1H NMR, and 13C NMR spectroscopic
data showed that the product 7 is formed. There are two stereo-
genic centers in the bis-spiro products, therefore it is expected that
two pairs of diastereomers would be observed, but the results only
showed meso products. Because the second stereogenic center was
formed after the generation of the first stereogenic center, the
chirality of this center therefore depends on the first stereocenter.
In the first step the racemic mixture of the compounds containing
the first stereocenter was obtained, which in turn induced the
configuration of the second stereocenter in the course of the re-
action. This reaction was performed with both of 1,10-(propane-1,3-
diyl)bis-isatins 4k0 and 4l0. The product obtained from 4k0 was
identified spectroscopically, while the low solubility of product
achieved from isatin 4l0 was imposed limitation on spectroscopic
characterization. Tris-isatin 4m0 has also been used instead of bis-
isatins in a pseudo seven-component reaction (Scheme 4) and
the results showed that the reaction was carried out similarly to 1-
acyl isatin in Table 1 (entries 7, 14).
Table 3
Synthesized spiro[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones 6 in
optimized conditiona
Entry
Barbituric acid
Isatin
Product
Yieldb (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3c
3d
4a0
4b0
4d0
4e0
4g0
4h0
4i0
6{aa0a00}
6{ab0a00}
6{ad0a00}
6{ae0a00}
6{ag0a00}
6{ah0a00}
6{ai0a00}
6{aa0a00}
6{ba0a00}
6{bb0a00}
6{bd0a00}
6{be0a00}
6{bf0a00}
6{bg0a00}
6{ba0a00}
6{cg0a00}
6{dd0a00}
88
72
63
66
59
56
57
68
71
73
51
54
58
47
57
73
60
4j0
9
4a0
4b0
4d0
4e0
4f0
10
11
12
13
14
15
16
17
4g0
4j0
4g0
4d0
There is no established mechanism for the formation of spiro
[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones;
a reasonable possibility is shown for spiro[indoline-isoxazolo
[40,30:5,6]pyrido[2,3-d]pyrimidine]triones 6{aa0a00} in Scheme 5.
a
Isatin (1 mmol), barbituric acid (1 mmol), 5-amino-3-methyl isoxazole 5a00
(1 mmol) in solvent (5 mL), 24 h.
b
Isolated yield.

A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
8475
H
N
O
N
O
N
N
O
O
NH2
O
2
O
O
p-TsOH
N
N
N
O
+
2
+
N
N
O
N
O
water
70 °C
O
O
5a//
/
3b
4k
N
O
O
N
N
O
O
N
N
H
7⎨b
k
/a//
⎬
Scheme 3. Pseudo five-component synthesis of 1,10-(propane-1,3-diyl)spiro[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones 7.
O
HN
O
OH
HO
O
O
O
N
O
NH2
O
3
O
p-TsOH
O
+
OH
O
N
+
3
+
N
N
N
O
N
N
water
70 °C
O
O
O
O
O
O
N
N
H
O
5a//
N
O
O
3b
/
4m
6{aa'a''}
8
Scheme 4. Pseudo seven-component reaction.
H
HO
N
O
HO
NH
1a'
O
NH
O
O
H-transfer
O
O
O
NH
N
O
O
N
H
H
4a
9
H
N
O H2N
NH
HN
O
O
NH
O
O
N
O
NH
NH
p-TsOH
O
NH2
OH
O
O
O
N
-H2O
O
N
H
O
N
H
O
N
H
11
12
10
O
O
HN
NH
HN
NH
H-transfer
O
HO
O
NH2
O
NH
Tautomerization
O
O
N
O
N
O
N
H
O
N
H
13
14
HN
NH
NH
O
O
N
O
N
H
6{aa'a''}
Scheme 5. Mechanism of reaction.

8476
A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
The reaction presumably proceeds via knoevenagel condensa-
tion between isatin 4a0 and the barbituric acid 3a to give
37.2, 112.8, 114.8, 119.4, 126.5, 139.6, 149.3, 157.9, 182.0 ppm; Anal.
Found: C, 46.59; H, 2.45; N, 5.62. C19H12Br2N2O4 requires C,
46.37; H, 2.46; N, 5.69%.
a,b-
unsaturated compound 11. Then, compound 11 is converted into
intermediate 13 through a Michael addition of 5-aminoisoxazole
5a00. Finally product 6 was obtained by intramolecular cycliza-
tion of compound 14 (Scheme 5).
4.3. Procedure for the synthesis of 1,3,5-tris(2,3-dioxoindoline-
1-carbonyl)benzene 4m0
The structure of all products 4(k0em0), 6 and 7 was deduced
from their IR, 1H NMR, 13C NMR spectroscopic data and elemental
analysis.
A mixture of isatin 1a (882 mg, 6 mmol) and DBU (0.900 mL,
6 mmol) were stirred in DMSO (2 mL) at room temperature for 2 h.
Then benzene-1,3,5-tricarbonyl trichloride (527 mg, 2 mmol) was
added to this mixture and stirred for 5 h. Then 25 mL of dichloro-
methane or ether was added. The participate was filtered and after
drying, it was washed immediately by water and then with meth-
anol (six times, every time with 5 mL) to give the pure product
(383 mg, yield 32%) as an orange powder, mp 221 ꢀC (dec); Rf (25%
MeOH/EtOAc) 0.33; nmax (KBr) 1732, 1710, 1624, 1451, 1212,
3. Conclusion
In conclusion, a novel, green, and efficient three-component
condensation reaction of some typical isatins, 5-amino-3-methyl
isoxazole, and barbituric derivatives was developed for the syn-
thesis of spiro[indoline-isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimi-
dine]triones. The simple one-pot nature of the reaction makes it an
interesting alternative to other multi-step approaches. Also mod-
erate to good yields of products are the advantages of this method.
The reactions are carried out in water, which is a considerably safe,
non-toxic, environmentally friendly, and inexpensive solvent. In
addition, the existences of four different importance heterocycles,
such as oxindole, pyrimidinone, dihydropyridine, and isoxazole
rings in a one molecule is fantastic because each of this rings could
have a wide range of useful biological and pharmacological
activities.
730 cmꢁ1
; dH (400 MHz, DMSO-d6) 6.92e8.78 (12H, m, 12CH) ppm;
dC (100 MHz, DMSO-d6) 122.74, 123.15, 131.24, 132.58, 133.19,
133.97, 138.79, 157.06, 159.32, 166.84, 179.13 ppm; Anal. Found: C,
66.71; H, 3.00; N, 6.94. C35H15N3O9 requires C, 66.34; H, 2.53; N,
7.03%.
4.4. General procedure for the synthesis of spiro[indoline-
isoxazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]triones (6)
A solution of isatin (1 mmol), barbituric acid (1 mmol), 3-amino-
5-methyl isoxazole (1 mmol), and p-TsOH (0.2 mmol) in water
(10 mL) was stirred for 24 h at 70 ꢀC in oil bath. After completion of
the reaction, which was followed by TLC (n-hexane/EtOAc), the
warm reaction mixture was filtered. The residue was washed with
water and then recrystallized from ethanol to give the pure
product.
4. Experimental
4.1. General procedure
All chemicals except 4k0, 4l0 and 4m0 were purchased from Acros
and/or Alfa-Aesar companies and used without any further purifi-
cation. Melting points were determined on an Electrothermal 9100
apparatus. IR spectra were recorded on a FT Infrared Spectroscope
instrument JASCO, FT/IR-6300 model as KBr discs. The 1H NMR and
13C NMR, spectra were recorded on a Bruker-AVANCE 400 MHz
(tope spine) NMR instrument using DMSO-d6 as solvent. Elemental
analyses were performed using a Heraeus CHNS Rapid analyzer.
4.4.1. 30-Methyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido[2,3-d]
pyrimidine]-2,50,70(1H,60H,80H,90H)-trione (6{aa0a00}). White pow-
der (296 mg, 88%), mp 280 ꢀC (dec); Rf (20% n-hexane/EtOAc) 0.32;
nmax (KBr) 3311, 2932, 2822, 1757, 1735, 1682, 1641, 1546, 1524,
1473, 1446, 743 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.51 (3H, s, CH3),
6.82 (1H, d, J 7.6 Hz, CHarom), 6.88 (1H, dd, J 7.2, 6.4 Hz, CHarom),
6.96 (1H, d, J 6.4 Hz, CHarom), 7.16 (1H, dd, J 7.6, 7.2 Hz, CHarom),
10.54 (1H, s, NH), 10.85 (1H, s, NH), 11.07 (1H, s, NH) ppm; dC
(100 MHz, DMSO-d6) 9.3, 47.8, 88.2, 93.6, 109.5, 122.4, 124.1, 128.7,
135.3, 142.1, 146.8, 150.5, 157.5, 160.2, 162.4, 178.7 ppm; Anal.
Found: C, 56.87; H, 3.30; N, 20.70. C16H11N5O4 requires C, 56.98; H,
3.29; N, 20.76%.
4.2. Procedure for the synthesis of 1,10-(propane-1,3-diyl)bis-
isatins 4k0 and 4l0
A solution of isatin 4a0 or 5-bromoisatin 4e0 (4 mmol) and K2CO3
(552 mg, 4 mmol) in DMSO (4 mL) was stirred at room temperature.
After 2 h, 1,3-dibromopropane (402 mg, 2 mmol) was added, and
the mixture was stirred for 24 h at room temperature. After com-
pletion of the reaction, the precipitate was filtrated and washed
with methanol (three times, every time with 5 mL) to give the pure
product.
HN
O
O
H3C
NH
N
4.2.1. 1,10-(Propane-1,3-diyl)bis-isatins 4k0. Orange powder (414 mg,
62%), mp 328e329 ꢀC; Rf (50% EtOAc/n-hexane) 0.26; nmax (KBr)
O
N
H
N
H
O
3033, 2924, 1740, 1609, 1470, 1357 cmꢁ1
; dH (400 MHz, DMSO-d6)
6{aa'a''}
1.96e1.99 (2H, m, CH2), 3.78 (4H, t, J 6.8 Hz, 2CH2), 7.11 (2H, dd, J 7.6,
7.2 Hz, CHarom), 7.22 (2H, d, J 7.6 Hz, 2CHarom), 7.53 (2H, d, J 7.2 Hz,
CHarom), 7.62 (2H, dd, J 7.6, 7.6 Hz, 2CHarom) ppm; dC (100 MHz,
DMSO-d6) 24.6, 37.4, 110.6, 117.6, 123.1, 124.4, 138.0, 150.4, 158.2,
183.3 ppm; Anal. Calcd for C19H14N2O4: C, 68.26; H, 4.22; N, 8.38.
Found: C, 68.45; H, 4.25; N, 8.42%.
4.4.2. 5,30-Dimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]-2,50,70(1H,60H,80H,90H)-trione (6{ab0a00}). White
powder (253 mg, 72%), mp 280 ꢀC (dec); Rf (20% n-hexane/EtOAc)
0.29; nmax (KBr) 3650, 3489, 3390, 3330, 3267, 2921, 1721, 1681,
4.2.2. 1,10-(Propane-1,3-diyl)bis-isatins
(559 mg, 57%), mp 245e246 ꢀC; Rf (50% MeOH/EtOAc) 0.15; nmax
(KBr) 3086, 2949, 1744, 1605, 1469, 1440 cmꢁ1
dH (400 MHz,
4l0. Orange
powder
1661, 1624, 1547, 1526, 1492, 1450 cmꢁ1
; dH (400 MHz, DMSO-d6)
1.53 (3H, s, CH3), 2.16 (3H, s, CH3), 6.71e6.95 (3H, m, CHarom), 10.43
(1H, s, NH), 10.84 (2H, s, 2NH), 11.07 (1H, s, NH) ppm; dC (100 MHz,
DMSO-d6) 9.3, 21.0, 47.9, 88.3, 93.8, 109.2, 124.7, 128.9, 131.3, 135.4,
139.6, 146.7, 150.5, 157.6, 160.2, 162.4, 178.6 ppm; Anal. Found: C,
;
DMSO-d6) 2.00e2.15 (2H, m, CH2), 3.80 (4H, t, J 6.8 Hz, 2CH2),
7.20e7.78 (6H, m, 6CHarom) ppm; dC (100 MHz, DMSO-d6) 24.4,

A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
8477
58.29; H, 3.79; N, 19.80. C17H13N5O4 requires C, 58.12; H, 3.73; N,
19.93%.
157.3, 160.7, 162.6, 179.3 ppm; Anal. Found: C, 49.99; H, 2.60; N,
22.08. C16H10N6O6 requires C, 50.27; H, 2.64; N, 21.98%.
HN
HN
CH3
NO2
O
O
O
O
H3C
H3C
NH
NH
N
N
O
O
N
H
N
H
O
N
H
N
H
O
6{ab'a''}
6{ag'a''}
4.4.6. 30,5,7-Trimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]-2,50,70(1H,60H,80H,90H)-trione (6{ah0a00}). White
powder (204 mg, 56%), mp 304 ꢀC (dec); Rf (20% n-hexane/EtOAc)
4.4.3. 50-Chloro-3-methyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyr-
ido[2,3-d]pyrimidine]-2,50,70(1H,60H,80H,90H)-trione
(6
{ad0a00}). White powder (245 mg, 63%), mp 273e275 ꢀC; Rf (20% n-
hexane/EtOAc) 0.39; nmax (KBr) 3591, 3521, 3396, 3167, 3036, 2964,
0.44; nmax (KBr) 3211, 2818, 1730, 1683, 1634, 1527, 1489, 1451 cmꢁ1
;
2826, 1721, 1703, 1680, 1641, 1542, 1477, 1449, 1420, 1108 cmꢁ1
; dH
dH (400 MHz, DMSO-d6) 1.53 (3H, s, CH3), 2.14 (3H, s, CH3), 2.20 (3H,
s, CH3), 6.60 (1H, s, CHarom), 6.79 (1H, s, CHarom), 10.46 (1H, s, NH),
10.81 (1H, s, NH),11.25 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 8.7,
16.2, 20.4, 47.6, 87.8, 93.4, 117.8, 121.5, 129.9, 130.6, 134.7, 137.7,
146.3, 150.1, 157.1, 159.7, 161.8, 178.6 ppm; Anal. Found: C, 59.31; H,
4.20; N, 19.03. C18H15N5O4 requires C, 59.18; H, 4.14; N, 19.17%.
(300 MHz, DMSO-d6) 1.56 (3H, s, CH3), 6.84 (1H, d, J 8.1 Hz, CHarom),
7.13 (1H, d, J 1.9 Hz, CHarom), 7.21 (1H, dd, J 8.1, 1.9 Hz, CHarom), 10.68
(1H, s, NH), 10.89 (1H, s, NH), 11.04 (1H, s, NH) ppm; dC (75 MHz,
DMSO-d6) 9.3, 48.1, 87.7, 93.0, 110.9, 124.4, 126.4, 128.6, 137.2, 141.0,
147.0, 150.5, 157.4, 160.4, 162.4, 178.5 ppm; Anal. Found: C, 51.44; H,
2.78; N, 19.01. C16H10ClN5O4 requires C, 51.70; H, 2.71; N, 18.84%.
H3C
HN
Cl
HN
CH3
O
O
O
O
H3C
H3C
NH
NH
N
N
O
O
N
H
N
H
O
N
H
N
H
O
6{ad'a''}
6{ah'a''}
4.4.7. 1,30-Dimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido[2,3-
d]pyrimidine]-2,50,70(60H,80H,90H)-trione (6{ai0a00}). White powder
(200 mg, 57%), mp 280 ꢀC (dec); Rf (20% n-hexane/EtOAc) 0.36; nmax
(KBr) 3527, 3421, 3275, 2964, 1718, 1684, 1648, 1612, 1542,
4.4.4. 5-Bromo-30-methyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyr-
ido[2,3-d]pyrimidine]-2,50,70(1H,60H,80H,90H)-trione (6{ae0a00}). Gray
powder (274 mg, 66%), mp 300 ꢀC (dec); Rf (20% n-hexane/EtOAc)
0.24; nmax (KBr) 3452, 3528, 3154, 3036, 1707, 16.83, 1651, 1613,
1457 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.43 (3H, s, CH3), 3.19 (3H, s,
1554, 1528 cmꢁ1
;
dH (400 MHz, DMSO-d6) 1.56 (3H, s, CH3), 6.80
(1H, s, CHarom), 7.24e7.34 (2H, m, 2CHarom), 10.69 (1H, s, NH), 10.98
(1H, s, NH), 11.08 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) : 8.8,
NCH3), 6.98 (1H, dt, J 7.4, 1.0 Hz, CHarom), 7.03 (2H, d, J 7.4 Hz,
2CHarom(overlap)), 7.28 (1H, dt, J 7.4, 1.0 Hz, CHarom), 10.86 (1H, s,
NH), 11.08 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 8.7, 26.2, 46.9,
87.5, 92.9, 107.9, 122.6, 123.3, 128.4, 133.9, 143.1, 146.3, 145.0, 157.0,
159.8, 161.8, 176.6 ppm; Anal. Found: C, 58.31; H, 3.67; N, 20.01.
C17H13N5O4 requires C, 58.12; H, 3.73; N, 19.93.
d
48.1, 87.2, 92.5, 110.9, 113.6, 126.6, 130.9, 137.1, 141.0, 146.5, 149.9,
156.9, 159.9, 161.9, 177.8 ppm; Anal. Found: C, 46.29; H, 2.37; N,
16.76. C16H10BrN5O4 requires C, 46.17; H, 2.42; N, 16.83%.
HN
Br
H3C
N
O
O
H3C
O
O
H3C
NH
N
NH
O
N
H
N
H
O
N
O
N
H
N
H
O
6{ae'a''}
6{ai'a''}
4.4.5. 30-Methyl-5-nitro-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]-2,50,70(1H,60H,80H,90H)-trione
(6{ag0a00}). White
4.4.8. 3,60,80-Trimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido
[2,3-d]pyrimidine]-2,50,70(1H,90H)-trione (6{ba0a00}). White crystal
(259 mg, 71%), mp 264e266 ꢀC; Rf (25% n-hexane/EtOAc) 0.39; nmax
(KBr) 3288, 3065, 2955, 2880, 2818, 1721, 1701, 1680, 1627, 1529,
powder (225 mg, 59%), mp 170 ꢀC (dec); Rf (20% n-hexane/EtOAc)
0.20; nmax (KBr) 3205, 3028, 2934, 1733,1705, 1683, 1655,1624,1538,
1480, 1446, 1392, 1338 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.56 (3H, s,
CH3), 7.05 (1H, d, J 8.4 Hz, CHarom), 7.94 (1H, br s, NH), 7.97 (1H, d, J
1.8 Hz, CHarom), 8.16 (1H, dd, J 8.4, 1.8 Hz, CHarom), 10.92 (1H, s, NH),
11.18 (1H, s, NH), 11.28 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 9.4,
48.0, 87.4, 92.4, 109.7, 120.1, 126.8, 136.1, 143.1, 147.3, 148.6, 150.5,
1473, 1447 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.56 (3H, s, CH3), 3.02
(3H, s, NCH3), 3.48 (3H, s, NCH3), 6.85e7.15 (4H, m, CHarom), 10.54
(1H, s, NH), 11.30 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 9.3, 28.0,
31.2, 48.7, 88.6, 93.7, 109.5, 122.4, 124.1, 128.6, 135.5, 142.1, 146.9,

8478
A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
150.7, 157.5, 160.4, 160.4, 178.8 ppm; Anal. Found: C, 59.25; H, 4.19;
N, 19.05. C18H15N5O4 requires C, 59.18; H, 4.14; N, 19.17.
CH3), 3.03 (3H, s, NCH3), 3.47 (3H, s, NCH3), 6.03 (1H, s, CHarom), 7.23
(1H, s, CHarom), 7.34 (1H, s, CHarom), 10.69 (1H, s, NH), 11.37 (1H, s,
NH) ppm; dC (100 MHz, DMSO-d6) 9.4, 28.1, 31.2, 48.1, 88.1, 93.2,
111.4, 114.0, 127.1, 131.4, 137.8, 141.4, 147.1, 150.7, 157.3, 160.4, 160.6,
178.4 ppm; Anal. Found: C, 49.00; H, 3.22; N, 15.69. C18H14BrN5O4
requires C, 48.67; H, 3.18; N, 15.76.
HN
O
O
N
H3C
CH3
O
N
HN
Br
N
O
N
H
O
O
H3C
CH3
CH3
O
N
N
6{ba'a''}
O
N
H
N
CH3
4.4.9. 5,30,60,80-Trimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyr-
ido[2,3-d]pyrimidine]-2,50,70(1H,90H)-trion (6{bb0a00}). Gray crystal
(277 mg, 73%), mp 265e269 ꢀC; Rf (25% n-hexane/EtOAc) 0.44; nmax
(KBr) 3506, 3227, 3187, 2973, 1714, 1676, 1630, 1519, 1494,
6{be'a''}
1451 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.57 (3H, s, CH3), 2.16 (3H, s,
4.4.12. 5-Iodo-30,60,80-trimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]
pyrido[2,3-d]pyrimidine]-2,50,70(1H,90H)-trione (6{bf0a00}). White
crystal (285 mg, 58%), mp 276e281 ꢀC; Rf (25% n-hexane/EtOAc) 0.34;
nmax (KBr) 3418, 3215, 2923, 1718, 1681, 1617, 1531, 1469, 1420 cmꢁ1
dH (400 MHz, DMSO-d6) 1.60 (3H, s, CH3), 3.03 (3H, s, NCH3), 3.34 (3H,
s, NCH3), 6.69 (1H, d, J 8.0 Hz, CHarom), 7.34 (1H, s, CHarom), 7.50 (1H, d,
J 8.0 Hz, CHarom), 10.67 (1H, s, NH), 11.36 (1H, s, NH) ppm; dC
(100 MHz, DMSO-d6) 9.4, 28.1, 31.2, 48.7, 85.2, 88.1, 93.2, 112.0, 132.5,
137.3, 138.1, 141.9, 147.1, 150.7, 157.3, 160.4, 160.6, 178.2 ppm; Anal.
Found: C, 44.22; H, 2.89; N, 14.37. C18H14IN5O4 requires C, 44.01; H,
2.87; N, 14.26.
CH3), 3.03 (3H, s, NCH3), 3.48 (3H, s, NCH3), 6.73 (1H, d, J 7.6 Hz,
CHarom), 6.81 (1H, s, CHarom), 7.48 (1H, d, J 7.6 Hz, CHarom), 10.44 (1H,
s, NH),11.30 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 8.8, 20.6, 27.5,
30.7, 48.2, 88.1, 93.4, 108.7, 124.2, 125.4, 130.7, 135.2, 139.1, 146.4,
150.3, 157.0, 159.8, 160.0, 178.2 ppm. Anal. Found: C, 60.27; H, 4.47;
N, 18.54. C19H17N5O4 requires C, 60.15; H, 4.52; N, 18.46.
;
HN
CH3
O
O
N
H3C
CH3
O
N
N
O
N
H
HN
I
CH3
O
O
N
H3C
CH3
O
6{bb'a''}
N
N
O
N
H
4.4.10. 5-Chloro-30,60,80-trimethyl-spiro[indoline-3,40-isoxazolo
CH3
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(1H,90H)-trione
(6
{bd0a00}). Cream powder (184 mg, 51%), mp 280e284 ꢀC; Rf (25% n-
hexane/EtOAc) 0.31; nmax (KBr) 3583, 3220, 2871, 2809, 1718, 1676,
6{bf'a''}
1622, 1533, 1476, 1448 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.60 (3H, s,
CH3), 3.03 (3H, s, NCH3), 3.47 (3H, s, NCH3), 6.84 (1H, d, J 8.0 Hz,
CHarom), 7.12 (1H, s, CHarom), 7.21 (1H, d, J 8.0 Hz, CHarom), 10.68 (1H,
s, NH), 11.35 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 9.4, 28.1, 31.2,
49.0, 88.1, 93.5, 110.9, 124.4, 126.3, 128.6, 137.5, 141.0, 147.1, 150.7,
157.3, 160.5, 160.6, 178.5 ppm; Anal. Found: C, 53.89; H, 3.61; N,
17.62. C18H14ClN5O4 requires C, 54.08; H, 3.53; N, 17.52.
4.4.13. 5-Nitro-30,60,80-trimethyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]
pyrido[2,3-d]pyrimidine]-2,50,70(1H,90H)-trione (6{bg0a00}). Yellow
crystal (193 mg, 47%), mp 281e285 ꢀC; Rf (25% n-hexane/EtOAc) 0.27;
nmax (KBr) 3433, 3285, 3104, 1726, 1684, 1639, 1539, 1518, 1339 cmꢁ1
dH (400 MHz, DMSO-d6) 1.61 (3H, s, CH3), 3.02 (3H, s, NCH3), 3.49 (3H,
s, NCH3), 7.06 (1H, d, J 8.6 Hz, 1CHarom), 7.98 (1H, br d, J 2.0 Hz,
CHarom), 8.16 (1H, dd, J 8.6, 2.0 Hz, CHarom), 11.29 (1H, s, NH) ppm; dC
(100 MHz, DMSO-d6) 9.4, 28.1, 31.2, 48.8, 87.7, 92.5,109.7,125.9,126.2,
128.7, 136.3, 143.1, 147.4, 150.7, 157.2, 160.6, 160.9, 179.3 ppm; Anal.
Found: C, 52.52; H, 3.35; N, 20.26. C18H14N6O6 requires C, 52.69; H,
3.44; N, 20.48.
;
HN
Cl
O
O
H3C
CH3
O
N
N
O
N
H
N
CH3
HN
NO2
O
O
N
H3C
6{bd'a''}
CH3
O
N
N
4.4.11. 5-Bromo-30,60,80-trimethyl-spiro[indoline-3,40-isoxazolo
O
N
H
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(1H,90H)-trione
(6{be-
CH3
0a00}). White crystal (240 mg, 54%), mp 272e277 ꢀC; Rf (25% n-
hexane/EtOAc) 0.31; nmax (KBr) 3586, 3217, 3141, 2938, 2811, 1718,
6{bg'a''}
1680, 1620, 1532, 1472 cmꢁ1
; dH (400 MHz, DMSO-d6) 1.61 (3H, s,

A. Rahmati, Z. Khalesi / Tetrahedron 68 (2012) 8472e8479
8479
4.4.14. 30-Methyl-70-thiohydroxy-spiro[indoline-3,40-isoxazolo
J 7.2 Hz, 2CHarom), 7.08 (2H, d, J 7.2 Hz, 2CHarom), 7.22e7.29 (4H, m,
4CHarom), 11.40 (2H, br s, 2NH) ppm; dC (100 MHz, DMSO-d6) 8.9,
27.6, 30.7, 38.0, 47.9, 56.0, 87.9, 93.0, 108.1, 122.5, 123.6, 128.3, 134.3,
142.4, 146.6, 150.2, 156.9, 160.0, 160.2, 176.7 ppm; Anal. Found: C,
60.51; H, 4.52; N, 18.04. C39H34N10O8 requires C, 60.77; H, 4.45; N,
18.17.
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50(1H,60H,90H)-dione
(6
{cg0a00}). Cream powder (290 mg, 73%), mp 278 ꢀC (dec); Rf (33% n-
hexane/EtOAc) 0.44; nmax (KBr) 3534, 3184, 3064, 2966, 2889, 1710,
1686, 1648, 1620, 1569, 1521, 1479, 1451, 1337 cmꢁ1
; dH (400 MHz,
DMSO-d6) 1.57 (3H, s, CH3), 3.15 (1H, s, SH), 7.06 (1H, d, J 8.2 Hz,
CHarom), 8.08 (1H, s, CHarom), 8.18 (1H, d, J 8.2 Hz, CHarom), 11.33 (1H,
s, NH),12.36 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 9.4, 47.9, 91.7,
92.4, 109.8, 120.5, 126.4, 135.5, 143.2, 146.7, 148.6, 157.4, 160.0, 160.2,
174.7, 178.8 ppm; Anal. Found: C, 48.03; H, 3.00; N, 21.27; S, 8.11.
C16H10N6O5S requires C, 48.24; H, 2.53; N, 21.10; S, 8.05.
N
H3C
O
N
O
CH3
O
N
CH3
O
O
HN
N
N
NH
H3C
N
O
N
CH3
HN
O
NO2
O
H3C
N
O
O
N
H3C
7{bk'a''}
NH
SH
N
O
N
H
Acknowledgements
6{cg'a''}
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan. Also the authors would like to
express sincere thanks to Dr. Fariborz Momenbeik for his careful
editing of the manuscript.
4.4.15. 5-Chloro-60,80-diethyl-30-methyl-70-thiooxo-spiro[indoline-
3,40-isoxazolo[40,30:5,6]pyrido [2,3-d]pyrimidine]-2,50(1H,90H)-dione
(6{dd0a00}). White crystal (266 mg, 60%), mp 265e267 ꢀC; Rf (33% n-
hexane/EtOAc) 0.58; nmax (KBr) 3416, 3180, 3075, 2928, 2882, 1712,
References and notes
1684, 1637, 1596, 1526, 1469, 1165, 1126 cmꢁ1
; dH (400 MHz, DMSO-
1. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005.
d6) 1.05 (3H, t, J 6.8 Hz, CH3), 1.33 (3H, t, J 6.8 Hz, CH3), 1.59 (3H, s,
CH3), 4.21 (2H, q, J 6.8 Hz, CH3), 4.31 (2H, q, J 6.8 Hz, CH3), 6.87 (1H,
d, J 8.2 Hz, CHarom), 7.13 (1H, s, CHarom), 7.22 (1H, d, J 8.2 Hz, CHarom),
10.68 (1H, s, NH) ppm; dC (100 MHz, DMSO-d6) 8.9, 11.4, 12.2, 20.7,
42.7, 45.3, 87.3, 93.4, 110.4, 124.0, 125.4, 125.9, 128.1, 137.8, 140.4,
145.3, 156.5, 157.7, 173.4, 175.0 ppm; Anal. Found: C, 54.28; H, 3.99;
N, 15.61; S, 7.20. C20H18ClN5O3S requires C, 54.11; H, 4.09; N, 15.78;
S, 7.22.
2. (a) Organic Reactions in Aqueous Media; Li, C. J., Chan, T. H., Eds.; Wiley: New
York, NY, 1997; (b) Grieco, P. A. Organic Synthesis in Water; Blackie Academic
and Professional: 1998; (c) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109,
725e748; (d) Pirrung, M. C.; Sarma, K. D. J. Am. Chem. Soc. 2004, 126, 444e445.
3. Kandhasamy, K.; Gnanasambandam, V. Curr. Org. Chem. 2009, 13, 1820e1841.
4. Andrade, C. K. Z.; Alves, L. M. Curr. Org. Chem. 2005, 9, 195e218.
5. (a) Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12,
273e324; (b) Abdel-Rahman, A. H.; Keshk, E. M.; Hanna, M. A.; El-Bady, S. M.
Bioorg. Med. Chem. 2004, 12, 2483e2488.
6. Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892e898.
7. Okita, T.; Isobe, M. Tetrahedron 1994, 50, 11143e11152.
8. Rosenmond, P.; Hosseini-Merescht, M.; Bub, C. Liebigs Ann. Chem. 1994, 2,
151e158.
HN
Cl
O
O
N
H3C
9. Crosignani, S.; Page, P.; Missotten, M.; Colovray, V.; Cleva, C.; Arrighi, J. F.;
Atherall, J.; Macritchie, J.; Martin, T.; Humbert, Y.; Gaudet, M.; Pupowicz, D.;
Maio, M.; Pittet, P. A.; Golzio, L.; Giachetti, C.; Rocha, C.; Bernardinelli, G.; Fil-
inchuk, Y.; Scheer, A.; Schwarz, M. K.; Chollet, A. J. Med. Chem. 2008, 51,
2227e2243.
10. (a) Usui, T.; Kondoh, M.; Cui, C.-B.; Mayumi, T.; Osada, H. Biochem. J. 1998, 333,
543e548; (b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832e835.
11. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Horsfiline, B. B. J. Org. Chem.
1991, 56, 6523e6527.
N
N
O
N
H
S
6{dd'a''}
12. Edmonson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc.
1999, 121, 2147e2155.
13. Carroll, W. A.; Grieco, P. A. J. Am. Chem. Soc. 1993, 115, 1164e1165.
14. (a) Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Vit, I.;
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4.5. General procedure for the synthesis of 1,3-bis(3,60,80-tri-
methyl-spiro[indoline-3,40-isoxazolo[40,30:5,6]pyrido[2,3-d]
pyrimidine]-2,50,70(90H)-trione) propanes (7{bk0a00})
A solution of isatin 4k0 (1 mmol), barbituric acid (2 mmol), 3-
amino-5-methyl isoxazole (2 mmol), and p-TsOH (0.2 mmol) in
water (10 mL) was stirred for 24 h at 70 ꢀC in oil bath. After com-
pletion of the reaction, which was followed by TLC (25% MeOH/
EtOAc), the warm reaction mixture was filtered. The residue was
washed with water and then recrystallized from ethanol to give the
pure title compound (362 mg, 47%) as a cream powder, mp
275e280 ꢀC; Rf (25% MeOH/EtOAc) 0.28; nmax (KBr) 3433, 3176,
3099, 2966, 1711, 1682, 1610, 1522, 1464, 1417, 1365 cmꢁ1
; dH
(400 MHz, DMSO-d6) 1.48 (6H, s, 2CH3), 2.08 (2H, m, CH2), 3.04 (6H,
s, 2NCH3), 3.51 (6H, s, 2NCH3), 3.91e3.97 (4H, m, 2CH2), 6.96 (2H, d,