One-pot and three-component synthesis of spiro[chromeno[2,3-d] pyrimidine-5,3′-indoline]-diones and spiro[chromeno[2,3-c] pyrazole-4,3′-indoline]-diones

Article abstract of DOI:10.1002/jhet.399

A novel, clean, one-pot and three-component synthesis of new spiro[chromeno [2,3-d]pyrimidine-5,3′-indoline]-2′,6(7H)-diones and spiro[chromeno[2,3-c] pyrazole-4,3′-indoline]-2′,5(6H)-diones via cyclo-condensation reaction of isatins, 1,3-cyclohexadiones, and 2-methylpyrimidine-4,6-diol or 3-methyl-1-phenyl-1H-pyrazol-5-ol, in aqueous media is reported.

Full text of DOI:10.1002/jhet.399

July 2010
One-Pot and Three-Component Synthesis of Spiro[chromeno[2,3-d]
pyrimidine-5,30-indoline]-diones and Spiro[chromeno[2,3-c] pyrazole-
4,30-indoline]-diones
967
Ramin Ghahremanzadeh,a Fatemeh Fereshtehnejad,b Zahra Yasaei,b
Tayebeh Amanpour,b and Ayoob Bazgirb*
aNanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
bDepartment of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
*E-mail: a_bazgir@sbu.ac.ir
Received November 23, 2009
DOI 10.1002/jhet.399
Published online 21 June 2010 in Wiley InterScience (www.interscience.wiley.com).
A novel, clean, one-pot and three-component synthesis of new spiro[chromeno[2,3-d]pyrimidine-5,30-
indoline]-20,6(7H)-diones and spiro[chromeno[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-diones via cyclo-
condensation reaction of isatins, 1,3-cyclohexadiones, and 2-methylpyrimidine-4,6-diol or 3-methyl-1-
phenyl-1H-pyrazol-5-ol, in aqueous media is reported.
J. Heterocyclic Chem., 47, 967 (2010).
INTRODUCTION
reported that sharing of the indole 3-carbon atom in the
formation of spiroindolines can highly enhance biologi-
cal activity [19–21]. The spirooxindole nucleus occurs
in several natural alkaloids and pharmacologically active
substances displaying a broad range of biological activ-
ity [22–25]. Therefore, a number of methods have been
reported for the preparation of spirooxindole fused het-
erocycles [26–30].
Multi-step reactions usually produce significant
amount of waste, principally due to a series of isolation
procedures which often involves toxic, hazardous, and
expensive solvents after each step. Thus, multi-compo-
nent reactions (MCRs) constitute an efficient synthetic
strategy for the rapid and effective libratory organic
transformations. Because, products are prepared in a
one-pot and the diversity can be obtained directly by
changing the reacting components [1,2]. On the other
hand, polyfunctionalized heterocycles play considerable
roles in the drug discovery process, and analysis of
drugs shows that most of them are polyfunctionalized
heterocycles [3]. Therefore, research on the multi-com-
ponent synthesis of polyfunctionalized heterocyclic com-
pounds is an interesting challenge.
In continuation of our previous works for the synthe-
sis of heterocyclic compounds [31–43], we performed
the preparation of some new spirooxindole containing
chromene ring fragments via three-component condensa-
tion reaction employing water as the reaction medium.
Organic transformations in water without using toxic or-
ganic solvents are one of the current focuses today espe-
cially in our environmentally conscious society.
Pyrimidine and its derivatives are important heterocy-
clic compounds with wide applications in medicinal
chemistry, as antibacterial, antiviral, and antitumor
agents [4]. A number of heterocycles fused with pyrimi-
dines are known for their varied biological activities [5–
8]. Similarly, chromene derivatives are an important
group of compounds, widely exist in plants, including
edible vegetables and fruits [9]. Synthetic analogues
were developed over the years, some of them displaying
remarkable effects as pharmaceuticals [10–13], including
antifungal [12,14] and antimicrobial activity [15–17].
The indole skeleton is common in many natural prod-
ucts and medicinal agents [18]. Furthermore, it has been
RESULTS AND DISCUSSION
First, we carried out the three-component reaction of
dimedone 1a, isatin 2a, and 2-methylpyrimidine-4,6-diol
3 as a model reaction in different solvents in the presence
of p-toluenesulfonic acid (p-TSA) as an inexpensive cata-
lyst (Scheme 1). It was found that refluxing water was a
best condition for the reaction and the desired product
obtained in good yield after 15 h (Table 1).
Encouraged by this result, we extended the reaction
of cyclic 1,3-dicarbonyls 1a,b and 2-methylpyrimidine-
4,6-diol 3 with a range of isatins 2 under similar
C
V
2010 HeteroCorporation

968
R. Ghahremanzadeh, F. Fereshtehnejad, Z. Yasaei, T. Amanpour, and A. Bazgir
Vol 47
Scheme 2
Scheme 1
conditions (Water/p-TSA) for 15 h, furnishing the re-
spective 4-hydroxy-2-methyl-8,9-dihydrospiro[chromeno
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-diones 4a–n in
good yields (Scheme 2, Table 2).
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100
apparatus. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionization potential of
70 eV. 1H NMR and 13C NMR spectra were recorded on a
BRUKER DRX-300 AVANCE spectrometer at 300.13 and
75.47 MHz, respectively. IR spectra were recorded using a
Shimadzu IR-470 apparatus. Elemental analyses were per-
formed using a Heracus CHN-O-Rapid analyzer.
The results were good in terms of yields and product
purity in the presence of p-TSA, while without p-TSA the
yields of products were very low (<30%) even after 48 h.
To the best of our knowledge, this new procedure
provides the first example of an efficient and three-com-
ponent method for the synthesis of 8,9-dihydrospiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-diones.
Compounds 4a–n are stable solids whose structures
Typical procedure for the preparation of 4-hydroxy-2-
methyl-8,9-dihydrospiro[chromeno[2,3-d]pyrimidine-5,30-in-
doline]-20,6(7H)-diones (4a–n). A mixture of dimedone or
1,3-cyclohexadione (1 mmol), 2-methylpyrimidine-4,6-diol (1
mmol), isatins (1 mmol), and p-TSA (0.05 g) in refluxing
water (5 mL) was stirred for 15 h (the progress of the reaction
was monitored by TLC). After completion, the reaction mix-
ture was filtered and the precipitate washed with water (10
mL) and recrystallized by EtOH to afford the pure product 4.
4-Hydroxy-2,8,8-trimethyl-8,9-dihydrospiro[chromeno [2,3-
d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4a). Light Brown
powder (85%); m.p 205ꢀC (dec). IR (KBr): 3450, 2952, 1718,
1
were established by IR, H NMR, and 13C NMR spec-
troscopy and elemental analysis. We have not estab-
lished an exact mechanism for the formation of spiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
4, however, a reasonable possibility is shown in Scheme 3.
To further explore the potential of this protocol for
spiro-heterocyclic synthesis, we investigated reaction of
malononitrile 5 instead of 1,3-cyclohexadione 1 and
obtained spiro[indoline-3,50-pyrano[2,3-d]pyrimidine]-60-
carbonitriles 6a–d selectively, in good yields for 24 h
(Scheme 4, Table 3).
1
1670, 1622, 1596 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼
0.97 (3H, s, CH3), 1.03 (3H, s, CH3), 2.05, 2.21 (2H, ABq, J
¼ 15.9 Hz, CH2), 2.25 (3H, s CH3), 2.57, 2.67 (2H, ABq, J ¼
18.4 Hz, CH2), 6.70–6.78 (2H, m, ArH), 6.85–6.87 (1H, m,
ArH), 7.05–7.10 (1H, m, ArH), 10.37 (1H, s, NH), 12.49 (1H,
s, OH). 13C NMR (75 MHz, DMSO-d6): d ¼ 12.2, 27.1, 28.3,
32.2, 46.6, 50.9, 100.6, 108.9, 112.8, 121.2, 123.2, 128.3,
133.9, 144.3, 159.8, 160.5, 161.1, 164.9, 178.1, 195.4. MS, m/
To further expand the scope of the reaction, we
replaced 2-methylpyrimidine-4,6-diol 3 with 3-methyl-1-
phenyl-1H-pyrazol-5-ol
7
and desired spiro[chro-
8
meno[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-diones
was selectively synthesized in good yields for 24 h
(Scheme 5, Table 4).
Finally, when we extended this reaction to acenaph-
thylene-1,2-dione 9, product of 30,70,70-trimethyl-10-phe-
nyl-70,80-dihydro-10H,2H-spiro[acenaphthylene-1,40-chro-
meno[2,3-c]pyrazole]-2,50(60H)-dione 10 was generated
in 70% yield after 24 h (Scheme 6).
Table 2
Synthesis of spirochromenopyrimidine-indolines 4a–n.
Product 4
R
R’
X
Yield (%)a
a
b
c
d
e
f
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
NO2
H
85
89
75
80
84
80
82
76
80
77
75
74
75
77
PhCH2
Me
Me
Me
Et
Table 1
Conditions effect on the reaction.a
H
NO2
Br
g
h
i
NO2
Br
NO2
H
Entry
Conditions
Time (h)
Yield (%)
H
H
1
2
3
4
5
Water (80ꢀC)
Water (reflux)
CH3CN (reflux)
EtOH (reflux)
DMF (100ꢀC)
24
15
24
24
24
63
85
60
67
60
H
j
k
l
m
n
H
H
Me
Et
H
H
H
PhCH2
Me
Et
H
Br
H
NO2
a Dimedone (1 mmol), 2-methylpyrimidine-4,6-diol (1 mmol), isatin (1
mmol), and p-TSA (0.05 g).
a Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
One-Pot and Three-Component Synthesis of Spiro[chromeno[2,3-d]pyrimidine-
5,30-indoline]-diones and Spiro[chromeno[2,3-c]pyrazole-4,30-indoline]-diones
969
Scheme 3
Table 3
Synthesis of spiro[indoline-pyranopyrimidine]-carbonitriles 6a–d.
Product 6
R
X
Yield (%)
a
b
c
d
H
H
H
80
82
65
63
NO2
NO2
NO2
Me
Et
2.27 (3H, s, CH2), 2.61, 2.71 (2H, ABq, J ¼ 17.0 Hz, CH2),
4.84, 4.94 (2H, ABq, J ¼ 16.0 Hz, NCH2), 6.53 (1H, d, J ¼
8.8 Hz, ArH), 6.82–6.87 (1H, m, ArH), 6.98 (1H, d, J ¼ 8.4
Hz, ArH), 7.03–7.08 (1H, m, ArH), 7.25–7.34 (3H, m, ArH),
7.63–7.66 (2H, m, ArH), 12.64 (1H, s, OH). MS, m/z: 467
(Mþ). Anal. Calcd. for C28H25N3O4: C, 71.93; H, 5.39; N,
8.99. Found: C, 71.88; H, 5.44; N, 8.91.
4-Hydroxy-10,2,8,8-tetramethyl-8,9-dihydrospiro [chromeno
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
(4d). Light
Brown powder (80%); m.p 218ꢀC (dec). IR (KBr): 3527,
2952, 1694, 1671, 1596 cmꢁ1 1H NMR (300 MHz, DMSO-
.
d6): d ¼ 0. 98 (3H, s, CH3), 1.03 (3H, s, CH3), 2.04, 2.18 (2H,
ABq, J ¼ 16.0 Hz, CH2), 2.26 (3H, s, CH3), 2.59, 2.67 (2H,
ABq, J ¼ 17.1 Hz, CH2), 3.13 (3H, s, NCH3), 6.82–6.94 (3H,
m, ArH), 7.16–7.21 (1H, m,ArH), 12.44 (1H, s, OH). 13C
NMR (75 MHz, DMSO-d6): d ¼ 21.3, 26.9, 27.2, 28.3, 32.2,
46.1, 50.8, 100.4, 107.8, 112.6, 122.0, 123.0, 128.6, 133.0,
145.7, 159.9, 160.5, 160.9, 165.1, 176.8, 195.4, 195.6. MS, m/
z: 391 (Mþ). Anal. Calcd. for C22H21N3O4: C, 67.51; H, 5.41;
N, 10.74. Found: C, 67.47; H, 5.36; N, 10.69.
z: 377 (Mþ). Anal. Calcd. for C21H19N3O4: C, 66.83; H, 5.07;
N, 11.13. Found: C, 66.88; H, 5.01; N, 11.06.
4-Hydroxy-10,2,8,8-tetramethyl-50-nitro-8,9-dihydrospiro [chro-
meno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4e). Light
Brown powder (84%); m.p 207ꢀC (dec). IR (KBr): 3548,
4-Hydroxy-2,8,8-trimethyl-50-nitro-8,9-dihydrospiro [chro-
meno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
(4b).
Light Brown powder (89%); m.p 245ꢀC (dec). IR (KBr):
3445, 2957, 1737, 1680, 1627, 1600 cmꢁ1 1H NMR (300
2967, 1740, 1686, 1609 cmꢁ1 1H NMR (300 MHz, DMSO-
.
.
d6): d ¼ 0. 99 (3H, s, CH3), 1.02 (3H, s, CH3), 2.12–2.15 (2H,
m, CH2), 2.27 (3H, s, CH3), 2.63–2.69 (2H, m, CH2), 3.24
(3H, s, NCH3), 7.19 (1H, d, J ¼ 8.7 Hz, ArH), 7.92 (1H, s,
ArH), 8.19 (1H, d, J ¼ 8.7 Hz, ArH), 12.57 (1H, s, OH). 13C
NMR (75 MHz, DMSO-d6): d ¼ 21.4, 27.3, 27.7, 27.8, 32.2,
32.3, 46.0, 50.5, 99.3, 107.9, 111.7, 118.6, 126.2, 133.9, 142.7,
151.8, 160.6, 160.8, 161.2, 166.3, 177.7, 196.0. MS, m/z: 436
(Mþ). Anal. Calcd. for C22H20N4O6: C, 60.55; H, 4.62; N,
12.84. Found: C, 60.61; H, 4.66; N, 12.89.
MHz, DMSO-d6): d ¼ 1.00 (3H, s, CH3), 1.03 (3H, s, CH3),
2.07–2.22 (2H, m, CH2), 2.26 (3H, s, CH3), 2.60–2.73 (2H, m,
CH2), 6.62–6.96 (1H, m, ArH), 7.87 (1H, m ArH), 8.11 (1H,
d, J ¼ 8.5 Hz, ArH), 11.17 (1H, s, NH), 12.60 (1H,s, OH).
13C NMR (75 MHz, DMSO-d6): d ¼ 21.3, 27.5, 27.7, 32.3,
46.6, 50.6, 99.5, 108.8, 111.8, 119.0, 126.1, 134.8, 142.2,
151.0, 160.4, 160.7, 161.3, 165.0, 166.1, 178.8, 196.0. MS, m/
z: 422 (Mþ). Anal. Calcd. for C21H18N4O6: C, 59.71; H, 4.30;
N, 13.26. Found: C, 59.65; H, 4.35; N, 13.19.
50-Bromo-4-hydroxy-10,2,8,8-tetramethyl-8,9-dihydrospiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4f).
Light Brown powder (80%); m.p 230ꢀC (dec). IR (KBr):
Due to very low solubility of the product 4c, we can not
report the 13C NMR data for this product.
10-Bnzoyl-4-hydroxy-2,8,8-trimethyl-8,9-dihydrospiro [chro-
meno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4c). Light
Brown powder (74%); mp 125–135ꢀC (dec). IR (KBr): 3452,
3517, 2952, 1703, 1677, 1653, 1607 cmꢁ1 1H NMR (300
.
MHz, DMSO-d6): d ¼ 0. 99 (3H, s, CH3), 1.02 (3H, s, CH3),
2.05–2.10 (2H, m, CH2), 2.26 (3H, s, CH3), 2.63 (2H, brs, CH2),
3.12 (3H, s, NCH3), 6.90 (1H,d, J ¼ 8.4 Hz, ArH), 7.16 (1H, s,
ArH), 7.37 (1H, d, J ¼ 8.6 Hz, ArH), 12.50 (1H, s, OH). 13C
2957, 1730, 1673, 1608 cmꢁ1 1H NMR (300 MHz, DMSO-
.
d6): d ¼ 1. 21 (3H, t, J ¼ 6.7 Hz, CH3), 0.99 (3H, s, CH3),
1.05 (3H, s, CH3), 2.09, 2.25 (2H, ABq, J ¼ 16.0 Hz, CH2),
Scheme 5
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

970
R. Ghahremanzadeh, F. Fereshtehnejad, Z. Yasaei, T. Amanpour, and A. Bazgir
Vol 47
Table 4
DMSO-d6): d ¼ 20.2, 21.3, 26.8, 27.5, 37.2, 46.1, 100.4,
107.7, 113.7, 122.0, 123.1, 128.5, 133.1, 145.6, 159.8, 160.3,
160.9, 167.0, 176.9, 195.6. MS, m/z: 363 (Mþ). Anal. Calcd.
for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C,
66.17; H, 4.68; N, 11.62.
Synthesis of spiro[chromenopyazole-indoline]-diones 8a–e.
Product 8
R
R’
X
Yield (%)
10-Ethyl-4-hydroxy-2-methyl-8,9-dihydrospiro
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
[chromeno
(4k). Light
a
b
c
d
e
Me
Me
Me
H
H
H
H
H
H
H
NO2
Br
H
NO2
80
75
81
73
70
Brown powder (72%); m.p 235ꢀC (dec). IR (KBr): 3435,
1
2931, 1683, 1599 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼
H
1. 21 (3H, t, J ¼ 6.7 Hz, CH3), 1.89–1.90 (2H, m, CH2),
2.18–2.25 (5H, m, CH2, and CH3), 2.70–2.71 (2H, m, CH2),
3.67–3.71 (2H, m, NCH2), 6.80–6.85 (1H, m, ArH), 6.90–6.92
(2H, m, ArH), 7.14–7.19 (1H, m, ArH), 12.43 (1H, s, OH).
13C NMR (75 MHz, DMSO-d6): d ¼ 12.1, 20.2, 21.3, 27.5,
34.7, 37.2, 46.3, 100.5, 107.6, 113.8, 121.7, 123.3, 128.5,
133.3, 144.7, 159.8, 160.3, 160.9, 166.9, 176.1, 195.5. MS, m/
z: 377 (Mþ). Anal. Calcd. for C21H19N3O4: C, 66.83; H, 5.07;
N, 11.13. Found: C, 66.77; H, 5.00; N, 11.07.
NMR (75 MHz, DMSO-d6): d ¼ 21.3, 27.0, 27.7, 27.8, 32.2,
46.2, 50.7, 99.8, 109.7, 112.1, 113.7, 126.0, 131.2, 135.3, 145.2,
160.2, 160.6, 161.3, 165.7, 176.5, 195.7, 195.8. MS, m/z: 471
(Mþ), 469 (Mþ). Anal. Calcd. for C22H20BrN3O4: C, 56.18; H,
4.29; N, 8.93. Found: C, 56.23; H, 4.23; N, 8.85.
10-Ethyl-4-hydroxy-2,8,8-trimethyl-50-nitro-8,9-dihydrospiro
[chromeno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4g).
Light Brown powder (82%); m.p 240ꢀC (dec). IR (KBr):
Due to very low solubility of the product 4l, we can not
report the 13C NMR data for this product.
3530, 2952, 1735, 1680, 1608 cmꢁ1 1H NMR (300 MHz,
.
10-Benzoyl-4-hydroxy-2-methyl-8,9-dihydrospiro [chromeno
DMSO-d6): d ¼ 0. 99 (3H, s, CH3), 1.02 (3H, s, CH3), 1.22
(3H, t, J ¼ 6.9 Hz, CH3), 2.09–2.15 (2H, m, CH2), 2.60–2.74
(2H, m, CH2), 3.80–3.82 (2H, m, NCH2), 7.21 (1H, d, J ¼ 8.7
Hz, ArH), 7.91 (1H, s, ArH), 8.18 (1H, d, J ¼ 8.4 Hz, ArH),
12.57 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): d ¼ 12.1,
21.4, 27.7, 32.2, 32.3, 35.3, 50.5, 50.6, 99.4, 107.8, 111.7,
118.7, 126.2, 134.1, 142.5, 151.0, 160.5, 160.8, 161.2, 165.2,
166.2, 177.1, 195.9. MS, m/z: 450 (Mþ). Anal. Calcd. for
C23H22N4O6: C, 61.33; H, 4.92; N, 12.44. Found: C, 61.39; H,
4.97; N, 12.38.
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
(4l). Light
Brown powder (75%); m.p 129ꢀC (dec). IR (KBr): 3440,
2921, 1734, 1671, 1609 cmꢁ1 1H NMR (300 MHz, DMSO-
.
d6): d ¼ 1.93 (2H, brs, CH2), 2.27 (5H, brs, CH3 and CH2),
2.75 (2H, brs, CH2), 4.87–4.96 (2H, m, NCH2), 6.52 (1H, d, J
¼ 7.1 Hz, ArH), 6.83 (1H, m, HAAr), 6.97 (1H, m, ArH),
7.03–7.10 (1H, m, Ar H), 7.31–7.33 (3H, m, ArH ), 7.56–7.64
(2H, m, ArH ), 12.62 (1H, s, OH). MS, m/z: 439 (Mþ). Anal.
Calcd. for C26H19N3O4: C, 71.06; H, 4.82; N, 9.56. Found: C,
71.00; H, 4.87; N, 9.48.
50-Bromo-4-hydroxy-2-methyl-8,9-dihydrospiro [chromeno
50-Bromo-4-hydroxy-10,2-dimethyl-8,9-dihydro spiro [chro-
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
(4h). Light
Brown powder (74%); m.p 240ꢀC (dec). IR (KBr): 3404,
2957, 1748, 1704, 1647, 1615 cmꢁ1 1H NMR (300 MHz,
meno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
(4m).
Light Brown powder (75%); m.p 232ꢀC (dec). IR (KBr):
3471, 2926,1702, 1688, 1599 cmꢁ1 1H NMR (300 MHz,
.
.
DMSO-d6): d ¼ 1. 92 (2H, brs, CH2), 2.25 (5H, brs, CH2, and
CH3), 2.71 (2H, brs, CH2), 6.68 (1H, d, J ¼ 8.1 Hz, ArH),
7.11 (1H, s, ArH), 7.25 (1H, d, J ¼ 8.1 Hz, ArH), 10.55 (1H,
s, NH), 12.53 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): d
¼ 20.1, 21.3, 27.6, 37.2, 46.9, 100.1, 110.7, 112.9, 113.3,
125.9, 126.2, 131.0, 136.4, 143.7, 160.4, 160.1, 167.3, 177.9,
195.8. MS, m/z: 427 (Mþ). Anal. Calcd. for C19H14BrN3O4: C,
53.29; H, 3.30; N, 9.81. Found: C, 53.23; H, 3.36; N, 9.88.
DMSO-d6): d ¼ 1.91–1.93 (2H, m, CH2), 2.26 (3H, s, CH3),
2.50 (2H, brs, CH2), 3.12 (3H, s, NCH3), 3.38 (2H, brs, CH2),
6.89 (1H, d, J ¼ 7.5 Hz, ArH), 7.20 (1H, s, ArH), 7.36 (1H, d,
J ¼ 8.4 Hz, ArH), 12.48 (1H, s, OH). 13C NMR (75 MHz,
DMSO-d6): d ¼ 20.1, 21.4, 26.9, 27.6, 46.3, 100.0, 109.6,
113.1, 113.7, 126.1, 131.1,m 135.4, 145.1, 160.2, 160.4, 161.0,
167.6, 176.5, 195.8. MS, m/z: 441 (Mþ). Anal. Calcd. for
C20H16BrN3O4: C, 54.31; H, 3.65; N, 9.50. Found: C, 54.26;
H, 3.61; N, 9.56.
4-Hydroxy-2-methyl-50-nitro-8,9-dihydrospiro
[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione
[chromeno
(4i). Light
10-Ethyl-4-hydroxy-2-methyl-50-nitro-8,9-dihydrospiro [chro-
meno[2,3-d]pyrimidine-5,30-indoline]-20,6(7H)-dione (4n). Light
Brown powder (77%); m.p 228ꢀC (dec). IR (KBr): 3527,
Brown powder n(80%); m.p 250ꢀC (dec). IR (KBr): 2450,
3203, 1717, 1682, 1627 cmꢁ1 1H NMR (300 MHz, DMSO-
.
2936, 1704, 1683, 1605 cmꢁ1 1H NMR (300 MHz, DMSO-
.
d6): d ¼ 1.93 (2H, brs, CH2), 2.27 (5H, brs, CH2, and CH3),
2.50 (2H, brs, CH2), 6.93 (1H,d, J ¼ 8.7 Hz, ArH), 7.89 (1H,
s, ArH), 8.10 (1H,d, J ¼ 8.6 Hz, ArH), 11.18 (1H, s, NH),
12.58 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): d ¼ 20.1,
21.3, 27.6, 37.0, 46.7, 99.6, 108.8, 112.8, 119.2, 126.1, 134.9,
142.2, 150.9, 160.4, 160.6, 161.2, 168.0, 178.9, 196.1. MS, m/
z: 394 (Mþ). Anal. Calcd. for C19H14N4O6: C, 57.87; H, 3.58;
N, 14.21. Found: C, 57.92; H, 3.53; N, 14.15.
d6): d ¼ 0.97 (3H, s, CH3), 1.22 (3H, t, J ¼ 6.6 Hz, CH3),
1.93 (2H, brs, CH2), 2.23–2.26 (5H, m, CH2, and CH3), 2.75
(2H, brs, CH2), 3.79–3.82 (2H, m, NCH2), 7.20 (1H, d, J ¼
8.7 Hz, ArH), 7.95 (1H, s, ArH), 8.18 (1H, d, J ¼ 8.7 Hz,
Scheme 6
4-Hydroxy-10,2-dimethyl-8,9-dihydrospiro[chromeno[2,3-d]
pyrimidine-5,30-indoline]-20,6(7H)-dione (4j). Light Brown
powder (76%); m.p 246ꢀC (dec). IR (KBr): 3450, 2936, 1693,
1
1647, 1607 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 1. 91
(2H, brs, CH2), 2.19–2.25 (5H, m, CH2, and CH3), 2.72 (2H,
brs, CH2), 3.13 (3H, s, NCH3), 6.82–6.95 (3H, m, ArH), 7.15–
7.20 (1H, m, ArH), 12.43 (1H, s, OH). 13C NMR (75 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
One-Pot and Three-Component Synthesis of Spiro[chromeno[2,3-d]pyrimidine-
5,30-indoline]-diones and Spiro[chromeno[2,3-c]pyrazole-4,30-indoline]-diones
971
ArH), 12.56 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): d ¼
12.1, 20.1, 21.4, 27.6, 35.3, 36.9, 46.2, 99.4, 107.7, 112.7,
119.0, 126.1, 134.2, 142.5, 151.0, 160.5, 161.2, 168.2, 177.1,
196.1. MS, m/z: 422 (Mþ). Anal. Calcd. for C21H18N4O6: C,
59.71; H, 4.30; N, 13.26. Found: C, 59.77; H, 4.36; N, 13.20.
70-Amino-40-hydroxy-20-methyl-2-oxospiro[indoline-3,50-pyr-
ano[2,3-d]pyrimidine]-60-carbonitrile (6a). Cream powder
(80%); m.p 287ꢀC (dec). IR (KBr): 3378, 3306, 3142, 2207,
3,7,7-Trimethyl-50-nitro-1-phenyl-7,8-dihydro-1H-spiro [chro-
meno[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-dione (8b). Cream
powder (75%); m.p 315ꢀC (dec). IR (KBr): 3424, 2957, 1749,
1
1649 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 1.04 (6H, s,
2CH3), 1.61 (3H, s, CH3), 2.21 (2H, bs, CH2), 2.78 (2H, bs,
CH2), 7.08–8.15 (8H, m, ArH), 11.38 (1H, s, NH). MS, m/z:
470 (Mþ). Anal. Calcd. for C26H22N4O5: C, 66.37; H, 4.71; N,
11.91. Found: C, 66.42; H, 4.75; N, 11.97.
1716, 1676 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d ¼ 2.27
3,7,7-Trimethyl-50-bromo-1-phenyl-7,8-dihydro-1H-spiro[chro-
meno[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-dione (8c). Cream
powder (81%); m.p 244ꢀC (dec). IR (KBr): 3441, 2955, 1734,
(3H, s, CH3), 6.78–7.18 (4H, m, ArH), 7.31 (2H, s, NH2),
10.49 (1H, s, NH), 12.61 (1H, s, OH). 13C NMR (75 MHz,
DMSO-d6): d ¼ 21.4, 47.9, 57.1, 98.3, 109.7, 117.9, 122.2,
124.0, 128.8, 134.0, 142.6, 160.0, 160.3, 160.8, 161.0, 177.9.
MS, m/z: 321 (Mþ). Anal. Calcd. for C16H11N5O3: C, 59.81;
H, 3.45; N, 21.80. Found: C, 59.76; H, 3.41; N, 21.86.
1
1646 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 1.05 (6H, s,
2CH3), 1.64 (3H, s, CH3), 2.22 (2H, bs, CH2), 2.77 (2H, bs,
CH2), 6.84–7.53 (8H, m, ArH), 10.79 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): d ¼ 12.2, 27.6, 27.8, 32.6, 41.2, 47.3,
50.6, 99.4, 109.5, 113.9, 120.9, 122.3, 123.6, 127.2, 128.5,
129.9, 131.4, 137.6, 141.9, 144.7, 145.3, 166.4, 178.3, 196.3.
MS, m/z: 505 (Mþþ2), 503 (Mþ). Anal. Calcd. for
C26H22BrN3O3: C, 61.91; H, 4.40; N, 8.33. Found: C, 61.95;
H, 4.35; N, 8.40.
70-Amino-40-hydroxy-20-methyl-5-nitro-2-oxospiro[indoline-
3,50-pyrano[2,3-d]pyrimidine]-60-carbonitrile
(6b). Cream
powder (82%); m.p 270ꢀC (dec). IR (KBr): 3471, 3363, 3193,
1
2202, 1704, 1658 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼
2.28 (3H, s, CH3), 7.02 (1H, d, J ¼ 8.8 Hz, ArH), 7.50 (2H, s,
NH2), 8.04 (1H, s, ArH), 8.16 (1H, d, J ¼ 8.6 Hz, ArH),
11.24 (1H, s, NH), 12.68 (1H, s, OH). 13C NMR (75 MHz,
DMSO-d6): d ¼ 21.5, 48.1, 55.4, 97.2, 109.9, 117.7, 120.0,
126.4, 134.9, 142.9, 149.1, 160.4, 160.8, 161.1, 161.2, 178.7.
MS, m/z: 366 (Mþ). Anal. Calcd. for C16H10N6O5: C, 52.46;
H, 2.75; N, 22.94. Found: C, 52.50; H, 2.80; N, 22.88.
3-Methyl-1-phenyl-7,8-dihydro-1H-spiro[chromeno[2,3-c]pyr-
azole-4,30-indoline]-20,5(6H)-dione (8d). Light brown powder
(73%); m.p 312ꢀC (dec). IR (KBr): 3193, 3085, 1730, 1634
cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d ¼ 1.60 (3H, s,
CH3), 1.97 (2H, bs, CH2), 2.29 (2H, bs, CH2), 2.85 (2H, bs,
CH2), 6.86–7.74 (9H, m, ArH), 10.64 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): d ¼ 12.2, 20.5, 28.0, 37.2, 47.3, 99.1,
109.5, 113.3, 120.9, 122.2, 123.8, 127.1, 128.6, 129.9, 134.8,
137.7, 142.5, 144.9, 145.0, 168.3, 178.2, 196.2. MS, m/z: 397
(Mþ). Anal. Calcd. for C24H19N3O3: C, 72.53; H, 4.82; N,
10.57. Found: C, 72.49; H, 4.85; N, 10.62.
70-Amino-40-hydroxy-1,20-dimethyl-5-nitro-2-oxospiro [indo-
line-3,50-pyrano[2,3-d]pyrimidine]-60-carbonitrile (6c). powder
(65%); m.p 180ꢀC (dec). IR (KBr): 3429, 3322, 2202, 1730,
1
1667 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 2.29 (3H, s,
CH3), 3.25 (3H, s, CH3), 7.30 (1H, d, J ¼ 9.0 Hz, ArH), 7.57
(2H, s, NH2), 8.11 (1H, s, ArH), 8.27 (1H, d, J ¼ 8.9 Hz,
ArH), 12.66 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): d ¼
21.5, 27.3, 47.7, 55.1, 97.1, 108.9, 117.6, 119.6, 126.4, 134.2,
143.4, 150.1, 160.6, 160.9, 161.0, 161.1, 177.3. MS, m/z: 380
(Mþ). Anal. Calcd. for C17H12N6O5: C, 53.69; H, 3.18; N,
22.10. Found: C, 53.64; H, 3.22; N, 22.18.
Due to very low solubility of the products 8e and 10, we
can not report the 13C NMR data for these products.
3-Methyl-50-nitro-1-phenyl-7,8-dihydro-1H-spiro [chromeno
[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-dione
(8e). Cream
powder (70%); m.p 310ꢀC (dec). IR (KBr): 3290, 2952, 1750,
1
1640 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 1.63 (3H, s,
CH3), 2.14 (2H, m, CH2), 2.46 (2H, m, CH2), 2.91 (2H, m,
CH2), 7.02–8.54 (8H, m, ArH), 10.73 (1H, s, NH). MS, m/z:
442 (Mþ). Anal. Calcd. for C24H18N4O5: C, 65.15; H, 4.10; N,
12.66. Found: C, 65.19; H, 4.06; N, 12.60.
70-Amino-1-ethyl-40-hydroxy-20-methyl-5-nitro-2-oxospiro [in-
doline-3,50-pyrano[2,3-d]pyrimidine]-60-carbonitrile (6d). Cream
powder (63%); m.p 233ꢀC (dec). IR (KBr): 3481, 3325, 2197,
1
1755, 1668, 1647 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼
30,70,70-Trimethyl-10-phenyl-70,80-dihydro-10H,2H-spiro [ac-
enaphthylene-1,40-chromeno[2,3-c]pyrazole]-2,50(60H)-dione
(10). Cream powder (70%); m.p 188ꢀC (dec). IR (KBr): 3162,
1.17 (3H, t, J ¼ 8.4 Hz, CH3), 2.22 (3H, s, CH3), 3.74 (2H, m,
CH2), 7.10 (1H, d, J ¼ 8.9 Hz, ArH), 8.14 (1H, d, J ¼ 8.9 Hz,
ArH), 8.14 (1H, s, ArH), 12.16 (3H, bs, NH2 and OH). 13C
NMR (75 MHz, DMSO-d6): d ¼ 11.9, 18.0, 34.9, 39.07, 48.5,
95.3, 107.5, 118.4, 125.3, 135.3, 141.8, 150.6, 158.2, 161.4,
171.8, 178.6. MS, m/z: 394 (Mþ). Anal. Calcd. for C18H14N6O5:
C, 54.82; H, 3.58; N, 21.31. Found: C, 54.86; H, 3.63; N, 21.36.
3,7,7-Trimethyl-1-phenyl-7,8-dihydro-1H-spiro [chromeno
1
3055, 1704, 1643 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼
1.02 (6H, s, 2CH3), 1.22 (3H, s, CH3), 2.10 (2H, bs, CH2),
2.80 (2H, bs, CH2), 7.31–8.26 (1H, m, ArH). MS, m/z: 460
(Mþ). Anal. Calcd. for C30H24N2O3: C, 78.24; H, 5.25; N,
6.08. Found: C, 78.19; H, 5.29; N, 6.15.
[2,3-c]pyrazole-4,30-indoline]-20,5(6H)-dione
(8a). Cream
powder (80%); m.p 243ꢀC (dec). IR (KBr): 3142, 2880, 1703,
1
1591 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 1.04 (6H, s,
REFERENCES AND NOTES
2CH3), 1.61 (3H, s, CH3), 2.19 (2H, bs, CH2), 2.78 (2H, bs,
CH2), 6.87–7.73 (9H, m, ArH), 10.64 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): d ¼ 12.2, 27.5, 27.9, 32.5, 41.1, 47.2,
50.8, 99.1, 109.6, 112.3, 120.8, 122.3, 123.7, 127.1, 128.6,
129.9, 134.6, 137.7, 142.5, 144.9, 145.2, 166.4, 178.1, 196.1.
MS, m/z : 397 (Mþ). Anal. Calcd. for C26H23N3O3: C, 73.39;
H, 5.45; N, 9.88. Found: C, 73.35; H, 5.40; N, 9.82.
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