A novel biginelli-like reaction: An efficient one-pot synthesis of spiro[oxindole-quinazoline/pyrimidine]ones

Article abstract of DOI:10.2174/157017810791130577

Some new spiro[oxindole-quinazoline/pyrimidine]ones were synthesized via a novel three-component Biginelli-like reaction between isatin, cyclic or acyclic 1,3-dicarbonyl compounds, and urea, N-methyl urea or thiourea in one pot and good yields.

Full text of DOI:10.2174/157017810791130577

Letters in Organic Chemistry, 2010, 7, 277-282
277
A Novel Biginelli-Like Reaction: An Efficient One-pot Synthesis of
Spiro[oxindole-quinazoline/pyrimidine]ones
Hassan Kefayati*,1, Kurosh Rad-Moghadam2, Masoumeh Zamani1 and Sanaz Hosseyni1
1Chemistry Department, Islamic Azad University, P. O. Box 41335-3516, Rasht Branch, Iran
2Chemistry Department, Faculty of Sciences, University of Guilan, Rasht, Iran
Received May 13, 2009: Revised February 18, 2010: Accepted February 22, 2010
Abstract: Some new spiro[oxindole-quinazoline/pyrimidine]ones were synthesized via a novel three-component
Biginelli-like reaction between isatin, cyclic or acyclic 1,3-dicarbonyl compounds, and urea, N-methyl urea or thiourea in
one pot and good yields.
Keywords: Quinazolinone, pyrimidinone, spiro oxindole, multi-component reaction, Biginelli-like reaction, isatin.
INTRODUCTION
preparation of DHPMs via Biginelli-like reactions have been
reported, which remarkably have broadened the scope of
Biginelli reactions [26-29]. In spite of their potential utility,
all of the so far reported synthetic methods on Biginelli and
Biginelli-like reactions start from substrates which are
limited to aromatic aldehydes, acetophenone or ꢀ-dicarbonyl
compounds, and urea or thiourea.
Indole nucleus is probably one of the most studied
heterocycles, a common and important feature of a variety of
natural products and medicinal agents [1]. Compounds
carrying the indole moiety exhibit antibacterial and
antifungal activities [2]. Synthesis and high throughput
screening of indoles have revealed that sharing of indole 3-
carbon atom in the formation of spiroindoline derivatives
highly enhances their biological activities [3-5].
As a finding of a research project in continuation of our
previous work on the Biginelli-like reaction [30], herein we
report, for the first time, a simple approach to novel
Recently, 3,4-dihydropyrimidine-2(1H)-ones have attrac-
ted great attention of synthetic organic chemists due to their
anti-hypertensive activities as well behaving as calcium
channel blockers, ꢀ-1a-antagonists and neuropeptides-Y
antagonists [6-8]. The Biginelli reaction is one of the well
spiro[oxindole-quinazoline/pyrimidine]ones via
a
new
Biginelli-like reaction consisting of a three-component
cyclocondensation of cyclic or acyclic dicarbonyl com-
pounds, urea or N-methyl urea and isatin derivatives instead
of aromatic aldehydes.
O
NH
2
3
4
1
O
8a
4'
7'
HN
O
O
(E)
8
3'a
7'a
5'
6'
7
3'
1' 2'
+
4a
+
5
6
H2N
NH2
N
O
N
O
O
O
H
H
1a
3a
4a
2a
Scheme 1.
established multicomponent reactions (MCRs) which
frequently was employed for synthesis of 3,4-
dihydropyrimidine-2(1H)-ones (DHPMs). The traditional
Biginelli reactions are referred to the one-pot condensations
between a ꢀ-dicarbonyl compound, an aldehyde, and urea
under strongly acidic conditions [9]. There are a wealth of
reports on improvements and extending of this reaction using
new techniques, variety of catalysts and various reactants
[10-25]. In recent years, several synthetic procedures for
RESULT AND DISCUSSION
Our preliminary experiment using isatin instead of
aldehydes in the traditional condition of Biginelli reaction
was successful as a mixture of isatin 1a (5 mmol), dimedone
2a (7.5 mmol) and urea 3a (5 mmol) in the presence of a
catalytic amount of acetic acid afforded the spiro[oxindole-
quinazolin]dione 4a in low yield (Scheme 1). Delighted by
this result we set out to improve the yield by screening some
possible catalysts, so we chose the condensation of
dimedone, isatin, and urea as the model reaction being
performed in the presence of various protic and Lewis acids.
As is indicated in Table 1, the best yields were obtained in
the presence of HCl.
*Address correspondence to this author at the Department of Chemistry,
Islamic Azad University, P. O. Box 41335-3516, Rasht Branch, Iran; Tel:
+98 911 1321849; Fax: +98 131 4223621; E-mail: kefayati@iaurasht.ac.ir
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

278 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Kefayati et al.
Table 1. Three-Component Reaction of Isatin, Urea and
Dimedone in the Presence of 10% mmol of Different
Catalysts*
Also, to verify the scope of substrates in this synthetic
method, a set of reactions of isatin derivatives and urea with
some other cyclic 1,3-dicarbonyl compounds such as 1,3-
cyclohexadione and barbituric acid were examined under the
same conditions (Scheme 2). As was shown in Table 2, the
results account for the viability of the reactions with all the
selected substrates [31, 32].
Entry
Catalyst
Yield (%)
1
2
3
4
5
6
CH3COOH
HCl
52
86
60
55
47
45
However, we have not determined the mechanism of
reaction. A reasonable and more accepted one for formation
of the spiro products 4a-h is depicted in Scheme 3. The
process represents a typical cascade reaction in which the
isatin 1 first condenses with urea 3 to afford the intermediate
5. Then, the iminium intermediate 5 subjects to the 1,2-
addition of cyclic 1,3-dicarbonyl compound 2 to give the
compound 6 followed by cyclocondensation of the amidic
NH4Cl
NaHSO4
FeCl3
AlCl3
*Isatin (5 mmol), urea (5 mmol) and dimedone (7.5 mmol) in absolute ethanol.
X
NR3
O
(E)
O
R1
O
X
R1
HN
+
+
O
H2N
NHR3
O
NR2
NR2
O
X=O,S
1
3
4a-h
2
Scheme 2.
Table 2. Synthesis of Spiro[oxindole-quinazoline/pyrrimidine]ones by the Reaction of Isatin Derivatives, Urea or N-methyl Urea or
Thiourea and Cyclic 1,3-dicarbonyl Compounds in the Presence of a Catalytic Amount of HCl
Products
4a
R1
R2
R3
Cyclic-1,3-dicarbonyl
Time (h)
Structure of Products
Mp(0C)
Yield (%)
O
O
H
H
H
3:30
350-352
82
HN
NH
O
O
O
N
H
O
O
4b
H
H
Me
3
336-338
78
HN
NH
O
O
O
N
H
O
O
4c
Br
H
H
Me
1
2
344-346
345-347
77
72
HN
NMe
Br
O
O
N
O
H
O
O
4d
H
H
HN
NH
O
O
O
N
H

A Novel Biginelli-Like Reaction
Letters in Organic Chemistry, 2010, Vol. 7, No. 4
279
(Table 2). Contd…..
Yield (%)
Products
4e
R1
R2
R3
Cyclic-1,3-dicarbonyl
Time (h)
Structure of Products
Mp(0C)
O
O
H
H
H
1:40
270-272
96
92
85
72
HN
NH
NH
NH
O
O
N
H
O
O
O
O
O
N
O
H
N
H
O
O
O
4f
4g
4h
H
Me
H
H
H
3
2
328-330
238-240
365-367
HN
NH
NH
NH
NH
NH
N
H
O
N
O
Me
N
H
O
O
O
Br
Br
H
HN
NH
Br
NH
O
N
H
O
O
N
H
N
O
H
S
O
H
3:20
HN
NH
Br
NH
O
N
H
O
O
N
H
N
O
H
H
NH2
O
O
NH2
H
N
N+
HO
(Z)
H2N
NH2
H+
-H2O
O
O
O
O
3
O
N
N
N
H
H
H
1
5
O
OH
O
H+
..
OH
O
..
NH2
NH
O
H
N
2
O
O
O
O
O
NH
O
-H+
N
H
N
H
6
+
OH2
H
H
O
N
N
O
(E)
HN
H
O
NH
O
-H2O
O
O
N
H
N
H
4
Scheme 3.

280 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Kefayati et al.
NR3
X
R1
O
X
o
o
R2
R1
HN
+
+
R2
H2N
NHR3
O
N
H
O
O
N
H
X=O,S
1
3
8a-i
7
Scheme 4.
Table 3. Synthesis of Spiro[oxindole-pyrrimidine]-2-ones by the Reaction of Isatin Derivatives, Urea or N-methyl Urea and Acyclic
1,3-dicarbonyl Compounds in the Presence of a Catalytic Amount of HCl
Products
R1
R2
R3
X
Time (h)
Yield (%)
Mp (0C)
8a
8b
8c
8d
8e
8f
H
Br
H
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
HNC6H5
H
H
O
O
O
O
O
O
O
S
6
5:30
5:30
5
90
87
85
81
80
88
86
68
69
297-299
293-295
248-250
175-178
298-300
265-268
295-297
323-325
331-333
CH3
CH3
H
Br
H
7
H
HNC6H5
CH3
H
6
8g
8h
8i
Br
Br
H
HNC6H5
6:30
7
OCH2CH3
HNC6H5
H
H
S
8:20
function, with a carbonyl group of the 1,3-dicarbonyl moiety
to form the desired products 4a-h (Scheme 3) [33]. Also,
there is another frequently suggested mechanism which was
based on Knoevenagel condensation between 1,3-dicarbonyl
compounds and isatin, followed by Michael addition of urea
to form an ꢀ,ꢁ-unsaturated carbonyl transient. The process
entails with a cyclocondensation of the final intermediate to
afford the spiro products.
adopted in combinatorial chemistry to synthesize the related
spiro oxindoles of potent biological importance for
screening.
ACKNOWLEDGEMENT
We are grateful to the research council of Islamic Azad
University of Rasht Branch for financial support of this
project.
In the course of further exploring the scope of substrates,
applicable to this synthesis, we used of ethyl acetoacetate as
an acyclic 1,3-dicarbonyl compound (Scheme 4). Refluxing
a solution of 5 mmol isatin 1 with 7.5 mmol ethyl
acetoacetate 7 and 5 mmol urea 3 in ethanol, afforded
spiro[oxindole-pyrimidine]one 8a, but the yield was not so
high (37%) (Scheme 4). In order to increase the yield, we
examined the effects of amount of urea and catalyst on the
formation of 8a. Fortunately, we found that, with increasing
the amount of urea from 5 mmol to 10 mmol and HCl from
10% mmol to 15% mmol the yield of 8a is also increases to
90%.
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[7]
[8]
for
synthesis
of
some
novel
spiro[oxindole-
pyrimidine/quinazoline]ones. This method has shown the
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[13]
[14]
recorded on
a Shimadzu QP 1100 BX mass spectrometer.
Elemental analysis were carried out on a Thermo Finnigan Flash
EA 1112 series instrument.
[32]
General procedure for the synthesis of spiro[oxindole-
quinazoline/pyrrimidine]ones 4a-h: A mixture of isatin derivatives
1 (5 mmol), cyclic 1,3-dicarbonyl compound 2 (7.5 mmol), urea or
N-methyl urea or thiourea 3 (5mmol) and HCl (10% mmol) in
absolute ethanol (5 mL) refluxed for appropriate time according to
Table 2 (Scheme 2). Upon completion, as monitored by TLC on
silica gel using ethyl acetate as eluent, the reaction mixture was
allowed to cool to room temperature. The solid was filtered off and
washed with cold ethanol (3ꢀ0.5 ml) to give white powders of 4a-
h.
[15]
[16]
[17]
[18]
Spiro[4.3ꢁ]oxindole-3,4,7,8-tetrahydro-7,7-dimethylquinazoline-2,
5-(1H,6H)-dione (4a): Mp 350-352 ˚C, IR (KBr) (ꢂmax cm-1): 3367,
1
3258, 3165, 1722, 1689, 1635; H NMR (300 MHz, DMSO-d6) ꢃ:
0.95 (s, 3H, CH3), 1.00 (s, 3H, CH3),1.93 (d, J=16.0 Hz, 1H, H-8a),
2.08 (d, J=16.0 Hz, 1H, H-8b), 2.31 (d, J=17.1 Hz, 1H, H-6a), 2.43
(d, J=17.1 Hz, 1H, H-6b), 6.74-7.14 (m, 4H, H-aromatic), 7.87 (s,
1H, NH), 9.69 (s, 1H, NH), 10.27 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) ꢃ: 26.7, 26.8, 28.0, 32.2, 49.7, 61.7, 105.2, 109.2, 121.4,
122.9, 129.6, 133.5, 141.9, 150.2, 153.9, 176.4, 191.9 ppm. Anal.
Calcd. for C17H17N3O3: C, 65.58; H, 5.50; N, 13.50. Found: C,
65.62; H, 5.53; N, 13.35.
Spiro[4.3ꢁ]oxindole-3,4,7,8-tetrahydro-1,7,7-trimethylquinazoline-
2,5-(1H,6H)-dione (4b): Mp 336-338 ˚C; IR (KBr) (ꢂmax cm-1):
3220, 3200, 3082, 2935, 1732, 1685; 1H NMR (300 MHz, DMSO-
d6) ꢃ: 0.97 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.93 (d, J=15.9 Hz, 1H,
H-8a), 2.01 (d, J=15.9 Hz, 1H, H-8b), 2.47 (d, J=3.0 Hz, 1H, H-
6a), 2.50 (d, J=3.0 Hz, 1H, H-6b), 3.31 (s, 3H, CH3), 6.73-7.13 (m,
4H, H-aromatic), 8.04 (s, 1H, NH), 10.22 (s, 1H, NH); 13C NMR
(75 MHz, DMSO-d6) ꢃ: 27.1, 27.1, 28.2, 29.2, 32.0, 48.9, 61.0,
107.4, 109.3, 121.4, 123.0, 128.7, 133.6, 142.0, 150.7, 155.3,
176.5, 192.3 ppm; MS (70 eV): m/z (%): 325 (5, M+), 295 (5.5),
280 (50), 241 (100), 212 (22).
5ꢁ-Bromo-spiro[4.3ꢁ]oxindole-3,4,7,8-tetrahydro-1,7,7-trimethylqu-
inazoline-2,5-(1H,6H)-dione (4c): Mp 344-346 ˚C; IR (KBr) (ꢂmax
cm-1): 3207, 3089, 2947, 1728, 1689; 1H NMR (300 MHz, DMSO-
d6) ꢃ:1.01 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.99 (d, J=9.5 Hz, 1H,
H-8a), 2.01 (d, J=9.5 Hz, 1H, H-8b), 2.62 (d, J=9.5 Hz, 1H, H-6a),
2.65 (d, J=9.5 Hz, 1H, H-6b), 3.32 (s, 3H, CH3), 6.72-7.33 (m, 3H,
H-aromatic), 8.11 (s, 1H, NH), 10.39 (s, 1H, NH). 13C NMR (75
MHz, DMSO-d6) ꢃ: 28.4, 28.7, 30.2, 32.9, 49.1, 56.8, 62.1, 107.6,
112.1, 113.8, 126.8, 132.2, 136.8, 142.3, 151.40, 156.8, 177.1,
193.3 ppm.
[19]
[20]
[21]
[22]
[23]
[24]
Spiro[4.3ꢁ]oxindole-3,4,7,8-tetrahydro
quinazoline-2,5-(1H,6H)-
[25]
[26]
dione (4d): Mp 345-347 ˚C; IR (KBr) (ꢂmax cm-1): 3311, 3228,
1
3118, 1712, 1695, 1631; H NMR (300 MHz, DMSO-d6) ꢃ: 1.86-
2.15 (m, 4H, H-7,8), 2.50 (m, 2H, H-6), 6.74-7.14 (m, 4H, H-
aromatic), 7.83 (s, 1H, NH), 9.68 (s, 1H, NH), 10.25 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) ꢃ: 21.6, 27.0, 37.2, 62.8, 107.5,
110.1, 122.3, 124.1, 129.5, 134.5, 142.9, 151.0, 156.9, 177.5, 193.0
ppm. Anal. Calcd. for C15H13N3O3: C, 63.60; H, 4.63; N, 14.83.
Found: C, 63.66; H, 4.69; N, 14.76.
[27]
[28]
Wang, Z.T.; Xu, L.W.; Xia, C.G.; Wang, H.Q. Novel Biginelli-like
three-component cyclocondensation reaction: efficient synthesis of
5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron
Lett., 2004, 45, 7951.
Spiro[5.3ꢁ]oxindole-5,6-dihydropyrimido[4,5-b]pyrimidine-2,4,7-
(1H,3H,8H)-trione (4e): Mp 270-272 ˚C; IR (KBr) (ꢂmax cm-1):
1
3367, 3301, 3265, 1762, 1749, 1712, 1690; H NMR (300 MHz,
DMSO-d6) ꢃ: 6.67-7.13 (m, 4H, H-aromatic), 10.54 (s, 1H, NH),
11.17 (m, 4H, NH); 13C NMR (75 MHz, DMSO-d6) ꢃ: 53.4, 109.4,
121.4, 124.2, 128.0, 128.7, 143.1, 150.2, 167.4, 175.6 ppm. Anal.
Calcd. for C13H9N5O4: C, 52.18; H, 3.03; N, 23.40. Found: C,
52.23; H, 2.99; N, 23.44.
Sabitha, G.; Reddy, K.B.; Srinivas, R.; Yadav, J.S.
Iodotrimethylsilane-accelerated
one-pot
synthesis
of
5-
unsubstituted 3,4-dihydropyrimidin-2(1H)-ones: A novel procedure
for the Biginelli-like cyclocondensation reaction at room
temperature. Helv. Chim. Acta, 2005, 11, 2996.

282 Letters in Organic Chemistry, 2010, Vol. 7, No. 4
Kefayati et al.
Spiro[5.3ꢀ]-1ꢀ-N-Methyl-oxindole-5,6-dihydropyrimido[4,5-d]pyri-
midine-2,4,7-(1H,3H,8H)-trione (4f): Mp 228-230 ˚C; IR (KBr)
2H, CH2), 6.75-7.20 (m, 4H, H-aromatic), 7.93 (s, 1H, NH), 10.25
(s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) ꢂ: 13.8, 17.3, 30.2,
60.2, 62.8, 101.0, 110.3, 122.5, 124.1, 129.9, 134.4, 143.0, 151.7,
152.3, 165.8, 178.0 ppm; MS (70 eV): m/z (%): 315 (16, M+), 286
(90), 242 (100), 214 (35), 199 (13), 103 (9), 91 (7), 77 (9), 56 (70),
42 (8).
5ꢀ-Bromo-spiro[4.3']oxindole-ethyl-1,2,3,4-tetrahydro-1,6-dimethyl-
2-oxo-pyrimidine-5-carboxylate (8d): Mp 175-178 ˚C; IR (KBr)
(ꢁmax cm-1): 3452, 3217, 1740, 1712, 1649. 1H NMR (300 MHz,
DMSO-d6) ꢂ: 0.64 (t, 3H, CH3), 2.27 (s, 3H, CH3), 3.01 (s, 3H,
CH3), 3.59 (m, 2H, CH2), 6.46-7.13 (m, 3H, H-aromatic), 7.29 (s,
1H, NH), 9.80 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6) ꢂ: 13.5,
14.4, 17.3, 60.3, 63.0, 100.2, 111.8, 114.5, 126.9, 132.2, 135.9,
141.3, 151.9, 152.0, 165.3, 177.9 ppm. MS (70 eV): m/z (%): 393
(6, M+), 364 (40), 320 (38), 292 (12), 277 (8), 103(8), 91 (7), 77
(7), 56 (100), 42 (15).
1
(ꢁmax cm-1): 3380, 3184, 3097, 2981, 1740, 1710, 1690; H NMR
(300 MHz, DMSO-d6) ꢂ: 3.03 (s, 3H, CH3), 6.91-7.28 (m, 4H, H-
aromatic), 11.2 (m, 4H, NH); 13C NMR (75 MHz, DMSO-d6) ꢂ:
53.5, 56.9, 109.2, 123.0, 124.7, 128.4, 129.8, 145.4, 151.0, 168.6,
175.1 ppm.
5ꢀ-Bromo-spiro[5,3ꢀ]oxindole-5,6-dihydropyrimido[4,5-d]pyrimi-
dine-2,4,7-(1H,3H,8H)- trione (4g): Mp 238-240 ˚C; IR (KBr) (ꢁmax
cm-1): 3334, 3211, 3093, 1731, 1689; 1H NMR (300 MHz, DMSO-
d6) ꢂ: 6.68-7.35 (m, 3H, H-aromatic), 10.74 (s, 1H, NH), 11.25 (m,
4H, NH); 13C NMR (75 MHz, DMSO-d6) ꢂ: 56.9, 112.1, 113.8,
128.1, 131.6, 132.3, 143.6, 151.0, 168.0, 176.3 ppm.
5ꢀ-Bromo-spiro[5,3ꢀ]oxindole-5,6,7,8-tetrahydro-7-thioxopyrimido
[4,5-d]pyrimidine-2,4-(1H,3H)-dione (4h): Mp 365-367 ˚C; IR
(KBr) (ꢁmax cm-1): 3328, 3151, 3098, 1710, 1681; 1H NMR (300
MHz, DMSO-d6) ꢂ: 6.73-8.27 (m, 3H, H-aromatic), 10.63 (s, 1H,
NH), 11.20 (m, 2H, NH), 11.32 (m, 2H, NH); 13C NMR (75 MHz,
DMSO-d6) ꢂ: 57.3, 112.8, 112.9, 128.6, 132.1, 132.7, 143.9, 168.3,
176.7, 178.1 ppm.
Kappe, C.O. A reexamination of the mechanism of the Biginelli
dihydropyrimidine synthesis. Support for an N-acyliminium ion
intermediate. J. Org. Chem. 1997, 62, 7201.
General procedure for the synthesis of spiro[oxindole-
pyrrimidine]ones 8a-i: A mixture of isatin derivative 1 (5 mmol),
acyclic 1,3-dicarbonyl compound 7 (7.5 mmol), urea or N-methyl
urea or thiourea 3 (10 mmol), HCl (15% mmol) and ethanol (5 mL)
refluxed for appropriate time according to Table 3 (Scheme 4). The
reaction after completion, as monitored by TLC on silica gel using
ethyl acetate as eluent, was allowed to cool to room temperature.
Then 30 mL distilled water was added to the beaker and stirred for
10 minute. The precipitate thus obtained was filtered off. The crude
product was purified by recrystallization from ethanol 95.5% and
dried.
Spiro[4.3']oxindole-ethyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-pyri-
midine-5-carboxylate (8a): Mp 297-299 ˚C; IR (KBr) (ꢁmax cm-1):
3436, 3201, 3089, 2970, 1716, 1664; 1H NMR (300 MHz, DMSO-
d6) ꢂ: 0.80 (t, 3H, CH3 ), 2.44 (s, 3H, CH3), 3.72 (m, 2H, CH2),
6.75-7.19 (m, 4H, H-aromatic), 7.80 (s, 1H, NH), 9.37 (s, 1H, NH),
10.23 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) ꢂ: 14.0, 19.0,
19.4, 63.9, 97.86, 110.2, 122.5, 124.1, 129.7, 135.1, 143.0, 150.8,
151.3, 165.4, 178.2 ppm; MS (70 eV): m/z (%): 301 (10, M+), 272
(64), 228 (100), 200 (34), 131 (7), 103 (10), 91 (8), 77 (8), 56 (7),
42 (17). Anal. Calcd. for C15H15N3O4: C, 59.79; H, 5.02; N, 13.95.
Found: C, 59.85; H, 4.86; N, 14.00.
Spiro[4.3']oxindole-N-Phenyl-1,2,3,4-tetrahydro-6-methyl-2-oxo-
pyrimidine-5-carboxamide (8e): Mp 298-300 ˚C; IR (KBr) (ꢁmax
1
cm-1): 3400, 3298, 1722, 1700. H NMR (300 MHz, DMSO-d6) ꢂ:
2.01 (s, 3H, CH3), 6.69-7.38 (m, 9H, H-aromatic), 7.56 (s, 1H,
NH), 8.92 (s, 1H, NH), 9.69 (s, 1H, NH), 10.13 (s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6) ꢂ: 18.3, 64.2, 105.3, 110.3, 120.0,
122.3, 123.9, 124.7, 129.3, 133.2, 139.7, 139.8, 143.3, 152.8,
165.0, 178.3 ppm. Anal. Calcd. for C19H16N4O3: C, 65.51; H, 4.63;
N, 16.08. Found: C, 65.46; H, 4.55; N, 16.12.
[33]
[34]
Spiro[4.3']oxindole-N-Phenyl-1,2,3,4-tetrahydro-1,6-dimethyl-2-
oxo-pyrimidine-5-carboxamide (8f): Mp 265-268 ˚C; IR (KBr)
1
(ꢁmax cm-1): 3410, 3298, 1718, 1700. H NMR (300 MHz, DMSO-
d6) ꢂ: 2.16 (s, 3H, CH3), 3.15 (s, 3H, CH3), 6.69-7.36 (m, 9H, H-
aromatic), 7.72 (s, 1H, NH), 9.91 (s, 1H, NH), 10.16 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6) ꢂ: 18.3, 30.0, 63.1, 107.8, 110.3,
120.2, 122.3, 124.0, 125.0, 129.3, 130.0, 132.4, 139.6, 140.5,
143.2, 153.6, 165.3, 178.0 ppm.
5ꢀ-Bromo-spiro[4.3']oxindole-N-Phenyl-1,2,3,4-tetrahydro-6-met-
hyl-2-oxo-pyrimidine-5-carboxamide (8g): Mp 295-297 ˚C; IR
(KBr) (ꢁmax cm-1): 3405, 3220, 1712, 1690. 1H NMR (300 MHz,
DMSO-d6) ꢂ: 2.02 (s, 3H, CH3), 6.67-7.39 (m , 8H, H-aromatic),
7.67 (s, 1H, NH), 9.01 (s, 1H, NH), 9.74 (s, 1H, NH), 10.30 (s, 1H,
NH). 13C NMR (75 MHz, DMSO-d6) ꢂ: 18.4, 64.3, 104.6, 112.3,
113.7, 120.0, 120.2, 124.0, 127.5, 129.4, 132.6, 135.8, 139.6,
140.5, 142.6, 152.5, 164.9, 177.8 ppm.
5ꢀ-Bromo-spiro[4.3']oxindole-ethyl-1,2,3,4-tetrahydro-6-methyl-2-
thio-pyrimidine-5-carboxylate (8h): Mp 323-325 ˚C; IR (KBr) (ꢁmax
cm-1): 3407, 3315, 3132, 1715, 1709; 1H NMR (300 MHz, DMSO-
d6) ꢂ: 0.88 (t, 3H, CH3), 2.35 (s, 3H, CH3), 3.78 (m, 2H, CH2),
6.46-7.13 (m, 3H, H-aromatic), 7.76 (s, 1H, NH), 9.54 (s, 1H, NH),
10.48 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) ꢂ: 15.1, 20.4,
20.9, 69.7, 100.6, 114.1, 115.8, 127.6, 132.1, 141.9, 151.3, 165.4,
174.7, 178.1 ppm.
5ꢀ-Bromo-spiro[4.3']oxindole-ethyl-1,2,3,4-tetrahydro-6-methyl-2-
oxo-pyrimidine-5-carboxylate (8b): Mp 293-295 ˚C; IR (KBr) (ꢁmax
1
cm-1): 3420, 3310, 3145, 1730, 1705, 1640; H NMR (300 MHz,
DMSO-d6) ꢂ: 0.85 (t, 3H, CH3), 2.24 (s, 3H, CH3), 3.76 (m, 2H,
CH2), 6.71-7.37 (m, 3H, H-aromatic), 7.87 (s, 1H, NH), 9.44 (s,
1H, NH), 10.39 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) ꢂ:
14.0, 19.0, 19.1, 64.0, 97.0, 112.2, 113.9, 126.9, 132.4, 142.3,
151.0, 151.7, 165.2, 177.9 ppm; MS (70 eV): m/z (%): 379 (14,
M+), 350 (75), 306 (100), 278 (19), 263 (12), 210 (11), 131 (12),
103 (14), 91 (10), 77 (9), 42 (43).
Spiro[4.3']oxindole-ethyl-1,2,3,4-tetrahydro-1,6-dimethyl-2-oxo-
pyrimidine-5-arboxylate (8c): Mp 248-250 ˚C; IR (KBr) (ꢁmax cm-
1): 3320, 3259, 1735, 1710, 1664; 1H NMR (300 MHz, DMSO-d6)
ꢂ: 0.78 (t, 3H, CH3), 2.43 (s, 3H, CH3), 3.17 (s, 3H, CH3), 3.69 (m,
Spiro[4.3']oxindole-N-Phenyl-1,2,3,4-tetrahydro-6-methyl-2-thio-
pyrimidine-5-carboxamide (8i): Mp 331-333 ˚C; IR (KBr) (ꢁmax
1
cm-1): 3408, 3301, 1718, 1703. H NMR (300 MHz, DMSO-d6) ꢂ:
2.08 (s, 3H, CH3), 6.72-7.43 (m, 9H, H-aromatic), 7.50 (s, 1H,
NH), 9.01 (s, 1H, NH), 9.73 (s, 1H, NH), 10.53 (s, 1H, NH). 13C
NMR (75 MHz, DMSO-d6) ꢂ: 19.3, 64.8, 106.3, 111.2, 119.8,
122.7, 124.1, 124.9, 130.2, 133.1, 139.9, 140.0, 143.9, 165.9,
175.6, 177.1 ppm.