A novel, one-pot, efficient synthesis of 2-aroyl-1,4-diaryl-7,9-dimethyl-7, 9-diazaspiro[4.5]deca-1,3-diene-6,8,10-triones

Article abstract of DOI:10.1055/s-0028-1083157

A novel and efficient synthesis of 2-aroyl-1,4-diaryl-7,9-dimethyl-7,9- diazaspiro[4.5]deca-1,3-diene-6,8,10-triones is described. The reactive 1:1 zwitterionic intermediate, formed by the addition of triphenylphosphine to diaroylacetylenes, was trapped by a Knoevenagel condensation product prepared in situ by reaction of AyV-dimethylbarbituric acid and aromatic aldehydes, to afford the title compounds in excellent yields under mild reaction conditions.

Full text of DOI:10.1055/s-0028-1083157

PAPER
3289
A Novel, One-Pot, Efficient Synthesis of 2-Aroyl-1,4-diaryl-7,9-dimethyl-7,9-
diazaspiro[4.5]deca-1,3-diene-6,8,10-triones
S
ynthesis of 2-Aroyl-1
e
,4-diaryl-7,
h
9-dimethyl-7
d
,9-diazaspiro
i
[4.5]deca-1,3
A
-diene-6,8,10-trio
d
nes ib,*a Mohammad Hosein Sayahi,a Hakimeh Ziyadi,a Long-Guan Zhu,b Hamid Reza Bijanzadehc
a
School of Chemistry, University College of Science, University of Tehran, P.O. Box 14155-6455, Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
c
Chemistry Department, Zhejiang University, Hangzhou 310027, P. R. of China
Department of Chemistry, Tarbiat Modarres University, P.O. Box 14115-175, Tehran, Iran
Received 8 February 2008; revised 2 July 2008
turic acid have been discovered.18 Phenobarbital
(Figure 1) is the most widely used anticonvulsant world-
wide and the oldest still in use.19 It also has sedative and
hypnotic properties.20 Some examples have matrix metal-
Abstract: A novel and efficient synthesis of 2-aroyl-1,4-diaryl-7,9-
dimethyl-7,9-diazaspiro[4.5]deca-1,3-diene-6,8,10-triones is de-
scribed. The reactive 1:1 zwitterionic intermediate, formed by the
addition of triphenylphosphine to diaroylacetylenes, was trapped by
a Knoevenagel condensation product prepared in situ by reaction of loproteinase (MMP) inhibitory activity (Figure 1).21 In
N,N-dimethylbarbituric acid and aromatic aldehydes, to afford the
title compounds in excellent yields under mild reaction conditions.
addition to the pharmaceutical value, 5,5-dialkylated bar-
bituric acids are also useful building blocks for the assem-
Key words: spiro compounds, cyclopentadienes, cyclizations,
aldehydes, alkynes, heterocycles
bly of supramolecular structures via non-covalent
interactions.22 In this respect, Fenniri et al. recently de-
vised helical nanotubes.23
Spirobarbiturates are a class of compounds known for
their interesting physiological activity.24 Compound 1
(Figure 1) has been used as a conformationally locked
unit in the construction of modified oligonucleotides.25
Cyclopentadienes (Cps) are highly useful synthetic inter-
mediates. Considerable attention has been focused on the
synthesis of substituted Cps as useful construction units of
fused-ring systems via inter- and intramolecular Diels–
Alder reactions, as ligands in coordination chemistry and
homogeneous catalysis for olefin polymerization.1
O
O
O
HN
HN
HN
NH
NH
NH
Several interesting methods have been reported for the di-
rect preparation of substituted Cps, including: [3+2] annu-
lation of allylidenetriphenylphosphoranes with 1,2-
diacylethylenes,2 reaction between isocyanides or triphe-
nylphosphine, dimethyl acetylenedicarboxylate, and elec-
trophilic styrenes,3 Pt(II)- or Au(I)-catalyzed cyclization
of 1,2,4-trienes,4 acid-catalyzed cyclization of 1,4-penta-
dien-3-ols,5 Pd-mediated cyclization of 1,5-hexadien-3-
ols,6 reaction of 1,1-dibromo-2-vinylcyclopropanes with
methyl lithium,7 cycloaddition of a,b-unsaturated Fischer
carbene complexes to alkynes or alkenes,8 electrophilic
allylation of enolizable 1,3-dicarbonyl compounds and
successive acid-catalyzed cyclizations,9 insertion of aroyl
cyanides or acid chlorides to zirconacyclopentenes,10 re-
action of zirconacyclopentadienes with a one-carbon-unit
building block such as aldehydes, propynoates, acyl ha-
lides or 1,1-dihalides11 and reaction of 1,4-dilithio-1,3-
dienes with carboxylic acid derivatives, aldehydes or ke-
tones.12
O
O
O
O
O
O
n-C8H17
CO2Et
HO
OH
1
Phenobarbital
an MMP inhibitor
Figure 1 Examples of pharmaceutically or pharmacologically
important barbiturates
Herein we report a novel synthesis of spirocyclopentadi-
enyl-N,N-dimethylbarbituric acids using simple starting
materials. Thus, a mixture of N,N¢-dimethylbarbituric acid
(2), aromatic aldehydes 3 and diaroylacetylenes 5, in the
presence of triphenylphosphine, underwent a smooth
reaction at ambient temperature to afford 2-aroyl-1,4-
diaryl-7,9-dimethyl-7,9-diazaspiro[4.5]deca-1,3-diene-
6,8,10-triones 6a–i in 90–96% yield (Scheme 1, Table 1).
The reactions were carried out by first dissolving N,N-
dimethylbarbituric acid in hot water and then adding the
aldehyde. After a few minutes, when nearly complete con-
version into the corresponding 5-arylmethylidene-N,N-
dimethylbarbituric acid 426 was indicated by TLC, a solu-
tion of triphenylphosphine in dichloromethane was added
to the mixture. A solution of dibenzoylacetylene in
dichloromethane was then slowly added and the reaction
mixture was stirred at ambient temperature. The reaction
proceeded spontaneously and went to completion within
Barbituric acid has widely been used in the manufacture
of plastics,13 textiles,14 polymers15 and pharmaceuti-
cals.16,17 Pharmacologically active barbituric acids are
either mono- or di-C-substituted derivatives. Several im-
portant drug molecules based on 5,5-disubstituted barbi-
SYNTHESIS 2008, No. 20, pp 3289–3294
x
x.
x
x
.
2
0
0
8
Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083157; Art ID: T02408SS
1
one hour. The H NMR spectra of the crude products
© Georg Thieme Verlag Stuttgart · New York

3290
M. Adib et al.
PAPER
O
Me
O
Me
O
O
N
N
Ph3P
Me
N
Me
O
Me
O
Me
O
Ar'OC
C
CCOAr' (5)
H2O
N
N
N
O
Ar'
Ph P=O
+
ArCHO
+
3
Ar
CH Cl
5 min
2, r.t., 1 h
2
O
Ar'
Ar
O
3
4
2
6
Scheme 1
clearly indicated the formation of the spirocyclopentadi- of 6b showed four signals arising from the spiro-carbon
enyl-N,N-dimethylbarbituric acids 6 in excellent yields. atom (d = 74.0 ppm), urea carbonyl (d = 150.6 ppm), two
No product other than 6 and triphenylphosphine oxide equivalent amide carbonyls (d = 164.5 ppm) and the ke-
could be detected by NMR spectroscopy.
tone function (d = 192.6 ppm) as well as eighteen other
distinct resonances, which are in agreement with the pro-
posed structure. Partial assignments of these resonances
are given in the experimental section. Single-crystal X-ray
analysis of 6b conclusively confirmed the structure of the
isolated products. An ORTEP diagram of 6b is shown in
Figure 2.27
The structures of the isolated products 6a–i were con-
firmed by IR, 1H and 13C NMR spectroscopy, mass spec-
trometry and elemental analysis. The mass spectrum of 6b
displayed the molecular ion [M+] peak at m/z = 476, which
was consistent with the structure of the isolated product.
The 1H NMR spectrum of 6b exhibited three single sharp
lines arising from the aryl methyl group (d = 2.22 ppm),
N-methyl substituents (d = 3.26 ppm) and the vinylic pro-
ton of the five-membered ring (d = 7.18 ppm), along with
the characteristic signals with appropriate chemical shifts
and coupling constants for the fourteen protons of the
1
three aryl groups. The H-decoupled 13C NMR spectrum
Table 1 Synthesis of 7,9-Diazaspiro[4.5]deca-1,3-diene-6,8,10-tri-
ones 6a–i
6
a
Ar
Ar¢
Yield (%)a
96
Figure 2 Molecular structure of 6b
A mechanistic rationalization for this reaction is provided
in Scheme 2. On the basis of the well-established chemis-
try of trivalent phosphorus nucleophiles,28–31 it is reason-
able to assume that the zwitterionic intermediate 7,
formed from the initial addition of triphenylphosphine to
the electron-deficient acetylenic compound 5, is trapped
by the electron-deficient 5-arylmethylidene-N,N-dimeth-
ylbarbituric acid 4 prepared in situ, leading to the 1:1:1
adduct 8, which undergoes intramolecular cyclization to
betaine 9. This intermediate can undergo a proton shift to
form a new betaine 10, from which triphenylphosphine
oxide is removed to afford the isolated spirocyclopentadi-
enyl-N,N-dimethylbarbituric acids 6.
b
c
92
90
d
e
f
95
95
95
91
92
F
Cl
Br
In summary, we have succeeded in synthesizing 2-aroyl-
1,4-diaryl-7,9-dimethyl-7,9-diazaspiro[4.5]deca-1,3-di-
ene-6,8,10-triones of potential synthetic and pharmaco-
logical interest via a novel, one-pot reaction between N,N-
dimethylbarbituric acid, aromatic aldehydes and diaroyl-
acetylenes, in the presence of triphenylphosphine. High
yields of the products, relatively short reaction times and
the use of simple starting materials are the main advan-
tages of this method. The reaction is performed under neu-
tral, mild conditions, and the starting materials and
g
h
O
S
i
94
F
a Isolated yield.
Synthesis 2008, No. 20, 3289–3294 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aroyl-1,4-diaryl-7,9-dimethyl-7,9-diazaspiro[4.5]deca-1,3-diene-6,8,10-triones
3291
O
Me
O
Me
O
O
N
N
Me
O
Me
O
N
O
N
+
O
C
O
C
Ph3P
_
_
Ar
CCOAr'
Ar'
Ar'
O
Ph3P
C
C
+
Ar
(4)
Ar'OC
Ar'
PPh3
Ar'
+
7
5
8
O
O
O
N
Me
Me
O
Me
O
Me
Me
O
Me
O
N
N
N
N
N
O
O
proton shift
Ar'
Ar'
Ar
Ar
Ar'
Ar
Ph3P=O
+
_
O
_
O
+
+
Ar'
Ar'
Ar'
PPh3
PPh3
O
O
O
6
9
10
Scheme 2
2-Benzoyl-7,9-dimethyl-1,4-diphenyl-7,9-diazaspiro[4.5]deca-
1,3-diene-6,8,10-trione (6a)
Yield: 0.89 g (96%); yellow crystals; mp 189–190 °C.
reagents can be mixed without any activation or modifica-
tion. In view of extensive use of cyclopentadienes and
barbituric acid derivatives in chemistry and medicinal
chemistry, the spirocyclopentadienyl-N,N-dimethylbarbi-
turic acids prepared in the present study may find useful
applications in synthetic organic, bioorganic and medici-
nal chemistry.
IR (KBr): 1745 and 1686 (C=O), 1589, 1495, 1445, 1375, 1339,
1283, 1247, 1175, 1121, 1043, 885, 858, 752, 725, 694 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.22 (s, 6 H, 2 × CH3), 6.96 (dd,
J = 7.6, 1.2 Hz, 2 H, 2 × CH), 7.11–7.17 (m, 3 H, 3 × CH), 7.18 (s,
1 H, CH), 7.21 (dd, J = 7.0, 1.4 Hz, 2 H, 2 × CH), 7.25–7.33 (m,
5 H, 5 × CH), 7.40 (t, J = 7.4 Hz, 1 H, CH), 7.83 (d, J = 7.3 Hz, 2 H,
2 × CH).
13C NMR (125 MHz, CDCl3): d = 28.9 (NCH3), 73.9 (C), 125.6,
128.0, 128.3, 128.4, 128.7, 129.1, 129.2 and 129.4 (8 × CH), 131.4
and 132.0 (2 × C), 133.2 and 133.4 (2 × CH), 136.3, 145.1, 147.8
and 149.1 (4 × C), 150.4 (C=O, urea), 164.3 (C=O, amide), 192.3
(C=O, ketone).
Triphenylphosphine, N,N-dimethylbarbituric acid and aldehydes
were obtained from Merck (Germany) and Fluka (Switzerland), and
were used without further purification. Diaroylacetylenes 5 were
prepared according to literature procedures.32 Melting points were
measured on an Electrothermal 9100 apparatus. Elemental analyses
for C, H and N were performed using a Heraeus CHN-O-Rapid an-
alyzer. Mass spectra were recorded on a FINNIGAN-MATT 8430
mass spectrometer operating at an ionization potential of 20 eV. 1H
and 13C NMR spectra were measured as solutions in CDCl3 with a
Bruker DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz,
respectively. IR spectra were recorded on a Shimadzu IR-460 spec-
trometer. Chromatography columns were prepared from Merck sil-
ica gel 60 mesh.
MS: m/z (%) = 462 (100) [M+], 348 (19), 302 (8), 271 (18), 243
(12), 215 (27), 174 (12), 105 (59), 77 (21).
Anal. Calcd for C29H22N2O4: C, 75.31; H, 4.79; N, 6.06. Found: C,
75.2; H, 4.9; N, 5.9.
2-Benzoyl-7,9-dimethyl-1-(4-methylphenyl)-4-phenyl-7,9-di-
azaspiro[4.5]deca-1,3-diene-6,8,10-trione (6b)
Yield: 0.88 g (92%); pale-yellow crystals; mp 185 °C.
Compounds 6; General Procedure
N,N-Dimethylbarbituric acid (2; 0.312 mg, 2 mmol) was dissolved
in hot H2O (60 °C, 5 mL) and the appropriate aldehyde (2 mmol)
was rapidly added and stirred at ambient temperature for 5 min. The
Knoevenagel condensation product, 5-arylmethylidene-N,N-di-
methylbarbituric acid, was precipitated under the reaction condi-
tions. A solution of triphenylphosphine (0.524 g, 2 mmol) in
CH2Cl2 (1 mL) was added to the reaction mixture and a solution of
the appropriate diaroylacetylene (2 mmol) in CH2Cl2 (1 mL) was
added over 5 min. The reaction mixture was stirred at 25 °C for 1 h.
The aqueous layer was separated from the heterogeneous reaction
mixture by suction, the organic solvent was evaporated and the solid
residue was purified by column chromatography (n-hexane–
EtOAc, 3:1). The solvent was removed and the residue was recrys-
tallized (n-hexane-EtOAc, 1:1). The yields refer to the products ob-
tained by column chromatography before recrystallization.
IR (KBr): 1747 and 1686 (C=O), 1591, 1501, 1445, 1375, 1339,
1281, 1246, 1177, 1119, 1045, 885, 858, 752, 719, 690 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.22 (s, 3 H, CH3), 3.26 (s, 6 H,
2 × CH3), 6.87 (d, J = 8.0 Hz, 2 H, 2 × CH), 6.97 (d, J = 8.0 Hz,
2 H, 2 × CH), 7.18 (s, 1 H, CH), 7.22 (dd, J = 7.0, 1.5 Hz, 2 H,
2 × CH), 7.28–7.36 (m, 5 H, 5 × CH), 7.44 (tt, J = 7.3, 1.3 Hz, 1 H,
CH), 7.87 (dd, J = 8.0, 1.3 Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 21.2 (CH3), 29.1 (NCH3), 74.0
(C), 125.8, 128.0 and 128.4 (3 × CH), 128.6 (C), 128.8, 129.2,
129.3 and 129.6 (4 × CH), 132.2 (C), 133.3 and 133.6 (2 × CH),
136.5, 139.3, 145.0, 147.8 and 149.5 (5 × C), 150.6 (C=O, urea),
164.5 (C=O, amide), 192.6 (C=O, ketone).
MS: m/z (%) = 476 (86) [M+], 461 (23), 430 (7), 361 (12), 277 (20),
257 (16), 236 (21), 181 (14), 149 (14), 119 (14), 105 (100), 77 (57).
Anal. Calcd for C30H24N2O4: C, 75.62; H, 5.08; N, 5.88. Found: C,
75.6; H, 5.1; N, 5.8.
Synthesis 2008, No. 20, 3289–3294 © Thieme Stuttgart · New York

3292
M. Adib et al.
PAPER
2-Benzoyl-7,9-dimethyl-1-(3-methylphenyl)-4-phenyl-7,9-di-
azaspiro[4.5]deca-1,3-diene-6,8,10-trione (6c)
Anal. Calcd for C29H21ClN2O4: C, 70.09; H, 4.26; N, 5.64. Found:
C, 69.9; H, 4.5; N, 5.5.
Yield: 0.86 g (90%); pale-yellow crystals; mp 117–118 °C.
2-Benzoyl-1-(4-bromophenyl)-7,9-dimethyl-4-phenyl-7,9-di-
azaspiro[4.5]deca-1,3-diene-6,8,10-trione (6f)
Yield: 1.03 g (95%); pale-yellow crystals; mp 207–208 °C.
IR (KBr): 1749, 1686 and 1645 (C=O), 1597, 1580, 1437, 1373,
1348, 1277, 1247, 1179, 1124, 1040, 899, 866, 750, 727, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.17 (s, 3 H, CH3), 3.25 (s, 6 H,
2 × CH3), 6.77 (d, J = 9.0 Hz, 1 H, CH), 6.78 (s, 1 H, CH), 7.00 (d,
J = 7.6 Hz, 1 H, CH), 7.05 (t, J = 7.4 Hz, 1 H, CH), 7.22 (s, 1 H,
CH), 7.23 (dd, J = 7.5, 1.5 Hz, 2 H, 2 × CH), 7.28–7.36 (m, 5 H,
5 × CH), 7.43 (tt, J = 7.3, 1.2 Hz, 1 H, CH), 7.83 (dd, J = 7.8, 1.3
Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 21.1 (CH3), 29.0 (NCH3), 74.1
(C), 125.1, 125.7, 128.4, 128.5, 128.8, 129.0, 129.2, 129.5 and
130.0 (9 × CH), 131.4 and 132.2 (2 × C), 133.2 and 133.5 (2 × CH),
136.6, 138.2, 145.0, 147.7 and 149.6 (5 × C), 150.6 (C=O, urea),
164.5 (C=O, amide), 192.5 (C=O, ketone).
IR (KBr): 1749 and 1686 (C=O), 1595, 1505, 1449, 1373, 1337,
1283, 1240, 1175, 1115, 1069, 1047, 885, 856, 750, 720 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.27 (s, 6 H, 2 × CH3), 6.80 (d,
J = 8.5 Hz, 2 H, 2 × CH), 7.13 (s, 1 H, CH), 7.20 (dd, J = 7.6, 1.6
Hz, 2 H, 2 × CH), 7.30 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.31–7.37 (m,
5 H, 5 × CH), 7.49 (t, J = 7.4 Hz, 1 H, CH), 7.86 (dd, J = 7.5, 1.3
Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 29.2 (NCH3), 73.9 (C), 123.7 (C),
125.9, 128.6, 129.1, 129.2, 129.6 and 129.7 (6 × CH), 130.6 (C),
131.9 (CH), 132.0 (C), 133.5 and 133.6 (2 × CH), 136.2, 146.1,
147.6 and 148.5 (4 × C), 150.4 (C=O, urea), 164.2 (C=O, amide),
192.2 (C=O, ketone).
MS: m/z (%) = 476 (100) [M+], 461 (50), 361 (16), 347 (16), 285
(17), 228 (19), 173 (20), 105 (94), 77 (34).
MS: m/z (%) = 542 (59) [M+, 81Br], 540 (58) [M+, 79Br], 426 (18),
349 (12), 289 (17), 270 (25), 213 (63), 174 (75), 159 (24), 105
(100), 77 (50).
Anal. Calcd for C30H24N2O4: C, 75.62; H, 5.08; N, 5.88. Found: C,
75.4; H, 5.2; N, 5.7.
2-Benzoyl-1-(4-fluorophenyl)-7,9-dimethyl-4-phenyl-7,9-diaza-
spiro[4.5]deca-1,3-diene-6,8,10-trione (6d)
Anal. Calcd for C29H21BrN2O4: C, 64.34; H, 3.91; N, 5.17. Found:
C, 64.3; H, 3.9; N, 5.1.
Yield: 0.91 g (95%); pale-yellow crystals; mp 213 °C.
2-Benzoyl-1-(2-furyl)-7,9-dimethyl-4-phenyl-7,9-diaza-
spiro[4.5]deca-1,3-diene-6,8,10-trione (6g)
Yield: 0.82 g (91%); yellow crystals; mp 175–177 °C.
IR (KBr): 1749, 1686 and 1666 (C=O), 1595, 1552, 1500, 1445,
1375, 1339, 1285, 1255, 1223, 1175, 1164, 1123, 1043, 887, 858,
752, 714 cm–1.
IR (KBr): 1744, 1684 and 1675 (C=O), 1593, 1487, 1443, 1416,
1371, 1333, 1281, 1244, 1165, 1124, 1042, 908, 876, 814, 752, 716,
685 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.38 (s, 6 H, 2 × CH3), 6.34 (dd,
J = 3.5, 1.6 Hz, 1 H, CH), 6.75 (d, J = 3.5 Hz, 1 H, CH), 6.99 (s,
1 H, CH), 7.20 (d, J = 7.3 Hz, 2 H, 2 × CH), 7.28 (d, J = 1.6 Hz,
1 H, CH), 7.29–7.34 (m, 3 H, 3 × CH), 7.48 (dd, J = 7.5, 7.7 Hz,
2 H, 2 × CH), 7.58 (t, J = 7.3 Hz, 1 H, CH), 8.02 (d, J = 7.3 Hz, 2 H,
2 × CH).
13C NMR (125 MHz, CDCl3): d = 29.2 (NCH3), 70.9 (C), 113.1,
113.8, 125.8, 128.8, 128.9, 129.2 and 129.6 (6 × CH), 132.2 (C),
133.6 and 134.4 (2 × CH), 136.7, 139.0 and 140.7 (3 × C), 143.6
(CH), 147.1 and 147.3 (2 × C), 151.3 (C=O, urea), 164.7 (C=O,
amide), 192.1 (C=O, ketone).
MS: m/z (%) = 452 (100) [M+], 338 (45), 309 (11), 281 (17), 261
(13), 252 (18), 205 (20), 176 (20), 155 (16), 126 (11), 105 (96), 77
(40).
1H NMR (500 MHz, CDCl3): d = 3.26 (s, 6 H, 2 × CH3), 6.86 (dd,
3
3JF–H = 8.6 Hz, JH–H = 8.7 Hz, 2 H, 2 × CH), 6.98 (dd, 3JH–H = 8.7
4
Hz, JF–H = 4.9 Hz, 2 H, 2 × CH), 7.17 (s, 1 H, CH), 7.21 (dd,
J = 7.4, 1.5 Hz, 2 H, 2 × CH), 7.30–7.37 (m, 5 H, 5 × CH), 7.47 (tt,
J = 7.4, 1.0 Hz, 1 H, CH), 7.84 (dd, J = 7.3, 1.3 Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 29.1 (NCH3), 74.1 (C), 115.8 (d,
4
2JF–C = 21.8 Hz, CH), 125.8 (CH), 127.7 (d, JF–C = 3.4 Hz, C),
3
128.5, 129.0, 129.2 and 129.5 (4 × CH), 130.2 (d, JF–C = 8.4 Hz,
CH), 132.1 (C), 133.4 and 133.5 (2 × CH), 136.3, 145.8, 148.0 and
148.2 (4 × C), 150.4 (C=O, urea), 163.0 (d, 1JF–C = 250.6 Hz, CF),
164.3 (C=O, amide), 192.3 (C=O, ketone).
MS: m/z (%) = 480 (29) [M+], 430 (9), 366 (12), 302 (14), 279 (19),
167 (43), 149 (100), 105 (38), 83 (42), 69 (64), 57 (79).
Anal. Calcd for C29H21FN2O4: C, 72.49; H, 4.41; N, 5.83. Found: C,
72.3; H, 4.5; N, 5.6.
2-Benzoyl-1-(4-chlorophenyl)-7,9-dimethyl-4-phenyl-7,9-diaza-
spiro[4.5]deca-1,3-diene-6,8,10-trione (6e)
Yield: 0.94 g (95%); pale-yellow crystals; mp 215–216 °C.
Anal. Calcd for C27H20N2O5: C, 71.67; H, 4.46; N, 6.19. Found: C,
71.6; H, 4.6; N, 6.1.
IR (KBr): 1749, 1685 and 1668 (C=O), 1595, 1580, 1549, 1495,
1445, 1375, 1337, 1285, 1248, 1175, 1119, 1088, 1043, 887, 856,
750, 708 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.27 (s, 6 H, 2 × CH3), 6.95 (d,
J = 8.5 Hz, 2 H, 2 × CH), 7.15 (s, 1 H, CH), 7.16 (d, J = 8.5 Hz,
2 H, 2 × CH), 7.21 (dd, J = 7.4, 1.5 Hz, 2 H, 2 × CH), 7.30–7.37 (m,
5 H, 5 × CH), 7.48 (t, J = 7.4 Hz, 1 H, CH), 7.86 (dd, J = 7.2, 1.1
Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 29.2 (NCH3), 74.0 (C), 128.6,
128.9, 129.0, 129.2, 129.4, 129.5 and 129.6 (7 × CH), 130.2 and
132.0 (2 × C), 133.5 and 133.6 (2 × CH), 135.5, 136.3, 146.1, 147.5
and 147.6 (5 × C), 150.4 (C=O, urea), 164.3 (C=O, amide), 192.2
(C=O, ketone).
2-Benzoyl-7,9-dimethyl-4-phenyl-1-(2-thienyl)-7,9-diaza-
spiro[4.5]deca-1,3-diene-6,8,10-trione (6h)
Yield: 0.86 g (92%); pale-yellow crystals; mp 172–173 °C.
IR (KBr): 1745, 1687 and 1672 (C=O), 1595, 1497, 1444, 1375,
1338, 1284, 1247, 1178, 1117, 1045, 900, 875, 812, 752, 720, 690
cm–1.
1H NMR (500 MHz, CDCl3): d = 3.33 (s, 6 H, 2 × CH3), 6.80 (dd,
J = 3.8, 5.0 Hz, 1 H, CH), 6.84 (dd, J = 3.7, 1.0 Hz, 1 H, CH), 7.05
(s, 1 H, CH), 7.19 (d, J = 7.3 Hz, 2 H, 2 × CH), 7.27 (dd, J = 5.0, 3.9
Hz, 1 H, CH), 7.29–7.33 (m, 3 H, 3 × CH), 7.37 (dd, J = 7.8, 7.6 Hz,
2 H, 2 × CH), 7.49 (t, J = 7.4 Hz, 1 H, CH), 7.93 (dd, J = 7.2, 1.2
Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): d = 29.2 (NCH3), 73.2 (C), 125.8,
127.8, 127.9, 128.6, 129.0, 129.1, 129.2 and 129.6 (8 × CH), 132.1
and 132.7 (2 × C), 133.6 and 134.0 (2 × CH), 136.1, 141.8, 144.9
MS: m/z (%) = 498 (32) [M+, 37Cl], 496 (81) [M+, 35Cl], 382 (27),
305 (19), 270 (18), 249 (16), 213 (31), 174 (36), 105 (100), 77 (44).
Synthesis 2008, No. 20, 3289–3294 © Thieme Stuttgart · New York

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Synthesis of 2-Aroyl-1,4-diaryl-7,9-dimethyl-7,9-diazaspiro[4.5]deca-1,3-diene-6,8,10-triones
3293
and 148.5 (4 × C), 150.8 (C=O, urea), 164.4 (C=O, amide), 192.7
(C=O, ketone).
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1988, 29, 5641.
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Nakajima, K. Tetrahedron Lett. 1996, 37, 7521.
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(b) Takahashi, T.; Sun, W.-H.; Xi, C.; Kotora, M. Chem.
Commun. 1997, 2069. (c) Takahashi, T.; Xi, Z.; Kotora, M.;
Xi, C.; Nakajima, K. Tetrahedron Lett. 1996, 37, 7521.
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Tetrahedron Lett. 2000, 41, 7471.
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Chem. 2007, 1267. (b) Fang, H. Y.; Li, G. T.; Mao, G. L.;
Xi, Z. F. Chem. Eur. J. 2004, 10, 3444.
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59, 185.
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B. Org. Lett. 2003, 5, 3143. (b) McClenaghan, N. D.;
Absalon, C.; Bassani, D. M. J. Am. Chem. Soc. 2003, 125,
13004.
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J. Org. Chem. 2003, 68, 4684. (b) Brunner, H.; Ittner, K. P.;
Lunz, D.; Schmatloch, S.; Schmidt, T.; Zabel, M. Eur. J.
Org. Chem. 2003, 855.
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Lett. 2002, 43, 1603. (b) Jursic, B. S.; Neumann, D. M.
Tetrahedron Lett. 2001, 42, 8435. (c) Jursic, B. S.;
Neumann, D. M. Tetrahedron Lett. 2001, 42, 4103.
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Biochem. Behav. 1996, 54, 633.
MS: m/z (%) = 468 (100) [M+], 354 (39), 325 (9), 261 (10), 174 (15),
155 (10), 105 (96), 77 (36).
Anal. Calcd for C27H20N2O4S: C, 69.22; H, 4.30; N, 5.98. Found: C,
69.2; H, 4.3; N, 5.9.
2-(2,5-Dimethylbenzoyl)-4-(2,5-dimethylphenyl)-1-(4-fluoro-
phenyl)-7,9-dimethyl-7,9-diazaspiro[4.5]deca-1,3-diene-6,8,10-
trione (6i)
Yield: 1.01 g (94%); pale-yellow crystals; mp 147–148 °C.
IR (KBr): 1747, 1686 and 1654 (C=O), 1566, 1501, 1439, 1371,
1283, 1252, 1217, 1161, 1113, 1049, 839, 825, 748 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.20, 2.24, 2.27 and 2.47 (4 × s,
12 H, 4 × CH3), 3.16 (s, 6 H, 2 × CH3), 6.72 (br s, 1 H, CH), 6.78
(dd, 3JF–H = 8.6 Hz, 3JH–H = 8.7 Hz, 2 H, 2 × CH), 6.84 (s, 1 H, CH),
6.95 (d, J = 7.7 Hz, 1 H, CH), 6.99 (dd, J = 7.7, 1.1 Hz, 1 H, CH),
3
4
7.03 (dd, JH–H = 8.7 Hz, JF–H = 5.3 Hz, 2 H, 2 × CH), 7.06 (d,
J = 1.1 Hz, 1 H, CH), 7.13 (d, J = 7.8 Hz, 1 H, CH), 7.39 (br s, 1 H,
CH).
13C NMR (125 MHz, CDCl3): d = 19.2, 20.1, 20.6 and 20.8
2
(4 × CH3), 28.9 (NCH3), 77.9 (C), 115.2 (d, JF–C = 21.8 Hz, CH),
4
128.6 (CH), 129.2 (d, JF–C = 3.4 Hz, C), 129.9 (CH), 130.3 (d,
3JF–C = 8.6 Hz, CH), 130.7, 131.1 and 131.3 (3 × CH), 131.6 (C),
132.1 (CH), 134.2, 134.8, 135.0 and 135.1 (4 × C), 136.1 (CH),
136.8, 146.0, 146.8 and 149.3 (4 × C), 150.3 (C=O, urea), 162.7 (d,
1JF–C = 249.5 Hz, CF), 164.5 (C=O, amide), 194.6 (C=O, ketone).
MS: m/z (%) = 536 (57) [M+], 427 (28), 393 (6), 380 (19), 273 (20),
261 (9), 246 (13), 133 (100), 105 (37), 79 (13).
Anal. Calcd for C33H29FN2O4: C, 73.87; H, 5.45; N, 5.22. Found: C,
73.7; H, 5.6; N, 5.1.
(20) Whittle, S. R.; Turner, A. J. Biochem. Pharmacol. 1982, 31,
2891.
(21) Kim, S.-H.; Pudzianowski, A. T.; Leavitt, K. J.; Barbosa, J.;
McDonnell, P. A.; Metzler, W. J.; Rankin, B. M.; Liu, R.;
Vaccaro, W.; Pitts, W. Bioorg. Med. Chem. Lett. 2005, 15,
1101.
Acknowledgment
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
(22) (a) Prins, L. J.; Jolliffe, K. A.; Hulst, R.; Timmerman, P.;
Reinhoudt, D. N. J. Am. Chem. Soc. 2000, 122, 3617.
(b) Timmerman, P.; Prins, L. J. Eur. J. Org. Chem. 2001,
3191.
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Hallenga, K.; Wood, K. V.; Stowell, J. G. J. Am. Chem. Soc.
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