Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones catalyzed by heteropolyacids

Article abstract of DOI:10.1007/s11164-012-0936-8

1,2,9-Trisubstituted purin-6(9H)-ones have been synthesized in high yield by reaction of 5-amino-N,1-dimethyl-1H-imidazole-4-carboxamide with aromatic aldehydes in the presence of heteropolyacids, H₃PMo ₁₂O₄₀ and H₅

Full text of DOI:10.1007/s11164-012-0936-8

Res Chem Intermed
DOI 10.1007/s11164-012-0936-8
Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones
catalyzed by heteropolyacids
•
Zheng Dong Fang Di Fang Quan Chen
•
Received: 5 October 2012 / Accepted: 17 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract 1,2,9-Trisubstituted purin-6(9H)-ones have been synthesized in high yield
by reaction of 5-amino-N,1-dimethyl-1H-imidazole-4-carboxamide with aromatic
aldehydes in the presence of heteropolyacids, H3PMo12O40 and H5PV2Mo10O40. The
catalytic activity of H3PMo12O40 is lower than that of H5PV2Mo10O40. This is an
effective synthesis of l,2,9-trisubstituted guanine derivatives with the advantages of
mild reaction conditions, simple operation, and good yields.
Keywords Purine Á Heteropolyacid Á Synthesis Á Catalyst
Introduction
Purines are ubiquitous nitrogen-containing heterocycles that occur at relatively high
concentrations in living organisms. A great variety of the substituted purines
described in the literature have been found to be potent inhibitors of chaperone
HSP90, protein kinases, sulfotransferases, phosphodiesterases, and microtubule
assembly, and antagonists of adenosine receptors and corticotrophin-releasing
hormone receptors [1–3]. This wide range of biological activity results from
judicious choice of the substituents attached to the N-1, C-2, N-3, C-6, N-7, C-8,
and N-9 centers of the purine moiety.
The classical method of synthesis of purines is by heterocyclization [4, 5]. Purines
bearing C-substituents at position 2 are available by cyclization of 4-aminoimidazole-
5-carboxamides or nitriles with derivatives of carboxylic acids (esters, orthoesters,
Z. D. Fang (&) Á D. Fang Á Q. Chen
College of Chemistry and Environmental Engineering, Hubei Normal University,
Huangshi 435002, Hubei, People’s Republic of China
e-mail: zdfang@hotmail.com
123

Z. D. Fang et al.
etc.), whereas purines bearing C-substituents at position 8 are prepared by analogous
cyclization of 5,6-diaminopyrimidines. Synthesis of 6-substituted purines is much
more difficult, and requires multistep construction and cyclization of 4-substituted 5,6-
diaminopyrimidines. Other possible means of synthesis of purines include radical or
nucleophilic substitution. In general, synthesis of purines by multistep heterocycliza-
tion results in rather low yields, which limits its applicability [6, 7]. Purines bearing
C-substituent(s) linked to carbon atoms of the purine moiety in position(s) 1, 2, and 9
have rarely been studied, because of the limited availability of these compounds by
conventional chemistry. However, this subclass of purine derivatives may be of great
interest [8–10].
In our recent research we have been interested in the synthesis of new derivatives
of purine and related compounds [11, 12]. Herein, we report heterocyclic reaction of
5-amino-N,1-dimethyl-1H-imidazole-4-carboxamide with aromatic aldehydes in the
presence of heteropolyacids to synthesize 1,2,9-trisubstituted-1,9-dimethylpurin-
6(9H)-ones (Scheme 1). This is an effective means of synthesis of l,2,9-trisubsti-
tuted guanine derivatives, with the advantages of mild reaction conditions, simple
operation, and good yields.
Results and discussion
In our investigation, 5-amino-N,1-dimethyl-1H-imidazole-4-carboxamide could be
converted to the corresponding 1,2,9-trisubstituted-1,9-dimethylpurin-6(9H)-ones
by treatment with aromatic aldehyde in acetic acid in the presence of catalytic
amounts of heteropolyacids. When TLC showed the starting material had been
consumed, the reaction mixture was filtered and the purines were obtained as a
powder in high yield. The results are listed in Table 1.
To identify the effect of other solvent on this reaction, 4-fluorobenzaldehyde and
H5PV2Mo10O40 were chosen as starting substrates. On completion of the reactions
different results were obtained, as listed in Table 2. The results in Table 2 indicate that
solvents affected the efficiency of the reaction. Yields were poor in dichloromethane,
acetone, methanol and ethanol. Better yields were obtained in acetonitrile and
tetrahydrofuran. However, the best result was obtained in acetic acid.
O
O
C
NHCH3
CH3
Ar
N
N
N
heteropolyacid
+
ArCHO
NH2
N
N
N
CH3
CH3
Scheme 1 Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones
123

Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones
Table 1 Preparation of the
Compd. Ar
Yield (%)
H5PV2Mo10O40
Yield (%)
H3PMo12O40
title compounds
a
b
c
d
e
f
Ph
83
80
76
72
68
63
61
54
74
70
4-Me–C6H4
4-Et–C6H4
4-MeO–C6H4 71
2-MeO–C6H4 70
4-Cl–C6H4
86
83
g
2,4-diCl–
C6H3
h
i
2-F–C6H4
4-F–C6H4
89
91
73
82
69
63
j
4-NO2–C6H4 84
k
2,4-diNO2–
C6H3
77
Table 2 Effect of solvent on
the model reaction
Entry
Solvent
Acetone
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
7
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
1.5
1.5
1.5
1.5
1.5
1.5
1.5
29
34
51
56
63
74
91
Dichloromethane
Ethanol
Methanol
Tetrahydrofuran
Acetonitrile
Acetic acid
There is interest in replacing liquid catalysts (e.g. H2SO4, HF, p-toluenesulfonic
acid)—because they are corrosive, toxic, and difficult to separate from reaction
solution—by more environmentally friendly solid acids [13, 14]. Use of heteropoly-
acids as catalysts has attracted much attention, particularly in heterocyclic reactions.
Heteropolyacids are low in toxicity, highly stable toward humidity, recyclable, air
stable, and very important in green chemistry [15, 16]. These solid acids are usually
insoluble in non-polar solvents but highly soluble in polar solvents. Our results
indicated that the highest yield of 1,2,9-trisubstituted-1,9-dimethylpurin-6(9H)-one
derivatives was obtained with H5PV2Mo10O40 as catalyst (Table 1). This behavior
was found to be quite general. The high activity of H5PV2Mo10O40 in comparison
with H3PW12O40 confirmed the additional V5? ion is probably involved in catalysis of
the reaction.
To ascertain whether the catalyst succumbed to poisoning and lost its catalytic
activity during the reaction, the reusability of the catalyst was investigated. For this
purpose, after completion of the model reaction, dichloromethane was added to the
solid reaction mixture. All the products were soluble in dichloromethane but the
123

Z. D. Fang et al.
catalyst was insoluble. Thus, the catalyst was separated by simple filtration, washed
with dichloromethane, dried at 90 °C for 1 h, then reused in another reaction with
the same substrate. Even after use in five consequent reactions, the catalytic activity
of H5PV2Mo10O40 was almost the same as that of the fresh catalyst. The IR spectra
of the resulting solids indicated that the catalyst can be recovered without structural
degradation.
The effects of different substituents on a range of aromatic aldehydes were
examined using H5PV2Mo10O40 as catalyst. Halogens and nitro groups were chosen
as electron-withdrawing groups whereas methyl and methoxy groups were chosen
as electron-donating substituents. The yields were generally very good with no
obvious relationship between aromatic substituent and yield.
In accordance with the product, a possible mechanism is presented in Scheme 2.
First, the 5-amino-N,1-dimethyl-1H-imidazole-4-carboxamide and aromatic alde-
hyde react to give a condensation compound; this is then dehydrated, catalyzed by
heteropolyacid. Finally, a cyclization reaction occurs to give the title product.
The structures of the 1,2,9-trisubstituted-1,9-dimethylpurin-6(9H)-ones obtained
were confirmed by analytical and spectral data (IR, 1H NMR, and MS). For
example, the IR spectrum of g contained a C=O absorption band at 1,672 cm-1
.
Strong bands at 1,595–1,653 cm-1 were attributed to stretching vibrations of C=N
groups. The 1H NMR spectrum of g contains signals at 2.75 ppm of NCH3 linked to
the pyrimidine ring and a singlet at 3.63 ppm of NCH3 linked to imidazole ring.
Signals attributable to the imidazole-H are found at 7.95 ppm as a singlet and other
Ar–H signals are observed at 7.32–7.78 ppm as a multiplet. The ESI-MS spectrum
of g contains a strong molecular ion peak at m/z 309.07 (M ? H)?.
O
O
C
NHCH3
NH2
C
NHCH3
NH
N
heteroployacid
N
OH
O
C
heteroployacid
N
N
H
Ar
CH3
H
Ar
N
CH3
O
O
O
OH
NHCH3
Ar
N
N
NHCH3
N
N
NHCH3
Ar
heteroployacid
H
Ar
H
NH
N
H
N
N
H
OH
CH3
CH3
CH3
O
N
O
N
CH3
Ar
N
N
NHCH3
Ar
N
N
N
H
CH3
CH3
Scheme 2 Proposed reaction mechanism for synthesis of the title compounds
123

Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones
Conclusions
We have successfully developed an efficient and facile method of preparation of
1,2,9-trisubstituted purin-6(9H)-ones by reaction of 5-amino-N,1-dimethyl-1H-
imidazole-4-carboxamide with aromatic aldehydes in the presence of heteropoly-
acids. The reaction products were well characterized and could be obtained by use
of an environmentally friendly solid acid catalyst. These compounds are certain to
be of substantial interest to organic chemists.
Experimental
Melting points were determined by use of an X-4 model apparatus and are
uncorrected. IR spectra were recorded on a Nicolet 7500 NXR infrared spectrometer
1
as KBr pellets, with absorption given in cm-1. H NMR spectra were recorded in
CDCl3 on a Bruker Advance 300 NMR spectrometer and chemical shifts (d) are
given in ppm with (CH3)4Si used as internal reference (d = 0). Mass spectral (MS)
data were obtained on a Finnigan LCQ Advantage MAX mass spectrometer.
Elemental analysis was performed with a Perkin–Elmer CHN 2400 instrument. All
reagents and solvents used in this work were available commercially and were used
as received, unless otherwise indicated.
Preparation of H3PMo12O40
To 420 mL 2.85 M aqueous Na2MoO4 were added successively 6.8 mL 85 %
H3PO4 and 284 mL 70 % HClO4. The disodium salt precipitated from the yellow
solution. This powder was isolated by filtration and dried in air. Recrystallization
from a mixture of Et2O and H2O gave greenish microcrystals. An aqueous solution
of the greenish microcrystals was acidified by addition of HCl and extracted by
Et2O. When water was added to the denser layer, yellow crystals of H3PMo12O40
precipitated. IR (KBr, m, cm-1): 1067, 975, 963, 870, 810, 785, 593 cm-1
.
Preparation of H5PV2Mo10O40
Sodium metavanadate (12.2 g, 100 mmol) was dissolved by boiling in 50 mL water
then mixed with Na2HPO4 (3.55 g, 25 mmol in 50 mL of water). After cooling the
solution, concentrated sulfuric acid (5 mL, 17 M, 85 mmol) was added, whereupon the
solution developed a red color. Na2MoO4Á2H2O (60.5 g, 250 mmol) dissolved in
100 mL of water was added to the red solution with vigorous stirring, followed by slow
addition of concentrated sulfuric acid (42 mL, 17 M, 714 mmol). The hot solution was
left to cool to room temperature. The 10-molybdo-2-vanadophosphoric acid was then
extracted with 500 mL diethyl ether. Air was passed through the heteropoly etherate
(bottom layer) to free it from ether. The solid residue was dissolved in water,
concentrated to first crystal formation, then left to crystallize further. The large red
crystals that formed were isolated by filtration, washed with water, and dried in air. IR
(KBr, m, cm-1): 1165, 1085, 1060, 960, 920, 700–800 cm-1
.
123

Z. D. Fang et al.
General procedure for synthesis of 1,2,9-trisubstituted-1,9-dimethylpurin-6(9H)-
ones (a–k)
5-Amino-N,1-dimethyl-1H-imidazole-4-carboxamide 1 was purchased from Merck
and used without purification. A solution of 1 (0.9 mmol), an appropriate aromatic
aldehyde 2 (0.9 mmol), and an appropriate heteropolyacid (0.04 mmol) in acetic
acid (10 mL) was heated under reflux. The progress of the reaction was monitored
by TLC using chloroform–methanol 8:2 as mobile phase. When the reaction was
complete, the catalyst was removed by filtration and washed with warm acetic acid
(the catalyst is not soluble in acetic acid) and then, after filtration, with diethyl ether.
The filtrate was cooled and the solid obtained was isolated by filtration, washed with
water, dried, and re-crystallized from ethanol to give the 1,2,9-trisubstituted-
1,9-dimethylpurin-6(9H)-one.
1,9-Dimethyl-2-phenyl-1H-purin-6(9H)-one (a)
White crystals; m.p. 178–179 °C; IR (KBr, m, cm-1): 3308, 2946, 1693 (C=O),
1524, 1418, 1321 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.67 (3H, s, CH3),
3.37 (3H, s, CH3), 7.62–7.78 (5H, m, ArH), 7.93 (1H, s, imidazole-H); ESI-MS m/z:
241.13 (M ? H)?. Anal. calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found:
C, 64.78; H, 5.15; N, 23.19 %.
1,9-Dimethyl-2-(p-tolyl)-1H-purin-6(9H)-one (b)
White crystals; m.p. 227–228 °C; IR (KBr, m, cm-1): 3321, 2945, 1691 (C=O),
1524, 1420, 1343 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.34 (3H, s, CH3),
2.72 (3H, s, CH3), 3.57 (3H, s, CH3), 7.32 (2H, d, J = 7.2 Hz, ArH), 7.71 (2H, d,
ArH), 7.94 (1H, s, imidazole-H); ESI-MS m/z: 255.18 (M ? H)?. Anal. calcd for
C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C, 66.27; H, 5.61; N, 22.16 %.
2-(4-Ethylphenyl)-1,9-dimethyl-1H-purin-6(9H)-one (c)
White crystals; m.p. 263–264 °C; IR (KBr, m, cm-1): 3314, 2945, 1690 (C=O),
1523, 1427, 1343 cm-1 1H NMR (300 MHz, CDCl3) (d, ppm): 1.11 (3H, t,
;
J = 6.8 Hz, CH3), 2.39 (2H, q, J = 6.4 Hz, CH2), 2.71 (3H, s, CH3), 3.58 (3H, s,
CH3), 7.36 (2H, d, J = 7.2 Hz, ArH), 7.78 (2H, d, J = 7.2 Hz, ArH), 7.95 (1H, s,
imidazole-H); ESI-MS m/z: 269.15 (M ? H)?. Anal. calcd for C15H16N4O: C,
67.15; H, 6.01; N, 20.88. Found: C, 67.28; H, 5.93; N, 20.69 %.
2-(4-Methoxyphenyl)-1,9-dimethyl-1H-purin-6(9H)-one (d)
White crystals; m.p. 233–234 °C; IR (KBr, m, cm-1): 3316, 2921, 1678 (C=O),
1523, 1448, 1341 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.71 (3H, s, CH3),
3.59 (3H, s, CH3), 3.76 (3H, s, OCH3), 7.02 (2H, d, J = 7.2 Hz, ArH), 7.75 (2H, d,
J = 7.2 Hz, ArH), 7.95 (1H, s, imidazole-H); ESI-MS m/z: 271.17 (M ? H)?.
123

Synthesis of 1,2,9-trisubstituted purin-6(9H)-ones
Anal. calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 62.14; H, 5.35;
N, 20.66 %.
2-(2-Methoxyphenyl)-1,9-dimethyl-1H-purin-6(9H)-one (e)
White crystals; m.p. 251–252 °C; IR (KBr, m, cm-1): 3316, 2928, 1678 (C=O),
1556, 1474, 1346 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.73 (3H, s, CH3),
3.62 (3H, s, CH3), 3.74 (3H, s, OCH3), 7.02 (1H, d, J = 7.2 Hz, ArH), 7.09 (1H, d,
J = 7.2 Hz, ArH), 7.38 (1H, t, J = 7.2 Hz, ArH), 7.77 (1H, d, J = 7.2 Hz, ArH),
7.91 (1H, s, imidazole-H); ESI-MS m/z: 271.19 (M ? H)?. Anal. calcd for
C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 62.18; H, 5.31; N, 20.67 %.
2-(4-Chlorophenyl)-1,9-dimethyl-1H-purin-6(9H)-one (f)
White crystals; m.p. 276–277 °C; IR (KBr, m, cm-1): 3325, 2928, 1678 (C=O),
1555, 1416, 1371 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3),
3.65 (3H, s, CH3), 7.52 (2H, d, J = 7.2 Hz, ArH), 7.79 (2H, d, J = 7.2 Hz, ArH),
7.95 (1H, s, imidazole-H); ESI-MS m/z: 275.33 (M ? H)?. Anal. calcd for
C13H11N4OCl: C, 56.84; H, 4.04; N, 20.40. Found: C, 56.72; H, 4.15; N, 20.27 %.
2-(2,4-Dichlorophenyl)-1,9-dimethyl-1H-purin-6(9H)-one (g)
White crystals; m.p. [300 °C; IR (KBr, m, cm-1): 3325, 2928, 1672 (C=O), 1559,
1
1474, 1324 cm-1; H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3), 3.63
(3H, s, CH3), 7.32 (1H, d, J = 7.2 Hz, ArH), 7.51 (1H, s, ArH), 7.78 (1H, d,
J = 7.2 Hz, ArH), 7.95 (1H, s, imidazole-H); ESI-MS m/z: 309.07 (M ? H)?.
Anal. calcd for C13H10N4OCl2: C, 50.51; H, 3.26; N, 18.12. Found: C, 50.43; H,
3.19; N, 18.28 %.
2-(2-Fluorophenyl)-1,9-dimethyl-1H-purin-6(9H)-one (h)
White crystals; m.p. 265–266 °C; IR (KBr, m, cm-1): 3302, 2931, 1685 (C=O),
1514, 1426, 1332 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3),
3.63 (3H, s, CH3), 7.22 (1H, d, J = 7.2 Hz, ArH), 7.30 (1H, t, J = 7.2 Hz, ArH),
7.45 (1H, t, J = 7.2 Hz, ArH), 7.88 (1H, d, J = 7.2 Hz, ArH), 7.96 (1H, s,
imidazole-H); ESI-MS m/z: 259.09 (M ? H)?. Anal. calcd for C13H11N4OF: C,
60.46; H, 4.29; N, 21.69. Found: C, 60.49; H, 4.16; N, 21.75 %.
2-(4-Fluorophenyl)-1,9-dimethyl-1H-purin-6(9H)-one (i)
White crystals; m.p. 241–242 °C; IR (KBr, m, cm-1): 3321, 2928, 1678 (C=O),
1551, 1414, 1363 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3),
3.64 (3H, s, CH3), 7.20 (2H, d, J = 7.2 Hz, ArH), 7.89 (2H, d, J = 7.2 Hz, ArH),
7.97 (1H, s, imidazole-H); ESI-MS m/z: 259.03 (M ? H)?. Anal. calcd for
C13H11N4OF: C, 60.46; H, 4.29; N, 21.69. Found: C, 60.53; H, 4.21; N, 21.77 %.
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Z. D. Fang et al.
1,9-Dimethyl-2-(4-nitrophenyl)-1H-purin-6(9H)-one (j)
White crystals; m.p. 288–289 °C; IR (KBr, m, cm-1): 3336, 2933, 1686 (C=O),
1532, 1417, 1360 cm-1; 1H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3),
3.62 (3H, s, CH3), 7.97 (1H, s, imidazole-H), 8.20 (2H, d, J = 7.0 Hz, ArH), 8.49
(2H, d, J = 7.0 Hz, ArH); ESI-MS m/z: 286.12 (M ? H)?. Anal. calcd for
C13H11N4OF: C, 54.74; H, 3.89; N, 24.55. Found: C, 54.71; H, 3.73; N, 24.70 %.
1,9-Dimethyl-2-(2,4-dinitrophenyl)-1H-purin-6(9H)-one (k)
White crystals; m.p. [300 °C; IR (KBr, m, cm-1): 3312, 2974, 1668 (C=O), 1513,
1
1474, 1328 cm-1; H NMR (300 MHz, CDCl3) (d, ppm): 2.74 (3H, s, CH3), 3.63
(3H, s, CH3), 7.95 (1H, s, imidazole-H), 8.38 (1H, d, J = 7.2 Hz, ArH), 8.79 (1H, d,
J = 7.2 Hz, ArH), 9.31 (1H, s, ArH); ESI-MS m/z: 331.08 (M ? H)?. Anal. calcd
for C13H10N6O5: C, 47.28; H, 3.05; N, 25.45. Found: C, 47.41; H, 3.13; N, 25.37 %.
References
1. M. Legraverend, D.S. Grierson, Bioorg. Med. Chem. 14, 3987 (2006)
2. N.Y. Huang, Y.J. Liang, M.W. Ding, L.W. Fu, H.W. He, Bioorg. Med. Chem. Lett. 19, 831 (2009)
3. M. Arabi, M.M. Amini, M. Abedini, A. Nemati, M. Alizadeh, J. Mol. Catal. A Chem. 200, 105
(2003)
4. M.M. Heravi, R. Motamedia, N. Seifi, F.F. Bamoharram, J. Mol. Catal. A Chem. 249, 105 (2006)
5. H. Tao, Y.L. Kang, T. Taldone, G. Chiosis, Bioorg. Med. Chem. Lett. 19, 415 (2009)
6. E.S. Darwish, M.A. Mosselhi, F.M. Altalbawy, H.A. Saad, Molecules 16, 8788 (2011)
7. S. Sahnoun, S. Messaoudi, J. Peyrat, J.D. Brion, M. Alami, Tetrahedron Lett. 49, 7279 (2008)
8. M.M. Heravi, R. Motamedi, F.F. Bamoharram, N. Seify, Catal. Commun. 8, 1467 (2007)
9. G.P. Romanelli1, J.C. Autino, Mini-Rev. Org. Chem. 6, 359 (2009)
10. M.M. Heravi, V. Rasmi, F.F. Bamoharram, S. Sadjadi, L. Fotouhi, S. Sadjadi, B. Mehdi, Synth.
Commun. 39, 4109 (2009)
11. Z.D. Fang, X.H. Wei, J. Chem. Res. 36, 703 (2012)
12. Z.D. Fang, X.H. Wei, Heterocycles 85, 2757 (2012)
13. A. Davoodnia, M. Bakavoli, Gh Barakouhi, N. Tavakoli-Hoseini, Chin. Chem. Lett. 18, 1483 (2007)
14. M.M. Heravi, S. Sadjadi, J. Iran. Chem. Soc. 6, 1 (2009)
15. R. Hekmatshoar, S. Sajadi, M.M. Heravi, F.F. Bamoharram, Molecules 12, 2223 (2007)
16. A.M. Tikdari, S. Fozooni, H. Hamidian, Molecules 13, 3246 (2008)
123