A simple one-pot synthesis of new imidazol-2-yl-lh-quinolin-2-ones from the direct reaction of 2-chloroquinolin-3-carbaldehyde with aromatic o-diamines

Article abstract of DOI:10.1002/ejoc.200901014

An alternative and general one-pot synthesis of a library of novel imidazol-2-yl-1H-quinolin-2-one derivatives was performed in 70 % aqueous acetic acid by the direct reaction of 2-chloroquinolin-3-carbaldehyde with aromatic o-diamines. Experiments showed that adding Amberlyst (20% w/w) to the reaction media increased both the speed of reaction as well as the yield of products. Both DFT theoretical calculations and X-ray diffraction studies confirmed the proposed structures and the more stable conformation of the obtained products, Antitumor studies against sixty different cancer cell lines showed the potential of these kinds of compounds.

Full text of DOI:10.1002/ejoc.200901014

FULL PAPER
DOI: 10.1002/ejoc.200901014
A Simple One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones from the
Direct Reaction of 2-Chloroquinolin-3-carbaldehyde with Aromatic o-Diamines
Rodrigo Abonia,*[a] Juan Castillo,[a] Paola Cuervo,[a,b] Braulio Insuasty,[a] Jairo Quiroga,[a]
Alejandro Ortíz,[a] Manuel Nogueras,[c] and Justo Cobo[c]
Keywords: Antitumor agents / Synthetic methods / Biological activity / Cyclization / Nitrogen heterocycles / Hydrolysis
An alternative and general one-pot synthesis of a library of
novel imidazol-2-yl-1H-quinolin-2-one derivatives was per-
formed in 70% aqueous acetic acid by the direct reaction of
2-chloroquinolin-3-carbaldehyde with aromatic o-diamines.
Experiments showed that adding Amberlyst®-15 (20% w/w)
to the reaction media increased both the speed of reaction as
well as the yield of products. Both DFT theoretical calcula-
tions and X-ray diffraction studies confirmed the proposed
structures and the more stable conformation of the obtained
products. Antitumor studies against sixty different cancer cell
lines showed the potential of these kinds of compounds.
Introduction
Quinolines and their oxo derivatives are important com-
pounds due to their presence in naturally occurring prod-
ucts and their wide-ranging applications as drugs, pharma-
ceuticals, and agrochemicals.[1] In particular, 3-substituted
quinolin-2-one is an important moiety that is found in a
number of compounds with interesting biological activi-
ties.[2] Of these, hydroxy compound 1 is of particular phar-
maceutical interest,[2g] as are the novel and potent receptor
tyrosine kinase (RTK) inhibitors 2,[2h] indoloquinolin-2-
ones 3, and imidazoquinolin-2-ones 4, which have been
found to constitute a novel class of kinase insert domain-
containing receptor (KDR) inhibitors[2i–2k] (Scheme 1).
In this sense, Fraley et al.[2k] recently developed a two-
step sequence (involving relatively harsh reaction condi-
tions) for the synthesis of a series of imidazoquinolinones
4 to be assayed for KDR inhibition; the synthesis of the
methyl derivative 4b, shown in Scheme 2, affords the prod-
uct in acceptable yield.
Scheme 1. Some quinolin-2-one derivatives of biological interest.
On the other hand, we and other authors have previously
found that the target pharmacophore 1H-quinolin-2-one
moiety, which is present in the structure of 3-formylquin-
[a] Departamento de Química, Universidad del Valle,
A. A. 25360, Cali, Colombia
Fax: +57-2-3393248
E-mail: abonia@quimica.univalle.edu.co
[b] Departamento de Química, Universidad Nacional de Colom-
bia,
A. A. 14490, Bogotá, Colombia
[c] Departamento de Química Inorgánica y Orgánica, Universidad
de Jaén,
23071 Jaén, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901014.
Scheme 2. Previously reported approach to the synthesis of imid-
azoquinolin-2-one 4b.
Eur. J. Org. Chem. 2010, 317–325
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
317

R. Abonia et al.
FULL PAPER
olin-2-one (9), is readily obtained from the commercially larly, compound 4b was obtained in 92% yield by following
available 2-chloroquinoline-3-carbaldehyde (8) either this modified procedure. The Amberlyst®-15 was recovered
through hydrolysis in aqueous AcOH (70%)[2b] or by treat- and reused as described recently.[5] Table 1 summarizes the
ment with a 70% AcOH/Amberlyst®-15 (20% w/w) mix- optimization process for this methodology.
ture[3] according to Scheme 3. It was observed that a signifi-
The results of these optimization studies prompted us to
cant improvement could be achieved by including Am- use the reaction conditions described in Approach 2 to cre-
berlyst®-15 (A-15) in the reaction media.
ate a library of imidazoquinolinones 4a–m, starting from 2-
chloroquinoline-3-carbaldehyde (8) and various o-diamines
7a–m, as shown in Scheme 4.
Scheme 3. Synthesis of aldehyde 9 by hydrolysis of 2-chloroquin-
oline-3-carbaldehyde (8).
Scheme 4. General procedure established for the direct synthesis of
products 4.
Results and Discussion
According to Schemes 1, 2, and 3 and continuing with
our current studies on the synthesis of potential antitumor
agents,[4] we envisaged the possibility of combining both hy-
drolysis of the C–Cl bond and a cyclocondensation pro-
cesses into one step. In this way, we hoped to develop an
alternative and general approach through which to obtain
compound 4b and new analogues.
As an initial study, a mixture of o-phenylenediamine (7a)
and an equimolar amount of aldehyde 8 was subjected to
reflux for six hours in a 70:30 mixture (5 mL) of acetic acid
and water (This procedure will be referred to as Approach
1). However, the reaction had not gone to completion after
this time, and a mixture of the expected product 4a and the
hydrolyzed aldehyde 9 precipitated from the solution; this
mixture was found to be difficult to resolve. Finally, pure
compound 4a was obtained from the mixture in 29% yield
after repeated washings with hot ethanol. The same behav-
ior was observed for the synthesis of compound 4b – in this
case just 35% yield was obtained.
Although formation of the imidazole ring involved a de-
hydration process, which usually requires anhydrous reac-
tion conditions, interestingly in this case compounds 4 were
readily obtained in good yields; thus the presence of 30%
water did not affect the formation of these products. On the
other hand, formation of the imidazole ring in 4 requires
the presence of an oxidant in the reaction media; in our
experimental procedure this oxidant was atmospheric air,
the oxygen dissolved in the solvent being responsible for
the oxidation process as previously reported by Lin et al.[6]
Table 2 summarizes the structure of the starting o-diamines
7 and the compounds 4a–m obtained by using Approach 2.
Products 4 were characterized by analytical and spectro-
1
scopic methods (elemental analyses, FTIR, H-, 13C-, 1D-,
and 2D-NMR, and EIMS) as summarized in the Experi-
mental Section. The most relevant signal in the FTIR spec-
tra corresponded to an intense absorption band at 1651–
1689 cm–1, which was assigned to the carbonyl group of the
new amide functionality formed from the hydrolysis of the
C–Cl bond. The number of proton signals observed in the
1H NMR spectra and their chemical shifts also support the
proposed structures; the most relevant signals being a sing-
let (δ = 8.41–9.72 ppm) corresponding to 4-H and a broad
singlet (δ = 10.24–12.98 ppm) corresponding to the 1-
NHCO functionality. In the 13C NMR spectra of 4, the
signals assigned to C-4 (δ = 138.1–144.1 ppm) and to the 2-
carbonyl group (δ = 159.3–162.2 ppm) of the new amide
functionality were the most relevant features. In contrast,
the 13C NMR spectrum of free aldehyde 9 contained two
different carbonyl signals at δ = 161.8 ppm and 190.1 ppm
corresponding to the NHCO and CHO functionalities,
respectively, which agree with the proposed structure for 4.
A common base peak corresponding to the molecular ion
was observed in the mass spectra of compounds 4, except
for products 4h and 4l. For these two compounds the base
peak corresponded to m/z = 28 (i.e. a radical cation of CO).
These features also accompanied a commonly observed
ring-contraction process for the quinolin-2-one moiety in
all compounds of type 4. In this way, a decarbonylation
Taking into account that the presence of Amberlyst®-15
has been shown to improve both the hydrolysis of aldehyde
8 and efficiently catalyze a number of heterocyclization pro-
cesses,[5] we decided to repeat the above reaction in the pres-
ence of 20% w/w Amberlyst®-15[5] (This procedure will be
referred to as Approach 2). With this variation, the reaction
proceeded to completion in only 4 h (monitored by TLC)
without precipitation. After the Amberlyst®-15 was filtered
and the solution was reduced to one third of its initial vol-
ume, pure compound 4a precipitated in 84% yield. Simi-
Table 1. Optimization of the reaction conditions for the hydrolysis
of aldehyde 8 and the synthesis of imidazoquinolinones 4.
Approach
Reaction conditions[a]
Obtained compounds (% yield)
9
4a
4b
1
2
70% AcOH/reflux 6 h 93
70% AcOH/20% w/w 98
A-15/reflux 4 h
29
84
35
92
[a] A-15 = Amberlyst®-15.
318
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 317–325

One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones
Table 2. Structures and analytical data of the obtained imidazoquinolin-2-ones 4.
Eur. J. Org. Chem. 2010, 317–325
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
319

R. Abonia et al.
FULL PAPER
Table 2. (Continued)
[a] Isolated yield. [b] The synthesis of this compound has been previously reported[2k] following the procedure shown in Scheme 2 but no
analytical or spectroscopic data were supplied. [c] Synthesis of this compound was reported in a patent[2l] using a different procedure.
process led to the loss of 28 a.m.u. (corresponding to a CO
molecule) to furnish the relatively stable indolinic species
10a as shown in Scheme 5 for compound 4a.
Figure 1. Possible conformations for compounds 4.
Scheme 5. Main MS fragmentation for compounds 4.
To address this question, a DFT study was performed
In addition to other factors, it has been reported that the for compound 4a to help predict the most stable conforma-
antitumor activity of these kinds of compounds is favored tion. The calculations were carried out with a Gaussian 03
by coplanarity of the imidazole and quinolinone rings of 4 revision C 0.2 using the DFT-B3LYP base 6-31G**. The
and analogues, rather than a perpendicular orientation.[2k] computational study showed that the more stable confor-
The NMR spectroscopic study did not allow us to deter- mation of this compound was quite near to planarity (Fig-
mine whether the coplanar form (favored by an intramolec- ure 2), with a calculated dihedral angle between the atoms
ular hydrogen bond) or the perpendicular conformation N31–C32–C3–C2 of –0.03703°.
was the preferred arrangement for compounds of type 4
These findings support the possibility of an intramolecu-
(Figure 1).
lar hydrogen bond between O2···H–N31 atoms that could
320
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 317–325

One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones
yls.[7c] More recently, we have also used this heterogeneous
catalyst for efficient intramolecular heterocyclization reac-
tions of o-aminochalcones, also in the presence of acetic
acid.[5] Consequently, it is reasonable to suppose that, in
contrast to the use of aqueous acetic acid as reaction me-
dium (i.e. Approach 1), the acid strength of the Am-
berlyst®-15 catalyst increased the reactivity of aldehyde 8 in
Approach 2.
Anticancer Activity
Figure 2. Most stable conformation for compound 4a predicted
from DFT calculations.
The two-stage screening process started with an evalu-
ation of the nine compounds 4a, 4c, 4f–j, 4l, and 4m se-
lected by the National Cancer Institute (NCI), against 60
cell lines at a single dose of 1.0 µ. The output from the
single dose screen was reported as a mean graph available
for analysis by the COMPARE program.[8] The results of
the primary assay showed that all compounds were essen-
tially inactive, except for compound 4c (Table 3).
be responsible for the predicted planarity calculated for
compounds 4.
After several unsuccessful attempts to obtain crystals of
4, fortunately it was possible to grow single crystals of com-
pound 4a from methanol and to solve the structure by X-
ray diffraction analysis (Figure 3; see also the Experimental
Section). The crystal structure not only confirmed the pro-
posed structures for compounds 4 (previously assigned on
the basis of their spectroscopic data), but also confirmed
the existence of the intramolecular hydrogen bond in N31–
H31···O2, thus supporting the theoretical calculations that
predicted the stable coplanar conformation.
Table 3. Results of primary anticancer assay for nine compounds
selected by the NCI.
Compounds
Activity[a]
4a
4c
4f
4g
4h
4i
4j
4l
4m
NA
A
NA
NA
NA
NA
NA
NA
NA
[a] Activity denoted as: A = active; NA = not active.
Therefore, a secondary screening was performed in order
to determine the cytostatic activity of compound 4c against
the 60-cell-line panel representing leukemia, melanoma,
and cancers of the lung, colon, brain, ovary, breast, pros-
tate, and kidney. This compound was evaluated at five con-
centration levels (100, 10, 1.0, 0.1, and 0.01 µ). The test
consisted of a 48 hour continuous drug exposure protocol
using a sulforhodamide B (SRB) protein assay to estimate
cell growth. Details of this evaluation method and the com-
plementary information related to the activity pattern over
all cell lines have been published.[9] Table 4 shows that com-
pound 4c displayed the most remarkable activity against 59
human tumor cell lines, the most sensitive strains being
KM12 (colon cancer; GI50 = 0.38 µ) and CAKI-1 (renal
cancer; GI50 = 1.02 µ); both had LC50 values greater than
Figure 3. ORTEP drawing of imidazoquinolinone 4a. Hydrogen
bond framework showing the dimeric unit formed between two
molecules of 4a and molecules of water that links the dimeric units
into a 2D supramolecular network.
The effectiveness of Amberlyst®-15 as a catalyst can be 100 µ. Derivative 4c showed significant activity against
explained by considering that it is a macroreticular, polysty- other cell lines from the different panels of cancer types,
rene-based ion-exchange resin with strongly acidic sulfonic with a GI50 range of 0.38–100.0 µ. The cytotoxicities asso-
groups. The resin has been used as a very efficient acid cata- ciated with compound 4c were measured as LC50 values and
lyst for several reactions, such as the synthesis of acetals ranged from 48.1 to above 100 µ, for all cell lines, indicat-
from carbonyls and alcohols,[7a] the synthesis of esters from ing a low toxicity of this compound for normal human cell
alcohols and acids,[7b] and hydrolysis of acetals to carbon- lines, as required for potential antitumor agents.
Eur. J. Org. Chem. 2010, 317–325
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
321

R. Abonia et al.
FULL PAPER
Table 4. In vitro testing results expressed as growth inhibition of cancer cells by compound 4c.[a]
[a] Data obtained from NCI’s in vitro disease-oriented human tumor cell lines screen.[7] [b] GI50 was the drug concentration resulting in
a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. Determined at
five concentration levels (100, 10, 1.0, 0.1, and 0.01 µ). [c] LC50 is a parameter of cytotoxicity and reflects the molar concentration
needed to kill 50% of the cells.
322
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 317–325

One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Crystal system: monoclinic; space group: P21/c;
Conclusions
The one-pot synthesis and studies on the cytotoxic ac-
tivity of novel imidazol-2-yl-1H-quinolin-2-ones 4 have unit cell dimensions: 7.968 (6), 16.73 (2), 10.206 (11) Å, 109.56 (9)°;
volume: 1282 (2) A3; Z = 4; calculated density: 1.447 Mg/m3; µ =
been performed. The results show that the presence of Am-
0.100 mm–1; crystal size: 0. 1ϫ0.22ϫ0.51 mm; range of collection:
berlyst®-15 in the reaction media enhanced the reactivity of
the starting materials and consequently improved the yield
of products. X-ray diffraction analysis confirmed not only
the proposed structure of products 4 but also revealed the
presence of intramolecular hydrogen bonding and estab-
lished the planarity of compound 4a, which was predicted
from DFT theoretical calculations. The antitumor assays
showed that, among the nine imidazoquinolinones 4 evalu-
ated by the NCI, derivative 4c exhibited the highest activity
against a range of cancer cell lines with remarkable values.
2.95ϽθϽ27.5°; reflections collected/unique: 23135/2948 [Rint
0.112]. 99.9% completeness to θ = 27.50°. Multiscan absorption
correction was carried out with SADABS 2.0.[11] TMax/TMin
=
=
0.990/0.951. Refinement with SHELXL-97[12] using a full-matrix
least-squares on F2; S = 1.03; R1 = 0.083, wR2 = 0.277·W = [σ2(F2
+ (0.1633P)2]–1 where P = (F2 + 2F2 )/3.
)
o
o
c
3-(5-Methyl-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one
(4b):
Yield: 264 mg. FTIR (KBr): ν = 3352 (1-NHCO), 3166 (imidazole-
˜
1
NH), 1658 (2-C=O), 1570 (C=C) cm–1. H NMR (400 MHz, [D6]-
DMSO): δ = 2.44 (s, 3 H, CH3), 7.04 (d, J = 8.1 Hz, 1 H, Ar-H),
7.29 (t, J = 7.4 Hz, 1 H, 6-H), 7.42–7.56 (m, 3 H, 8-H and 2ϫAr-
H), 7.61 (t, J = 7.2 Hz, 1 H, 7-H), 7.95 (d, J = 7.2 Hz, 1 H, 5-H),
9.09 (s, 1 H, 4-H), 12.50 (s, 1 H, imidazole-NH), 12.55 (s, 1 H, 1-
NHCO) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 21.3 (CH3),
112.3, 115.2, 117.9, 119.2 (Cq), 120.2 (Cq), 122.6, 123.5, 128.9,
131.4, 132.5 (Cq), 134.7 (Cq), 138.6 (2 C, C-4 and Ar-Cq), 141.0
(Cq), 147.2 (Cq), 160.8 (2-C=O) ppm. MS (70 eV, EI): m/z (%) =
275 (100) [M]+, 247 (72) [M – CO], 123 (10), 77 (15). C17H13N3O
(275.11): calcd. C 74.17, H 4.76, N 15.26; found C 74.42, H 4.42,
N 15.54.
Experimental Section
Melting points were determined with a Büchi melting point appara-
tus and are uncorrected. IR spectra were recorded with a Shimadzu
FTIR 8400 spectrophotometer by using KBr disks. 1H and 13C
NMR spectra were recorded with a Bruker Avance 400 spectropho-
tometer operating at 400 MHz and 100 MHz, respectively, using
[D6]DMSO as solvent and tetramethylsilane as internal standard.
Mass spectra were measured with a SHIMADZU-GC–MS 2010-
DI-2010 spectrometer (equipped with a direct inlet probe) op-
erating at 70 eV. Microanalyses were performed with an Agilent
elemental analyzer, and the values are within Ϯ0.4% of the theoret-
ical values. Silica gel aluminum plates (Merck 60 F254) were used
for analytical TLC. Amberlyst®-15, the starting o-diamines 7a–g,
and 2-chloroquinolin-3-carbaldehyde (8) were purchased from Ald-
rich, Fluka, or Acros (analytical reagent grades) and were used
without further purification. The remaining o-diamines 7h–m were
synthesized by using literature procedures.[10]
3-(5-Chloro-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one
(4c):
Yield: 240 mg. FTIR (KBr): ν = 3240 (br., 1-NHCO and imidazole-
˜
NH), 1666 (2-C=O), 1622 (C=N), 1569 (C=C) cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.36 (t, J = 7.9 Hz, 1 H, 6-H), 7.52
(d, J = 8.1 Hz, 1 H, 8-H), 7.53 (dd, J = 8.7, J = 2.1 Hz, 1 H, Ar-
H), 7.74 (t, J = 7.9 Hz, 1 H, 7-H), 7.83 (d, J = 7.2 Hz, 1 H, 5-H),
7.87 (d, J = 7.2 Hz, 1 H, Ar-H), 7.88 (s, 1 H, Ar-H), 9.49 (s, 1 H,
4-H), 12.85 (s, 1 H, 1-NHCO) ppm; imidazole-NH is absent. 13C
NMR (100 MHz, [D6]DMSO): δ = 114.0, 114.1 (Cq), 115.8, 115.9,
118.2 (Cq), 123.4, 125.8, 129.6, 129.7 (Cq), 131.1 (Cq), 133.0 (Cq),
133.9, 139.7 (Cq), 143.6 (C-4), 146.5 (Cq), 159.3 (2-C=O) ppm. MS
(70 eV, EI): m/z (%) = 297/295 (30/100) [M]+, 269/267 (24/76) [M –
CO], 232 (27), 205 (11), 142 (36). C16H10ClN3O (295.72): calcd. C
64.98, H 3.41, N 14.21; found C 64.81, H 3.61, N 14.19.
General Procedure for the Synthesis of Compounds 4: A mixture of
2-chloroquinoline-3-carbaldehyde (8) (200 mg, 1 mmol), the corre-
sponding o-diamine 7 (1 mmol), Amberlyst®-15 (20% w/w) and aq.
AcOH (70%, 3 mL) was stirred at reflux for 1–4 h, and the progress
of the reaction was checked by TLC. When the reaction was com-
plete, Amberlyst®-15 was filtered, washed with fresh AcOH (1 mL),
and recovered by filtration. The combined fractions were concen-
trated under vacuum to one third of the original volume. The solids
formed were collected by Büchner filtration and washed with
AcOH/H2O (1:1, 2ϫ2 mL). No further purification was required
for the obtained products.
3-(5-Nitro-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one (4d): Yield:
262 mg. FTIR (KBr): ν = 3332 (1-NHCO), 3154 (imidazole-NH),
˜
1660 (2-C=O), 1618 (C=N), 1594 (C=C), 1513 (NO2), 1314
(NO2) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 7.30 (t, J =
7.2 Hz, 1 H, 6-H), 7.44 (d, J = 8.3 Hz, 1 H, 8-H), 7.64 (t, J =
7.9 Hz, 1 H, 7-H), 7.82 (d, J = 8.9 Hz, 1 H, Ar-H), 7.96 (d, J =
7.45 Hz, 1 H, 5-H), 8.10 (dd, J = 8.9, 2.3 Hz, 1 H, Ar-H), 8.56 (s,
1 H, Ar-H), 9.14 (s, 1 H, 4-H), 12.53 (s, 1 H, 1-NHCO) ppm;
imidazole-NH is absent. 13C NMR (100 MHz, [D6]DMSO): δ =
115.3 (2 C), 117.7, 118.7 (Cq), 118.9 (2 Cq), 122.7, 129.4 (2 C),
132.2, 139.1 (2 Cq), 140.8 (C-4), 142.6 (Cq), 152.3 (Cq), 160.5 (2-
C=O) ppm. MS (70 eV, EI): m/z (%) = 306 (100) [M]+, 278 (19)
[M – CO], 170 (40), 142 (30), 63 (45). C16H10N4O3 (306.28): calcd.
C 62.74, H 3.29, N 18.29; found C 62.62, H 3.40, N 18.18.
3-(1H-Benzo[d]imidazol-2-yl)quinolin-2(1H)-one
(4a):
Yield:
229 mg. FTIR (KBr): ν = 3350 (1-NHCO), 3161 (imidazole-NH),
˜
1659 (2-C=O), 1619 (C=N), 1570 (C=C) cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.37 (t, J = 7.2 Hz, 1 H, 6-H), 7.45–
7.60 (m, 3 H, 8-H and 2ϫAr-H), 7.74 (t, J = 7.1 Hz, 1 H, 7-H),
7.80–7.93 (m, 3 H, 5-H and 2ϫAr-H), 9.49 (s, 1 H, 4-H), 12.84 (s,
1
H, 1-NHCO) ppm; imidazole-NH is absent. 13C NMR
(100 MHz, [D6]DMSO): δ = 114.4 (Cq), 114.8 (2 C), 116.3, 118.6
(Cq), 123.9, 126.3 (2 C), 130.0, 132.0 (2 Cq), 134.4, 140.2 (Cq), 3-(1H-Naphtho[2,3-d]imidazol-2-yl)quinolin-2(1H)-one (4e): Yield:
144.1 (C-4), 145.6 (Cq), 159.8 (2-C=O) ppm. MS (70 eV, EI): m/z
(%) = 261 (100) [M]+, 233 (95) [M – CO], 205 (7), 116 (20).
C16H11N3O (261.09): calcd. C 73.55, H 4.24, N 16.08; found C
73.26, H 4.39, N 15.82. Crystallographic data for 4a·H2O were col-
lected at 120 K with a Bruker Nonius Kappa CCD area dif-
fractometer using Mo-Kα X-ray radiation (λ = 0.71073 Å). CCDC-
695467 contains the supplementary crystallographic data for this
260 mg. FTIR (KBr): ν = 3413 (1-NHCO), 3163 (imidazole-NH),
˜
1670 (2-C=O), 1641 (C=N), 1575 (C=C) cm1. 1H NMR (400 MHz,
[D6]DMSO): δ = 7.36 (td, J = 7.5, 1.0 Hz, 1 H, 6-H), 7.46–7.49 (m,
2 H, 2ϫAr-H), 7.51 (d, J = 8.3 Hz, 1 H, 8-H), 7.73 (td, J = 7.8,
1.4 Hz, 1 H, 7-H), 7.90 (dd, J = 8.1, 1.0 Hz, 1 H, 5-H), 8.05–8.10
(m, 2 H, 2ϫArH), 8.31 (br. s, 2 H, 2ϫArH), 9.49 (s, 1 H, 4-H),
12.70 (s, 1 H, 1-NHCO) ppm; imidazole-NH is absent. 13C NMR
Eur. J. Org. Chem. 2010, 317–325
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
323

R. Abonia et al.
FULL PAPER
(100 MHz, [D6]DMSO): δ = 111.0, 115.7, 118.4 (Cq), 123.2, 124.8
(2 C), 127.9 (br., 3 C), 129.6, 130.7 (br., 4Cq), 133.6, 139.8 (2Cq),
143.6 (C-4), 149.9 (Cq), 159.7 (2-C=O) ppm. MS (70 eV, EI): m/z
(%) = 311 (100) [M]+, 283 (51) [M – CO], 156 (15), 142 (19), 140
2.59 (s, 3 H, SCH3), 7.27 (t, J = 7.7 Hz, 1 H, 6-H), 7.45 (d, J =
8.1 Hz, 1 H, 8-H), 7.59 (t, J = 8.1 Hz, 1 H, 7-H), 7.86 (d, J =
7.9 Hz, 1 H, 5-H), 8.87 (s, 1 H, 4-H), 12.12 (br. s, 2 H, 2ϫNHCO)
ppm; imidazole-NH is absent. 13C NMR (100 MHz, [D6]DMSO):
(21), 115 (13). C20H13N3O (311.34): calcd. C 77.16, H 4.21, N δ = 12.4 (SCH3), 113.8 (Cq), 114.9, 116.1 (Cq), 118.6 (Cq), 122.1,
13.50; found C 77.05, H 4.26, N 13.65.
122.5 (Cq), 125.5 (Cq), 128.2, 129.5 (Cq), 130.9, 134.1 (Cq), 138.1
(C-4), 160.3 (2-C=O), 175.0 (C=O) ppm. MS (70 eV, EI): m/z (%) =
325 (100) [M]+, 278 (18), 251 (18), 171 (40), 153 (26). C15H11N5O2S
(325.06): calcd. C 55.38, H 3.41, N 21.53; found C 55.51, H 3.29,
N 21.62.
3-(3H-Imidazo[4,5-c]pyridin-2-yl)quinolin-2(1H)-one (4f): Yield:
216 mg. FTIR (KBr): ν = 3148 (br., 1-NHCO), 3112 (imidazole-
˜
NH), 1665 (2-C=O), 1632 (C=N), 1569 (C=C) cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.32 (t, J = 7.2 Hz, 1 H, 6-H), 7.51
(d, J = 8.1 Hz, 1 H, 8-H), 7.63–7.69 (m, 2 H, 7-H, Pyr-H), 7.99 (d,
J = 7.9 Hz, 1 H, 5-H), 8.32 (d, J = 4.5 Hz, 1 H, Pyr-H), 9.01 (s, 1
H, Pyr-H), 9.18 (s, 1 H, 4-H), 12.61 (imidazole-NH), 12.98 (s, 1 H,
NHCO) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 108.0, 113.0
(Cq), 115.4, 119.0 (Cq), 119.4 (Cq), 122.7, 129.3, 132.1, 139.1
(2Cq), 140.3, 141.2 (2 C, C-4, Ar-C), 149.5 (Cq), 160.6 (2-C=O)
ppm. MS (70 eV, EI): m/z (%) = 262 (100) [M]+, 234 (92) [M – CO],
131 (12), 89 (6). C15H10N4O (262.09): calcd. C 68.69, H 3.84, N
21.36; found C 68.80, H 3.92, N 21.28.
3-[6-Amino-2-(methylthio)-9H-purin-8-yl]quinolin-2(1H)-one (4k):
Yield: 277 mg. FTIR (KBr): ν = 3478 (1-NHCO), 3417, 3283 (br.),
˜
3097 (br., imidazole-NH), 1657 (2-C=O), 1597 (C=N), 1561
(C=C) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 2.47 (s, 3 H,
SCH3), 7.28 (t, J = 7.3 Hz, 1 H, 6-H), 7.35 (br. s, 2 H, NH2), 7.45
(d, J = 8.1 Hz, 1 H, 8-H), 7.61 (t, J = 7.6 Hz, 1 H, 7-H), 7.90 (d,
J = 8.0 Hz, 1 H, 5-H), 9.03 (s, 1 H, 4-H), 12.33 (s, 1 H, NHCO),
12.66 (s, 1 H, imidazolic) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 13.9 (SCH3), 109.2 (Cq), 115.8, 119.5 (Cq), 119.6 (Cq), 123.2,
129.6, 132.3, 139.2 (Cq), 140.5 (C-4), 148.2 (Cq), 151.6 (Cq), 159.7
(Cq), 161.0 (2-C=O), 164.3 (Cq) ppm. MS (70 eV, EI): m/z (%) =
324 (100) [M]+, 291 (15), 278 (34), 262 (19), 171 (78), 153 (56).
C15H12N6OS (324.08): calcd. C 55.54, H 3.73, N 25.91; found C
55.63, H 3.82, N 25.78.
2-(1,2-Dihydro-2-oxoquinolin-3-yl)-1H-benzo[d]imidazole-5-carbox-
ylic Acid (4g): Yield: 264 mg. FTIR (KBr): ν = 3620–3310 (br., 1-
˜
NHCO and OH acid), 3167 (imidazole-NH), 1705 (C=O acid),
1669 (2-C=O), 1571 (C=C) cm–1 1H NMR (400 MHz, [D6]-
.
DMSO): δ = 7.32 (td, J = 7.5, 1.0 Hz, 1 H, 6-H), 7.47 (d, J =
8.3 Hz, 1 H, 8-H), 7.69 (td, J = 7.8, 1.4 Hz, 1 H, 7-H), 7.83–7.88
(m, 2 H, 5-H and Ar-H), 7.98 (dd, J = 8.7, 1.6 Hz, 1 H, Ar-H),
8.37 (s, 1 H, Ar-H), 9.35 (s, 1 H, 4-H), 12.72 (s, 1 H, 1-NHCO)
ppm; imidazole-NH and CO2H are absent. 13C NMR (100 MHz,
[D6]DMSO): δ = 115.1, 116.1, 116.9, 118.9 (2Cq), 123.7, 126.0,
127.4 (Cq), 129.9 (Cq), 130.0, 133.9, 140.0 (2Cq), 143.2 (C-4), 148.6
(Cq), 160.2 (2-C=O), 167.5 (CO2H) ppm. MS (70 eV, EI): m/z (%)
= 305 (100) [M]+, 277 (71) [M – CO], 260 (8), 232 (15), 153 (14),
130 (10). C17H11N3O3 (305.29): calcd. C 66.88, H 3.63, N 13.76;
found C 66.75, H 3.70, N 13.91.
8-(1,2-Dihydro-2-oxoquinolin-3-yl)-1H-purine-2,6(3H,9H)-dione
(4l): Yield: 234 mg. FTIR (KBr): ν = 3420 (2ϫNHCO), 3264 (1-
˜
NHCO), 3149 (imidazole-NH), 1742 (2ϫC=O), 1666 (2-C=O),
1
1607 (C=N), 1574 (C=C), 1281 (C–N) cm–1. H NMR (400 MHz,
[D6]DMSO): δ = 7.17 (t, J = 7.9 Hz, 1 H, 6-H), 7.29 (d, J = 8.2 Hz,
1 H, 8-H), 7.44 (t, J = 7.6 Hz, 1 H, 7-H), 7.68 (d, J = 7.9 Hz, 1 H,
5-H), 9.72 (s, 1 H, 4-H), 10.14 (br. s, 1 H, NHCO), 11.80 (br. s, 1
H, NHCO) ppm; one NHCO and the imidazole-NH are absent.
13C NMR (100 MHz, [D6]DMSO): δ = 99.8 (Cq), 115.3, 120.2
(Cq), 122.4, 128.8, 130.0 (Cq), 130.4, 139.0 (Cq), 142.7 (C-4), 150.8
(Cq), 156.2 (Cq), 159.8 (NHCO), 162.2 (2-C=O), 174.6 (NHCO)
ppm. MS (70 eV, EI): m/z (%) = 295 (76) [M]+, 252 (16), 224 (23),
171 (90), 43 (87), 28 (100). C14H9N5O3 (295.07): calcd. C 56.95, H
3.07, N 23.72; found C 56.81, H 3.19, N 23.46.
8-(1,2-Dihydro-2-oxoquinolin-3-yl)-3-methyl-1H-purine-2,6(3H,9H)-
dione (4h): Yield: 261 mg. FTIR (KBr): ν = 3147 (br., 2ϫNHCO
˜
and imidazole-NH), 1702 (2ϫC=O), 1663 (2-C=O), 1612 (C=N),
1
1589 (C=C) cm–1. H NMR (400 MHz, [D6]DMSO): δ = 3.48 (s, 3
3-[6,9-Dihydro-1-methyl-2-(methylthio)-6-oxo-1H-purin-8-yl]quin-
H, CH3), 7.30 (t, J = 6.8 Hz, 1 H, 6-H), 7.46 (d, J = 7.6 Hz, 1 H,
8-H), 7.62 (t, J = 6.8 Hz, 1 H, 7-H), 7.92 (d, J = 7.6 Hz, 1 H, 5-
H), 8.83 (s, 1 H, 4-H), 12.31 (br. s, 1 H, NHCO), 12.60 (br. s, 1 H,
NHCO) ppm. MS (70 eV, EI): m/z (%) = 309 (2) [M]+, 149 (31),
28 (100). C15H11N5O3 (309.28): calcd. C 58.25, H 3.58, N 22.64;
found C 58.33, H 3.45, N 22.66.
olin-2(1H)-one (4m): Yield: 276 mg. FTIR (KBr): ν = 3360 (br., 1-
˜
NHCO), 3142 (imidazole-NH), 1689 (br., 2ϫC=O) cm–1. 1H
NMR (400 MHz, [D6]DMSO): δ = 2.67 (s, 3 H, SCH3), 3.55 (s, 3
H, NCH3), 7.29 (t, J = 7.7 Hz, 1 H, 6-H), 7.46 (d, J = 7.7 Hz, 1
H, 8-H), 7.61 (t, J = 7.7 Hz, 1 H, 7-H), 7.89 (d, J = 7.7 Hz, 1 H,
5-H), 8.92 (s, 1 H, 4-H), 12.24 (br. s, 1 H, 1-NHCO) ppm; imid-
azole-NH is absent. MS (70 eV, EI): m/z (%) = 339 (100) [M]+, 252
(35), 171 (42), 153 (29), 67 (25). C16H13N5O2S (339.08): calcd. C
56.63, H 3.86, N 20.64; found C 56.70, H 3.97, N 20.48.
3-(6,9-Dihydro-2-methoxy-1-methyl-6-oxo-1H-purin-8-yl)quinolin-
2(1H)-one (4i): Yield: 273 mg. FTIR (KBr): ν = 3455 (br., 1-NH
˜
amide), 3164 (imidazole-NH), 1703 (C=O), 1651 (2-C=O), 1614
(C=N), 1217 (C–O) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
3.22 (s, 3 H, NCH3), 3.99 (s, 3 H, OCH3), 7.22 (t, J = 8.0 Hz, 1 H,
6-H), 7.41 (d, J = 8.0 Hz, 1 H, 8-H), 7.61 (t, J = 8.0 Hz, 1 H, 7-
H), 7.84 (d, J = 8.0 Hz, 1 H, 5-H), 8.41 (s, 1 H, 4-H), 10.24 (br. s,
1 H, 1-NHCO) ppm; imidazole-NH is absent. 13 C NMR
(100 MHz, [D6]DMSO): δ = 40.4 (NCH3), 55.9 (OCH3), 115.5
(Cq), 116.1, 122.3 (Cq), 123.0, 123.1 (Cq), 129.1 (Cq), 130.6 (Cq),
131.1, 131.5 (Cq), 133.8, 134.6 (Cq), 142.9 (C-4), 160.5 (2-C=O),
190.1 (C=O) ppm. MS (70 eV, EI): m/z (%) = 323 (100) [M]+, 279
(11), 171 (42), 155 (37). C16H13N5O3 (323.1): calcd. C 59.44, H
4.05, N 21.66; found C 59.31, H 3.92, N 21.80.
Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR spectra for compounds 4a, 4b, and 4c are provided.
Acknowledgments
The authors wish to credit the Developmental Therapeutics Pro-
gram (DTP) of the National Cancer Institute of United States for
performing the screening of the selected compounds. R. A. and
P. C. thank COLCIENCIAS and Universidad del Valle for finan-
cial support. M. N. and J. C. thank the Spanish “Consejería de In-
novación, Ciencia y Empresa, Junta de Andalucía”, Servicios
Técnicos de la Universidad de Jaén and Ministerio de Ciencia e
3-[6,9-Dihydro-2-(methylthio)-6-oxo-1H-purin-8-yl]quinolin-2(1H)-
one (4j): Yield: 298 mg. FTIR (KBr): ν = 3410 (br., 2ϫNHCO),
˜
3127 (imidazole-NH), 1708 (C=O), 1687 (br., 2-C=O), 1631 Innovación (project reference SAF2008-04685-C02-02) for finan-
(C=N), 1579 (C=C) cm–1. 1H NMR (400 MHz, [D6]DMSO): δ =
cial support.
324
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 317–325

One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones
[4]
[5]
B. Insuasty, F. Orozco, C. Lizarazo, J. Quiroga, R. Abonia, M.
Hursthouse, M. Nogueras, J. Cobo, Bioorg. Med. Chem. 2008,
16, 8492–8500.
a) R. Abonia, P. Cuervo, B. Insuasty, J. Quiroga, M. Nogueras,
J. Cobo, H. Meier, E. Lotero, Open Org. Chem. J. 2008, 2, 26–
34; b) R. Abonia, P. Cuervo, J. Castillo, B. Insuasty, J. Quiroga,
M. Nogueras, J. Cobo, Tetrahedron Lett. 2008, 49, 5028–5031.
[1] a) J. Michael, Nat. Prod. Rep. 1997, 14, 605–618; b) M. Balsub-
ramanian, J. G. Keay in Comprehensive Heterocyclic Chemistry
II (Eds.: A. Katritzky, C. Rees, E. Scriven), Pergamon Press,
Oxford, 1996, vol. 5, ch. 5.06, p. 245; c) C. Wright, J. Addac-
Kyereme, A. Breen, J. Brown, M. Cox, S. Croft, Y. Gokcek, H.
Kendrick, R. Phillips, P. Pollet, J. Med. Chem. 2001, 44, 3187–
3194.
[6]
[7]
S. Lin, L. Yang, Tetrahedron Lett. 2005, 46, 4315–4319.
[2] a) C. Battram, S. Charlton, B. Cuenoud, M. Dowling, R. Fair-
hurst, D. Farr, J. Fozard, J. Leighton-Davies, Ch. Lewis, L.
McEvoy, R. Turner, A. Trifilieff, J. Pharmacol. Exp. Ther. 2006,
317, 762–770; b) M. Singh, A. Chandra, B. Singh, R. Singh,
Tetrahedron Lett. 2007, 48, 5987–5990; c) N. Shirode, K. Kulk-
arni, V. Gumaste, A. Deshmukh, Arkivoc 2005, 1, 53–64; d)
Ch. Beadle, J. Boot, N. Camp, N. Dezutter, J. Findlay, L. Hay-
hurst, J. Masters, R. Penariola, M. Walter, Bioorg. Med. Chem.
Lett. 2005, 15, 4432–4437; e) G. Muscia, M. Bollini, A. Bruno,
S. Asís, J. Chil. Chem. Soc. 2006, 51, 859–863; f) G. Moore, C.
Papamicaël, V. Levacher, J. Bourguignon, G. Dupas, Tetrahe-
dron 2004, 60, 4197–4204; g) Ch. Mitsos, A. Zografos, O. Ig-
glessi-Markopoulou, J. Org. Chem. 2003, 68, 4567–4569; h) P.
Renhowe, S. Pecchi, C. Shafer, T. Machajewski, E. Jazan, C.
Taylor, W. Antonios-McCrea, C. McBride, K. Frazier, M.
Wiesmann, G. Lapointe, P. Feucht, R. Warne, C. Heise, D.
Menezes, K. Aardalen, H. Ye, M. He, V. Le, J. Vora, J. Cansen,
M. Wernette-Hammond, A. Harris, J. Med. Chem. 2009, 52,
278–292; i) J. Kuethe, A. Wong, C. Qu, J. Smitrovich, I. Davies,
D. Hughes, J. Org. Chem. 2005, 70, 2555–2567; j) J. Kuethe, A.
Wong, I. Davies, Org. Lett. 2003, 5, 3975–3978; k) M. Fraley,
W. Hoffman, K. Arrington, R. Hungate, G. Hartman, R.
McFall, K. Coll, K. Rickert, K. Thomas, G. McGaughey, Curr.
Med. Chem. 2004, 11, 709–719; l) M. Fraley, S. Hambaugh, R.
Hungate, Patent WO/2001/028993.
a) S. Patwardhan, S. Dev, Synthesis 1974, 348–349; b) V. Stern-
berg, G. Vesley, D. Kubik, J. Org. Chem. 1971, 36, 2550–2551;
c) R. Coppola, M. Petrini, Synthesis 1984, 1021–1022.
For information about the COMPARE program, please visit
the web site: http://dtp.nci.nih.gov/compare/.
[8]
[9] a) W. C. Hubbard, M. C. Alley, G. N. Gray, K. C. Green, T. L.
McLemore, M. R. Boyd, Cancer Res. 1989, 49, 826–832; b)
A. P. Monks, D. A. Scudiero, P. Skehan, R. H. Shoemaker,
K. D. Paull, C. Vistica, C. Hose, J. Langley, P. Cronise, A. Vai-
gro-Wolff, M. Gray-Goodrich, H. Campbell, M. Mayo, M.
Boyd, J. Natl. Cancer Inst. 1991, 83, 757–766; c) J. N.
Weinstein, T. G. Myers, P. M. OЈConnor, S. H. Friend, A. J.
Fornace, K. W. Kohn, T. Fojo, S. E. Bates, L. V. Rubinstein,
N. L. Anderson, J. K. Boulanwini, W. W. van Osdol, A. P.
Monks, D. A. Scudiero, E. A. Sausiville, D. W. Zaharevitz, B.
Bunow, V. N. Viswanadhan, G. S. Jhonson, R. E. Wittes, K. D.
Paull Jr., Science 1997, 275, 343–349.
[10] a) M. Engelmann, Ber. Dtsch. Chem. Ges. 1909, 42, 177–182;
Chem. Abstr. 1909, 3, 897; b) C. Johns, B. Hendrix, J. Biol.
Chem. 1915, 20, 153–160; Chem. Abstr. 1915, 9, 912.
[11] G. M. Sheldrick, SADABS, version 2007/2, Bruker AXS Inc.,
Madison, Wisconsin, USA, 2007.
[12] a) G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112–122; b)
G. M. Sheldrick, SHELXS97 and SHELXL97, University of
Göttingen, Germany, 1997.
[3] This aldehyde was obtained in 90% yield by refluxing aldehyde
8 (500 mg) in an aq. mixture of Amberlyst®-15/AcOH/H2O,
20 mg:5 mL:0.5 mL over 3 h.
Received: September 5, 2009
Published Online: November 24, 2009
Eur. J. Org. Chem. 2010, 317–325
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
325