Synthesis and structure elucidation of five new pyrimido[5,4-c]quinoline- 4(3H)-one derivatives using 1D and 2D NMR spectroscopy

Article abstract of DOI:10.1002/mrc.2689

Five new 2-(amino/aroxy)-5-methylpyrimido[5,4-c]quinolin-4(3H)-one derivatives have been designed and synthesized via an aza-Wittig reaction, and the structure elucidation was accomplished using extensive 1D (¹H, ¹³C) and 2D NMR spec

Full text of DOI:10.1002/mrc.2689

MRC Letters
Received: 6 June 2010
Revised: 29 August 2010
Accepted: 14 September 2010
Published online in Wiley Online Library: 13 October 2010
(wileyonlinelibrary.com) DOI 10.1002/mrc.2689
Synthesis and structure elucidation of five new
pyrimido[5,4-c]quinoline-4(3H)-one
derivatives using 1D and 2D NMR spectroscopy
Yong Ai,a Guangzhong Yang,a∗ Jianchao Liu,b Yu Chen,c Lu Liud
and Xinxiang Leid∗
Five new 2-(amino/aroxy)-5-methylpyrimido[5,4-c]quinolin-4(3H)-one derivatives have been designed and synthesized via an
aza-Wittig reaction, and the structure elucidation was accomplished using extensive 1D (1H, 13C) and 2D NMR spectroscopic
c
studies (COSY, HSQC and HMBC experiments). Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Keywords: 1H NMR; 13C NMR; COSY; HSQC; HMBC; structure elucidation; pyrimido[5,4-c]quinoline-4(3H)-one
Introduction
Results and Discussion
Syntheses
Nitrogen-containing heterocycles are among the most common
scaffolds in drugs and pharmaceutically relevant substances.[1]
Their derivatives always exhibit high biological activities, good
environmental compatibilities as well as novel interacting-target
properties, and therefore they play important roles in the medical
and agricultural fields. The potent pharmacophoric character
and considerable wide structural diversity of nitrogen-containing
heterocycles have been greatly researched. Some investigations
on the modification of heterocycles have been carried out,
and a large number of heterocyclic compounds were obtained
and typically used for high-performance screening in the early
stages of drug discovery programs. Imiquimod, clioquinol and
enoxacin, which contain quinoline and pyrimidine systems, have
been currently developed as antiviral, antifungal and antibacterial
drugs.
Pyrimidoquinoline nuclei have been of appeal to organic,
medicinal and materials scientists over many years due to their
extremelyvariedbiologicalactivitiessuchasantimalarial,[2] antimi-
crobial,[3–6] analgesic,[5–8] anti-inflammatory,[5–8] antioxida-
nt,[6,8,9] antifungal,[10] antitumor,[11–14] and antiviral.[15] Recently,
attention has been focused on the synthesis and bioactivities of
pyrimido[5,4-c]quinoline derivatives.[9,16–20] Moreover, previous
researches have shown that they exhibited several pharmacologi-
cal activities (e.g. antioxidant,[9] antimalarials,[19] antiherpetic[20]).
Nevertheless, these derivatives suffered from serious limitations
such as the rapid development of drug resistance. Thus, novel,
potent and less toxic agents containing pyrimido[5,4-c]quinoline
system are still urgently needed to overcome the limitations.
In this article, we present the synthesis of five new py-
rimido[5,4-c]quinoline-4(3H)-one derivatives. High-resolution
electron impact mass spectrometry (HREIMS) as well as one-
dimensional (1D) and two-dimensional (2D) NMR experiments
were used to determine their structures and NMR spectral
assignments.
The synthesis route of designed pyrimido[5,4-c]quinoline-4(3H)-
one derivatives is shown in Scheme 1. In brief, the 2-amino-
benzonitrile 1 was converted to 4-amino-2-methylquinoline-3-
carboxylic acid ethyl ester 2 via reaction with acetoacetic ester
and tin tetrachloride under heating. The iminophosphorane 3 was
subsequently obtained in satisfactory yield when 2 was treated
with triphenylphosphine, hexachloroethane and triethylamine.
Iminophosphorane 3 upon reaction with substituted phenyl
isocyanate gave carbodiimide 4 by using the aza-Wittig reaction
under mild conditions. Carbodiimide 4 was converted easily into 5
insatisfactoryyieldatroomtemperaturefor12–13 husingsodium
ethanolate as a catalyst. Meanwhile, the reaction of carbodiimide4
with phenols produced 6a–d in good yields under heating
for 4–6 h in the presence of a catalytic amount of potassium
carbonate. The formation of 6 can be rationalized in terms of an
initial nucleophilic addition of phenoxides to the carbodiimide4
to give the intermediate 7, which was then cyclized to give 6a–d.
All products were obtained as white solid after purified by silica
∗
Correspondence to: Guangzhong Yang, Laboratory for Natural Product
Chemistry, College of Pharmacy, South Central University for Nationalities,
708 Minyuan Road, Wuhan 430074, P. R. China. E-mail: yanggz888@126.com
Xinxiang Lei, College of Chemistry and Material Engineering, Wenzhou
University, Wenzhou 325035, P. R. China. E-mail: Xinxianglei@yahoo.com.cn
a
b
c
Laboratory for Natural Product Chemistry, College of Pharmacy, South Central
University for Nationalities, Wuhan 430074, P. R. China
College of Chemistry, Central China Normal University, Wuhan 430079, P. R.
China
College of Chemistry and Material Sciences, South Central University for
Nationalities, Wuhan 430074, P. R. China
d
College of Chemistry and Material Engineering, Wenzhou University, Wenzhou
325035, P. R. China
c
Magn. Reson. Chem. 2010, 48, 955–959
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

Y. Ai et al.
X
NH
N
N
N=PPh
2
N
3
CN
NH
CO Et
2
CO Et
CO Et
2
(i)
2
(ii)
(iii)
Me
2
N
Me
N
4
Me
1
2
3
(iv)
NH
X
OAr
OAr
N
N
N
X
N
N
N
N
X
N
H
CO Et
2
O
O
(v)
Me
6a-d
Me
N
Me
7
5 X=Cl
6a. Ar=4-BrPh, X=F; 6b. Ar= 2,4-ClPh, X=Cl; 6c. Ar=2,5-MePh, X=Cl; 6d. Ar=Ph, X=Cl.
Reagents and conditions:
(i) CH COCH COOCH CH , SnCl ,130°C, 6h;
3
2
2
3
4
(ii) PPh , C Cl , Et N, CH CN, r.t., 24h;
3
2
6
3
3
(iii) 4-X-PhNCO, CH Cl , 45°C, 12h;
2
2
(iv) CH CH CH CH NH , r.t., 0.5-1h, CH CH ONa, CH CH OH, r.t., 12h;
3
2
2
2
2
3
2
3
2
(v) ArOH, K CO , 75°C, 4-6h.
2
3
Scheme 1. Synthesis of 2-(amino/aroxy)-5-methylpyrimido[5,4-c]quinolin-4(3H)-one derivatives 5 and 6a–d.
3'
gel column chromatography and were characterized by 1D and
2D NMR experiments.
3'
Br
4'
Cl
2' Cl
2'
1'
4'
E
1'
5'
O
5'
3"
O
2"
6'
3"
2"
6'
2
2
1"
1N
D
4" Cl
1"
NMR spectroscopic investigations
1N
N
4" F
N
10
7
10
A
13
4
C
13
4
11
9
8
6" 5"
11
9
8
6" 5"
O
The NMR spectra of 5 and 6a–d were almost similar because
of the structural similarity of these compounds. The complete
proton and carbon chemical shift assignments were achieved by
a combination of 1D and 2D NMR experiments. Unambiguous
proton chemical shift assignments of 5 and 6a–d were based on
O
14
14
B
Me
5
N
12
5 Me
N
12
7
6a
6b
3'
1
3'
the multiplicity pattern of H resonances and also on the use of
2'
1'
4'
2'
1'
1
homonuclear H–1H COSY spectra. With the proton resonances
4'
5'
O
5'
of 5 and 6a–d having been assigned, the chemical shifts of
the corresponding carbons were identified by an heteronuclear
single quantum coherence (HSQC) experiment. The remaining
quaternary carbons could be distinguished by the heteronuclear
multiple bond coherence (HMBC) experiment.
3"
2"
O
6'
3"
2"
6'
2
1N
4" Cl
1"
2
N
4
1N
4" Cl
1"
N
10
13
4
10
11
13
9
8
6" 5"
11
O
9
8
6" 5"
14
O
14
Me
5
N
12
Me
5
N
12
7
Consideringthestructureof6b(Fig. 1), the1D1HNMRspectrum
showed a singlet at δH = 3.12 ppm, integrating for three protons;
these data suggested that the signal belonged to 5-Me. The HSQC
showed that 5-Me correlates with the carbon at δC = 27.0 ppm.
7
6c
Figure 1. Structure of the compounds 6a–d.
6d
2
The long-range HMBC, giving J and 3J CH coupling constants,
allowed the assignment of a number of quaternary carbons. In
particular, theproton5-Mecorrelateswithtwoquaternarycarbons
at δC = 160.0 and 109.8 ppm. Their only possible assignments can
be C5 (δC = 160.0 ppm) and C14 (δC = 109.8 ppm).
corresponding protons were assigned to 7.82 ppm (1H, td, J = 8.0,
1.2 Hz, H8) and 7.50 ppm (1H, td, J = 8.0, 1.2 Hz, H9). Once H8 and
H9 were assigned, and considering the correlations obtained by
1H–1H COSY, H7 and H10 could be assigned easily. The respective
protonated carbons C7, C8, C9 and C10 were allotted from HSQC.
The quaternary carbon C13 on the B ring was authenticated at
δC = 153.2 ppm on the basis of the 3J correlation with the signal
at 8.16 ppm (1H, d, J = 8.0, H10) with δC = 132.5 (C8), 148.9 (C12)
and 153.2 ppm.
The four protons of the para-chloro aromatic ring (D ring)
forming the AAꢁXXꢁ system [H2ꢁꢁ(H6ꢁꢁ), H3ꢁꢁ(H5ꢁꢁ)] and relative
carbons were easily assigned: the HMBC 2J and 3J correlations
between δH = 7.60 ppm (2H, d, J = 8.0 Hz) and 7.45 ppm (2H,
d, J = 8.0 Hz) with the quaternary carbons with δC = 132.6 and
In the 1D 1H NMR spectrum of the compound 6b, four aromatic
proton signals of the A ring were observed at δH = 8.01 ppm
(1H, d, J = 8.0 Hz), 7.82 ppm (1H, td, J = 8.0, 1.2 Hz), 7.50 ppm
(1H, td, J = 8.0, 1.2 Hz) and 8.16 ppm (1H, d, J = 8.0). The 3J
correlations of the signal at 7.82 ppm (1H, td, J = 8.0, 1.2 Hz)
with those at δC = 148.9 and δH = 7.50 ppm (1H, td, J = 8.0,
1.2 Hz) with δC = 122.7 ppm in HMBC and the fact that the
chemical shift of C12 connecting to N atom would be larger than
chemicalshiftofC11helpedtoconfirmthetwoquaternarycarbons
C12 (δC = 148.9 ppm) and C11 (δC = 122.7 ppm). Moreover, the
c
wileyonlinelibrary.com/journal/mrc
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 955–959

Synthesis and structure elucidation of five new pyrimido[5,4-c]quinoline-4(3H)-one derivatives
a
Table 1. 1D and 2D NMR data of compounds 6a–d in CDCl3
6a
6b
6c
6d
Carbon
numbering
(Cn)
HMBC
(H–C)
HMBC
(H–C)
HMBC
(H–C)
HMBC
(H–C)
δH
δc
δH
δc
δH
δc
δH
δc
2
–
–
–
154.4
162.2
160.0
–
–
–
153.6
162.0
160.0
128.3
–
–
–
–
–
160.1
162.2
160.1
–
–
–
–
–
160.0
162.0
160.0
–
–
4
–
5
–
–
–
–
–
7
8.03 d (8.0) 128.3
7.82 t (8.0) 132.5
7.52 t (8.0) 126.3
11, 9
10, 12
7, 11
8.01 d (8.0)
11, 9
10, 12
7, 11
8.03 d (8.0) 128.1
7.81 t (8.0) 132.5
7.48 t (8.0) 126.2
–
8.06 d (8.0) 128.1
7.81 t (8.0) 132.5
–
8
7.82 td (8.0, 1.2) 132.6
7.50 td (8.0, 1.2) 126.3
10
11, 7
8
10
11
8
9
7.50 m
126.2
10
11
12
13
14
1ꢁ
8.28 d (8.0) 124.5 8, 12, 13
8.16 d (8.0)
124.4 8, 12, 13 8.22 d (8.0) 124.7
8.27 d (8.0) 124.6
–
–
–
–
–
122.7
148.9
153.2
109.7
150.4
–
–
–
–
–
–
122.7
148.9
153.2
109.8
146.1
132.6
130.3
127.8
–
–
–
–
–
–
–
–
122.9
149.8
154.3
109.6
149.8
126.6
–
–
–
–
–
–
122.8
148.3
151.4
109.7
151.4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2ꢁ
7.62 d (8.0) 132.6 1ꢁ, 4ꢁ, 6ꢁ
7.17 d (8.0) 123.4 4ꢁ, 1ꢁ, 5ꢁ
–
–
6ꢁ, 1ꢁ
–
7.26 d(8.0) 121.5
7.50 m 129.4
7.36 t (8.0) 126.4
7.50 m 129.4
7.26 d (8.0) 121.5
133.0
1ꢁ, 4ꢁ
1ꢁ, 5ꢁ
2ꢁ, 6ꢁ
3ꢁ, 1ꢁ
4ꢁ, 1ꢁ
–
3ꢁ
7.56 d (1.2)
7.19 d (8.0) 131.0
7.07 d (8.0) 127.3
5ꢁ, 1ꢁ
6ꢁ, 2ꢁ
–
4ꢁ
–
119.6
–
–
–
1ꢁ
5ꢁꢁ
7.17 d (8.0) 123.4 4ꢁ, 3ꢁ, 1ꢁ 7.42 dd (8.0, 1.2) 128.1
–
7.02 s
–
137.1
122.0
133.2
6ꢁꢁ
1ꢁꢁ
2
7.62 d (8.0) 132.6 4ꢁ, 2ꢁ, 1ꢁ
7.29 d (8.0)
124.7 4ꢁ, 2ꢁ, 1ꢁ
1ꢁ
–
161.9
117.0 1ꢁꢁ, 3ꢁꢁ, 6ꢁꢁ
–
–
7.45 d (8.0)
7.60 d (8.0)
–
132.6
–
–
–
7.31 m
7.42 m
–
129.5 1ꢁꢁ, 4ꢁꢁ, 3ꢁꢁ 7.40 d (8.0) 129.4 1ꢁꢁ, 4ꢁꢁ, 6ꢁꢁ 7.40 d (8.4) 129.5 1ꢁꢁ, 6ꢁꢁ, 4ꢁꢁ
3ꢁꢁ
4ꢁꢁ
5ꢁꢁ
6ꢁꢁ
2ꢁ-Me
5ꢁ-Me
5-Me
129.9
163.8
129.8
2ꢁꢁ, 4ꢁꢁ
–
1ꢁꢁ, 6ꢁꢁ
130.0
135.7
130.0
1ꢁꢁ, 4ꢁꢁ
7.59 d (8.0) 130.0 1ꢁꢁ, 4ꢁꢁ, 5ꢁꢁ 7.60 d (8.4) 130.0 1ꢁꢁ, 4ꢁꢁ, 5ꢁꢁ
135.5 135.4
7.59 d (8.0) 130.0 1ꢁꢁ, 4ꢁꢁ, 3ꢁꢁ 7.60 d (8.4) 130.0 1ꢁꢁ, 4ꢁꢁ, 3ꢁꢁ
–
–
–
–
–
7.42 m
7.31 m
–
7.60 d (8.0)
7.45 d (8.0)
–
1ꢁꢁ, 4ꢁꢁ
116.8 2ꢁꢁ, 4ꢁꢁ, 5ꢁꢁ
129.5 1ꢁꢁ, 4ꢁꢁ, 5ꢁꢁ 7.40 d (8.0) 129.4 1ꢁꢁ, 4ꢁꢁ, 2ꢁꢁ 7.40 d (8.4) 129.5 1ꢁꢁ, 2ꢁꢁ, 4ꢁꢁ
–
–
–
–
–
–
–
–
2.13 s
2.39 s
3.14 s
15.9 1ꢁ, 3ꢁ, 4ꢁ
20.9 6ꢁ, 5ꢁ, 4ꢁ
–
–
–
–
–
–
–
–
3.12 s
27
5, 14
3.12 s
27
5, 14
26.8
5, 14
3.15 s
27.0
5, 14
a J values are in parentheses and reported in Hz; chemical shifts are given in parts per million; assignments were confirmed by HSQC and HMBC
experiments.
135.7 ppm, and the fact that the chemical shift of C4ꢁꢁ would be
larger than that of C1ꢁꢁ due to the electron-withdrawing effect of
the para-chloro atom allowed us to confirm the high-frequency
signals at δC 132.6 and 135.7 ppm to C1ꢁꢁ and C4ꢁꢁ, respectively; the
same methodology was applied to the four protonated carbons
with δC = 130.0 (C3ꢁꢁ, 5ꢁꢁ) and 129.5 (C2ꢁꢁ, 6ꢁꢁ) ppm corresponding
to δH = 7.60 ppm (2H, d, J = 8.0 Hz, H3ꢁꢁ, 5ꢁꢁ) and 7.45 ppm (2H, d,
J = 8.0 Hz, H2ꢁꢁ, 6ꢁꢁ) from HSQC experiment. This could further be
authenticated through the homonuclear 1H–1H COSY spectra of
correlations of δH = 7.60 ppm (2H, d, J = 8.0 Hz) with 7.45 ppm
(2H, d, J = 8.0 Hz).
In addition, the remaining high-frequency signal at δC
=
162.0 ppm was assignable to the conjugated carbonyl (C4), while
the other one at δC = 153.6 ppm was attributed to C2. These
assignments of the two quaternary carbons without any HMBC
correlations were further attested by the comparison of the 13C
NMR data of 6b with those of 5 and 6c, d. The chemical shift of
C4 remained almost the same among compounds 5 and 6a–d
due to the same chemical environment of C4, while signals of C2
between 5 and 6a–d were quite different according to changes
in substituents.
All 1H and 13C data on 2-(2,4-dichlorophenoxy)-3-(4-chloro-
phenyl)-5-methyl-pyrimido[5,4-c]quinolin-4(3H)-one are given in
Table 1.
For compounds 5 and 6c, d, the protons and carbons were
assigned using the same strategy, and the full characterization is
presented in Fig. 2 and Table 1.
The three protons of the E ring with δH = 7.56 ppm (1H, d,
J = 1.2), 7.42 ppm (1H, dd, J = 8.0, 1.2) and 7.29 ppm (1H, d,
J = 8.0) obtained from the 1D 1H NMR spectrum of the compound
6b were effortlessly confirmed as H3ꢁ, H5ꢁ and H6ꢁ in combination
with 1H–1H COSY experiment. The corresponding protonated
carbons were directly assigned through an HSQC experiment and
the assignments of relative quaternary carbons were ascertained
through an HMBC experiment. The 2J and 3J correlations of
δH = 7.56 (1H, d, J = 1.2 Hz, H3ꢁ) with δC = 146.1 and 127.4 (C6ꢁ)
ppm, δH = 7.42 (1H, dd, J = 8.0, 1.2 Hz, H5ꢁ) with δC = 146.1 ppm,
and δH = 7.29 (1H, d, J = 8.0 Hz, H6ꢁ) with δC = 146.1, 132.6 and
127.8 ppm in the HMBC indicated the assignment of C1ꢁ, C2ꢁ and
C4ꢁ at δC 146.1, 132.6 and 127.8 ppm, respectively.
Experimental
All NMR spectra were recorded on a Bruker AVANCE-III-500
(resonance frequencies 500.13 MHz for 1H and 125.77 MHz for
13C) equipped with a 5-mm BBFO probe head equipped with a
shielded Z-gradient coil (1H 90◦ pulse width = 14 µs, 13C 90◦
c
Magn. Reson. Chem. 2010, 48, 955–959
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/mrc

Y. Ai et al.
powder, mp 157–159 ◦C; 1H NMR (300 MHz, CDCl3): δH = 2.82 (3H,
s), 1.43 (3H, t, J = 6.9 Hz), 4.41 (2H, q, J = 6.9 Hz), 7.11 (2H, br s,
NH2), 7.86 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.65 (1H, t,
J = 7.2 Hz) and 7.38 (1H, t, J = 7.5 Hz), which is consistent with
the reported data.[21]
3'
1'
H2
C
H2
C
H
H
4' H3C
C
3"
H2
NH
2'
2"
Cl
2
1"
4"
5"
1
N
3N
H
Synthesis of iminophosphorane 3
6"
10
4
H
H
To a solution of 2 (1.15 g, 5 mmol) in CH2Cl2 (60 ml) was added
Ph3P (2.62 g, 10 mmol), C2Cl6 (2.37 g, 10 mmol) and Et3N (5.0 ml),
in this order. The mixture was stirred for 24 h at room temperature.
Then,thesolutionwasconcentrated,andtheobtainedresiduewas
subjectedtocolumnchromatography(silicagel,eluent:petroleum
ether–acetone, 8 : 2) to afford 3 in 70% yield, mp 217–218.8 ◦C; 1H
NMR (600 MHz, CDCl3): δH = 1.09 (3H, t, J = 7.2 Hz), 2.56 (3H, s),
3.91 (2H, q, J = 7.2 Hz) and 6.97–7.80 (19H, m, 19 × Ph-H).
H
H
9
O
11
12
5
N
6
CH3
7
8
H
Figure 2. The structure and details of the key HMBC correlations observed
for compound 5.
pulse width = 8.5 µs) at room temperature with standard Bruker
pulse programs. The samples were dissolved in 0.6 ml of CDCl3.
Chemical shifts are given in values of ppm, referenced to residual
Synthesis of carbodiimides 4
To a solution of iminophosphorane 3 (1.1 g, 2 mmol) in dry methy-
lene chloride (20 ml) was added 1-fluoro-4-isocyanatobenzene
(0.27 g,2 mmol)or1-chloro-4-isocyanatobenzene(0.30 g,2 mmol)
under nitrogen at 45 ◦C. After the reaction mixture was stirred for
12 h, the solvent was removed under vacuum and Et2O/petroleum
ether (1 : 2 30 ml) was added to precipitate triphenylphosphine ox-
ide. Removalofthesolventgavecarbodiimides4, whichwereused
directly without further purification.
solvent signals (δ = 7.26 for H, δ = 77.0 for 13C in CDCl3). H
NMR data were collected with 64K complex data points and were
apodized with an exponential window function (lb = 0.3) prior
to Fourier transformation. 13C-jmod spectra with WALTZ16 1H
decoupling were acquired using 64K data points. Signal-to-noise
enhancement was achieved by multiplication of the FID with an
exponential window function (lb = 1 Hz).
1
1
The 2D spectra used 2048 × 128 (1H–1H COSY), 1024 × 256
(HSQC) and 4096 × 128 (HMBC) data point matrices, which
were zero-filled to 1024 × 1024, 1024 × 1024 and 2048 × 1024,
respectively. In the homonuclear 1H–1HCOSY (Bruker pulse
program cosygpqf) experiments, the relaxation delay was set
to 1.5 s and the 90◦ pulse width to 14 µs. HSQC experiments
(hsqcetgp) were measured with 16 scans per t1 increment,
200 µs delay for homospoil/gradient recovery (D16), 1.5 ms for
homospoil/gradient pulse (P16), and 4 : 1 gradient combination.
An average 1J(C, H) of 145 Hz was used. 1H, 13C long-range
spectra HMBC (hmbcgplpndqf) were acquired with the same D16
(200 µs), P16 (1.5 ms) and 5 : 3 : 4 gradient combination using a
pulse sequence optimized for 8 Hz.
Synthesis of 2-(butylamino)-3-(4-chlorophenyl)-5-methyl-
pyrimido[5,4-c]quinoline-4(3H)-one (5)
Butan-1-amine (2 mmol) was added to the solution of 4 prepared
as above in CH2Cl2 (10 ml). After the reaction mixture was stirred
continuously for 0.5–1 h at room temperature, the solvent was
removed and 10 ml of anhydrous ethanol with several drops of
sodium ethoxide in ethanol was added. After stirring for another
12 h at room temperature, the solution was concentrated and
the residue was purified by silica gel column chromatography
using a 7 : 3 mixture of petroleum ether–acetone as the eluent
to give 2-(butylamino)-3-(4-chloropheny)-5-methylpyrimido[5,4-
c]quinolin-4(3H)-one 5 as a white solid. Yield 34.7%; mp
296.3–297.0 ◦C; 1H NMR (500 MHz, CDCl3): δH = 3.05 (s, 3H, 5-
CH3), 8.01(d, 1H, J = 8.0 Hz, H7), 7.80 (t, 1H, J = 8.0 Hz, H8),
7.57 (t, 1H, J = 8.0 Hz, H9), 8.75 (d, 1H, J = 8.0 Hz, H10), 7.32
(d, 1H, J = 8.0 Hz, H2ꢁꢁ), 7.64 (d, 1H, J = 8.0 Hz, H3ꢁꢁ), 7.64 (d,
1H, J = 8.0 Hz, H5ꢁꢁ), 7.32 (d, 1H, J = 8.0 Hz, H6ꢁꢁ), 3.64 (q, 2H,
J = 7.2 Hz, H1ꢁ), 1.66 (m, 2H, -H2ꢁ), 1.37 (m, 2H, H3ꢁ), 1.00 (t, 3H,
J = 7.2 Hz, H4ꢁ) and 4.48 (br, H, NH); 13C NMR (125 MHz, CDCl3):
δC = 160.3 (C2), 162.0 (C4), 160.3 (C5), 26.9 (C5-Me), 128.0 (C7),
132.0 (C8), 125.5 (C9), 124.7 (C10), 123.1 (C11), 152.3 (C12), 155.0
(C13), 107.3 (C14), 41.9 (C1ꢁ), 31.3 (C2ꢁ), 20.0 (C3ꢁ), 13.7 (C4ꢁ), 136.4
(C1ꢁꢁ), 130.2 (C2ꢁꢁ), 131.2 (C3ꢁꢁ), 132.7 (C4ꢁꢁ), 131.2 (C5ꢁꢁ) and 130.2
(C6ꢁꢁ); HMBC (see Fig. 2); IR (KBr): 3630, 3063, 2659, 1689, 1497,
1439, 1372, 1091, 1016, 801, 766 and 646 cm−1; EI MS: m/z 394 ([M
+ 2]+, 30), 392 ([M]+, 90), 363 (15), 350 (43), 336 (100), 320 (19),
211 (12), 184 (14), 155 (36) and 75 (2); HREIMS m/z 392.1405 (calcd.
for C22H21ClN4O, 392.1405).
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. Infrared spectra were taken
as KBr discs on an FTIR spectrometer. Thin-layer chromatography
(TLC) used pre-coated silica gel GF254 plates (Qingdao Haiyang
Chemical Co., Ltd., P. R. China). Column chromatography was
performed using silica gel (200–300 mesh) from Qingdao Haiyang
Chemical Group Co. All solvents and materials were reagent grade
and purified as required.
Synthesis of 4-amino-2-methyl-quinoline-3-carboxylic acid
ethyl ester (2)
2-Aminobenzonitrile (1; 2.36 g, 20 mmol) and SnCl4 (3.7 ml,
32 mmol) were added to a stirred solution of ethyl acetoacetate
(2.6 ml, 20 mmol) in anhydrous toluene (50 ml). The reaction
mixture was stirred under nitrogen at room temperature for
0.5 h and then heated at reflux for 6 h (130 ◦C). The mixture
was added to a saturated aqueous Na2CO3 solution (150 ml,
pH 10), and the resulting suspension was extracted with AcOEt
(3 × 50 ml). The combined extracts were dried (Na2SO4) and
concentrated under reduced pressure, and the obtained residue
was subjected to column chromatography (silica gel, eluent:
petroleumether–acetone,7 : 3)toafford2in68%yield,paleyellow
General procedure for the preparation of 3-(4-chloro–
substituted-phenyl)-5-methyl -2-aryloxypyrimido[5,4-c]
quinolin-4(3H)-one (6a) and 3-(4-fluoro–substituted-phenyl)-
5-methyl-2-aryloxypyrimido[5,4-c]quinolin-4(3H)-one (6c, d)
To the solution of 4 (2 mmol) in CH3CN (15 ml) was added
substituted phenol (2 mmol) and solid K2CO3 (0.024 g, 0.2 mmol).
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2010, 48, 955–959

Synthesis and structure elucidation of five new pyrimido[5,4-c]quinoline-4(3H)-one derivatives
The mixture was stirred for 4–6 h at 75 ◦C and then filtered. References
The filtrate was condensed and the residue purified by silica
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dryness and the residue recrystallized from ethanol, giving the
expected compounds.
2-(4-Bromophenoxy)-3-(4-fluorophenyl)-5-methylpyrimido[5,4-
c]quinolin-4(3H)-one(6a): White solid, yield 39%, mp
238.0–240.1 ◦C; 1H NMR and 13C NMR (Table 1); IR (KBr):
3060, 2925, 1694, 1610, 1559, 1487, 1364, 1329, 1212, 1097, 1041,
1009, 839, 779, 711 and 650 cm−1; EI MS: m/z 477 ([M + 2]+,
21), 475 (M+, 21), 338 (28), 304 (38), 259 (100), 211 (8), 155 (82),
128 (30), 77 (8) and 75 (13); HREIMS m/z 475.0334 (calcd. for
C24H15BrFN3O2, 475.0334).
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2-(2,4-Dichlorophenoxy)-3-(4-chlorophenyl)-5-
methylpyrimido[5,4-c]quinolin-4(3H)-one (6b): White solid,
yield 33.8%, mp 193.2–194.9 ◦C; 1H NMR and 13C NMR (Table 1); IR
(KBr): 3058, 2925, 1695, 1611, 1559, 1487, 1367, 1331, 1226, 1096,
1047, 1016, 831, 808, 778, 734 and 646 cm−1; EI MS: m/z 485 ([M
+ 4]+, 15), 483 ([M + 2]+, 44), 481 ([M]+, 44), 449 (16), 446 (95),
328 (80), 320 (56), 293 (36), 211 (18), 155 (100), 128 (27) and 75 (5);
HREIMS m/z 481.0141 (calcd. for C24H14Cl3N3O2, 481.0142).
2-(2,5-Dimethylphenoxy)-3-(4-chlorophenyl)-5-
methylpyrimido[5,4-c]quinolin-4(3H)-one (6c): White solid,
yield 35.2%, mp 198.2–199.5 ◦C; 1H NMR and 13C NMR (Table 1);
IR(KBr): 3060, 2925, 1696, 1604, 1562, 1496, 1366, 1328, 1260,
1137, 1043, 928, 873, 814, 764, 712 and 598 cm−1; EI MS: m/z 443
([M + 2]+, 29), 441 ([M]+, 83), 424 (14), 320 (19), 288(100), 211
(22), 155 (65), 149 (19), 128 (22), 71 (22) and 57 (35); HREIMS m/z
441.1239 (calcd for C26H20ClN3O2, 441.1240).
3-(4-Chlorophenyl)-5-methyl-2-phenoxypyrimido[5,4-c]quinolin-
◦
1
4(3H)-one (6d): White solid, yield 31.4%, mp 229.4–231.2 C; H
NMR and 13C NMR (Table 1); IR (KBr): 3062, 2930, 1695, 1613, 1561,
1489, 1366, 1329, 1205, 1086, 1018, 829, 771 and 650 cm−1; EI MS:
m/z 415 ([M + 2]+, 14), 413 ([M]+, 44), 320 (29), 322 (10), 260 (10),
211 (5), 155 (41), 143 (9), 128 (11) and 77 (3); HREIMS m/z 413.0936
(calcd. for C24H16ClN3O2, 413.0936).
Acknowledgements
The project was supported by the Special Fund for Basic
Scientific Research of Central Colleges, South-Central University
for Nationalities (ZZZ10006).
c
Magn. Reson. Chem. 2010, 48, 955–959
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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