Base-catalyzed cyclization reaction of 2-chloroquinoline-3-carbonitriles and guanidine hydrochloride: A rapid synthesis of 2-amino-3H-pyrimido[4,5-b] quinolin-4-ones

Article abstract of DOI:10.1016/j.tet.2011.09.032

t-BuOK-catalyzed cyclization of 2-chloroquinoline-3-carbonitriles with guanidine hydrochloride provided simple and rapid synthesis of 2-amino-3H-pyrimido[4,5-b]quinolin-4-ones in very short reaction time with good yield. Other 1,3-binucleophiles are found to react at the same rate. This methodology could be extended with their 3-formyl and 3-ester derivatives for the synthesis of pyrimido annulated quinolines.

Full text of DOI:10.1016/j.tet.2011.09.032

Tetrahedron 67 (2011) 9219e9224
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base-catalyzed cyclization reaction of 2-chloroquinoline-3-carbonitriles and
guanidine hydrochloride: a rapid synthesis of 2-amino-3H-pyrimido[4,5-b]
quinolin-4-ones
*
Atish Chandra, Shraddha Upadhyay, Bhawana Singh, Neha Sharma, Radhey M. Singh
Department of Chemistry, Centre of Advance Studies, Banaras Hindu University, Varanasi, U.P., India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2011
Received in revised form 31 August 2011
Accepted 12 September 2011
Available online 16 September 2011
t-BuOK-catalyzed cyclization of 2-chloroquinoline-3-carbonitriles with guanidine hydrochloride pro-
vided simple and rapid synthesis of 2-amino-3H-pyrimido[4,5-b]quinolin-4-ones in very short reaction
time with good yield. Other 1,3-binucleophiles are found to react at the same rate. This methodology
could be extended with their 3-formyl and 3-ester derivatives for the synthesis of pyrimido annulated
quinolines.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidoquinoline
2-Chloroquinoline-3-carbonitrile
Base-catalyzed
Guanidine hydrochloride
1. Introduction
We have been engaged in exploring the reactivity and synthetic
applications of 2-chloroquinoline-3-carboxaldehyde derivatives.11
Quinoline derivatives are the core structure in the many alkaloid
family1 and well recognised by both synthetic and medicinal
chemists because of their wide ranging applications as pharma-
ceuticals, agrochemicals, dyestuffs2 and synthetic building blocks.3
Pyrimidoquinoline derivatives are of particular interest because
biological properties displayed by this class of compounds mainly
depend on nature and position of substituents and possess anti-
malerial,4 antiallergic,5 antimicrobial,6 anti-inflammatory7 and
anticancer8 activities.
Because of their importance as drug molecules, interest has
stimulated for the development of new methodology providing an
efficient synthesis of pyrimido[4,5-b]quinoline framework. The
classical synthesis reported to pyrimido[4,5-b]quinoline frame-
work involves either formation of the quinoline ring by cyclization
of suitable substituent of a pyrimidine or formation of the pyrim-
idine ring from the reaction of 2-aminoquinolines with 1,3-
binucleophioles and isothiocyanate, respectively.9 Similarly, in
pyrimido[4,5-b]pyridine derivative, formation of the pyrimidine
ring is reported from 2-chloropyridine-3-carbonitrile with guani-
dine in anhydrous DMSO.10 All these methods, however, suffer from
some drawbacks, such as high temperature, longer reaction time,
anhydrous conditions and poor yield of the products.
The easy accessibility of these precursors from the anilides via
Vilsmeier approach and their formyl group interconversion into
cyano and ester groups makes them attractive intermediates for
their further synthetic applications. We have recently demon-
strated that fused nitrogen and oxygen heterocycles with diverse
structural features and functionalities are accessible from 2-
chloroquinoline-3-carboxaldehyde by choice of suitable reagents,
catalyst and other reactive partners.12 However, their 3-carbonitrile
analogues for the synthesis of fused heterocycles are less ex-
plored.13 In continuation of these studies, we now report the base-
catalyzed cyclization reaction of 2-chloroquinoline-3-carbonitriles
and guanidine hydrochlorides providing an efficient route to the
synthesis of 2-amino-3H-pyrimido[4,5-b]quinolin-2-ones.
2. Results and discussion
The required 2-chloroquinoline-3-carbonitriles (1) were easily
prepared from their corresponding aldehydes using iodine in
aqueous ammonia.11b To study the construction of pyrimidine ring
in pyrimidine-fused quinolines, we first examined the reaction of 2-
chloroquinoline-3-carbonitrile (1a) and guanidine hydrochloride
using several bases and solvents to optimize the reaction condi-
tions and found that it proceeds readily and completed in very
shorter time when 1 mmol of 1a and 1 mmol of 2a in 3 mL ethanol
on heating with 0.5 equiv of t-BuOK14 at 90 ꢀC afforded the cyclized
* Corresponding author. Tel.: þ91 542 670 2482; fax: þ91 542 2368127; e-mail
address: rmohan@bhu.ac.in (R.M. Singh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.032

9220
A. Chandra et al. / Tetrahedron 67 (2011) 9219e9224
product 3a9m in 80% yield, which was characterized as 2-amino-
3H-pyrimido[4,5-b]quinolin-4-one from their spectral and analyt-
ical data (Scheme 1, Table 1, entry 1). Increasing the amount of base
to 1 equiv did not improve the yield (entry 2). Further, increasing or
occurred when triethylamine was used (entry 9). Among the vari-
ous solvents screened for reaction media (entries 1 and 10e14),
ethanol, t-BuOH and DMF were found equally effective with 80%,
80% and 79% yields, respectively (entries 1, 10 and 11). Further, no
cyclization reaction occurred in water (entry 15).
After optimizing cyclization reaction conditions with 1a, various
2-chloroquinoline-3-carbonitriles (1bei) with guanidine hydro-
chloride were screened under similar reaction conditions and
found to proceed smoothly providing the desired cyclized products
3bei in excellent yields. The results are summarized in Table 2
(entries 1e9). The electron donating and electron withdrawing
substituent at benzene ring of quinoline moiety have slightly better
yields of the cyclized products. To generalize the scope of the re-
action, 5-phenyl-2-chloropyridine-3-carbonitrile (1j) was then
tested with guanidine hydrochloride under optimized reaction
conditions and found that the reaction proceeds at the same time
with better yield (entry 10).
O
CHO
Cl
CN
Cl
2a
NH3 / I2
THF
NH
NH2
t-BuOK
R
R
R
EtOH 90
5 min
°C
N
N
N
N
3
1
NH.HCl
H2N NH2
2a =
Scheme 1. Synthesis of pyrimido[4,5-b]quinoline.
Table 1
Optimization of reaction in different solvents and bases
After optimizing cyclization reaction conditions with guanidine
hydrochloride, the scope of other 1,3-binucleophiles such as urea,
thiourea, S-benzylisothiourea chloride and cyano-guanidine with
1a was examined under similar reaction conditions and found that
the reactions completed at the same rate. The results are summa-
rized in Table 2 (entries 11e18, Scheme 2).
The cyclized products with urea were characterized as pyrimido
[4,5-b]quinoline-2,4-diones 4a and 4b, respectively, from spectral
and analytical data (entries 11 and 12) presuming that products
with guanidine hydrochloride and urea proceed via similar tauto-
meric structures. However, the cyclized products with thiourea and
other binucleophiles were characterized as 2-substituted-4-amino-
1H-pyrimido[4,5-b]quinoline derivatives indicating the absence of
such tautomeric structure (entries 14e18, Scheme 3). The substrate
bearing electron donating substituent gave better yield of the
cyclized products (entries 12 and 15). The cyclization reactions with
substrate bearing electron withdrawing substituent proceeded at
the same rate, providing unidentified products. It is noteworthy, no
cyclization reactions were found without base assuming anions of
binucleophiles were involved in the cyclization reactions.
Entry
Base (equivalent)
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
t-BuOK (0.5)
t-BuOK (1.0)
t-BuOK (1.5)
t-BuOK (0.2)
KOH (0.5)
K3PO4 (0.5)
K2CO3 (0.5)
Na2CO3 (0.5)
Et3N (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
t-BuOH
DMF
5
5
5
90
5
5
510
450
d
80
80
70
73
72
70
72
70
d
9
10
11
12
13
14
15
5
5
180
360
80
79
70
60
50
Sm
CH3CN
THF
Benzene
Water
15
Overnight
decreasing the base lowered the yield (entries 3 and 4). The use of
KOH and K3PO4 bases did not improve the yield under similar re-
action conditions (entries 5 and 6). K2CO3 and Na2CO3 required
longer reaction time for completion (entries 7 and 8). No reaction
Table 2
Synthesis of pyrimido[4,5-b]quinolines
Entry
1
Substrate
Binucleophile
Product
Time (min)
5
Yield (%)
80
O
CN
Cl
NH.HCl
NH
NH2
H2N NH2
N
2a
1a
N
N
3a
O
CN
NH.HCl
NH
NH2
2
3
5
89
85
H2N NH2
N
Cl
2a
1b
N
N
O
3b
CN
Cl
NH.HCl
NH
NH2
10
H2N NH2
N
2a
1c
N
N
3c
O
CN
Cl
NH.HCl
NH
NH2
4
5
10
89
85
H2N NH2
N
2a
N
N
1d
3d
O
N
O
CN
Cl
NH.HCl
O
NH
NH2
5
H2N NH2
2a
N
1e
N
3e

A. Chandra et al. / Tetrahedron 67 (2011) 9219e9224
9221
Table 2 (continued )
Entry
Substrate
Binucleophile
Product
Time (min)
Yield (%)
O
N
CN
Cl
NH.HCl
NH
NH2
6
7
5
90
85
H2N NH2
O
N
2a
1f
O
N
3f
O
CN
Cl
NH.HCl
NH
NH2
20
N
H2N NH2
2a
N
N
1g
3g
O
Br
CN
Cl
NH.HCl
Br
NH
NH2
8
10
10
5
88
90
90
79
H2N NH2
N
2a
1h
N
N
O
3h
CN
Cl
NH.HCl
NH
NH2
9
H2N NH2
2a
Cl
N
1i
Cl
N
N
3i
O
NH.HCl
CN
Cl
10
11
NH
NH2
H2N NH2
2a
1j
N
N
3j
N
O
CN
Cl
O
NH
5
H2N NH2
N
2b
1a
N
N
H
O
4a
O
CN
Cl
O
NH
12
13
14
15
16
17
5
82
H2N NH2
O
N
2b
O
N
N
H
O
1f
4b
O
CN
Cl
O
Overnight
0a
NH
H2N NH2
Cl
N
2b
Cl
N
N
H
O
1i
4c
NH2
N
CN
Cl
S
5
62
72
0a
H2N NH2
N
2c
N
N
H
S
1a
5a
NH2
N
CN
S
5
H2N NH2
O
N
Cl
2c
O
N
N
H
S
1f
5a'
NH2
N
CN
Cl
S
Overnight
H2N NH2
Cl
N
2c
Cl
N
N
H
S
1i
5a''
NH2
CN
Cl
NH2 Cl
N
5
79
H2N
S
Ph
N
2d
N
N
S
Ph
1a
5b
(continued on next page)

9222
A. Chandra et al. / Tetrahedron 67 (2011) 9219e9224
Table 2 (continued )
Entry
Substrate
Binucleophile
Product
NH2
Time (min)
5
Yield (%)
70
CN
Cl
NH
N
CN
18
H2N
N
H
CN
N
2 e
N
N
N
H
1a
5c
CHO
Cl
N
NH.HCl
19
20
10
5
79
80
H2N NH2
N
N
NH2
2a
N
1k
6
O
COOMe
Cl
NH.HCl
NH
NH2
H2N NH2
N
2a
1l
N
N
3a
a
Unidentified products.
NH2
N
A plausible mechanism for one-pot cyclization is presented in
Scheme 6. First step involves the release of free guanidine from the
reaction of its hydrochloride with t-BuOK. The second step is nu-
cleophilic aromatic substitution at 2-chloro carbon of 2-
chloroquinoline-3-carbonitrile 1a to generate A in situ, which on
subsequent intramolecular cyclization might provide 4-
iminopyrimido-fused quinoline B. Imine B on work up provides
the desired 2-amino-3H-pyrimido[4,5-b]quinolin-4-one (3a).
O
NH
O
CN
Cl
H2N NH2
t-BuOK
H2N
t-BuOK
X
NH
R
R
R
N
N
N
X
N
4
N
H
O
5
1
R= H, 7-MeO, 7-Cl
X= NHCN, SBenz, =S
Scheme 2. Reaction of 2-chloroquinoline-3-carbonitrile with different binucleophile.
NH
NH
NH
NH
t-BuOH + KCl
CN
NH
NH
NH2
NH2 Cl
NH2
1a
N
N
N
NH2
N
N
N
H
NH
tBuOK
HN
N
N
N
H
NH2
H2N
A
NH
NH
NH
NH
ROH
O
NH
N
N
N
OH
N
H
O
NH
NH2
NH
NH
-H
Hydrolysis
N
N
N
H
NH2
N
B
NH2
3a
Scheme 3. Tautomeric structures.
Scheme 6. Plausible mechanism.
The presence of amino group at 4-position in cyclized com-
pounds 5aec derived from the reaction of 1a with 1,3-
binucleophiles 2cee was further confirmed by their acetylations
with acetic anhydride providing 4-acetylamino-2-substituted-pyr-
imido[4,5-b]quinoline derivatives (6) (Scheme 4).
3. Conclusions
In summary, we have developed a simple and rapid synthesis of
2-amino-3H-pyrimido[4,5-b]quinolin-4-ones from t-BuOK-cata-
lyzed cyclization of 2-chloroquinoline-3-carbonitriles with guani-
dine hydrochlorides in very short reaction time in good yields. This
cyclization reaction is equally facile with other 1,3-binucleophiles
and with formyl and carbomethoxy derivatives of quinoline.
NH2
N
NHCOCH3
N
(CH3CO)2O
Reflux
N
N
X
N
6
N
X
5
X= SBenz, =S
Scheme 4. Acetylation of functionalized pyrimidoquinolines.
4. Experimental section
4.1. General
Encouraged by facile cyclization reaction of 2-chloroquinoline-3-
carbonitriles with guanidine hydrochloride, we extended the same
strategy to their 3-formyl and 3-carbomethoxy derivatives 1k and
1l. Thus, the treatment of 1k and 1l with guanidine hydrochloride
under optimized reaction condition provided the desired pyrimido
[4,5-b]quinoline derivatives 7 and 3a in short of time with 79% and
80% yields, respectively (Scheme 5, Table 2, entries 19 and 20).
Melting points are measured using Buchi Melting-point appa-
ratus in an open capillary tube and are uncorrected. IR spectra were
recorded on VARIAN 3300 FTIR spectrophotometers. 1H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded on JEOL AL 300 MHz
spectrometer. The chemical shifts (d ppm) and coupling constants
NH.HCl
CHO
Cl
(Hz) are reported in the standard fashion with reference to either
internal tetramethylsilane (for 1H) or the central line (77.0 ppm) of
CDCl3 (for 13C). Elemental analyses were performed on Exter Ana-
lytical Inc. ‘Model CE-400 CHN Analyzer’ from Department of
chemistry, BHU, Varanasi. Thin-layer chromatographies (TLC) were
performed on glass plates (7.5ꢁ2.5 and 7.5ꢁ5.0 cm) coated with
Loba Chemie’s silica gel GF254 and various combinations of ethyl
acetate and hexane were used as eluent. Visualization of spots was
N
/EtOH/t-BuOK
H2N NH2
N
N
O
NH2
N
1k
7
NH.HCl
H2N NH2
COOMe
Cl
NH
NH2
/EtOH/t-BuOK
N
N
N
1l
3a
Scheme 5. Reaction of guanidine with different functionalized chloroquinolines.

A. Chandra et al. / Tetrahedron 67 (2011) 9219e9224
9223
accomplished by exposure to UV light. Qualigen’s silica gel
(60e120 mesh) was used for column chromatography (approxi-
mately 15e20 g per 1 g of the crude product).
hexane) 0.20; 1H NMR (300 MHz, DMSO-d6):
d
¼3.92 (s, 3H), 6.74 (br
s, 2H, D2O exchangeable), 6.99e7.10 (m, 3H, 1H, D2O exchangeable),
7.72 (t, J¼9.0 Hz,1H), 8.97 (s,1H); 13C NMR (CDCl3, 75 MHz):
¼55.8,
d
115.3,126.4,127.0,128.3,129.0,130.2,135.4,144.4,154.8,157.7,170.4;
IR (KBr, cmꢂ1): 1654, 3444. Anal. Calcd for C12H10N4O2: C, 59.50; H,
4.16; N, 23.13. Found: C, 59.62; H, 4.12; N, 23.15.
4.2. General procedure for the synthesis of 2-amino-3H-
pyrimido[4,5-b]quinolin-4-one (3)
4.2.7. 2-Amino-9-ethyl-3H-pyrimido[4,5-b]quinolin-4-one
To a mixture of 1 (1 mmol) and binucleophile 2 (1 mmol) in
2e3 mL of EtOH was added t-BuOK (0.5 mmol), reaction mixture
was stirred at 90 ꢀC. After completion of the reaction, mixture
poured into ice-cold water, solid product filtered and washed with
water (3ꢁ5 mL) and further purified by column chromatography on
silica gel (60e120 mesh) using EtOAc/hexane as eluent in 4:6 ratio
to yielded pure product 3.
(3g). Yellow solid; yield: 85%; mp 242 ꢀC; Rf (40% EtOAc/hexane)
0.31; 1H NMR (300 MHz, DMSO-d6):
d
¼1.27 (t, J¼6.9 Hz, 3H), 3.12
(q, J¼7.2 Hz, 2H), 6.50 (br s, 2H, D2O exchangeable), 7.27 (t, J¼7.5 Hz,
1H), 7.53e7.66 (m, 3H,1H, D2O exchangeable), 9.01 (s,1H); 13C NMR
(CDCl3, 75 MHz):
d
¼21.5, 50.8, 127.3, 127.9, 128.0, 128.1, 128.5, 129.0,
135.7, 139.3, 148.0, 155.2, 170.5; IR (KBr, cmꢂ1): 1654, 3447. Anal.
Calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 65.12; H,
5.01; N, 23.28.
4.2.1. 2-Amino-3H-pyrimido[4,5-b]quinolin-4-one (3a). Yellow solid;
yield: 80%; mp 296e298 ꢀC; Rf (40% EtOAc/hexane) 0.13; 1H NMR
4.2.8. 2-Amino-7-bromo-3H-pyrimido[4,5-b]quinolin-4-one
(300 MHz, DMSO-d6):
d
¼6.54 (br s, 2H, D2O exchangeable), 7.35 (t,
(3h). Yellow solid; yield: 88%; mp 321 ꢀC; Rf (40% EtOAc/hexane)
J¼7.8 Hz, 1H), 7.69e7.82 (m, 4H, 1H, D2O exchangeable), 9.03 (s,
0.10; 1H NMR (300 MHz, DMSO-d6):
d
¼6.55 (br s, 2H, D2O ex-
changeable), 7.36 (t, J¼7.5 Hz, 1H), 7.67e7.84 (m, 3H, 1H, D2O ex-
changeable), 9.05 (s, 1H); 13C NMR (CDCl3, 75 MHz,):
1H); 13C NMR (CDCl3, 75 MHz):
d¼113.2, 122.3, 126.3, 126.9, 127.8,
128.2, 128.4, 131.8, 137.4, 153.6, 170.1; IR (KBr, cmꢂ1): 1654, 3402.
Anal. Calcd for C11H8N4O: C, 62.26; H, 3.80; N, 26.40. Found: C,
61.98; H, 3.74; N, 26.51.
d
¼115.1, 126.6,
128.3, 128.4, 128.5, 133.2, 135.3, 140.3, 149.3, 155.4, 170.3; IR (KBr,
cmꢂ1): 1655, 3404. Anal. Calcd for C11H7N4OBr: C, 45.39; H, 2.42; N,
19.25. Found: C, 45.53; H, 2.47; N, 19.21.
4.2.2. 2-Amino-7-methyl-3H-pyrimido[4,5-b]quinolin-4-one
(3b). Yellow solid; yield: 89%; mp 305e307 ꢀC; Rf (40% EtOAc/
4.2.9. 2-Amino-8-chloro-3H-pyrimido[4,5-b]quinolin-4-one
hexane) 0.50; 1H NMR (300 MHz, DMSO-d6):
d
¼2.50 (s, 3H), 6.54
(3i). Yellow solid; yield: 90%; mp 370 ꢀC (d); Rf (40% EtOAc/hexane)
(br s, 2H, D2O exchangeable), 7.21 (d, J¼7.8 Hz, 1H), 7.54 (s, 1H),
0.30; 1H NMR (300 MHz, DMSO-d6):
d
¼6.53 (br s, 2H, D2O ex-
changeable), 7.36 (t, J¼8.8 Hz, 1H), 7.67e7.84 (m, 3H, 1H, D2O ex-
changeable), 9.05 (s, 1H); 13C NMR (CDCl3, 75 MHz,):
7.72e7.73 (m, 2H, 1H, D2O exchangeable), 8.99 (s, 1H); 13C NMR
(CDCl3, 75 MHz):
d
¼21.5, 127.3, 127.9, 128.0, 128.1, 128.5, 129.0,
d
¼115.9, 127.0,
135.3, 136.8, 148.0, 155.2, 170.3; IR (KBr, cmꢂ1) 1651, 3447. Anal.
Calcd for C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found: C, 63.87; H,
4.40; N, 24.67.
127.8, 128.6, 129.0, 134.9, 135.3, 148.6, 152.3, 153.9, 169.1; IR (KBr,
cmꢂ1): 1655, 3404. Anal. Calcd for C11H7N4OCl: C, 53.56; H, 2.86; N,
22.71. Found: C, 53.47; H, 2.91; N, 22.58.
4.2.3. 2-Amino-8-methyl-3H-pyrimido[4,5-b]quinolin-4-one
4.2.10. 2-Amino-6-phenyl-3H-pyrido[2,3-d]pyrimidin-4-one
(3c). Yellow solid; yield: 85%; mp 307 ꢀC; Rf (40% EtOAc/hexane)
(3j). Yellow solid; yield: 89%; mp 235 ꢀC; Rf (40% EtOAc/hexane)
0.40; 1H NMR (300 MHz, DMSO-d6):
d
¼2.45 (s, 3H), 6.54 (br s, 2H,
0.15; 1H NMR (300 MHz, DMSO-d6):
d
¼6.42 (br s, 2H, D2O ex-
D2O exchangeable), 7.21 (d, J¼7.81 Hz, 1H), 7.54 (s, 1H), 7.71e7.73
changeable), 7.41e7.46 (m, 3H, 1H, D2O exchangeable), 7.68 (d,
J¼7.2 Hz, 1H), 7.76 (d, J¼7.2 Hz, 1H), 8.29 (s, 1H), 8.71 (d, J¼5.4 Hz,
(m, 2H, 1H, D2O exchangeable), 8.99 (s, 1H); 13C NMR (CDCl3,
75 MHz):
d
¼22.3, 127.2,128.0,128.4, 129.0, 129.2,135.4,139.8,147.9,
1H), 8.99 (s, 1H); 13C NMR (CDCl3, 75 MHz):
d¼127.0, 128.0, 128.6,
149.6, 155.2, 170.4; IR (KBr, cmꢂ1): 1654, 3447. Anal. Calcd for
C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found: C, 63.91; H, 4.37; N,
24.65.
128.8, 129.0, 129.3, 134.8, 135.2, 135.7, 136.3, 168.4; IR (KBr, cmꢂ1):
1654, 3401. Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52.
Found: C, 65.71; H, 4.19; N, 23.45.
4.2.4. 2-Amino-9-methyl-3H-pyrimido[4,5-b]quinolin-4-one
4.2.11. 1H-Pyrimido[4,5-b]quinoline-2,4-dione (4a). Green solid;
yield: 79%; mp 225 ꢀC; Rf (10% EtOAc/hexane) 0.40; 1H NMR
(3d). Yellow solid; yield: 89%; mp 380 ꢀC (d); Rf (40% EtOAc/hex-
ane) 0.16; 1H NMR (300 MHz, DMSO-d6):
2H, D2O exchangeable), 6.90 (s, 1H, D2O exchangeable), 7.26 (t,
d
¼2.61 (s, 3H), 6.57 (br s,
(300 MHz, DMSO-d6):
d
¼7.32e7.44 (m, 2H), 7.72e7.85 (m, 3H, 1H,
D2O exchangeable), 8.83 (s, 1H), 12.52 (s, 1H, D2O exchangeable);
J¼8.8 Hz, 1H), 7.57(d, J¼6.6 Hz, 1H), 7.66(d, J¼8.1 Hz, 1H), 9.02 (s,
13C NMR (DMSO-d6, 75 MHz,):
d
¼95.4, 122.0, 122.7, 124.5, 126.4,
1H); 13C NMR (CDCl3, 75 MHz,):
d
¼18.1, 126.2, 126.4, 127.2, 127.9,
134.5, 142.7, 143.6, 157.6, 170.4, 179.4; IR (KBr, cmꢂ1): 1656, 3321.
Anal. Calcd for C11H7N3O2: C, 61.97; H, 3.31; N, 19.71. Found: C,
62.15; H, 3.28; N, 19.63.
128.4, 133.0, 135.4, 136.3, 140.4, 155.4, 170.4; IR (KBr, cmꢂ1): 1654,
3401. Anal. Calcd for C12H10N4O: C, 63.71; H, 4.46; N, 24.76. Found:
C, 63.78; H, 4.50; N, 24.69.
4.2.12. 8-Methoxy-1H-pyrimido[4,5-b]quinoline-2,4-dione
4.2.5. 2-Amino-7-methoxy-3H-pyrimido[4,5-b]quinolin-4-one
(4b). Yellow solid; yield: 82%; mp 278e280 ꢀC; Rf (70% EtOAc/
(3e). Yellow solid; yield: 85%; mp 298e301 ꢀC; Rf (40% EtOAc/hex-
hexane) 0.12; 1H NMR (300 MHz, DMSO-d6):
d
¼3.78 (s, 3H),
ane) 0.29; 1H NMR (300 MHz, DMSO-d6):
d
¼3.90 (s, 3H), 6.52 (br s,
6.80e6.91 (m, 3H, 1H, D2O exchangeable), 7.68 (s, 1H), 8.63 (s, 1H),
2H, D2O exchangeable), 6.95e7.08 (m, 3H, 1H, D2O exchangeable),
12.29 (s, 1H, D2O exchangeable); 13C NMR (DMSO-d6, 75 MHz,):
7.70 (t, J¼8.4 Hz,1H), 8.92 (s,1H); 13C NMR (CDCl3, 75 MHz,):
d¼55.8,
d
¼55.7, 97.9, 101.9, 112.2, 112.6, 131.1, 137.4, 142.4, 149.0, 159.1, 163.8,
126.6,127.0,128.0,128.2,129.6,130.1,135.3,143.1,154.8,157.7,170.4;
IR (KBr, cmꢂ1): 1656, 3404. Anal. Calcd for C12H10N4O2: C, 59.50; H,
4.16; N, 23.13. Found: C, 59.70; H, 4.09; N, 23.11.
184.3; IR (KBr, cmꢂ1): 1651. Anal. Calcd for C12H9N3O3: C, 59.26; H,
3.73; N, 17.28. Found: C, 59.31; H, 3.78; N, 17.22.
4.2.13. 4-Amino-1H-pyrimido[4,5-b]quinoline-2-thione (5a). Yellow
solid; yield: 62%; mp 220 ꢀC; Rf (4% MeOH/Chloroform) 0.23; 1H
4.2.6. 2-Amino-8-methoxy-3H-pyrimido[4,5-b]quinolin-4-one
(3f). Yellow solid; yield: 90%; mp 300e303 ꢀC; Rf (40% EtOAc/
NMR (300 MHz, DMSO-d6):
d¼7.12 (m, 1H), 7.86e7.96 (m, 3H), 8.70

9224
A. Chandra et al. / Tetrahedron 67 (2011) 9219e9224
(s, 2H, D2O exchangeable), 9.17 (s, 1H), 12.56 (s, 1H, D2O ex-
Supplementary data
changeable); 13C NMR (75 MHz, CDCl3):
d¼126.6, 127.2, 128.1, 128.3,
128.5, 129.0, 129.5, 135.3, 140.3, 149.3, 155.4; IR (KBr, cmꢂ1): 1614,
3386. Anal. Calcd for C11H8N4S: C, 57.88; H, 3.53; N, 24.54. Found: C,
57.65; H, 3.56; N, 24.71.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.09.032.
References and notes
4.2.14. 4-Amino-8-methoxy-1H-pyrimido[4,5-b]quinoline-2-thione
1. (a) Elderfield, R. C. In Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley:
New York, NY, London, 1960; Vol. 4; Chapter 1, p 1; (b) Wright, C. W.; Addac-
Kyereme, J. A.; Breen, G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek, Y.; Ken-
drick, H.; Phillips, R. M.; Pollet, P. L. J. Med. Chem. 2001, 44, 3187; (c) Sahu, N. S.;
Pal, C.; Mandal, N. B.; Nanerjee, S.; Raha, M.; Kundu, A. P.; Basu, A.; Ghosh, M.;
Roy, K.; Bandyopadhyay, S. Bioorg. Med. Chem. 2002, 10, 1687; (d) Bringman, G.;
Reichert, Y.; Kane, V. Tetrahedron 2004, 60, 3539; (e) Kournetsov, V. V.; Mendez,
L. Y. V.; Gomez, C. M. M. Curr. Org. Chem. 2005, 9, 141.
2. (a) Yates, F. S. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: New York, NY, 1984; Vol. 2, Chapter 2.09; (b) Bentley, K. W.
In The Isoquinoline Alkaloids; Harwood Academic: Amsterdam, 1998.
3. (a) Kalita, P. K.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2007, 47, 7779; (b)
Zhong, W.; Lin, F.; Chen, R.; Su, W. Synthesis 2009, 2333.
4. (a) Joshi, A. A.; Viswanathan, C. L. Anti-Infect. Agents Med. Chem. 2006, 5, 105; (b)
Dlugosz, A.; Dus, D. Farmaco 1996, 51, 364.
5. Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K. Biochem. Pharmacol. 1992,
44, 1211.
6. (a) El-Sayed, O. A.; Al-Bassam, B. A.; Hussein, M. E. Arch. Pharm. (Weinheim)
2002, 335, 403.
(5a0). Yellow solid; yield: 72%; mp 240 ꢀC; Rf (4% MeOH/Chloro-
form) 0.21; 1H NMR (300 MHz, DMSO-d6):
d
¼3.94 (s, 3H),
7.15e7.19 (m, 2H), 7.80 (d, J¼9.0 Hz, 1H), 8.58 (br s, 2H, D2O ex-
changeable), 9.03 (s, 1H), 12.48 (br s, 1H, D2O exchangeable); 13C
NMR (75 MHz, CDCl3):
d
¼55.8, 103.8, 105.2, 118.9, 120.2, 130.7,
135.0, 149.6, 151.9, 159.1, 163.5, 183.9; IR (KBr, cmꢂ1): 1615. Anal.
Calcd for C12H10N4OS: C, 55.80; H, 3.90; N, 21.69. Found: C, 55.68;
H, 3.98; N, 21.75.
4.2.15. 2-Benzylsulfanyl-pyrimido[4,5-b]quinolin-4-ylamine
(5b). Yellow solid; yield: 79%; mp 278 ꢀC; Rf (40% EtOAc/hexane)
0.30; 1H NMR (300 MHz, DMSO-d6):
d
¼4.65 (s, 2H), 7.24e7.34 (m,
5H, 2H D2O exchangeable), 7.52e7.54 (m, 2H), 7.65 (t, J¼7.5 Hz, 1H),
7.91e8.05 (m, 3H), 8.97 (s, 1H); 13C NMR (75 MHz, DMSO-d6):
7. (a) Gavrilov, MY.; Mardanova, L. G.; Kolla, V. E.; Konshin, M. E. Pharm. Chem. J.
1988, 22, 554; (b) El-Sayed, O. A.; Al-Turki, T. M.; Al-Daffiri, H. M.; Al-Bassam, B.
A.; Hussein, M. E. Boll. Chim. Farm. 2004, 143, 227.
8. (a) El-Sayed, O. A.; El-Bieh, F. M.; Al-Bassam, B. A. Boll. Chim. Farm. 2002, 141,
461; (b) Alqasoumi, S. I.; Al-Taweel, A. M.; Alafeefy, A. M.; Noaman, E.; Ghorab,
M. M. Eur. J. Med. Chem. 2010, 45, 738.
d
¼43.8, 113.9, 113.9, 114.0, 121.3, 122.0, 125.2, 126.7, 127.4, 128.3,
128.6, 131.4, 138.0, 139.8, 148.4, 154.7; IR (KBr, cmꢂ1): 1644, 3448.
Anal. Calcd for C18H14N4S: C, 67.90; H, 4.43; N, 17.60. Found: C,
67.72; H, 4.49; N, 17.73.
9. (a) Kokel, B. J. Heterocycl. Chem. 1994, 31, 845; (b) Conrad, M.; Reinbach, H. Ber.
Dtsch. Chem. Ges. 1901, 34, 1339; (c) Troger, J.; Cohaus, C. J. Prakt. Chem. 1927, 117,
4.2.16. 4-Amino-pyrimido[4,5-b]quinolin-2-yl-cyanamide
€
(5c). Green solid; yield: 70%; mp 232 ꢀC; Rf (10% EtOAc/hexane)
97; (d) King, F. E.; King, T. J. J. Chem. Soc. 1947, 726; (e) Jie, O.; Jin-Jun, W.;
Guang-Fan, H.; Yu-Tian, L.; Gui-Ji, J. Youji Huaxue 1995, 15, 99; (f) Baumgarten,
H.; Pedersen, D. L.; Hunt, M. W. J. Am. Chem. Soc. 1958, 80, 1977; (g) O’Brien, D.
E.; Wienstock, L. T.; Cheng, C. C. J. Heterocycl. Chem. 1970, 7, 99; (h) Fenner, H.;
Michaelis, P. Arch. Pharmacol. 1972, 305, 751; (i) King, F. E.; King, T. J.; Thomp-
son, G. B. J. Chem. Soc. 1948, 552; (j) Taylor, E. C.; Kalenda, N. W. J. Am. Chem. Soc.
1956, 78, 5108; (k) Gakhar, H. K.; Kaur, R.; Gupta, A.; Gupta, S. B. Indian J. Chem.
1990, 29, 992; (l) El Sayed, O. A.; El-Bieh, F. M.; El-Aqeel, S. I.; Al-Bassam, B. A.;
Hussein, M. E.; Roy, R. U.; Desai, K. R. Indian J. Heterocycl. Chem. 2005, 14, 327;
(m) Althius, T. H.; Moore, P. F.; Hess, H. J. J. Med. Chem. 1979, 22, 44; (n) Donkor,
I. O.; Gangjee, A.; Kisliuk, R. L.; Gaumont, Y. J. Heterocycl. Chem. 1991, 28, 1651;
(o) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69; (p) Elkholy, Y. M.;
Morsy, M. A. Molecules 2006, 11, 890.
0.40; 1H NMR (300 MHz, DMSO-d6):
d
¼6.90 (br s, 3H, D2O ex-
changeable), 7.22 (t, J¼7.2 Hz, 1H), 7.54e7.61 (m, 2H), 7.77 (d,
J¼7.8 Hz, 1H) 8.14 (s, 1H); 13C NMR (75 MHz, CDCl3):
¼95.4, 116.5,
d
121.3, 126.7, 126.9, 127.4, 128.0, 128.6, 135.0, 138.6, 143.2, 153.3; IR
(KBr, cmꢂ1): 3423, 2233. Anal. Calcd for C12H8N6: C, 61.01; H, 3.41;
N, 35.57. Found: C, 61.17; H, 3.48; N, 35.43.
4.2.17. Pyrimido[4,5-b]quinolin-2-ylamine (5f). Yellow solid; yield:
80%; mp 298 ꢀC; Rf (40% EtOAc/hexane) 0.60; 1H NMR (300 MHz,
€
€
10. Schonfeld, F.; Troschutz, R. Heterocycles 2001, 55, 1679.
DMSO-d6):
d
¼6.57 (br s, 2H, D2O exchangeable), 7.36 (t, J¼7.2 Hz,
11. (a) Singh, R. M.; Srivastava, A. Indian J. Chem. 2005, 44B, 1868; (b) Singh, R. M.;
Upadhyay, S.; Chandra, A. Indian J. Chem. 2009, 48B, 152.
1H), 7.70e7.83 (m, 3H), 9.05 (s, 1H,); 13C NMR (CDCl3, 75 MHz):
d
¼126.6, 128.1, 128.3, 128.5, 129.0, 129.5, 133.2, 135.3, 140.3, 149.3,
12. (a) Singh, M. K.; Chandra, A.; Singh, B.; Singh, R. M. Tetrahedron Lett. 2007,
48, 5987; (b) Singh, B.; Chandra, A.; Upadhyay, S.; Singh, R. M. Tetrahedron
Lett. 2008, 49, 6423; (c) Singh, R. M.; Chandra, A.; Singh, B.; Khanna, R. S. J.
Org. Chem. 2009, 74, 5664; (d) Singh, R. M.; Chandra, A.; Singh, B.; Upad-
hyay, S. Tetrahedron 2008, 64, 11680; (e) Singh, R. M.; Srivastava, A.; Chandra,
A. Indian J. Chem. 2007, 46B, 303; (f) Singh, R. M.; Chandra, A.; Singh, M. K.
Synth. Commun. 2007, 37, 1689; (g) Singh, R. M.; Singh, B.; Chandra, A.;
Singh, S. Tetrahedron 2011, 67, 503; (h) Singh, R. M.; Singh, B.; Chandra, A.
Tetrahedron 2011, 67, 2441.
155.4; IR (KBr, cmꢂ1): 1639, 3447. Anal. Calcd for C11H8N4: C, 67.34;
H, 4.11; N, 28.55. Found: C, 67.42; H, 4.08; N, 28.64.
Acknowledgements
13. (a) Selvi, S. T.; Natraj, V.; Mohan, S.; Sasi, R.; Hema, M. Bioorg. Med. Chem. 2006,
14, 3896; (b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Shivanyuk, A.
N.; Tolmachev, A. A. Synthesis 2007, 2872; (c) Belmont, P.; Andrez, J.-C.; Allan, C.
S. M. Tetrahedron Lett. 2004, 45, 2783.
We thank to CSIR, New Delhi for financial support and S.R.F. to
B.S. and S.U. We also thankful to UGC, New Delhi for D.S. Kothari
post doctoral fellowship to A.C. and J.R.F. to N.S.
14. Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J. Org. Chem. 2010, 75, 1162.