An alternative synthesis of pyrimido[4,5-b]quinoline-4-ones via metal-free amination in water and Vilsmeier-Haack cyclization

Article abstract of DOI:10.1016/j.tet.2012.10.004

Two-step synthesis of pyrimido[4,5-b]quinoline-4-ones is described from 2-chloroquinoline-3-carbonitries via amination and cyclization reactions, respectively. The amination reactions proceeded much faster in water via simple S_NAr displacement

Full text of DOI:10.1016/j.tet.2012.10.004

Tetrahedron 68 (2012) 10318e10325
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An alternative synthesis of pyrimido[4,5-b]quinoline-4-ones via metal-free
amination in water and VilsmeiereHaack cyclization
*
Radhey M. Singh , Neha Sharma, Ritush Kumar, Mrityunjaya Asthana, Shraddha Upadhyay
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 28 June 2012
Received in revised form 27 September 2012
Accepted 1 October 2012
Available online 9 October 2012
Two-step synthesis of pyrimido[4,5-b]quinoline-4-ones is described from 2-chloroquinoline-3-
carbonitries via amination and cyclization reactions, respectively. The amination reactions proceeded
much faster in water via simple SNAr displacement reactions of chlorine. The cyclization reactions using
Vilsmeier reagent at 60 ꢀC gave the best yield of the products. The isolation of starting compound from
the reaction of cyclized product with I2/K2CO3 provided further chemical proof of the structure of the
cyclized product. Plausible mechanism for cyclization is proposed.
Keywords:
2-Chloroquinoline-3-carbonitrile
Amination
Ó 2012 Elsevier Ltd. All rights reserved.
Aqueous media
VilsmeiereHaack reaction
Pyrimido[4,5-b]quinoline-4-one
1. Introduction
Recently, Jiao J. et al. have reported organic solvent and ligand-free
Cu powder catalyzed Ullmann arylation with aqueous methyl ami-
VilsmeiereHaack reagent is an economical and mild reagent and
has been used extensively for different course of reactions namely
formylation,1 cyclization2 and ring annulations.3 2-Chloroquino-
line-3-carboxaldehydes4 an example of annulations reactions, are
conveniently prepared in one-pot from acetanilides using Vils-
meiereHaack reagent and widely used for nitrogen, oxygen and
sulfur hetero-annulation reactions.5 Many of them are the constit-
uents of natural products, agrochemicals and pharmaceuticals.6 In
contrast, 3-cyano analogues, prepared from 2-chloroquinoline-3-
carboxaldehydes with aqueous ammonia and iodine,7a are not
much explored as precursors in annulations reactions.7b,c
The amination of aryl and heteroaryl halides is an important re-
action for the synthesis of organic compounds containing the N-aryl
moiety. Transition metal-catalyzed,8 microwave-assisted9 and
metal-free10 procedures are generally used for carbonenitrogen
bond forming processes. The amination of quinoline derivatives are
generally reported with 2- and 4-chloroquinoline either with ba-
ses,11 metal catalysts12 or under solvent free conditions.13 All these
reactions required harsh conditions such as high temperature and
longer reaction periods. The reactions in aqueous media are of great
interest for both economic and safety reasons and have been suc-
cessfully adopted in copper-catalyzed N-arylation reactions.14
ne.12f Although, Sreedhar et al. have reported base and catalyst free
synthesis of biaryl sulphides in aqueous medium from the reaction
of heteroaryl halides with thiols via SNAr pathway.15 However, the
amination of haloquinolineswas not reported inwater. Thus, this has
prompted us to study the amination reaction of 2-chloroquinoline-
3-carbonitriles with or without metal catalysts in water.
Pyrimido annulated quinolines are of particular importance be-
cause of the biological properties exhibited by this class of com-
pounds such as antimalarial,16 antiallergic,17 antimicrobial,18 anti-
inflammatory19 and anticancer20 activities, which mainly depend on
nature and position of the substituent. The traditionalpreparations of
pyrimido[4,5-b]quinoline derivatives involve the cyclization re-
actions of 2-aminoquinoline-3-carbonitriles with formamide, formic
acid, urea, thiourea, carbon disulfide or isothiocyanate.21 2-
Aminoquinoline-3-carbonitrile framework was generally prepared
from the multi component reactions involving cyclohexanone or
cyclohexandione, a,b
-unsaturated malanonitrile and amines.22 Sim-
ilarly, pyrimidine nucleus in analogues furo-, thieno- and benzo-
fused pyrimidine derivatives are reported from 2-amino-3-cyano
derivatives in two steps by conventional or microwave irradiation
methods, respectively.23 All these methods however suffer from
some drawbacks such as high temperature, longer reaction period
and anhydrous reaction conditions. Zhang R. et al. have recently used
Vilsmeier reagent for the synthesis of pyrimidin-4(3H)-ones.24
Recently, we reported the synthesis of 2-amino-3H-pyrimidio
[4,5-b]quinoline-4-ones from the base-catalyzed reaction of 2-
* 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 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.004

R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
10319
Table 2
chloroquinoline-3-carbonitriles with guanidine hydrochloride in
high yields.25 As a part of our current interest in developing of new
methodology for annulated quinolines, we envisioned that pyr-
imido[4,5-b]quinoline framework could be synthesized from 2-
chloroquinoline-3-carbonitriles by an alternative route such as
amination followed by cyclization reactions. Thus, we describe
herein two-step synthesis of pyrimido[4,5-b]quinoline-4-ones
from 2-chloroquinoline-3-carbonitriles involving the metal-free
amination reaction with aliphatic amines in water and sub-
sequent cyclization reaction with VilsmeiereHaack reagent.
Amination of 2-choloroquinoline/pyridine-3-carbonitriles with different amines in
aqueous medium
CN
CN
NH2R'/H2O
90oC
NH
R'
N
2
N
Cl
R
R
1
Entry
R
R’
Product
Time (min)
Yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
H
H
H
H
H
H
H
H
H
H
Benzyl
Methyl
Ethyl
n-Butyl
Cyclohexyl
Isopropyl
N,N-Dimethyl
Piperidine
Morpholine
Aniline
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
2a
55
10
25
80
30
35
20
25
25
30h
55
60
55
60
55
55
45
45
65
15
90
35
30
82
85
82
80
87
90
80
92
90
00
82
85
80
82
86
90
80
78
80
82
82
78
82
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
SM
2b
2c
2d
2e
2f
2g
2. Results and discussion
In our initial study, reaction between 2-chloroquinoline-3-
carbonitrile 1a and benzyl amine was selected for optimizing the
reaction conditions. The reaction was carried out using 3 equiv of
benzyl amine in various organic solvents at 90 ꢀC in 3 h. The re-
action proceeded smoothly via SNAr displacement of the chlorine
atom and gave the desired product 2a in moderate to good yields,
Scheme 1. Among the various solvents such as EtOH, MeOH, CH3CN
and DMF screened, ethanol was found to be the best solvent (Table
1, entries 1e4). Surprisingly, reaction with aqueous methyl amine in
ethanol at 90 ꢀC proceeded much faster and completed in 10 min
with 95% yield (entry 5). Encouraged by this finding, the reaction of
benzyl amine with 1a was reinvestigated in water, reaction com-
pleted in 55 min with 82% yield (entry 6). Using 2 equiv of benzyl
amine did not reach full conversion even after 24 h (entry 7).
Noteworthy, without solvent the amination reaction resulted in
incomplete conversion even at higher temperature (130 ꢀC) on
prolonged heating (entry 8).
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
6-Me
6-OMe
7-Me
7-OMe
8-Me
8-Et
6-Br
7-Cl
3
2h
2i
4a
4b
4c
Benzyl
Methyl
n-Butyl
N,N-Dimethyl
Morpholine
3
3
3
3
4d
4e
alkyl chain does not show significant variation in the yields (entries
2e4). However, branching of the alkyl chain enhances the yield of
the products under similar reaction conditions. This variation of
yields could be attributed to inductive effect of alkyl groups (entries
5 and 6). In contrast to secondary aliphatic amine (entry 7), cyclic
secondary amines enhance the yields significantly (entries 8 and 9).
It is noteworthy that aromatic amine failed to react even at higher
temperature (entry 10).
We further examined the general scope of amination reactions
with other 2-chloroquinoline-3-carbonitrile derivatives (1bei) and
benzyl amine. Results are summarized in Table 2 (entries 11e18).
The electron withdrawing groups at benzene ring increase the rate
of the reaction while electron donating groups decrease the rate of
the reaction with little enhancement in the yields.
CN
NH
CN
Cl
NH2CH2Ph/H2O
90oC
N
2
N
R
R
1
R=H,Me,OMe,Et,Cl,Br
No Column Chromatography
Scheme 1. Synthesis of 2-aminosubstituted quinoline-3-carbonitriles (2) from
2-choloroquinoline-3-carbonitriles (1).
Next, we examined the pyridine derivative with various
aliphatic amines under optimized conditions with a view to further
generalize the scope of reactions and effect of fused-benzene ring
in quinoline moiety 1 on the rates and yields (Scheme 2). Thus, the
reaction of 2-chloro-5-phenylpyridin-3-carbonitrile (3) with
various amines afforded amino pyridines 4aee in good yields. The
results are summarized in Table 2 (entries 19e23). The longer
reaction times show that fused-benzene ring in quinolines
accelerate the reaction rates.
Table 1
Optimization of amination reaction conditions on 2-choloroquinoline-3-carbonitrile
(1a) with benzyl aminea
Entry
Solvent
Time (h)
Yield of 2ab (%)
1.
2.
3.
EtOH
MeOH
CH3CN
DMF
H2O
H2O
H2O
d
3.0
3.5
5.0
3.5
10 (min)
55 (min)
24
92
62
78
50
95
82
30
40
4.
5.c
6.
7.d
8.
49
a
2-Choloroquinoline-3-carbonitrile (1 mmol), benzyl amine (3.0 mmol), sol-
vent(1 ml/mmol), 90 ꢀC.
CN
CN
Cl
R'NH2/H2O
90oC
b
Isolated yields.
c
2-Choloroquinoline-3-carbonitrile (1 mmol), methyl amine (3.0 mmol),
N
NH
R'
N
water(1 ml/mmol), 90 ꢀC.
3
4
d
Using 2 equiv of benzyl amine.
Scheme 2. Synthesis of 2-aminosubstituted pyridine-3-carbonitrile (4a) from
2-choloropyridine-3-carbonitrile (3).
Next, we examined the generality of amination with other
amines under similar reaction conditions in water. The reactions
proceeded smoothly with primary and secondary amines. The re-
sults are summarized in Table 2 (entries 1e9). Lengthening of the
We next focused our attention to develop the optimal reaction
conditions for cyclization of 2-aminoquinoline-3-carbonitriles 2

10320
R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
Table 4
with Vilsmeier reagent to afford pyrimidoquinoline moiety. Thus,
2-benzylaminoquinoline-3-carbonirtile 2a was chosen as the
model system for cyclization reaction with Vilsmeier reagent
(Scheme 3). Initially, our previous cyclization reaction conditions
for the quinoline synthesis via Vilsmeier reagent using 1:3 molar
ratios of DMF and POCl3 at 90 ꢀC were attempted with 2a. The re-
action completed in 20 min affording the cyclized product 5a in
78% yield (Table 3, entry 1), which was characterized as 1-benzyl-
1H-pyrimido[4,5-b]quinolin-4-one from the spectral and analytical
data. On lowering reaction temperature the yield of cyclized
product was enhanced (entries 2 and 3) and the best yield up to 98%
was obtained at 60 ꢀC in 45 min. On increasing the reaction tem-
perature to 100 ꢀC provided lower yield of the product (entry 4).
Synthesis of pyrimido[4,5-b]quinolin-4-ones
Entry
Substrate
Product
Time (min) Yielda (%)
O
CN
N
N
NH
1.
45
98
N
N
2a
5a
O
N
CN
N
N
2.
3.
4.
120
150
270
89
87
90
N
NH
N
2ab
5ab
O
CN
O
N
CN
NH
N
DMF/POCl3
60oC
N
R
N
NH
R'
N
N
R
N
R'
5
2
2ac
5ac
O
R= H,Me,Et,OMe,Cl,Br
R'=Bz,Me,Et,n-Butyl,cyclohexyl
CN
N
Scheme 3. Synthesis of 1-benzyl-1H-pyrimido[4,5-b]quinolin-4-ones,
2-aminosubstituted quinoline-3-carbonitriles, 2.
5
from
N
N
H
N
N
5ad
2ad
Table 3
Optimization of VilsmeiereHaack reaction condition
O
CN
NH
Entry
DMF
POCl3
Temp (ꢀC)
Time (min)
Yield (%)
N
N
1.
2.
3.
4.
5.
6.
1
1
1
1
1
1
3
3
3
3
2
1
90
70
60
100
60
60
20
30
45
10
60
24 (h)
78
82
98
68
70
SM
5.
6.
7.
150
86
82
85
N
N
2ae
5ae
O
CN
N
N
NH
35
N
N
Changing the molar ratio to 1:2 of DMF and POCl3 in Vilsmeier
reagent reduced both the reaction rate and yield of the product
(entry 5). Notably, no product was obtained using 1:1 molar ratio
even after prolonged reaction time could be presumed to non ex-
istence of Vilsmeier reagent (entry 6). Thus, Vilsmeier reaction with
1:3 molar ratios of DMF and POCl3 at 60 ꢀC was found the best
optimal reaction conditions for cyclization to afford excellent yield
of the product (98%). The generality of the cyclization reaction was
further screened with various 2-alkylaminosubstituted quinoline-
3-carbonitriles 2abeae (Table 4, entries 2e5). Lengthening and
branching of alkyl chain of amines decrease both reaction rates and
yields of the products significantly.
To examine the scope of Vilsmeier reagent for the cyclization,
other 2-benzylaminoquinoline-3-carbonitriles 2bei were screened.
The reaction proceeded smoothly as indicated from TLC and afforded
the desired cyclized products 5bei in excellent yields. The results are
summarized in Table 4 (entries 6e13). The electron donating sub-
stituents at position-7 afforded better yields of the products than the
substituents at position-6 (entries 6e9). Notably, ethyl group affor-
ded the better yield of the product than the methyl group at position-
8 (entries 10 and 11). However, the electronwithdrawing substituent
at position-6/7 gave the better yield of the product (entries 12 and
13). Noteworthy, the faster reaction rates with methoxy group could
be attributed to the resonance effect of the group.
2b
5b
O
N
O
CN
NH
O
N
N
15
N
N
2c
5c
O
N
CN
NH
N
8.
9.
42
20
90
92
N
2d
5d
O
N
CN
NH
N
O
N
O
N
2e
5e
O
CN
NH
N
To further generalize the scope of reactions, pyridine derivative
was screened with Vilsmeier reagent. Thus, compound 4a was
allowed to react with Vilsmeier reagent under optimized reaction
conditions and found that the reaction proceeded smoothly
affording the cyclized product 6 in good yield (entry 14), which was
N
10.
40
86
N
N
2f
5f

R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
10321
Table 4 (continued )
cyclic structure of 5a. The reaction transformations are shown in
Time (min) Yielda (%)
Scheme 5.
Entry
Substrate
Product
O
CN
NH
N
I
I
I
O
N
O
N
N
11.
45
95
CN
CHO
N
N
N
N
I2/K2CO3 / ACN
2g
5g
N
OH
RT
N
O H
N
N
O
5a
Br
CN
Br
N
N
CN
NH
N
N
NH
12.
13.
45
40
90
85
N
N
N
H2O
N
2h
5h
2a
O
N
CN
NH
Scheme 5.
Cl
Cl
Although, spectral data and chemical evidence were sufficient to
establish the structure of cyclized products 5, single crystal X-ray
crystallographic analysis26 of 5g was performed to establish the
structure of the cyclized products 5. An ORTEP representation of the
molecule 5g is given in Fig. 1.
2i
5i
O
CN
NH
N
14.
40
82
N
N
N
4a
6
a
Isolated yields.
characterized as 1-benzyl-6-phenyl-1H-pyrido[2,3-d]pyrimidin-4-
one from spectral and analytical data. The result illustrated that
fused-benzene ring in quinoline framework enhances the yield.
A Plausible mechanism using VilsmeiereHaack reaction for cy-
clization is illustrated in Scheme 4.
Fig. 1. ORTEP drawing of the X-ray structure of 5g.
3. Conclusions
In conclusion, we have developed conditions for amination of 2-
chloroquinoline-3-carbonitriles in water with good yields. The re-
action in water proceeded with faster rates via simple SNAr dis-
placement. We have also developed new methodology to the
synthesis of pyrimido[4,5-b]quinolin-4-ones from the reaction of 2-
benzylaminoquinoline-3-carbonitriles with Vilsmeier reagent at
lower temperature in good to excellent yields.
4. Experimental section
4.1. General
Scheme 4. Plausible mechanism.
The amidines type skeleton present in pyrimidine nucleus in
product 5 could be readily hydrolyzed by acids and alkalis, in turn,
open the pyrimidine ring to afford quinoline derivatives. Thus,
the reaction of product 5a with I2/K2CO3 in acetonitrile at room
temperature for 1.5 h afforded compound 2a identified from
TLC, spectral and elemental data, supporting chemically the
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

10322
R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
coupling constants (Hz) are reported in the standard fashion with
reference to either internal tetramethylsilane (for 1H) or the cen-
tral line (77.0 ppm) of CDCl3 (for 13C). Elemental analyses were
performed on Exter Analytical Inc. ‘Model CE-400 CHN Analyzer’
from Department of Chemistry, BHU, Varanasi and Mass spectral
analyses were performed on Thermo LCQ Advantage Max (ESI and
APCI) Ion Trap (LCeMS/MS) from SAIF CDRI, Lucknow. 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 accomplished by exposure to
UV light. Qualigen’s silica gel (60e120 mesh) was used for column
chromatography (approximately 15e20 g per 1 g of the crude
product).
(KBr): 2218 (CN), 3400 (NH). Anal. Calcd for C16H17N3 C, 74.92; H,
6.37; N, 17.71%. Found: C, 74.90; H, 6.36; N, 17.70%.
4.2.6. 2-Isopropylaminoquinoline-3-carbonitrile (2af). Yellow solid;
yield: 90%; mp: 110e112 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼1.32 (d,
J¼6.3 Hz, 6H), 4.44e4.55 (m, 1H), 5.01 (s, 1H, D2O exchangeable),
7.55e7.72 (m, 3H); 7.92 (t, J¼7.8 Hz, 1H), 8.18 (s, 1H); 13C NMR
(75 MHz, CDCl3):
d
¼22.6, 42.8, 95.7, 116.5, 120.9, 123.1, 126.8, 128.6,
132.7, 143.7, 149.5, 153.1; IR (KBr, cmꢂ1): 2228 (CN), 3447 (NH).
Anal. Calcd for C13H13N3 C, 73.91; H, 6.20; N, 19.89%. Found: C,
73.89; H, 6.19; N, 19.88%.
4.2.7. 2-Dimethylaminoquinoline-3-carbonitrile (2ag). Light green
solid; yield: 80%; mp 192 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼3.33 (s,
6H), 7.60e7.71 (m, 4H), 8.32 (s, 1H); 13C NMR (75 MHz, CDCl3):
4.2. General procedure for synthesis of 2-aminoquinoline-3-
carbonitriles (2)
d
¼40.6, 96.2, 118.5, 121.3, 123.6, 126.9, 127.6, 132.8, 146.8, 148.7,
156.6; IR (KBr, cmꢂ1): 2221 (CN), 3382 (NH). Anal. Calcd for C12H11N3
C, 73.07; H, 5.62; N, 21.30%. Found: C, 72.03; H, 5.60; N, 21.29%.
A mixture of 2-chloroquinoline-3-carbonitrile 1 (1.0 equiv) and
amine (3.0 equiv) in 3 ml water was stirred at 90 ꢀC. After com-
pletion of the reaction, the reaction mixture was poured into ice-
cold water, solid product was filtered and washed with water
(3e5 mL) and dried. The crude product was characterized and was
pure enough for further use.
4.2.8. 2-Piperidine-1-yl-quinoline-3-carbonitrile
solid; yield: 92%; mp 170 ꢀC; 1H NMR (300 MHz, CDCl3):
¼1.69e1.78 (m, 6H), 3.66 (t, J¼4.8 Hz, 4H), 7.34 (t, J¼7.4 Hz, 1H);
7.63e7.76 (m, 3H), 8.33 (s, 1H); 13C NMR (75 MHz, CDCl3):
24.5,
25.7, 50.1, 99.3, 117.8, 122.0, 124.3, 127.3, 127.6, 132.6, 146.0, 148.5,
158.2; IR (KBr): 2231 (CN), 3421 (NH). Anal. Calcd for C15H15N3: C,
75.92; H, 6.37; N, 17.71%. Found: C, 74.90; H, 6.36; N, 17.70%.
(2ah). Yellow
d
d
4.2.1. 2-Benzylaminoquinoline-3-carbonitrile (2a). Light green
solid; yield: 82%; mp 118 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼4.83 (d,
J¼5.1 Hz, 2H), 5.54 (s, 1H, D2O exchangeable), 7.33e7.44 (m, 3H),
7.59e7.73 (m, 6H), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3):
4.2.9. 2-Morpholine-4-yl-quinoline-3-carbonitrile
Green solid; yield: 90%; mp 80 ꢀC; 1H NMR (300 MHz, CDCl3):
¼3.70 (t, J¼4.5 Hz, 4H), 3.91 (t, J¼4.8 Hz, 4H), 7.40 (t, J¼6.9 Hz, 1H),
7.67e7.81 (m, 3H), 8.38 (s, 1H); 13C NMR (75 MHz, CDCl3):
(2ai). Light
d
¼45.4,
95.7, 116.3, 121.3, 123.4, 126.9, 127.5, 128.0, 128.1, 128.7, 132.8, 138.4,
143.8, 149.3, 153.6; IR (KBr, cmꢂ1): 2216 (CN), 3380 (NH). Anal.
Calcd for C17H13N3: C, 78.74; H, 5.05; N, 16.20%. Found: C, 78.64; H,
5.01; N, 16.18%.
d
d¼49.2,
66.7, 99.0, 117.5, 122.4, 125.1, 127.6, 127.7, 132.9, 146.2, 148.3, 157.6;
IR (KBr, cmꢂ1): 2216 (CN). Anal. Calcd for C14H13N3O: C, 70.28; H,
5.48; N, 17.56%. Found: C, 70.20; H, 5.45; N, 17.57%.
4.2.2. 2-Methylaminoquinoline-3-carbonitrile (2ab). Light green
solid; yield: 85%; mp 120 ꢀC (d); 1H NMR (300 MHz, CDCl3):
d
¼3.17
4.2.10. 2-Benzylamino-6-methyl-quinoline-3-carbonitrile
(d, J¼4.5 Hz, 3H), 5.83 (s, 1H, D2O exchangeable), 7.58e7.74 (m, 4H),
(2b). Light green solid; yield: 82%; mp 135 ꢀC (decomp.); 1H NMR
8.20 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
¼48.3, 95.7, 116.5, 121.0,
(300 MHz, CDCl3):
D2O exchangeable), 7.26e7.44 (m, 5H), 7.50 (d, J¼9.3 Hz, 1H),
7.62e7.65 (m, 2H), 8.15 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼2.45 (s, 3H), 4.81 (d, J¼5.7 Hz, 2H), 5.46 (s, 1H,
123.2, 126.8, 128.1, 132.8, 143.6, 149.4, 154.4; IR (KBr, cmꢂ1): 2223
(CN), 3386 (NH). Anal. Calcd for C11H9N3 C, 72.11; H, 4.95; N, 22.94%.
Found: C, 72.09; H, 4.94; N, 21.31%.
d
¼21.0,
45.4, 95.4, 116.5, 121.2, 126.6, 126.9, 127.4, 127.9, 128.6, 133.1, 135.0,
138.5, 143.2, 147.6, 153.2; IR (KBr, cmꢂ1): 2214 (CN), 3337 (NH).
Anal. Calcd for C18H15N3: C, 79.10; H, 5.53; N, 15.37%. Found: C,
78.92; H, 5.41; N, 15.18%.
4.2.3. 2-Ethylaminoquinoline-3-carbonitrile
(2ac). Light green
solid; yield: 82%; mp 60e63 ꢀC; 1H NMR (300 MHz, CDCl3):
d¼1.33
(t, J¼7.2 Hz, 3H), 3.65 (q, J¼7.2 Hz, 2H), 5.18 (br s, 1H, D2O ex-
changeable), 7.57e7.68 (m, 4H), 8.19 (s, 1H); 13C NMR (75 MHz,
4.2.11. 2-Benzylamino-6-methoxy-quinoline-3-carbonitrile
CDCl3):
d
¼14.6, 36.3, 95.7, 116.5, 121.0, 123.2, 126.8, 128.0, 132.8,
(2c). Light green solid; yield: 85%; mp 122 ꢀC; 1H NMR (300 MHz,
143.7, 149.5, 153.8; IR (KBr, cmꢂ1): 2220 (CN), 3398 (NH). Anal.
Calcd for C12H11N3 C, 73.06; H, 5.62; N, 21.31%. Found: C, 73.03; H,
5.60; N, 21.31%.
CDCl3):
changeable), 6.90 (s, 1H), 7.25e7.43 (m, 6H), 7.64 (d, J¼9.3 Hz, 1H),
8.14 (s,1H); 13C NMR (75 MHz, CDCl3):
d¼3.87 (s, 3H), 4.79 (d, J¼5.4 Hz, 2H), 5.39 (s, 1H, D2O ex-
d¼45.5, 55.5, 95.6,105.9,116.6,
121.7, 125.1, 127.4, 128.0, 128.4, 128.6, 138.7, 142.4, 145.2, 152.8, 155.6;
IR (KBr, cmꢂ1): 2221 (CN), 3379 (NH). Anal. Calcd for C18H15N3O: C,
74.72; H, 5.23; N, 14.52%. Found: C, 74.69; H, 5.04; N, 14.48%.
4.2.4. 2-n-Butylaminoquinoline-3-carbonitrile (2ad). Light green
solid; yield: 80%; mp: 190 ꢀC (decomp.); 1H NMR (300 MHz, CDCl3):
d
¼0.99 (t, J¼7.2 Hz, 3H), 1.43e1.54 (m, 1H), 1.64e1.73 (m, 2H), 3.62
(m, 2H); 5.20 (br s, 1H, D2O exchangeable), 7.56e7.70 (m, 4H), 8.19
(s, 1H); 13C NMR (75 MHz, CDCl3):
13.8, 20.1, 31.4, 41.1, 95.6, 116.5,
4.2.12. 2-Benzylamino-7-methyl-quinoline-3-carbonitrile
d
(2d). Light green solid; yield: 80%; mp 122e125 ꢀC; 1H NMR
121.0, 123.1, 126.8, 128.0, 132.7, 143.6, 149.4, 153.9; IR (KBr): 2216
(CN), 3367 (NH). Anal. Calcd for C14H15N3 C, 74.64; H, 6.71; N,
18.65%. Found: C, 74.63; H, 5.60; N, 18.60%.
(300 MHz, CDCl3):
1H, D2O exchangeable), 7.11 (d, J¼7.5 Hz,1H), 7.29e7.52 (m, 7H), 8.18
(s, 1H); 13C NMR (75 MHz, CDCl3):
125.6,126.2,127.4,127.7,127.8,128.6,138.4,143.4,143.8,149.4,153.7;
IR (KBr, cmꢂ1): 2214 (CN), 3429 (NH). Anal. Calcd for C18H15N3: C,
79.10; H, 5.53; N, 15.37%. Found: C, 79.04; H, 5.47; N, 15.35%.
d
¼2.49 (s, 3H), 4.81 (d, J¼5.4 Hz, 2H), 5.49 (br s,
d
¼22.1, 45.2, 94.5, 116.6, 120.3,
4.2.5. 2-Cyclohexylaminoquinoline-3-carbonitrile
solid; yield: 87%; mp: 132 ꢀC; 1H NMR (300 MHz, CDCl3):
¼1.25e1.30 (m, 4H), 1.66e1.83 (m, 4H), 2.11e2.15 (m, 2H),
4.13e4.23 (m, 1H), 5.09 (br s, 1H, D2O exchangeable), 7.55e7.68 (m,
4H), 8.18 (s, 1H); 13C NMR (75 MHz, CDCl3):
¼13.8, 20.1, 31.3, 41.1,
95.6, 116.4, 120.9, 123.0, 126.7, 128.0, 132.7, 143.6, 149.4, 153.8; IR
(2ae). Yellow
d
4.2.13. 2-Benzylamino-7-methoxy-quinoline-3-carbonitrile
d
(2e). Light green solid; yield: 82%; mp 125 ꢀC; 1H NMR (300 MHz,
CDCl3):
d¼3.96 (s, 3H), 4.79 (d, J¼5.4 Hz, 2H), 5.38 (br s, 1H, D2O

R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
10323
exchangeable), 6.91 (s, 1H), 7.11 (s, 1H), 7.25e7.41 (m, 2H), 7.51e7.54
(m, 1H), 7.65 (d, J¼9.3 Hz, IH), 7.96 (d, J¼9.3 Hz, 1H), 8.14 (s, 1H),
31.5, 41.4, 91.2, 116.8, 125.2, 126.1, 127.4, 129.0, 136.5, 139.3, 151.1,
157.5; IR (KBr, cmꢂ1): 2216 (CN), 3360 (NH). Anal. Calcd for C16H17N3:
C, 76.46; H, 6.82; N, 16.72%. Found: C, 76.40; H, 6.79; N, 16.58%.
8.43 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼42.7, 55.5, 97.6, 105.7,
112.0, 116.5,117.6, 123.6, 126.7, 127.2, 128.0, 128.6, 138.6, 143.1, 148.5,
152.4; IR (KBr, cmꢂ1): 2214 (CN), 3390 (NH). Anal. Calcd for
C18H15N3: C, 74.72; H, 5.23; N, 14.52%. Found: C, 74.70; H, 5.19; N,
14.42%.
4.2.21. 2-Dimethylamino-5-phenyl-pyridine-3-carbonitrile
(4d). Light green solid; yield: 78%; mp: 121 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
¼3.34 (s, 6H), 7.34e7.49 (m, 5H), 7.93 (s, 1H), 8.53 (s, 1H);
13C NMR (75 MHz, CDCl3):
d
¼40.3, 90.8, 119.2, 125.3, 126.0, 127.5,
4.2.14. 2-Benzylamino-8-methyl-quinoline-3-carbonitrile (2f). Light
129.1, 136.2, 142.3, 150.2, 158.4; IR (KBr, cmꢂ1): 2215 (CN), 3362
(NH). Anal. Calcd for C14H13N3: C, 75.31; H, 5.87; N, 18.82%. Found:
C, 75.10; H, 5.80; N, 18.78%.
green solid; yield: 86%; mp 121 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼2.60 (s, 3H), 4.83 (d, J¼5.7 Hz, 2H), 5.62 (br s, 1H, D2O exchange-
able), 7.17 (t, J¼7.5 Hz,1H), 7.25e7.37 (m, 2H), 7.43e7.52 (m, 5H), 8.20
(s, 1H); 13C NMR (75 MHz, CDCl3):
d
¼17.7, 45.4, 95.0, 116.6, 121.0,
4.2.22. 2-Morpholin-4-yl-5-phenyl-pyridine-3-carbonitrile
123.0,125.8,127.3,127.9,128.5,132.9134.9,138.8,144.0,148.0,152.7;
IR (KBr, cmꢂ1): 2222 (CN), 3450 (NH). Anal. Calcd for C18H15N3: C,
79.10; H, 5.53; N, 15.37%. Found: C, 78.99; H, 5.46; N, 15.19%.
(4e). Light brown solid; yield: 82%; mp: 108 ꢀC; 1H NMR (300 MHz,
CDCl3):
d
¼3.76 (d, J¼4.5 Hz, 4H), 3.85 (d, J¼4.8 Hz, 4H), 7.40e7.48
(m, 5H), 7.98 (s, 1H), 8.58 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼48.4,
66.7, 94.8, 117.9, 126.2, 127.8, 127.9, 129.2, 135.8, 141.9, 150.1, 159.5;
IR (KBr, cmꢂ1): 2221 (CN), 3362 (NH). Anal. Calcd for C16H15N3O: C,
72.43; H, 5.70; N, 15.84%. Found: C, 72.30; H, 5.68; N, 15.78%.
4.2.15. 2-Benzylamino-8-ethyl-quinoline-3-carbonitrile (2g). Light
green solid; yield: 90%; mp 119e121 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼1.26 (t, J¼7.5 Hz, 3H), 3.06 (q, J¼7.5 Hz, 2H), 4.83 (d, J¼5.4 Hz, 1H),
5.62 (s,1H, D2O exchangeable), 7.18e7.37 (m, 3H), 7.42e7.52 (m, 5H),
8.22 (s,1H); 13C NMR (75 MHz, CDCl3):
121.2, 123.3, 125.8, 127.3, 127.8, 128.6, 131.4, 138.9, 140.7, 144.1, 147.4,
152.7; IR (KBr, cmꢂ1): 2226 (CN), 3446 (NH). Anal. Calcd for C19H17N3:
C, 79.41; H, 5.96; N, 14.62%. Found: C, 79.37; H, 5.58; N, 14.60%.
4.3. General synthetic method for synthesis of N-benzyl-1H-
pyrimido[4,5-b]quinoline-4-ones (5)
d¼14.5, 24.5, 45.5, 95.0,116.6,
To
a
solution of 2-alkylaminoquinoline-3-carbonitrile
2
(1.0 equiv) in DMF (1.0 equiv) was dropwise added POCl3
(3.0 equiv), the reaction mixture was stirred at 60 ꢀC. After com-
pletion of the reaction (as monitored by TLC), the reaction mixture
was poured into ice-cold water, solid product was filtered and
washed with water (3ꢁ5 mL) and dried. The crude product was
purified by column chromatography using EtOAc/hexane as eluent
in 4:6 ratio to yield pure product 5.
4.2.16. 2-Benzylamino-6-bromoquinoline-3-carbonitrile (2h). Light
green solid; yield: 80%; mp: 160 ꢀC (decomp.); 1H NMR (300 MHz,
CDCl3):
7.33e7.44 (m, 3H), 7.59e7.73 (m, 5H), 8.23 (s, 1H); 13C NMR
(75 MHz, CDCl3):
d¼4.83 (d, J¼5.4 Hz, 2H), 5.54 (br s, 1H, D2O exchangeable),
d
¼45.4, 95.8, 116.0,119.7,124.4, 127.6, 128.0, 128.4,
128.5, 128.6131.5, 138.2, 143.4, 149.8, 154.1; IR (KBr): 2216 (CN),
3371 (NH). Anal. Calcd for C17H12BrN3: C, 60.37; H, 3.58; N, 12.43%.
Found: C, 60.30; H, 3.57; N, 12.42%.
4.3.1. 1-Benzyl-1H-pyrimido[4,5-b]quinolin-4-one
solid; yield: 98%; mp 129e131 ꢀC; Rf (40% EtOAc/hexane) 0.30; 1H
NMR (300 MHz, CDCl3):
(5a). Yellow
d
¼5.64 (s, 2H, NCH2), 7.33e7.45 (m, 5H,
4.2.17. 2-Benzylamino-7-chloroquinoline-3-carbonitrile (2i). Light
phenyl), 7.60 (t, J¼7.5 Hz, 1H, H-8), 7.88 (t, J¼7.8 Hz, 1H, H-7), 8.03
(d, J¼8.4 Hz, 1H, H-9), 8.08 (d, J¼8.7 Hz, 1H, H-6), 8.58 (s, 1H, H-5),
green solid; yield: 78%; mp: 142 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼4.82 (d, J¼5.4 Hz, 2H), 5.53 (br s, 1H, D2O exchangeable),
9.21 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3):
d
¼50.8, 115.1, 126.5,
7.25e7.44 (m, 4H), 7.59e7.73 (m, 4H), 8.23 (s, 1H); 13C NMR
127.1,128.1,128.3,128.4, 128.9, 129.4, 133.1, 135.3,140.4,147.8,149.3,
155.4, 170.3; IR (KBr, cmꢂ1): 1659 (CO). MS: m/z 288 (MþH)þ. Anal.
Calcd for C18H13N3O: C, 75.25; H, 4.56; N,14.63%. Found: C, 75.18; H,
4.52; N, 14.60%.
(75 MHz, CDCl3):
d
¼43.9, 94.0,116.5,119.3,125.6,126.2,127.5,128.6,
138.5, 143.2, 143.8, 149.4, 153.7; IR (KBr, cmꢂ1): 2212 (CN), 3390
(NH). Anal. Calcd for C17H12ClN3: C, 69.51; H, 4.12; N,14.30%. Found:
C, 69.50; H, 4.10; N, 14.24%.
4.3.2. 1-Methyl-1H-pyrimido[4,5-b]quinolin-4-one
solid; yield: 89%; mp 133 ꢀC; Rf (40% EtOAc/hexane) 0.28; 1H NMR
(300 MHz, CDCl3):
(5ab). Yellow
4.2.18. 2-Benzylamino-5-phenyl-pyridine-3-carbonitrile
(4a). White solid; yield: 80%; mp: 132 ꢀC (decomp.); 1H NMR
d
¼3.97 (s, 3H, NCH3), 7.32 (t, J¼7.5 Hz, 1H, H-8),
(300 MHz, CDCl3):
exchangeable), 7.37e7.38 (m, 4H), 7.44e7.46 (m, 4H), 7.89 (s, 1H),
8.55 (s, 1H); 13C NMR (75 MHz, CDCl3):
d
¼4.76 (d, J¼5.4 Hz, 2H), 5.50 (br s, 1H, D2O
7.44 (d, J¼8.4 Hz, 1H, H-9), 7.60 (t, J¼7.5 Hz, 1H, H-7), 8.05 (d,
J¼8.7 Hz, 1H, H-6), 8.50 (s, 1H, H-5), 9.22 (s, 1H, H-2); 13C NMR
d¼40.3, 45.4, 91.6, 116.6,
(75 MHz, CDCl3):
d
¼35.7, 126.6, 128.1, 128.3, 129.5, 129.7, 133.2,
126.1,127.6,128.7,129.1,136.9,138.2,139.4,142.3, 150.2, 151.2,157.2;
IR (KBr, cmꢂ1): 2215 (CN), 3362 (NH). Anal. Calcd for C19H15N3: C,
79.98; H, 5.30; N, 14.73%. Found: C, 79.92; H, 5.28; N, 14.70%.
133.6, 140.2, 140.3, 155.7, 170.4; IR (KBr, cmꢂ1): 1655 (CO). Anal.
Calcd for C12H9N3O: C, 68.24; H, 4.29; N, 19.89%. Found: C, 68.20; H,
4.25; N, 19.80%.
4.2.19. 2-Methylamino-5-phenyl-pyridine-3-carbonitrile (4b). Light
4.3.3. 1-Ethyl-1H-pyrimido[4,5-b]quinolin-4-one
solid; yield: 87%; mp 146 ꢀC; Rf (40% EtOAc/hexane) 0.26; 1H NMR
(300 MHz, CDCl3):
(5ac). Yellow
green solid; yield: 82%; mp: 118 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼3.11 (d, J¼4.8 Hz, 3H), 5.23 (br s,1H, D2O exchangeable), 7.44e7.46
d
¼1.33 (t, J¼7.2 Hz, 3H, CH3), 4.46 (q, J¼7.2 Hz,
(m, 5H), 7.86 (s, 1H), 8.55 (s, 1H); 13C NMR (75 MHz, CDCl3):
d¼41.5,
2H, NCH2), 7.60 (t, J¼7.5 Hz,1H, H-8), 7.82 (t, J¼7.5 Hz,1H, H-7), 8.05
(d, J¼8.4 Hz, 1H, H-9), 8.08 (d, J¼8.7 Hz, 1H, H-6), 8.48 (s, 1H, H-5),
91.5,116.6,125.7,125.8,126.3,127.2,129.1,136.1,139.4,151.8,157.6; IR
(KBr, cmꢂ1): 2216 (CN), 3360 (NH). Anal. Calcd for C13H11N3: C, 74.62;
H, 5.30; N, 20.08%. Found: C, 74.60; H, 5.19; N, 19.92%.
9.20 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3):
126.2, 127.6, 128.5, 129.6, 133.4, 140.4, 144.1, 149.3, 155.3, 170.4; IR
(KBr, cmꢂ1): 1654 (CO). Anal. Calcd for C13H11N3O: C, 69.32; H, 4.92;
N, 18.66%. Found: C, 69.27; H, 4.85; N, 18.60%.
d
¼32.7, 48.8, 114.8,
4.2.20. 2-Butylamino-5-phenyl-pyridine-3-carbonitrile (4c). Green
solid; yield: 82%; mp: 82 ꢀC; 1H NMR (300 MHz, CDCl3):
d
¼0.98e1.00 (m, 3H), 1.41e1.48 (m, 2H), 1.63e1.68 (m, 2H),
3.51e3.58 (m, 2H), 5.18 (br s, 1H, D2O exchangeable), 7.34e7.45 (m,
5H), 7.84 (s,1H), 8.52 (s,1H); 13C NMR (75 MHz, CDCl3):
¼13.8, 20.0,
4.3.4. 1-Butyl-1H-pyrimido[4,5-b]quinolin-4-one
solid; yield: 90%; mp 170 ꢀC (decomp.); Rf (40% EtOAc/hexane) 0.23;
1H NMR (300 MHz, CDCl3):
¼1.01 (t, J¼7.2 Hz, 3H, CH3), 1.43e1.55
(5ad). Yellow
d
d

10324
R.M. Singh et al. / Tetrahedron 68 (2012) 10318e10325
(m, 2H, CH2), 1.89e1.99 (m, 2H, CH2), 4.43 (t, J¼7.5 Hz, 2H, NCH2),
7.60 (t, J¼8.1 Hz, 1H, H-8), 7.88 (t, J¼8.4 Hz, 1H, H-7), 8.03 (d,
J¼8.4 Hz, 1H, H-9), 8.05 (d, J¼8.7 Hz, 1H, H-6), 8.44 (s, 1H, H-5), 9.21
148.5, 155.4, 163.1, 170.4; IR (KBr, cmꢂ1): 1654 (CO). Anal. Calcd for
C19H15N3O: C, 75.73; H, 5.02; N, 13.94%. Found: C, 75.70; H, 5.01; N,
13.93%.
(s, 1H, H-2); 13C NMR (75 MHz, CDCl3):
d¼13.6, 19.8, 31.4, 48.3,
115.2,126.4, 127.1, 128.2128.4, 129.4, 133.0, 140.2, 149.4,155.5, 170.5;
IR (KBr, cmꢂ1): 1652 (CO). Anal. Calcd for C15H15N3O: C, 71.13; H,
5.97; N, 16.59. Found: C, 71.12; H, 5.95; N, 16.55.
4.3.11. 1-Benzyl-9-ethyl-1H-pyrimido[4,5-b]quinolin-4-one
(5g). Yellow solid; yield: 95%; mp 129e132 ꢀC; Rf (40% EtOAc/
hexane) 0.44; 1H NMR (300 MHz, CDCl3):
d
¼1.30 (t, J¼7.5 Hz, 3H,
CH3), 3.23 (q, J¼7.5 Hz, 2H, CH2), 5.62 (s, 2H, NCH2), 7.30e7.42 (m,
5H, phenyl), 7.51 (t, J¼7.1 Hz, 1H, H-7), 7.71 (d, J¼6.6 Hz, 1H, H-8),
7.87 (d, J¼8.1 Hz, 1H, H-6), 8.59 (s, 1H, H-5), 9.18 (s, 1H, H-2); 13C
4.3.5. 1-Cyclohexyl-1H-pyrimido[4,5-b]quinolin-4-one
(5ae). Yellow solid; yield: 86%; mp 112 ꢀC; Rf (40% EtOAc/hexane)
0.27; 1H NMR (300 MHz, CDCl3):
d
¼1.25e1.40 (m, 2H, CH2),1.56e1.80
NMR (75 MHz, CDCl3):
d
¼14.6, 24.6, 51.2, 114.7, 125.9, 126.5, 127.2,
(m, 4H, CH2CH2), 1.85e1.90 (m, 2H, CH2), 2.01e2.15 (m, 2H, CH2),
5.43e5.51 (m, 1H, NCH), 7.60 (t, J¼7.5 Hz, 1H, H-8), 7.88 (t, J¼7.2 Hz,
1H, H-7), 8.02 (d, J¼8.4 Hz, 1H, H-9), 8.04 (d, J¼8.7 Hz, 1H, H-6), 8.56
127.5, 128.9, 131.5, 135.4, 140.3, 141.9, 146.6, 147.7,155.5, 163.1, 170.4;
IR (KBr, cmꢂ1): 1652 (CO). Anal. Calcd for C20H17N3O: C, 76.17; H,
5.43; N, 13.32%. Found: C, 76.15; H, 5.40; N, 13.27%.
(s,1H, H-5), 9.23 (s,1H, H-2); 13C NMR (75 MHz, CDCl3):
d¼25.3, 25.9,
32.7, 54.9, 115.2, 126.4, 126.9, 128.4, 129.4, 133.0, 140.3, 147.6, 149.2,
153.2, 170.2; IR (KBr, cmꢂ1): 1671 (CO). Anal. Calcd for C17H17N3O: C,
73.10; H, 6.13; N, 15.04. Found: C, 73.08; H, 6.11; N, 15.01.
4.3.12. 1-Benzyl-7-bromo-1H-pyrimido[4,5-b]quinolin-4-one
(5h). Yellow solid; Yield: 90%; mp145 ꢀC; Rf (40% EtOAc/hexane)
0.38; 1H NMR (300 MHz, CDCl3):
d
¼5.64 (s, 2H, NCH2), 7.33e7.46
(m, 4H, phenyl and H-6), 7.45 (t, J¼8.1 Hz, 1H, phenyl), 7.60 (t,
J¼8.1 Hz, 1H, phenyl), 7.85e8.09 (m, 2H, H-6 and H-8), 8.56 (s, 1H,
4.3.6. 1-Benzyl-7-methyl-1H-pyrimido[4,5-b]quinolin-4-one
(5b). Yellow solid; yield: 82%; mp 152 ꢀC (decomp.); Rf (40% EtOAc/
H-5), 9.21 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3):
d¼50.8, 115.1,
hexane) 0.42; 1H NMR (300 MHz, CDCl3):
d
¼2.57 (s, 3H, CH3), 5.63
126.5, 127.1, 128.1, 128.3, 128.4, 128.9, 129.4, 133.1, 135.3, 140.2, 147.7,
149.2, 155.4, 170.3; IR (KBr, cmꢂ1): 1654 (CO). Anal. Calcd for
C18H12N3OBr: C, 59.03; H, 3.30; N, 11.47%. Found: C, 59.00; H, 3.20;
N, 11.45%.
(s, 2H, NCH2), 7.33e7.45 (m, 5H, phenyl), 7.72 (d, J¼8.1 Hz, 1H, H-8),
7.78 (s, 1H, H-6), 7.99 (d, J¼8.7 Hz, 1H, H-9), 8.54 (s, 1H, H-5), 9.12 (s,
1H, H-2); 13C NMR (75 MHz, CDCl3):
128.0, 128.1, 128.5, 129.0, 135.3, 135.8, 136.8, 139.3, 147.2, 148.0,
155.2,170.2; IR (KBr, cmꢂ1): 1584 (CO). Anal. Calcd for C19H15N3O: C,
75.73; H, 5.02; N, 13.94%. Found: C, 75.70; H, 5.01; N, 13.94%.
d
¼21.5, 50.8, 115.1, 127.3, 127.9,
4.3.13. 1-Benzyl-8-chloro-1H-pyrimido[4,5-b]quinolin-4-one
(5i). Yellow solid; yield: 85%; mp 165 ꢀC; Rf (40% EtOAc/hexane)
0.25; 1H NMR (300 MHz, CDCl3):
d
¼5.64 (s, 2H, NCH2), 7.33e7.45
4.3.7. 1-Benzyl-7-methoxy-1H-pyrimido[4,5-b]quinolin-4-one
(m, 4H, H-9 and phenyl), 7.60 (t, J¼7.2 Hz, 1H, phenyl), 7.88 (t,
J¼7.2 Hz, 1H, phenyl), 8.02e8.09 (m, 2H, H-6 and H-7), 8.56 (s, 1H,
(5c). Yellow solid; yield: 85%; mp 135 ꢀC; Rf (40% EtOAc/hexane) 0.26;
1H NMR (300 MHz, CDCl3):
d
¼3.96 (s, 3H, OCH3), 5.62 (s, 2H, NCH2),
H-5), 9.21 (s, 1H, H-2); 13C NMR (75 MHz, CDCl3):
d
¼50.8, 115.2,
7.11e7.44 (m, 5H, phenyl), 7.54 (d, J¼9.3 Hz,1H, H-8), 7.97 (d, J¼9.3 Hz,
126.5, 127.2, 128.1, 128.3, 128.5, 129.0, 129.4, 133.1, 135.3, 140.3,
147.8, 149.3, 155.4, 170.3; IR (KBr, cmꢂ1): 1656 (CO). Anal. Calcd for
C18H12N3OCl: C, 67.19; H, 3.76; N,13.06%. Found: C, 67.15; H, 3.70; N,
13.00%.
1H, H-9), 8.43 (s, 1H, H-6), 8.53 (s, 1H, H-5), 9.07 (s,1H, H-2); 13C NMR
(75 MHz, CDCl3):
d
¼50.7, 55.8, 105.1, 107.9, 115.2, 126.6, 127.0, 128.0,
128.2,129.6,130.1,135.3,143.1,154.8,157.7,159.1,170.4; IR (KBr, cmꢂ1):
1660 (CO). MS: m/z 318 (MþH)þ. Anal. Calcd for C19H15N3O2: C, 71.91;
H, 4.76; N, 13.24%. Found: C, 71.80; H, 4.68; N, 13.20%.
4.3.14. 1-Benzyl-6-phenyl-1H-pyrido[2,3-d]pyrimidin-4-one
(6). White solid; yield: 82%; mp 148 ꢀC; Rf (40% EtOAc/hexane)
4.3.8. 1-Benzyl-8-methyl-1H-pyrimido[4,5-b]quinolin-4-one
(5d). Yellow solid; yield: 90%; mp 139 ꢀC; Rf (40% EtOAc/hexane)
0.42; 1H NMR (300 MHz, CDCl3):
d
¼5.67 (s, 2H, NCH2), 7.36e7.38
(m, 2H, phenyl), 7.42 (s, 2H, phenyl), 7.50e7.52 (m, 3H, phenyl),
7.64e7.67 (m, 3H, phenyl), 8.83 (s,1H, H-6), 8.97 (s,1H, H-5), 9.07 (s,
0.38; 1H NMR (300 MHz, CDCl3):
d
¼2.61 (s, 3H, CH3), 5.62 (s, 2H,
NCH2), 7.33e7.42 (m, 5H, phenyl), 7.45 (d, J¼8.4 Hz, H-6), 7.86 (s,
1H, H-2); 13C NMR (75 MHz, CDCl3):
d¼51.3, 116.0, 127.0, 128.0,
1H, H-9), 7.93 (d, J¼8.4 Hz, 1H, H-7), 8.54 (s, 1H, H-5), 9.15 (s, 1H, H-
128.6, 128.8, 129.0, 129.3, 134.8, 135.2, 135.7, 136.3, 148.5, 152.4,
154.0, 168.4; IR (KBr, cmꢂ1): 1599 (CO). Anal. Calcd for C20H15N3O:
C, 76.66; H, 4.82; N, 13.41%. Found: C, 76.64; H, 4.80; N, 13.40%.
2); 13C NMR (75 MHz, CDCl3):
128.4, 129.0, 129.1, 135.4, 139.8, 144.4, 147.9, 149.6, 155.2, 159.5,
170.4; IR (KBr, cmꢂ1): 1654 (CO). Anal. Calcd for C19H15N3O: C,
75.73; H, 5.02; N, 13.94%. Found: C, 75.72; H, 5.00; N, 13.90%.
d
¼22.3, 50.7, 114.1, 125.4, 127.2, 128.0,
Acknowledgements
4.3.9. 1-Benzyl-8-methoxy-1H-pyrimido[4,5-b]quinolin-4-one
We thank to CSIR, New Delhi for financial support and S.R.F. to
S.U. We are thankful to UGC, New Delhi for S.R.F. to N.S., meritorious
fellowship to M.A. and fellowship to R.K. We are also thankful to
Prof. Dr. S. Bhattacharya, Banaras Hindu University for his kind help
in solving X-ray crystallographic data.
(5e). Yellow solid; yield: 92%; mp 169 ꢀC (decomp.); Rf (40% EtOAc/
hexane) 0.24; 1H NMR (300 MHz, CDCl3):
d
¼3.98 (s, 3H, OCH3), 5.63
(s, 2H, NCH2), 7.31e7.36 (m, 5H, phenyl), 7.74 (d, J¼9.0 Hz, 1H, H-7),
7.98 (s,1H, H-9), 8.02 (d, J¼9.0 Hz,1H, H-6), 8.42 (s,1H, H-5), 9.08 (s,
1H, H-2); 13C NMR (75 MHz, CDCl3):
115.4,120.4,120.7,121.9,127.9,128.4,129.0,129.1,130.6,143.7,150.6,
164.2; IR (KBr, cmꢂ1): 1659 (CO). Anal. Calcd for C19H15N3O2: C,
71.91; H, 4.76; N, 13.24%. Found: C, 71.89; H, 4.73; N, 13.22%.
d
¼50.6, 55.9,104.9,105.8,107.1,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.004.
4.3.10. 1-Benzyl-9-methyl-1H-pyrimido[4,5-b]quinolin-4-one
(5f). Yellow solid; yield: 86%; mp 135 ꢀC; Rf (40% EtOAc/hexane)
References and notes
0.45; 1H NMR (300 MHz, CDCl3):
d
¼2.77 (s, 3H, CH3), 5.64 (s, 2H,
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26. Crystal data for 5g: Empirical formula, C20H17N3O; formula weight, 315.36;
crystal colour, habit: colourless, block; crystal system, monoclinic; lattice
3
ꢀ
ꢀ
parameters, a¼12.1269(13), b¼8.3449(6), c¼16.871(3) A; V¼1657.0(4) A ;
space group P21/n; Z¼4; Dcalcd¼1.264 g/cm3; F000¼664.00; residuals: R¼0.
0594; Rw¼0.1657. Crystallographic data (excluding structure factors) for the
structures in this Letter have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication number CCDC 902280.
Copies of the data can be obtained free of charge on an application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: þ44 1223336033 or e-mail: deposit@
ccdc.cam.ac.uk].