Synthesis and biological evaluation of novel quinazoline derivatives obtained by Suzuki C-C coupling

Article abstract of DOI:10.1007/s00044-013-0839-2

In the present investigation, two series of novel urea/thiourea-based quinazoline analogs (7a-g/8a-g) have been synthesized by introducing C-C Suzuki coupling between quinazoline and phenyl ring followed by condensation of various N-phenyl isocyanates/iso

Full text of DOI:10.1007/s00044-013-0839-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2338–2346
DOI 10.1007/s00044-013-0839-2
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel quinazoline
derivatives obtained by Suzuki C–C coupling
•
Amit B. Patel Kishor H. Chikhalia
•
Premlata Kumari
Received: 31 July 2013 / Accepted: 7 October 2013 / Published online: 16 October 2013
Ó Springer Science+Business Media New York 2013
Abstract In the present investigation, two series of novel
urea/thiourea-based quinazoline analogs (7a–g/8a–g) have
been synthesized by introducing C–C Suzuki coupling
between quinazoline and phenyl ring followed by conden-
sation of various N-phenyl isocyanates/isothiocyanates.
The synthesized analogs were investigated for their antimi-
crobial activity against two Gram-positive bacteria, three
Gram-negative bacteria, and two fungal species. They were
also tested for the antimycobacterial activity against Myco-
bacterium tuberculosis H37Rv. The biological screening
data revealed that majority of the compounds have demon-
strated noticeable activity (MIC; 6.25–50 lg/mL) against
most of the microorganisms. All the synthesized analogs
were well characterized through IR, 1H NMR, 13C NMR, and
elemental analyses.
global TB report, 2012). In recent years, quinazoline
derivatives have occupied significant position and have
been commonly found in a wide variety of natural pro-
ducts, synthetic pharmaceutical molecules, and other
functional materials. It has been reported that quinazoline
ring skeleton possesses a broad spectrum of biological and
pharmaceutical activities, such as anticancer (Wu et al.,
2011; Noolvi et al., 2011), antifungal (Ryu et al., 2012),
antibacterial (Kumar et al., 2011), antimicrobial (Modh
et al., 2012), anticonvulsant (Amir et al., 2013), analgesic
(Alagarsamy et al., 2008), cytotoxic (Liu et al., 2006),
antimycobacterial (Pandit and Dodiya, 2013), anti-HIV
(Corbett et al., 2000), anti-inflammatory (Laddha and
Bhatnagar, 2009), etc. Similarly, various aryl urea and
thiourea cores-incorporated natural products also exhibit a
broad range of biological activities (Tale et al., 2012;
Alagarsamy et al., 2007; Kane et al., 2003; Keche et al.,
2012). Thus, their synthesis has been of great interest for
the elaboration of biologically active heterocyclic
compounds.
Keywords Quinazoline Á Suzuki coupling Á Urea Á
Thiourea Á Antimicrobial Á Antimycobacterial activity
Introduction
The development of new synthetic methods leading to
structures, which incorporates various biologically active
moieties in a single molecule, has attracted great attention
in synthetic organic chemistry (Karnakar et al., 2012).
Since many decades, the Suzuki cross-coupling reactions
of aryl halides with arylboronic acids have emerged as an
important tool in organic synthesis (Franzen and Xu, 2005;
Thimmaiah and Fang, 2007; Pan et al., 2008). We herein,
report the synthesis of 1-phenyl-3-(4-(4-(m-tolyloxy)qui-
nazolin-2-yl)phenyl)urea/thiourea derivatives (7a–g/8a–
g) by applying the palladium-catalyzed Suzuki cross-cou-
pling reaction on quinazoline. The synthesized compounds
were further tested for their antimicrobial activity against
two Gram-positive, three Gram-negative bacteria, two
fungal, and Mycobacterium tuberculosis H37Rv.
The worldwide inexorable growth of multidrug resistant in
pathogenic microbes has emphasized the need for the dis-
covery of new therapeutic drugs (Bonde et al., 2010; WHO
A. B. Patel Á P. Kumari (&)
Department of Applied Chemistry, S. V. National Institute
of Technology, Surat 395007, India
e-mail: premlatakumari1@gmail.com
K. H. Chikhalia
Department of Chemistry, School of Science, Gujarat
University, Ahmedabad 380009, India
123

Med Chem Res (2014) 23:2338–2346
Results and discussion
Chemistry
2339
with 4-(4-(m-tolyloxy)quinazolin-2-yl)aniline (6). It was
observed that diverse functional groups played a significant
role in governing the product yields. N-phenyl isocyanate/
isothiocynate with substitution of electron-donating groups
at para-position reacted very well with analog 6 and gave
the good product yields compared to the electron-with-
drawing groups. Spectral data IR, 1H NMR, and 13C NMR
of the newly synthesized analogs 7a–j/8a–j were in full
agreement with their proposed structures.
The synthetic route for the target analogs 7a–g/8a–g is
outlined in Scheme 1. The synthetic protocol involved the
Suzuki cross-coupling reaction, to facilitate the C–C bond
formation between the quinazoline ring and phenyl ring,
followed by the condensation of various N-phenyl iso-
cyanates/isothiocyanates. The initial derivative 2,4-di-
chloroquinazoline (4) was synthesized according to the
reported literature (Kumar et al., 2009; Zhu et al., 2011;
Yokoyama et al., 2008; Pogorelic et al., 2007; Kanuma
et al., 2006). Treatment of analog 4 with m-cresol in the
presence of anhydrous K2CO3 at 80 °C in ethanol has
provided the ether derivative 5. The compound 5 was
further reacted with 4-aminophenylboronic acid pinacol
ester in the presence of a catalytic amount of tetrakis-(tri-
phenylphosphine)palladium(0) in basic media to produce
the intermediate 6. Finally, the compound 6 reacted with
different phenyl isocyanates/isothiocyanates (2a–g/3a–
g) in anhydrous toluene at reflux temperature to furnish the
final analogs 7a–g/8a–g. The scope of this novel transfor-
mation was expanded by examining the reaction of dif-
ferent p-substituted N-phenyl isocyanates/isothiocyanates
Pharmacology
In vitro antimicrobial activity
The antimicrobial activity (Table 1) of synthesized analogs
has been carried out against two Gram-positive bacteria (S.
aureus, MTCC 96 and B. cereus, MTCC 430), three Gram-
negative bacteria (E. coli, MTCC 739; P. aeruginosa,
MTCC 741; and K. pneumoniae, MTCC 109), and two
fungal species (A. niger, MTCC 282 and C. albicans,
MTCC 183) (Gillespie, 1994; Hawkey and Lewis, 1994).
Here, ampicillin, gentamicina, and fluconazole were used as
standards for antimicrobial drugs. The results revealed that
majority of synthesized analogs showed varying degrees of
inhibition against the test panel of mentioned microorganisms.
Scheme 1 Synthetic protocol
for the analogs 7a–g/8a–
CH3
CH3
g. Reagents and conditions a
K2CO3, m-cresol, EtOH, 80 °C;
b 4-aminophenylboronic acid
pinacol ester, Pd(PPh3)4,
Na2CO3, DME, 90 °C; and c
toluene, reflux
Cl
N
a
b
O
N
O
N
N
N
N
Cl
Cl
NH2
4
5
6
CH3
O
c
X
C
N
R
N
R
X
C
2a-g/3a-g
N
N
N
H
H
7a-g/8a-g
2a, 7a, X=O, R= H; 3a, 8a, X= S, R= H; 2b, 7b, X=O, R= Cl; 3b, 8b, X= S, R= Cl
2c, 7c, X=O, R= Br; 3c, 8c, X= S, R= Br; 2d, 7d, X=O, R= F; 3d, 8d, X= S, R= F
2e, 7e, X=O, R= CH3; 3e, 8e, X= S, R= CH3; 2f, 7f, X=O, R= OCH3; 3f, 8f, X= S, R= OCH3
2g, 7g, X=O, R= OCH2CH3; 3g, 8g, X= S, R= OCH2CH3
123

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Med Chem Res (2014) 23:2338–2346
Table 1 In vitro antimicrobial activity of analogs 7a–g/8a–g
Entry
X
R
Zone of inhibition in mm (MIC in lg/mL)a
S. aureus
B. cereus
E. coli
P. aeruginosa
K. pneumoniae
A. niger
C. albicans
7a
O
O
O
O
O
O
O
S
H
22 (200)
25 (50)
24 (12.5)
22 (200)
23 (100)
23 (25)
22 (50)
27 (200)
24 (12.5)
29 (6.25)
24 (25)
22 (50)
25 (12.5)
22 (12.5)
30 (12.5)
32 (6.25)
–
20 (250)
24 (100)
28 (12.5)
21 (100)
24 (250)
22 (50)
24 (25)
24 (50)
27 (50)
26 (12.5)
27 (200)
21 (200)
24 (50)
19 (100)
28 (12.5)
30 (6.25)
–
23 (100)
27 (62.5)
27 (62.5)
23 (62.5)
24 (25)
24 (200)
24 (200)
26 (250)
27 (25)
25 (50)
27 (25)
23 (50)
27 (25)
24 (62.5)
31 (6.25)
29 (12.5)
–
21 (62.5)
24 (50)
25 (25)
23 (100)
27 (25)
26 (25)
26 (50)
25 (50)
26 (12.5)
25 (25)
25 (50)
23 (50)
27 (25)
26 (12.5)
28 (25)
33 (12.5)
–
19 (100)
23 (62.5)
24 (50)
21 (200)
24 (50)
26 (200)
25 (25)
22 (200)
27 (25)
27 (12.5)
24 (100)
21 (50)
24 (50)
23 (25)
33 (25)
30 (25)
–
22 (200)
26 (200)
22 (62.5)
23 (25)
21 (200)
23 (50)
23 (50)
23 (50)
24 (12.5)
23 (25)
22 (50)
18 (200)
21 (50)
26 (25)
–
23 (250)
21 (100)
24 (50)
26 (12.5)
24 (50)
25 (25)
27 (50)
25 (200)
28 (25)
27 (12.5)
25 (6.25)
23 (50)
28 (12.5)
22 (50)
–
7b
Cl
7c
Br
7d
F
7e
CH3
7f
OCH3
OCH2CH3
H
7g
8a
8b
S
Cl
8c
S
Br
8d
S
F
8e
S
CH3
8f
S
OCH3
OCH2CH3
8g
S
Ampicillin
Gentamicina
Fluconazole
DMSO
a
–
–
30 (6.25)
–
31 (12.5)
–
–
–
–
–
–
Each value is the mean of three independent experiments
Bromo-group-substituted thiourea derivative 8c has shown
extremely significant inhibitory efficacy against Gram-posi-
tive bacteria S. aureus at MIC 6.25 lg/mL and B. cereus at
MIC 12.5 lg/mL with zone of inhibition 29 mm and 26 mm,
respectively. Itwasalso foundto be activeagainst some Gram-
negative bacteria such as K. pneumoniae at MIC 12.5 lg/mL
and P. aeruginosa at MIC 25 lg/mL with zone of inhibition of
27 mm and 25 mm, respectively. However, urea linked ana-
log 7c with similar bromo-functional group showed good
activity but was lesser than that of analog 8c. Chloro- and
fluoro-substituted thiourea derivatives were succeeded to
indicate remarkable activity against S. aureus at MIC 12.5 and
25 lg/mL, respectively. In addition, analog 8b was also active
against P. aeruginosa at MIC 12.5 lg/mL with 25-mm inhi-
bition zone. The analogs 8f and 8g with substitution of
methoxy- and ethoxy-groups were significantly active against
S. aureus at MIC 12.5 lg/mL. Analogs 8b and 8d with pre-
sence of chloro- and fluoro-substituents have exhibited sig-
nificant activity against S. aureus at MIC 12.5 and 25 lg/mL,
respectively.
MIC 12.5 lg/mL. Analogs 8c and 8f with the presence of
bromo- and methoxy-substituents have displayed good
antifungal activity against C. albicans at MIC 12.5 lg/mL
with zone of inhibition 27 and 28 mm, respectively.
Interestingly, the chloro-group-substituted thiourea analog
8b was found to be active against A. niger at MIC 12.5 lg/
mL with 24 mm zone of inhibition. From the biological
screening results, it can be stated that thiourea derivatives
were more active against majority of the microorganisms
as compared with the urea derivatives.
In vitro antimycobacterial activity
In vitro antimycobacterial activity of the synthesized ana-
logs was assessed against Mycobacterium tuberculosis
H37Rv using L. J. (Lowenstein and Jensen) MIC method
(Isenberg, 1992) for the measurement of MIC. Rifampicin,
isoniazid, ethambutol, and pyrazinamide were used as
standard antimycobacterial drugs. The results observed
from Lowenstein Jensen MIC method along with the
measurement of the potency of the standard drugs are
mentioned in Table 2. The bromo-substituted thiourea
analog 8c has displayed highest antimycobacterial efficacy
at MIC 12.5 lg/mL with 99 % inhibition. This analog was
considered to display half-fold efficacy to the standard drug
pyrazinamide. However, some other analogs 7c, 8b, and 8d
were moderately active.
Moreover, the in vitro antifungal activity of synthesized
analogs indicated that the halogenated thiourea-substituted
quinazoline analogs have shown high efficacy against C.
albicans. Fluoro-substituted thiourea analog 8d was found
50 % more potent than the standard fluconazole (MIC
12.5 lg/mL) against C. albicans. However, in the case of
similar urea derivative 7d, activity slightly decreased to
123

Med Chem Res (2014) 23:2338–2346
2341
(Mumbai, India) and Rankem (Surat, India). All reactions
were routinely checked by Thin Layer Chromatography. TLC
was performed on aluminum-backed silica gel plates (silica
gel 60 F254 grade, Merck DC) with spots visualized by UV
light. Column chromatography was performed on silica gel
LC 60A (70–200 micron). The uncorrected melting points
were determined in open capillaries on a Veego electronic
apparatus VMP-D. FT-IR spectra (4000–400 cm-1) of the
synthesized analogswererecordedona Shimadzu 8400-SFT-
IR spectrophotometer by preparing KBr pellets. The ele-
mental analysis was performed by Perkin Elmer 2400 CHN
Elemental Analyser. 1H and 13C NMR spectra were recorded
ona Varian 400 MHz model spectrometer using DMSO-d6as
Table 2 In vitro antimycobacterial activity of analogs 7a–g/8a–g
Entry
X
R
MIC (lg/mL)a Inhibition (%)a
7a
O
O
O
O
O
O
O
S
H
250
100
25
95
98
99
97
95
94
96
95
98
99
96
94
97
95
99
99
99
99
–
7b
Cl
7c
Br
7d
F
62.5
200
62.5
7e
CH3
OCH3
7f
7g
OCH2CH3 100
8a
H
100
25
8b
S
Cl
8c
S
Br
12.5
50
1
a solvent and TMS as internal standard with H resonant
8d
S
F
frequency of 400 MHz and 13C resonant frequency of
100 MHz. The 1H and 13C NMR chemical shifts were
reported as parts per million (ppm) downfield from TMS
(Me4Si). The splitting patterns were designated as follows: s,
singlet; br s, broad singlet; d, doublet; t, triplet; m, multiplet;
dd, doublet of doublet; and td, triplet of doublet.
8e
S
CH3
OCH3
100
100
8f
S
8g
S
OCH2CH3 200
Ethambutol
Pyrazinamide
Rifampicin
Isoniazid
DMSO
a
3.12
6.25
0.25
0.20
–
Synthesis of 2-chloro-4-(m-tolyloxy)quinazoline (5)
Each value is the mean of three independent experiments
Mixture of potassium carbonate (10 mmol) and solution of
m-cresol (2 mmol) in anhydrous ethanol (20 mL) was
stirred for 5 min in an oven dried flat-bottomed flask,
equipped with a magnetic stir bar. Then, the compound
2,4-dichloroquinazoline 4 (2 mmol) was added into the
reaction mixture and refluxed for 12 h. The progress of the
reaction was monitored by TLC using n-hexane:ethyl
acetate (6:4) solvent system. After cooling to the room
temperature, the reaction mixture was treated with 200 mL
ice cold water, and the resulting precipitate was filtered off.
The crude product 5 was recrystallized from DMF (Zeng
et al., 2010; Wang et al., 2009). White solid, Yield: 81 %,
mp 133–135 °C. IR (KBr, cm-1): 2989 (Ar–CH), 1578
Conclusion
In conclusion, we report an efficient protocol for the pal-
ladium-catalyzed Suzuki C–C coupling of novel urea/
thiourea-based quinazolines. Some of the final analogs
have shown remarkable activity against the mentioned
microorganisms compare with the standards. From the
bioassay results, it can be concluded that the thiourea
linkage is essential for biological activity, especially hal-
ogen group-substituted thiourea-linked quinazoline deriv-
atives have shown an exceptional antimicrobial as well as
antimycobacterial activities. The synthesized analogs have
displayed extremely significant antimicrobial activity in the
range of 6.25–50 lg/mL. Moreover, some of the analogs
have also portended good antimycobacterial activity in the
range of 12.5–25 lg/mL. So in the end, this study has
widened the scope of developing quinazoline derivatives as
promising bioactive agents.
1
(CN), 1245 (C–O–C), 645 (C–Cl). H NMR (400 MHz,
DMSO-d6): d 8.29 (dd, J = 6.8, 1.4 Hz, 1H, quinazoline),
7.98 (dd, J = 6.8, 1.4 Hz, 1H, quinazoline), 7.66–7.17 (m,
3H, Ar–H), 6.58–6.48 (m, 3H, Ar–H, m-tolyloxy ring),
2.15 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6): d
165.2 (C-4), 154.7 (C-12), 153.4 (C-2), 151.3 (C-10), 142.5
(C-16), 135.0 (C-8), 128.9 (C-17), 127.4 (C-6), 125.2
(C-9), 124.6 (C-7), 122.8 (C-14), 119.8 (C-13), 118.5
(C-15), 114.6 (C-5), 21.4 (CH3). Anal. Calcd for
C15H11ClN2O: C, 66.55; H, 4.10; N, 10.35; Found: C,
66.39; H, 3.89; N, 10.47.
Experimental
General
Synthesis of 4-(4-(m-tolyloxy)quinazolin-
2-yl)aniline (6)
All reactions were carried out under the nitrogen atmosphere.
Air- and moisture-sensitive solvents and solutions were
transferred via syringe or stainless steel cannula. All solvents
and chemicals were purchased from Sigma Aldrich chemicals
In an oven dried flat-bottomed flask, a mixture of com-
pound5 (60 mmol), tetrakis-(triphenylphosphine)palladium(0)
123

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Med Chem Res (2014) 23:2338–2346
(0.75 mmol), 2 M sodium carbonate solution (50 mL), and
4-aminophenylboronic acid pinacol ester (90 mmol) in
dimethoxyethane (DME) solvent (300 mL) was stirred under
nitrogen atmosphere for 15 min and heated to refluxed
temperature for 24 h. The progress of the reaction was
monitored by TLC using n-hexane:ethyl acetate (6:4) solvent
system. At the end of the reaction, the solvent was evapo-
rated at reduced pressure. The residue was dissolved in
methylene dichloride and filtered through a pad of Celite.
The filtrate was washed with water (2 9 500 mL), and the
organic layer was dried with sodium sulfate. The filtrate was
concentrated and purified through silica gel column chro-
matography to obtain the desired product 6 (Patel et al.,
2013). White solid, Yield: 68 %, mp 201–204 °C. IR (KBr,
125.4 (C-31, C-33), 125.1 (C-16), 124.8 (C-17), 121.9
(C-24), 120.7 (C-32), 120.3 (C-23), 119.2 (C-30, C-34),
118.2 (C-6, C-10), 117.3 (C-25), 113.2 (C-15), 20.7 (CH3).
Anal. Calcd for C28H22N4O2: C, 75.32; H, 4.97; N, 12.55;
Found: C, 74.89; H, 5.59; N, 12.48.
1-(4-chlorophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7b)
White solid, IR (KBr, cm-1): 3410 (N–H), 2981 (C–H),
1681 (C=O), 1240 (C–O–C), 615 (C–Cl). 1H NMR
(400 MHz, DMSO-d6): d 9.15 (s, 1H, –CONH), 8.89 (s,
1H, –NHCO), 8.43 (dd, J = 7.8 Hz, 2.6, 1H, quinazoline),
8.21 (dd, J = 9.2, 2.6 Hz, 1H, quinazoline), 7.95–7.72 (m,
4H, Ar–H), 7.67–7.18 (m, 8H, Ar–H, m-tolyloxy quinaz-
oline), 6.77 (t, 1H), 6.56 (d, J = 8.7 Hz, 1H), 2.39 (s, 3H,
–CH3). 13C NMR (100 MHz, DMSO-d6): d 169.7 (C=O),
161.5 (C-14), 154.9 (C-12), 153.6 (C-22), 151.4 (C-20),
141.7 (C-5), 141.4 (C-26), 139.5 (C-29), 136.7 (C-8), 133.9
(C-18), 130.4 (C-7, C-9), 129.1 (C-27), 128.6 (C-19), 126.3
(C-31, C-33), 125.7 (C-32), 125.1 (C-16), 124.5 (C-17),
123.9 (C-24), 122.7 (C-23), 121.2 (C-30, C-34), 120.8 (C-
6, C-10), 118.3 (C-25), 111.8 (C-15), 22.4 (CH3). Anal.
Calcd for C28H21ClN4O2: C, 69.92; H, 4.40; N, 11.65;
Found: C, 70.74; H, 4.59; N, 12.22.
1
cm-1): 3360 (N–H), 1245 (C–O–C). H NMR (400 MHz,
DMSO-d6): d 8.42 (dd, J = 6.8, 1.4 Hz, 1H, quinazoline),
8.13 (dd, J = 6.6, 1.5 Hz, 1H, quinazoline), 7.62–7.21 (m,
7H, Ar–H), 6.74–6.62 (m, 3H, Ar–H, m-tolyloxy ring), 4.67
(br s, 2H, –NH2), 2.32 (s, 3H, –CH3). 13C NMR (100 MHz,
DMSO-d6): d 164.1 (C-11), 153.7 (C-9), 152.4 (C-19), 150.8
(C-17), 149.2(C-2), 138.6 (C-23), 135.2 (C-15), 129.0 (C-4,
C-6), 128.4 (C-24), 127.8 (C-16), 126.3 (C-13), 125.9 (C-5),
125.1 (C-14), 123.6 (C-21), 122.3 (C-20), 118.2 (C-22),
116.9 (C-3, C-7), 113.3 (C-12), 22.6 (CH3). Anal. Calcd for
C21H17N3O: C, 77.04; H, 5.23; N, 12.84; Found: C, 76.79;
H, 5.35; N, 12.57.
General synthetic procedure for analogs (7a–g/8a–g)
1-(4-bromophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7c)
In an oven dried flat-bottomed flask, a mixture of com-
pound 6 (50 mmol) and phenyl isocyanates (2a–g)/iso-
thiocyanates (3a–g) (50 mmol) was refluxed for 6–8 h in
50 mL of anhydrous toluene. After the completion of
reaction, the solvent was evaporated at reduced pressure
and the resulting residue was recrystallized with DMF to
obtained final analogs 7a–g/8a–g. The progress of the
reaction was monitored by TLC using n-hexane:ethyl
acetate (8:2) solvent system (Kaswala et al., 2009).
Light greenish solid, IR (KBr, cm-1): 3352 (N–H), 2978
(C–H), 1680 (C=O), 1252 (C–O–C), 936 (C–Br). 1H NMR
(400 MHz, DMSO-d6): d 9.32 (s, 1H, –CONH), 9.01 (s,
1H, –NHCO), 8.83 (d, J = 8.2 Hz, 1H, quinazoline), 8.42
(dd, J = 6.8, 1.5 Hz, 1H, quinazoline), 7.83 (t, 1H),
7.73–7.53 (m, 5H, Ar–H), 7.41–7.32 (m, 6H, Ar–H, m-
tolyloxy quinazoline), 7.12 (t, 1H), 6.89 (d, J = 8.4 Hz,
1H), 2.28 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6):
d 170.9 (C=O), 161.1 (C-14), 154.7 (C-12), 152.4 (C-22),
149.5 (C-20), 140.1 (C-5), 136.9 (C-26), 134.5 (C-29),
133.8 (C-8), 133.3 (C-18), 128.9 (C-7, C-9), 128.4 (C-31,
C-33), 127.9 (C-27), 126.6 (C-19), 124.5 (C-16), 124.3 (C-
17), 123.6 (C-24), 122.9 (C-23), 122.2 (C-30, C-34), 119.6
(C-6, C-10), 119.2 (C-32), 118.9 (C-25), 112.4 (C-15), 21.6
(CH3). Anal. Calcd for C28H21BrN4O2: C, 64.01; H, 4.03;
N, 10.66; Found: C, 65.74; H, 4.59; N, 9.95.
1-phenyl-3-(4-(4-(m-tolyloxy)quinazolin-2-yl)phenyl)urea
(7a)
Pale white solid, IR (KBr, cm-1): 3350 (N–H), 3111
(C–H), 1687 (C = O), 1212 (C–O–C). 1H NMR
(400 MHz, DMSO-d6): d 8.97 (s, 1H, –CONH), 8.72 (s,
1H, –NHCO), 8.19 (d, J = 8.4 Hz, 2H, quinazoline), 8.13
(dd, J = 7.5, 1.5 Hz, 1H, quinazoline), 7.98 (t, 1H),
7.78–7.61 (m, 5H, Ar–H), 7.53–7.22 (m, 5H, Ar–H, m-
tolyloxy ring), 6.98 (t, 1H), 6.67 (d, J = 8.1 Hz, 2H), 2.12
(s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6): d 172.4
(C=O), 163.1 (C-14), 152.2 (C-12), 151.6 (C-22), 150.1 (C-
20), 142.7 (C-5), 139.2 (C-26), 138.7 (C-29), 136.2 (C-8),
133.8 (C-18), 128.4 (C-7, C-9), 125.6 (C-27), 125.5 (C-19),
1-(4-fluorophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7d)
White solid, IR (KBr, cm-1): 3391 (N–H), 2981 (C–H),
1678 (C=O), 1215 (C–O–C), 1193 (C–F). 1H NMR
(400 MHz, DMSO-d6): d 9.19 (s, 1H, –CONH), 8.96
123

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(s, 1H, –NHCO), 8.75 (d, J = 8.4 Hz, 1H, quinazoline),
8.38 (dd, J = 7.2, 1.8 Hz, 1H, quinazoline), 7.81 (t, 1H),
7.71–7.48 (m, 5H, Ar–H), 7.39–7.21 (m, 6H, Ar–H,
m-tolyloxy quinazoline), 7.03 (t, 1H), 6.65 (d, J = 9.2 Hz,
1H), 2.25 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6):
d 171.7 (C=O), 162.8 (C-14), 153.4 (C-12), 152.1 (C-32),
151.6 (C-22), 150.3 (C-20), 140.4 (C-5), 139.5 (C-26),
138.9 (C-8), 136.8 (C-29), 133.1 (C-18), 129.1 (C-7, C-9),
128.1 (C-27), 127.3 (C-19), 126.6 (C-16), 125.7 (C-17),
124.4 (C-24), 123.9 (C-23), 121.7 (C-30, C-34), 121.3 (C-
6, C-10), 120.1 (C-31, C-33), 119.2 (C-25), 117.7 (C-15),
22.1 (CH3). Anal. Calcd for C28H21FN4O2: C, 72.40; H,
4.56; N, 12.06; Found: C, 72.01; H, 4.68; N, 11.92.
C29H24N4O3: C, 73.09; H, 5.08; N, 11.76; Found: C, 72.74;
H, 5.59; N, 11.32.
1-(4-ethoxyphenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7g)
White solid, IR (KBr, cm-1): 3420 (N–H), 3118 (C–H),
1682 (C=O), 1252 (C–O–C). 1H NMR (400 MHz, DMSO-
d6): d 9.08 (s, 1H, –CONH), 8.94 (s, 1H, –NHCO), 8.73
(d, J = 7.8 Hz, 1H, quinazoline), 8.40 (dd, J = 6.4,
1.5 Hz, 1H, quinazoline), 7.75 (t, 1H), 7.65–7.59 (m, 5H,
Ar–H), 7.56–7.43 (m, 6H, Ar–H, m-tolyloxy quinazoline),
7.17 (t, 1H), 6.63 (d, J = 8.8 Hz, 1H), 3.98 (q, J = 7.2 Hz,
2H, –OCH2CH3), 2.28 (s, 3H, –CH3), 1.35 (t, J = 6.8 Hz,
3H, –OCH2CH3). 13C NMR (100 MHz, DMSO-d6): d
169.9 (C = O), 161.0 (C-14), 153.1 (C-12), 152.7 (C-22),
152.1 (C-32), 144.1 (C-5), 140.2 (C-26), 139.9 (C-8), 133.8
(C-18), 131.9 (C-29), 129.5 (C-7, C-9), 128.4 (C-27), 127.1
(C-19), 126.2 (C-16), 124.4 (C-17), 124.1 (C-24), 122.9
(C-23), 121.7 (C-6, C-10), 120.1 (C-30, C-34), 119.6
(C-31, C-33), 118.8 (C-25), 112.9 (C-15), 65.1 (–OCH2
CH3), 21.7 (CH3), 15.2 (–OCH2CH3). Anal. Calcd for
C30H26N4O3: C, 73.45; H, 5.34; N, 11.42; Found: C, 73.85;
H, 5.59; N, 11.63.
1-(4-methylphenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7e)
Pale brown solid, IR (KBr, cm-1): 3303 (N–H), 2958
1
(C–H), 1678 (C=O), 1236 (C–O–C). H NMR (400 MHz,
DMSO-d6): d 9.47 (s, 1H, –CONH), 9.13 (s, 1H, –NHCO),
8.83 (dd, J = 7.8, 2.4 Hz, 1H, quinazoline), 8.23 (dd,
J = 6.2, 1.3 Hz, 1H, quinazoline), 7.81–7.68 (m, 5H, Ar–
H), 7.45–7.39 (m, 6H, Ar–H, m-tolyloxy quinazoline), 7.11
(t, 1H), 6.71 (d, J = 8.1 Hz, 2H), 2.86, 2.71 (s, 6H, –CH3).
13C NMR (100 MHz, DMSO-d6): d 172.1 (C = O), 161.7
(C-14), 152.5 (C-12), 151.3 (C-22), 148.9 (C-20), 142.6
(C-5), 139.9 (C-26), 137.1 (C-29), 134.3 (C-8), 131.7
(C-18), 129.0 (C-32), 127.6 (C-7, C-9), 126.3 (C-31, C-33),
125.8 (C-27), 124.4 (C-19), 124.1 (C-16), 122.8 (C-17),
121.2 (C-24), 120.9 (C-23), 119.8 (C-6, C-10), 118.0 (C-
30, C-34), 117.8 (C-25), 113.6 (C-15), 22.3 (C-28), 21.9
(C-35). Anal. Calcd for C29H24N4O2: C, 75.63; H, 5.25; N,
12.17; Found: C, 75.14; H, 5.86; N, 12.51.
1-phenyl-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8a)
Pale white solid, IR (KBr, cm-1): 3430 (N–H), 3100
1
(C–H), 1510 (C=S), 1236 (C–O–C). H NMR (400 MHz,
DMSO-d6): d 9.17 (s, 1H, –SONH), 9.04 (s, 1H, –NHSO),
8.68 (d, J = 8.6 Hz, 1H, quinazoline), 8.49 (dd, J = 7.2,
1.8 Hz, 1H, quinazoline), 7.83–7.61 (m, 4H, Ar–H),
7.45–7.26 (m, 8H, Ar–H, m-tolyloxy quinazoline), 6.95 (t,
1H), 6.73 (d, J = 7.6 Hz, 2H), 2.23 (s, 3H, –CH3). 13C
NMR (100 MHz, DMSO-d6): d 171.6 (S=O), 162.4 (C-14),
153.1 (C-12), 152.8 (C-22), 152.1 (C-20), 142.9 (C-5),
142.2 (C-26), 141.3 (C-29), 138.9 (C-8), 133.6 (C-18),
129.9 (C-7, C-9), 128.8 (C-27), 126.4 (C-19), 125.5 (C-31,
C-33), 125.1 (C-16), 123.1 (C-17), 122.8 (C-24), 121.3
(C-32), 120.5 (C-23), 120.3 (C-30, C-34), 119.8 (C-6,
C-10), 118.1 (C-25), 113.2 (C-15), 21.4 (CH3). Anal. Calcd
for C28H22N4OS: C, 72.70; H, 4.79; N, 12.11; Found: C,
72.88; H, 4.39; N, 12.47.
1-(4-methoxyphenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)urea (7f)
Pale brown solid, IR (KBr, cm-1): 3380 (N–H), 2975
1
(C–H), 1680 (C=O), 1220 (C–O–C). H NMR (400 MHz,
DMSO-d6): d 8.95 (s, 1H, –CONH), 8.76 (s, 1H, –NHCO),
8.49 (dd, J = 7.8, 1.5 Hz, 2H, quinazoline), 8.19
(dd, J = 8.2, 2.4 Hz, 1H, quinazoline), 7.68–7.49 (m, 6H,
Ar–H), 7.43–7.28 (m, 6H, Ar–H, m-tolyloxy quinazoline),
6.95 (t, 1H), 6.78 (d, J = 7.4 Hz, 1H), 3.25 (s, 3H,
–OCH3), 2.32 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-
d6): d 170.6 (C=O), 163.1 (C-14), 152.8 (C-12), 152.1
(C-22), 151.4 (C-32), 151.0 (C-20), 144.7 (C-5), 142.2 (C-
26), 140.9 (C-8), 139.8 (C-18), 136.1 (C-29), 130.5 (C-7,
C-9), 128.2 (C-27), 126.1 (C-19), 125.9 (C-16), 125.1
(C-17), 123.7 (C-24), 122.8 (C-23), 121.1 (C-30, C-34),
120.2 (C-6, C-10), 119.5 (C-31, C-33), 117.9 (C-25), 111.2
(C-15), 56.4 (–OCH3), 22.1 (CH3). Anal. Calcd for
1-(4-chlorophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8b)
White solid, IR (KBr, cm-1): 3392 (N–H), 3142 (C–H),
1460 (C=S), 1230 (C–O–C), 632 (C–Cl). 1H NMR
(400 MHz, DMSO-d6): d 9.53 (s, 1H, –SONH), 9.27
123

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Med Chem Res (2014) 23:2338–2346
1-(p-tolyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
(s, 1H, –NHSO), 8.91 (d, J = 7.8 Hz, 2H, quinazoline),
8.56 (dd, J = 8.8, 2.6 Hz, 1H, quinazoline), 7.71 (t, 1H),
7.62–7.43 (m, 4H, Ar–H), 7.38–7.19 (m, 6H, Ar–H,
m-tolyloxy quinazoline), 6.81 (t, 1H), 6.68 (d, J = 6.1 Hz,
1H), 2.15 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6):
d 172.3 (S=O), 163.9 (C-14), 151.6 (C-12), 151.1 (C-22),
149.6 (C-20), 139.8 (C-5), 138.2 (C-26), 136.1 (C-29),
135.2 (C-8), 129.0 (C-18), 127.5 (C-7, C-9), 126.7 (C-27),
125.1 (C-31, C-33), 124.8 (C-19), 122.3 (C-32), 121.8
(C-16), 120.0 (C-17), 119.3 (C-24), 118.3 (C-23), 117.2
(C-30, C-34), 116.9 (C-6, C-10), 116.6 (C-25), 114.8 (C-
15), 22.2 (CH3). Anal. Calcd for C28H21ClN4OS: C, 67.66;
H, 4.26; N, 11.27; Found: C, 68.14; H, 4.59; N, 11.84.
yl)phenyl)thiourea (8e)
Pale greenish solid, IR (KBr, cm-1): 3409 (N–H), 2998
1
(C–H), 1522 (C=S), 1237 (C–O–C). H NMR (400 MHz,
DMSO-d6): d 9.45 (s, 1H, –SONH), 8.99 (s, 1H, –NHSO),
8.41 (d, J = 7.8 Hz, 1H, quinazoline), 8.25 (dd, J = 6.9,
1.5 Hz, 1H, quinazoline), 7.59–7.25 (m, 5H, Ar–H),
7.19–7.08 (m, 6H, Ar–H, m-tolyloxy quinazoline), 6.86 (t,
1H), 6.61 (d, J = 7.5 Hz, 2H), 2.31, 2.26 (s, 6H, –CH3).
13C NMR (100 MHz, DMSO-d6): d 169.9 (S=O), 163.0
(C-14), 152.9 (C-12), 152.4 (C-22), 151.1 (C-20), 144.3
(C-5), 142.2 (C-26), 140.9 (C-29), 138.7 (C-8), 136.9
(C-18), 128.7 (C-32), 126.4 (C-7, C-9), 124.3 (C-31, C-33),
123.3 (C-27), 122.0 (C-19), 121.2 (C-16), 120.4 (C-17),
120.0 (C-24), 119.3 (C-23), 118.9 (C-30, C-34), 118.2
(C-6, C-10), 117.5 (C-25), 114.9 (C-15), 22.8 (C-28), 22.3
(C-35). Anal. Calcd for C29H24N4OS: C, 73.08; H, 5.08; N,
11.76; Found: C, 73.56; H, 5.61; N, 11.09.
1-(4-bromophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8c)
Brown solid, IR (KBr, cm-1): 3434 (N–H), 2979 (C–H),
1519 (C=S), 1242 (C–O–C), 945 (C–Br). 1H NMR
(400 MHz, DMSO-d6): d 9.21 (s, 1H, –SONH), 8.98 (s,
1H, –NHSO), 8.56 (d, J = 8.2 Hz, 1H, quinazoline), 8.21
(dd, J = 9.2, 3.2 Hz, 1H, quinazoline), 7.85 (t, 1H),
7.66–7.39 (m, 4H, Ar–H), 7.27–7.13 (m, 6H, Ar–H,
m-tolyloxy quinazoline), 6.93 (t, 1H), 6.74 (d, J = 7.6 Hz,
1H), 2.38 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6):
d 169.4 (S=O), 161.7 (C-14), 151.5 (C-12), 151.1 (C-22),
150.6 (C-20), 140.2 (C-5), 139.3 (C-26), 136.1 (C-29),
133.0 (C-8), 129.9 (C-18), 128.0 (C-31, C-33), 127.5 (C-7,
C-9), 126.1 (C-27), 125.3 (C-19), 124.8 (C-16), 122.9
(C-17), 122.1 (C-24), 121.5 (C-23), 120.1 (C-30, C-34),
119.3 (C-6, C-10), 119.1 (C-32), 118.5 (C-25), 115.1
(C-15), 23.1 (CH3). Anal. Calcd for C28H21BrN4OS: C, 62.11;
H, 3.91; N, 10.35; Found: C, 63.08.74; H, 4.31; N, 10.13.
1-(4-methoxyphenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8f)
White solid, IR (KBr, cm-1): 3397 (N–H), 3123 (C–H),
1
1495 (C=S), 1241 (C–O–C). H NMR (400 MHz, DMSO-
d6): d 9.61 (s, 1H, –SONH), 9.21 (s, 1H, –NHSO), 8.75
(d, J = 9.2 Hz, 2H, quinazoline), 8.51 (dd, J = 8.8,
2.2 Hz, 1H, quinazoline), 7.95 (t, 1H), 7.89–7.68 (m, 4H,
Ar–H), 7.59–7.36 (m, 6H, Ar–H, m-tolyloxy quinazoline),
7.12 (t, 1H), 6.69 (d, J = 7.4 Hz, 1H), 3.84 (s, 3H,
–OCH3), 2.32 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-
d6): d172.1 (S=O), 163.1 (C-14), 154.3 (C-12), 152.3
(C-32), 151.9 (C-22), 150.0 (C-20), 142.3 (C-5), 139.9
(C-26), 139.1 (C-8), 133.8 (C-18), 133.1 (C-29), 129.9 (C-
7, C-9), 128.8 (C-27), 128.0 (C-19), 127.5 (C-16), 126.1
(C-17), 125.3 (C-24), 124.9 (C-23), 123.0 (C-30, C-34),
122.6 (C-6, C-10), 121.0 (C-31, C-33), 119.8 (C-25), 115.1
(C-15), 55.3 (–OCH3), 20.9 (CH3). Anal. Calcd for
C29H24N4O2S: C, 70.71; H, 4.91; N, 11.37; Found: C,
70.13; H, 4.59; N, 11.88.
1-(4-fluorophenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8d)
Pale brown solid, IR (KBr, cm-1): 3390 (N–H), 3125
1
(C–H), 1540 (C=S), 1355 (C–F), 1240 (C–O–C). H NMR
(400 MHz, DMSO-d6): d 9.04 (s, 1H, –SONH), 8.89 (s,
1H, –NHSO), 8.61 (d, J = 8.4 Hz, 1H, quinazoline), 8.32
(dd, J = 7.8, 1.4 Hz, 1H, quinazoline), 7.91 (t, 1H),
7.72–7.34 (m, 5H, Ar–H), 7.28–7.19 (m, 6H, Ar–H,
m-tolyloxy quinazoline), 7.03 (t, 1H), 6.79 (d, J = 6.2 Hz,
1H), 2.19 (s, 3H, –CH3). 13C NMR (100 MHz, DMSO-d6):
d 170.0 (S=O), 162.2 (C-14), 153.5 (C-12), 151.9 (C-32),
150.8 (C-22), 148.7 (C-20), 140.8 (C-5), 139.0 (C-26),
136.6 (C-29), 134.9 (C-8), 128.1 (C-18), 127.4 (C-7, C-9),
126.9 (C-27), 126.3 (C-19), 125.8 (C-16), 122.8 (C-17),
122.1 (C-24), 121.8 (C-23), 120.1 (C-30, C-34), 119.5
(C-6, C-10), 118.3 (C-31, C-33), 117.1 (C-25), 113.9
(C-15), 20.5 (CH3). Anal. Calcd for C28H21FN4OS: 69.98;
H, 4.40; N, 11.66; Found: C, 70.74; H, 3.95; N, 11.23.
1-(4-ethoxyphenyl)-3-(4-(4-(m-tolyloxy)quinazolin-2-
yl)phenyl)thiourea (8g)
Pale brown solid, IR (KBr, cm-1): 3428 (N–H), 2988 (C–
H), 1522 (C=S), 1233 (C–O–C). 1H NMR (400 MHz,
DMSO-d6): d 9.32 (s, 1H, –SONH), 9.11 (s, 1H, –NHSO),
8.63 (d, J = 7.8 Hz, 2H, quinazoline), 8.45 (dd, J = 7.5,
1.5 Hz, 1H, quinazoline), 7.86–7.59 (m, 5H, Ar–H),
7.51–7.29 (m, 6H, Ar–H, m-tolyloxy quinazoline), 7.01 (t,
1H), 6.76 (d, J = 8.2 Hz, 2H), 4.09 (q, J = 6.2 Hz, 1H,
–OCH2CH3), 2.91 (s, 3H, –CH3), 2.28 (t, J = 6.4 Hz, 3H,
–OCH2CH3). 13C NMR (100 MHz, DMSO-d6): d 169.1
123

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2345
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(S=O), 162.2 (C-14), 152.2 (C-12), 151.9 (C-32), 150.7
(C-22), 150.2 (C-20), 144.3 (C-5), 139.2 (C-26), 138.8
(C-8), 133.0 (C-18), 132.7 (C-29), 130.1 (C-7, C-9), 129.2
(C-27), 128.6 (C-19), 126.3 (C-16), 125.8 (C-17), 124.1
(C-24), 123.6 (C-23), 120.3 (C-30, C-34), 119.7 (C-6,
C-10), 119.3 (C-31, C-33), 118.2 (C-25), 114.0 (C-15),
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