Synthesis of promising antimicrobial agents: A novel series of N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoacetamides

Article abstract of DOI:10.1007/s00044-012-0121-z

A series of novel compounds N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl) pyrimidin-2-yl)-2-morpholinoacetamides (5a-l) were synthesized by a series of multistep reactions. Newly synthesized compounds have been characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral data. Antimicrobial screening of title compounds 5a-l was examined against Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and three fungi (Candida albicans, Aspergillus niger, and Aspergillus clavatus) by serial broth dilution method. Synthesized compounds showed potent inhibitory action against test organisms. Screened compounds 5e-g and 5i-l were associated with considerably higher antibacterial and antifungal activities than commercially used antibiotics.

Full text of DOI:10.1007/s00044-012-0121-z

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1172–1183
DOI 10.1007/s00044-012-0121-z
ORIGINAL RESEARCH
Synthesis of promising antimicrobial agents: a novel series
of N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-
morpholinoacetamides
•
N. C. Desai K. M. Rajpara V. V. Joshi
•
•
•
H. V. Vaghani H. M. Satodiya
Received: 1 February 2012 / Accepted: 22 May 2012 / Published online: 7 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of novel compounds N-(4-(2,6-dichlo-
roquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholinoac-
etamides (5a–l) were synthesized by a series of multistep
reactions. Newly synthesized compounds have been char-
quinolones, tetracyclins, chloramphenicol, and macrolides,
are becoming a major concern (Davies, 1996; Chu et al.,
1996). In particular, the emergences of multiple drug-
resistant Gram-positive and Gram-negative bacteria have
caused life-threatening infectious diseases in many coun-
tries around the world (Grare et al., 2007). Thus, devel-
opment of novel antimicrobial drugs is a crucial need to
combat the multidrug-resistant infections.
1
acterized by IR, H NMR, 13C NMR, and mass spectral
data. Antimicrobial screening of title compounds 5a–l was
examined against Gram-positive bacteria (Staphylococcus
aureus and Streptococcus pyogenes), Gram-negative bac-
teria (Escherichia coli and Pseudomonas aeruginosa), and
three fungi (Candida albicans, Aspergillus niger, and
Aspergillus clavatus) by serial broth dilution method.
Synthesized compounds showed potent inhibitory action
against test organisms. Screened compounds 5e–g and
5i–l were associated with considerably higher antibacterial
and antifungal activities than commercially used antibiotics.
In the contemporary research, quinoline nucleus has
gathered an immense attention among chemists as well as
biologists as it is one of the key building blocks for many
naturally occurring compounds. Among the important
heterocyclic moieties of biological and pharmacological
interest, the quinoline ring is endowed with various activ-
ities, such as antituberculosis (Lilienkampf et al., 2009),
antimalarial (Nasveld and Kitchener, 2005), anti-inflam-
matory (Leatham et al., 1983), anticancer (Denny et al.,
2006), antibiotic (Mahamoud et al., 2006), antihyperten-
sive (Muruganantham et al., 2004), tyrokinase PDGF-RTK
inhibiting agents (Maguire et al., 1994), and anti-HIV
(Ahmed et al., 2010). In spite of its wide range of phar-
macological activities, very few activity studies have been
reported against tuberculosis in comparison with other
classes. Keeping these aspects in mind, we have designed
new series of quinoline derivatives with possibly a new
mode of action. The design concepts are drawn in Fig. 1,
which explains the structural similarity of our new target
compounds with renowned drug chloroquine. Pyrimidine
plays an essential role in several biological processes,
found in nucleoside antibiotics, antibacterials, cardiovas-
cular as well as considerable chemical reactions, and also
occupies a prominent place in the pharmaceutical area
(Zoltewicz and Uray, 1994).
Keywords Quinoline Á Pyrimidine Á Morpholine Á
Vilsmeier–Haack reaction Á Antimicrobial activity Á
MIC
Introduction
Microbial infections are a growing problem in contempo-
rary medicine, yet only a few antimicrobial agents are used
in clinical practice. The increasing incidences of bacterial
resistance to large number of antibacterial agents, such as
glycopeptides, sulfonamides, b-lactams, nitroimidazoles,
N. C. Desai (&) Á K. M. Rajpara Á V. V. Joshi Á
H. V. Vaghani Á H. M. Satodiya
Division of Medicinal Chemistry, Department of Chemistry,
Maharaja Krishnakumarsinhji Bhavnagar University, Mahatma
Gandhi Campus, Bhavnagar 364 002, Gujarat, India
e-mail: dnisheeth@rediffmail.com
Condensed pyrimidine derivatives have been reported as
antimicrobial (Ungureanu et al., 1998), anti-inflammatory
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Med Chem Res (2013) 22:1172–1183
1173
-
O
+
N
H2N
NH2
O
N
HN
O
N
O
N
N
H
N
N
F
Cl
N
O
Linezolid
Chloroquine
Minoxidil
Fig. 1 Commercially available drug candidate containing quinoline, pyrimidine, and morpholine nucleus
(Amr et al., 2007), anti-HIV (Fujiwara et al., 2008), anti-
tubercular (Ballell et al., 2007), antitumor (Wagner et al.,
2008), antineoplastic (Tiwari et al., 2002), antimalarial
(Gorlitzer et al., 1997), diuretic (Ukrainets et al., 2008),
and cardiovascular (Hernandez Prada et al., 2008) agents.
Pyrimidine compounds are also used as hypnotic drugs for
the nervous system (Wang et al., 2004), calcium-sensing
receptor antagonists (Yang et al., 2009), and also for
antagonists of the human A2A adenosine receptor (Gillespie
et al., 2009). Promising diverse pharmacological activities
are shown by various N-functionalized morpholines. They
are reported to exert a number of important physiological
activities, such as antibacterial, antifungal (Govindaraju
et al., 2009), platelet aggregation inhibitors (Ranise et al.,
1991), antiemetic (Hale et al., 2000), and antidepressants
(Avramova et al., 1998). Certain commercially available
drugs containing quinoline, pyrimidine, and morpholine
nucleus are shown in Fig. 1.
typical Vilsmeier–Haack reagent derived from phospho-
rus oxychloride-dimethylformamide (Meth-Cohn, 1993).
Although the reaction proceeded uneventfully, the products
formed were isolated by silica gel column chromatography.
The reaction sequences employed for synthesis of the tar-
get compounds (5a–l) are illustrated in Scheme 1. The key
chalcone intermediates (2a–l) were synthesized through the
Claisen–Schmidt condensation of equimolar amounts of
acetophenone derivatives and chloroquinoline aldehyde (1)
through stirring the reactants in aqueous ethanolic solution
containing 20 % sodium hydroxide at room temperature
for 24 h, in accordance with the method described in the
literature (Elgazwy, 2008). When 3-(2,6-dichloroquinolin-
3-yl)-1-(aryl)prop-2-en-1-ones (2a–l) were refluxed with
guanidine nitrate in the presence of sodium hydrox-
ide, 4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-amines
1
(3a–l) were formed. H NMR spectra of compound (3a)
revealed a singlet characteristic peak for primary amine
protons at d = 5.63 ppm which was confirmed by disap-
pearance of peak when exchanged with D2O. The IR
spectra for (3a) showed specific bands for primary amine
at 3,452 and 3,342 cm-1. The 13C NMR spectrum of
the same compound revealed seventeen unequivalent car-
bons. Pyrimidine carbons displayed characteristic peaks
at d = 103.5 (C-5), 163.1 (C-2), 164.8 (C-6), and 165.2
(C-4) ppm. Moreover, the mass spectrum of (3a) showed a
molecular ion peak at m/z = 366 (M?) corresponding to a
molecular formula C19H12Cl2N4.
It is envisaged that these three active pharmacophores, if
linked together would generate novel molecular templates
which are likely to exhibit interesting biological properties.
The above-cited applications prompted us to synthesize a
series of new compounds reported in this article. Owing to
the importance, and in continuation, of our work on syn-
thesis of biologically active compounds (Desai et al.,
2012a, b, c; Dandia et al., 2004), now we wish to describe
the synthesis of new pyrimidine derivatives from chloro-
quinoline aldehyde (Scheme 1). The compounds were
screened for their in vitro antimicrobial study. Thus, we
have created new avenues to explore the potent heterocy-
clic moieties for the pharmacological activities in medici-
nal chemistry.
Various substituted 2-chloro-N-(4-(2,6-dichloroquino-
lin-3-yl)-6-(aryl)pyrimidin-2-yl)acetamides (4a–l) were
synthesized by electrophilic substitution reaction of chlo-
roacetyl chloride with the corresponding parents 4-(2,6-
dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-amines (3a–l)
in the presence of triethylamine as base and toluene as
solvent. The structures of compounds (4a–l) were deter-
mined by spectral data and elemental analysis, which gave
the molecular formula (see experimental). Condensation
of 2-chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(aryl)pyr-
imidin-2-yl)acetamides (4a–l) with morpholine in the
presence of anhydrous potassium carbonate furnished N-(4-
(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-mor-
pholinoacetamides (5a–l). Structures of the isolated
Results and discussion
Chemistry
The Vilsmeier–Haack reaction on acetanilide provided a
vital and efficient intermediate for the synthesis of sev-
eral newer substituted heterocyclic compounds. The reac-
tion was performed at 100 °C for 15–20 h, using the
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Med Chem Res (2013) 22:1172–1183
Scheme 1 Synthetic route for
synthesis of final compounds
(5a–l). (a) Ethanol, stirring,
24 h.
(b) NH2C(=NH)NH2ÁHNO3,
ethanol, reflux 10 h, NaOH.
(c) ClCOCH2Cl, chloroform,
reflux 12 h, Et3N.
O
N
Cl
Cl
(b)
R
5
2
Cl
4
N
Cl
6
N
R
3
1
(2a-l)
N
NH2
(3a-l)
O
CH3
(d) Morpholine, dry toluene,
reflux 8–10 h, Anhy. K2CO3
Cl
CHO
(a)
+
(c)
N
Cl
R
(1)
N
Cl
N
Cl
R
R
5
5
2
Cl
Cl
4
3
6
4
3
6
N
1
1
(d)
N
2
N
N
HN
N
O
HN
O
Cl
(4a-l)
O
(5a-l)
R= Different substituents
products (5a–l) were confirmed on the basis of their ele-
mental analysis and spectral data.
observed that compounds 5e (2-Cl), 5f (4-Cl), 5g (2-F), 5i
(4-F), 5j (2-NO2), 5k (3-NO2), and 5l (3-NO2) were the
most active compounds. On the basis of antibacterial
screening results, it was observed that compounds 5e (2-Cl)
and 5g (2-F) possessed very good activities against E. coli.
Replacement of hydrogen in 5a by 4-F and 2-NO2 groups
gave corresponding compounds 5i and 5j which possessed
excellent activities against E. coli. Compounds 5g (2-F) and
5j (2-NO2) possessed very good activities against P. aeru-
ginosa. It was observed that if 5a was replaced with chlorine
atom at fourth position of phenyl ring, the activity was
enhanced and excellent activity against P. aeruginosa was
displayed. Compound 5l (4-NO2) possessed very good
activity against S. aureus. It was our observation that on
replacement of hydrogen by 2-F and 4-NO2 groups in
compound 5a, the activity was enhanced and excellent
activity against S. aureus was shown. Compound 5f (4-Cl)
displayed very good activity against S. pyogenes. When we
replaced hydrogen in 5a by 2-NO2 group, the activity
was enhanced and it possessed excellent activity against
S. pyogenes. Antifungal activity showed that compounds
5g (2-F) and 5l (4-NO2) possessed very good activities
against C. albicans. When we replaced hydrogen by 4-Cl
and 2-NO2 in 5a, the activity was enhanced and it possessed
excellent activity against C. albicans. Compound 5k
(3-NO2) showed very good activity against A. niger. When
we replaced hydrogen of 5a by 2-F and 2-NO2 substituents,
the activity was enhanced, and it showed excellent activity
against A. niger. Compounds 5g (2-F) and 5j (2-NO2)
IR spectrum of compound (5a) revealed absorption bands
at 3314, 3237, and 1686 cm-1 which were characteristic to
secondary amine and carbonyl groups. Absorption bands at
2962, 2920, and 2850 cm-1 were due to stretching vibration
1
corresponding to methylene group. Its H NMR spectrum
revealed two triplet signals at d = 2.63 and 3.45 ppm with
coupling constants of nearly 4.5 and 4.8 Hz assignable to
N(CH2)2 and O(CH2)2 of morpholine ring, respectively.
Protons of methylene group displayed a singlet at
d = 3.93 ppm. Proton of secondary amine in amide linkage
showed a singlet at d = 10.24 ppm. Aromatic protons
showed a multiplet centered on d = 7.36–8.49 ppm. The
13C NMR spectrum of compound (5a) revealed 21
unequivalent carbons. The carbonyl carbon was displayed at
d = 173.1 ppm. Other important signals were displayed at
d = 45.4 and 67.4 ppm for N(CH2)2 and O(CH2)2, respec-
tively, while methylene carbon appeared downfield at d =
63.5 ppm. Moreover, the mass spectrum of (5a) showed a
molecular ion peak at m/z = 493 (M?) corresponding to a
molecular formula C25H21Cl2N5O2.
Antimicrobial screening
Compounds 5a–l were evaluated against Gram-positive,
Gram-negative bacteria, and fungi strains. The individual
minimum inhibitory concentrations (MIC, lg/mL) obtained
for compounds 5a–l are presented in Table 1. It was
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Med Chem Res (2013) 22:1172–1183
possessed very good activity against A. clavatus. When we
replaced hydrogen by 2-Cl, 4-F, and 4-NO2 substituents in
5a, the activity was enhanced, and it possessed excellent
activity against A. clavatus. Owing to the presence of methyl,
methoxy, and hydroxyl groups, the enhanced activities were
observed in the title compounds. The minimum inhibitory
concentration (MIC) values were determined by comparison
with ampicillin and griseofulvin as reference drugs.
diluted to obtain 200, 125, 100, 62.5, 50, 25, and 12.5 lg/mL
concentrations for secondary screening to test in a second set
of dilution against all microorganisms. Inoculum size for test
strain was adjusted to 108 CFU/mL (Colony Forming Unit
per milliliter) by comparing the turbidity (turbidimetric
method). Mueller–Hinton Broth was used as a nutrient
medium to grow and dilute the compound suspension for test
bacteria. 2 % DMSO was used as a diluent/vehicle to obtain
the desired concentration of synthesized compounds and
standard drugs to test upon standard microbial strains. Syn-
thesized compounds were diluted to 1,000 lg/mL concen-
tration, as a stock solution. The control tube containing no
antibiotic was immediately subcultured [before inoculation]
by spreading a loopful evenly over a quarter of plate of
medium suitable for the growth of test organisms. The tubes
were then incubated at 37 °C for 24 h for bacteria. 10 lg/mL
suspensions were further inoculated on an appropriate media
and growth was noted after 24 and 48 h. The highest dilution
(lowest concentration) preventing appearance of turbidity
was considered as minimum inhibitory concentration (MIC,
lg/mL), i.e., the amount of growth from the control tube
before incubation (which represents the original inoculum)
was compared. A set of tubes containing only seeded broth
and solvent controls were maintained under identical con-
ditions so as to make sure that the solvent had no influence on
strain growth. The result of this was greatly affected by the
size of inoculum. The test mixture should contain 108 CFU/
mL organisms. The standard drug used in the present study
was ‘‘ampicillin’’ for evaluating antibacterial activity which
showed 100, 100, 250, and 100 lg/mL MIC against E. coli,
P. aeruginosa, S. aureus, and S. pyogenes, respectively.
Structure–activity relationship study
Structure–activity relationship study of the substitution
pattern of the aryl ring at sixth position in pyrimidine ring
toward antimicrobial activity has shown the electron
withdrawing and releasing groups responsible for variation
in activity. The electronic nature of the substituent groups
led to a significant variation in antimicrobial activity.
Compound 5j showed maximum antibacterial activity
(MIC 12.5 lg/mL) and 5i showed excellent activity (MIC
25 lg/mL) against E. coli, while compound 5f showed
maximum antibacterial activity (MIC 25 lg/mL) against
P. aeruginosa. Compounds 5g and 5k showed maximum
antibacterial activity (MIC 50 lg/mL) against S. aureus,
while compound 5j showed maximum antibacterial activity
(MIC 12.5 lg/mL) against S. pyogenes. Compounds bear-
ing electron releasing groups possessed stronger antibac-
terial activities than electron withdrawing compounds.
Compounds 5f and 5j showed maximum antifungal activity
(MIC 100 lg/mL) against C. albicans, while compounds
5g and 5j showed maximum antifungal activity (MIC
25 lg/mL) against A. niger. Compound 5i displayed
maximum activity (MIC 12.5 lg/mL) against A. clavatus.
Antifungal assay
Biological screening
The same compounds (5a–l) were tested for antifungal
activity as primary screening in six sets against C. albicans,
A. niger, and A. clavatus at various concentrations of 1000,
500, and 250 lg/mL. The compounds found to be active in
primary screening were similarly diluted to obtain 200,
125, 100, 62.5, 50, 25, and 12.5 lg/mL concentrations for
secondary screening to test in a second set of dilution
against all microorganisms. Griseofulvin was used as a
standard drug for antifungal activity, which showed 500,
100, and 100 lg/mL MIC against C. albicans, A. niger, and
A. clavatus, respectively. For fungal growth, in the present
protocol, we have used Sabourauds dextrose broth at 22 °C
in an aerobic condition for 72 h.
Antibacterial assay
The newly synthesized compounds (5a–l) were screened for
their antibacterial activities against Gram-positive bacteria
[S. aureus (MTCC-96), S. pyogenes (MTCC-442)] and
Gram-negative bacteria [E. coli (MTCC-443), P. aeruginosa
(MTCC-1688)]. All MTCC cultures were collected from the
Institute of Microbial Technology, Chandigarh, India. The
activity of compounds was determined as per the National
Committee for Clinical Laboratory Standards (NCCLS)
protocol using Mueller–Hinton Broth (Becton–Dickinson,
USA) (Al-Bayati and Al-Mola, 2008; Finegold and Garrod,
1995). Compounds were screened for their antibacterial
activities as primary screening in six sets against E. coli,
S. aureus, P. aeruginosa, and S. pyogenes at different con-
centrations of 1000, 500, and 250 lg/mL. The compounds
found to be active in primary screening were similarly
Statistical analysis
Standard deviation value was expressed in terms of SD.
On the basis of calculated value by one-way ANOVA
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1177
method followed by independent two-sample t-test, it has
been observed that differences below 0.001 level were
considered as statistically significant.
crude product was dried and crystallized from ethanol
(95 %).
Physical constants and characterization of synthesized
compounds (3a–l)
Conclusion
4-(2,6-Dichloroquinolin-3-yl)-6-phenylpyrimidin-2-amine
(3a) Light brown crystal, yield: 71 %; m.p.: 189–191 °C;
IR (KBr) mmax/cm-1: 3452, 3342 (NH2), 3071 (C–H, aro-
The present research article is an example of successful
synthesis and antimicrobial studies of a new series of
quinoline derivatives carrying biologically active entities
viz., pyrimidine and morpholine. Their screening results
revealed that all the compounds showed moderate to very
good activities against pathogenic strains. On the basis of
structure–biological activity relationship, it can be con-
cluded that a combination of hetero-aryl group on quino-
line core showed an increased antimicrobial activity and
hence, they are ideally suited for further modifications to
obtain more efficacious antimicrobial agents.
1
matic), 1571 (C=N), 1513 (C=C), 727 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 5.63 (s, 2H, NH2, D2O
exch.), 6.59 (s, 1H, pyrimidine-H), 7.37–8.57 (m, 9H, Ar–
H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 103.5 (C-5),
126.8–143.5 (C-arom), 152.3 (C–Cl, quinoline), 163.1 (C-
2), 164.8 (C-6), 165.2 (C-4); LCMS (m/z): 366 (M?); Anal.
Calcd. For C19H12Cl2N4: C-62.14, H-3.29, N-15.26;
Found: C-62.20, H-3.33, N-15.22 %.
2-(2-Amino-6-(2,6-dichloroquinolin-3-yl)pyrimidin-4-yl)
phenol (3b) Light yellow crystal, yield: 74 %; m.p.:
201–203 °C; IR (KBr) mmax/cm-1: 3415 (OH), 3451, 3365
(NH2), 3064 (C–H, aromatic), 1578 (C=N), 1510 (C=C),
730 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 5.64
(s, 2H, NH2, D2O exch.), 6.63 (s, 1H, pyrimidine-H),
6.93–8.53 (m, 8H, Ar–H), 9.12 (s, 1H, OH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 103.8 (C-5),
121.5–143.8 (C-arom), 152.7 (C–Cl, quinoline), 156.2 (C–
OH), 163.4 (C-2), 164.6 (C-6), 165.2 (C-4); LCMS (m/z):
382 (M?); Anal. Calcd. For C19H12Cl2N4O: C-59.55,
H-3.16, N-14.62; Found: C-59.60, H-3.23, N-14.70 %.
Materials and methods
General
All reactions except those in aqueous media were carried
out by standard techniques with the exclusion of moisture.
Melting points were determined on an electrothermal
melting point apparatus and are reported uncorrected. TLC
on silica gel plates (Merck, 60, F254) was used for purity
checking and reaction monitoring. Column chromatogra-
phy on silica gel (Merck, 70–230 and 230–400 mesh
ASTH for flash chromatography) was applied when nec-
essary to isolate and purify the reaction products. Ele-
mental analysis (% C, H, and N) was carried out using a
Perkin-Elmer 2400 CHN analyzer. IR spectra of all com-
pounds have been recorded on a Perkin-Elmer FT-IR
spectrophotometer in KBr. 1H NMR spectra were recorded
on Varian Gemini 300 MHz and 13C NMR spectra on
Varian Mercury-400 100 MHz in DMSO-d6 as a solvent
and tetramethylsilane (TMS) as an internal standard. Mass
spectra were recorded on a Shimadzu LCMS 2010 spec-
trometer. Anhydrous reactions were carried out in oven-
dried glassware in nitrogen atmosphere.
4-(2-Amino-6-(2,6-dichloroquinolin-3-yl)pyrimidin-4-yl)
phenol (3c) Light orange crystal, yield: 75 %; m.p.:
163–165 °C; IR (KBr) mmax/cm-1:3417 (OH), 3443, 3358
(NH2), 3079 (C–H, aromatic), 1571 (C=N), 1513 (C=C),
724 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 5.62
(s, 2H, NH2, D2O exch.), 6.62 (s, 1H, pyrimidine-H),
6.86–8.48 (m, 8H, Ar–H), 9.09 (s, 1H, OH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 104.1 (C-5),
116.7–143.5 (C-arom), 152.4 (C–Cl, quinoline), 158.2 (C–
OH), 163.1 (C-2), 164.5 (C-6), 165.7 (C-4); LCMS (m/z):
382 (M?); Anal. Calcd. For C19H12Cl2N4O: C-59.55,
H-3.16, N-14.62; Found: C-59.50, H-3.10, N-14.68 %.
General procedure for the preparation of 4-(2,6-
dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-amines (3a–l)
4-(2,6-Dichloroquinolin-3-yl)-6-(4-methoxyphenyl)pyrimi-
din-2-amine (3d) Light reddish brown crystal, yield:
75 %; m.p.: 190–192 °C; IR (KBr) mmax/cm-1: 3433, 3365
(NH2), 3069 (C–H, aromatic), 2923 (C–H, OCH3), 1573
(C=N), 1513 (C=C), 740 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 3.68 (s, 3H, OCH3), 5.65 (s, 2H, NH2,
D2O exch.), 6.71 (s, 1H, pyrimidine-H), 7.04–8.45 (m, 8H,
Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 56.4
(–OCH3), 104.1 (C-5), 114.5–143.7 (C-arom), 152.5
A mixture of compounds (2a–l) (0.01 mol) and guanidine
nitrate (0.01 mol) in ethanol (99.9 %) was refluxed, while a
solution of sodium hydroxide (0.05 mol) in water was
added dropwise for 2 h. Refluxing was continued for fur-
ther 10 h and the mixture was poured into ice-cold water.
The solid product formed was separated by filtration. The
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Med Chem Res (2013) 22:1172–1183
(C–Cl, quinoline), 160.4 (C–OCH3), 163.7 (C-2), 164.3
(C-6), 165.8 (C-4); LCMS (m/z): 396 (M?); Anal. Calcd.
For C20H14Cl2N4O: C-60.47, H-3.55, N-14.10; Found:
C-60.55, H-3.60, N-14.17 %.
C-59.24, H-2.88, N-14.54; Found: C-59.20, H-2.94,
N-14.48 %.
4-(2,6-Dichloroquinolin-3-yl)-6-(4-fluorophenyl)pyrimi-
din-2-amine (3i) Light reddish crystal, yield: 78 %; m.p.:
194–196 °C; IR (KBr) mmax/cm-1: 3450, 3340 (NH2), 3071
(C–H, aromatic), 1552 (C=N), 1516 (C=C), 1149 (C–F),
743 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 5.72
(s, 2H, NH2, D2O exch.), 6.69 (s, 1H, pyrimidine-H),
7.38–8.55 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 104.4 (C-5), 116.0–144.5 (C-arom), 152.8 (C–Cl,
quinoline), 162.8 (C–F), 163.2 (C-2), 164.8 (C-6), 165.4
(C-4); LCMS (m/z): 384 (M?); Anal. Calcd. For
C19H11Cl2FN4: C-59.24, H-2.88, N-14.54; Found: C-59.17,
H-2.82, N-14.43 %.
4-(2-Chlorophenyl)-6-(2,6-dichloroquinolin-3-yl)pyrimi-
din-2-amine (3e) Light yellow crystal, yield: 71 %; m.p.:
184–186 °C; IR (KBr) mmax/cm-1: 3442, 3351 (NH2), 3067
(C–H, aromatic), 1563 (C=N), 1518 (C=C), 748 (C–Cl); 1H
NMR (300 MHz, DMSO-d6, d, ppm): 5.72 (s, 2H, NH2,
D2O exch.), 6.69 (s, 1H, pyrimidine-H), 7.31–8.52 (m, 8H,
Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 103.6
(C-5), 124.3–144.3 (C-arom), 152.7 (C–Cl, quinoline),
163.3 (C-2), 164.7 (C-6), 165.2 (C-4); LCMS (m/z): 400
(M?); Anal. Calcd. For C19H11Cl3N4: C-56.81, H-2.76,
N-13.95; Found: C-56.86, H-2.82, N-13.90 %.
4-(2,6-Dichloroquinolin-3-yl)-6-(2-nitrophenyl)pyrimidin-
2-amine (3j) Dark yellow crystal, yield: 72 %; m.p.:
182–184 °C; IR (KBr) mmax/cm-1: 3455, 3337 (NH2), 3058
(C–H, aromatic), 1573 (C=N), 1510 (C=C), 1458, 1353
(NO2), 751 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 5.72 (s, 2H, NH2, D2O exch.), 6.69 (s, 1H, pyrimi-
dine-H), 7.58-8.57 (m, 8H, Ar–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 104.4 (C-5), 124.2–149.4 (C-arom),
148.8 (C-NO2), 153.1 (C–Cl, quinoline), 163.6 (C-2), 164.4
(C-6), 165.9 (C-4); LCMS (m/z): 411 (M?); Anal. Calcd.
For C19H11Cl2N5O2: C-55.36, H-2.69, N-16.99; Found:
C-55.30, H-2.64, N-16.93 %.
4-(4-Chlorophenyl)-6-(2,6-dichloroquinolin-3-yl)pyrimi-
din-2-amine (3f) Yellow crystal, yield: 73 %; m.p.:
201–203 °C; IR (KBr) mmax/cm-1: 3455, 3329 (NH2), 3078
(C–H, aromatic), 1560 (C=N), 1512 (C=C), 751 (C–Cl); 1H
NMR (300 MHz, DMSO-d6, d, ppm): 5.70 (s, 2H, NH2,
D2O exch.), 6.66 (s, 1H, pyrimidine-H), 7.52–8.49 (m, 8H,
Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 103.6
(C-5), 124.7–144.6 (C-arom), 152.5 (C–Cl, quinoline),
163.4 (C-2), 164.1 (C-6), 165.7 (C-4); LCMS (m/z): 400
(M?); Anal. Calcd. For C19H11Cl3N4: C-56.81, H-2.76,
N-13.95; Found: C-56.72, H-2.70, N-13.87 %.
4-(2,6-Dichloroquinolin-3-yl)-6-(2-fluorophenyl)pyrimi-
din-2-amine (3g) Light gray crystal, yield: 77 %; m.p.:
182–184 °C; IR (KBr) mmax/cm-1: 3436, 3326 (NH2), 3060
(C–H, aromatic), 1563 (C=N), 1521 (C=C), 1146 (C–F),
743 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 5.77
(s, 2H, NH2, D2O exch.), 6.75 (s, 1H, pyrimidine-H),
7.25–8.50 (m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 104.2 (C-5), 114.7–144.2 (C-arom), 153.1 (C–Cl,
quinoline), 158.1 (C–F), 163.8 (C-2), 164.4 (C-6), 165.2
(C-4); LCMS (m/z): 384 (M?); Anal. Calcd. For
C19H11Cl2FN4: C-59.24, H-2.88, N-14.54; Found: C-59.32,
H-2.83, N-14.59 %.
4-(2,6-Dichloroquinolin-3-yl)-6-(3-nitrophenyl)pyrimidin-
2-amine (3k) Orange yellow crystal, yield: 75 %; m.p.:
213–215 °C; IR (KBr) mmax/cm-1: 3456, 3321 (NH2), 3067
(C–H, aromatic), 1574 (C=N), 1518 (C=C), 1452, 1360
(NO2), 743 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 5.77 (s, 2H, NH2, D2O exch.), 6.63 (s, 1H, pyrimi-
dine-H), 7.61–8.67 (m, 8H, Ar–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 103.8 (C-5), 104.2–144.8 (C-arom),
148.4 (C-NO2), 152.6 (C–Cl, quinoline), 163.4 (C-2), 164.7
(C-6), 165.6 (C-4); LCMS (m/z): 411 (M?); Anal. Calcd.
For C19H11Cl2N5O2: C-55.36, H-2.69, N-16.99; Found:
C-55.42, H-2.74, N-17.07 %.
4-(2,6-Dichloroquinolin-3-yl)-6-(3-fluorophenyl)pyrimi-
din-2-amine (3h) Light brown crystal, yield: 73 %; m.p.:
179–181 °C; IR (KBr) mmax/cm-1: 3446, 3360 (NH2), 3077
(C–H, aromatic), 1578 (C=N), 1526 (C=C), 1140 (C–F), 739
4-(2,6-Dichloroquinolin-3-yl)-6-(4-nitrophenyl)pyrimidin-
2-amine (3l) Yellow crystal, yield: 82 %; m.p.: 184–
186 °C; IR (KBr) mmax/cm-1: 3446, 3337 (NH2), 3067
(C–H, aromatic), 1562 (C=N), 1514 (C=C), 1459, 1348
(NO2), 740 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 5.74 (s, 2H, NH2, D2O exch.), 6.67 (s, 1H,
pyrimidine-H), 7.60–8.54 (m, 8H, Ar–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 104.4 (C-5), 124.2–144.8
(C-arom), 147.9 (C-NO2), 153.4 (C–Cl, quinoline), 163.6
(C-2), 164.3 (C-6), 165.7 (C-4); LCMS (m/z): 411 (M?);
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 5.68 (s,
2H, NH2, D2O exch.), 6.79 (s, 1H, pyrimidine-H), 7.15–8.53
(m, 8H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm):
103.9 (C-5), 115.3–144.8 (C-arom), 152.8 (C–Cl, quino-
line), 162 (C–F), 163.6 (C-2), 164.8 (C-6), 165.2 (C-4);
LCMS (m/z): 384 (M?); Anal. Calcd. For C19H11Cl2FN4:
123

Med Chem Res (2013) 22:1172–1183
1179
Anal. Calcd. For C19H11Cl2N5O2: C-55.36, H-2.69,
N-16.99; Found: C-55.31, H-2.74, N-16.94 %.
2H, CH2), 6.93 (s, 1H, pyrimidine-H), 6.78–8.50 (m, 8H,
Ar–H), 9.11 (s, 1H, OH, D2O exch.), 9.73 (s, 1H, NH, D2O
exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 60.6
(CH2), 101.1 (C-5), 116.4–145.3 (C-arom), 153.2 (C–Cl,
quinoline), 158.4 (C–OH), 162.4 (C-2), 164.1 (C-6), 165.6
(C-4), 171.7 (C=O); LCMS (m/z): 458 (M?); Anal. Calcd.
For C21H13Cl3N4O2: C-54.87, H-2.85, N-12.19; Found:
C-54.93, H-2.92, N-12.14 %.
General procedure for the preparation of 2-chloro-N-(4-
(2,6-dichloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)aceta-
mides (4a–l) An equimolar amount of compounds (3a–l)
(0.01 mol) and chloroacetyl chloride (0.01 mol) in chlo-
roform was refluxed in the presence of catalytic amount of
triethylamine for about 12 h. Excess of solvent was
removed under reduced pressure and the residue was stirred
with water. The crude product was dried and crystallized
from ethanol (95 %).
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-methoxy-
phenyl)pyrimidin-2-yl)acetamide (4d) Light brown crys-
tal, yield: 68 %; m.p.: 174–176 °C; IR (KBr) mmax/cm-1
:
3357, 3225 (NH), 3054 (C–H, aromatic), 2879, 2921 (C–H,
CH2, CH3), 1687 (C=O), 1618 (C=N), 1519 (C=C), 775
Physical constants and characterization of synthesized
compounds (4a–l)
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 3.56 (s,
3H, OCH3), 4.13 (s, 2H, CH2), 6.84 (s, 1H, pyrimidine-H),
7.09–8.50 (m, 8H, Ar–H), 9.69 (s, 1H, NH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 55.3 (OCH3),
60.1 (CH2), 101.3 (C-5), 114.7–145.1 (C-arom), 154.1 (C–
Cl, quinoline), 160.4 (C–OCH3), 162.5 (C-2), 164.0 (C-6),
165.1 (C-4), 171.4 (C=O); LCMS (m/z): 473 (M?); Anal.
Calcd. For C22H15Cl3N4O2: C-55.78, H-3.19, N-11.83;
Found: C-55.83, H-3.25, N-11.89 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-phenylpyrimi-
din-2-yl)acetamide (4a) Light yellow crystal, yield: 72 %;
m.p.: 194–196 °C; IR (KBr) mmax/cm-1: 3353, 3217 (NH),
3054 (C–H, aromatic), 2858 (C–H, CH2), 1681 (C=O), 1617
(C=N), 1578 (C=C), 767 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 4.10 (s, 2H, CH2), 6.94 (s, 1H, pyrimi-
dine-H), 7.42–8.53 (m, 9H, Ar–H), 9.78 (s, 1H, NH, D2O
exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 60.4
(CH2), 101.2 (C-5), 124.1–145.6 (C-arom), 153.6 (C–Cl,
quinoline), 162.3 (C-2), 164.1 (C-6), 165.4 (C-4), 171.2
(C=O); LCMS (m/z): 442 (M?); Anal. Calcd. For
C21H13Cl3N4O: C-56.84, H-2.95, N-12.63; Found: C-56.79,
H-2.89, N-12.69 %.
2-Chloro-N-(4-(2-chlorophenyl)-6-(2,6-dichloroquinolin-
3-yl)pyrimidin-2-yl)acetamide (4e) Light yellow crystal,
yield: 74 %; m.p.: 195–197 °C; IR (KBr) mmax/cm-1: 3363,
3236 (NH), 3076 (C–H, aromatic), 2865 (C–H, CH2), 1689
1
(C=O), 1610 (C=N), 1534 (C=C), 756 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 4.22 (s, 2H, CH2), 6.88 (s,
1H, pyrimidine-H), 7.30-8.55 (m, 8H, Ar–H), 9.74 (s, 1H,
NH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
60.6 (CH2), 101.1 (C-5), 127.3–146.1 (C-arom), 153.6 (C–
Cl, quinoline), 162.2 (C-2), 164.5 (C-6), 165.7 (C-4), 171.4
(C=O); LCMS (m/z): 475 (M?); Anal. Calcd. For
C21H12Cl4N4O: C-52.75, H-2.53, N-11.72; Found:
C-52.81, H-2.60, N-11.78 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(2-hydroxy-
phenyl)pyrimidin-2-yl)acetamide (4b) Light brown crys-
tal, yield: 70 %; m.p.: 218–220 °C; IR (KBr) mmax/cm-1
3415 (OH), 3343, 3228 (NH), 3072 (C–H, aromatic), 2867
:
(C–H, CH2), 1686 (C=O), 1613 (C=N), 1569 (C=C), 773
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.15 (s,
2H, CH2), 6.89 (s, 1H, pyrimidine-H), 7.00–8.46 (m, 8H,
Ar–H), 9.14 (s, 1H, OH, D2O exch.), 9.76 (s, 1H, NH, D2O
exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm): 60.3
(CH2), 101.2 (C-5), 117.6–145.2 (C-arom), 153.4 (C–Cl,
quinoline), 155.2 (C–OH), 162.0 (C-2), 164.4 (C-6), 165.1
(C-4), 171.5 (C=O); LCMS (m/z): 458 (M?); Anal. Calcd.
For C21H13Cl3N4O2: C-54.87, H-2.85, N-12.19; Found:
C-54.92, H-2.79, N-12.14 %.
2-Chloro-N-(4-(4-chlorophenyl)-6-(2,6-dichloroquinolin-
3-yl)pyrimidin-2-yl)acetamide (4f) Light yellow crystal,
yield: 67 %; m.p.: 164–166 °C; IR (KBr) mmax/cm-1: 3372,
3233 (NH), 3070 (C–H, aromatic), 2871 (C–H, CH2), 1686
1
(C=O), 1600 (C=N), 1519 (C=C), 762 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 4.27 (s, 2H, CH2), 6.92 (s,
1H, pyrimidine-H), 7.45-8.53 (m, 8H, Ar–H), 9.64 (s, 1H,
NH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
60.7 (CH2), 101.5 (C-5), 127.7–145.7 (C-arom), 153.0 (C–
Cl, quinoline), 162.7 (C-2), 164.3 (C-6), 165.5 (C-4), 171.9
(C=O); LCMS (m/z): 475 (M?); Anal. Calcd. For
C21H12Cl4N4O: C-52.75, H-2.53, N-11.72; Found: C-52.69,
H-2.48, N-11.67 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-hydroxy-
phenyl)pyrimidin-2-yl)acetamide (4c) Light brown crys-
tal, yield: 71 %; m.p.: 168–170 °C; IR (KBr) mmax/cm-1
3424 (OH), 3347, 3219 (NH), 3070 (C–H, aromatic), 2874
:
(C–H, CH2), 1680 (C=O), 1610 (C=N), 1514 (C=C), 768
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.17 (s,
123

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Med Chem Res (2013) 22:1172–1183
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(2-fluoro-
phenyl)pyrimidin-2-yl)acetamide (4g) Light brown crys-
(C-2), 164.2 (C-6), 165.8 (C-4), 171.6 (C=O); LCMS (m/z):
487 (M?); Anal. Calcd. For C21H12Cl3N5O3: C-51.61,
H-2.47, N-14.33; Found: C-51.65, H-2.53, N-14.40 %.
tal, yield: 71 %; m.p.: 182–184 °C; IR (KBr) mmax/cm-1
:
3351, 3242 (NH), 3065 (C–H, aromatic), 2865 (C–H, CH2),
1690 (C=O), 1589 (C=N), 1523 (C=C), 1150 (C–F), 771
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(3-nitrophenyl)
pyrimidin-2-yl)acetamide (4k) Yellow crystal, yield:
69 %; m.p.: 180–182 °C; IR (KBr) mmax/cm-1: 3354, 3267
(NH), 3075 (C–H, aromatic), 2867 (C–H, CH2), 1694
(C=O), 1578 (C=N), 1512 (C=C), 1482, 1354 (NO2), 785
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.29 (s,
2H, CH2), 6.95 (s, 1H, pyrimidine-H), 7.25–8.58 (m, 8H,
Ar–H), 9.67 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 60.2 (CH2), 101.4 (C-5), 114.7–146.4
(C-arom), 152.6 (C–Cl, quinoline), 158.3 (C–F), 162.2 (C-
2), 164.5 (C-6), 165.2 (C-4), 171.4 (C=O); LCMS (m/z):
460 (M?); Anal. Calcd. For C21H12Cl3FN4O: C-54.63,
H-2.62, N-12.13; Found: C-54.70, H-2.67, N-12.21 %.
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.23 (s,
2H, CH2), 6.95 (s, 1H, pyrimidine-H), 7.53–8.56 (m, 9H,
Ar–H), 9.68 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 60.7 (CH2), 101.5 (C-5), 103.2–146.3
(C-arom), 148.4 (C–NO2), 152.8 (C–Cl, quinoline), 162.0
(C-2), 164.4 (C-6), 165.9 (C-4), 171.7 (C=O); LCMS (m/z):
487 (M?); Anal. Calcd. For C21H12Cl3N5O3: C-51.61,
H-2.47, N-14.33; Found: C-51.54, H-2.42, N-14.42 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(3-fluoro-
phenyl)pyrimidin-2-yl)acetamide (4h) Light reddish
brown crystal, yield: 66 %; m.p.: 156–157 °C; IR (KBr)
m
max/cm-1: 3356, 3256 (NH), 3069 (C–H, aromatic), 2864
(C–H, CH2), 1688 (C=O), 1578 (C=N), 1519 (C=C), 1148
(C–F), 765 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d,
ppm): 4.26 (s, 2H, CH2), 6.91 (s, 1H, pyrimidine-H),
7.17–8.52 (m, 8H, Ar–H), 9.73 (s, 1H, NH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 60.7 (CH2),
101.5 (C-5), 115.5–146.3 (C-arom), 153.4 (C–Cl, quino-
line), 162.0 (C–F), 162.3 (C-2), 164.1 (C-6), 165.4 (C-4),
171.5 (C=O); LCMS (m/z): 460 (M?); Anal. Calcd. For
C21H12Cl3FN4O: C-54.63, H-2.62, N-12.13; Found:
C-54.58, H-2.55, N-12.08 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-nitrophenyl)
pyrimidin-2-yl)acetamide (4l) Dark yellow crystal, yield:
73 %; m.p.: 224–226 °C; IR (KBr) mmax/cm-1: 3369, 3289
(NH), 3088 (C–H, aromatic), 2859 (C–H, CH2), 1687
(C=O), 1585 (C=N), 1522 (C=C), 1478, 1350 (NO2), 790
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.29 (s,
2H, CH2), 6.98 (s, 1H, pyrimidine-H), 7.56–8.59 (m, 8H,
Ar–H), 9.77 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 60.5 (CH2), 101.3 (C-5), 124.1–146.3
(C-arom), 147.8 (C–NO2), 152.4 (C–Cl, quinoline), 162.2
(C-2), 164.5 (C-6), 165.8 (C-4), 171.4 (C=O); LCMS (m/z):
487 (M?); Anal. Calcd. For C21H12Cl3N5O3: C-51.61,
H-2.47, N-14.33; Found: C-51.67, H-2.52, N-14.40 %.
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-fluoro-
phenyl)pyrimidin-2-yl)acetamide (4i) Light brown crys-
tal, yield: 69 %; m.p.: 188–190 °C; IR (KBr) mmax/cm-1
:
3347, 3255 (NH), 3074 (C–H, aromatic), 2870 (C–H, CH2),
1692 (C=O), 1570 (C=N), 1512 (C=C), 1156 (C–F), 776
General procedure for the preparation of N-(4-(2,6-di-
chloroquinolin-3-yl)-6-(aryl)pyrimidin-2-yl)-2-morphol-
inoacetamides (5a–l) A mixture of compounds (4a–l)
(0.01 mol), anhydrous potassium carbonate (0.02 mol),
and morpholine (0.01 mol) in dry toluene was refluxed for
about 8–10 h. After completion of the reaction, potassium
carbonate was removed by filtration and excess of solvent
was removed under reduced pressure. The obtained resi-
dues were filtered, dried, and crystallized from DMF.
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.29 (s,
2H, CH2), 6.94 (s, 1H, pyrimidine-H), 7.34–8.51 (m, 8H,
Ar–H), 9.77 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 60.4 (CH2), 101.5 (C-5), 116.0–162.7
(C-arom), 152.7 (C–Cl, quinoline), 162.1 (C-2), 162.8
(C–F), 164.5 (C-6), 165.7 (C-4), 171.4 (C=O); LCMS (m/z):
460 (M?); Anal. Calcd. For C21H12Cl3FN4O: C-54.63,
H-2.62, N-12.13; Found: C-54.55, H-2.68, N-12.18 %.
Physical constants and characterization of synthesized
compounds (5a–l)
2-Chloro-N-(4-(2,6-dichloroquinolin-3-yl)-6-(2-nitrophenyl)
pyrimidin-2-yl)acetamide (4j) Orange yellow crystal,
yield: 66 %; m.p.: 167–169 °C; IR (KBr) mmax/cm-1: 3367,
3286 (NH), 3053 (C–H, aromatic), 2853 (C–H, CH2), 1688
(C=O), 1580 (C=N), 1522 (C=C), 1488, 1360 (NO2), 770
N-(4-(2,6-dichloroquinolin-3-yl)-6-phenylpyrimidin-2-yl)-2-
morpholinoacetamide (5a) Light brown crystal, yield:
54 %; m.p.: 204–206 °C; IR (KBr) mmax/cm-1: 3314, 3237
(NH), 3070 (C–H, aromatic), 2962, 2920, 2850 (C–H,
CH2), 1683 (C=O), 1609 (C=N), 1572 (C=C), 1360 (C–N),
1
(C–Cl); H NMR (300 MHz, DMSO-d6, d, ppm): 4.27 (s,
2H, CH2), 6.87 (s, 1H, pyrimidine-H), 7.51–8.58 (m, 8H,
Ar–H), 9.73 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 60.5 (CH2), 101.6 (C-5), 124.2–146.2
(C-arom), 148.8 (C-NO2), 152.2 (C–Cl, quinoline), 162.4
1
1236 (C–O), 720 (C–Cl); H NMR (300 MHz, DMSO-d6,
d, ppm): 2.63 (t, 4H, J = 4.5 Hz, N(CH2)2), 3.45 (t, 4H,
J = 4.8 Hz, O(CH2)2), 3.93 (s, 2H, CH2), 6.76 (s, 1H,
123

Med Chem Res (2013) 22:1172–1183
1181
pyrimidine-H), 7.36–8.49 (m, 9H, Ar–H), 10.24 (s, 1H,
NH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
45.4 (N(CH2)2), 63.5 (CH2), 67.4 (O(CH2)2), 101.3 (C-5),
124.2–145.2 (C-arom), 151.8 (C–Cl, quinoline), 163.4 (C-
2), 164.5 (C-6), 165.3 (C-4), 173.1 (C=O); LCMS (m/z):
493 (M?); Anal. Calcd. For C25H21Cl2N5O2: C-60.74,
H-4.28, N-14.17; Found: C-60.80, H-4.35, N-14.23 %.
(m, 8H, Ar–H), 10.10 (s, 1H, NH, D2O exch.); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 45.5 (N(CH2)2), 55.4
(OCH3), 63.6 (CH2), 67.2 (O(CH2)2), 101.5 (C-5),
113.8–145.7 (C-arom), 152.3 (C–Cl, quinoline), 160.5 (C–
OCH3), 163.7 (C-2), 164.4 (C-6), 165.7 (C-4), 173.4
(C=O); LCMS (m/z): 523 (M?); Anal. Calcd. For
C26H23Cl2N5O3: C-59.55, H-4.42, N-13.36; Found:
C-59.62, H-4.50, N-13.42 %.
N-(4-(2,6-dichloroquinolin-3-yl)-6-(2-hydroxyphenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5b) Light yellow
N-(4-(2-chlorophenyl)-6-(2,6-dichloroquinolin-3-yl)pyrim-
idin-2-yl)-2-morpholinoacetamide (5e) Light yellow
crystal, yield: 53 %; m.p.: 164–166 °C; IR (KBr) mmax
/
cm-1: 3410 (OH), 3315, 3238 (NH), 3065 (C–H, aro-
matic), 2965, 2929, 2854 (C–H, CH2), 1687 (C=O), 1585
(C=N), 1578 (C=C), 1357 (C–N), 1228 (C–O), 726 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.67 (t, 4H,
J = 4.9 Hz, N(CH2)2), 3.47 (t, 4H, J = 4.7 Hz, O(CH2)2),
3.92 (s, 2H, CH2), 6.79 (s, 1H, pyrimidine-H), 7.01–8.43
(m, 8H, Ar–H), 9.23 (s, 1H, OH, D2O exch.), 10.17 (s, 1H,
NH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d, ppm):
45.5 (N(CH2)2), 63.8 (CH2), 67.3 (O(CH2)2), 101.7 (C-5),
117.4–145.5 (C-arom), 151.6 (C–Cl, quinoline), 155.3 (C–
OH), 163.2 (C-2), 164.3 (C-6), 165.5 (C-4), 173.3 (C=O);
LCMS (m/z): 509 (M?); Anal. Calcd. For C25H21Cl2N5O3:
C-58.83, H-4.15, N-13.72; Found: C-58.90, H-4.22,
N-13.80 %.
crystal, yield: 55 %; m.p.: 193–195 °C; IR (KBr) mmax
/
cm-1: 3325, 3238 (NH), 3069 (C–H, aromatic), 2964,
2937, 2854 (C–H, CH2), 1694 (C=O), 1605 (C=N), 1568
1
(C=C), 1357 (C–N), 1234 (C–O), 743 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 2.68 (t, 4H, J = 4.3 Hz,
N(CH2)2), 3.46 (t, 4H, J = 4.9 Hz, O(CH2)2), 3.90 (s, 2H,
CH2), 6.76 (s, 1H, pyrimidine-H), 7.33–8.48 (m, 8H, Ar–
H), 10.29 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 45.1 (N(CH2)2), 63.3 (CH2), 67.7
(O(CH2)2), 101.3 (C-5), 124.3–146.4 (C-arom), 152.5 (C–
Cl, quinoline), 163.4 (C-2), 164.8 (C-6), 165.1 (C-4), 173.5
(C=O); LCMS (m/z): 527 (M?); Anal. Calcd. For
C25H20Cl3N5O2: C-56.78, H-3.81, N-13.24; Found:
C-56.84, H-3.75, N-13.30 %.
N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-hydroxyphenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5c) Light reddish
brown crystal, yield: 51 %; m.p.: 205–206 °C; IR (KBr)
N-(4-(4-chlorophenyl)-6-(2,6-dichloroquinolin-3-yl)pyrim-
idin-2-yl)-2-morpholinoacetamide (5f) Light reddish
brown crystal, yield: 50 %; m.p.: 164–166 °C; IR (KBr)
m
max/cm-1: 3418 (OH), 3314, 3225 (NH), 3068 (C–H,
m
max/cm-1: 3337, 3214 (NH), 3074 (C–H, aromatic), 2964,
aromatic), 2964, 2935, 2856 (C–H, CH2), 1684 (C=O),
1583 (C=N), 1576 (C=C), 1358 (C–N), 1223 (C–O), 736
(C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.67
(t, 4H, J = 4.4 Hz, N(CH2)2), 3.44 (t, 4H, J = 4.6 Hz,
O(CH2)2), 3.90 (s, 2H, CH2), 6.71 (s, 1H, pyrimidine-H),
6.88–8.44 (m, 8H, Ar–H), 9.17 (s, 1H, OH, D2O exch.),
10.25 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 45.7 (N(CH2)2), 63.5 (CH2), 67.7
(O(CH2)2), 101.5 (C-5), 115.7–145.6 (C-arom), 151.6
(C–Cl, quinoline), 158.3, (C–OH), 163.2 (C-2), 164.4 (C-
6), 165.3 (C-4), 173.8 (C=O); LCMS (m/z): 509 (M?);
Anal. Calcd. For C25H21Cl2N5O3: C-58.83, H-4.15,
N-13.72; Found: C-58.78, H-4.09, N-13.66 %.
2926, 2852 (C–H, CH2), 1682 (C=O), 1597 (C=N), 1563
1
(C=C), 1361 (C–N), 1235 (C–O), 741 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 2.65 (t, 4H, J = 4.5 Hz,
N(CH2)2), 3.44 (t, 4H, J = 4.3 Hz, O(CH2)2), 3.93 (s, 2H,
CH2), 6.73 (s, 1H, pyrimidine-H), 7.50–8.54 (m, 8H, Ar–
H), 10.25 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 45.3 (N(CH2)2), 63.1 (CH2), 67.5
(O(CH2)2), 101.6 (C-5), 124.5–146.1 (C-arom), 152.2 (C–
Cl, quinoline), 163.1 (C-2), 164.4 (C-6), 165.2 (C-4), 173.4
(C=O); LCMS (m/z): 527 (M?); Anal. Calcd. For
C25H20Cl3N5O2: C-56.78, H-3.81, N-13.24; Found:
C-56.84, H-3.86, N-13.18 %.
N-(4-(2-6-dichloroquinolin-3-yl)-6-(2-fluorophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5g) Light yellow
N-(4-(2,6-dichloroquinolin-3-yl)-6-(4-methoxyphenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5d) Light pink crystal,
yield: 55 %; m.p.: 175–177 °C; IR (KBr) mmax/cm-1: 3325,
3212 (NH), 3078 (C–H, aromatic), 2963, 2935, 2853 (C–H,
CH2), 1683 (C=O), 1592 (C=N), 1575 (C=C), 1357 (C–N),
1233, 1135 (C–O), 730 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.63 (t, 4H, J = 4.7 Hz, N(CH2)2),
3.49 (t, 4H, J = 4.5 Hz, O(CH2)2), 3.64 (s, 3H, OCH3),
3.96 (s, 2H, CH2), 6.82 (s, 1H, pyrimidine-H), 7.09–8.44
crystal, yield: 56 %; m.p.: 188–190 °C; IR (KBr) mmax
/
cm-1: 3326, 3228 (NH), 3071 (C–H, aromatic), 2954,
2923, 2855 (C–H, CH2), 1685 (C=O), 1583 (C=N), 1567
(C=C), 1353 (C–N), 1234 (C–O), 1143 (C–F), 741 (C–Cl);
1H NMR (300 MHz, DMSO-d6, d, ppm): 2.72 (t, 4H,
J = 4.7 Hz, N(CH2)2), 3.53 (t, 4H, J = 4.1 Hz, O(CH2)2),
3.93 (s, 2H, CH2), 6.85 (s, 1H, pyrimidine-H), 7.18–8.59
(m, 8H, Ar–H), 10.27 (s, 1H, NH, D2O exch.); 13C NMR
123

1182
Med Chem Res (2013) 22:1172–1183
(100 MHz, DMSO-d6, d, ppm): 45.5 (N(CH2)2), 63.7
(CH2), 67.2 (O(CH2)2), 101.5 (C-5), 114.3–158.2 (C-
arom), 153.1 (C–Cl, quinoline), 158.2 (C–F), 163.2 (C-2),
164.5 (C-6), 165.6 (C-4), 173.2 (C=O); LCMS (m/z): 511
(M?); Anal. Calcd. For C25H20Cl2FN5O2: C-58.60, H-3.93,
N-13.67; Found: C-58.66, H-3.86, N-13.61 %.
(C-arom), 148.3 (C–NO2), 152.6 (C–Cl, quinoline), 163.7
(C-2), 164.2 (C-6), 165.3 (C-4), 173.7 (C=O); LCMS (m/z):
538 (M?); Anal. Calcd. For C25H20Cl2N6O4: C-55.67,
H-3.74, N-15.58; Found: C-55.73, H-3.80, N-15.64 %.
N-(4-(2-6-dichloroquinolin-3-yl)-6-(3-nitrophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5k) Dark
yellow
N-(4-(2-6-dichloroquinolin-3-yl)-6-(3-fluorophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5h) Light pink crystal,
yield: 53 %; m.p.: 173–175 °C; IR (KBr) mmax/cm-1: 3343,
3247 (NH), 3083 (C–H, aromatic), 2965, 2912, 2846 (C–H,
CH2), 1684 (C=O), 1586 (C=N), 1565 (C=C), 1344 (C–N),
1237 (C–O), 1124 (C–F), 749 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.75 (t, 4H, J = 4.8 Hz, N(CH2)2),
3.58 (t, 4H, J = 4.6 Hz, O(CH2)2), 3.96 (s, 2H, CH2), 6.80
(s, 1H, pyrimidine-H), 7.25–8.55 (m, 8H, Ar–H), 10.32 (s,
1H, NH, D2O exch.); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 45.7 (N(CH2)2), 63.8 (CH2), 67.1 (O(CH2)2), 101.0
(C-5), 115.4–146.2 (C-arom), 153.3 (C–Cl, quinoline),
162.3 (C–F), 163.1 (C-2), 164.4 (C-6), 165.3 (C-4), 173.0
(C=O); LCMS (m/z): 511 (M?); Anal. Calcd. For
C25H20Cl2FN5O2: C-58.60, H-3.93, N-13.67; Found:
C-58.55, H-3.98, N-13.74 %.
crystal, yield: 51 %; m.p.: 154–156 °C; IR (KBr) mmax
/
cm-1: 3363, 3254 (NH), 3065 (C–H, aromatic), 2980,
2947, 2835 (C–H, CH2), 1690 (C=O), 1584 (C=N), 1522
(C=C), 1482, 1348 (NO2 group), 1360 (C–N), 1235 (C–O),
725 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.74
(t, 4H, J = 4.6 Hz, N(CH2)2), 3.56 (t, 4H, J = 4.3 Hz,
O(CH2)2), 3.92 (s, 2H, CH2), 6.80 (s, 1H, pyrimidine-H),
7.70–8.67 (m, 8H, Ar–H), 10.30 (s, 1H, NH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 45.1 (N(CH2)2),
63.4 (CH2), 67.7 (O(CH2)2), 101.5 (C-5), 103.7–145.8 (C-
arom), 148.3 (C–NO2), 152.7 (C–Cl, quinoline), 163.2 (C-
2), 164.6 (C-6), 165.8 (C-4), 173.6 (C=O); LCMS (m/z):
538 (M?); Anal. Calcd. For C25H20Cl2N6O4: C-55.67,
H-3.74, N-15.58; Found: C-55.60, H-3.68, N-15.50 %.
N-(4-(2-6-dichloroquinolin-3-yl)-6-(4-nitrophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5l) Dark orange yel-
N-(4-(2-6-dichloroquinolin-3-yl)-6-(4-fluorophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5i) Light brown crys-
low crystal, yield: 55 %; m.p.: 188–190 °C; IR (KBr) mmax
/
cm-1: 3352, 3248 (NH), 3079 (C–H, aromatic), 2970,
2945, 2823 (C–H, CH2), 1689 (C=O), 1590 (C=N), 1517
(C=C), 1478, 1359 (NO2 group), 1367 (C–N), 1240 (C–O),
737 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.70
(t, 4H, J = 4.5 Hz, N(CH2)2), 3.54 (t, 4H, J = 4.8 Hz,
O(CH2)2), 3.95 (s, 2H, CH2), 6.75 (s, 1H, pyrimidine-H),
7.63–8.58 (m, 8H, Ar–H), 10.36 (s, 1H, NH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 45.5 (N(CH2)2),
63.2 (CH2), 67.5 (O(CH2)2), 101.2 (C-5), 124.1–145.8 (C-
arom), 147.8 (C–NO2), 151.8 (C–Cl, quinoline), 163.8 (C-
2), 164.5 (C-6), 165.2 (C-4), 173.7 (C=O); LCMS (m/z):
538 (M?); Anal. Calcd. For C25H20Cl2N6O4: C-55.67,
H-3.74, N-15.58; Found: C-55.76, H-3.79, N-15.51 %.
tal, yield: 57 %; m.p.: 209–211 °C; IR (KBr) mmax/cm-1
:
3354, 3246 (NH), 3076 (C–H, aromatic), 2971, 2956, 2837
(C–H, CH2), 1687 (C=O), 1579 (C=N), 1537 (C=C), 1356
1
(C–N), 1235 (C–O), 1143 (C–F), 737 (C–Cl); H NMR
(300 MHz, DMSO-d6, d, ppm): 2.73 (t, 4H, J = 4.7 Hz,
N(CH2)2), 3.56 (t, 4H, J = 4.4 Hz, O(CH2)2), 3.96 (s, 2H,
CH2), 6.75 (s, 1H, pyrimidine-H), 7.30–8.52 (m, 8H, Ar–
H), 10.30 (s, 1H, NH, D2O exch.); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 45.2 (N(CH2)2), 63.6 (CH2), 67.7
(O(CH2)2), 101.3 (C-5), 116.2–146.3 (C-arom), 152.8 (C–
Cl, quinoline), 162.8 (C–F), 163.5 (C-2), 164.2 (C-6),
165.7 (C-4), 173.3 (C=O); LCMS (m/z): 511 (M?); Anal.
Calcd. For C25H20Cl2FN5O2: C-58.60, H-3.93, N-13.67;
Found: C-58.53, H-3.99, N-13.72 %.
Acknowledgments We express our sincere gratitude to the
Department of Chemistry, Mahatma Gandhi Campus, Maharaja
Krishnakumarsinhji Bhavnagar University, Bhavnagar for providing
research and library facilities.
N-(4-(2-6-dichloroquinolin-3-yl)-6-(2-nitrophenyl)pyrimi-
din-2-yl)-2-morpholinoacetamide (5j) Yellow orange
crystal, yield: 56 %; m.p.: 220–222 °C; IR (KBr) mmax
/
cm-1: 3358, 3238 (NH), 3067 (C–H, aromatic), 2980,
2953, 2837 (C–H, CH2), 1694 (C=O), 1590 (C=N), 1539
(C=C), 1485, 1347 (NO2 group), 1362 (C–N), 1230 (C–O),
737 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.76
(t, 4H, J = 4.9 Hz, N(CH2)2), 3.51 (t, 4H, J = 4.7 Hz,
O(CH2)2), 3.95 (s, 2H, CH2), 6.82 (s, 1H, pyrimidine-H),
7.62–8.56 (m, 8H, Ar–H), 10.34 (s, 1H, NH, D2O exch.);
13C NMR (100 MHz, DMSO-d6, d, ppm): 45.4 (N(CH2)2),
63.7 (CH2), 67.9 (O(CH2)2), 101.3 (C-5), 124.2–146.0
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