Synthesis of Benzazolyl Pyrimidines Under Ultrasonication and Their Antimicrobial Activity

Article abstract of DOI:10.1002/jhet.3134

(1) The benzoxazolyl/benzothiazolyl/benzimidazolyl pyrimidines were prepared under ultrasonication in the presence of pyridine/dimethylaminopyridine and triethylamine. (2) Better yields were recorded in 4-(N,N-dimethylamino)pyridine and Et₃N. (3) The presence of electron withdrawing chloro, bromo, and nitro substituents enhanced antimicrobial activity (13c, 13e, 14e: minimum inhibitory concentration?=?6.25?μg/well against Bacillus subtilis; 13e, 14e: minimum inhibitory concentration?=?6.25?μg/well against Aspergillus niger).

Full text of DOI:10.1002/jhet.3134

Month 2018
Synthesis of Benzazolyl Pyrimidines Under Ultrasonication and Their
Antimicrobial Activity
*
and Padmavathi Venkatapuram
Narendra Babu Kayathi, Donthamsetty V. Sowmya, Padmaja Adivireddy,
Department of Chemistry, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India
*
E-mail: vkpuram2001@yahoo.com
Received November 30, 2017
DOI 10.1002/jhet.3134
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
(1) The benzoxazolyl/benzothiazolyl/benzimidazolyl pyrimidines were prepared under ultrasonication
in the presence of pyridine/dimethylaminopyridine and triethylamine. (2) Better yields were recorded in
4-(N,N-dimethylamino)pyridine and Et3N. (3) The presence of electron withdrawing chloro, bromo, and
nitro substituents enhanced antimicrobial activity (13c, 13e, 14e: minimum inhibitory concentra-
tion = 6.25 μg/well against Bacillus subtilis; 13e, 14e: minimum inhibitory concentration = 6.25 μg/well
against Aspergillus niger).
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
longer reaction times [15–17]. Thus, the beneficial effects
of ultrasonic sonochemistry and our interest to develop and
to improve the synthetic methodologies prompted to adopt
ultrasonic irradiation to synthesize benzazolyl pyrimidines
and to study their antimicrobial activity.
Molecules with benzazole scaffold belongs to a
significant class of heterocyclic compounds that are
encountered in a number of natural products of medicinal
importance. Benzoxazole-containing bicyclic systems –
calcimycin an antimicrobial agent and carboxamycin an
antibiotic drug – are isolated from various strains of
Streptomyces [1]. Frentizole [2], bentaluron, and
ethoxazolamide [3] are some of the drugs having
benzothiazole moiety. Benzimidazole-based entities, viz.,
albendazole, fenbendazole, and benomyl are currently
under usage as antimicrobial and anthelmentic drugs [4–6].
Moreover, benzazoles are associated with diverse
pharmacological activies, viz., analgesic [7], anti-
inflammatory [8], antioxidant [9], and antiviral [10]. In
addition to these, brodimorphin [11] (an antibacterial
agent) and raltegravir [12] (an anti-HIV drug) possess
pyrimidine moiety (Fig. 1). In fact, for the last couple of
years, we have involved in the synthesis of biologically
potential heterocycles adopting facile synthetic
methodologies [13,14]. Ultrasound irradiation is one of the
powerful techniques for the promotion of organic
reactions, wherein shorter reaction times and higher yields
are the unique advantages under this method when
compared with conventional methods which required
RESULTS AND DISCUSSION
The benzoxazol-2-methyl chloride (4) and benzothiazol-2-
methyl chloride (5) were prepared by the cyclocondensation
of 2-aminophenol (2)/2-aminothiophenol (3) with chloro
acetylchloride (1) in acetic acid under ultrasonication.
The benzimidazol-2-methyl chloride (8) was prepared by
the reaction of O-phenylenediamine (7) with chloroacetic
acid (6) under ultrasonication [18]. The 2-amino-4,6-
diarylpyrimidine (11) was prepared by the reaction of
chalcone (9) with guanidine hydrochloride (10) in the
presence of sodium isopropoxide in isopropanol under
ultrasonication [19] (Scheme 1).
The condensation of heteroaryl amines and
heteroarylmethyl chlorides was reported in the presence
of diisopropyl ethylamine [20], triethylamine [21],
potassium carbonate [22], and sodium hydride [23] under
conventional methods. Many of the reactions required
longer reaction times, maintenance of anhydrous
© 2018 Wiley Periodicals, Inc.

N. B. Kayathi, D. V. Sowmya, P. Adivireddy, and P. Venkatapuram
Vol 000
Figure 1. Drugs containing benzoxazoles, benzthiazoles, benzimidazoles and pyrimidine moieties. [Color figure can be viewed at
wileyonlinelibrary.com]
conditions and also in some instances leading to lower
Scheme 1. Synthesis of benzazolyl methylene chlorides and pyrimidine
yields. In order to overcome these difficulties, we tried to
achieve the reaction under mild reaction conditions. As
such when the reaction between 4 and 11 was carried out
in the presence of pyridine in dichloromethane under
amines.
ultrasonication,
2-ylmethyl)-4,6-diarylpyrimidin-2-amine
the
product
N-(benzo[d]oxazol-
(12) was
obtained in 55–65% yield (Method A & Scheme 2). In
order to achieve more yields the reaction was repeated
with 4-(N,N-dimethylamino)pyridine (DMAP) and
Scheme 2. Synthesis of Pyrimidinyl benzoxazole, benzthiazoles and
benzimidazoles.
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Synthesis of Benzazolyl Pyrimidines
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. B. Kayathi, D. V. Sowmya, P. Adivireddy, and P. Venkatapuram
Vol 000
triethylamine in dichloromethane under ultrasonication
wherein the product 12 was obtained in 82–88% (Method
the presence of N,N-dimethylamino group at 4-position.
The H NMR spectra of 12a, 13a, and 14a presented a
1
B
&
Scheme 2). Adopting similar methodolgy
singlet at δ 4.34, 4.40, and 4.35 due to methylene protons
and a broad singlet at 8.51, 8.61, and 8.54 ppm due to
NH. The compound 14a showed another broad singlet at
11.65 ppm due to NH of imidazole. The signals of NH
disappeared on deuteration.
pyrimidinyl benzothiazoles (13) and pyrimidinyl
benzimidazoles (14) were prepared by the reaction of 5
and 8 with 11. High yields were recorded in Method B.
This may be due to the basicity of DMAP, enhanced by
Figure 2. The in vitro antibacterial activity of compounds 12–14. [Color figure can be viewed at wileyonlinelibrary.com]
Table 2
The in vitro antifungal activity of compounds 12–14.
Zone of inhibition (mm)
A. niger
P. chrysogenum
Compound
12.5 μg/well 25 μg/well 50 μg/well 100 μg/well 12.5 μg/well 25 μg/well 50 μg/well 100 μg/well
12a
12b
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
12c
12d
11 1.2
–
12 1.4
–
15 1.1
–
18 1.2
–
9
1.4
11 1.5
–
12 1.3
–
16 1.4
–
–
12e
13a
13b
15 1.1
18 1.2
–
17 1.1
20 1.3
–
20 1.3
23 1.5
–
22 1.5
24 1.1
–
10 1.1
12 1.5
–
12 1.3
13 1.2
–
15 1.4
16 1.1
–
17 1.4
19 1.5
–
13c
13d
13e
14a
24 1.2
23 1.3
30 1.2
21 1.3
–
26 1.5
25 1.1
32 1.3
22 1.2
–
28 1.4
27 1.2
35 1.1
23 1.3
–
29 1.3
28 1.4
37 1.2
26 1.1
–
18 1.1
16 1.5
23 1.5
14 1.2
–
19 1.2
18 1.3
25 1.2
15 1.4
–
22 1.5
20 1.2
26 1.1
18 1.3
–
24 1.3
22 1.4
29 1.4
21 1.2
–
14b
14c
14d
14e
28 1.1
26 1.2
32 1.3
29 1.4
–
30 1.3
27 1.5
34 1.2
31 3.1
–
31 1.4
29 1.2
36 1.1
33 2.3
–
33 1.2
30 1.5
39 1.1
36 2.5
–
22 1.4
20 1.3
26 1.2
33 2.7
–
24 1.3
23 1.2
28 1.3
35 1.6
–
26 1.4
24 1.3
29 1.2
36 2.1
–
28 1.2
26 1.3
30 1.1
38 2.9
–
Ketoconazole
Control (DMSO)
(–) No activity. ( ) Standard deviation.
Journal of Heterocyclic Chemistry
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Month 2018
Synthesis of Benzazolyl Pyrimidines
ANTIMICROBIAL STUDIES
pyrimidinyl benzimidazoles (14) showed greater activity
than pyrimidinyl benzoxazoles (12). In fact, 13e and 14e
displayed higher activity on Aspergillus niger than the
standard drug ketoconazole at all tested concentrations.
The compounds which showed greater antibacterial and
antifungal activities are further assayed for minimum
inhibitory concentration (MIC), minimum bactericidal
concentration (MBC), and minimum fungicidal
concentration (MFC), and the values are listed in Table 3.
MIC is the lowest concentration of an antimicrobial that
will inhibit the visible growth of a microorganism. (But it
is not sure that the microorganisms are completely killed).
The MBC/MFC is the lowest concentration of antibiotic
The results of antibacterial activity presented in Table 1
and Figure 2 indicated that all the compounds exhibited
higher activity on Gram-postive bacteria than on Gram-
negative bacteria except 12a, 12b, 13b, and 14b. The
pyrimidinyl benzothiazoles (13) showed greater activity
than pyrimidinyl benzimidazoles (14) and pyrimidinyl
benzoxazoles (12). Among the latter compounds, 14
displayed higher activity than 12. The presence of
electron withdrawing substituents on the aromatic ring
increased the activity. It was observed that with
increasing electron withdrawing effect the activity
increased. In fact, chloro, nitro substituted pyrimidinyl
benzothiazoles (13c and 13e), and nitro substituted
pyrimidinyl benzimidazole (14e) displayed greater
activity than the standard drug Chloramphenicol on
Bacillus subtilis at all tested concentrations.
required to kill
a particular bacterium/fungi. The
MBC/MFC involves an additional set of steps performed
once the MIC is determined. The antimicrobials are
usually regarded as bactericidal/fungicidal if MBC/MFC
is not greater than four times MIC [24]. The compounds
13c, 13e, and 14e exhibited low MIC against B. subtilis
when compared with 14c. In fact, MIC of 13c, 13e, and
14e against B. subtilis is equal to standard drug
All the compounds inhibited the spore germination of
tested fungi except 12a, 12b, 12d, 13b, and 14b (Table 2
and Fig. 3). The pyrimidinyl benzothiazoles (13) and
Figure 3. The in vitro antifungal activity of compounds 12–14. [Color figure can be viewed at wileyonlinelibrary.com]
Table 3
MIC, MBC, and MFC of compounds 13c, 13e, 14c, and 14e.
Minimum inhibitory concentration
MIC (MBC/MFC) μg/well
Compound
S. aureus
B. subtilis
P. aeruginosa
K.pneumoniae
A. niger
P. chrysogenum
13c
13e
14c
14e
25(100)
25(100)
100(>200)
50(200)
6.25
6.25(12.5)
6.25(12.5)
25(100)
6.25(12.5)
6.25
50(200)
50(200)
100(>200)
100(>200)
6.25
200(-)
100(>200)
200(-)
200(-)
12.5
25(100)
6.25(12.5)
12.5(50)
6.25(12.5)
—
200(-)
200(-)
200(-)
100(>200)
—
Chloramphenicol
Ketoconazole
—
—
—
—
6.25
12.5
(—) No activity. MBC, minimum bactericidal concentration; MFC, minimum fungicidal concentration; MIC, minimum inhibitory concentration.
Journal of Heterocyclic Chemistry
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N. B. Kayathi, D. V. Sowmya, P. Adivireddy, and P. Venkatapuram
Vol 000
Chloramphenicol; and MBC is 2 × MIC. Moreover, the
compounds 13e and 14e displayed low MIC on A. niger
than the other tested compounds and MFC is 2 × MIC.
This suggested that chloro and nitro substituted
pyrimidinyl benzothiazoles (13c and 13e) and nitro
substituted pyrimidinyl benzimidazole (14e) are potential
antibacterial agents against B. subtilis. The compounds
13e and 14e are also potential antifungal agents against
A. niger.
(1 mmol) were dissolved in dichloromethane (10 mL) and to
this pyridine (2 mmol) was added dropwise. The contents
were subjected to ultrasound irradiation at a frequency of
35 kHz for 35–40 min at room temperature. After completion
of reaction (checked by thin-layer chromatography), the
residue was poured onto crushed ice and solid separated was
filtered, dried, and recrystallized from ethanol.
Method
B.
2-Amino-4,6-diarylpyrimidine
(11)
(1.0 mmol) and benzoxazol-2-methyl chloride (4)/
benzthiazol-2-methyl chloride (5)/benzimidazol-2-methyl
chloride (8) (1.0 mmol) were dissolved in
dichloromethane (10 mL). To this DMAP (1 mmol) and
triethylamine (1 mmol) were added dropwise and
sonicated at a frequency of 35 kHz at room temperature
for 25–30 min. After completion of the reaction, the
contents were poured onto crushed ice. The resultant
solid was filtered, dried, and recrystallized from ethanol.
CONCLUSION
A variety of pyrimidinyl benzazoles linked by
aminomethane
moiety
were
prepared
under
ultrasonication in the presence of pyridine/4-(N,N-
dimethylamino)pyridine and triethylamine, studied their
antimicrobial activity. The chloro substituted pyrimidinyl
benzothioazoles (13c and 13e) and nitro substituted
pyrimidinyl benzimidazole (14e) are the potential
antibacterial agents against B. subtilis. However, 13e and
14e displayed potential antifungal activity against A. niger.
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-diphenylpyrimidin-2-
amine (12a). Yield 66%; mp 133–135°C; IR (KBr): 1592
;
(C═N), 1616 (C═C), 3302 (NH) cmꢀ1 1H–NMR
(400 MHz, DMSO-d6): δ 4.34 (s, 2H, CH2), 7.32–7.98
(m, 15H, Ar–H), 8.51 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 53.8 (CH2) 102.3 (C-5), 154.1
(C-20), 164.4 (C-2), 165.9 (C-4 and C-6), 111.6, 120.1,
124.9, 126.1, 128.1, 129.7, 130.3, 136.4, 143.2, 151.9
(aromatic carbons) ppm; MS: HRMS (m/z): 401.4241
[M + Na]. Anal.Cald. for C24H18N4O: C, 76.17; H, 4.79;
EXPERIMENTAL
Melting points were determined in open capillaries on an
open Mel-Temp apparatus (Thermo Electron Scientific
Instruments LLC, Madison, WI) and are uncorrected. The
IR spectra were recorded on a Thermo Nicolet IR 200
FTIR spectrometer (USA) as KBr pellets, and the wave
N, 14.81; Found C, 76.26; H, 4.82; N, 14.93%.
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-di-p-tolylpyrimidin-2-
amine (12b). Yield 69%; mp 129–131°C; IR (KBr): 1585
1
numbers were given in cmꢀ1. The H–NMR spectra were
;
(C═N), 1620 (C═C), 3318 (NH) cmꢀ1 1H–NMR
recorded in DMSO-d6 on
a
Jeol JNM (USA)
(400 MHz, DMSO-d6): δ 2.34 (s, 6H, 2CH3), 4.32 (s,
2H, CH2), 7.18–7.79 (m, 13H, Ar–H), 8.49 (bs, 1H, NH)
ppm; 13C–NMR (100 MHz, DMSO-d6): δ 23.2 (CH3),
53.1 (CH2) 101.7 (C-5), 153.9 (C-20), 163.5 (C-2), 166.1
(C-4 and C-6), 112.1, 119.3, 124.3, 125.2, 125.8, 130.1,
132.9, 133.7, 142.7, 151.6 (aromatic carbons) ppm; MS:
HRMS (m/z): 429.4780 [M + Na]. Anal.Cald. for
C26H22N4O: C, 76.83; H, 5.46; N, 13.78; Found C,
76.94; H, 5.48; N, 13.93%.
λ-400 MHz. The 13C–NMR spectra were recorded in
DMSO-d6 on a Joel JNM spectrometer operating at
100 MHz. All chemical shifts are reported in δ (ppm)
using tetramethylslane as an internal standard. High-
resolution mass spectra were recorded on Micromass Q-
TOF micro-mass spectrometer (HRMS New Objective,
Inc., Woburn, MA) using electrospray ionization.
Ultrasonication was performed in a Bandelin Sonorex RK
(USA) 102H ultrasonic bath operating at frequency of
35 kHz. The microanalyses were performed on a Perkin-
Elmer 240C elemental analyzer (Waltham, MA). The
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-bis(4-chlorophenyl)
pyrimidin-2-amine (12c). Yield 67%; mp 146–148°C; IR
1
(KBr): 1576 (C═N), 1618 (C═C), 3311 (NH) cmꢀ1; H–
compounds
benzoxazol-2-methyl
chloride
(4),
NMR (400 MHz, DMSO-d6): δ 4.31 (s, 2H, CH2), 7.39–
7.94 (m, 13H, Ar–H), 8.56 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 54.5 (CH2) 102.2 (C-5), 154.8
(C-20), 165.6 (C-2), 166.8 (C-4 and C-6), 112.6, 120.4,
124.5, 125.3, 130.0, 130.5, 134.6, 135.4, 142.1, 152.1
(aromatic carbons) ppm; MS: HRMS (m/z): 470.3096
[M + Na]. Anal.Cald. for C24H16Cl2N4O: C, 64.44; H,
3.61; N, 12.53; Found C, 64.58; H, 3.66; N, 12.53%.
benzothiazol-2-methyl chloride (5), benzimidazol-2-
methyl chloride (8), and 2-amino-4,6-diarylpyrimidine
(11) were prepared as per the literature procedures [18,19].
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-diarylpyrimidin-2-amine
(12)/N-(Benzo[d]thiazol-2-ylmethyl)-4,6-diarylpyrimidin-2-amine
(13)/N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-diarylpyrimidin-
2-amine (14). General procedure.
Method A.
2-Amino-4,6-diarylpyrimidine (11) (1 mmol)
and benzoxazole-2-methyl chloride (4) /benzthiazole-2-
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-bis(4-bromophenyl)
methyl chloride (5)/benzimidazol-2-methyl chloride (8)
pyrimidin-2-amine (12d). Yield 70%; mp 139–141°C; IR
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Synthesis of Benzazolyl Pyrimidines
(KBr): 1590 (C═N), 1621 (C═C), 3309 (NH) cmꢀ1; H–
NMR (400 MHz, DMSO-d6): δ 4.30 (s, 2H, CH2), 7.36–
7.82 (m, 13H, Ar–H), 8.47 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 54.6 (CH2) 102.9 (C-5), 154.4
(C-20), 164.7 (C-2), 166.4 (C-4 and C-6), 111.5, 120.8,
123.5, 123.9, 124.7, 129.1, 133.6, 136.7, 142.1, 152.3
(aromatic carbons) ppm; MS: HRMS (m/z): 559.2159
[M + Na]. Anal.Cald. for C24H16Br2N4O: C, 53.76; H,
3.01; N, 10.45; Found C, 53.84; H, 3.04; N, 10.45%.
N-(Benzo[d]thiazol-2-ylmethyl)-4,6-bis(4-bromophenyl)
1
pyrimidin-2-amine (13d). Yeild 68%; mp 137–139°C; IR
1
(KBr): 1601 (C═N), 1621 (C═C), 3295 (NH) cmꢀ1; H–
NMR (400 MHz, DMSO-d6): δ 4.33 (s, 2H, CH2), 7.38–
7.81 (m, 13H, Ar–H), 8.55 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 54.8 (CH2) 101.2 (C-5), 163.7
(C-2), 166.5 (C-4 and C-6), 170.4 (C-20), 123.3, 123.7,
124.4, 125.4, 126.1, 129.7, 133.5, 135.8, 137.3, 153.6
(aromatic carbons) ppm; MS: HRMS (m/z): 575.2769
[M + Na]. Anal.Cald. for C24H16Br2N4S: C, 52.19; H,
2.92; N, 10.14; Found C, 52.11; H, 2.88; N, 9.98%.
N-(Benzo[d]oxazol-2-ylmethyl)-4,6-bis(4-nitrophenyl)
pyrimidin-2-amine (12e). Yeild 72%; mp 157–159°C; IR
1
(KBr): 1594 (C═N), 1615 (C═C), 3297 (NH) cmꢀ1; H–
N-(Benzo[d]thiazol-2-ylmethyl)-4,6-bis(4-nitrophenyl)
pyrimidin-2-amine (13e). Yeild 70%; mp 145–147°C; IR
NMR (400 MHz, DMSO-d6): δ 4.39 (s, 2H, CH2), 7.48–
8.05 (m, 13H, Ar–H), 8.58 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 54.1 (CH2) 103.5 (C-5), 150.1
(C-20), 165.4 (C-2), 167.1 (C-4 and C-6), 112.5, 121.1,
124.3, 125.1, 126.2, 127.3, 143.4, 143.7, 149.1, 151.3
(aromatic carbons) ppm; MS: HRMS (m/z): 491.4198
[M + Na]. Anal.Cald. for C24H16N6O5: C, 61.54; H, 3.44;
N, 17.94; Found C, 61.66; H, 3.44; N, 17.94%.
1
(KBr): 1578 (C═N), 1610 (C═C), 3298 (NH) cmꢀ1; H–
NMR (400 MHz, DMSO-d6): δ 4.40 (s, 2H, CH2), 7.75–
8.09 (m, 13H, Ar-H), 8.58 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 56.7 (CH2) 103.4 (C-5), 165.8
(C-2), 166.3 (C-4 and C-6), 171.6 (C-20), 122.9, 123.5,
125.1, 127.1, 127.3, 128.3, 137.4, 143.6, 149.1, 154.9
(aromatic carbons) ppm; MS: HRMS (m/z): 507.4798
[M + Na]. Anal.Cald. for C24H16N6O4S: C, 59.50; H,
3.33; N, 17.35; Found C, 59.60; H, 3.38; N, 17.20%.
N-(Benzo[d]thiazol-2-ylmethyl)-4,6-diphenylpyrimidin-2-
amine (13a). Yeild 65%; mp 133–135°C; IR (KBr): 1576
(C═N), 1613 (C═C), 3285 (NH) cmꢀ1
;
1H–NMR
N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-
diphenylpyrimidin-2-amine (14a).
Yeild 69%; mp 155–
(400 MHz, DMSO-d6): δ 4.40 (s, 2H, CH2), 7.50–8.10
(m, 15H, Ar–H), 8.61 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 56.4 (CH2) 103.1 (C-5), 163.4
(C-2), 165.6 (C-4 and C-6), 170.8 (C-20), 122.6, 122.8,
126.5, 127.3, 129.3, 130.8, 131.4, 137.2, 137.9, 154.8
(aromatic carbons) ppm; MS: HRMS (m/z): 417.4849
[M + Na]. Anal.Cald. for C24H18N4S: C, 73.07; H, 4.60;
N, 14.20; Found C, 72.94; H, 4.60; N, 14.20%.
157°C; IR (KBr): 1587 (C═N), 1623 (C═C), 3283 (NH)
1
cmꢀ1; H–NMR (400 MHz, DMSO-d6): δ 4.35 (s, 2H,
CH2), 7.24–7.96 (m, 15H, Ar–H), 8.54 (bs, 1H, NH),
11.65 (bs, 1H, imidazole NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 45.3 (CH2) 102.6 (C-5), 143.1
(C-20), 164.1 (C-2), 166.4 (C-4 and C-6), 117.4, 124.1,
128.2, 129.3, 130.1, 136.2, 139.5 (aromatic carbons)
ppm; MS: HRMS (m/z): 400.4401 [M + Na]. Anal.Cald.
for C24H19N5: C, 76.37; H, 5.07; N, 18.55; Found C,
76.49; H, 5.05; N, 18.67%.
N-(Benzo[d]thiazol-2-ylmethyl)-4,6-di-p-tolylpyrimidin-2-
amine (13b). Yeild 67%; mp 126–128°C; IR (KBr): 1597
;
(C═N), 1625 (C═C), 3315 (NH) cmꢀ1 1H–NMR
(400 MHz, DMSO-d6): δ 2.40(s, 6H, 2CH3), 4.36 (s, 2H,
CH2), 7.28–7.95 (m, 13H, Ar–H), 8.53 (bs, 1H, NH)
ppm; 13C–NMR (100 MHz, DMSO-d6): δ 22.9 (CH3),
55.6 (CH2) 102.8 (C-5), 163.1 (C-2), 165.6 (C-4 and C-
6), 170.2 (C-20), 122.7, 132.1, 125.2, 125.9, 126.7, 128.5,
133.4, 134.2, 136.9, 154.1 (aromatic carbons) ppm; MS:
HRMS (m/z): 445.5387 [M + Na]. Anal.Cald. for
C26H22N4S: C, 73.91; H, 5.25; N, 13.26; Found C,
74.00; H, 5.29; N, 13.43%.
N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-di-p-
tolylpyrimidin-2-amine (14b). Yeild 72%; mp 148–150°C;
IR (KBr): 1600 (C═N), 1630 (C═C), 3311 (NH) cmꢀ1
;
1H–NMR (400 MHz, DMSO-d6): δ 2.37 (s, 6H, 2CH3),
4.41 (s, 2H, CH2), 7.21–7.88 (m, 13H, Ar–H), 8.49 (bs,
1H, NH), 11.33 (bs, 1H, imidazole NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 23.7 (CH3), 45.1 (CH2), 104.9
(C-5), 142.4 (C-20), 163.2 (C-2), 166.7 (C-4 and C-6),
116.8, 123.9, 124.8, 125.1, 132.6, 133.2, 139.8 (aromatic
carbons) ppm; MS: HRMS (m/z): 428.4948 [M + Na].
Anal.Cald. for C26H23N5: C, 77.01; H, 5.72; N, 17.27;
Found C, 76.90; H, 5.75; N, 17.63%.
N-(Benzo[d]thiazol-2-ylmethyl)-4,6-bis(4-chlorophenyl)
pyrimidin-2-amine (13c). Yeild 64%; mp 141–143°C; IR
1
(KBr): 1580 (C═N), 1619 (C═C), 3307 (NH) cmꢀ1; H–
NMR (400 MHz, DMSO-d6): δ 4.38 (s, 2H, CH2), 7.26–
7.96 (m, 13H, Ar–H), 8.52 (bs, 1H, NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 56.2 (CH2) 103.6 (C-5), 164.5
(C-2), 167.4 (C-4 and C-6), 171.9 (C-20), 122.2, 122.5,
126.7, 127.3, 130.1, 131.8, 135.8, 136.1, 137.8, 155.2
(aromatic carbons) ppm; MS: HRMS (m/z): 486.3709
[M + Na]. Anal.Cald. for C24H16Cl2N4S: C, 62.21; H,
3.48; N, 12.09; Found C, 62.35; H, 3.48; N, 12.09%.
N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-bis(4-
chlorophenyl)pyrimidin-2-amine (14c).
Yeild 66%; mp
174–176°C; IR (KBr): 1582 (C═N), 1617 (C═C), 3286
1
(NH) cmꢀ1; H–NMR (400 MHz, DMSO-d6): δ 4.38 (s,
2H, CH2), 7.33–7.97 (m, 13H, Ar-H), 8.57 (bs, 1H, NH),
11.54 (bs, 1H, imidazole NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 45.8 (CH2) 102.9 (C-5), 143.7
(C-20), 164.8 (C-2), 167.5 (C-4 and C-6), 117.8, 124.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. B. Kayathi, D. V. Sowmya, P. Adivireddy, and P. Venkatapuram
Vol 000
129.5, 130.4, 134.7, 135.6, 139.6 (aromatic carbons) ppm;
MS: HRMS (m/z): 469.3248 [M + Na]. Anal.Cald. for
C24H17Cl2N5: C, 64.58; H, 3.84; N, 15.69; Found C,
64.71; H, 3.90; N, 15.82%.
10 mL NB). Increasing concentrations of the test
samples (1.25, 2.5, 5, 10, 20, and 40 μL of stock
solution contains 6.25, 12.5, 25, 50, 100, and
200 μg/well of the compounds) were added to the test
tubes containing bacterial and fungal cultures. All the
tubes were incubated at 37°C for 24 h for bacteria and
at 28°C for 48 h for fungi. The tubes were examined for
visible turbidity using NB as control. Control without
test samples and with solvent was assayed
simultaneously. The lowest concentration that inhibited
visible growth of the tested organisms was recorded as
MIC. To determine MBC [29] and MFC [30] for each
set of test tubes in the MIC determination, a loopful of
broth was collected from those tubes which did not
show any growth and inoculated on sterile nutrient broth
(for bacteria) and PDA (for fungi) by streaking. Plates
inoculated with bacteria and fungi were incubated at
37°C for 24 h and at 28°C for 48 h, respectively. After
incubation, the lowest concentration was noted as MBC
(for bacteria) or MFC (for fungi) at which no visible
growth was observed.
N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-bis(4-
bromophenyl)pyrimidin-2-amine (14d).
Yeild 68%; mp
169–171°C; IR (KBr): 1591 (C═N), 1622 (C═C), 3281
1
(NH) cmꢀ1; H–NMR (400 MHz, DMSO-d6): δ 4.37 (s,
2H, CH2), 7.29–7.79 (m, 13H, Ar–H), 8.59 (bs, 1H, NH),
11.92 (bs, 1H, imidazole NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 46.3 (CH2) 103.3 (C-5), 142.5
(C-20), 163.9 (C-2), 167.3 (C-4 and C-6), 117.5, 123.8,
124.3, 129.1, 133.5, 135.6, 140.5 (aromatic carbons)
ppm; MS: HRMS (m/z): 558.2328 [M + Na]. Anal.Cald.
for C24H17Br2N5: C, 53.86; H, 3.20; N, 13.08; Found C,
53.77; H, 3.24; N, 13.22%.
N-((1H-Benzo[d]imidazol-2-yl)methyl)-4,6-bis(4-
nitrophenyl)pyrimidin-2-amine (14e). Yeild 71%; mp 193–
195°C; IR (KBr): 1578 (C═N), 1620 (C═C), 3281 (NH)
1
cmꢀ1; H–NMR (400 MHz, DMSO-d6): δ 4.44 (s, 2H,
CH2), 7.42–8.06 (m, 13H, Ar–H), 8.57 (bs, 1H, NH),
12.01 (bs, 1H, imidazole NH) ppm; 13C–NMR
(100 MHz, DMSO-d6): δ 46.1 (CH2) 101.3 (C-5), 142.2
(C-20), 165.1 (C-2), 167.8 (C-4 and C-6), 117.9, 123.7,
126.4, 128.2, 139.9, 140.7, 149.9 (aromatic carbons)
ppm; MS: HRMS (m/z): 490.4348 [M + Na]. Anal.Cald.
for C24H17N7O4: C, 61.67; H, 3.67; N, 20.98; Found C,
61.81; H, 3.62; N, 21.08%.
Acknowledgments. The authors are grateful to CSIR
(Council of Scientific and Industrial Research), New
Delhi, for financial assistance under major research project.
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