Synthesis and Antimicrobial Activity of Azolyl Pyrimidines

Article abstract of DOI:10.1002/jhet.2615

A new class of azolyl pyrimidines linked by diamino sulfone moiety was prepared and studied their antimicrobial activity. Chloro-substituted and nitro-substituted thiazolyl pyrimidines (9c and 9e) showed excellent antibacterial activity against Bacillus subtilis, while imidazolyl pyrimidines (10c and 10e) exhibited promising antifungal activity against Aspergillus niger.

Full text of DOI:10.1002/jhet.2615

Month 2016
Synthesis and Antimicrobial Activity of Azolyl Pyrimidines
*
Ragavendra Butta, Sowmya Donthamsetty V, Padmaja Adivireddy, and Padmavathi Venkatapuram
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh 517 502, India
*
E-mail: vkpuram2001@yahoo.com
Received October 19, 2015
DOI 10.1002/jhet.2615
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A new class of azolyl pyrimidines linked by diamino sulfone moiety was prepared and studied their
antimicrobial activity. Chloro-substituted and nitro-substituted thiazolyl pyrimidines (9c and 9e) showed
excellent antibacterial activity against Bacillus subtilis, while imidazolyl pyrimidines (10c and 10e)
exhibited promising antifungal activity against Aspergillus niger.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
RESULTS AND DISCUSSION
Molecules having pyrimidine as a core unit exhibit vari-
ous biological activities such as antiviral [1], antibacterial
[2], antitumor [3], anti-inflammatory [4], and antifungal
[5]. Oxazoles are well-known common motifs in natural
products including phenoxan [6], noricumazoles [7],
hennoxazoles [8], and leiodolides A and B [9], and many
of them possess significant antimicrobial [10], cytotoxic
[11], and anthelmintic [12] activities. Thiazole derivatives
are important components in medicinal chemistry because
of their broad applications in drug development as antiviral
[13], anticancer [14], antibacterial [15], antifungal [16], and
anti-inflammatory [17] agents. Imidazoles are common scaf-
folds in highly significant biomolecules including biotin, his-
tidine, and histamine. Medicinal properties of imidazole-
containing compounds include anticancer [18], antimicrobial
[19,20], and antioxidant [21]. Thus, polyfunctionalized
heteroaromatics have gained importance in drug discovery
and structural identification of macromolecules. Besides, sul-
fonamide drugs are associated with a variety of biological ac-
tivities and in fact brought an antibiotic revolution in
medicine. As such, scientific efforts have continuously been
directed towards the synthesis of heteroaromatics linked by
different pharmacophores. In continuation of our efforts to
develop a variety of heteroaromatic compounds [22,23],
the present work, synthesis, and antimicrobial activity of
azolyl pyrimidines have been taken up (Scheme 1).
The synthetic intermediate 4,6-diarylpyrimidin-2-amine
(3) was prepared by the cyclocondensation of chalcone
(1) with guanidine hydrochloride (2) in the presence
of NaOH in ethanol under ultrasonication [24].
Chlorosulfonylation of amino group in 3 was achieved by
the treatment of 3 with sulfuryl chloride in the presence
of diisopropylethylamine under nitrogen atmosphere to ob-
tain 4,6-diarylpyrimidin-2-ylsulfamoyl chloride (4). The
1H-NMR spectrum of 4a showed a broad singlet at δ
8.39 ppm because of NH that disappeared on deuteration.
The signal corresponding to C(5)-H of pyrimidine appeared
at downfield region and merged with aromatic protons. The
2-amino-4-aryloxazoles (5) and 2-amino-4-arylthiazoles
(6) were prepared by the cyclocondensation of phenacyl
bromide with urea and thiourea in methanol [25]. The
2-amino-4-arylimidazoles (7) were obtained by the reaction
of phenacyl bromide with acetyl guanidine followed by
hydrolysis in the presence of sulfuric acid [26]. The reaction
of 4 with 5 in the presence of 4-dimethylaminopyridine
(DMAP) and triethylamine in CH2Cl2 under ultrasonication
resulted in N-((4-phenyloxazol-2-ylamino)sulfonyl)-4,6-
diarylpyrimidin-2-amine (8). Similar reaction of 4 with 6 gave
N-((4-arylthiazol-2-ylamino)sulfonyl)-4,6-diarylpyrimidin-2-
amine (9). The N-((4-aryl-1H-imidazol-2-ylamino)sulfonyl)-
4,6-diarylpyrimidin-2-amine (10) was prepared by the treat-
1
ment of 4 with 7 under similar conditions. The H-NMR
© 2016 Wiley Periodicals, Inc.

R. Butta, S. Donthamsetty V, P. Adivireddy, and P. Venkatapuram
Vol 000
Scheme 1. Synthesis of azolyl pyrimidines.
spectra of 8a, 9a, and 10a showed a broad singlet at δ 8.45,
8.43, and 8.47 ppm, respectively, because of NH that disap-
peared on deuteration. The singlets corresponding to C(5)-H
of pyrimidine and C(5′)-H of azole appeared at downfield re-
gion and merged with aromatic protons. The structures of the
compounds were further established by IR, 13C-NMR, and el-
emental analyses.
The presence of electron-withdrawing substituents on the
aromatic ring increases the activity. In fact, 9e, 10c, and
10e displayed activity greater than the standard drug Keto-
conazole at the tested concentrations (Table 2).
CONCLUSION
A new class of diamino sulfonyl azolyl pyrimidines was
prepared from 4,6-diarylpyrimidin-2-ylsulfamoyl chlorides
(4) and 2-amino azoles and tested for antimicrobial activ-
ity. The effect of substituents on the aromatic ring indicates
that the presence of electron-withdrawing substituents
increases the activity. In fact, chloro-substituted and
nitro-substituted thiazolyl pyrimidines (9c and 9e) showed
excellent antibacterial activity against B. subtilis. However,
chloro-substituted and nitro-substituted imidazolyl pyrimi-
dines (10c and 10e) exhibited promising antifungal activity
against A. niger.
ANTIMICROBIAL STUDIES
Compounds 8–10 were screened for antibacterial activity
at two concentrations 50 and 100 μg per well. The results
presented in Table 1 revealed that Gram-positive bacteria
are more susceptible towards the tested compounds than
Gram-negative bacteria. All the compounds displayed
higher activity on Bacillus subtilis than on Staphylococcus
aureus. Among oxazolyl pyrimidines (8), thiazolyl pyrimi-
dines (9), and imidazolyl pyrimidines (10), compound 9
showed greater activity than 8 and 10. However, 10
displayed good activity than 8. The presence of electron-
withdrawing substituents on the aromatic ring increases
the activity. In fact, compounds 9c, 9e, and 10e displayed
activity higher than the standard drug Chloramphenicol
against B. subtilis. On the other hand, compounds having
methyl substituent on the aromatic ring displayed least ac-
tivity. Compounds 8a, 8b, and 10b showed no activity
against both bacteria.
EXPERIMENTAL
Melting points were determined in open capillaries on a
Mel-Temp apparatus and are uncorrected. The IR spectra
were recorded on a Thermo Nicolet IR 200 FTIR spec-
trometer (USA) as KBr pellets, and the wave numbers were
1
given in cmꢀ1. The H-NMR spectra were recorded in
All the tested compounds except 8a, 8b, and 9b
inhibited the spore germination against tested fungi. Most
of the compounds displayed higher activity against Asper-
gillus niger than on Penicillium chrysogenum. The
imidazolyl pyrimidines (10) showed higher activity than
oxazolyl pyrimidines (8) and thiazolyl pyrimidines (9).
DMSO-d6 on a Jeol JNM (USA) λ–400MHz. The 13C-
NMR spectra were recorded in DMSO-d6 on a Jeol JNM
spectrometer operating at 100MHz. All chemical shifts
are reported in δ (ppm) using TMS as an internal standard.
High-resolution mass spectra were recorded on Micromass
Q-TOF micro-mass spectrometer using electrospray
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis and Antimicrobial Activity of Azolyl Pyrimidines
Table 1
The in vitro antibacterial activity of compounds 8–10.
Zone of inhibition (mm)
Gram-positive bacteria
Staphylococcus aureus Bacillus subtilis
Gram-negative bacteria
Pseudomonas aeruginosa Klebsiella pneumoniae
50 μg per
100 μg per
50 μg per
100 μg per
50 μg per
100 μg per
50 μg per
100 μg per
Compound
well
well
well
well
well
well
well
well
8a
8b
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
8c
8d
8e
9a
9b
9c
9d
9e
15 2.3
13 1.6
17 2.7
13 3.2
10 1.5
24 1.7
22 3.1
25 2.6
12 3.5
-
17 1.4
16 3.3
19 1.8
15 1.2
13 2.5
25 3.1
23 2.5
27 1.2
14 2.7
-
22 3.1
20 2.7
24 3.4
20 1.6
15 3.7
36 2.3
32 1.4
39 3.5
18 1.9
-
25 1.5
23 3.3
27 2.2
22 1.4
17 1.8
40 3.2
35 3.3
42 1.7
21 3.3
-
8
9
2.6
1.8
9
8
1.2
2.8
15 2.6
13 3.4
17 3.3
12 1.5
18 1.7
17 1.2
20 1.9
15 3.5
10 2.6
27 1.3
25 3.4
30 2.5
12 1.7
-
-
11 2.1
2.4
-
-
8
-
8 1.2
17 1.2
14 3.1
18 2.3
-
19 3.5
16 1.7
21 3.6
-
24 2.4
22 1.1
27 1.9
10 3.2
-
10a
10b
-
-
10c
10d
10e
20 2.8
19 1.4
22 1.6
33 1.7
-
22 3.1
20 2.3
24 3.4
35 3.7
-
34 1.7
27 2.6
35 2.2
34 2.9
-
39 2.4
30 1.2
40 3.3
38 1.7
-
12 3.2
11 1.8
15 1.5
27 2.3
-
15 1.2
13 3.2
18 1.3
30 1.7
-
20 2.5
18 1.5
24 3.6
40 3.4
-
23 1.4
22 2.7
26 1.9
42 2.4
-
Chloramphenicol
Control (DMSO)
(-), no activity.
Table 2
The in vitro antifungal activity of compounds 8–10.
Zone of inhibition (mm)
Aspergillus niger
Penicillium chrysogenum
Compound
50 μg per well
100 μg per well
50 μg per well
100 μg per well
8a
-
-
-
-
8b
-
-
-
-
8c
8d
8e
9a
21 2.7
18 3.2
27 2.1
13 1.8
-
23 1.3
20 2.4
28 1.5
16 2.3
-
10 2.5
8 1.6
13 3.1
13 1.7
11 3.3
16 1.1
9 3.1
-
-
-
9b
9c
9d
9e
10a
10b
10c
10d
10e
31 2.6
22 1.4
34 3.7
16 2.3
10 1.1
35 4.2
29 3.3
37 2.1
33 1.2
-
33 1.7
25 2.1
37 1.3
19 1.2
13 3.4
38 2.6
30 1.7
40 1.5
36 2.4
-
16 1.2
12 3.4
19 2.6
-
19 3.5
14 1.1
21 1.2
9
8
3.6
2.3
-
22 3.1
14 2.2
25 1.3
36 3.2
-
25 1.7
16 3.6
27 2.2
38 1.5
-
Ketoconazole
Control (DMSO)
(-), no activity.
ionization. Ultrasonication was performed in a Bandelin
Sonorex RK (USA) 102H ultrasonic bath operating at fre-
quency of 35kHz. The microanalyses were performed on a
Perkin–Elmer 240C elemental analyzer. The synthetic
intermediates 4,6-diarylpyrimidin-2-amine (3), 2-amino-
4-aryloxazoles (5) and 2-amino-4-arylthiazoles (6), and 2-
amino-4-arylimidazoles (7) were prepared as per the litera-
ture procedures [24–26].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Butta, S. Donthamsetty V, P. Adivireddy, and P. Venkatapuram
Vol 000
4,6-Diarylpyrimidin-2-ylsulfamoyl chloride (4). General
procedure. To a solution of diisopropylethylamine (2mL)
in chloroform (6mL) kept at 0°C, sulfuryl chloride
(0.2mmol) was added dropwise while stirring at the same
temperature under nitrogen atmosphere. After the addition
was completed, the reaction mixture was brought to room
temperature and continued the stirring for a further period of
1h. The 4,6-diarylpyrimidin-2-amine (3) (0.1mmol) was
added to the contents of the flask and refluxed for 4–6h. The
reaction mixture was cooled and poured onto crushed ice.
The separated solid was collected, washed with cold water,
dried, and recrystallized from chloroform–petroleum ether.
(400MHz, DMSO-d6): δ 7.53–8.29 (m, 9H, Ar-H and C
(5)-H), 8.49 (bs, 1H, NH) ppm; 13C-NMR (100MHz,
DMSO-d6): δ 103.7 (C-5), 165.6 (C-4 and C-6), 172.1 (C-
2), 123.2, 125.6, 141.3, 146.8 (aromatic carbons) ppm; MS:
HRMS (m/z): 458.7872 [M+ Na]. Anal. Calcd. for
C16H10ClN5O6S: C, 44.10; H, 2.31; N, 16.07; Found: C,
44.20; H, 2.34; N, 16.18%.
N-((4-Aryloxazol-2-ylamino)sulfonyl)-4,6-diarylpyrimidin-
2-amine (8)/N-((4-Arylthiazol-2-ylamino)sulfonyl)-4,6-diaryl
pyrimidin-2-amine (9)/N-((4-Aryl-1H-imidazol-2-ylamino)sul
fonyl)-4,6-diarylpyrimidin-2-amine (10). General procedure.
To a solution of 5/6/7 (3.0mmol) in dichloromethane
(10mL), triethylamine (3.1mmol) and 4-dimethy
laminopyridine (DMAP) (0.1mmol) were added and
stirred at room temperature for 15min. Then,
4,6-diarylpyrimidin-2-ylsulfamoyl chloride (4) (3.3mmol)
in dichloromethane (5mL) was added dropwise, and the
reaction mixture was stirred at 40°C under nitrogen
atmosphere for 6–10h. After completion of reaction, the
solvent was removed in vacuo. The resultant residue was
neutralized with saturated NaHCO3 solution. The aqueous
layer was extracted with ethyl acetate, washed with water,
and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the resultant solid
was purified by column chromatography (silica gel, 60–
120mesh) using hexane ethyl acetate (3:1) as eluent.
N-((4-Phenyloxazol-2-ylamino)sulfonyl)-4,6-diphenylpyrimidin-
2-amine (8a). Yield 65%; mp 156–158°C; IR (KBr): 1141,
4,6-Diphenylpyrimidin-2-ylsulfamoyl chloride (4a).
Yield
70%; mp 149–151°C; IR (KBr): 1136, 1329 (SO2), 1574
(C¼N), 3339 (NH) cmꢀ1; 1H-NMR (400 MHz, DMSO-d6): δ
7.38–7.81 (m, 11H, Ar-H and C(5)-H), 8.39 (bs, 1H, NH)
ppm; 13C-NMR (100 MHz, DMSO-d6): δ 103.4 (C-5), 164.2
(C-4 and C-6), 171.3 (C-2), 127.2, 128.6, 129.1, 135.1
(aromatic carbons) ppm; MS: HRMS (m/z): 368.7941 [M
+Na]. Anal. Calcd. for C16H12ClN3O2S: C, 55.57; H, 3.50;
N, 12.15; Found: C, 55.66; H, 3.53; N, 12.27%.
4,6-Bis(p-tolyl)pyrimidin-2-ylsulfamoyl chloride (4b). Yield
72%; mp 136–138°C; IR (KBr): 1132, 1325 (SO2), 1569
1
(C¼N), 3336 (NH) cmꢀ1; H-NMR (400MHz, DMSO-d6):
δ 2.36 (s, 6H, Ar-CH3), 7.32–7.78 (m, 9H, Ar-H and C(5)-
H), 8.32 (bs,1H, NH) ppm; 13C-NMR (100MHz,
DMSO-d6): δ 24.1 (Ar-CH3), 102.5 (C-5), 164.7 (C-4 and
C-6), 171.5 (C-2), 122.4, 129.1, 130.8, 132.7 (aromatic
carbons) ppm; MS: HRMS (m/z): 396.8457 [M+ Na]. Anal.
Calcd. for C18H16ClN3O2S: C, 57.83; H, 4.31; N, 11.24;
Found: C, 57.88; H, 4.33; N, 11.37%.
1336 (SO2), 1586 (C¼N), 1641 (C¼C), 3367 (NH) cmꢀ1
;
1H-NMR (400 MHz, DMSO-d6): δ 7.33–7.80 (m, 17H, Ar-
H, C(5)-H and C(5′)-H), 8.45 (bs, 2H, C(2′)-NH and C(2)-
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 105.3 (C-5),
141.1 (C-5′), 145.3 (C-4′), 153.6 (C-2′), 167.5 (C-4 and C-
6), 174.8 (C-2), 125.1, 126.6, 127.2, 127.9, 128.3, 128.8,
131.6, 136.7 (aromatic carbons) ppm; MS: HRMS (m/z):
492.5037 [M +Na]. Anal. Calcd. for C25H19N5O3S: C,
63.95; H, 4.08; N, 14.92; Found: C, 63.82; H, 4.11; N,
14.70%.
4,6-Bis(4-chlorophenyl)pyrimidin-2-ylsulfamoyl chloride
(4c).
Yield 69%; mp 155–157°C; IR (KBr): 1145,
1338 (SO2), 1571 (C¼N), 3347 (NH) cmꢀ1; H-NMR
(400 MHz, DMSO-d6): δ 7.48–7.95 (m, 9H, Ar-H and C
(5)-H), 8.43 (bs, 1H, NH) ppm; 13C-NMR (100 MHz,
DMSO-d6): δ 102.9 (C-5), 165.4 (C-4 and C-6), 172.2
(C-2), 128.5, 129.1, 132.9, 133.6 (aromatic carbons)
ppm; MS: HRMS (m/z): 437.6839 [M + Na]. Anal.
Calcd. for C16H10Cl3N3O2S: C, 46.34; H, 2.43; N,
10.13; Found: C, 46.22; H, 2.45; N, 9.96%.
1
N-((4-p-tolyloxazol-2-ylamino)sulfonyl)-4,6-bis(p-tolyl)pyrimidin-
2-amine (8b). Yield 63%; mp 143–145°C; IR (KBr): 1137,
1329 (SO2), 1573 (C¼N), 1636 (C¼C), 3362 (NH) cmꢀ1
;
4,6-Bis(4-bromophenyl)pyrimidin-2-ylsulfamoyl
chloride
1H-NMR (400 MHz, DMSO-d6): δ 2.29 (s, 6H, Ar-CH3),
2.35 (s, 3H, Ar-CH3), 7.37–7.71 (m, 14H, Ar-H, C(5)-H and
C(5′)-H), 8.44 (bs, 2H, C(2′)-NH and C(2)-NH) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 21.7 and 23.1 (Ar-
CH3), 104.8 (C-5), 141.6 (C-5′), 144.8 (C-4′), 153.1
(C-2′), 166.8 (C-4 and C-6), 173.5 (C-2), 124.3, 125.4,
125.7, 126.4, 127.3, 129.1, 130.3, 133.6 (aromatic
carbons) ppm; MS: HRMS (m/z): 534.5853 [M + Na].
Anal. Calcd. for C28H25N5O3S: C, 65.74; H, 4.93; N,
13.69; Found: C, 65.81; H, 4.89; N, 13.81%.
(4d). Yield 74%; mp 162–164°C; IR (KBr): 1139, 1334
(SO2), 1576 (C¼N), 3342 (NH) cmꢀ1
;
1H-NMR
(400MHz, DMSO-d6): δ 7.41–7.87 (m, 9H, Ar-H and C
(5)-H), 8.36 (bs, 1H, NH) ppm; 13C-NMR (100MHz,
DMSO-d6): δ 103.1 (C-5), 164.8 (C-4 and C-6), 171.7 (C-
2), 122.9, 128.2, 131.6, 134.1 (aromatic carbons) ppm;
MS: HRMS (m/z): 526.5845 [M+Na]. Anal. Calcd. for
C16H10Br2ClN3O2S: C, 38.16; H, 2.00; N, 8.34; Found: C,
38.08; H, 2.04; N, 8.21%.
4,6-Bis(4-nitrophenyl)pyrimidin-2-ylsulfamoyl
chloride
N-((4-(4-Chlorophenyl)oxazol-2-ylamino)sulfonyl)-4,6-bis
(4e). Yield 75%; mp 179–181°C; IR (KBr): 1148, 1341
(4-chlorophenyl)-pyrimidin-2-amine (8c).
172–174°C; IR (KBr): 1147, 1340 (SO2), 1575 (C¼N), 1639
Yield 64%; mp
(SO2), 1582 (C¼N), 3351 (NH) cmꢀ1
;
1H-NMR
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Month 2016
Synthesis and Antimicrobial Activity of Azolyl Pyrimidines
(C¼C), 3354 (NH) cmꢀ1; 1H-NMR (400 MHz, DMSO-d6): δ
7.45–7.86 (m, 14H, Ar-H, C(5)-H and C(5′)-H), 8.51 (bs, 2H,
C(2′)-NH and C(2)-NH) ppm; 13C-NMR (100MHz,
DMSO-d6): δ 105.6 (C-5), 142.1 (C-5′), 145.1 (C-4′), 154.6
(C-2′), 168.9 (C-4 and C-6), 174.2 (C-2), 127.3, 127.9, 128.5,
130.7, 133.4, 134.7, 135.6, 136.2 (aromatic carbons) ppm;
MS: HRMS (m/z): 595.8413 [M+ Na]. Anal. Calcd. for
C25H16Cl3N5O3S: C, 52.42; H, 2.82; N, 12.23; Found: C,
52.48; H, 2.84; N, 12.10%.
130.2, 131.1, 132.4 (aromatic carbons) ppm; MS: HRMS (m/
z): 550.6489 [M+ Na]. Anal. Calcd. for C28H25N5O2S2: C,
63.73; H, 4.78; N, 13.27; Found: C, 63.85; H, 4.81; N, 13.16%.
N-((4-(4-Chlorophenyl)thiazol-2-ylamino)sulfonyl)-4,6-bis
(4-chlorophenyl) pyrimidin-2-amine (9c). Yield 65%; mp
159–161°C; IR (KBr): 1145, 1336 (SO2), 1591 (C¼N),
;
1645 (C¼C), 3378 (NH) cmꢀ1 1H-NMR (400MHz,
DMSO-d6): δ 7.47–7.79 (m, 14H, Ar-H, C(5)-H and C(5′)-
H), 8.46 (bs, 2H, C(2′)-NH and C(2)-NH) ppm; 13C-NMR
(100MHz, DMSO-d6): δ 106.1 (C-5), 109.9 (C-5′), 154.3
(C-4′), 169.3 (C-4 and C-6), 175.1 (C-2), 178.1 (C-2′),
127.9, 128.6, 129.4, 129.9, 131.5, 132.1, 132.7, 133.1
(aromatic carbons) ppm; MS: HRMS (m/z): 611.9044 [M
+Na]. Anal. Calcd. for C25H16Cl3N5O2S2: C, 50.99; H, 2.74;
N, 11.89; Found: C, 50.93; H, 2.76; N, 11.76%.
N-((4-(4-bromophenyl)oxazol-2-ylamino)sulfonyl)-4,6-bis(4-
bromophenyl)-pyrimidin-2-amine (8d).
Yield 67%; mp
177–179°C; IR (KBr): 1142, 1337 (SO2), 1588 (C¼N),
1632 (C¼C), 3351 (NH) cmꢀ1
;
1H-NMR (400MHz,
DMSO-d6): δ 7.41–7.89 (m, 14H, Ar-H, C(5)-H and C(5′)-
H), 8.46 (bs, 2H, C(2′)-NH and C(2)-NH) ppm; 13C-NMR
(100MHz, DMSO-d6): δ 104.5 (C-5), 141.7 (C-5′), 143.5
(C-4′), 154.8 (C-2′), 168.3 (C-4 and C-6), 173.9 (C-2),
127.1, 128.3, 128.7, 129.2, 131.5, 132.6, 133.5, 134.2
(aromatic carbons) ppm; MS: HRMS (m/z): 729.1921 [M
+Na]. Anal. Calcd. for C25H16Br3N5O3S: C, 42.52; H, 2.28;
N, 9.92; Found: C, 42.43; H, 2.31; N, 10.04%.
N-((4-(4-Bromophenyl)thiazol-2-ylamino)sulfonyl)-4,6-bis
(4-bromophenyl) pyrimidin-2-amine (9d). Yield 66%; mp
167–169°C; IR (KBr): 1138, 1328 (SO2), 1579 (C¼N),
1637 (C¼C), 3369 (NH) cmꢀ1
;
1H-NMR (400MHz,
DMSO-d6): δ 7.40–7.84 (m, 14H, Ar-H, C(5)-H and C(5′)-
H), 8.56 (bs, 2H, C(2′)-NH and C(2)-NH) ppm; 13C-NMR
(100MHz, DMSO-d6): δ 105.8 (C-5), 108.7 (C-5′), 153.9
(C-4′), 168.7 (C-4 and C-6), 174.7 (C-2), 177.8 (C-2′),
125.4, 126.7, 127.1, 127.7, 128.6, 129.7, 131.1, 132.3
(aromatic carbons) ppm; MS: HRMS (m/z): 745.2573 [M
+Na]. Anal. Calcd. for C25H16Br3N5O2S2: C, 41.57; H,
2.23; N, 9.70; Found: C, 41.51; H, 2.26; N, 9.83%.
N-((4-(4-Nitrophenyl)oxazol-2-ylamino)sulfonyl)-4,6-bis(4-
nitrophenyl)pyrimidin-2-amine (8e). Yield 68%; mp 185–
187°C; IR (KBr): 1150, 1343 (SO2), 1594 (C¼N), 1643
1
(C¼C), 3369 (NH) cmꢀ1; H-NMR (400 MHz, DMSO-d6):
δ 7.47–7.88 (m, 14H, Ar-H, C(5)-H and C(5′)-H), 8.54 (bs,
2H, C(2′)-NH and C(2)-NH) ppm; 13C-NMR (100MHz,
DMSO-d6): δ 106.3 (C-5), 142.0 (C-5′), 145.7 (C-4′), 153.9
(C-2′), 167.7 (C-4 and C-6), 175.6 (C-2), 129.3, 130.2,
132.6, 135.6, 135.8, 136.5, 137.0, 137.3 (aromatic carbons)
ppm; MS: HRMS (m/z): 627.4987 [M +Na]. Anal. Calcd.
for C25H16N8O9S: C, 49.67; H, 2.67; N, 18.54; Found: C,
49.76; H, 2.70; N, 18.67%.
N-((4-(4-Nitrophenyl)thiazol-2-ylamino)sulfonyl)-4,6-bis
(4-nitrophenyl)pyrimidin-2-amine (9e).
Yield 65%; mp
183–185°C; IR (KBr): 1153, 1346 (SO2), 1585 (C¼N),
1648 (C¼C), 3383 (NH) cmꢀ1
;
1H-NMR (400MHz,
DMSO-d6): δ 7.49–7.91 (m, 14H, Ar-H, C(5)-H and C(5′)-
H), 8.49 (bs, 2H, C(2′)-NH and C(2)-NH) ppm; 13C-NMR
(100MHz, DMSO-d6): δ 106.7 (C-5), 109.6 (C-5′), 154.4
(C-4′), 169.5 (C-4 and C-6), 175.4 (C-2), 178.3 (C-2′),
129.9, 131.1, 131.7, 132.4, 133.5, 134.3, 135.1, 135.9
(aromatic carbons) ppm; MS: HRMS (m/z): 643.5621 [M
+Na]. Anal. Calcd. for C25H16N8O8S2: C, 48.39; H, 2.60; N,
18.06; Found: C, 48.31; H, 2.57; N, 18.19%.
N-((4-Phenylthiazol-2-ylamino)sulfonyl)-4,6-diphenylpyrimi
din-2-amine (9a). Yield 64%; mp 163–165°C; IR (KBr):
1135, 1325 (SO2), 1581 (C¼N), 1629 (C¼C), 3365 (NH)
cmꢀ1 1H-NMR (400 MHz, DMSO-d6): δ 7.39–7.75 (m,
;
17H, Ar-H, C(5)-H and C(5′)-H), 8.43 (bs, 2H, C(2′)-NH
and C(2)-NH) ppm; 13C-NMR (100MHz, DMSO-d6): δ
104.3 (C-5), 108.9 (C-5′), 153.5 (C-4′), 168.7 (C-4 and C-
6), 174.5 (C-2), 177.8 (C-2′), 128.0, 128.6, 129.7, 130.1,
132.4, 132.9, 134.3, 135.4 (aromatic carbons) ppm; MS:
HRMS (m/z): 508.5718 [M + Na]. Anal. Calcd. for
C25H19N5O2S2: C, 61.84; H, 3.94; N, 14.42; Found: C,
61.76; H, 3.95; N, 14.54%.
N-((4-Phenyl-1H-imidazol-2-ylamino)sulfonyl)-4,6-diphenyl
pyrimidin-2-amine (10a).
Yield 68%; mp 179–181°C; IR
(KBr): 1136, 1331 (SO2), 1575 (C¼N), 1634 (C¼C), 3352
1
(NH) cmꢀ1; H-NMR (400 MHz, DMSO-d6): δ 7.34–7.83
(m, 17H, Ar-H, C(5)-H and C(5′)-H), 8.47 (bs, 2H, C(2′)-NH
and C(2)-NH), 11.44 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 106.1 (C-5), 122.4 (C-5′), 140.8 (C-
2′), 145.4 (C-4′), 168.0 (C-4 and C-6), 173.2 (C-2), 127.3,
128.2, 128.9, 129.7, 130.6, 131.4, 132.8, 133.9 (aromatic
carbons) ppm; MS: HRMS (m/z): 491.5213 [M+ Na]. Anal.
Calcd. for C25H20N6O2S: C, 64.09; H, 4.30; N, 17.94; Found:
C, 64.16; H, 4.34; N, 17.81%.
N-((4-p-tolylthiazol-2-ylamino)sulfonyl)-4,6-bis(p-tolyl)pyrimidin-
2-amine (9b). Yield 67%; mp 151–153°C; IR (KBr): 1131,
1322 (SO2), 1573 (C¼N), 1621 (C¼C), 3359 (NH) cmꢀ1
;
1H-NMR (400MHz, DMSO-d6): δ 2.33 (s, 6H, Ar-CH3),
2.37 (s, 3H, Ar-CH3), 7.35–7.69 (m, 14H, Ar-H, C(5)-H and
C(5′)-H), 8.52 (bs, 2H, C(2′)-NH and C(2)-NH) ppm; 13C-
NMR (100MHz, DMSO-d6): δ 21.3 and 22.7 (Ar-CH3),
105.2 (C-5), 109.4 (C-5′), 153.2 (C-4′), 168.6 (C-4 and C-6),
173.2 (C-2), 177.4 (C-2′), 125.4, 125.9, 126.4, 127.2, 128.7,
N-((4-p-tolyl-1H-imidazol-2-ylamino)sulfonyl)-4,6-bis(p-tolyl)
pyrimidin-2-amine (10b).
Yield 65%; mp 165–167°C; IR
(KBr): 1132, 1327 (SO2), 1578 (C¼=N), 1628 (C¼C), 3349
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Butta, S. Donthamsetty V, P. Adivireddy, and P. Venkatapuram
Vol 000
1
(NH) cmꢀ1; H-NMR (400MHz, DMSO-d6): δ 2.31 (s, 6H,
sterile pipettes. Simultaneously, the standard antibiotics,
chloramphenicol for antibacterial activity, and
Ar-CH3), 2.35 (s, 3H, Ar-CH3), 7.33–7.70 (m, 14H, Ar-H, C
(5)-H and C(5′)-H), 8.53 (bs, 2H, C(2′)-NH and C(2)-NH),
11.42 (bs, 1H, NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ
22.1 and 24.4 (Ar-CH3), 105.4 (C-5), 122.7 (C-5′), 140.2 (C-
2′), 144.7 (C-4′), 167.7 (C-4 and C-6), 175.3 (C-2), 124.8,
125.5, 126.1, 126.9, 128.7, 129.9, 130.7, 132.1 (aromatic
carbons) ppm; MS: HRMS (m/z): 533.5986 [M + Na]. Anal.
Calcd. for C28H26N6O2S: C, 65.86; H, 5.13; N, 16.46; Found:
C, 65.95; H, 5.15; N, 16.59%.
ketoconazole for antifungal activity (as positive control)
were tested against the pathogens. The samples were
dissolved in DMSO, which showed no zone of inhibition
acts as negative control. The plates were incubated at 37°
C for 24h for bacteria and at 28°C for 48h for fungi.
After appropriate incubation, the diameter of zone of
inhibition of each well was measured. Triplicates were
maintained, and the average values were calculated for
eventual antimicrobial activity.
N-((4-(4-Chlorophenyl)-1H-imidazol-2-ylamino)sulfonyl)-
4,6-bis(4-chlorophenyl)pyrimidin-2-amine (10c).
Yield
67%; mp 184–186°C; IR (KBr): 1144, 1341 (SO2), 1581
(C¼N), 1637 (C¼C), 3376 (NH) cmꢀ1; 1H-NMR (400MHz,
DMSO-d6): δ 7.39–7.80 (m, 14H, Ar-H, C(5)-H and C
(5′)-H), 8.57 (bs, 2H, C(2′)-NH and C(2)-NH), 11.49 (bs, 1H,
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 105.9 (C-5),
123.0 (C-5′), 141.1 (C-2′), 145.8 (C-4′), 166.2 (C-4 and C-6),
174.3 (C-2), 126.4, 127.7, 128.5, 129.4, 130.5, 131.7, 133.1,
133.9 (aromatic carbons) ppm; MS: HRMS (m/z): 594.8563
[M +Na]. Anal. Calcd. for C25H17Cl3N6O2S: C, 52.51; H,
3.00; N, 14.70; Found: C, 52.44; H, 3.03; N, 14.81%.
Acknowledgments. The authors are grateful to BRNS (Board of
Research in Nuclear Sciences) (400085) Trombay, Mumbai, for
financial assistance under major research project.
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4,6-bis(4-bromophenyl)pyrimidin-2-amine (10d).
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DMSO-d6): δ 7.37–7.76 (m, 14H, Ar-H, C(5)-H and C
(5′)-H), 8.49 (bs, 2H, C(2′)-NH and C(2)-NH), 11.46 (bs, 1H,
NH) ppm; 13C-NMR (100 MHz, DMSO-d6): δ 106.3 (C-5),
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bis(4-nitrophenyl)-pyrimidin-2-amine (10e). Yield 65%; mp
196–198°C; IR (KBr): 1149, 1346 (SO2), 1592 (C¼N), 1646
(C¼C), 3381 (NH) cmꢀ1; 1H-NMR (400 MHz, DMSO-d6): δ
7.41–7.80 (m, 14H, Ar-H, C(5)-H and C(5′)-H), 8.55 (bs, 2H,
C(2′)-NH and C(2)-NH), 11.53 (bs, 1H, NH) ppm; 13C-NMR
(100 MHz, DMSO-d6): δ 107.1 (C-5), 123.2 (C-5′), 141.3 (C-
2′), 146.1 (C-4′), 168.7 (C-4 and C-6), 175.9 (C-2), 128.1,
128.8, 129.6, 130.5, 131.1, 131.7, 133.5, 134.3 (aromatic
carbons) ppm; MS: HRMS (m/z): 626.5139 [M + Na]. Anal.
Calcd. for C25H17N9O8S: C, 49.75; H, 2.84; N, 20.89; Found:
C, 49.84; H, 2.86; N, 20.76%.
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