Synthesis and antimicrobial activity of a new class of sulfonylmethane linked bisheterocycles

Article abstract of DOI:10.1002/jhet.1874

A new class of sulfonylmethane linked bisheterocycles were prepared and studied their antimicrobial activity.

Full text of DOI:10.1002/jhet.1874

November 2014 Synthesis and Antimicrobial Activity of a New Class of Sulfonylmethane
Linked Bisheterocycles
1757
*
Padmavathi Venkatapuram, Seenaiah Dandu, Premakumari Chokkappagari, and Padmaja Adivireddy
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
*
E-mail: vkpuram2001@yahoo.com
Received August 28, 2012
DOI 10.1002/jhet.1874
Published online 8 May 2014 in Wiley Online Library (wileyonlinelibrary.com).
N
X
N
X
N
SH
S
O
O
Y
1 / 2 / 3
13 - 21
1, 13, 16, 19 : X = O
2, 14, 17, 20 : X = S
3, 15, 18, 21 : X = NH
13, 14, 15 : Y = O
16, 17, 18 : Y = S
19, 20, 21 : Y = NH
A new class of sulfonylmethane linked bisheterocycles were prepared and studied their antimicrobial activity.
J. Heterocyclic Chem., 51, 1757 (2014).
INTRODUCTION
a variety of heterocycles, in this report, we describe the
synthesis of oxazolyl/thiazolyl/imidazolyl–benzoxazoles,
benzothiazoles, and benzimidazoles.
The design and study of new molecules of biological
potency is the main target in recent years. In fact, the use
of oxazoline, thiazoline, and imidazoline building blocks
in pharmaceutical drug discovery is continually increasing
[1]. Oxazolines are known as important heterocyclic
compounds that are used as chemotherapeutic agents
especially as analgesic [2] and anti-inflammatory [3]. A
large number of methods are reported for the synthesis of
2-oxazolines. A simple one-pot reaction via nitrile was first
described by Witte and Seeliger [4] where the nitrile is
converted to the corresponding 2-oxazoline by the reaction
with an amino alcohol in the presence of a Lewis-acid
catalyst. In addition to this, condensation of imidate hydro-
chlorides [5], carboxylic acids [3,6], ortho esters [7], and
imino ether hydrochlorides [8] with amino alcohols
produced 2-oxazolines. Thiazolines are found in numerous
interesting biologically active natural products such as
curacin A, thiangazole, mirabazole B, and lissoclinamides
[9]. Thiazolines have been prepared (i) by the condensation
of amino thiols with nitriles [10], esters [11], imino ethers
[12], or imino triflates [13]; (ii) from N-acyl-2-aminoetha-
nols [14] or b-hydroxy thioamides [15]; and (iii) by multi-
step conversions from oxazolines. Imidazoline derivatives
are of great importance because they exhibit significant bi-
ological and pharmacological activities including antihy-
pertensive [16], antihyperglycemic [17], antidepressive
[18], and anti-inflammatory [19]. There are several meth-
ods for the synthesis of 2-imidazolines from carboxylic
acids [20], esters [21], nitriles [22], orthoesters [23], hydro-
ximoylchlorides [24], hydroxy amides [25], and so forth.
In continuation of our studies towards the development of
RESULTS AND DISCUSSION
The synthetic intermediates, benzoxazole-2-thiol (1),
benzothiazole-2-thiol (2), and 1H-benzimidazole-2-thiol
(3) were prepared by the reaction of 2-aminophenol/2-ami-
nothiophenol/1,2-phenylenediamine with carbon disulfide
in the presence of potassium hydroxide in ethanol [26].
The reaction of compounds 1/2/3 with chloroacetic acid
in the presence of sodium hydroxide in methanol resulted
in 2-(benzoxazol-2-ylthio)acetic acid (4), 2-(benzothiazol-
2-ylthio)acetic acid (5) [27], and 2-(1H-benzimidazol-
2-ylthio)acetic acid (6) [28]. Oxidation of the latter
compounds with hydrogen peroxide gave 2-(benzoxazol-
2-ylsulfonyl)acetic acid (7), 2-(benzothiazol-2-ylsulfonyl)
acetic acid (8), and 2-(1H-benzimidazol-2-ylsulfonyl)
acetic acid (9) (Scheme 1 and Table 1). The absorption
bands observed in the IR spectra of 7, 8, and 9 at 1140–
1156 and 1349–1357, 1560–1582, 1688–1695, and
3415–3433 cmꢀ1 were attributed to SO2, C═N, C═O,
and OH, respectively. Besides, the compound 9 showed
a broad absorption band at 3226 cmꢀ1 because of NH (-
1
Table 2). The H-NMR spectra of 7, 8, and 9 presented a
sharp singlet at d 4.41, 4.54, and 4.39 because of methy-
lene protons present between carboxylic acid and sulfonyl
group. Moreover, a broad singlet was observed at 10.46,
10.58, and 10.43 ppm in these compounds because of
OH. The compound 9 exhibited another broad singlet at
11.30 ppm for NH of benzimidazole. The signals of NH
and OH were disappeared on deuteration. The 13C-NMR
© 2014 HeteroCorporation

1758
P. Venkatapuram, S. Dandu, P. Chokkappagari, and P. Adivireddy
Vol 51
Scheme 1
Table 1
Physical and analytical data of compounds 7–21.
Analysis (%) Calcd/found
Compound
mp (ꢁC)
Yield (%)
Mol. formula (MW)
C
H
N
7
8
9
156–158
132–134
178–180
104–106
71–72
126–128
175–177
166–168
182–184
179–181
165–167
193–195
198–200
179–181
202–204
82
76
84
86
84
80
70
73
69
72
66
68
64
67
68
C9H7NO5S (241.22)
44.81 44.74
42.01 41.94
45.00 45.09
47.06 47.13
44.27 44.16
47.24 47.33
49.62 49.51
46.7 46.65
49.80 49.93
46.79 46.85
44.27 44.16
46.96 46.82
49.80 49.70
46.96 47.04
49.99 50.06
2.92 2.96
2.74 2.80
3.36 3.23
3.55 3.63
3.34 3.41
3.96 3.87
3.79 3.70
3.57 3.50
4.18 4.24
3.57 3.51
3.38 3.43
3.94 3.86
4.18 4.25
3.94 3.84
4.58 4.63
5.81 5.92
5.44 5.56
11.66 11.71
5.49 5.37
C9H7NO4S2 (257.29)
C9H8N2O4S (240.24)
C10H9NO5S (255.25)
C10H9NO4S2 (271.31)
C10H10N2O4S (254.26)
C11H10N2O4S (266.27)
C11H10N2O3S2 (282.34)
C11H11N3O3S (265.29)
C11H10N2O3S2 (282.34)
C11H10N2O2S3 (298.40)
C11H11N3O2S2 (281.35)
C11H11N3O3S (265.29)
C11H11N3O2S2 (281.35)
C11H12N4O2S (264.30)
10
11
12
13
14
15
16
17
18
19
20
21
5.16 5.05
11.02 10.94
10.52 10.63
9.92 10.03
15.84 15.78
9.92 9.87
9.39 9.46
14.93 14.88
15.84 15.92
14.93 15.00
21.20 21.07
spectra of 7, 8, and 9 displayed signals at d 60.5, 60.8, 60.1
(CH2), 161.3, 164.3, 150.5 (C-2), and 169.6, 168.7,
170.2 ppm (CO2H). The compounds 7, 8, and 9 on esterifi-
cation with methanol in the presence of concentrated
H2SO4 produced methyl 2-(benzoxazol-2-ylsulfonyl)ace-
tate (10), methyl 2-(benzothiazol-2-ylsulfonyl)acetate
(11), and methyl 2-(1H-benzimidazol-2-ylsulfonyl)acetate
(12) (Scheme 1 and Table 1). The IR spectra of these
compounds displayed an absorption band at 1716, 1720,
and 1715 cmꢀ1 for ester functionality besides the bands
for the functional groups SO2 and C═N. Moreover, the
compound 12 exhibited an absorption band at 3229 cmꢀ1
for NH (Table 2). The H-NMR spectra of 10, 11, and 12
exhibited two sharp singlets at d 3.81, 3.85, 3.78 and
4.45, 4.57, 4.43 that were attributed to methoxy protons
of carbomethoxy group and methylene protons present
between sulfonyl and carbomethoxy group, respectively.
The compound 12 showed another broad singlet at
11.43 ppm because of NH of benzimidazole that disap-
peared on deuteration. The 13C-NMR spectra of 10, 11,
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
Synthesis and Antimicrobial Activity of a New Class of Sulfonylmethane Linked
Bisheterocycles
1759
Table 2
IR data of compounds 7–21.
IR (KBr) cmꢀ1
Compound
SO2
C═N
C═O
NH
OH
7
8
9
1154
1156
1140
1155
1157
1142
1148
1159
1145
1160
1152
1155
1161
1163
1147
1352
1357
1349
1356
1358
1353
1357
1359
1355
1358
1360
1356
1361
1363
1355
1575
1582
1560
1601
1587
1596
1602
1578
1575
1590
1605
1580
1592
1595
1585
1690
1695
1688
1716
1720
1715
—
—
—
—
—
—
—
3226
—
—
3229
—
—
3332
—
3426
3433
3415
—
—
—
—
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
—
—
—
—
—
—
—
—
—
3340
3338
3343
3335
—
and 12 displayed signals at d 52.7, 53.1, 52.5; 60.9, 61.1,
60.8; 154.7, 164.8, 147.7; and 165.0, 165.4, 164.8 ppm
for OCH3, CH2, C-2, and CO2Me, respectively.
band at 3340 cmꢀ1 (NH) (Table 2). The 1H-NMR spectra of
16, 17, and 18 displayed a singlet and two triplets at d 4.48,
4.54, 4.45; 4.29, 4.22, 4.30; and 3.37, 3.34, 3.41 ppm that
were attributed to methy0lene protons flanked between SO2
The cyclocondensation of 10, 11, and 12 with 2-ami-
noethanol and n-butyllithium complexed with a suspension
of 5–10% molar equivalent of anhydrous samarium(III)
chloride in toluene afforded 2-((40,50-dihydrooxazol-20-yl)
methylsulfonyl)benzoxazole (13), 2-((40,50-dihydrooxazol-
20-yl)methylsulfonyl)benzothiazole (14), and 2-((40,50-
dihydrooxazol-20-yl)-methylsulfonyl)-1H-benzimidazole (15)
(Scheme 1 and Table 1). The compounds 13, 14, and 15
in their IR spectra showed absorption bands at 1145–1159,
1355–1359, and 1575–1602 cmꢀ1 because of SO2 and
C═N. Besides, compound 15 exhibited another absorption
band at 3332 cmꢀ1 because of NH (Table 2). The 1H-NMR
spectra of 13, 14, and 15 presented a singlet at d 4.47, 4.58,
and 4.38 because of methylene protons. In addition, two
triplets were observed at 3.42, 3.46, 3.40 and 3.93,
3.95, 3.85 that were assigned to oxazoline ring protons,
0
and heterocyclic ring, C4 —H, and C5 —H, respectively. In
addition to these, a broad singlet at 11.61 ppm was observed
in 18 because of NH that disappeared on deuteration. The
13C-NMR spectra of 16 presented signals at d 37.9, 61.6,
63.2, 163.7, 173.7, 17 at 38.7, 61.9, 62.8, 165.4, 173.5, and
18 at 37.7, 61.4, 61.9, 154.2, 174.7 ppm because of C-50,
CH2, C-40, C-2, C-20, respectively. Adopting similar method-
ology, the compounds 2-((40,50-dihydro-10H-imidazol-20-yl)
methylsulfonyl)benzoxazole (19), 2-((40,50-dihydro-10H-imi-
dazol-20-yl)methylsulfonyl)benzothiazole (20), and 2-((40,50-
dihydro-10H-imidazol-20-yl)methylsulfonyl)-1H-benzimidazole
(21) were prepared from 10/11/12 and 1,2-ethanediamine in
the presence of n-butyllithium and samarium(III) chloride
(Scheme 1 and Table 1). The IR spectra of 19, 20, and 21
exhibited absorption bands at 1147–1163, 1355–1363
(SO2), 1585–1595 (C═N), and 3335–3343cmꢀ1 (NH)
(Table 2). The 1H-NMR spectra of 19, 20, and 21 displayed
a singlet at d 4.53, 4.57, and 4.39 because of methylene
protons and another singlet at 3.45, 3.48, and 3.42 because
of imidazoline ring protons. In compound 21, another broad
singlet was observed at 11.75 ppm because of NH of
benzimidazole. The latter signal disappeared when D2O
was added. The 13C-NMR spectra of 19 showed signals at
d 52.8, 62.3, 158.5, 164.9, 20 at 53.1, 62.5, 159.6, 165.8,
and 21 at 51.9, 61.9, 158.9, 152.5 ppm that were assigned
to C-40, C-50, CH2, C-20, and C-2, respectively (Table 3).
Thus, a new class of bisheterocycles, oxazolyl/thiazolyl/
imidazolyl–benzoxazoles, benzothiazoles, and benzimida-
zoles were prepared adopting simple and well-versed
synthetic methodology.
0
0
C4 —H, and C5 —H. Besides, compound 15 displayed a
broad singlet at 11.53 ppm because of NH of benzimidazole
that disappeared when D2O was added. The 13C-NMR
pectra of 13, 14, and 15 displayed signals at d 51.2,
52.6, 50.8 (C-40), 61.3, 61.5, 61.1 (CH2), 62.7, 62.9, 61.9
(C-50), 162.3, 163.8, 153.9 (C-2), and 164.5, 165.1,
163.7 ppm (C-20).
Similar cyclocondensation of 10, 11, and 12 with 2-
aminoethanethiol furnished 2-((40,50-dihydrothiazol-20-yl)
methylsulfonyl)benzoxazole (16), 2-((40,50-dihydrothiazol-
20-yl)methyl-sulfonyl)benzothiazole (17), and 2-((40,50-
dihydrothiazol-20-yl)methylsulfonyl)-1H-benzimidazole (18)
(Scheme 1 and Table 1). The IR spectra of these compounds
exhibited absorption bands at 1152–1160, 1356–1360 (SO2),
1580–1605 (C═N), and the compound 18 showed another
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1760
P. Venkatapuram, S. Dandu, P. Chokkappagari, and P. Adivireddy
Vol 51
Table 3
1H-NMR and 13C-NMR data of compounds 7–21.
Compound
1H-NMR (CDCl3/DMSO-d6) d, (ppm)
4.41 (s, 2H, CH2), 7.31–7.60
(m, 4H, Ar—H), 10.46 (bs, 1H, OH)
4.54 (s, 2H, CH2), 7.37–7.68
(m, 4H, Ar—H), 10.58 (bs, 1H, OH)
4.39 (s, 2H, CH2), 7.46–7.71
(m, 4H, Ar—H), 10.43
13C-NMR (CDCl3/DMSO-d6) d, (ppm)
7
8
9
60.5 (CH2), 161.3 (C-2), 169.6 (CO2H), 117.8,
121.3, 125.6, 126.4, 141.5, 145.1 (aromatic carbons)
60.8 (CH2), 164.3 (C-2), 168.7 (CO2H), 122.2,
122.6, 125.6, 125.9, 135.5, 141.2 (aromatic carbons)
60.1 (CH2), 150.5 (C-2), 170.2 (CO2H), 117.2, 117.9,
128.5, 128.7, 138.2, 138.6 (aromatic carbons)
(bs, 1H, OH), 11.30 (bs, 1H, NH)
3.81 (s, 3H, OCH3), 4.45
(s, 2H, CH2), 7.59–7.78 (m, 4H, Ar—H)
3.85 (s, 3H, OCH3), 4.57
(s, 2H, CH2), 7.50–7.68 (m, 4H, Ar—H)
3.78 (s, 3H, OCH3), 4.43
(s, 2H, CH2), 7.47–7.65
10
11
12
52.7 (OCH3), 60.9 (CH2), 154.7 (C-2), 165.0 (CO2Me),
118.1, 121.7, 125.9, 126.7, 141.8, 148.6 (aromatic carbons)
53.1 (OCH3), 61.1 (CH2), 164.8 (C-2), 165.4 (CO2Me),
122.7, 123.1, 126.1, 126.3, 135.9, 151.5 (aromatic carbons)
52.5 (OCH3), 60.8 (CH2), 147.7 (C-2), 164.8 (CO2Me),
117.7, 118.1, 128.8, 128.9, 138.7, 138.9 (aromatic carbons)
(m, 4H, Ar—H), 11.43 (bs, 1H, NH)
0
13
14
15
3.42 (t, 2H,0C4 —H, J = 7.4 Hz), 3.93
51.2 (C-40), 61.3 (CH2), 62.7 (C-50), 162.3 (C-2), 164.5
(t, 2H, C5 —H, J = 7.4 Hz), 4.47
(C-20), 118.5, 122.1, 126.2, 126.9, 142.1, 148.9 (aromatic carbons)
(s, 2H, CH2), 7.51–7.69 (m, 4H, Ar—H)
0
3.46 (t, 2H,0C4 —H, J = 7.6 Hz), 3.95
52.6 (C-40), 61.5 (CH2), 62.9 (C-50), 163.8 (C-2), 165.1 (C-20),
122.9, 123.5, 126.6, 126.8, 136.1, 146.8 (aromatic carbons)
(t, 2H, C5 —H, J = 7.6 Hz), 4.58
(s, 2H, CH2), 7.48–7.71 (m, 4H, Ar—H)
0
3.40 (t, 2H,0C4 —H, J = 7.3 Hz), 3.85
50.8 (C-40), 61.1 (CH2), 61.9 (C-50), 153.9 (C-2), 163.7 (C-20),
118.1, 118.5, 129.1, 129.2, 139.2, 139.4 (aromatic carbons)
(t, 2H, C5 —H, J = 7.3 Hz), 4.38
(s, 2H, CH2), 7.53–7.72
(m, 4H, Ar—H), 11.53 (bs, 1H, NH)
0
16
17
18
3.37 (t, 2H,0C5 —H, J = 7.7 Hz), 4.29
37.9 (C-50), 61.6 (CH2), 63.2 (C-40), 163.7 (C-2), 173.7 (C-20),
118.8, 122.6, 126.5, 127.1, 142.4, 149.2 (aromatic carbons)
(t, 2H, C4 —H, J = 7.7 Hz), 4.48
(s, 2H, CH2), 7.37–7.50 (m, 4H, Ar—H)
0
3.34 (t, 2H,0C5 —H, J = 7.8 Hz), 4.22
38.7 (C-50), 61.9 (CH2), 62.8 (C-40), 165.4 (C-2), 173.5 (C-20), 123.1,
123.7, 126.9, 127.7, 136.4, 152.3 (aromatic carbons)
(t, 2H, C4 —H, J = 7.8 Hz), 4.54
(s, 2H, CH2), 7.21–7.52 (m, 4H, Ar—H)
0
3.41 (t, 2H,0C5 —H, J = 7.5 Hz), 4.30
37.7 (C-50), 61.4 (CH2), 61.9 (C-40), 154.2 (C-2), 174.7 (C-20), 118.4,
118.8, 129.6, 129.9, 139.7, 139.8 (aromatic carbons)
(t, 2H, C4 —H, J = 7.5 Hz), 4.45
(s, 2H, CH2), 7.20–7.48
(m, 4H, Ar—H), 11.61 (bs, 1H, NH)
3.45 (s, 4H, C4 —H and C5 —H),
4.53 (s, 2H, CH2), 5.09
0
0
19
20
21
52.8 (C-40 & C-50), 62.3 (CH2), 158.5 (C-20), 164.9 (C-2), 118.9,
122.9, 123.1, 127.3, 142.7, 149.5 (aromatic carbons)
(s, 1H, NH), 7.29–7.99 (m, 4H, Ar—H)
3.48 (s, 4H, C4 —H and C5 —H), 4.57
(s, 2H, CH2), 5.11 (s, 1H, NH),
0
0
53.1 (C-40 & C-50), 62.5 (CH2), 159.6 (C-20), 165.8 (C-2), 123.6,
123.8, 127.3, 127.4, 136.8, 152.5 (aromatic carbons)
7.31–8.02 (m0, 4H, Ar—H0)
3.42 (s, 4H, C4 —H and C5 —H), 4.39
(s, 2H, CH2), 5.12 (s, 1H, NH), 7.26–7.96
(m, 4H, Ar—H), 11.75 (bs, 1H, NH)
51.9 (C-40 & C-50), 61.9 (CH2), 152.5 (C-2), 158.9 (C-20), 118.6,
118.9, 129.8, 130.1, 139.7, 139.9 (aromatic carbons)
ANTIMICROBIAL STUDIES
the tested compounds than gram-positive ones. The
compounds benzimidazole in combination with thiazoline
(18) and imidazoline (21) exhibited greater activity
when compared with other compounds. The compounds
benzothiazole in combination with thiazoline (17) and imida-
zoline (20) showed moderate to good activity. The com-
pounds 13, 14, 15, and 16 displayed least activity against
the tested bacteria.
All the compounds inhibited the spore germination
against tested fungi. The compounds showed slightly higher
antifungal activity towards P. chrysogenum than A. niger.
The compound 21 displayed excellent activity particularly
against P. chrysogenum. However, the compounds 13, 14,
15, and 16 exhibited least activity.
The bisheterocycles 13–21 are screened for their antibac-
terial and antifungal activity at two different concentrations
50 and 100 mg. For antibacterial studies, microorganisms
employed are Staphylococcus aureus, Bacillus subtilis
(gram-positive) and Pseudomonas aeruginosa, Klebsiella
pneumoniae (gram-negative). For antifungal, Aspergillus
niger and Penicillium chrysogenum are used as microorgan-
isms. Chloramphenicol and Ketoconazole are used as standard
drugs for antibacterial and antifungal studies, respectively.
The results of the compounds of preliminary antimicrobial
testing are shown in Tables 4 and 5. The results indicated
that gram-negative bacteria were more susceptible towards
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2014
Synthesis and Antimicrobial Activity of a New Class of Sulfonylmethane Linked
Bisheterocycles
1761
Table 4
The in vitro antibacterial activity of compounds 13–21.
Diameter of zone of inhibition (mm)
Gram-positive bacteria
Gram-negative bacteria
Pseudomonas aeruginosa Klebsiella pneumoniae
Concentration
Compound
(mg/well)
Staphylococcus aureus
Bacillus subtilis
13
50
100
50
100
50
100
50
100
50
100
50
100
50
100
50
100
50
6
8
8
10
10
13
8
7
9
10
12
12
15
14
17
12
14
19
21
22
25
16
18
19
22
24
28
27
30
–
13
14
14
16
19
21
13
16
22
25
30
34
23
27
27
29
35
37
40
42
–
14
10
11
12
14
8
15
16
9
10
18
20
25
28
13
14
17
20
31
33
34
38
–
17
17
19
23
26
11
13
18
20
28
30
33
35
–
18
19
20
21
100
50
100
Chloramphenicol
Control (DMSO)
The symbol (–) means no activity.
CONCLUSIONS
Table 5
A new class of sulfonylmethane linked bisheterocycles was
prepared adopting simple and well-versed methodologies.
Preliminary antimicrobial studies of these compounds showed
that the compounds benzimidazole in combination with thiazo-
line and imidazoline exhibited excellent antimicrobial activity.
The in vitro antifungal activity of compounds 13–21.
Diameter of zone of inhibition
(mm)
Concentration
(mg/well)
Aspergillus
niger
Penicillium
chrysogenum
Compound
EXPERIMENTAL
13
50
100
50
100
50
100
50
100
50
100
50
100
50
100
50
100
50
6
8
7
10
16
18
7
10
20
22
25
28
11
13
23
25
29
31
33
36
–
8
10
10
12
23
25
12
15
26
28
30
32
18
21
27
30
32
35
36
38
–
General. Melting points were determined in open capillaries
on a Mel-Temp apparatus (India) and are uncorrected. The purity
of the compounds was checked by TLC (silica gel H, BDH,
hexane/ethyl acetate, 3:1). The IR spectra were recorded on a
Thermo Nicolet IR 200 FTIR spectrometer (US) as KBr pellets,
and the wavenumbers were given in reciprocal centimeters.
14
15
16
17
1
The H-NMR spectra were recorded in CDCl3/DMSO-d6 on a
Jeol JNM (US) l-400 MHz. The 13C-NMR spectra were
recorded in CDCl3/DMSO-d6 on a Jeol JNM (US) spectrometer
operating at l-100 MHz. All chemical shifts are reported in
parts per million using TMS as an internal standard. The
starting compounds 1–6 were prepared by following the
literature precedent [26–28].
18
19
20
21
2-(Benzoxazol-2-ylsulfonyl)acetic acid (7), 2-(benzothiazol-
2-ylsulfonyl)acetic acid (8), and 2-(1H-benzimidazol-2-
ylsulfonyl)acetic acid (9): general procedure. An ice-cold solution
of 2-(benzoxazol-2-ylthio)acetic acid (4), 2-(benzothiazol-2-ylthio)
acetic acid (5), and 2-(1H-benzimidazol-2-ylthio)acetic acid (6)
(10 mmol) in glacial acetic acid (50mL) was treated with 30%
hydrogen peroxide (20mL) in portions. The contents were
100
50
100
Ketoconazole
Control
(DMSO)
The symbol (–) means no activity.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1762
P. Venkatapuram, S. Dandu, P. Chokkappagari, and P. Adivireddy
Vol 51
allowed to attain laboratory temperature and then refluxed for 3 h.
The reaction mixture was cooled, and acetic acid was removed in
vacuo. The residual portion was poured onto crushed ice, and the
product obtained was collected by filtration. It was washed with
cold water and dried. The crude compound was purified by
recrystallization from water.
was extracted with chloroform and washed with water followed
by brine solution. The solvent was removed in vacuo. The solid
obtained was purified by column chromatography (silica gel,
hexane/ethyl acetate, 3:1).
Methyl 2-(benzoxazol-2-ylsulfonyl)acetate (10), methyl 2-(benzo-
thiazol-2-ylsulfonyl)-acetate (11), and methyl 2-(1H-benzimidazol-
Acknowledgments. The authors thank the Council of Scientific
and Industrial Research (CSIR), New Delhi, for financial
assistance under major research project.
2-ylsulfonyl)acetate (12): general procedure.
A solution of 2-
(benzoxazol-2-ylsulfonyl)acetic acid (7), 2-(benzothiazol-2-
ylsulfonyl)acetic acid (8), and 2-(1H-benzimidazol-2-ylsulfonyl)
acetic acid (9) (10 mmol) in methanol (10 mL) and concentrated
H2SO4 (1.5 mL) was refluxed on a steam bath for 5–6h. The
contents of the flask were cooled and poured onto crushed ice. The
crude product was purified by recrystallization from aqueous
methanol.
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2-((40,50-Dihydrooxazol-20-yl)methylsulfonyl)benzoxazole (13),
2-((40,50-dihydro-oxazol-20-yl)methylsulfonyl)benzothiazole (14),
and 2-((40,50-dihydrooxazol-20-yl)methyl-sulfonyl)-1H-benzimidazole
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2-aminoethanol (20mmol) was added followed by n-butyllithium
(22mmol) at 0ꢁC. The reaction mixture was stirred at 0ꢁC for
30min and heated to reflux. Then, methyl 2-(benzoxazol-2-
ylsulfonyl)acetate (10)/methyl 2-(benzothiazol-2-yl-sulfonyl)
acetate (11)/methyl 2-(1H-benzimidazol-2-ylsulfonyl)acetate (12)
(10mmol) was added to the contents and continued refluxion for
an additional period of 7–9 h. The suspension was cooled to RT
and filtered. The filtrate was extracted with chloroform and
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2-((40,50-Dihydrothiazol-20-yl)methylsulfonyl)benzoxazole (16),
2-((40,50-dihydro-thiazol-20-yl)methylsulfonyl)benzothiazole (17),
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samarium(III) chloride (1mmol) and dry toluene (20mL),
2-aminoethanethiol (20 mmol) was added followed by
n-butyllithium (22 mmol) at 0ꢁC. The reaction mixture was stirred
at 100ꢁC for 15 min and heated to reflux. Then, methyl
2-(benzoxazol-2-ylsulfonyl)acetate (10)/methyl 2-(benzothiazol-2-
ylsulfonyl)acetate (11)/methyl 2-(1H-benzimidazol-2-ylsulfonyl)
acetate (12) (10 mmol) was added to the contents and continued
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cooled to RT and filtered. The filtrate was extracted with
chloroform and washed with water followed by brine solution.
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acetate, 3:1).
2-((40,50-Dihydro-10H-imidazol-20-yl)methylsulfonyl)benzo-
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2-(benzothiazol-2-ylsulfonyl)acetate (11)/methyl 2-(1H-benzimi-
dazol-2-ylsulfonyl)acetate (12) (10mmol) was added to the
contents, and refluxion was continued for an additional period of
9–10h. The suspension was cooled to RT and filtered. The filtrate
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DOI 10.1002/jhet

November 2014
Synthesis and Antimicrobial Activity of a New Class of Sulfonylmethane Linked
Bisheterocycles
1763
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