Synthesis and bioassay of oxazolyl/thiazolyl selenadiazoles, thiadiazoles and diazaphospholes

Article abstract of DOI:10.1248/cpb.57.561

A new class of bis heterocycles, oxazolyl/thiazolyl selenadiazoles, thiadiazoles and diazaphospholes were prepared from phenacylsulfonylacetic acid methyl ester and tested for their antimicrobial and antioxidant properties.

Full text of DOI:10.1248/cpb.57.561

June 2009
Chem. Pharm. Bull. 57(6) 561—566 (2009)
561
Synthesis and Bioassay of Oxazolyl/Thiazolyl Selenadiazoles, Thiadiazoles
and Diazaphospholes
Venkatapuram PADMAVATHI,* Konda MAHESH, Annaji Venkata NAGENDRA MOHAN, and
Adivireddy PADMAJA
Department of Chemistry, Sri Venkateswara University; Tirupati–517 502, India.
Received October 9, 2008; accepted February 27, 2009; published online March 10, 2009
A new class of bis heterocycles, oxazolyl/thiazolyl selenadiazoles, thiadiazoles and diazaphospholes were pre-
pared from phenacylsulfonylacetic acid methyl ester and tested for their antimicrobial and antioxidant proper-
ties.
Key words oxazolyl/thiazolyl selenadiazole; thiadiazole; antioxidant property; diazaphosphole antimicrobial activity
Heterocycles, the largest classical division of organic and thiazolines directly from carboxylic esters. In continua-
chemistry are of immense importance biologically, industri- tion of our efforts to develop bis heterocycles the ester func-
ally and indeed to the functioning of any developed human tionality in (4-aryl[1,2,3]selenadiazole-5-sulfonyl)acetic acid
society. The development of simple, facile and efficient syn- methyl ester (3), (4-aryl[1,2,3]thiadiazole-5-sulfonyl)acetic
thetic methods for the synthesis of five-membered heterocy- acid methyl ester (4) and (2-phenyl-5-aryl-2H-[1,2,3]diaza-
cles is one of the major challenges in organic synthesis. In phosphole-4-sulfonyl)acetic acid methyl ester (6) was used
fact, we have reported the synthetic utility of multifunctional for oxazolines and thiazolines.
synthetic intermediate phenacylsulfonylacetic acid methyl
To achieve the desired bis heterocycles, (4-aryl[1,2,3]sele-
ester for the synthesis of different heterocyclic systems.1—4) nadiazole-5-sulfonyl)acetic acid methyl ester (3) was treated
In continuation of our studies in this direction we wish to re- with 2-aminoethanol in the presence of n-butyllithium com-
port a new class of bis heterocycles viz., selenadiazoles, thia- plexed with a suspension of 5—10% molar equivalents of an-
diazoles and 2H-diazaphospholes in combination with oxa- hydrous SmCl3 in toluene. The compound obtained was iden-
zolines and thiazolines.
tified as 5-(4ꢀ,5ꢀ-dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-aryl-
1,2,3-selenadiazole (7). On the other hand, when the reaction
of 3 was carried out with 2-aminoethanethiol in the presence
Chemistry
In our earlier communication we have reported the synthe- of SmCl3, 5-(4ꢀ,5ꢀ-dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-
1
sis of 1,2,3-selenadiazoles, thiadiazoles and 2H-diazaphos- aryl-1,2,3-selenadiazole (9) was obtained (Chart 2). The H-
pholes by exploiting a-ketomethylene group in phenacylsul- NMR spectra of 7a and 9a displayed three signals at 3.68,
fonylacetic acid methyl ester3) (Chart 1). In fact, the prepara- 3.71 (C4ꢀ-H), 4.97, 3.32 (C5ꢀ-H) and at 4.28, 4.25 ppm for
tion of oxazolines and thiazolines was reported by the tradi- (SO2–CH2). The 13C-NMR spectrum of 7a exhibited signals
tional four step three intermediate route.5) However, a one- at 160.4 (C-2ꢀ), 52.4 (C-4ꢀ), 59.2 (C-5ꢀ), 159.1 (C-4), 157.7
pot methodology was developed for the preparation of oxa- (C-5), 55.2 ppm (SO2–CH2), whereas 9a at 160.9 (C-2ꢀ), 52.8
zolines and thiazolines from the sulfonylacetic acid methyl (C-4ꢀ), 37.4 (C-5ꢀ), 158.7 (C-4), 157.8 (C-5), 55.4 ppm
esters exploiting lanthanide chemistry.1,6) Indeed this method (SO2–CH2) besides signals due to aromatic carbons.
provides a simple and elegant route to develop oxazolines
In a much similar way, 5-(4ꢀ,5ꢀ-dihydrooxazol-2ꢀ-yl-
Chart 1
∗ To whom correspondence should be addressed. e-mail: vkpuram2001@yahoo.com
© 2009 Pharmaceutical Society of Japan

562
Vol. 57, No. 6
Chart 2
Table 1. Antibacterial Activity of 7—12
methylsulfonyl)-4-aryl-1,2,3-thiadiazole (8) and 5-(4ꢀ,5ꢀ-di-
hydrothiazol-2ꢀ-yl-methylsulfonyl)-4-aryl-1,2,3-thiadiazole
(10) were prepared by the reaction of (4-aryl[1,2,3]thiadi-
azole-5-sulfonyl)acetic acid methyl ester (4) with 2-amino-
ethanol/2-aminoethanethiol in the presence of n-butyllithium
complexed with 5—10% molar equivalents of anhydrous
SmCl3 (Chart 2). The 1H-NMR spectra of 8a and 10a showed
signals at 3.72, 3.74 (C4ꢀ-H), 4.92, 3.36 (C5ꢀ-H) and at 4.20,
4.23 ppm for (SO2–CH2). The 13C-NMR spectrum of 8a ex-
hibited signals at 160.3 (C-2ꢀ), 52.3 (C-4ꢀ), 59.7 (C-5ꢀ),
158.6 (C-4), 157.7 (C-5), 55.8 ppm (SO2–CH2) whereas 10a
at 160.6 (C-2ꢀ), 52.0 (C-4ꢀ), 37.1 (C-5ꢀ), 159.2 (C-4), 158.6
(C-5), 55.1 ppm (SO2–CH2).
Zone of inhibition (mm)
Gram (ꢁ)ve Gram (ꢂ)ve
Concentration
Compound
(mg/ml)
K.
S. aureus B. subtilis
E. coli
pneumoniae
7a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
11
14
9
10
12
8
8
9
—
9
7b
—
—
8
—
—
—
—
16
19
14
17
20
23
9
11
12
15
22
26
18
22
23
27
15
18
11
13
18
24
27
31
22
25
32
34
10
12
9
11
9
7c
13
23
26
18
23
22
25
17
21
11
14
19
23
25
28
20
24
29
33
9
10
16
20
13
16
19
21
11
14
9
8a
The ester functionality in (2-phenyl-5-aryl-2H-[1,2,3]di-
azaphosphole-4-sulfonyl)-acetic acid methyl ester (6) was
also exploited to synthesize 4-(4ꢀ,5ꢀ-dihydrooxazol-2ꢀ-yl-
methylsulfonyl)-2-phenyl-5-aryl-2H-1,2,3-diazaphosphole
(11) and 4-(4ꢀ,5ꢀ-dihydrothiazol-2ꢀ-yl-methylsulfonyl)-2-
phenyl-5-aryl-2H-1,2,3-diazaphosphole (12). Thus, the treat-
ment of 6 with 2-aminoethanol/2-aminoethanethiol in the
presence of n-butyllithium and 5—10% molar equivalents of
8b
8c
9a
11
10
12
14
11
21
23
16
19
23
25
—
—
—
—
8
9b
12
16
18
20
24
17
20
22
26
—
—
—
—
9
9c
1
SmCl3 produced 11 and 12, respectively (Chart 2). The H-
NMR spectra of 11a and 12a showed two triplets and a sin-
glet at 3.66, 4.96, 4.24 and 3.78, 3.33, 4.22 ppm for C4ꢀ-H,
C5ꢀ-H and SO2CH2. The 13C-NMR spectrum of 11a dis-
played signals at 161.2 (C-2ꢀ), 52.8 (C-4ꢀ), 59.7 (C-5ꢀ),
158.1 (C-4), 147.7 (C-5), 55.6 (SO2–CH2) whereas 12a at
161.8 (C-2ꢀ), 52.3 (C-4ꢀ), 37.5 (C-5ꢀ), 157.2 (C-4), 148.2 (C-
5), 55.1 ppm for (SO2–CH2).
Antimicrobial Testing The compounds 7—12 were
tested for antimicrobial activity at two different concentra-
tions 100 and 200 mg/ml. The antibacterial activity was
screened against Staphylococcus aureus, Bacillus subtilis
(Gram-positive bacteria) and Escherichia coli, Klebsiella
pneumoniae (Gram-negative bacteria) on nutrient agar plates
at 37 °C for 24 h using chloramphenicol (25 mg per disc) as
reference drug. The compounds were also evaluated for their
antifungal activity against Fusarium solani, Curvularia lu-
nata and Aspergillus niger using ketoconazole (25 mg per
disc) as standard drug. Fungi cultures were grown on potato
dextrose agar medium (PDA) at 25 °C for 3 d. The spore sus-
pension was adjusted to 106 pores/ml at a mg/ml concentra-
tion by the Vincent and Vincent method.7)
10a
10b
10c
11a
12
9
11b
11
12
15
25
28
19
23
27
29
35
39
10
10
14
23
27
19
24
26
29
38
41
11c
11
19
22
15
18
20
23
40
44
9
12a
12b
18
22
14
17
22
24
42
45
12c
Chloramphenicol

June 2009
563
The results of the compounds of preliminary antibacterial against both bacteria. All the test compounds exhibited mod-
testing are shown in Table 1. The results revealed that, in erate (7a—c, 8a—c, 9a—c, 11a—c) to high (10a—c, 12a—
general, the inhibitory activity against the Gram-positive c) inhibitory effect towards tested fungi (Table 2).
bacteria was higher than that of the Gram-negative bacteria.
The minimal inhibitory concentration (MIC) values were
The compounds having thiadiazole moiety showed greater determined as the lowest concentration that completely in-
activity than the compounds having selenadiazole unit. Simi- hibited visible growth of the microorganisms (Table 3). The
larly, compounds with thiazoline unit showed greater activity structure–antimicrobial activity relationship of the synthe-
than compounds with oxazoline unit. In fact, the compounds sized compounds revealed that the compounds having sele-
10a, 10c, 12a and 12c showed excellent activity against nadiazole and diazaphosphole rings in combination with oxa-
Gram-positive bacteria (inhibitory zone ꢃ27 mm) and good zoline moiety exhibited less activity when compared with
activity against Gram-negative bacteria (inhibitory zone compounds having thiadiazole with thiazoline moiety.
ꢃ22 mm). The compounds 7 and 11 displayed less activity Among the substituents on the aryl group, 4-chlorophenyl
derivatives were the most active. The maximum activity was
Table 2. Antifungal Activity of 7—12
observed with compounds 10a, 10c and 12c.
Antioxidant Testing The compounds 7—12 were tested
Zone of inhibition (mm)
for antioxidant property by nitric oxide8,9) and 1,1-diphenyl-
Concentration
Compound
2-picrylhydrazyl (DPPH)10) methods. The compounds 7a, 7c,
(mg/ml)
F. solani
C. lunata
A. niger
9a and 9c exhibited high antioxidant property in both nitric
oxide and DPPH methods at 100 mM concentration (Table 4).
7a
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
100
200
15
18
14
18
17
20
25
27
22
26
28
32
22
25
19
21
23
25
33
36
28
32
34
37
17
20
16
19
17
21
29
32
26
30
33
35
38
42
16
19
15
18
17
21
26
28
23
25
28
30
23
25
20
23
23
26
33
35
27
33
34
38
16
18
15
18
17
20
26
32
25
28
32
36
41
44
16
20
17
21
15
19
25
29
22
24
26
29
20
24
18
20
21
24
30
34
28
32
33
37
17
21
16
20
18
21
25
28
26
31
30
34
36
39
7b
Conclusion
A new class of bis heterocycles-oxazolyl/thiazolyl selena-
diazoles, thiadiazoles and diazaphospholes were developed
by appropriate functionalization of a-ketomethylene and
ester functionalities in phenacylsulfonylacetic acid methyl
ester. The compounds thiazolyl thiadiazoles and thiazolyl di-
azaphospholes exhibited good antimicrobial activity. How-
ever, oxazoyl/thiazolyl selenadiazoles showed good antioxi-
7c
8a
8b
8c
9a
9b
Table 4. Antioxidant Property of 7—12
9c
% Inhibition at 100 mM
Compound
10a
Nitric oxide method
DPPH method
10b
7a
7b
7c
8a
8b
8c
9a
9b
9c
10a
10b
10c
11a
11b
11c
12a
12b
12c
81.17
41.44
88.14
32.27
40.74
34.69
89.64
41.52
91.42
34.71
38.16
24.11
32.62
24.32
36.44
29.58
22.43
39.42
83.52
43.68
86.48
33.74
39.57
36.74
91.21
42.29
92.31
34.79
39.14
25.65
34.71
26.21
34.52
28.65
21.28
38.69
10c
11a
11b
11c
12a
12b
12c
Ketoconazole
Table 3. Minimal Inhibitory Concentrations (MIC, mg/ml) of Compounds 10a, 10c and 12c
Minimal inhibitory concentration (MIC, mg/ml)
Compound
S. aureus
B. subtilis
E. coli
K. pneumoniae
F. solani
C. lunata
A. niger
10a
10c
12c
12.5
25
100
6.25
—
50
100
200
6.25
—
12.5
50
50
6.25
—
50
50
100
12.5
—
50
100
100
—
12.5
50
100
—
6.25
25
100
100
—
Chloramphenicol
Ketoconazole
12.5
6.25

564
Vol. 57, No. 6
129.4, 131.2, 132.1 (aromatic carbons): Anal. Calcd for C12H11N3O3S2: C,
46.59 ; H, 3.58; N, 13.58 ; Found: C, 46.68; H, 3.63; N, 13.66.
dant property.
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-p-methylphenyl-1,2,3-
Experimental
thiadiazole (8b): White solid, yield 68%, mp 187—188 °C; IR (KBr) cmꢂ1
:
Melting points were determined in open capillaries on a Mel-Temp appa-
ratus and were uncorrected. The purity of the compounds was checked by
TLC (silica gel H, British Drug House (BDH), ethyl acetate–hexane, 0.5 : 2).
The IR spectra were recorded on a Thermo Nicolet IR 200 FT-IR spectrome-
1582 (CꢄN), 1447 (NꢄN), 1342, 1137 (SO2), 721 (C–S); 1H-NMR
(DMSO-d6) d: 2.25 (s, 3H, Ar-CH3), 3.63 (t, 2H, C-4ꢀ, Jꢄ5.5 Hz), 4.26 (s,
2H, SO2–CH2), 4.90 (t, 2H, C-5ꢀ, Jꢄ5.5 Hz), 7.25—7.60 (m, 4H, Ar-H);
13C-NMR (DMSO-d6) d: 21.8 (Ar-CH3), 51.2 (C-4ꢀ), 55.3 (SO2–CH2), 58.9
(C-5ꢀ), 157.3 (C-5), 158.2 (C-4), 160.8 (C-2ꢀ), 126.0, 128.4, 129.6, 131.7
(aromatic carbons): Anal. Calcd for C13H13N3O3S2: C, 48.28; H, 4.05; N,
12.99; Found: C, 48.22; H, 4.08; N, 13.06.
ter as KBr pellets and the wave numbers were given in cmꢂ1. The H-NMR
1
spectra were recorded in CDCl3/DMSO-d6 on a Varian EM-360 spectrome-
ter (300 MHz). The 13C-NMR spectra were recorded in CDCl3/DMSO-d6 on
a Varian VXR spectrometer operating at 75.5 MHz. All chemical shifts were
reported in d (ppm) using tetramethylsilane (TMS) as an internal standard.
The microanalyses were performed on Perkin-Elmer 240C elemental ana-
lyzer. The antioxidant property was carried out by using Shimadzu UV-2450
spectrophotometer. The starting compounds (4-aryl[1,2,3]selenadiazole-
5-sulfonyl)acetic acid methyl ester (3), (4-aryl[1,2,3]thiadiazole-5-
sulfonyl)acetic acid methyl ester (4) and (2-phenyl-5-aryl-2H-[1,2,3]diaza-
phosphole-4-sulfonyl)acetic acid methyl ester (6) were prepared by the liter-
ature procedure.3)
General Procedure of Synthesis of 5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-
methylsulfonyl)-4-aryl-1,2,3-selenadiazole (7a—c) To a flask charged
with anhydrous samarium chloride (0.1 mmol), dry toluene (10 ml) and 2-
aminoethanol (2 mmol) followed by n-butyllithium (2.2 mmol) were added
at 0 °C. The reaction mixture was stirred at the same temperature for 30 min.
Then the contents were refluxed to 100—120 °C and (4-aryl[1,2,3]selenadia-
zole-5-sulfonyl)acetic acid methyl ester (3) (1 mmol) was added and contin-
ued the refluxion for an additional period of 12—14 h. The suspension was
cooled to room temperature and filtered. The filtrate was extracted with
chloroform, washed with water followed by brine solution. The solvent was
removed in vacuo. The product was purified by column chromatography
(hexane–ethyl acetate, 1.5 : 1).
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-p-chlorophenyl-1,2,3-
thiadiazole (8c): White solid, yield 70%, mp 195—196 °C; IR (KBr) cmꢂ1
:
1589 (CꢄN), 1452 (NꢄN), 1338, 1141 (SO2), 726 (C–S); 1H-NMR
(DMSO-d6) d: 3.67 (t, 2H, C-4ꢀ, Jꢄ5.3 Hz), 4.24 (s, 2H, SO2–CH2), 5.00 (t,
2H, C-5ꢀ, Jꢄ5.3 Hz), 7.34—7.67 (m, 4H, Ar-H); 13C-NMR (DMSO-d6) d:
50.8 (C-4ꢀ), 55.1 (SO2–CH2), 59.3 (C-5ꢀ), 158.7 (C-5), 158.9 (C-4), 161.8
(C-2ꢀ), 128.2, 129.5, 130.6, 132.6 (aromatic carbons): Anal. Calcd for
C12H10ClN3O3S2: C, 41.92; H, 2.93; N, 12.22; Found: C, 41.97; H, 3.00; N,
12.28.
General Procedure of Synthesis of 5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-
methylsulfonyl)-4-aryl-1,2,3-selenadiazole (9a—c) Dry toluene (10 ml)
and 2-aminoethnethiol (2 mmol) were added to a flask charged with anhy-
drous samarium chloride (0.1 mmol). Then n-buyllithium (2.2 mmol) was
added at 0 °C portion-wise while stirring and the flask was allowed to attain
room temperature. To this, (4-aryl[1,2,3]selenadiazole-5-sulfonyl)acetic acid
methyl ester (3) was added and refluxed for 9—12 h. The suspension was
cooled to room temperature, filtered and washed with chloroform. The fil-
trate was extracted with chloroform and washed with water. The solvent was
removed in vacuo. The solid obtained was purified by column chromatogra-
phy (hexane–ethyl acetate, 2 : 1.4).
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-phenyl-1,2,3-selenadi-
azole (9a): Red solid, yield 62%, mp 145—147 °C; IR (KBr) cmꢂ1: 1591
(CꢄN), 1451 (NꢄN), 1334, 1139 (SO2), 722 (C–Se); 1H-NMR (DMSO-d6)
d: 3.32 (t, 2H, C-5ꢀ, Jꢄ7.3 Hz), 3.71 (t, 2H, C-4ꢀ, Jꢄ7.3 Hz), 4.25 (s, 2H,
SO2–CH2), 7.31—7.64 (m, 5H, Ar-H); 13C-NMR (DMSO-d6) d: 37.4 (C-5ꢀ),
52.8 (C-4ꢀ), 55.4 (SO2–CH2), 157.8 (C-5), 158.7 (C-4), 160.9 (C-2ꢀ), 127.9,
129.4, 130.4, 132.4 (aromatic carbons): Anal. Calcd for C12H11N3O2S2Se: C,
38.71; H, 2.98; N, 11.29; Found: C, 38.79; H, 2.92; N, 11.21.
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-phenyl-1,2,3-selenadia-
zole (7a): Red solid, yield 65%, mp 136—138 °C; IR (KBr) cmꢂ1: 1579
(CꢄN), 1444 (NꢄN), 1336, 1137 (SO2), 731 (C–Se); 1H-NMR (DMSO-d6)
d: 3.68 (t, 2H, C-4ꢀ Jꢄ5.1 Hz), 4.28 (s, 2H, SO2–CH2), 4.97 (t, 2H, C-5ꢀ,
Jꢄ5.1 Hz), 7.30—7.60 (m, 5H, Ar-H); 13C-NMR (DMSO-d6) d: 52.4 (C-4ꢀ),
55.2 (SO2–CH2), 59.2 (C-5ꢀ), 157.7 (C-5), 159.1 (C-4), 160.4 (C-2ꢀ), 127.2,
130.7, 135.3, 135.9 (aromatic carbons): Anal. Calcd for C12H11N3O3SSe: C,
40.46; H, 3.11; N, 11.79; Found: C, 40.58; H, 3.18; N, 11.90.
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-p-methylphenyl-1,2,3-
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-p-methylphenyl-1,2,3-
selenadiazole (9b): Red solid, yield 70%, mp 152—154 °C; IR (KBr) cmꢂ1
:
selenadiazole (7b): Red solid, yield 62%, mp 125—127 °C; IR (KBr) cmꢂ1
:
1588 (CꢄN), 1455 (NꢄN), 1345, 1140 (SO2), 727 (C–Se); 1H-NMR
(DMSO-d6) d: 2.29 (s, 3H, Ar-CH3), 3.35 (t, 2H, C-5ꢀ, Jꢄ7.1 Hz), 3.76 (t,
2H, C-4ꢀ, Jꢄ7.1 Hz), 4.21 (s, 2H, SO2–CH2), 7.34—7.69 (m, 4H, Ar-H);
13C-NMR (DMSO-d6) d: 22.6 (Ar-CH3), 38.1 (C-5ꢀ), 51.7 (C-4ꢀ), 55.0
(SO2–CH2), 157.3 (C-5), 158.2 (C-4), 161.3 (C-2ꢀ), 126.5, 128.3, 129.8,
131.4 (aromatic carbons): Anal. Calcd for C13H13N3O2S2Se: C, 40.41; H,
3.39; N, 10.88; Found: C, 40.50; H, 3.43; N, 10.95.
1584 (CꢄN), 1431 (NꢄN), 1332, 1131 (SO2), 729 (C–Se); 1H-NMR
(DMSO-d6) d: 2.22 (s, 3H, Ar-CH3), 3.65 (t, 2H, C-4ꢀ, Jꢄ5.5 Hz), 4.22 (s,
2H, SO2–CH2), 4.93 (t, 2H, C-5ꢀ, Jꢄ5.5 Hz), 7.32—7.61 (m, 4H, Ar-H);
13C-NMR (DMSO-d6) d: 22.4 (Ar-CH3), 51.8 (C-4ꢀ), 55.8 (SO2–CH2), 58.6
(C-5ꢀ), 157.5 (C-5), 158.1 (C-4), 160.1 (C-2ꢀ), 126.2, 130.4, 132.8, 135.6
(aromatic carbons): Anal. Calcd for C13H13N3O3SSe: C, 42.17; H, 3.54; N,
11.35; Found: C, 42.25; H, 3.58; N, 11.30.
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-p-chlorophenyl-1,2,3-
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-p-chlorophenyl-1,2,3-
selenadiazole (9c): Red solid, yield 65%, mp 159—161 °C; IR (KBr) cmꢂ1
:
selenadiazole (7c): Red solid, yield 67%, mp 140—142 °C; IR (KBr) cmꢂ1
:
1594 (CꢄN), 1459 (NꢄN), 1339, 1146 (SO2), 734 (C–Se); 1H-NMR
(DMSO-d6) d: 3.39 (t, 2H, C-5ꢀ, Jꢄ7.6 Hz), 3.79 (t, 2H, C-4ꢀ, Jꢄ7.6 Hz),
4.27 (s, 2H, SO2–CH2), 7.35—7.71 (m, 4H, Ar-H); 13C-NMR (DMSO-d6) d:
37.8 (C-5ꢀ), 52.3 (C-4ꢀ), 55.6 (SO2–CH2), 158.0 (C-5), 158.9 (C-4), 161.7
(C-2ꢀ), 128.7, 128.8, 129.4, 135.4 (aromatic carbons): Anal. Calcd for
C12H10ClN3O2S2Se: C, 35.43; H, 2.48; N, 10.33; Found: C, 35.39; H, 2.54;
N, 10.38.
1581 (CꢄN), 1452 (NꢄN), 1340, 1140 (SO2), 724 (C–Se); 1H-NMR
(DMSO-d6) d: 3.70 (t, 2H, C-4ꢀ, Jꢄ5.3 Hz), 4.25 (s, 2H, SO2–CH2), 5.02 (t,
2H, C-5ꢀ, Jꢄ5.3 Hz), 7.34—7.66 (m, 4H, Ar-H); 13C-NMR (DMSO-d6) d:
51.6 (C-4ꢀ), 55.6 (SO2–CH2), 60.2 (C-5ꢀ), 158.1 (C-5), 159.3 (C-4), 161.0
(C-2ꢀ), 128.7, 128.8, 129.4, 133.4 (aromatic carbons): Anal. Calcd for
C12H10ClN3O3SSe: C, 36.89; H, 2.58; N, 10.75; Found: C, 36.80; H, 2.55; N,
10.85.
General Procedure of Synthesis of 5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-
methylsulfonyl)-4-aryl-1,2,3-thiadiazole (10a—c) Dry toluene (10 ml)
and 2-aminoethanethiol (2 mmol) were added to the flask charged with anhy-
drous samarium chloride (0.1 mmol). To this, n-butyllithium (2.2 mmol) was
added at 0 °C and stirred at the same temperature for 15 min. Then (4-
aryl[1,2,3]thiadiazole-5-sulfonyl)acetic acid methyl ester (4) (1 mmol) was
added and the reaction mixture was refluxed for 8—10 h. The suspension
was cooled to room temperature and filtered. The filtrate was extracted with
chloroform and washed with water. The solvent was removed under reduced
pressure. The resultant solid was purified by column chromatography
(hexane–ethyl acetate, 2 : 1.5).
General Procedure of Synthesis of 5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-
methylsulfonyl)-4-aryl-1,2,3-thiadiazole (8a—c) To a mixture of anhy-
drous samarium chloride, (0.1 mmol), dry toluene (10 ml) and 2-
aminoethanol, (2 mmol), n-butyllithium (2.2 mmol) was added at 0 °C and
stirred for 15 min. Then the contents were allowed to attain room tempera-
ture. To this (4-aryl[1,2,3]thiadiazole-5-sulfonyl)acetic acid methyl ester (4)
(1 mmol) was added and the reaction mixture was refluxed for a period of
13—15 h. The suspension was cooled to room temperature and filtered. The
filtrate was extracted with chloroform, washed with water and the solvent
was removed under reduced pressure. The solid obtained was purified by
column chromatography (hexane–ethyl acetate, 1.3 : 1).
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-phenyl-1,2,3-thiadiazole
5-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-4-phenyl-1,2,3-thiadiazole
(10a): White solid, yield 72%, mp 178—180 °C; IR (KBr) cmꢂ1: 1596
(8a): White solid, yield 64%, mp 180—182 °C; IR (KBr) cmꢂ1: 1586
1
1
(CꢄN), 1453 (NꢄN), 1331, 1132 (SO2), 720 (C–S); H-NMR (DMSO-d6)
(CꢄN), 1449 (NꢄN), 1331, 1133 (SO2), 719 (C–S); H-NMR (DMSO-d6)
d: 3.36 (t, 2H, C-5ꢀ, Jꢄ7.0 Hz), 3.74 (t, 2H, C-4ꢀ, Jꢄ7.0 Hz), 4.23 (s, 2H,
SO2–CH2), 7.36—7.71 (m, 5H, Ar-H); 13C-NMR (DMSO-d6) d: 37.1 (C-5ꢀ),
52.0 (C-4ꢀ), 55.1 (SO2–CH2), 158.6 (C-5), 159.2 (C-4), 160.6 (C-2ꢀ), 127.0,
d: 3.72 (t, 2H, C-4ꢀ, Jꢄ5.2 Hz), 4.20 (s, 2H, SO2–CH2), 4.92 (t, 2H, C-5ꢀ,
Jꢄ5.2 Hz), 7.28—7.63 (m, 5H, Ar-H); 13C-NMR (DMSO-d6) d: 52.3 (C-4ꢀ),
55.8 (SO2–CH2), 59.7 (C-5ꢀ), 157.7 (C-5), 158.6 (C-4), 160.3 (C-2ꢀ), 128.4,

June 2009
565
cmꢂ1: 1586 (CꢄN), 1330, 1137 (SO2); 1H-NMR (DMSO-d6) d: 3.33 (t, 2H,
C-5ꢀ, Jꢄ7.2 Hz), 3.78 (t, 2H, C-4ꢀ, Jꢄ7.2 Hz), 4.22 (s, 2H, SO2–CH2),
7.61—7.70 (m, 10H, Ar-H); 13C-NMR (DMSO-d6) d: 37.5 (C-5ꢀ), 52.3 (C-
4ꢀ), 55.1 (SO2–CH2), 148.2 (C-5), 157.2 (C-4), 161.8 (C-2ꢀ), 128.7, 129.4,
130.2, 131.6, 132.1, 132.8, 133.7, 134.0 (aromatic carbons): Anal. Calcd for
C18H16N3O2PS2: C, 53.85; H, 4.02; N, 10.47; Found: C, 53.92; H, 4.00; N,
10.40.
4-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-5-p-methylphenyl-2-
phenyl-2H-1,2,3-diazaphosphole (12b): Yellow solid, yield 69%, mp 149—
151 °C; IR (KBr) cmꢂ1: 1588 (CꢄN), 1342, 1145 (SO2); 1H-NMR (DMSO-
d6) d: 2.26 (s, 3H, Ar-CH3), 3.37 (t, 2H, C-5ꢀ, Jꢄ7.5 Hz), 3.72 (t, 2H, C-4ꢀ,
Jꢄ7.5 Hz), 4.30 (s, 2H, SO2–CH2), 7.64—7.71 (m, 9H, Ar-H); 13C-NMR
(DMSO-d6) d: 22.7 (Ar-CH3), 37.9 (C-5ꢀ), 53.1 (C-4ꢀ), 54.2 (SO2–CH2),
148.9 (C-5), 156.9 (C-4), 161.1 (C-2ꢀ), 128.1, 129.8, 130.7, 131.3, 132.5,
133.2, 133.9, 134.2 (aromatic carbons): Anal. Calcd for C19H18N3O2PS2: C,
54.93; H, 4.37; N, 10.11; Found: C, 54.88; H, 4.40; N, 10.15.
4-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-5-p-chlorophenyl-2-
phenyl-2H-1,2,3-diazaphosphole (12c): Yellow solid, yield 63%, mp 162—
164 °C; IR (KBr) cmꢂ1: 1592 (CꢄN), 1333, 1141 (SO2); 1H-NMR (DMSO-
d6) d: 3.40 (t, 2H, C-5ꢀ, Jꢄ7.8 Hz), 3.76 (t, 2H, C-4ꢀ, Jꢄ7.8 Hz), 4.23 (s,
2H, SO2–CH2), 7.62—7.79 (m, 9H, Ar-H); 13C-NMR (DMSO-d6) d: 37.1
(C-5ꢀ), 52.6 (C-4ꢀ), 55.4 (SO2–CH2), 148.0 (C-5), 157.6 (C-4), 160.5 (C-2ꢀ),
128.5, 129.1, 130.4, 131.9, 132.7, 133.1 133.9, 134.8 (aromatic carbons):
Anal. Calcd for C18H15ClN3O2PS2: C, 49.60; H, 3.47; N, 9.64; Found: C,
49.67; H, 3.49; N, 9.70.
128.4, 130.4, 131.6 (aromatic carbons): Anal. Calcd for C12H11N3O2S3: C,
44.29; H, 3.41; N, 12.91; Found: C, 44.25; H, 3.37; N, 12.95.
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-p-methylphenyl-1,2,3-
thiadiazole (10b): White solid, yield 70%, mp 171—173 °C; IR (KBr) cmꢂ1
:
1582 (CꢄN), 1459 (NꢄN), 1340, 1146 (SO2), 729 (C–S); 1H-NMR
(DMSO-d6) d: 2.23 (s, 3H, Ar-CH3), 3.38 (t, 2H, C-5ꢀ, Jꢄ7.4 Hz), 3.70 (t,
2H, C-4ꢀ, Jꢄ7.4 Hz), 4.26 (s, 2H, SO2–CH2), 7.31—7.62 (m, 4H, Ar-H);
13C-NMR (DMSO-d6) d: 22.2 (Ar-CH3), 37.9 (C-5ꢀ), 52.2 (C-4ꢀ), 55.3
(SO2–CH2), 157.9 (C-5), 159.6 (C-4), 160.1 (C-2ꢀ), 127.8, 128.1, 129.2,
130.6 (aromatic carbons): Anal. Calcd for C13H13N3O2S3: C, 46.00; H, 3.86;
N, 12.38; Found: C, 46.10; H, 3.91; N, 12.31.
5-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-4-p-chlorophenyl-1,2,3-
thiadiazole (10c): White solid, yield 74%, mp 185—186 °C; IR (KBr) cmꢂ1
:
1599 (CꢄN), 1452 (NꢄN), 1332, 1141 (SO2), 737 (C–S); 1H-NMR
(DMSO-d6) d: 3.42 (t, 2H, C-5ꢀ, Jꢄ7.7 Hz), 3.76 (t, 2H, C-4ꢀ, Jꢄ7.4 Hz),
4.21 (s, 2H, SO2–CH2), 7.34—7.69 (m, 4H, Ar-H); 13C-NMR (DMSO-d6) d:
37.6 (C-5ꢀ), 52.7 (C-4ꢀ), 55.9 (SO2–CH2), 158.7 (C-5), 159.2 (C-4), 160.6
(C-2ꢀ), 128.2, 129.6, 130.4, 131.4 (aromatic carbons): Anal. Calcd for
C12H10ClN3O2S3: C, 40.05; H, 2.80; N, 11.68; Found: C, 40.11; H, 2.83; N,
11.74.
General Procedure of Synthesis of 4-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-
methylsulfonyl)-2-phenyl-5-aryl-2H-1,2,3-diazaphospholes (11a—c) To
a flask charged with anhydrous samarium chloride (0.1 mmol), dry toluene
(10 ml) and 2-aminoethanol (2 mmol) were added followed by n-butyl-
lithium (2.2 mmol) at 0 °C. the reaction mixture was stirred at 0 °C for 30—
40 min. Then the contents were refluxed to 100—120 °C and (2-phenyl-5-
aryl-2H-[1,2,3]diazaphosphole-4-sulfonyl)acetic acid methyl ester (6)
(1 mmol) was added and continued the refluxion for an additional period of
14—18 h. The suspension was cooled to room temperature and filtered. The
filtrate was extracted with dichloromethane, washed with water followed by
brine solution. the solvent was removed in vacuo. The product was purified
by column chromatography (hexane–ethyl acetate, 2 : 1).
4-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-2,5-diphenyl-2H-1,2,3-di-
azaphosphole (11a): Yellow solid, yield 62%, mp 160—162 °C; IR (KBr)
cmꢂ1: 1581 (CꢄN), 1331, 1132 (SO2); 1H-NMR (DMSO-d6) d: 3.66 (t, 2H,
C-4ꢀ, Jꢄ5.5 Hz), 4.24 (s, 2H, SO2–CH2), 4.96 (t, 2H, C-5ꢀ, Jꢄ5.5 Hz),
7.64—7.72 (m, 10H, Ar-H); 13C-NMR (DMSO-d6) d: 52.8 (C-4ꢀ), 55.6
(SO2–CH2), 59.7 (C-5ꢀ), 147.7 (C-5), 158.1 (C-4), 161.2 (C-2ꢀ), 128.2,
129.7, 130.8, 131.2, 132.2, 133.8, 134.2, 134.4 (aromatic carbons): Anal.
Calcd for C18H16N3O3PS: C, 56.10; H, 4.18; N, 10.90; Found: C, 56.16; H,
4.22; N, 10.96.
4-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-5-p-methylphenyl-2-
phenyl-2H-1,2,3-diazaphosphole (11b): Yellow solid, yield 66%, mp 155—
157 °C; IR (KBr) cmꢂ1: 1576 (CꢄN), 1340, 1146 (SO2); 1H-NMR (DMSO-
d6) d: 2.30 (s, 3H, Ar-CH3), 3.63 (t, 2H, C-4ꢀ, Jꢄ5.1 Hz), 4.34 (s, 2H,
SO2–CH2), 4.89 (t, 2H, C-5ꢀ, Jꢄ5.1 Hz), 7.30—7.68 (m, 9H, Ar-H) 13C-
NMR (DMSO-d6) d: 22.3 (Ar-CH3), 51.2 (C-4ꢀ), 55.4 (SO2–CH2), 58.9 (C-
5ꢀ), 148.4 (C-5), 159.0 (C-4), 161.6 (C-2ꢀ), 127.3, 128.7, 129.3, 130.6,
131.1, 131.9, 132.7, 133.9 (aromatic carbons): Anal. Calcd for
C19H18N3O3PS: C, 57.14; H, 4.54; N, 10.52; Found: C, 57.10; H, 4.51; N,
10.55.
4-(4ꢀ,5ꢀ-Dihydrooxazol-2ꢀ-yl-methylsulfonyl)-5-p-chlorophenyl-2-phenyl-
2H-1,2,3-diazaphosphole (11c): Yellow solid, yield 65%, mp 168—170 °C;
IR (KBr) cmꢂ1: 1584 (CꢄN), 1334, 1149 (SO2); 1H-NMR (DMSO-d6) d:
3.69 (t, 2H, C-4ꢀ, Jꢄ5.4 Hz), 4.29 (s, 2H, SO2–CH2), 4.99 (t, 2H, C-5ꢀ,
Jꢄ5.4 Hz), 7.38—7.82 (m, 9H, Ar-H); 13C-NMR (DMSO-d6) d: 51.8 (C-4ꢀ),
55.9 (SO2–CH2), 59.5 (C-5ꢀ), 148.9 (C-5), 157.9 (C-4), 161.4 (C-2ꢀ), 128.3,
128.9, 129.6, 131.5, 132.6, 133.4, 133.9, 134.8 (aromatic carbons): Anal.
Calcd for C18H15ClN3O3PS: C, 51.50; H, 3.60; N, 10.01; Found: C, 51.56; H,
3.65; N, 10.08.
Antimicrobial Testing The compounds 7—12 were dissolved in di-
methyl sulfoxide (DMSO) at different concentrations of 100, 200 and
800 mg/ml.
Antibacterial and Antifungal Assays Preliminary antimicrobial activ-
ity of compounds 7—12 was tested by agar disc-diffusion method. Sterile
filter paper discs (6 mm diameter) moistened with the test compound solu-
tion in DMSO of specific concentration 100 mg and 200 mg/disc were care-
fully placed on the agar culture plates that had been previously inoculated
separately with the microorganisms. The plates were incubated at 37 °C and
the diameter of the growth inhibition zones were measured after 24 h in case
of bacteria and after 48 h in case of fungi.
The MICs of the compound assays were determined using microdilution
susceptibility method. Chloramphenicol was used as reference antibacterial
agent. Ketoconazole was used as reference antifungal agent. The test com-
pounds, chloramphenicol and ketoconazole were dissolved in DMSO at con-
centration of 800 mg/ml. The two-fold dilution of the solution was prepared
(400, 200, 100, …, 6.25 mg/ml). The microorganism suspensions were incu-
bated at 36 °C for 24 and 48 h for bacteria and fungi, respectively. The mini-
mum inhibitory concentrations of the compounds were recorded as the low-
est concentration of each chemical compounds in the tubes with no turbidity
(i.e. no growth) of inoculated bacteria/fungi.
Antioxidant Testing The compounds 7—12 are tested for antioxidant
property by nitric oxide and DPPH methods.
Assay for Nitric Oxide (NO) Scavenging Activity Sodium nitroprus-
side (5 mM) in phosphate buffer pH 7.4 was incubated with 100 mM concen-
tration of test compounds dissolved in a suitable solvent (dioxane/methanol)
and tubes were incubated at 25 °C for 120 min. Control experiment was con-
ducted with equal amount of solvent in an identical manner. At intervals,
0.5 ml of incubation solution was taken and diluted with 0.5 ml of griess
reagent (1% sulfanilamide, 0.1% N-naphthylethylenediamine dihydrochlo-
ride and 2% O-phosphoric acid dissolved in distilled water). The absorbance
of the chordophone formed during diazotization of nitrite with sulfanilamide
and subsequent N-naphthylethylenediamine dihydrochloride was read at l
546 nm. The experiment was repeated in triplicate.
Reduction of 1,1-Diphenyl-2-picrylhydrazyl (DPPH) Free Radical
(DPPH Method) The nitrogen centered stable free radical 1,1-diphenyl-2-
picrylhydrazyl (DPPH) has often been used to characterize antioxidants. It is
reversibly reduced and the odd electron in the DPPH free radical gives a
strong absorption maximum at l 517 nm, which is purple in color. This
property makes it suitable for spectrophotometric studies. A radical scaveng-
ing antioxidant reacts with DPPH stable free radical and converts into 1,1-
diphenyl-2-picrylhydrazine. The resulting decolorization is stoichiometric
with respect to the number of electrons captured. The change in the ab-
sorbance produced in this reaction has been used to measure antioxidant
properties.
General Procedure of Synthesis of 4-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-
methylsulfonyl)-2-phenyl-5-aryl-2H-1,2,3-diazaphospholes (12a—c)
Anhydrous samarium chloride (0.1 mmol), dry toluene (10 ml) and 2-
aminoethanethiol (2 mmol) were taken into a flask, and to this, n-butyl-
lithium (2.2 mmol) was added at 0 °C. After the reaction mixture was stirred
at 0 °C for 15 min, the flask was heated to reflux. Then (2-phenyl-5-aryl-2H-
[1,2,3]diazaphosphole-4-sulfonyl)acetic acid methyl ester (6) (1 mmol) was
added and refluxed for an additional period of 10—12 h. The suspension was
cooled to room temperature and filtered. The filtrate was extracted with
chloroform, washed with water, and the solvent was removed under vacuum.
The product was purified by column chromatography (hexane–ethyl acetate,
2 : 0.8).
The solutions of test compounds (100 mM) were added to DPPH (100 mM)
in dioxane/ethanol. The tubes were kept at an ambient temperature for
20 min and the absorbance was measured at l 517 nm. The difference be-
tween the test and the control experiments was taken and expressed as the
4-(4ꢀ,5ꢀ-Dihydrothiazol-2ꢀ-yl-methylsulfonyl)-2,5-diphenyl-2H-1,2,3-di-
azaphosphole (12a): Yellow solid, yield 67%, mp 176—178 °C: IR (KBr)

566
Vol. 57, No. 6
per cent scavenging of the DPPH radical.
4) Padmavathi V., Nagendra Mohan A. V., Mahesh K., J. Heterocycl.
Chem., 45, 1131— 1138 (2008).
Acknowledgements The authors are thankful to UGC, New Delhi,
India for financial assistance under major research project. One of the au-
thors K. Mahesh is thankful to CSIR, New Delhi, India for the sanction of
Senior Research Fellowship.
5) Padmavathi V., Obula Reddy B. C., Venkata Subbaiah D. R. C., Pad-
maja A., Indian J. Chem., 43B, 2456—2458 (2004).
6) Padmavathi V., Obula Reddy B. C., Nagendra Mohan A. V., Padmaja
A., J. Heterocycl. Chem., 44, 459—462 (2007).
7) Vincent J. C., Vincent H. W., Proc. Soc. Exp. Biol. Merd., 55, 162—
164 (1944).
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