CsF-Celite catalyzed facile N-alkylation of 2(3H)-benzoxazolones and antimicrobial properties of 2-substituted benzoxazole and 3-substituted-2(3H)- benzoxazolone derivatives

Article abstract of DOI:10.1007/s00044-010-9367-5

The synthesis and antimicrobial activity studies of a new series of cyclic amine containing benzoxazoles and benzoxazolone-2(3H)-ones derivatives were described. The alkylation of benzoxazolone was carried out using cesium fluoride-Celite. The newly synthesized compounds with the influence of the induction of the cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to the antibacterial and antifungal activity. The 2-cyclic amine-1,3-benzoxazoles (5a-l), 5-chloro-3-alkyl substituted-1,3- benzoxazol-2(3H)-ones (8a-f), and 3-[3- (cyclic amine)propyl]-1,3-benzoxazol- 2(3H)-ones (9a-f) were synthesized. These derivatives were tested for antibacterial and antifungal activity. Among the compounds tested, 8c and 9f showed moderate to good antibacterial and antifungal activity. Compound 8a showed good antifungal activity. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9367-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:626–636
DOI 10.1007/s00044-010-9367-5
ORIGINAL RESEARCH
CsF–Celite catalyzed facile N-alkylation of 2(3H)-benzoxazolones
and antimicrobial properties of 2-substituted benzoxazole
and 3-substituted-2(3H)-benzoxazolone derivatives
M. S. R. Murty
J. S. Yadav U. S. N. Murty
•
•
Kesur R. Ram
•
•
Rayudu Venkateswara Rao
K. Pranay Kumar
•
Received: 11 February 2010 / Accepted: 5 May 2010 / Published online: 29 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The synthesis and antimicrobial activity studies
of a new series of cyclic amine containing benzoxazoles
and benzoxazolone-2(3H)-ones derivatives were described.
The alkylation of benzoxazolone was carried out using
cesium fluoride–Celite. The newly synthesized compounds
with the influence of the induction of the cyclic amine
moiety in the benzoxazole scaffold have been evaluated
with respect to the antibacterial and antifungal activity. The
Introduction
An essential component of the search for new leads in a
drug designing program is the synthesis of molecules,
which are novel yet resemble known biologically active
molecules by virtue of the presence of some critical
structural features. Certain small heterocyclic molecules
act as highly functionalized scaffolds. These are known
pharmacophores of a number of biologically active and
medicinally useful molecules (Silverman, 1992; Thompson
and Ellman, 1996; Robert, 2000). The rapidly increasing
occurrence of multiple drug-resistant microbial strains is a
serious problem. As the emergence of anti resistant bacteria
is inevitable, there is an urgency for the discovery of novel
active agents, which is of the highest priority (Norrby,
2001; Tomasz, 1994). Previous reports reveal that benz-
oxazole derivatives are biologically significant compounds
and are known to exhibit various biological activities such
as anticancer (Kumar et al., 2002; Easmon et al., 2001;
Jauhari et al., 2008; Rida et al., 2005), antimicrobial
2
-cyclic amine-1,3-benzoxazoles (5a–l), 5-chloro-3-alkyl
substituted-1,3-benzoxazol-2(3H)-ones (8a–f), and 3-[3-
cyclic amine)propyl]-1,3-benzoxazol-2(3H)-ones (9a–f)
(
were synthesized. These derivatives were tested for anti-
bacterial and antifungal activity. Among the compounds
tested, 8c and 9f showed moderate to good antibacterial
and antifungal activity. Compound 8a showed good anti-
fungal activity.
Keywords Benzoxazole Á Benzoxazolone Á
Cyclic amine Á Cesium fluoride–Celite Á
Antibacterial and antifungal
(
(
Kumar et al., 2002; Temiz-Arpacı et al., 2005), anti-HIV
Rida et al., 2005; Temiz-Arpacı et al., 2005), and dopa-
mine D4 agonists (Wang et al., 2005). The substitution at
second position in benzoxazole skeleton is influential for
the biological activity of the molecule. Thus, the 2-
substituted bis(benzoxazole), UK-1 (A) is a natural product
(Fig. 1) (Ueki et al., 1993) and it showed a wide spectrum
of potent anticancer activity against leukemia and lym-
phoma. The cytotoxicity of the synthetic analogs (Kerwin
and Mckee, 2008) of UK-1 was studied toward selective
cancer cell lines. Routiennocin (B) (Fig. 1) is a spiroketal
antibiotic, isolated from a strain of Streptomyces chart-
reusis possessing a benzoxazole ring in its molecular
structure, was found to be very active especially against
some Gram-positive bacteria by acting as a good ionophore
Dedicated to Dr. J. Madhusudhana Rao, Director Grade Scientist &
Head, Organic Chemistry Division-I, I.I.C.T., Hyderabad, India on his
6
0th Birth Day.
M. S. R. Murty (&) Á K. R. Ram Á R. V. Rao Á J. S. Yadav
Discovery Laboratory, Organic Chemistry Division-I, Indian
Institute of Chemical Technology, Uppal Road, Hyderabad
500607, India
e-mail: msrmurty@ymail.com
U. S. N. Murty Á K. Pranay Kumar
Biology Division, Indian Institute of Chemical Technology,
Uppal Road, Hyderabad 500607, India
1
23

Med Chem Res (2011) 20:626–636
627
(
Prudhomme et al., 1986; Martin et al., 1992). Chlorzox-
molecule frame work has been the subject of considerable
synthetic effort.
azone (C) is a muscle relaxant, benoxaprofen (D) and
flunoxaprofen (E) are anti-inflammatory drugs and these
molecules contain benzoxazole pharmacophore. The
chemical structures of the drugs are depicted in Fig. 1.
The 2(3H)-benzoxazolone heterocycles are considered
as ‘‘privileged scaffolds’’ in the design of pharmacological
probes. The 2(3H)-benzoxazolone heterocycles and its
bioisosteric surrogates such as 2(3H)-benzothiazolinone,
benzoxazinone, etc., have received considerable attention
from the medicinal chemists owing to their capacity to
mimic a phenol or a catechol moiety in a metabolically
stable template (Poupaert et al., 2005). The benzoxazolone
heterocycle has high flexibility in chemical modifications,
allowing changes to the characteristics of side-chains on a
rigid platform (Chiarotto et al., 2009). Due to that, this
template has very broad therapeutic applications. The
Discussion
Chemistry
In our on going research program of drug designing for new
leads, various 2-cyclic amine substituted-1,3-benzoxazoles
(5a–l), 5-chloro-3-alkyl substituted-1,3-benzoxazol-2(3H)-
ones (8a–f), and 3-[3-(cyclic amine)propyl]-1,3-ben-
zoxazol-2(3H)-ones (9a–f) were synthesized and were
evaluated for antibacterial and antifungal activities. The 2-
chlorobenzoxazole (3) was commercially available chemi-
cal and also otherwise we prepared starting from 2-amino
phenol (1) (Yamada et al., 1998). The 2-aminophenol was
treated with carbon disulfide under basic conditions to
obtain 2-mercapto-1,3-benzoxazole (2), which was further
2
(3H)-benzoxazolone heterocycles exhibits various bio-
logical activities like anti-HIV (Deng et al., 2006), anti-
cancer (Ivanova et al., 2007), analgesic (Unlu et al., 2003),
anti-inflammatory (Koksal et al., 2005), antinociceptive
reacted with phosphorus pentachloride (PCl ) to obtain
5
2-chlorobenzoxazole (3). The 2-chlorobenzoxazole was
treated with various cyclic amines (4) in acetonitrile at 0°C
to obtain the compounds 5a–l (Scheme 1). The products and
the corresponding yields are listed in Table 1. When
1 equivalent of 2-methylpiperazine was reacted with 2-
chlorobenzoxazole, only mono alkylated product 5i formed,
i.e., alkylation occurred at the less hindered nitrogen. Sim-
ilarly, when 1 equivalent homopiperazine reacted with
2-chlorobenzoxazole, only mono alkylated product 5j formed.
Compounds 8a–f and 9a–f were synthesized starting from
commercially available 5-chlorobenzoxazolone (6) as shown
in Scheme 2 and the results were mentioned in Table 2.
The alkylation of benzoxazolone under basic conditions,
which makes use of base like K CO , is known in literature
(
Onkol et al., 2001), antimicrobial (Koksal et al., 2002),
anticonvulsant (Ucar et al., 1998), antimalarial (Courtois
et al., 2004), PPARc agonist (Blanc-Delmas et al., 2006).
The functionalization of the nitrogen atom at the third
position of benzoxazole is of interest since the electronic
characteristics of this atom can be decisive for the bio-
logical activity. Several nitrogen heterocycles containing
piperazine moiety have been described as potent chemo-
therapeutic agents. This cyclic amine moiety is also found
in drug candidates displaying antiallergic (John et al.,
1
995), antibacterial (Michel et al., 1992), antianxiety,
antiemetic, antimigraine (Christine et al., 1996), and anti-
inflammatory (Dogruer et al., 1998; Gulcan et al., 2003)
activities. As a consequence, the development of general
economical methods for the synthesis of benzoxazole
derivatives containing piperidine moiety in a single
2
3
(Soyer et al., 2005). The method involves tedious work up,
gives poor to moderate yield with less purity of the prod-
uct. Hence, herein we report a practical and convenient
Fig. 1 Structures of
benzoxazole drugs and
biomolecules
A
B
COOCH3
HO
OH
O
O
N
H
O
N
COOH
N
O
N
H
O
O
C
D
E
H
N
Cl
HO
HO
N
O
N
O
O
Cl
F
O
O
O
123

6
28
Med Chem Res (2011) 20:626–636
Scheme 1 Synthesis of
-cyclic amine benzoxazoles
5a–l)
OH
O
N
(ii)
O
2
(
(i)
SH
Cl
N
NH2
1
3
2
3
O
N
(
iii)
O
+
Cl
HN
X
N
X
N
4
5a-l
o
Reagents:(i) CS , KOH, Ethanol(reflux); (ii) PCl , dry Toluene; (iii) Acetonitrile, 0 C-rt
2
5
X = N-methyl, N-ethyl, N-benzyl, N-phenyl, N-pyridyl, N-pyrimidyl, N-(3-chlorophenyl),
N-(2-hydroxyethyl), CH , O.
2
entry 9: 2-(3-methylpiperazin-1-yl)-1,3-benzoxazole.
entry 10: 2-(1,4-Diazepan-1-yl)-1,3-benzoxazole.
Table 1 Newly synthesized piperazinyl benzoxazoles (5a–l) derivatives
O
N
X
N
5
a
b
a
b
Entry
X
Product
Yield (%)
Entry
X
Product
Yield (%)
1
2
3
N-methyl
N-ethyl
5a
5b
5c
70
65
75
7
8
9
N-3-chlorophenyl
N-2-hydroxyethyl
–
5g
5h
82
70
69
N-benzyl
CH3
NH
O
N
N
N
5
i
4
N-phenyl
5d
80
10
–
74
O
N
NH
5
j
5
6
a
N-2-pyridyl
5e
5f
78
85
13
11
12
CH
O
2
5k
5l
78
68
N-2-pyrimidyl
1
All the products were characterized by H NMR, C NMR, Mass and IR spectroscopy
b
Isolated and optimized yields
method for the alkylation of benzoxazolone using cesium
non-corrosive, and eco-friendly reagent for the alkylation
process. The preparation of the CsF–Celite was carried out
in the same manner as described earlier (Hayat et al.,
2001). A comparative yields of alkylations using K CO
fluoride–Celite (CsF–Celite). The synthetic utility of CsF–
Celite to synthesize ethers and esters was earlier reported
(
Shah et al., 2002; Polshettiwar and Kaushik, 2005). The
2
3
alkylation of benzoxazolone catalyzed by CsF–Celite was
carried out under mild reaction conditions with high yields
and simple work up. Thus, we explored the utility of CsF–
Celite system as an efficient, inexpensive, economical,
(Method A) and CsF–Celite (Method B) was mentioned in
Table 2. N-alkylation of 5-chlorobenzoxazolone was con-
-
1
firmed by the presence of carbonyl stretching at 1774 cm
in the IR spectrum of 5-chloro-3-(3-chloropropyl)-1,3-
1
23

Med Chem Res (2011) 20:626–636
629
Scheme 2 Synthesis of
3
(
R
H
N
-substituted benzoxazolones
8a–f and 9a–f)
Cl
Cl
N
(
i)
+
R
Br
O
O
O
O
6
7
8a-f
Y
Cl
N
Cl
N
(ii)
Cl
N
O
O
O
+
HN
Y
O
8a
4
9a-f
Reagents: (i) Method A: K CO , Acetonitrile, rt; Method B: CsF-Celite, THF, rt;
2
3
0
(
ii) Method A: K CO , DMF, 100 C; Method B: CsF-Celite, THF, Reflux
2 3
R=3-chloropropyl, allyl, propagyl, benzyl, 3-butenyl, 3-methyl-2-butenyl
Y=N-benzyl, N-phenyl, N-Pyridyl, N-Pyrimidyl, N-3-chlorophenyl, O
Table 2 Newly synthesized benzoxazole-2(3H)-ones (8a–f, 9a–f) derivatives
Y
N
R
Cl
Cl
N
O
N
O
O
O
8
9
a
b
a
b
Entry
R
Product
Yield (%)
Entry
Y
Product
Yield (%)
Method A
Method B
Method A
Method B
1
2
3
4
5
6
a
3-Chloropropyl
Allyl
8a
8b
8c
8d
8e
8f
65
77
80
80
70
78
13
86
90
92
94
88
92
7
N-benzyl
9a
9b
9c
9d
9e
9f
67
72
77
73
78
75
89
88
92
90
91
88
8
N-phenyl
N-2-pyridyl
Propagyl
9
Benzyl
10
11
12
N-2-pyrimidyl
N-3-chlorophenyl
O
3-Butenyl
3-Methyl-2-butenyl
1
All the products were characterized by H NMR, C NMR, Mass and IR spectroscopy
b
Isolated and optimized yield
1
3
benzoxazol-2(3H)-one (8a). The C chemical shift value
for the carbonyl carbon (d = 152.6 ppm) of the 5-chor-
and B are mentioned in Table 2. The synthesized com-
pounds 5a–l, 8a–f, and 9a–f were tested for antibacterial
and antifungal activity.
1
3
obenzoxazolone was retained in the C spectra of 8a
d = 154.2 ppm). The compounds 9a–f were synthesized
(
by conventional conditions (Method A), i.e., by reacting 8a
with various cyclic amines 4 and K CO (Saxena et al.,
Biology
2
3
2
007). A facile synthesis of the compounds 9a–f was car-
ried out by reacting 8a with various cyclic amines 4 in the
presence of catalytic amount of CsF–Celite (Method B) to
obtain products in high yields with excellent purity
Antibacterial activity
All the 24 synthesized compounds were evaluated for
antibacterial activity and the results were summarized in
(
Scheme 2). The comparative yields of the two methods A
123

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30
Med Chem Res (2011) 20:626–636
Table 3 Antibacterial activity
of 5a–l, 8a–f, and 9a–f
MIC(lg/ml)
Compound
Gram-positive
Gram-negative
B. subtilis
S. aureus
S. epidermidis
E. coli
P. aeroginosa
K. pneumoniae
5
5
5
5
5
5
5
5
5
5
5
5
8
8
8
8
8
8
9
9
9
9
9
9
a
b
c
d
e
f
150
150
150
150
150
150
150
150
150
150
150
150
150
150
75
150
150
150
150
150
150
75
75
75
150
150
150
75
150
150
75
150
75
75
150
150
150
75
150
150
150
150
150
150
150
150
150
150
150
75
75
150
150
150
150
75
75
75
g
h
i
150
75
150
75
75
150
150
150
75
150
75
150
75
j
75
k
l
150
150
150
150
37.5
150
150
150
150
150
150
150
150
37.5
12.5
6.25
150
150
150
75
150
37.5
150
37.5
75
a
b
c
d
e
f
150
150
75
37.5
150
150
75
150
150
150
150
150
150
150
150
75
75
75
75
150
150
150
150
150
150
150
75
150
75
37.5
150
150
150
150
150
150
75
a
b
c
d
e
f
75
75
150
150
150
150
75
150
75
150
150
37.5
12.5
1.562
Penicillin
1.562
6.25
1.562
6.25
3.125
3.125
6.25
3.125
Streptomycin
Table 3. In the 5 series of benzoxazole derivatives 5h, 5j,
and 5l showed moderate antibacterial activity against some
bacteria, while other compounds were inactive. Among
these three compounds, 5h contains N-(2-hydroxyethyl)
group while 5j and 5l contains NH and O at the fourth
position of cyclic amine.
butenyl group showed moderate activity. In the 9 series
compounds, only 9f with N-(3-morpholinyl)propyl group
showed moderate activity. None of the compound has
shown higher antimicrobial activity than drugs used as a
standard. These results indicate that larger groups at fourth
position of cyclic amine and third position of benzoxazo-
lone have no significant contribution to the antimicrobial
activity of these compounds. The benzoxazolone deriva-
tives were comparatively more active than benzoxazole
derivatives toward antimicrobial activity. This may be
attributed to the more functionality sites in the ben-
zoxazolone skeleton to interact with the biological system
in comparison with benzoxazole motif.
Among the 8 and 9 series of benzoxazolone derivatives,
c with N-propagyl group and 9f with N-(3-morpholi-
8
nyl)propyl group exhibited moderate activity against both
Gram-positive and Gram-negative bacteria.
Antifungal activity
All the 24 synthesized compounds were evaluated for
antifungal activity and the results are summarized in
Table 4. Among the antifungal activity of the 5 series
compounds, 5k with piperidine as cyclic amine showed
moderate activity. In the 8 series compounds, 8a with N-3-
chloropropyl group and 8c with N-propagyl group showed
good antifungal activity, while 8f with N-3-methyl-2-
Conclusions
Various 2-substituted benzoxazoles and 3-substituted-
2(3H)-benzoxazolone derivatives were synthesized. The
utility of CsF–Celite as a solid base for alkylation of
1
23

Med Chem Res (2011) 20:626–636
631
Table 4 Antifungal activity of
5
Compound
C. albicans
S. cerevisiae
R. oryzae
A. niger
a–l, 8a–f, and 9a–f
1
00 lg
150 lg
100 lg
150 lg
100 lg
150 lg
100 lg
150 lg
a
5
5
5
5
5
5
5
5
5
5
5
5
8
8
8
8
8
8
9
9
a
b
c
d
e
f
–
8
–
–
8
–
–
–
–
–
9
7
–
–
–
–
–
–
–
10
9
7
9
–
–
9
12
9
12
–
10
–
–
9
–
9
–
–
–
–
10
–
–
–
–
–
–
–
–
–
8
10
–
–
–
g
h
i
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
j
–
–
–
8
10
11
–
–
–
k
l
12
9
9
12
–
8
8
10
–
–
–
–
a
b
c
d
e
f
14
–
19
8
12
–
15
–
11
–
15
–
13
8
17
10
18
–
8
11
–
14
–
18
–
15
–
19
–
15
–
–
–
–
–
–
9
13
9
–
–
7
10
9
8
10
–
–
8
11
9
a
b
–
–
–
–
7
–
–
–
–
–
–
–
–
a
Not active
9c
–
–
–
–
–
–
–
–
Concentration used:
00 lg/150 lg
Negative control: DMSO
no activity)
9d
–
–
–
–
–
–
–
–
1
9
9
e
f
–
–
–
–
–
–
–
–
8
10
8
10
10
24
13
8
10
(
Amphotericin-B
50 lg)
23.5
22
25
Positive control: amphotericin-
B (50 lg)
(
benzoxazolone was explored. The method offers advanta-
ges like easy work-up and excellent yields. The catalyst is
non-corrosive, easy to handle, and can be easily prepared.
Totally, 24 compounds were synthesized and evaluated for
antibacterial and antifungal activity. Two compounds 8a
and 8c showed good antifungal activity. The results indi-
cate that larger groups at fourth position of cyclic amine
and third position of benzoxazolone have no significant
contribution to the antimicrobial activity of these com-
pounds. The benzoxazolone derivatives are comparatively
more active than benzoxazole derivatives. Further work to
synthesize more active compounds is under progress.
performed on Elemental VARIO EL elemental analyzer. IR
spectra were recorded on Perkin-Elmer Infrared-683.
Typical procedure for preparation
of 2-(4-methylpiperazin-1-yl)-1,3-benzoxazole (5a)
as a typical procedure
The 2-chlorobenzoxazole (3) (2.6 mmol, 400 mg) was
added to a solution of 1-methyl piperazine (2.6 mmol,
260 mg) in dry acetonitrile (30 ml) at 0°C. The mixture
was stirred at 0°C–rt for 30 min, quenched in ice water
(30 ml), extracted with ethyl acetate (3 9 20 ml), and
dried over Na SO . After concentration, the residue was
2
4
purified by flash chromatography to obtain the pure product
and was crystallized from methanol.
Experimental
White solid. m.p. 37–38°C; IR (KBr) m 3057, 2933, 2854,
1
2796, 1639, 1578, 1456, 1363. H NMR (200 MHz, CDCl )
Melting points were determined on a Buchi capillary
1
melting point apparatus. The H NMR (200 and 300 MHz)
3
d: 7.22 (t, 2H, J = 7.3 Hz); 7.09 (t, 1H, J = 7.3 Hz); 6.95
(t, 1H, J = 7.3 Hz); 3.67 (t, 4H, J = 5.1 Hz); 2.48 (t, 4H,
?
J = 5.1 Hz); 2.30 (s, 3H). EI-MS (m/z): 217 (M ). Anal.
1
3
and C NMR (75 MHz) spectra was recorded on Varian
Gemini and Bruker Avance spectrometers using TMS as an
internal standard. The mass spectra were recorded on a VG
Auto Spec mass spectrometer. Elemental analyses were
calcd for C H N O (217): C, 66.34; H, 6.96; N, 19.34.
12 15 3
Found: C, 66.36; H, 6.94; N, 19.37.
123

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Med Chem Res (2011) 20:626–636
2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-1,3-benzoxa (5f)
White solid. m.p. 183–185°C; IR (KBr) m 2911, 2860,
2
-(4-Ethylpiperazin-1-yl)-1,3-benzoxazole (5b)
White solid. m.p. 78–80°C; IR (KBr) m 2970, 2931, 2813,
1
1
638, 1578, 1525, 1459, 1399. H NMR (200 MHz,
1
1651, 1581, 1542, 1490, 1451, 1393. H NMR (200 MHz,
CDCl ) d: 7.30 (d, 1H, J = 7.7 Hz); 7.20 (d, 1H,
CDCl ) d: 8.30 (d, 2H, J = 5.0 Hz); 7.33 (d, 1H, J =
3
3
J = 7.7 Hz); 7.11 (t, 1H, J = 7.7 Hz); 6.96 (t, 1H, J =
7.7 Hz); 3.70 (t, 4H, J = 4.9 Hz); 2.54 (t, 4H, J = 4.9 Hz);
7.6 Hz); 7.23 (d, 1H, J = 7.6 Hz); 7.13 (t, 1H, J = 7.6 Hz);
6.99 (t, 1H, J = 7.6 Hz); 6.51 (t, 1H, J = 5.0 Hz); 4.04–3.94
13
2
.45 (q, 2H, J = 7.2 Hz); 1.11 (t, 3H, J = 7.2 Hz). EI-MS
(m, 4H); 3.81–3.72 (m, 4H). C NMR (75 MHz, CDCl ) d:
3
?
m/z): 231 (M ). Anal. calcd for C H N O (231): C, 67.51;
H, 7.41; N, 18.17. Found: C, 67.54; H, 7.39; N, 18.15.
(
166.6, 161.4, 157.8, 148.6, 144.4, 124.3, 121.1, 116.3, 110.6,
13 17 3
?
108.9, 45.5, 43.2. EI-MS (m/z): 281 (M ). Anal. calcd for
C H N O (281): C, 64.04; H, 5.37; N, 24.89. Found: C,
15 15 5
64.08; H, 5.41; N, 24.94.
2
-(4-Benzylpiperazin-1-yl)-1,3-benzoxazole (5c)
White solid. m.p. 230–231°C; IR (KBr) m 3028, 2917,
860, 2821, 1640, 1578, 1494, 1455,1 395. NMR
300 MHz, CDCl ) d: 7.34–7.25 (m, 6H); 7.19 (d, 1H,
2-[4-(3-Chlorophenyl)piperazin-1-yl]-1,3-benzoxazole
2
(5g)
(
3
J = 7. 8 Hz); 7.11 (t, 1H, J = 7. 8 Hz); 6.96 (t, 1H, J =
.8 Hz); 3.70 (t, 4H, J = 4.7 Hz); 3.54 (s, 2H); 2.56 (t, 4H,
White solid. m.p. 134–136°C; IR (KBr) m 3015, 2913, 1769,
1
1739, 1625, 1593, 1478, 1397. H NMR (200 MHz, CDCl
7
3
)
1
3
J = 4.7 Hz). C NMR (75 MHz, CDCl ) d: 162.1, 148.7,
d: 7.33 (d, 1H, J = 6.8 Hz); 7.23 (d, 1H, J = 7.6 Hz); 7.17
(d, 1H, J = 7.6 Hz); 7.13 (t, 1H, J = 7.6 Hz); 7.00 (t, 1H,
J = 7.6 Hz); 6.90 (t, 1H, J = 2.3 Hz); 6.85 (d, 1H, J =
7.6 Hz); 6.79 (d, 1H, J = 7.6 Hz); 3.84 (t, 4H, J = 5.3 Hz);
3
1
43.0, 136.9, 129.2, 128.4, 127.4, 123.9, 120.6, 116.2,
?
08.7, 62.9, 52.1, 45.4. EI-MS (m/z): 293(M ). Anal. calcd
1
for C H N O (293): C, 73.70; H, 6.53; N, 14.32. Found:
8 19 3
1
1
3
C, 73.74; H, 6.52; N, 14.33.
3.31 (t, 4H, J = 5.3 Hz,). C NMR (75 MHz, CDCl
3
) d:
61.9, 151.9, 150.9, 142.8, 135.0, 130.1, 124.1, 120.9, 120.3,
16.6, 116.4, 114.7, 108.8, 48.6, 45.3. EI-MS (m/z): 313
1
1
?
2
-(4-Phenylpiperazin-1-yl)-1,3-benzoxazole (5d)
(
M ). Anal. calcd for C H ClN O (313): C, 65.07; H, 5.14;
17 16 3
N, 13.39. Found: C, 65.09; H, 5.14; N, 13.36.
White solid. m.p. 147–148°C; IR (KBr) m 2980, 2914,
1
822, 1629, 1575, 1497, 1455. H NMR (300 MHz,
2
CDCl ) d: 7.33 (d, 1H, J = 7.6 Hz); 7.26 (d, 1H,
2-[4-(1,3-Benzoxazol-2-yl)piperazine-1-yl]ethanol (5h)
3
J = 7.6 Hz); 7.23 (d, 2H, J = 6.8 Hz); 7.14 (t, 1H,
J = 6.8 Hz); 6.99 (t, 1H, J = 7.6 Hz); 6.92 (d, 2H, J =
Brown solid. m.p. 35–36°C; IR (KBr) m 3423, 2936, 2855,
1
6
3
1
1
.8 Hz); 6.88 (t, 1H, J = 7.6 Hz); 3.85 (t, 4H, J = 5.3 Hz);
3
1631, 1578, 1483, 1458. H NMR (200 MHz, CDCl ) d:
3
1
.29 (t, 4H, J = 5.3 Hz). C NMR (75 MHz, CDCl ) d:
7.42 (d, 1H, J = 7.6 Hz); 7.30 (d, 1H, J = 7.6 Hz); 7.19 (t,
1H, J = 7.6 Hz); 7.11 (t, 1H, J = 7.6 Hz); 4.64 (t, 2H,
J = 6.0 Hz); 2.82 (t, 2H, J = 6.0 Hz); 2.52 (t, 4H, J =
5.2 Hz); 1.60 (t, 4H, J = 5.2 Hz); 1.49–1.38 (m, 1H).
3
61.8, 150.8, 148.6, 142.6, 129.2, 124.1, 120.9, 120.8,
?
16.9, 116.3, 108.8, 49.2, 45.5. EI-MS (m/z): 279 (M ).
Anal. calcd for C H N O (279): C, 73.10; H, 6.13; N,
7 17 3
1
?
1
5.04. Found: C, 73.08; H, 6.12; N, 15.05.
EI-MS (m/z): 247(M ).
2
-[4-(Pyridin-2-yl)piperazin-1-yl]-1,3-benzoxazole (5e)
2-(3-Methylpiperazin-1-yl)-1,3-benzoxazole (5i)
White solid. m.p. 186–188°C; IR (KBr) m 2993, 2917,
Brown solid. m.p. 51–52°C; IR (KBr) m 3321, 3057, 2958,
2921, 2856, 1638, 1578, 1458, 1400. H NMR (200 MHz,
1
846, 1635, 1576, 1480, 1459, 1435. H NMR (200 MHz,
1
2
CDCl ) d: 8.19–8.15 (m, 1H); 7.51–7.44 (m, 1H); 7.33 (d,
CDCl ) d: 7.30 (d, 1H, J = 7.6 Hz); 7.19 (d, 1H,
3
3
1
H, J = 7.7 Hz); 7.23 (d, 1H, J = 7.7 Hz); 7.13 (dt, 1H,
J = 6.6, 1.1 Hz); 6.99 (dt, 1H, J = 6.6, 1.3 Hz); 6.68–6.61
J = 7.6 Hz); 7.11 (t, 1H, J = 7.6 Hz); 6.95 (t, 1H, J =
7.6 Hz); 4.11 (d, 2H, J = 11.3 Hz); 3.07 (t, 2H, J =
9.0 Hz); 2.91 (t, 2H, J = 9.0 Hz); 2.71 (t, 1H, J = 8.3 Hz);
1
m, 2H); 3.88–3.77 (m, 4H); 3.74–3.67 (m, 4H). C NMR
3
(
13
(
75 MHz, CDCl ) d: 161.9, 158.2, 148.7, 146.8, 142.8,
1.80 (s, 1H); 1.11 (d, 3H, J = 8.3 Hz). C NMR (75 MHz,
CDCl ) d: 162.2, 148.8, 143.1, 124.5, 120.8, 116.4, 108.9, 53.2,
50.5, 46.2, 45.7, 19.8. EI-MS (m/z): 217 (M ). Anal. calcd for
O (217): C, 66.34; H, 6.96; N, 19.34. Found: C,
66.36; H, 6.99; N, 19.29.
3
1
38.4, 124.0, 120.9, 116.4, 113.8, 108.8, 107.8, 45.2, 44.9.
3
?
EI-MS (m/z): 280 (M ). Anal. calcd for C H N O (280):
?
1
6 16 4
C, 68.55; H, 5.75; N, 19.99. Found: C, 68.59; H, 5.78; N,
9.96.
C H N
12 15 3
1
1
23

Med Chem Res (2011) 20:626–636
633
2
-(1,4-Diazepan-1-yl)-1,3-benzoxazole (5j)
Method B
Brown solid. m.p. 195–198°C; IR (KBr) m 3399, 3050,
A mixture of 5-chlorobenzoxazolone (6) (3.0 mmol) and
CsF–Celite (4.5 mmol) in dry THF (15 ml) was stirred for
1
934, 1639, 1578, 1459, 1402. H NMR (200 MHz,
2
CDCl ) d: 7.31 (d, 1H, J = 7.6 Hz); 7.23 (d, 1H,
10 min under N atmosphere. 3-Chloro-1-bromopropane
2
3
J = 7.6 Hz); 7.13 (t, 1H, J = 7. 6 Hz); 6.98 (t, 1H,
J = 7.6 Hz); 3.96 (s, 2H); 3.76 (t, 4H, J = 6.0 Hz); 3.07 (t,
(3.2 mmol) was added through syringe to the above mix-
ture and stirred for 4 h. After the reaction was completed
(TLC), the reaction mixture was filtered through Celite and
solid was washed with ethylacetate (2 9 10 ml). The
combined filtrate was dried (Na SO ) and evaporated to
1
H, J = 5.2 Hz); 2.91 (t, 1H, J = 5.2 Hz); 2.27(q, 1H,
3
1
J = 6.0 Hz); 1.97 (q, 1H, J = 6.0 Hz).
(
C NMR
75 MHz, CDCl ) d: 161.6, 148.9, 143.1, 124.0, 120.6,
3
2
4
1
16.2, 108.7, 49.5, 49.1, 48.4, 47.4, 26.7. EI-MS (m/z): 217
give the pure product.
?
M ). Anal. calcd for C H N O (217): C, 66.34; H, 6.96;
(
White solid. m.p. 82–84°C; IR (KBr) m 3063, 2933,
1774, 1611, 1485, 1369, 1247, 1061, 829, 721. H NMR
1
2 15 3
1
N, 19.34. Found: C, 66.31; H, 6.97; N, 19.32.
-(Piperidin-1-yl)-1,3-benzoxazole (5k)
Brown solid. m.p. 71–72°C; IR (KBr) m 3057, 2936, 2854,
(
200 MHz, CDCl ) d: 7.17–7.03 (m, 3H); 3.99 (t, 2H,
3
2
J = 7.0 Hz); 3.62 (t, 2H, J = 5.5 Hz); 2.28 (quintet, 2H,
1
3
J = 7.0 Hz). C NMR (300 MHz, CDCl ) d: 154.2, 141.1,
3
132.1, 129.5, 122.4, 109.9, 108.6, 41.6, 39.7, 30.3. EI-MS
1
?
(m/z): 246 (M ). Anal. calcd for C H Cl NO (246): C,
48.81; H, 3.69; N, 5.69. Found: C, 48.84; H, 3.71; N, 5.65.
1
638, 1577, 1525, 1455, 1394. H NMR (300 MHz,
1
0
9
2
2
CDCl ) d: 7.33 (d, 1H, J = 7.9 Hz); 7.23 (d, 1H,
3
J = 7.9 Hz); 7.14 (t, 1H, J = 7.9 Hz); 6.99 (t, 1H,
3
1
J = 7.9 Hz); 3.70 (s, 4H); 1.74 (s, 6H). C NMR
75 MHz, CDCl ) d: 161.9, 148.4, 142.2, 124.1, 120.7,
5-Chloro-3-(prop-2-en-1-yl)-1,3-benzoxazol-2(3H)-one
(8b)
(
3
?
15.8, 108.7, 46.8, 25.2, 23.9. EI-MS (m/z): 202 (M ).
1
Anal. calcd for C H N O (202): C, 71.26; H, 6.98; N,
2 14 2
White solid. m.p. 64–66°C; IR (KBr) m 3070, 2932, 1768,
1607, 1487, 1374, 1341, 1245, 1006, 801, 704. H NMR
1
1
1
2
3.85. Found: C, 71.29; H, 7.00; N, 13.82.
(
200 MHz, CDCl ) d: 7.15–7.02 (m, 2H); 6.91 (d, 1H,
3
J = 1.7 Hz); 6.00-5.79 (m, 1H); 5.39–5.27 (m, 2H); 4.42
3
-(Morpholin-4-yl)-1,3-benzoxazole (5l)
1
(
d, 2H, J = 6.1 Hz). C NMR (300 MHz, CDCl ) d:
3
1
54.1, 141.0, 131.9, 130.0, 129.3, 122.3, 119.2, 110.7,
Brown solid. m.p. 205–206°C; IR (KBr) m 3057, 2966,
?
09.4, 44.7. EI-MS (m/z): 210 (M ). Anal. calcd for
1
1
920, 2863, 1637, 1578, 1525, 1454, 1398. H NMR
2
C H ClNO (210): C, 57.30; H, 3.85; N, 6.68. Found: C,
1
0
8
2
(
200 MHz, CDCl ) d: 7.32 (d, 1H, J = 7.9 Hz); 7.21 (d,
3
57.33; H, 3.83; N, 6.72.
1
H, J = 7.9 Hz); 7.13 (t, 1H, J = 7.9 Hz); 6.98 (t, 1H,
J = 7.9 Hz); 3.77 (t, 4H, J = 4.5 Hz); 3.64 (t, 4H,
1
3
J = 4.5 Hz). C NMR (75 MHz, CDCl ) d: 161.2, 148.2,
5-Chloro-3-(prop-2-yn-1-yl)-1,3-benzoxazol-2(3H)-one
(8c)
3
1
2
5
41.1, 124.3, 121.3, 116.0, 108.9, 66.0, 45.8. EI-MS (m/z):
?
04 (M ). Anal. calcd for C H N O (204): C, 64.69; H,
1
1 12 2 2
.92; N, 13.72. Found: C, 64.65; H, 5.94; N, 13.69.
White solid. m.p. 91–93°C; IR (KBr) m 3087, 2925, 2125,
1
779, 1605, 1485, 1377, 1350, 1200, 1023, 813, 747. H
1
NMR (200 MHz, CDCl ) d: 7.18-6.99 (m, 3H); 4.57 (d,
2
3
Typical procedure for the preparation of the 5-chloro-3-
3-chloropropyl)-1,3-benzoxazol-2(3H)-one (8a)
1
H, J = 2.6 Hz); 2.48 (t, 1H, J = 2.6 Hz). C NMR
3
(
(
300 MHz, CDCl ) d: 153.4, 140.9, 130.8, 129.5, 122.8,
3
?
10.8, 109.7, 74.9, 74.4, 31.9. EI-MS (m/z): 208 (M ).
1
Method A (Soyer et al., 2005)
Anal. calcd for C H ClNO (208): C, 57.85; H, 2.91; N,
1
0
6
2
6.75. Found: C, 57.84; H, 2.95; N, 6.73.
A mixture of 5-chlorobenzoxazolone (6) (3.0 mmol) and
K CO (4.5 mmol) in dry acetonitrile (15 ml) was stirred
2
3
for 10 min under N atmosphere. 3-Chloro-1-bromopro-
2
3-Benzyl-5-chloro-1,3-benzoxazol-2(3H)-one (8d)
pane (3.2 mmol) was added through syringe to the above
mixture and stirred for 8 h. After the reaction completed
White solid. m.p. 172–174°C; IR (KBr) m 3064, 2937,
1769, 1610, 1484, 1341, 1251, 1012, 811, 700. H NMR
1
(
TLC), cold water was added to the reaction mixture and
stirred for 30 min. The separated solid was filtered, washed
with cold water, and crystallized from ethanol to give the
pure product.
(300 MHz, CDCl ) d: 7.40–7.26 (m, 5H); 7.13–7.00 (m,
3
1
2H); 6.78 (d, 1H, J = 1.5 Hz); 4.95 (s, 2H). C NMR
3
(300 MHz, CDCl ) d: 154.5, 140.9, 134.1, 131.8, 129.3,
3
123

6
34
Med Chem Res (2011) 20:626–636
1
29.1, 128.5, 127.6, 122.4, 110.8, 109.3, 46.2. EI-MS (m/
THF (15 ml) and stirred under reflux for 4 h. After com-
pletion of the reaction (TLC), the mixture was filtered
through Celite and the solid was washed with ethylacetate
?
z): 260 (M ). Anal. calcd for C H ClNO (260): C,
1
4
10
2
6
4.75; H, 3.88; N, 5.39. Found: C, 64.77; H, 3.85; N, 5.43.
(2 9 10 ml). The combined filtrate was dried (Na SO )
2 4
and evaporated to give the pure product.
3
-(But-3-en-1-yl)-5-chloro-1,3-benzoxazol-2(3H)-one
8e)
Brown solid. m.p. 103–105°C; IR (KBr) m 2939, 2811,
782, 1612, 1488, 1370, 1248, 1010, 804, 744. H NMR
(
1
1
(
300 MHz, CDCl ) d: 7.31–7.16 (m, 5H); 7.13 (d, 1H,
3
White solid. m.p. 53–54°C; IR (KBr) m 3059, 2953, 1763,
J = 2.3 Hz); 7.09–6.98 (m, 2H); 3.86 (t, 2H, J = 6.8 Hz);
.49 (s, 2H); 2.55–2.29 (m, 10H); 1.91 (quintet, 2H,
13
1
612, 1487, 1343, 1246, 1060, 796, 682. H NMR
1
3
(
300 MHz, CDCl ) d: 7.13–7.02 (m, 2H); 6.93 (d, 1H,
3
J = 6.8 Hz). C NMR (300 MHz, CDCl ) d: 154.4, 141.0,
3
J = 2.3 Hz); 5.88–5.71 (m, 1H); 5.16–5.06 (m, 2H); 3.85
1
37.9, 132.7, 129.2, 129.1, 128.2, 126.9, 121.9, 110.6,
?
09.2, 63.0, 54.5, 53.0, 40.3, 24.5. EI-MS (m/z): 386 (M ).
1
t, 2H, J = 7.6 Hz); 2.53 (quartet, 2H, J = 7.6). C NMR
3
(
(
1
300 MHz, CDCl ) d: 154.4, 141.1, 133.2, 132.1, 129.3,
3
Anal. calcd for C H ClN O (386): C, 65.36; H, 6.27; N,
2
1
24
3 2
1
22.3, 118.6, 110.8, 108.9, 41.8, 32.0. EI-MS (m/z): 224
?
1
0.89. Found: C, 65.34; H, 6.28; N, 10.91.
(
M ). Anal. calcd for C H ClNO (224): C, 59.07; H,
11 10 2
4
.51; N, 6.26. Found: C, 59.03; H, 4.52; N, 6.29.
5-Chloro-3-[3-(4-phenylpiperazin-1-yl)propyl]-1,3-
benzoxazol-2(3H)-one (9b)
5
2
-Chloro-3-(3-methylbut-2-en-1-yl)-1,3-benzoxazol-
(3H)-one (8f)
Brown solid. m.p. 128–129°C; IR (KBr) m 3056, 3010,
2
940, 2827, 1783, 1598, 1489, 1355, 1241, 1058, 834, 751.
1
White solid. m.p. 74–75°C; IR (KBr) m 3065, 2925, 1772,
1
H NMR (200 MHz, CDCl ) d: 7.30–6.98 (m, 5H); 6.92–
3
1
612, 1484, 1343, 1248, 1007, 834, 748. H NMR
6.75 (m, 3H); 3.91 (t, 2H, J = 6.3 Hz); 3.14 (t, 4H,
J = 5.5 Hz); 2.52 (t, 4H, J = 5.5 Hz); 2.42 (t, 2H,
(
200 MHz, CDCl ) d: 7.13–6.98 (m, 2H); 6.85 (s, 1H);
3
1
J = 6.3 Hz); 1.97 (quintet, 2H, J = 6.3 Hz). C NMR
3
5
3
1
4
.26 (t, 1H, J = 6.8 Hz); 4.37 (d, 2H, J = 6.8 Hz); 1.85 (s,
1
3
H); 1.77 (s, 3H). C NMR (300 MHz, CDCl ) d: 154.2,
(300 MHz, CDCl ) d: 154.3, 151.1, 141.0, 132.6, 129.1,
3
3
41.0, 138.9, 131.9, 129.1, 122.2, 116.5, 110.6, 109.1,
129.0, 122.0, 119.7, 116.7, 110.7, 109.1, 54.6, 52.0, 49.0,
?
40.3, 24.4. EI-MS (m/z): 372 (M ). Anal. calcd for
0.3, 25.7, 18.0. EI-MS (m/z): 239 (M ? 1). Anal. calcd
for C H ClNO (238): C, 60.64; H, 5.09; N, 5.89. Found:
1
C H ClN O (372): C, 64.60; H, 5.96; N, 11.33. Found:
20 22 3 2
2
12
2
C, 60.62; H, 5.12; N, 5.93.
C, 64.63; H, 5.92; N, 11.34.
Typical procedure for the preparation of the 5-chloro-3-
5-Chloro-3-{3-[4-(pyridin-2-yl)piperazin-1-yl]propyl}-
[
3-(4-benzylpiperazin-1-yl)propyl]-1,3-benzoxazol-
(3H)-one (9a)
1,3-benzoxazol-2(3H)-one (9c)
2
White solid. m.p. 132–133°C; IR (KBr) m 2944, 2826,
1780, 1594, 1487, 1370, 1250, 1060, 774. H NMR
1
Method A (Saxena et al., 2007)
(
300 MHz, CDCl ) d: 8.12 (dd, 1H, J = 3.8, 1.5 Hz); 7.41
3
A mixture of N-benzylpiperazine (2 mmol) and K CO
2
(dt, 1H, J = 7.6, 1.5 Hz); 7.14 (d, 1H, J = 1.5 Hz); 7.11–
7.00 (m, 2H); 6.58 (dt, 2H, J = 7.6, 2.3); 3.91 (t, 2H,
J = 6.8 Hz); 3.49 (t, 4H, J = 5.3 Hz); 2.46 (t, 4H,
J = 5.3 Hz); 2.40 (t, 2H, J = 6.0 Hz); 1.96 (quintet, 2H,
3
(
3 mmol) in dry N,N-dimethyl formamide (10 ml) was
stirred for 10 min under N atmosphere. 5-Chloro-3-(3-chlo-
2
ropropyl)-2,3-dihydro-1,3-benzoxazol-2-one (8a) (2 mmol)
in dry N,N-dimethyl formamide (5 ml) was added through
syringe to the above mixture and stirred for 5 h at 100°C.
After the reaction completed (TLC), cold water was added to
the reaction mixture and was stirred for 30 min. The sepa-
rated solid was filtered, washed with cold water, and crys-
tallized from ethanol to give the pure product.
1
3
J = 6.0 Hz). C NMR (300 MHz, CDCl ) d: 159.4, 154.5,
3
148.0, 140.7, 137.4, 132.8, 129.2, 122.0, 113.3, 110.5,
108.9, 107.0, 54.8, 53.0, 44.9, 40.2, 24.6. EI-MS (m/z): 373
?
(M ). Anal. calcd for C H ClN O (373): C, 61.21; H,
1
9
21
4 2
5.68; N, 15.03. Found: C, 61.23; H, 5.65; N, 15.01.
5-Chloro-3-{3-[4-(pyrimidin-2-yl)piperazin-1-
Method B
yl]propyl}-1,3-benzoxazol-2(3H)-one (9d)
CsF–Celite (3 mmol) was added to a solution of N-ben-
zylpiperazine (2 mmol) and 5-chloro-3-(3-chloropropyl)-
White solid. m.p. 125–126°C; IR (KBr) m 2927, 2853,
1781, 1585, 1488, 1362, 1252, 981, 801, 750. H NMR
1
2
,3-dihydro-1,3-benzoxazol-2-one (8a) (2 mmol) in dry
(500 MHz, CDCl ) d: 8.24 (d, 2H, J = 4.9 Hz); 7.14 (d,
3
1
23

Med Chem Res (2011) 20:626–636
635
1
H, J = 2.0 Hz); 7.11–7.03 (m, 2H); 6.43 (t, 1H,
J = 4.9 Hz); 3.93 (t, 2H, J = 6.8 Hz); 3.78 (t, 4H,
J = 4.9 Hz); 2.45–2.38 (m, 6H); 1.98 (quintet, 2H,
Standard antibacterial agents like Penicillin and Strep-
tomycin were also screened under identical conditions for
comparison. The minimum inhibitory concentration (MIC)
values are presented in Table 3.
1
3
J = 6.8 Hz). C NMR (300 MHz, CDCl ) d: 161.6, 157.4,
3
1
54.8, 150.8, 132.9, 129.4, 122.1, 110.7, 109.8, 109.1,
?
4.8, 53.0, 43.4, 40.3, 24.3. EI-MS (m/z): 374 (M ). Anal.
5
calcd for C H ClN O (374): C, 57.83; H, 5.39; N, 18.73.
1
Antifungal activity
8
20
5 2
Found: C, 57.80; H, 5.43; N, 18.76.
In vitro antifungal activity of the 5a–l, 8a–f, and 9a–f was
studied against the fungal strains, Candida albicans
5
-Chloro-3-{3-[4-(3-chlorophenyl)piperazin-1-
(
MTCC 227), Saccharomyces cereviseae (MTCC 36),
Rhizopus oryzae (MTCC 262), Aspergillus niger (MTCC
82) by agar well diffusion method (Linday, 1962). Stan-
yl]propyl}-1,3-benzoxazol-2(3H)-one (9e)
2
Brown solid. m.p. 138–140°C; IR (KBr) m 2947, 2824,
dard antifungal agent Amphotericin-B was also screened
under identical conditions for comparison. The zone of
inhibition values of the tested compounds was mentioned
in Table 4.
1
781, 1594, 1487, 1372, 1246, 985, 770. H NMR
1
(
300 MHz, CDCl ) d: 7.17–7.01 (m, 4H); 6.86–6.68 (m,
3
3
H); 3.91 (t, 2H, J = 6.2 Hz); 3.14 (t, 4H, J = 5.0 Hz);
.50 (t, 4H, J = 4.9 Hz); 2.42 (t, 2H, J = 6.4 Hz); 1.96
2
The ready-made potato dextrose agar (PDA) medium
1
3
(
quintet, 2H, J = 6.2 Hz). C NMR (300 MHz, CDCl ) d:
3
(
(
Hi-media, 39 g) was suspended in distilled water
1000 ml) and heated to boiling until it dissolved com-
1
1
2
52.2, 141.1, 135.0, 132.6, 130.0, 129.3, 122.1, 120.0,
19.3, 115.7, 113.8, 110.7, 109.0, 54.6, 52.9, 48.5, 40.3,
?
4.4. EI-MS (m/z): 406 (M ). Anal. calcd for C H
pletely, the medium and Petri dishes were autoclaved at
2
pressure of 15 lb/in. for 20 min. Agar well bioassay was
2
0
21
Cl N O (406): C, 59.12; H, 5.21; N, 10.34. Found: C,
2 3 2
employed for testing antifungal activity. The medium was
poured into sterile Petri dishes under aseptic conditions in a
laminar air flow chamber. When the medium in the plates
solidified, 0.5 ml of (week old) culture of test organism
was inoculated and uniformly spread over the agar surface
with a sterile L-shaped rod. Solutions were prepared by
dissolving the compound in DMSO and different concen-
trations were made. After inoculation, wells were scooped
out with 6 mm sterile cork borer and the lids of the dishes
were replaced. To each well, different concentrations of
test solutions were added. Controls were maintained. The
treated and the controls were kept at 27°C for 48 h. Inhi-
bition zones were measured and the diameter was calcu-
lated in millimeter. Three to four replicates were
maintained for each treatment.
5
9.15; H, 5.22; N, 10.32.
5
-Chloro-3-[3-(morpholin-4-yl)propyl]-1,3-
benzoxazol-2(3H)-one (9f)
Brown solid. m.p. 97–99°C; IR (KBr) m 2953, 2855, 1782,
1
1
613, 1488, 1370, 1251, 1117, 805, 750. H NMR
(
300 MHz, CDCl ) d: 7.13–7.01 (m, 3H); 3.89 (t, 2H,
3
J = 6.4 Hz); 3.63 (t, 4H, J = 4.5 Hz); 2.40–2.29 (m, 6H);
1
1
3
.93 (quintet, 2H, J = 6.4 Hz). C NMR (300 MHz,
CDCl ) d: 154.6, 153.1, 141.2, 129.4, 122.1, 110.8, 109.0,
6
3
?
6.9, 55.0, 53.4, 40.3, 24.0. EI-MS (m/z): 297 (M ). Anal.
calcd for C H ClN O (297): C, 56.66; H, 5.77; N, 9.44.
2 3
1
4
17
Found: C, 56.62; H, 5.78; N, 9.47.
Acknowledgment K.R.R., R.V.R., and K.P.K. thank Council of
Scientific and Industrial Research (CSIR, New Delhi, India) for the
award of fellowships.
Antibacterial activity
Determination of minimum inhibitory concentration
The minimum inhibitory concentrations (MIC) of the new
compounds 5a–l, 8a–f, and 9a–f were tested against three
representative Gram-positive organisms viz. Bacillus sub-
tilis (MTCC 441), Staphylococcus aureus (MTCC 96),
Staphylococcus epidermidis, and Gram-negative organisms
viz Escherichia coli (MTCC 443), Pseudomonas aerugin-
osa (MTCC 741), and klebsiella pneumoniae (MTCC 618)
by broth dilution method recommended by National
Committee for Clinical Laboratory (NCCL) standards
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