Synthesis, SAR and antibacterial studies on novel chalcone oxazolidinone hybrids

Article abstract of DOI:10.1016/j.ejmech.2006.10.013

With an intention to synergise the antibacterial activity of chalcones and oxazolidinones, several hybrid compounds possessing both chalcone and oxazolidinone moieties were synthesized and tested for antibacterial activity. The hybrid molecules containing

Full text of DOI:10.1016/j.ejmech.2006.10.013

European Journal of Medicinal Chemistry 42 (2007) 538e543
http://www.elsevier.com/locate/ejmech
Short communication
Synthesis, SAR and antibacterial studies on novel chalcone
oxazolidinone hybrids*
*
N. Selvakumar , G. Sunil Kumar, A. Malar Azhagan, G. Govinda Rajulu,
Shikha Sharma, M. Sitaram Kumar, Jagattaran Das, Javed Iqbal, Sanjay Trehan
Anti-infectives Discovery Group, Discovery Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, India
Received 17 July 2006; received in revised form 20 October 2006; accepted 26 October 2006
Available online 5 December 2006
Abstract
With an intention to synergise the antibacterial activity of chalcones and oxazolidinones, several hybrid compounds possessing both chalcone
and oxazolidinone moieties were synthesized and tested for antibacterial activity. The hybrid molecules containing heterocycles instead of
aromatic ring were found to be active. A SAR study with various heterocycles resulted in a lead molecule 20, which was converted to one
of the potent antibacterial compounds 27.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: Oxazolidinones; Antibacterial; Chalcones; Linezolid
1. Introduction
a lead molecule that was converted to one of the potent
molecules following the protocols developed during our
earlier efforts [8].
The emergence of multi-drug-resistant Gram-positive
bacteria including methicillin-resistant Staphylococcus aureus
(MRSA) and Staphylococcus epidermitis (MRSE) and vanco-
mycin resistant enterococci (VRE) is of major concern [1e5].
Oxazolidinones, exemplified by DuP-721 [6], are a new class
of synthetic antibacterials with activity against Gram-positive
bacteria and anaerobic bacteria, including resistant pathogens.
As chalcone compounds are known to be effective antibacte-
rial compounds [7], we initiated a program to synergise the
antibacterial activity of both chalcones and oxazolidinones
by preparing hybrid molecules having the features of both ox-
azolidinones and chalcones in an effort to discover potent
antibacterials. In this paper, we describe a systematic SAR
study performed in this area that resulted in identification of
DuP-721 1 was a potent oxazolidinone antibacterial devel-
oped by DuPont [9]. In a hypothetical hybridization of 1 with
the chalcone structure 2, there resulted two chalconeeoxazo-
lidinone hybrid structures 3 and 4 (Diagram 1). The hybrid
structure 3 possessing the carbonyl group away from oxazoli-
dinone ring is called Type A hybrid molecules and the struc-
ture 4 possessing the carbonyl group close to oxazolidinone
ring is called Type B hybrids. Both regioisomeric chalconee
oxazolidinone hybrid molecules were synthesized and studied
for antibacterial activity.
2. Chemistry
The aldehyde intermediate 5, served as the starting material
for Type A hybrid molecules, was prepared as per our reported
protocol [10]. The starting materials, DuP-721 1 [9] and its
fluorinated compound 17 [11], for Type B hybrid molecules
were prepared as per literature reports. All the chalcone
molecules described in Table 1 were synthesized from the
*
DRL publication no. 218-A. A part of this work was presented in the 42nd
Interscience Conference on Antimicrobial Agents and Chemotherapy, Septem-
ber 27e30, 2002, San Diego, USA.
* Corresponding author. Tel.: þ91 40 23045439; fax: þ91 40 23045438.
E-mail address: selvakumarn@drreddys.com (N. Selvakumar).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.10.013

N. Selvakumar et al. / European Journal of Medicinal Chemistry 42 (2007) 538e543
539
O
O
O
N
O
H
N
+
M
e
O
Oxazolidinone
DuP-721, 1
Chalcone, 2
Hybridise
O
O
O
O
N
O
N
O
H
H
N
Me
N
M
e
O
4
3
O
Type A Hybrid possessing carbonyl
away from oxazolidinone ring
Type B Hybrid possessing carbonyl
close to oxazolidinone ring
Diagram 1.
oxazolidinone aldehyde 5 by aldol condensation with respec-
tive acetophenones under basic conditions. The compounds
8, 9 and 10 were obtained as inseparable mixtures of geomet-
rical isomers. Analogously, the compounds appearing in Table
2 were obtained by aldol condensation of DuP-721 1 with
respective aromatic aldehydes using identical reaction condi-
tions. Appropriate heterocyclic aldehydes were employed in
aldol condensation of either DuP-721 1 or the compound 17
in the preparation of compounds illustrated in Table 3.
The thiocarbamate compound 27 was synthesized from
the intermediate 17 as depicted in Scheme 1 following
a modified condition for the requisite aldol condensation.
Initially, the acetamide intermediate 17 was converted to
the corresponding thiocarbamate 27 by hydrolysis to the
amine 25 followed by conversion of the amine functionality
to the thiocarbamate 26 under standard conditions. The at-
tempted aldol condensation of the thiocarbamate 26 with
2-pyridine carboxaldehyde under usual conditions did not
result in the requisite chalcone 27 presumably due to the
interference of the thiocarbamte functionality. Consequently,
the aldol reaction was attempted with a variety of bases of
which LDA was found to be suitable affording the required
thiocarbamate 27 in modest yield.
3. Results and discussion
The chalconeeoxazolidinone hybrid molecules prepared
above were screened for in vitro activity against a panel of
Gram-positive organisms and the results are summarized in Ta-
bles 1 and 2. The Type A hybrid molecules 6e11 were designed
in such a way that the aromatic ring would have a substituent
starting from strong electron donating to strong electron with-
drawing nature (Table 1). They exhibited only trace or no activ-
ity against all the organisms tested. Similarly, the Type B hybrid
molecules 12e16 (Table 2) possessing various substituents on
the aromatic ring were also inactive. However, moderate activity
was observed for compounds 18 and 19 when the aromatic ring
of the chalcone was replaced with heterocycles (entries 1e2,
Table 1
In vitro antibacterial activity (MIC, mg/mL)a of Type A hybrid moleculesb
O
O
O
R
O
R
OHC
N
O
N
O
Me
H
N
H
N
Me
Me
K2CO3, DMF
6-11
5
O
O
S. no.
Compound
R
S.a 019
S.a 213
S.a 035
E.f 034
E.f 153
E.fm 154
1
2
3
4
5
6
4-OMe
4-Me
H
>32
32
>32
32
>32
>32
>32
>64
32
>32
32
>32
32
>32
32
7
8
>32
64
>32
>64
32
>32
>64
32
>32
>64
32
>32
>64
32
9
3-F
4-NO2
2,4-(Cl)2-6-F
10
11
32
>32
6
>32
>32
>32
>32
>32
a
S.a 019 ¼ Staphylococcus aureus ATCC 33591 (methicillin-resistant); S.a 213 ¼ Staphylococcus aureus ATCC 49951; S.a 035 ¼ Staphylococcus aureus ATCC
29213; E.f 034 ¼ Enterococcus faecalis ATCC 29212 (vancomycin sensitive); E.f 153 ¼ Enterococcus faecalis NCTC 12201 (vancomycin resistant) and E.fm
154 ¼ Enterococcus faecium ATCC 12202 (vancomycin resistant).
b
Compounds exist as a mixture of E and Z isomers.

540
N. Selvakumar et al. / European Journal of Medicinal Chemistry 42 (2007) 538e543
Table 2
In vitro antibacterial activity (MIC, mg/mL)a of Type B hybrid molecules
O
R
O
O
CHO
O
R
N
O
N
O
H
N
H
N
K2CO3, DMF
M
e
M
e
12-16
O
O
1: DuP 721
S. no.
Compound
R or heterocycle
S.a 019
S.a 213
S.a 035
E.f 034
E.f 153
E.fm 154
1
2
3
4
12
13
14
15
16
3,4,5-(OMe)3
3,4-(OMe)2
H
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
>32
4-F
4-COOMe
5
a
See footnote ‘a’ of Table 1 for details about the organisms.
Table 3). At this stage, it was envisioned that introducing a fluo-
rine atom in the aromatic ring would enhance the activity. In-
deed, these heterocycle substituted hybrid molecules 20 and
21 showed better antibacterial activity than the non-fluorine
analogues (entries 3e4, Table 3). But, the introduction of thio-
phene and imidazole heterocycles resulted in compounds 22e
24 that were inferior in activity. In this SAR study, compound
20 possessing a pyridine ring was found to be the best molecule
showing acceptable antibacterial activity (MIC 4 mg/mL)
against an MRSA strain.
Having found a molecule exhibiting moderate activity, we
used our experience of converting the acetamide group of 20
Table 3
In vitro antibacterial activity (MIC, mg/mL)a of Type B hybrid molecules possessing heterocycles
X
O
O
O
CHO
O
Het
N
O
Het
N
O
H
N
H
N
Me
M
e
K2CO3, DMF
X
O
O
X = H, 18 and 19
X = F, 20-24
1: X = H, DuP-721
17: X = F
S. no.
1
Compound
R or heterocycle
S.a 019
S.a 213
S.a 035
E.f 034
64
E.f 153
64
E.fm 154
64
18
32
32
32
N
O
19
2
3
32
4
16
4
16
8
32
16
32
16
32
16
20
21
22
23
24
N
O
4
5
6
7
8
32
32
8
32
32
8
32
32
16
32
32
16
32
32
16
32
32
S
N
N
Me
N
16
16
16
16
16
16
N
H
Linezolid
Vancomycin
1
2
2
1
2
1
2
2
2
>32
2
>32
a
See footnote ‘a’ of Table 1 for details about the organisms.

N. Selvakumar et al. / European Journal of Medicinal Chemistry 42 (2007) 538e543
541
F
F
F
O
O
1. CSCl2, NaHCO3
O
O
O
6N HCl, MeOH
reflux, 78%
N
N
O
O
N
O
2. MeOH, reflux
82% for two steps
H
N
M
e
NH2
O
S
25
17
O
O
O
LDA, THF
N
O
H
N
H
N
O
Me
N
O
Me
N
CHO
F
22%
S
27
26
Scheme 1. Synthesis of thiocarbamate compound 27.
to the corresponding thiocarbamate [8]. The resultant molecule
27 exhibited in vitro activity in the range of 0.25e2 mg/mL
(Table 4). It is important to note that this compound 27 is
many fold superior in activity when compared to its acetamide
analogue 20.
Chemical shifts are reported in d units with respect to TMS
as internal standard. Mass spectra were recorded on a HP-
5989A spectrometer. All HPLC0s were run with a system
that consisted of Hichrom RPB column (250 mm), 0.01 M
KH2PO4/CH3CN 50:50 at 1 mL/min flow rate, 220 nm.
4. Conclusion
5.1. General procedure for the synthesis of chalcones
A systematic SAR study in the novel area of chalconeeox-
azolidinone hybrids was undertaken. Although both the Type
A and Type B hybrid molecules were inactive, the introduction
of heterocycles instead of an aromatic ring led to new mole-
cules possessing moderate in vitro activity. Introduction of
a variety of heterocycles resulted in a lead molecule 20
possessing a pyridine-aromatic hybrid structure. Based on
our experience in the area of oxazolidinones, this moderately
active molecule 20 was transformed to one of the potent
compounds 27.
A suspension of an appropriate acetophenone (1 mmol), the
corresponding benzaldehyde (1 mmol) and K2CO3 (3 mmol)
in dry DMF (5 mL) was stirred at rt. The reaction was
monitored by TLC and was warmed to 60e80 ꢀC if required.
The reaction mixture was worked up, upon completion of the
reaction as judged by TLC, by adding water and extracting
with ethyl acetate. The combined organic extracts were
washed with water, brine and dried. The residue obtained
upon evaporation of solvent was chromatographed over silica
gel to afford the required product. The following chalcone
molecules were prepared using this general procedure.
5. Experimental protocols
5.1.1. N-(3-{4-[3-(4-Methoxy-phenyl)-3-oxo-propenyl]-
phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 6
Yield: 72%; m.p. 174 ꢀC; IR (KBr): 1750, 1658,
Melting points are uncorrected. IR spectra were recorded
on a PerkineElmer 1650 spectrophotometer. All 1H NMR
were recorded at 200 MHz on a Varian Gemini spectrometer.
1
1523 cmꢁ1; H NMR (CDCl3): d 8.04 (d, J ¼ 8.8 Hz, 1H),
Table 4
Comparison of in vitro antibacterial activity (MIC, mg/mL)a of 20 with 27
S. no.
1
Compound
Structure
S.a 019
S.a 213
S.a 035
E.f 034
E.f 153
E.fm 154
O
O
20
N
O
H
N
4
4
8
16
16
16
N
M
e
F
O
2
27
O
O
N
O
H
0.25
1
0.5
2
1
2
N
N
OMe
F
S
a
See footnote ‘a’ of Table 1 for details about the organisms.

542
N. Selvakumar et al. / European Journal of Medicinal Chemistry 42 (2007) 538e543
7.88e7.26 (m, 8H), 6.98 (d, J ¼ 8.8 Hz, 1H), 6.10 (bs, 1H),
4.79 (m, 1H), 4.10 (t, J ¼ 8.8 Hz, 1H), 3.89 and 3.86 (2s,
3H), 3.85e3.67 (m, 3H), 2.02 (s, 3H); MS (DIP): 394, 350,
266; HPLC: 88.2% purity.
5.1.8. N-{2-Oxo-3-[4-(3-phenyl-acryloyl)-phenyl]-
oxazolidin-5-ylmethyl}-acetamide 14
Yield: 49%; m.p. 230 ꢀC; IR (KBr): 1735, 1653, 1409,
1230 cmꢁ1 1H NMR (DMSO-d6): d 8.25e7.40 (m, 12H),
;
4.80 (bs, 1H), 4.30e3.20 (m, 4H), 1.84 (s, 3H); MS (CI-
method): 365 (Mþ þ 1), 321, 235; HPLC: 85.6% purity.
5.1.2. N-{2-Oxo-3-[4-(3-oxo-3-p-tolyl-propenyl)-phenyl]-
oxazolidin-5-ylmethyl}-acetamide 7
5.1.9. N-(3-{4-[3-(4-Fluoro-phenyl)-acryloyl]-phenyl}-
2-oxo-oxazolidin-5-ylmethyl)-acetamide 15
Yield: 53%; m.p. 195 ꢀC; IR (KBr): 1745, 1655, 1517,
1
1228 cmꢁ1; H NMR (CDCl3): d 7.94 (d, J ¼ 7.8 Hz, 1H),
Yield: 81%; m.p. 252 ꢀC; IR (KBr): 1734, 1654, 1586,
7.58e7.22 (m, 9H), 6.07 (bs, 1H), 4.80 (bs, 1H), 4.10 (t,
J ¼ 8.8 Hz, 1H), 3.83 (t, J ¼ 8.8 Hz, 1H), 3.72e3.56 (m,
2H), 2.44 and 2.39 (2s, 3H), 2.03 (s, 3H); MS (DIP): 378
(Mþ), 334, 250, 119; HPLC: 89.6% purity.
1224 cmꢁ1
;
1H NMR (CDCl3 þ DMSO-d6): d 8.07 (d,
J ¼ 8.8 Hz, 1H), 7.90e7.20 (m, 8H), 7.13 (t, J ¼ 8.8 Hz,
1H), 4.95e4.70 (m, 1H), 4.18e4.83 (m, 2H), 3.61e3.59 (m,
2H), 1.98 (s, 3H); MS (CI-method): 383 (Mþ þ 1), 277,
235; HPLC: 99.7% purity.
5.1.3. N-{2-Oxo-3-[4-(3-oxo-3-phenyl-propenyl)-phenyl]-
oxazolidin-5-ylmethyl}-acetamide 8
5.1.10. N-(3-{4-[3-(4-Carbomethoxy-phenyl)-acryloyl]-
phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 16
Yield: 40%; m.p. 250 ꢀC; IR (KBr): 1733, 1654, 1607,
Yield: 59%; m.p. 182 ꢀC; IR (KBr): 1750, 1678,
1
1517 cmꢁ1; H NMR (CDCl3): d 8.04e7.40 (m, 10H), 6.03
(bs, 1H), 4.82 (bs, 1H), 4.18e3.20 (m, 4H), 2.02 (s, 3H);
MS (CI-method): 365 (Mþ þ 1), 277, 263; HPLC: 93.0%
purity.
1283 cmꢁ1 1H NMR (DMSO-d6): d 8.40e7.70 (m, 10H),
;
4.90e4.70 (m, 1H), 4.23 (t, J ¼ 8.8 Hz, 1H), 3.89 (s, 3H),
4.00e3.20 (m, 3H), 1.84 (s, 3H); MS (CI-method): 423
(Mþ þ 1), 379; HPLC: 96.5% purity.
5.1.4. N-(3-{4-[3-(3-Floro-phenyl)-3-oxo-propenyl]-
phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 9
Yield: 75%; m.p. 165 ꢀC; IR (neat): 1751, 1684, 1588,
5.1.11. N-{2-Oxo-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxazolidin-5-ylmethyl}-acetamide 18
Yield: 73%; m.p. 180 ꢀC; IR (KBr): 1740, 1657, 1596,
1
1435 cmꢁ1; H NMR (CDCl3): d 7.74e7.25 (m, 10H), 6.02
1221 cmꢁ1
;
1H NMR (DMSO-d6): d 8.70 (d, J ¼ 4.4 Hz,
(bs, 1H), 4.80 (bs, 1H), 4.02 (t, J ¼ 8.8 Hz, 1H), 3.77e3.27
(m, 3H), 2.00 (s, 3H); MS (CI-method): 383 (Mþ þ 1), 339,
139; HPLC: 86.9% purity.
1H), 8.27e8.14 (m, 4H), 7.91 (d, J ¼ 4.0 Hz, 2H), 7.77e
7.69 (m, 3H), 7.50 (dd, J ¼ 4.4 and 8.8 Hz, 1H), 4.81e4.70
(m, 1H), 4.21 (t, J ¼ 9.3 Hz, 1H), 3.84 (t, J ¼ 7.3 Hz, 1H),
3.45 (t, J ¼ 4.8 Hz, 2H), 1.84 (s, 3H); MS (CI-method): 366
(Mþ þ 1), 321, 237, 132; HPLC: 95.4% purity.
5.1.5. N-(3-{4-[3-(4-Nitro-phenyl)-3-oxo-propenyl]-
phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 10
Yield: 37%; m.p. 190 ꢀC; IR (neat): 1754, 1674,
5.1.12. N-{3-[4-(3-Furan-2-yl-acryloyl)-phenyl]-2-
oxo-oxazolidin-5-ylmethyl}-acetamide 19
1
1580 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 8.38e8.07 (m,
4H), 7.85e7.26 (m, 6H), 4.80 (bs, 1H), 4.11e3.43 (m, 4H),
1.99 (s, 3H); MS (CI-method): 410 (Mþ þ 1), 336, 166;
HPLC: 90.1% purity.
Yield: 71%; m.p. 195 ꢀC; IR (KBr): 1769, 1649,
1
1604 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 8.20e7.20 (m,
6H), 6.55 (bs, 3H), 6.12 (bs, 1H), 4.90e4.80 (m, 1H), 4.20e
3.50 (m, 4H), 2.03 (s, 3H); MS (CI-method): 354 (Mþ þ 1),
310, 226; HPLC: 97.2% purity.
5.1.6. N-(2-Oxo-3-{4-[3-(3,4,5-trimethoxy-phenyl)-
acryloyl]-phenyl}-oxazolidin-5-ylmethyl)-acetamide 12
Yield: 76%; m.p. 225 ꢀC; IR (KBr): 1760, 1649,
;
1459 cmꢁ1 1H NMR (DMSO-d6): d 8.25e7.72 (m, 7H),
7.24 (s, 2H), 4.80 (bs, 1H), 4.21 (m, 1H), 3.88e3.45 (m,
12H), 1.83 (s, 3H); MS (CI-method): 455 (Mþ þ 1), 411;
HPLC: 92.7% purity.
5.1.13. N-{3-[3-Fluoro-4-(3-pyridin-2-yl-acryloyl)-phenyl]-
2-oxo-oxazolidin-5-ylmethyl}-acetamide 20
Yield: 61%; m.p. 170 ꢀC; IR (KBr): 1744, 1620,
1
1218 cmꢁ1; H NMR (CDCl3): d 8.69 (d, J ¼ 4.4 Hz, 1H),
8.00e7.20 (m, 8H), 6.10 (bs, 1H), 4.90e4.70 (m, 1H), 4.11
(t, J ¼ 8.8 Hz, 1H), 3.85 (t, J ¼ 7.3 Hz, 1H), 3.72e3.65 (m,
2H), 2.04 (s, 3H): MS (CI-method): 385 (Mþ þ 1), 340;
HPLC: 98.5% purity.
5.1.7. N-(3-{4-[3-(3,4-Dimethoxy-phenyl)-acryloyl]-
phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide 13
Yield: 68%; m.p. 216 ꢀC; IR (KBr): 1765, 1650,
5.1.14. N-{3-[3-Fluoro-4-(3-furan-2-yl-acryloyl)-phenyl]-2-
oxo-oxazolidin-5-ylmethyl}-acetamide 21
1
1456 cmꢁ1; H NMR (CDCl3): d 8.07 (d, J ¼ 8.8 Hz, 2H),
7.80e7.10 (m, 6H), 6.91 (d, J ¼ 8.3 Hz, 1H), 6.04 (bs, 1H),
4.90 (bs, 1H), 4.11 (t, J ¼ 8.8 Hz, 1H), 3.96 (s, 3H), 3.94 (s,
3H), 3.93e3.68 (m, 3H), 2.03 (s, 3H); MS (CI-method): 425
(Mþ þ 1), 381, 277, 235; HPLC: 99.9% purity.
Yield: 83%; m.p. 120 ꢀC; IR (KBr): 1744, 1618, 1404,
1222 cmꢁ1
;
1H NMR (CDCl3): d 7.92 (t, J ¼ 8.3 Hz, 1H),
7.63e7.20 (m, 4H), 7.38 (d, J ¼ 2.9 Hz, 1H), 6.74 (d,
J ¼ 2.9 Hz, 1H), 6.52 (bs, 1H), 6.01 (bs, 1H), 4.90e4.75 (m,

N. Selvakumar et al. / European Journal of Medicinal Chemistry 42 (2007) 538e543
543
1H), 4.11 (t, J ¼ 9.3 Hz, 1H), 3.84 (t, J ¼ 6.8 Hz, 1H), 3.71e
3.65 (m, 2H), 2.04 (s, 3H); MS (CI-method): 373 (Mþ þ 1),
253; HPLC: 97.4% purity.
washed with ether and dried under vacuum to yield the thio-
carbamate 26.
To a solution of LDA (0.14 mmol), prepared by the addi-
tion of diisopropylamine (20 mL, 0.14 mmol) to a solution of
n-BuLi (1.6 M in hexanes, 88 mL, 0.14 mmol) in dry THF
(2 mL) at ꢁ78 ꢀC under argon, was added a solution of the
thiocarbamate 26 (40 mg, 0.13 mmol) in dry THF (0.5 mL).
After stirring the reaction mixture for 30 min at the same
5.1.15. N-{3-[3-Fluoro-4-(3-thiophen-2-yl-acryloyl)-
phenyl]-2-oxo-oxazolidin-5-ylmethyl)-acetamide 22
Yield: 66%; m.p. 130 ꢀC; IR (KBr) 1745, 1656, 1618,
1
1402 cmꢁ1; H NMR (CDCl3): d 8.00e7.80 (m, 2H), 7.64e
7.21 (m, 5H), 7.09 (t, J ¼ 4.4 Hz, 1H), 6.03 (bs, 1H), 4.90e
4.70 (m, 1H), 4.11 (t, J ¼ 8.8 Hz, 1H), 3.84 (t, J ¼ 6.8 Hz,
1H), 3.72e3.49 (m, 2H), 2.04 (s, 3H); MS (CI-method): 389
(Mþ þ 1), 345, 295; HPLC: 98.7% purity.
temperature,
a
solution of pyridine-2-carboxaldehyde
(15 mg, 0.14 mmol) in dry THF (0.5 mL) was added. The re-
action mixture was allowed to warm to rt and stirred for fur-
ther 12 h before being quenched with saturated NH4Cl
solution. The resultant mixture was extracted with ethyl ace-
tate. The combined organic extracts were washed with water,
brine and dried. The residue obtained upon evaporation of
solvent was chromatographed on silica gel to obtain the thi-
ocarbamate 27 (12 mg, 22%) as an off-white solid. M.p.
5.1.16. N-(3-{3-Fluoro-4-[3-(1-methyl-1H-imidazol-2-yl)-
acryloyl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-
acetamide 23
Yield: 48%; m.p. 208 ꢀC; IR (neat) 3345, 1752, 1614,
1
1
1408 cmꢁ1; H NMR (CDCl3 þ DMSO-d6): d 8.10e8.00 (m,
139 ꢀC; IR (KBr): 2923, 1753, 1620, 1512 cmꢁ1; H NMR
2H), 7.67e7.62 (m, 3H), 7.37e7.32 (m, 2H), 4.84 (bs, 1H),
4.13 (t, J ¼ 8.8 Hz, 1H), 3.91 (m, 1H), 3.92 (s, 3H), 3.60e
3.57 (m, 2H), 1.97 (s, 3H); MS (CI-method): 387 (Mþ þ 1),
343, 111; HPLC: 99.6% purity.
(CDCl3): d 8.69 (t, J ¼ 3.8 Hz, 1H), 8.00e7.20 (m, 8H),
6.80e6.60 (bs, 1H), 5.05e4.90 (m, 1H), 4.20e3.90 (m,
4H), 4.01 (s, 3H); MS (CI-method) 372, 283, 110; HPLC:
89.1% purity.
5.1.17. N-{3-[3-Fluoro-4-(3-1H-imidazol-2-yl-acryloyl)-
Acknowledgements
phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 24
Yield: 58%; m.p. 224 ꢀC; IR (KBr) 1755, 1622, 1405 cmꢁ1
;
We are indebted to Dr. K. Anji Reddy for his constant sup-
port and encouragement. We also thank Dr. R. Rajagopalan for
his valuable discussions on this work. We appreciate the ser-
vices extended by the Analytical Research Department of Dis-
covery Research, Dr. Reddy0s Laboratories Ltd. for having
carried out all the analytical work.
1H NMR (DMSO-d6): d 8.28 (bs, 1H), 7.88 (t, J ¼ 8.3 Hz,
1H), 7.68e7.20 (m, 6H), 4.90e4.70 (m, 1H), 4.19 (t,
J ¼ 6.8 Hz 1H), 3.81 (t, J ¼ 6.8 Hz, 1H), 3.60e3.00 (m, 4H),
1.83 (s, 3H); MS (CI-method): 373 (Mþ þ 1), 353, 309;
HPLC: 96.1% purity.
5.1.18. {3-[3-Fluoro-4-(3-pyridin-2-yl-acryloyl)-phenyl]-2-
oxo-oxazolidin-5-ylmethyl}-thiocarbamicacid
O-methylester 27
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