Design and synthesis of novel 5-acetylthiomethyl oxazolidinone analogs

Article abstract of DOI:10.1080/00397910902756197

The oxazolidinone class of antimicrobial agents represents a promising advance in the fight against resistant Gram-positive bacterial infections. To improve antibacterial activity and expand the spectrum of activity including Gram-negative bacteria, a series of novel 5-acetylthiomethyl oxazolidinone analogs were designed and synthesized based on the structure-activity relationship studies. The structures of the target compounds and main intermediates were confirmed by 1H NMR, 13C NMR, infrared (IR), mass spectra (MS), and elemental analysis.

Full text of DOI:10.1080/00397910902756197

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Design and Synthesis of Novel 5-
Acetylthiomethyl Oxazolidinone Analogs
Lei Chen a , Jian-Wei Wang a , Li Hai a , Guang-Ming Wang b & Yong
Wu a
a Key Laboratory of Drug Targeting of National Education Ministry,
West China School of Pharmacy , Sichuan University , Chengdu,
China
b Chengdu Entry Scientific and Technological Development Co., Ltd ,
Chengdu, China
Published online: 22 Feb 2010.
To cite this article: Lei Chen , Jian-Wei Wang , Li Hai , Guang-Ming Wang & Yong Wu (2010) Design
and Synthesis of Novel 5-Acetylthiomethyl Oxazolidinone Analogs, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:6, 789-798, DOI:
10.1080/00397910902756197
To link to this article: http://dx.doi.org/10.1080/00397910902756197
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Synthetic Communications1, 40: 789–798, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902756197
DESIGN AND SYNTHESIS OF NOVEL
5-ACETYLTHIOMETHYL OXAZOLIDINONE ANALOGS
Lei Chen,1 Jian-Wei Wang,1 Li Hai,1 Guang-Ming Wang,2
and Yong Wu1
1Key Laboratory of Drug Targeting of National Education Ministry,
West China School of Pharmacy, Sichuan University, Chengdu, China
2Chengdu Entry Scientific and Technological Development Co., Ltd,
Chengdu, China
The oxazolidinone class of antimicrobial agents represents a promising advance in the fight
against resistant Gram-positive bacterial infections. To improve antibacterial activity
and expand the spectrum of activity including Gram-negative bacteria, a series of novel
5-acetylthiomethyl oxazolidinone analogs were designed and synthesized based on the
structure–activity relationship studies. The structures of the target compounds and main
intermediates were confirmed by 1H NMR, 13C NMR, infrared (IR), mass spectra
(MS), and elemental analysis.
Keywords: Antibacterial agent; drug-resistant; oxazolidinone; synthesis
During the past decade, the emergence of multidrug-resistant Gram-positive bacteria
such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant
enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP) has
become a serious medical problem in hospital and community settings.[1–3] There-
fore, there is an urgent need for the search and discovery of new structural classes
of antimicrobial agents effective against these resistant pathogens.
Oxazolidinones typified by linezolid (Fig. 1) are a novel class of totally synthetic
antimicrobial agents with potent activity against resistant Gram-positive organisms
including MRSA, PRSP, and VRE.[4–8] They have been shown to selectively bind
to the 50S ribosomal subunit and inhibit bacterial translation at the initiation phase
of the protein synthesis.[9,10] This unique mode of action results in an important lack
of cross-resistance between oxazolidinones and other classes of antibacterial
agents.[11] Oxazolidinones have taken an important position in the field of treatment
of multidrug-resistant Gram-positive infections.[12,13] However, the resistance to line-
zolid has been reported in clinical isolates of vancomycin-resistant Enterococcus
faecium (VREF) and S. aureus.[14,15] Because of the development of resistance, it is
Received September 24, 2008.
Address correspondence to Yong Wu, Key Laboratory of Drug Targeting of National Education
Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. E-mail:
smile.hl@hotmail.com; wviagra@tom.com
789

790
L. CHEN ET AL.
Figure 1. Structures of linezolid and target compounds.
necessary to further explore and synthesize novel oxazolidinone analogs that are more
potent and less prone to develop resistance.
We have had long-standing interest in improving antibacterial activity and
spectrum of oxazolidinones. After having thoroughly studied the structure–activity
relationship (SAR) of oxazolidinones, we found that the oxazolidinones exhibited
enhanced antibacterial potency and spectrum when their 5-acetamidomethyl side
chain was replaced by thio-containing functional groups (such as thioamide, thio-
urea, thiocarbamate, etc.).[16–20] The oxazolidinones in which the morpholine ring
(C-ring, see Fig. 1) of linezolid was substituted with various nitrogen-containing
heterocycles expanded the spectrum of activity, including activity against clinically
relevant fastidious Gram-negative pathogens.[21,22] Furthermore, we found that
the balance between hydrophilic substituents in C-5 side chain and hydrophobic
substituents in C-ring was important for the antibacterial activity of oxazolidi-
nones.[23–25] Based on these reports, we focused our attention on modifying the C-ring
and C-5 side chain. We modified the C-5 side chain by replacing the nitrogen atom
with the bulkier sulfur atom. Introduction of sulfur was expected to bring in a bulky
polarizable atom, thus altering geometry, polarizability, stability, lipophilicity, and
steric and electronic characteristics of the molecule. On the other hand, we modified
the C-ring with various nitrogen-containing heterocycles.
In this communication, we report our design and synthesis of a series of novel
nitrogen-containing heterocycle oxazolidinone analogs bearing a 5-acetylthiomethyl
group (Fig. 1). We anticipated that such modification would improve the antibacter-
ial activity and spectrum of the novel 5-acetylthiomethyl oxazolidinone analogs.
The novel 5-acetylthiomethyl oxazolidinone analogs described herein were
synthesized as shown in Scheme 1, wherein RH represents (throughout this article)
eight different nitrogen-containing heterocycles. Commencing with 3,4-difluoronitro-
benzene 2, nucleophilic aromatic substitution reaction with excess nitrogen-
containing heterocycle RH selectively gave the p-substituted nitro compounds 3 in
excellent yield.[21,26] Compounds 3 were reduced by catalytic hydrogenation in
tetrahydrofuran (THF) at room temperature for 12 h to give 4. Without purification,
the intermediates 4 were readily reacted with benzyl chloroformate in the presence of
NaHCO3 in THF=H2O to provide the benzyloxycarbamate derivatives 5 in 75–88%
yields. Next, the oxazolidinone ring was assembled in one step in 80–86% yields by

5-ACETYLTHIOMETHYL OXAZOLIDINONE ANALOGS
791
Scheme 1. Synthetic route of novel 5-acetylthiomethyl oxazolidinone analogs. Reagents and conditions:
(i) RH, K2CO3, DMSO, 90ꢁC; or RH, Et3N, EtOAc, rt; (ii) H2, 10% Pd-C, THF, rt; (iii) benzyl chloro-
formate, NaHCO3, THF=H2O, ꢀ10ꢁC to rt; (iv) (1) n-BuLi, THF, ꢀ78ꢁC; (2) R-glycidyl butyrate, ꢀ78ꢁC
to rt; (v) MsCl, Et3N, CH2Cl2, ꢀ5ꢁC to rt; and (vi) potassium thioacetate, DMF, rt.
reacting 5 with n-butyllithium in THF at ꢀ78ꢁC for 1 h followed by addition of
(R)-glycidyl butyrate at the same temperature for 2 h and then stirring at room tem-
perature for 24 h. The alcohols 6 were reacted with methanesulfonyl chloride in the
presence of triethylamine in dry methylene chloride to afford 7 in 82–91% yields.
Finally, treatment of Mesylates 7 with potassium thioacetate in DMF at room tem-
perature for 4 h gave target compounds 1 in 78–85% yields. The structures of the tar-
1
get compounds and main intermediates were confirmed by H NMR, 13C NMR,
infrared (IR), mass spectra (MS), and elemental analysis.
In conclusion, a series of novel 5-acetylthiomethyl oxazolidinone analogs were
successfully designed and synthesized. Preliminary investigations on antibacterial
activity of the novel oxazolidinone analogs 1 will be reported elsewhere.
EXPERIMENTAL
Melting points were determined on a WRS-1B digital melting-point apparatus
1
and are uncorrected. H NMR and 13C NMR spectra were recorded on a Varian
Inova 400 instrument at room temperature. Chemical shifts are reported in d units
(ppm) relative to tetramethylsilane (TMS) as internal standard. Coupling constants
(J) are expressed in hertz. MS were recorded on a Agilent 1946B ESI-MS instrument.
IR spectra were measured on a Perkin-Elmer Spectrum One. Optical rotations
were measured with a Perkin-Elmer polarimeter. Elemental analysis was carried
out with a CarloErba-1106 autoanalyzer. Thin-layer chromatography (TLC) analy-
ses were performed on silica-gel plates: E. Merck 0.2 mm precoated (gel 60, F254).
Column chromatography was carried out on silica gel 60 (230–400 mesh). Spots were

792
L. CHEN ET AL.
visualized by ultraviolet (UV) light or iodine. Unless specified, all commercially
available solvents and reagents were used without further purification. THF was
distilled under argon from sodium–benzophenone ketyl prior to use.
3-Fluoro-4-morpholinylnitrobenzene (3a)
3,4-Difluoronitrobenzene (11.0 mL, 100.3 mmol) was added slowly via an
addition funnel to a solution of morpholine (9.5 mL, 109.2 mmol) and triethylamine
(15.2 mL, 109.5 mmol) in ethyl acetate (100 mL). The flask was cooled in an ice bath,
the remaining 3,4-difluoronitrobenzene was added over the next 30 min, and the mix-
ture was gradually warmed to room temperature overnight. The mixture was filtered,
and the solid was washed with water and dried in a vacuum oven to give 3a (15.4 g) as
a yellow solid. The layers of the filtrate were separated, and the aqueous portion was
extracted with ethyl acetate. The combined organic portions were dried over Mg2SO4
and evaporated to give a yellow solid (7.5 g). Each lot was recrystallized from acetone
and water to give a total of 3a (22.3 g, yield 98.4%) as a yellow solid. Mp
1
111.5–112.2ꢁC (lit.[14] yield 98%; mp 111–112ꢁC). H NMR (400 MHz, CDCl3) d
7.97 (ddd, J ¼ 8.8, 2.4, 1.6 Hz, 1H), 7.89 (dd, J ¼ 12.8, 2.4 Hz, 1H), 6.91 (t, J ¼ 8.8 Hz,
1H), 3.86 (t, J ¼ 4.8 Hz, 4H), 3.27(t, J ¼ 4.8 Hz, 4H); IR (KBr): 2924, 1606, 1519,
1496, 1334, 1250, 1126, 950 cmꢀ1; MS (ESI) m=z 226 (Mþ).
Compounds 3b–e were respectively prepared from the corresponding
nitrogen-containing heterocycle in a similar procedure.
3-Fluoro-4-(1-pyrazolyl)nitrobenzene (3f)
The solution of pyrazole (9.5 g, 139.7 mmol), K2CO3 (38.6 g, 279.7 mmol), and
3,4-difluoronitro-benzene (13.8 mL, 125.8 mmol) in dimethylsulfoxide (DMSO)
(200 mL) was heated to 90ꢁC for 18 h. The reaction was cooled diluted with water
(150 mL), the mixture was filtered, and the solid was washed with water and dried
in a vacuum oven to give 3f (20.6 g) as an off-white solid. Ethyl acetate (100 mL)
and water (200 mL) were added to the filtrate, the phases were separated, and the
aqueous portion was extracted with ethyl acetate. The combined organic portions
were dried over Mg2SO4 and concentrated to give crude 3f (5.2 g) as a light yellow
solid. Each lot was recrystallized from acetone and water to give a total of 3f
(23.5 g, yield 90.2%) as an off-white solid. Mp 127.6–128.7ꢁC (lit.[13] yield 87%;
1
mp 128–129ꢁC). H NMR (400 MHz, CDCl3) d 8.24–8.28 (m, 1H), 8.13–8.19 (m,
3H), 7.81 (d, J ¼ 1.6 Hz, 1H), 6.56–6.58 (m, 1H); IR (KBr): 3435, 3064, 2926,
1629, 1515, 1335, 1225, 1130 cmꢀ1; MS (ESI) m=z 207 (Mþ).
Compounds 3g–h were respectively prepared from the corresponding
nitrogen-containing heterocycle in a similar procedure.
N-Carbobenzoxy-3-fluoro-4-morpholinylaniline (5a)
Palladium (10%) on carbon (1.5 g) was added to a solution of 3a (11.3 g,
50.0 mmol) in THF (150 mL), and the mixture was hydrogenated at room tempera-
ture under a hydrogen atmosphere (0.2 MPa) for 12 h. The mixture was filtered
through celite, treated with saturated NaHCO3 (10.1 g, 120.2 mmol) solution, and

5-ACETYLTHIOMETHYL OXAZOLIDINONE ANALOGS
793
cooled to ꢀ10ꢁC. Benzyl chloroformate (8.6 mL, 60.3 mol) was added and followed
by warming to ambient temperature for 24 h. The mixture was concentrated to ca.
half the original volume and diluted with ethyl acetate (100 mL), the phases were
separated, and the aqueous portion was extracted with ethyl acetate. The combined
organic portions were washed with water and brine. Drying over Mg2SO4 and con-
centration in vacuo afforded 5a (13.8 g, yield 83.6%) as a cream-colored solid, which
was recrystallized from acetone and water. Mp 122.5–123.7ꢁC. 1H NMR (400 MHz,
CDCl3) d 7.26–7.40 (m, 5H), 6.90–6.98 (m, 2H), 6.72 (s, 1H), 5.19 (s, 2H), 3.87 (t,
J ¼ 4.4 Hz, 4H), 3.04 (t, J ¼ 4.4 Hz, 4H); IR (KBr): 3320, 2925, 1706, 1539, 1376,
1280, 1237, 1120 cmꢀ1; MS (ESI) m=z 330 (Mþ).
Compounds 5b–h were respectively prepared from the corresponding 3b–h in a
similar procedure.
(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]
methanol (6a)
n-Butyllithium (13.6 mL of 2.2 M in hexane, 29.9 mmol) was added to a
solution of 5a (8.5 g, 25.8 mmol) in THF (100 mL) under nitrogen at ꢀ78ꢁC via syr-
inge. The solution was stirred at ꢀ 78ꢁC for 1 h, and then a THF solution of
(R)-glycidyl butyrate (4.2 mL, 29.7 mmol) was added dropwise via an addition
funnel. After stirring at ꢀ78ꢁC for 2 h, the bath was removed, and the reaction mix-
ture was stirred at room temperature for 24 h. The reaction was then quenched with
saturated ammonium chloride (80 mL), ethyl acetate (100 mL), and water (50 mL),
the phases were separated, and the aqueous portion was extracted twice with ethyl
acetate. The combined organic portion was washed with water and brine, dried over
Mg2SO4, and evaporated to give 6a (6.5 g, yield 85.1%) as a light gray amorphous
solid, which was recrystallized from ethyl acetate and hexane. Mp 111.5–112.6ꢁC.
1H NMR (400 MHz, CDCl3) d 7.45 (dd, J ¼ 14.4, 2.4 Hz, 1H), 7.10 (dd, J ¼ 9.2,
1.6 Hz, 1H), 6.94 (t, J ¼ 9.2 Hz, 1H), 4.70–4.76 (m, 1H), 3.93–4.01 (m, 3H), 3.87 (t,
J ¼ 4.8 Hz, 4H), 3.73 (dd, J ¼ 12.4, 3.2 Hz, 1H), 3.05 (t, J ¼ 4.8 Hz, 4H), 2.99 (s,
1H); IR (KBr): 3436, 3262, 2925, 1750, 1735, 1530, 1463, 1452, 1439, 1425,
20
1229 cmꢀ1; MS (ESI) m=z 296 (Mþ); ½aꢂD ꢀ54.06ꢁ (c 1.0, CHCl3).
Compounds 6b–h were respectively prepared from the corresponding 5b–h in a
similar procedure.
(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-
5-oxazolidinyl]methyl methanesulfonate (7a)
The alcohol 6a (14.8 g, 50.0 mmol) and triethylamine (14.0 mL, 100.5 mmol) were
cooled to ꢀ5ꢁC in methylene chloride (250 mL) and treated with methanesulfonyl
chloride (5.8 mL, 74.9 mmol) followed by stirring at 0ꢁC for 30 min. The reaction mix-
ture was stirred at room temperature for 2 h, diluted with methylene chloride (100 mL),
and washed with water and brine. Drying over Mg2SO4 and concentration in vacuo
afforded mesylate 7a (16.9 g, yield 90.4%) as an off-white solid, which was recrystal-
1
lized from acetonitrile and water. Mp 183.5–184.9ꢁC. H NMR (400 MHz, DMSO-
d6) d 7.50 (dd, J ¼ 15.2, 2.4 Hz, 1H), 7.21 (dd, J ¼ 9.2, 2.4 Hz, 1H), 7.07 (t, J ¼ 9.6 Hz,
1H), 4.97–5.03 (m, 1H), 4.43–4.53 (m, 2H), 4.15 (t, J ¼ 9.2 Hz, 1H), 3.80 (dd, J ¼ 9.2,

794
L. CHEN ET AL.
6.4 Hz, 1H), 3.74 (t, J ¼ 4.4 Hz, 4H), 3.25 (s, 3H), 2.96 (t, J ¼ 4.4 Hz, 4H); IR (KBr):
20
2925, 1750, 1512, 1358, 1346, 1232, 1183, 1110 cmꢀ1; MS (ESI) m=z 374 (Mþ); ½aꢂD
ꢀ50.18ꢁ (c 1.0, DMSO).
Compounds 7b–h were respectively prepared from the corresponding 6b–h in a
similar procedure.
General Procedure for the Synthesis of Thioacetate 1
Potassium thioacetate (5.7 g, 50.0 mmol) was added to a solution of mesylate 7
(20.0 mmol) in DMF (100 mL) at room temperature. The mixture was stirred at
room temperature for 4 h. Ethyl acetate (80 mL) and water (100 mL) were added
to the reaction mixture, the phases were separated, and the aqueous portion was
extracted twice with ethyl acetate. The combined organic portion was washed with
water and brine, dried over Mg2SO4, and evaporated to give thioacetate 1.
(R)-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1a)
White solid; mp 114.2–115.6ꢁC. 1H NMR (400 MHz, CDCl3) d 7.43 (dd,
J ¼ 14.4, 2.4 Hz, 1H), 7.09 (dd, J ¼ 8.8, 2.8 Hz, 1H), 6.94 (t, J ¼ 8.8 Hz, 1H),
4.75–4.81 (m, 1H), 4.05 (t, J ¼ 8.8 Hz, 1H), 3.87 (t, J ¼ 4.4 Hz, 4H), 3.63–3.67 (m,
1H), 3.26–3.36 (m, 2H), 3.05 (t, J ¼ 4.4 Hz, 4H), 2.39 (s, 3H); 13C NMR (200 MHz,
CDCl3) d 30.5, 32.5, 49.2, 50.9, 66.9, 70.9, 107.1, 107.7, 113.8, 118.8, 133.0, 136.3,
153.0, 154.0, 157.9, 194.6. IR (KBr): 2967, 2862, 1752, 1731, 1696, 1519, 1429,
20
1364, 1326, 1271, 1228, 1198, 1107 cmꢀ1; MS (ESI) m=z 354 (Mþ); ½aꢂD ꢀ33.58ꢁ(c 0.5,
DMSO). Anal. calcd. for C16H19FN2O4S: C, 54.22; H, 5.40; N, 7.90. Found: C, 54.08;
H, 5.36; N, 7.98.
(R)-[[3-[3-Fluoro-4-(1-piperidinyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1b)
White solid; mp 98.7–99.3ꢁC. 1H NMR (400 MHz, CDCl3)
d 7.38
(d, J ¼ 14.0 Hz, 1H), 7.10 (d, J ¼ 8.4 Hz, 1H), 6.96 (t, J ¼ 8.8 Hz, 1H), 4.76–4.83 (m,
1H), 4.07 (t, J ¼ 8.8 Hz, 1H), 3.65–3.69 (m, 1H), 3.28–3.38 (m, 2H), 3.00 (s, br,
4H), 2.42 (s, 3H), 1.72–1.79 (m, 4H) 1.58–1.62 (m, 2H); 13C NMR (200 MHz, CDCl3)
d 24.1, 26.0, 30.5, 32.5, 49.3, 52.2, 70.9, 107.1, 107.6, 113.8, 119.3, 132.3, 138.0, 153.1,
154.0, 157.9, 194.6. IR (KBr): 3463, 2932, 2820, 1742, 1692, 1516, 1417, 1362, 1224,
20
1116, 1089 cmꢀ1; MS (ESI) m=z 352 (Mþ); ½aꢂD ꢀ24.69ꢁ(c 0.5, DMSO). Anal. calcd.
for C17H21FN2O3S: C, 57.94; H, 6.01; N, 7.95. Found: C, 57.86; H, 5.98; N, 7.96.
(R)-[[3-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-2-oxo-
5-oxazolidinyl]methyl]thioacetate (1c)
White solid; mp 157.3–159.1ꢁC. 1H NMR (400 MHz, CDCl3) d 7.46 (dd,
J ¼ 14.8, 2.0 Hz, 1H), 7.17 (d, J ¼ 8.8 Hz, 1H), 7.04 (t, J ¼ 8.8 Hz, 1H), 4.76–4.83
(m, 1H), 4.13 (t, J ¼ 9.2 Hz, 1H), 3.66–3.69 (m, 1H), 3.25–3.35 (m, 2H), 2.96 (t,
J ¼ 4.4 Hz, 4H), 2.46 (s, br, 4H), 2.38 (s, 3H), 2.21 (s, 3H); 13C NMR (200 MHz,

5-ACETYLTHIOMETHYL OXAZOLIDINONE ANALOGS
795
CDCl3) d 30.5, 32.5, 46.0, 49.2, 50.5, 55.1, 70.9, 107.1, 107.6, 113.8, 119.0, 132.7,
136.6, 152.9, 154.0, 157.8, 194.6. IR (KBr): 3435, 2937, 2838, 1750, 1690, 1517,
20
1425, 1417, 1291, 1216, 1198, 1141 cmꢀ1; MS (ESI) m=z 367 (Mþ); ½aꢂD ꢀ23.49ꢁ
(c 0.5, DMSO). Anal. calcd. for C17H22FN3O3S: C, 55.57; H, 6.03; N, 11.44. Found:
C, 55.52; H, 5.97; N, 11.48.
(R)-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]-2-oxo-
5-oxazolidinyl]methyl]thioacetate (1d)
1
White solid; mp 129.7–131.5ꢁC. H NMR (400 MHz, DMSO-d6) d 7.49 (dd,
J ¼ 14.8, 2.4 Hz, 1H), 7.19 (dd, J ¼ 8.8, 1.2 Hz, 1H), 7.07 (t, J ¼ 8.8 Hz, 1H),
4.77–4.84 (m, 1H), 4.14 (t, J ¼ 9.2 Hz, 1H), 3.67–3.70 (m, 1H), 3.56–3.59 (m, 4H),
3.26–3.36 (m, 2H), 2.90–2.98 (m, 4H), 2.39 (s, 3H), 2.03 (s, 3H); 13C NMR
(200 MHz, CDCl3) d 21.2, 30.5, 32.4, 41.4, 46.0, 49.2, 71.0, 107.2, 107.7, 113.9,
119.4, 133.4, 135.9, 153.1, 154.0, 158.0, 169.0, 194.6. IR (KBr): 3436, 2919, 2840,
1751, 1691, 1654, 1520, 1426, 1370, 1235, 1162, 1109 cmꢀ1; MS (ESI) m=z 395
20
(Mþ); ½aꢂD ꢀ21.57ꢁ(c 0.5, DMSO). Anal. calcd. for C18H22FN3O4S: C, 54.67; H,
5.61; N, 10.63. Found: C, 54.58; H, 5.57; N, 10.56.
(R)-[[3-[3-Fluoro-4-(1-pyrrolidinyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1e)
1
Light yellow solid; mp 98.5–99.7ꢁC. H NMR (400 MHz, CDCl3) d 7.30 (d,
J ¼ 15.2 Hz, 1H), 7.01 (dd, J ¼ 8.8, 2.0 Hz, 1H), 6.65 (s, br, 1H), 4.72–4.79 (m, 1H),
4.03 (t, J ¼ 8.8 Hz, 1H), 3.61–3.65 (m, 1H), 3.25–3.35 (m, 6H), 2.39 (s, 3H),
1.98–2.04 (m, 4H); 13C NMR (200 MHz, CDCl3) d 25.0, 30.5, 32.6, 49.8, 70.9,
107.8, 108.3, 114.7, 115.1, 128.2, 134.5, 149.2, 154.1, 194.6. IR (KBr): 3386, 2961,
2878, 1743, 1704, 1520, 1421, 1356, 1319, 1227, 1195, 1134, 1103 cmꢀ1; MS (ESI)
20
m=z 338 (Mþ); ½aꢂD ꢀ23.27ꢁ(c 0.5, DMSO). Anal. calcd. for C16H19FN2O3S: C,
56.79; H, 5.66; N, 8.28. Found: C, 56.69; H, 5.67; N, 8.25.
(R)-[[3-[3-Fluoro-4-(1-pyrazolyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1f)
1
White solid; mp 118.5.7–120. 1ꢁC. H NMR (400 MHz, CDCl3) d 8.00 (t,
J ¼ 2.4 Hz, 1H), 7.89–7.93 (m, 1H), 7.73–7.77 (m, 2H), 7.24 (dd, J ¼ 9.2, 2.0 Hz,
1H), 6.50 (t, J ¼ 2.0 Hz, 1H), 4.83–4.89 (m, 1H), 4.15 (t, J ¼ 8.8 Hz, 1H), 3.73–3.77
(m, 1H), 3.31–3.41 (m, 2H), 2.43 (s, 3H); 13C NMR (200 MHz, CDCl3) d 30.6,
32.4, 48.9, 71.1, 106.6, 107.2, 113.5, 124.3, 130.5, 137.2, 140.7, 150.9, 153.7, 155.8,
194.6. IR (KBr): 3435, 2926, 1759, 1691, 1530, 1477, 1395, 1366, 1224, 1134,
20
1097 cmꢀ1; MS (ESI) m=z 335 (Mþ); ½aꢂD ꢀ26.46ꢁ(c 0.5, DMSO). Anal. calcd. for
C15H14FN3O3S: C, 53.72; H, 4.21; N, 12.53. Found: C, 53.65; H, 4.19; N, 12.60.
(R)-[[3-[3-Fluoro-4-(1-pyrrolyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1g)
White solid; mp 128.1–129.5ꢁC. 1H NMR (400 MHz, CDCl3) d 7.60 (dd, J ¼ 13.2,
2.4 Hz, 1H), 7.38 (t, J¼ 8.8 Hz, 1H), 7.26–7.28 (m, 1H), 7.00–7.01 (m, 2H), 6.35 (t,

796
L. CHEN ET AL.
J ¼ 2.0 Hz, 2H), 4.80–4.87 (m, 1H), 4.11 (t, J ¼ 8.8 Hz, 1H), 3.70–3.74 (m, 1H), 3.29–3.39
(m, 2H), 2.42 (s, 3H);13C NMR (200MHz, CDCl3) d 30.6, 32.4, 49.0, 71.1, 106.9, 107.4,
110.0, 113.7, 121.2, 125.0, 136.8, 152.4, 153.8, 157.3, 194.6. IR (KBr): 3474, 3075, 2972,
1746, 1696, 1590, 1530, 1414, 1343, 1313, 1220, 1201, 1103 cmꢀ1; MS (ESI) m=z 334
20
(Mþ); ½aꢂD ꢀ27.44ꢁ (c 0.5, DMSO). Anal. calcd. for C16H15FN2O3S: C, 57.47; H,
4.52; N, 8.38. Found: C, 57.42; H, 4.49; N, 8.41.
(R)-[[3-[3-Fluoro-4-(1-imidazolyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]thioacetate (1h)
1
Light yellow solid; mp 116.5–118.6ꢁC. H NMR (400 MHz, DMSO-d6) d 8.01
(s, 1H), 7.74 (dd, J ¼ 13.6, 2.4 Hz, 1H), 7.67 (t, J ¼ 9.2 Hz, 1H), 7.54 (d, J ¼ 1.6 Hz,
1H), 7.47 (dd, J ¼ 8.8, 1.6 Hz, 1H), 7.12 (s, 1H), 4.85–4.88 (m, 1H), 4.24 (t, J ¼ 8.8 Hz,
1H), 3.76–3.80 (m, 1H), 3.30–3.39 (m, 2H), 2.40 (s, 3H); 13C NMR (200 MHz, CDCl3)
d 30.6, 32.3, 48.9, 71.2, 106.8, 107.3, 113.8, 119.6, 125.4, 137.0, 138.5, 152.5, 153.6,
157.4, 194.6. IR (KBr): 3433, 3125, 3109, 3074, 2969, 2880, 1750, 1699, 1529, 1484,
20
1411, 1366, 1301, 1220, 1203, 1127 cmꢀ1; MS (ESI) m=z 335 (Mþ); ½aꢂD ꢀ26.72ꢁ (c
0.5, DMSO). Anal. calcd. for C15H14FN3O3S: C, 53.72; H, 4.21; N, 12.53. Found:
C, 53.68; H, 4.19; N, 12.48.
ACKNOWLEDGMENTS
We are grateful for the financial support of the National Natural Science
Foundation of China (No. 30672537) and Chengdu Entry Scientific and Technologi-
cal Development Co., Ltd.
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