Synthesis and antibacterial activity of 3-(substituted arylmethyl)-4- acylaminomethyloxazolidin-2-ones and derivatization to symmetrical twin-drug type molecules

Article abstract of DOI:10.1002/jhet.1522

In connection with our studies on antibacterial active compounds in the class of new oxazolidinones against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains, some molecular modifications were attempted. In this study, mol

Full text of DOI:10.1002/jhet.1522

March 2013
Synthesis and Antibacterial Activity of 3-(Substituted arylmethyl)-
4-acylaminomethyloxazolidin-2-ones and Derivatization to Symmetrical
Twin-Drug Type Molecules
417
Fumiko Fujisaki, Sachi Hiromatsu, Yumiko Matsumura, Aki Fukami, Nobuhiro Kashige, Fumio Miake, and
*
Kunihiro Sumoto
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
*
E-mail: kunihiro@adm.fukuoka-u.ac.jp
Received June 9, 2011
DOI 10.1002/jhet.1522
Published online 3 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
In connection with our studies on antibacterial active compounds in the class of new oxazolidinones
against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains, some molecular
modifications were attempted. In this study, molecular modifications of 4-aminomethyloxazolidin-2-ones (3a)
to the corresponding 4-acylaminomethyloxazolidin-2-one derivatives (3c–d) and preparations of the represented
twin-drug type molecules (10–14) were investigated. Some additional 4-dialkylaminomethyloxazolidin-2-ones
(2) were also synthesized. The synthesized compounds were evaluated for antibacterial activity with
Gram-positive (S. aureus) and Gram-negative (E. coli) strains.
J. Heterocyclic Chem., 50, 417 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
In the course of work on new antibacterial compounds,
extensive efforts have been made to find new promising
candidates. Many reports on synthetic molecular modifica-
tions have appeared [1].
In connection with our synthetic studies in the search for
new bioactive lead compounds, some molecular modifica-
tions of b-aminoalanines (4) to a new class of linezolid (1)
mimetic oxazolidin-2-ones [such as (2) or (3)] (Fig. 1) have
been reported [5–9].
Infection by bacteria is initiated by specific recognition
of host epithelial surfaces, and subsequent adhesion is
essential for invasion. In this process for recognition or
binding to glycoconjugates (glycans), microorganisms
usually use sugar-binding proteins such as lectins [2]. For
such molecular recognition of glycans, the major recogni-
tion patterns between the host and target guest molecules
are through suprafacial interactions. This suprafacial
interaction process is a logical path and is thought to direct
a controlled biological response [3]. We have been
interested in target compounds that interfere with such a
suprafacial recognition process in order to find new leads
for antibacterial agents [4]. In this article, synthesis of
target designed molecules (2, 3c–d, and 14–18) and results
of biological evaluation of the 4-acylaminomethyloxazolidin-
2-one derivatives for antibacterial activity are described.
Compounds 2 were synthesized by the same method as
that used for the preparation of 4-dialkylaminomethyloxa-
zolidn-2-ones reported previously [6]. Compounds 2a–c
were obtained from 3,4-methylendioxycinnamic acid and
corresponding b-aminoalanines (4a and 4b) as starting
materials. In the reduction stage (5 ! 6) prior to cycliza-
tion with NaAlH2(OCH2CH2OMe)2, the double bond in
cinnamoyl groups is easily hydrogenated, and we obtained
3-(3,4-methylenedioxyphenyl)propyl derivatives 2a and
2b as final products (Scheme 1). Compounds 2d and 2e
having a urea moiety in the molecules were prepared from
the addition of 3-aminophenylmethyl-4-pyrrolidinomethy-
loxazolidin-2-one (2c) obtained from the transformation
of b-aminoalanines (4a) to phenyl isothiocyanate or phenyl
isocyanate (Scheme 2).
© 2013 HeteroCorporation

418
F. Fujisaki, S Hiromatsu, Y Matsumura, A Fukami, N. Kashige, F. Miake, and K Sumoto
Vol 50
Scheme 2. Synthesis of compounds 2d and 2e.
Figure 1. Structures of linezolid and compounds 2 and 3.
We have already attempted molecular modification to the
compounds (3a and 3b) from serine methyl ester (7) as a
starting material [7]. These compounds were prepared with
4-aminomethyloxazolidin-2-ones (9a and 9b) generated in
situ from the corresponding phthalimide derivative (8a
and 8b). New acyl derivatives 3c and 3d were prepared
from direct N-acylation reaction of isolated intermediary
4-aminomethyloxazolidin-2-one (9a) with corresponding
acid derivatives (R3CO2H) (Scheme 3). Among these target
compounds (2–3) [10,11], compounds (3a and 3b) showed
bacteriostatic activity against Gram-positive (Staphylococcus
aureus) and Gram-negative (Escherichia coli) strains and
3a showed higher activity than that of 3b, which apparently
mimics linezolid (1) because of the presence of two substitu-
ents (morpholine and fluorine) on the phenyl ring in the
molecule (3b) [7,11].
For a suprafacial three-dimensional interaction for its
binding site, the substituent on the phenyl ring at N-3 of
oxazolidinone in linezolid is dictated largely by its van der
Waals interactions with the sugar residue in the bacterial
ribosome (rRNA residue in the peptide transferase center)
[12]. Because a compound with a phenyl azide substituent
instead of a morpholine on the phenyl ring was successfully
developed as one of the photoprobes [12], the biphenyl
group at N-3 of the oxazolidinone ring may have a good
shape for the binding site. In fact, a new molecular modifica-
tion of N-3 biphenyl derivatives on oxazolidin-2-one ring
of linezolid has been investigated to find new antibacterial
candidates [13,14]. Because many endogenous macromole-
cules regulating cell functions are known to be dimeric forms
Scheme 1. Synthesis of compounds 2a–c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis and Antibacterial Activity of 3-(Substituted arylmethyl)-4-
419
acylaminomethyloxazolidin-2-ones and Derivatization to Symmetrical Twin-Drug Type Molecules
Scheme 3. Synthesis of compounds 3c and 3d.
of subunits and some of these molecules frequently have
twofold symmetrical features [15,16], we designed symmet-
rical molecules in the search for antibacterial leads. In terms
of molecular symmetry, small symmetrical molecules
frequently appear in various synthetic twin-drug type
molecules and biologically active compounds. Biologically
active symmetrical molecules are usually constructed on
a symmetrical template. For linker mode twin-drug mole-
cules, the nature of a linker plays an important role in
binding to the receptor (or recognition) site for biological
activity [17,18]. Inspired by the antibacterial profiles of
compounds, it was thought worthwhile to undertake a
synthetic molecular modification study with the aim of
obtaining new candidates with antibacterial activity. From
this point of view, we therefore carried out further synthetic
investigation of new symmetrical molecules (10a,b–14a,b)
(Scheme 4).
Molecular modification to the represented new symmet-
rical molecules (10a,b–13a,b) can be considered to be an
identical twin-drug approach based on 4-aminomethyloxa-
zolidin-2-ones as a single drug moiety [18]. Furthermore,
we synthesized symmetrical target molecules (14a and
14b) having a simple flexible methylene group [-(CH2)3-]
as a linker for another identical twin-drug approach.
The structures of the synthesized compounds were
easily confirmed by NMR spectroscopic analysis. All of
the twin-drug type compounds except for compound 13
showed magnetically equivalent spectroscopic signal
patterns, indicating a symmetrical molecular feature in
DMSO-d6 [19] (see Experimental section).
Scheme 4. Synthesis of twin-drug type compounds 10–14.
Among the twin-drug type compounds described in this
paper, compound 10–14, except for 10b and 14a, showed
antibacterial activities (minimum inhibitory concentration
(MIC) = 0.171~0.184 mM/mL) against E. coli and antibac-
terial activities (MIC = 0.171–>0.184 mM/mL) against
S. aureus. We found that compounds 10b and 14a are
more active than the original prototype compound 3a
(MIC = >0.395 mM/mL against both strains) in the
compounds that have been tested. The determined MIC
(mM/mL) values for compounds 10b and 14a against Gram-
negative (E. coli) and Gram-positive (S. aureus) strains were
in the range of 0.078ꢀ0.097 and 0.155~0.194 mM/mL,
respectively [20]. These experimental results indicate the
importance of the nature of the linker used for N-acylation
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

420
F. Fujisaki, S Hiromatsu, Y Matsumura, A Fukami, N. Kashige, F. Miake, and K Sumoto
Vol 50
FABMS (positive) m/z: 335 (M + H)+. 1H-NMR (DMSO-d6) d:
0.89–0.93 (6H, m, N(CH2CH3)2), 1.67–1.82 (2H, m, Ph-
CH2CH2CH2), 2.33–2.60 (8H, m, N(CH2CH3)2, Ph-CH2CH2CH2
and CH2-N(CH2CH3)2), 3.11–3.17 (1H, m, Ph-CH2CH2CHH),
3.24–3.26 (1H, m, Ph-CH2CH2CHH), 3.85–3.90 (1H, m, Oxaz H-
4), 3.91–3.94 (1H, m, Oxaz H-5), 4.27 (1H, t, J = 8.0 Hz, Oxaz H-
5), 5.95 (2H, s, O-CH2-O), 6.65–6.67 (1H, m, Ar H-6), 6.67–6.80
(2H, m, Ar H-2, H-5). 13C-NMR (DMSO-d6) d: 11.5 (N
(CH2CH3)2), 28.8 (Ph-CH2CH2CH2), 31.9 (CH2N(CH2CH3)2),
41.6 (Ph-CH2CH2CH2), 46.8 (N(CH2CH3)2), 52.4 (Oxaz C-4),
55.3 (Ph-CH2CH2CH2), 66.1 (Oxaz C-5), 100.5 (O-CH2-O),
107.9 (Ar C-5), 108.6 (Ar C-2), 120.9 (Ar C-6), 135.1 (Ar C-1),
145.2 (Ar C-3), 147.1 (Ar C-4), 157.5 (Oxaz C-2). Anal. Calcd
for C18H26N2O4 ꢃ 0.1H2O: C, 64.30; H, 7.85; N, 8.33. Found: C,
64.27; H, 7.79; N, 8.24.
and also the substituent at C-3 of the oxazolidin-2-one ring
for antibacterial activity. Because two selected substituents
at C-3 of the oxazolidin-2-one ring (see compounds 9a
and 9b) were found to be effective for the derivatization to
twin-drug type compounds, we are now investigating
further synthetic applications of 4-aminomethyloxazolidin-
2-one derivatives (9) and performing biological evaluation
of the antibacterial (biological) properties of these single
drug N-acyl derivatives and related twin-drug type symmet-
rical derivatives to find a new candidate (or lead) for
antibacterial agents.
3-(3-Aminobenzyl)-4-(pyrrolidin-1-ylmethyl)oxazolidin-2-one
(2c).
This compound was obtained in 51.4% yield from
EXPERIMENTAL
compound 5c as an oil. IR (KBr) cmꢂ1: 1741. FABMS (positive)
m/z: 276 (M + H)+. 1H-NMR (DMSO-d6) d: 1.63–1.65 (4H,
m, Pyr H-3, H-4), 2.38–2.40 (4H, m, Pyr H-2, H-5), 2.46–2.49
(1H, m, Pyr-CHH), 2.50–2.69 (1H, m, Pyr-CHH), 3.69–3.72
(1H, m, Oxaz H-4), 4.01 (1H, dd, J = 8.5, 4.0 Hz, Oxaz H-5), 4.10
(1H, d, J = 15.0 Hz, Ph-CHH), 4.34 (1H, t, J = 8.5 Hz, Oxaz H-5),
4.44 (1H, d, J = 15.0 Hz, Ph-CHH), 5.04 (2H, br s, NH2), 6.39
(1H, d, J = 7.5 Hz, Ar H), 6.46–6.47 (2H, d, J = 7.5 Hz, Ar H),
6.96–6.99 (1H, m, Ar H). 13C-NMR (DMSO-d6) d: 23.1 (Pyr
C-3, C-4), 45.9 (CH2-Ph), 52.7 (Oxaz C-4), 53.9 (Pyr C-2,
C-5), 57.3 (CH2-Pyr), 66.2 (Oxaz C-5), 112.7 (Ar C-4),
113.0 (Ar C-2), 114.9 (Ar C-6), 128.9 (Ar C-5), 137.1 (Ar
C-1), 148.2 (Ar C-3), 157.7 (Oxaz C-2). Anal. Calcd for
C15H21N3O2 ꢃ 0.15H2O: C, 64.79; H, 7.72; N, 15.11. Found:
C, 64.87; H, 7.70; N, 14.90.
Melting points are uncorrected. IR spectra were measured by a
Shimadzu FT/IR-8100 spectrometer (Japan). The 1H- and 13C-
NMR spectra were obtained by a JEOL JNM A-500 (Japan) at
35ꢁC. The chemical shifts were expressed in d ppm downfield
from an internal TMS signal. The signal assignments were con-
firmed by 1H–1H 2D COSY and by 1H–13C HMQC and
1H–13C HMBC spectra. High FABMS spectra were obtained by
a JEOL JMS-HX110 mass spectrometer. The following abbrevia-
tions were used: Mor, morpholine ring; FAr, 3-fluorobenzene
ring; and Oxaz, oxazolidinones-2-one ring.
Assays for antibacterial activity.
We used S. aureus
ATCC6538P and E. coli NBRC14237 (NIHJ) (Gram-positive
and Gram-negative bacteria, respectively) as target organisms.
Synthesized compounds were dissolved in DMSO to
a
concentration of 1.280 mg/mL. The MIC of a standard strain
was measured by the authentic microdilution method to monitor
the bacterial growth turbidity in Mueller–Hinton broth
according to the Japanese Society of Chemotherapy [21,22].
Preparation of 3-alkyl-(4-N,N-disubstituted aminomethyl)
1-(3-((2-Oxo-4-(pyrrolidin-1-ylmethyl)oxazolidin-3-yl)methyl)
phenyl)-3-phenylthiourea (2d). Phenyl isothiocyanate (58 mg,
0.43mmol) was added to a solution of 2c (100mg, 0.36 mmol)
and 1 mL of aqueous K2CO3 (200mg, 1.44 mmol) in MeCN
(10 mL) and stirred for 10min at room temperature. The mixture
was stirred for another 10min at 50ꢁC, and the solvent was
removed under reduced pressure. Water was added to the
resulting residue, and the separated material was extracted with
AcOEt. The organic phase was washed with brine and dried
over anhydrous MgSO4. After concentration of the solvent, the
residue was purified by silica gel column chromatography
(successively with MeCN and EtOH) to give 2c (93 mg, 62.4%)
as amorphous white powder. IR (KBr) cmꢂ1: 1732. FABMS
(positive) m/z: 411 (M+ H)+. 1H-NMR (DMSO-d6) d: 1.63
(4H, br, Pyr H-3, H-4), 2.38 (4H, br, Pyr H-2, H-5), 2.50–2.52
(1H, m, Pyr-CHH), 2.71 (1H, dd, J = 12.5, 5.5 Hz, Pyr-CHH),
3.79–3.83 (1H, m, Oxaz H-4), 4.00–4.03 (1H, m, Oxaz H-5), 4.31
(1H, d, J = 15.5Hz, Ph-CHH-Oxaz), 4.35 (1H, t, J = 8.5 Hz, Oxaz
H-5), 4.55 (1H, d, J = 15.5 Hz, Ph-CHH-Oxaz), 7.03 (1H,
d, J = 7.5 Hz, Ar H), 7.12 (1H, t, J = 7.5 Hz, Ar H), 7.30 (1H,
d, J = 7.5 Hz, Ar H), 7.31–7.34 (3H, m, Ar H), 7.41–7.49
(3H, m, Ar H), 9.76, 9.79 (each 1H, s, NH). 13C-NMR
(DMSO-d6) d: 23.1 (Pyr C-3, C-4), 45.6 (Ph-CH2-Oxaz), 52.9
(Oxaz C-4), 53.9 (Pyr C-2, C-5), 57.5 (CH2-Pyr), 66.2
(Oxaz C-5), 122.3, 122.5, 123.5, 123.5, 124.3, 128.3, 128.5
(Ar C), 137.1 (1,3-disubstituted phenyl Ar C-3), 139.3
(monosubstituted phenyl Ar C-1), 139.6 (1,3-disubstituted
phenyl Ar C-1), 157.8 (Oxaz C-2), 179.6 (NHCSNH). Anal.
Calcd for C22H26N4O2S ꢃ 0.2H2O: C, 63.80; H, 6.43; N, 13.53.
Found: C, 63.75; H, 6.36; N, 13.32.
oxazolidin-2-ones
(2a–c).
3-Alkyl-(4-N,N-disubstituted
aminomethyl)oxazolidin-2-ones (2a–c) were prepared by the
same method as that described previously [6]. Physical and
spectroscopic data are shown below.
3-(3-(Benzo[d][1,3]dioxol-5-yl)propyl)-4-(pyrrolidine-1-ylmethyl)
oxazolidin-2-one (2a). This compound was obtained in 47.8%
yield from compound 5a as a hygroscopic oil. IR (KBr) cmꢂ1
:
1
1745. FABMS (positive) m/z: 333 (M+H)+. H-NMR (DMSO-d6)
d: 1.64–1.66 (4H, m, Pyr H-3, H-4), 1.80–1.82 (2H, m, Ph-
CH2CH2CH2), 2.42–2.50 (7H, m, Pyr H-2, H-5, Ph-CHHCH2CH2
and CH2-Pyr), 2.62–2.66 (1H, m, Ph-CHHCH2CH2), 3.09–3.15
(1H, m, Ph-CH2CH2CHH), 3.27–3.28 (1H, m, Ph-CH2CH2CHH),
3.88–3.92 (1H, m, Oxaz H-4), 3.92–3.98 (1H, m, Oxaz H-5), 4.28–
4.30 (1H, m, Oxaz H-5), 5.95 (2H, s, O-CH2-O), 6.65–6.67 (1H, m,
Ar H-6), 6.79–6.82 (2H, m, Ar H-2, H-5). 13C-NMR (DMSO-d6) d:
23.1 (Pyr C-3, C-4), 28.9 (Ph-CH2CH2CH2), 32.0 (CH2-Pyr), 41.6
(Ph-CH2CH2CH2), 53.1 (Oxaz C-4), 54.0 (Pyr C-2, C-5), 57.6
(Ph-CH2CH2CH2), 66.0 (Oxaz C-5), 100.5 (O-CH2-O), 107.9 (Ar
C-5), 108.6 (Ar C-2), 120.9 (Ar C-6), 135.1 (Ar C-1), 145.2 (Ar
C-3), 147.1 (Ar C-4), 157.5 (Oxaz C-2). Anal. Calcd for
C18H24N2O4 ꢃ 0.2H2O: C, 64.34; H, 7.32; N, 8.34. Found: C,
64.40; H, 7.16; N, 8.05.
3-(3-(Benzo[d][1,3]dioxol-5-yl)propyl)-4-(diethylaminomethyl)
oxazolidin-2-one (2b). This compound was obtained in 65.2%
yield from compound 5b as an oil. IR (KBr) cmꢂ1: 1749.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis and Antibacterial Activity of 3-(Substituted arylmethyl)-4-
421
acylaminomethyloxazolidin-2-ones and Derivatization to Symmetrical Twin-Drug Type Molecules
1-(3-((2-Oxo-4-(pyrrolidin-1-ylmethyl)oxazolidin-3-yl)methyl)
phenyl)-3-phenylurea (2e). This compound was prepared by the
same procedure as that described above. Compound 2e was obtained
in 89.0% yield as amorphous white powder. IR (KBr) cmꢂ1: 1733.
material was extracted with AcOEt. The organic layer was washed
with brine and dried over Na2SO4. After evaporation of the solvent,
the residue was purified by silica gel column chromatography with
AcOEt/n-hexane as a solvent to give 3d (620 mg, 56.4%). Mp
133–134ꢁC (with dec). IR (KBr) cmꢂ1: 3309, 1725, 1669, 1623.
FABMS (positive) m/z: 457 (M+ H)+. 1H-NMR (DMSO-d6) d:
3.45–3.47 (2H, m, CH2NHCO), 3.78–3.79 (1H, m, Oxaz H-4),
4.11 (1H, dd, J=9.0, 6.0 Hz. Oxaz H-5), 4.30–4.37 (2H, m, Oxaz
H-5 and CHH-Ph), 4.66 (1H, d, J=15.0 Hz, CHH-Ph), 6.06 (2H,
s, O-CH2-O), 6.48 (1H, d, J=16.0 Hz, CH═CH-CO), 6.95 (1H,
d, J=8.0 Hz, cinnamic acid Ar H-5), 7.07–7.09 (1H, m, cinnamic
acid Ar H-6), 7.16 (1H, d, J=1.0 Hz, cinnamic acid Ar H-2), 7.37
(1H, d, J=16.0 Hz, CH═CH-CO), 7.35–7.47 (6H, m, biphenyl Ar
H), 7.64–7.67 (3H, m, biphenyl Ar H), 8.16 (1H, t, J=6.0 Hz,
NH). 13C-NMR (DMSO-d6) d: 38.4 (Oxaz-CH2NH), 44.7
(CH2-Ph), 53.7 (Oxaz C-4), 64.9 (Oxaz C-5), 101.3 (O-CH2-O),
106.2 (cinnamic acid Ar C-2), 108.4 (cinnamic acid Ar C-5),
120.1 (CH═CH-CO), 123.3 (cinnamic acid Ar C-6), 126.5, 126.9,
127.4, 128.3, 128.8 (biphenyl Ar C), 129.1 (cinnamic acid Ar C-
1), 135.6 (biphenyl Ar C), 139.0 (CH═CH-CO), 139.4, 139.7
(biphenyl Ar C), 147.9 (cinnamic acid Ar C-3), 148.5 (cinnamic
acid Ar C-4), 157.7 (Oxaz C-2), 165.9 (NHCOCH═). Anal. Calcd
for C27H24N2O5 ꢃ 0.3H2O: C, 70.21; H, 5.37; N, 6.06. Found:
C, 70.29; H, 5.51; N, 5.92.
1
FABMS (positive) m/z: 395 (M + H)+. H-NMR (DMSO-d6) d: 1.64
(4H, t, J= 4.5 Hz, Pyr H-3, H-4), 2.38 (4H, br, Pyr H-2, H-5), 2.47–
2.51 (1H, m, Pyr-CHH), 2.71 (1H, dd, J = 12.5, 5.5 Hz, Pyr-CHH),
3.73–3.79 (1H, m, Oxaz H-4), 4.00–4.03 (1H, m, Oxaz H-5),
4.29 (1H, d, J = 15.5 Hz, Ph-CHH-Oxaz), 4.37 (1H, t, J = 8.5 Hz,
Oxaz H-5), 4.54 (1H, d, J = 15.5 Hz, Ph-CHH-Oxaz), 6.88 (1H, d,
J = 7.5 Hz, 1,3-disubstituted phenyl Ar H-4), 6.97 (1H, d,
J = 7.5 Hz, monosubstituted phenyl Ar H-4), 7.24–7.29 (3H, m,
1,3-disubstituted phenyl Ar H-5, monosubstituted phenyl Ar H-3,
H-5), 7.35 (1H, s, 1,3-disubstituted phenyl Ar H-2), 7.35–7.45
(3H, s, 1,3-disubstituted phenyl Ar H-6, and monosubstituted
phenyl Ar H-2, H-6), 8.58 (1H, s, monosubstituted phenyl-NH),
8.68 (1H, s, NH-1,3-disubstituted phenyl). 13C-NMR (DMSO-d6)
d: 23.1 (Pyr C-3, C-4), 45.8 (Ph-CH2-Oxaz), 52.9 (Oxaz C-4),
53.9 (Pyr C-2, C-5), 57.5 (CH2-Pyr), 66.2 (Oxaz C-5), 117.1,
117.2, 118.1, 121.0, 121.8, 128.7, 128.9 (Ar C), 137.5 (1,3-
disubstituted phenyl Ar C-3), 139.5 (monosubstituted phenyl
Ar C-1), 139.6 (1,3-disubstituted phenyl Ar C-1), 152.4
(NHCONH), 157.8 (Oxaz C-2). Anal. Calcd for
C22H26N4O3 ꢃ 0.2H2O: C, 66.38; H, 6.68; N, 14.07. Found: C,
66.38; H, 6.70; N, 13.96.
4-(Aminomethyl)-3-(biphenyl-4-ylmethyl)oxazolidin-2-one
(9a). A mixture of 2-((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-
4-yl)methyl)isoindoline-1,3-dione (8a) [23] (1.0 g, 2.43 mmol) and
aqueous 40% methylamine (7 mL) in EtOH (100 mL) was refluxed
for 1 h. The resulting mixture was concentrated under a reduced
pressure. The residue was purified by column chromatography
(SiO2/EtOH) to afford compound 9a (440 mg, 64.3%). Mp
90–92ꢁC. IR (KBr) cmꢂ1: 3370, 1743. FABMS (positive) m/z:
283 (M + H)+. 1H-NMR (DMSO-d6) d: 2.49–2.50 (2H, br,
NH2), 2.64–2.73 (2H, m, CH2NH2), 3.60–3.65 (1H, m, Oxaz
H-4), 4.17 (1H, dd, J = 8.5, 6.5 Hz, Oxaz H-5), 4.27 (1H, d,
J = 15.5 Hz, CHH-Ph), 4.30 (1H, t, J = 8.5 Hz, Oxaz H-5), 4.56
(1H, d, J= 15.5 Hz, CHH-Ph), 7.34–7.40 (3H, m, Ar H), 7.44–7.48
(2H, m, Ar H), 7.64–7.67 (4H, m, Ar H). 13C-NMR (DMSO-d6) d:
41.3 (NH2CH2-Oxaz), 44.8 (PhCH2), 55.9 (Oxaz C-4), 65.0 (Oxaz
C-5), 126.5, 126.8, 127.3, 128.2, 128.9 (Ar C), 136.1 (biphenyl Ar
C-1), 139.3 (biphenyl Ar C-4 or C-1′), 139.7 (biphenyl Ar C-1′
or C-4), 158.2 (Oxaz C-2). Anal. Calcd for C17H18N2O2: C,
72.32; H, 6.43; N, 9.92. Found: C, 72.28; H, 6.68; N, 9.93.
4-(Aminomethyl)-3-(3-fluoro-4-morpholinobenzyl)oxazolidin-2-
3-Amino-N-((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
methyl)benzamide (3c). To a solution of compound (9a) (180 mg,
0.64 mmol) and m-aminobenzoic acid (88 mg, 0.64 mmol) in DMF
(4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (WSCI) (122 mg, 0.64 mmol) at room temperature,
and the mixture was stirred for 3 h. After addition of water,
precipitated material was extracted with AcOEt. The organic layer
was washed with brine and dried over Na2SO4. After evaporation
of the solvent, the residue was purified by silica gel column
chromatography with AcOEt as a solvent to give 3c (180 mg,
70.3%) as a colorless oil. IR (KBr) cmꢂ1: 3352, 1736, 1644.
FABMS (positive) m/z: 402 (M + H)+. 1H-NMR (DMSO-d6) d:
3.43–3.54 (2H, m, Oxaz-CH2NH), 3.80–3.84 (1H, m, Oxaz H-4),
4.23 (1H, dd, J=9.0, 5.0 Hz. Oxaz H-5), 4.33 (1H, d, J=9.0 Hz,
Oxaz H-5), 4.37, 4.64 (each 1H, d, J= 16.0 Hz, Oxaz CH2-Ph),
5.20 (2H, s, NH2), 6.69–6.71 (1H, m, aminobenzene H-4),
6.90–6.92 (1H, m, aminobenzene H-6), 7.00–7.01 (1H, m,
aminobenzene H-2), 7.08 (1H, t, J = 8.0 Hz, aminobenzene H-
5), 7.35–7.40 (3H, m, biphenyl Ar H), 7.46 (2H, t, J = 8.0 Hz,
biphenyl Ar H), 7.65–7.67 (4H, m, biphenyl Ar H), 8.35
(1H, t, J = 6.0 Hz, NH). 13C-NMR (DMSO-d6) d: 39.2
(Oxaz-CH2NH), 44.8 (CH2-Ph), 53.7 (Oxaz C-4), 65.2 (Oxaz
C-5), 112.7 (aminobenzene C-2), 114.3 (aminobenzene C-6),
116.5 (aminobenzene C-4), 128.5 (aminobenzene C-5), 135.1
(aminobenzene C-1), 126.5, 126.9, 127.4, 128.3, 128.8
(biphenyl Ar C), 135.7 (biphenyl Ar C-1), 139.4 (biphenyl Ar
C-1′ or C-4), 139.7 (biphenyl Ar C-4 or C-1′), 148.6
(aminobenzene C-3), 157.7 (Oxaz C-2), 167.9 (NHCO). Anal.
Calcd for C24H23N3O3 ꢃ 0.6H2O: C, 69.92; H, 5.92; N, 10.19.
Found: C, 69.87; H, 6.02; N, 9.91.
one (9b).
A mixture of 2-((3-(3-fluoro-4-morpholinobenzyl)-2-
oxooxazolidin-4-yl)methyl)isoindoline-1,3-dione (8b) [24] (0.5g,
1.14 mmol) and aqueous 40% methylamine (4 mL) in EtOH
(50 mL) was refluxed for 1 h. The resulting mixture was
concentrated under a reduced pressure. The residue was purified by
column chromatography (SiO2/MeCN) to afford compound 9b
(163 mg, 46.3%) as an oil. IR (KBr) cmꢂ1: 3378, 1740. FABMS
1
(positive) m/z: 310 (M + H)+. H-NMR (DMSO-d6) d: 2.64–2.68
(2H, br, NH2), 2.99 (4H, t, J= 4.5 Hz, Mor H-2, H-6), 3.02–3.17
(2H, m, CH2NH2), 3.58–3.61 (1H, m, Oxaz H-4), 3.73 (4H, t,
J= 4.5 Hz, Mor H-3, H-5), 4.14 (1H, dd, J= 8.5, 6.0 Hz, Oxaz H-5),
4.15 (1H, d, J = 15.5 Hz, CHH-Ph), 4.28 (1H, t, J = 8.5 Hz, Oxaz
H-5), 4.44 (1H, d, J = 15.5 Hz, CHH-Ph), 7.01–7.09 (3H, m, Ar
H). 13C-NMR (DMSO-d6) d: 41.1 (CONHCH2), 44.2 (PhCH2),
50.4 (Mor C-2, C-6), 55.6 (Oxaz C-4), 64.9 (Oxaz C-5), 66.1
(Mor C-3, C-5), 115.4 (d, J= 20.7 Hz, FAr C-2), 119.0 (d, J=4.1Hz,
FAr C-5), 124.0 (d, J= 3.1 Hz, FAr C-6), 131.4 (d, J=7.2Hz, FAr
C-1), 138.8 (d, J = 8.3 Hz, FAr C-4), 154.6 (d, J = 245.2 Hz,
3-(Benzo[d][1,3]dioxol-4-yl)-N-((3-(biphenyl-4-ylmethyl)-2-
oxooxazolidin-4-yl)methyl)prop-2-enamide (3d). To a solution of
compound (9a) (680 mg, 2.41 mmol) and 3,4-(methylenedioxy)
cinnamic acid (460 mg, 2.40 mmol) in DMF (20 mL) was added
WSCI (510 mg, 2.66 mmol) at room temperature, and the mixture
was stirred for 1 h. After removal of the solvent under reduced
pressure, water was added to the residue, and the precipitated
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

422
F. Fujisaki, S Hiromatsu, Y Matsumura, A Fukami, N. Kashige, F. Miake, and K Sumoto
Vol 50
FAr C-3), 158.1 (Oxaz C-2). Anal. Calcd for C15H20N3O3Fꢃ 0.6H2O:
C, 56.27; H, 6.67; N, 13.13. Found: C, 56.33; H, 6.58; N, 12.92.
N4,N4′-Bis((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
N1,N4 -Bis((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
methyl)benzene-1,4-dicarbamide (11a).
This compound was
obtained in 76.6% yield. Mp >230ꢁC (hygroscopic). IR (KBr)
cmꢂ1: 3330, 1723, 1658 cmꢂ1. FABMS (positive) m/z: 695
(M + H)+. 1H-NMR (DMSO-d6) d: 3.52–3.60 (4H, m, CONHCH2),
3.85–3.88 (2H, m, Oxaz H-4), 4.25 (2H, dd, J= 8.5, 5.0 Hz, Oxaz
H-5), 4.37 (2H, t, J= 8.5 Hz, Oxaz H-5), 4.38 (2H, d, J= 15.5 Hz,
CHH-Ph), 4.66 (2H, d, J= 15.5 Hz, CHH-Ph), 7.35–7.41 (6H, m,
biphenyl Ar H), 7.45–7.48 (4H, m, Biphenyl br H), 7.64–7.66
(8H, m, biphenyl Ar H), 7.89 (4H, benzenedicarbamide Ar H), 8.70
(2H, t-like, NH). 13C-NMR (DMSO-d6) d: 39.6 (CONHCH2), 44.9
(PhCH2), 53.7 (Oxaz C-4), 65.3 (Oxaz C-5), 126.5, 126.9
(biphenyl Ar C), 127.2 (benzenedicarbamide Ar C-2, C-3, C-5,
C-6), 127.4 (biphenyl Ar C), 128.3, 128.9 (biphenyl Ar C),
135.7 (biphenyl Ar C-1), 136.5 (benzenedicarbamide Ar C-1,
C-4), 139.4 (biphenyl Ar C-4 or C-1′), 139.7 (biphenyl Ar C-1′
or C-4), 157.7 (Oxaz C-2), 166.4 (benzenedicarbamide C═O).
Anal. Calcd for C42H38N4O6 ꢃ 0.2H2O: C, 72.23; H, 5.54; N,
8.02. Found: C, 72.14; H, 5.59; N, 8.17.
methyl)biphenyl-4,4′-dicarbamide (10a).
To a solution of
compound (9a) (400 mg, 1.42 mmol) and NEt3 (143 mg,
1.42 mmol) in CH2Cl2 (10 mL) was added biphenyl-4,4′-
dicarbonyl dichloride (150 mg, 0.54 mmol), and the mixture
was refluxed for 2 h. After cooling, the insoluble product
10a (330 mg, 79.7%) was obtained by filtration. Mp >240ꢁC.
IR (KBr) cmꢂ1: 3356, 1728, 1657. FABMS (positive) m/z:
771 (M + H)+. 1H-NMR (DMF-d7) d: 3.61–3.77 (4H, m,
CONHCH2), 4.02–4.05 (2H, m, Oxaz H-4), 4.43 (2H, dd,
J = 9.0, 5.0 Hz, Oxaz H-5), 4.48 (2H, m, Oxaz H-5), 453, 4.78
(each 2H, d, J = 15.5 Hz, CH2-Ph), 7.37–7.40 (2H, m, CH2-
biphenyl Ar H-4′), 7.47–7.51 (8H, m, CH2-biphenyl Ar H),
7.71–7.73 (8H, m, CH2-biphenyl Ar H), 7.86 (4H, d,
J = 8.5 Hz, biphenyldicarbamide Ar H-3, H-5, H-3′, H-5′), 8.04
(4H, d, J = 8.5 Hz, biphenyldicarbamide Ar H-2, H-6, H-2′,
H-6′), 8.75 (2H, t, J = 6.0 Hz, NH). 13C-NMR (DMF-d7)
d: 40.4 (CONHCH2), 46.0 (PhCH2), 55.1 (Oxaz C-4), 66.3 (Oxaz
C-5), 127.4, 127.6, 127.8, 128.2, 128.7, 129.3, 129.6 (Ar C), 134.7
(biphenyldicarbamide Ar C-1, C-1′), 137.0 (CH2-biphenyl Ar C-1),
140.7 (CH2-biphenyl Ar C-4 or C-1′), 140.9 (CH2-biphenyl Ar C-1′
or C-4), 143.2 (biphenyldicarbamide Ar C-4, C-4′), 158.9 (Oxaz
C═O), 167.8 (biphenyldicarbamide C═O). Anal. Calcd for
C48H42N4O6 ꢃ 0.8H2O: C, 73.41; H, 5.60; N, 7.13. Found: C, 73.46;
H, 5.60; N, 7.15.
N1,N4-Bis((3-(3-fluoro-4-morpholinobenzyl)-2-oxooxazolidin-4-
yl)methyl)benzene-1,4-dicarbamide (11b).
This compound was
obtained in 91.0% yield. Mp 132–138ꢁC. IR (KBr) cmꢂ1: 3431,
1738, 1649 cmꢂ1. FABMS (positive) m/z: 749 (M + H)+. H-NMR
1
(DMSO-d6) d: 2.98 (8H, t, J= 4.5 Hz, Mor H-2, H-6), 3.28–3.54
(4H, m, CONHCH2), 3.72–3.73 (8H, m, Mor H-3, H-5),
3.82–3.83 (2H, m, Oxaz H-4), 4.21 (2H, dd, J = 9.0, 5.0 Hz,
Oxaz H-5), 4.27 (2H, d, J = 16.0 Hz, CHH-Ph), 4.34 (2H, t,
J = 8.5 Hz, Oxaz H-5), 4.44 (2H, d, J = 16.0 Hz, CHH-Ph),
6.98–7.09 (6H, m, FAr H), 7.87 (4H, s, benzenedicarbamide
Ar H), 8.69 (2H, t-like, NH). 13C-NMR (DMSO-d6) d: 40.0
(CONHCH2), 44.3 (PhCH2), 50.4 (Mor C-2, C-6), 53.6
(Oxaz C-4), 65.3 (Oxaz C-5), 66.1 (Mor C-3, C-5), 115.4 (d,
J= 20.7 Hz, FAr C-2), 119.0 (d, J= 4.1 Hz, FAr C-5), 124.1
(d, J= 3.1 Hz, FAr C-6), 127.1 (benzenedicarbamide Ar C), 131.0
(d, J = 6.2 Hz, FAr C-1), 136.5 (benzenedicarbamide Ar
C-1, C-4), 138.9 (d, J = 8.3 Hz, FAr C-4), 154.7 (d,
J = 245.1 Hz, FAr C-3), 157.6 (Oxaz C-2), 166.5
(benzenedicarbamide C═O). Anal. Calcd for C38H42N6O8
F2 ꢃ H2O: C, 59.52; H, 5.78; N, 10.96. Found: C, 59.61; H,
5.71; N, 10.85.
N4,N4′-Bis((3-(3-fluoro-4-morpholinobenzyl)-2-oxooxazolidin-4-
yl)methyl)biphenyl-4,4′-dicarbamide (10b).
To a solution of
compound (9b) (120 mg, 0.39 mmol) and NEt3 (30 mg, 0.30 mmol)
in CH2Cl2 (5 mL) was added biphenyl-4,4′-dicarbonyl dichloride
(42 mg, 0.15 mmol) at room temperature, and the mixture was stirred
for 20 min. Precipitated material was collected by filtration to
give compound 10b (120 mg, 96.8%) in a high state of purity. Mp
158–160ꢁC (dec). IR (KBr) cmꢂ1: 3315, 1729, 1649 cmꢂ1. FABMS
1
(positive) m/z: 825 (M + H)+. H-NMR (DMSO-d6) d: 2.99 (8H, t,
J= 4.5 Hz, Mor H-2, H-6), 3.47–3.58 (4H, m, CONHCH2), 3.73
(8H, t, J= 4.5 Hz, Mor H-3, H-5), 3.82–3.85 (2H, m, Oxaz H-4),
4.23–4.25 (2H, m, Oxaz H-5), 4.28 (2H, d, J= 15.5 Hz, CHH-Ph),
4.35 (2H, t, J = 8.5 Hz, Oxaz H-5), 4.54 (2H, d, J = 15.5 Hz,
CHH-Ph), 6.99–7.10 (6H, m, FAr H), 7.84 (4H, d, J = 8.5 Hz,
biphenyldicarbamide Ar H-3, H-5, H-3′, H-5′), 7.92 (4H, d,
J = 8.5 Hz, biphenyldicarbamide Ar H-2, H-6, H-2′, H-6′),
8.65 (2H, t, J = 6.0 Hz, NH). 13C-NMR (DMSO-d6) d: 39.3
(CONHCH2), 44.3 (PhCH2), 50.4 (d, J= 3.1 Hz, Mor C-2, C-6),
53.7 (Oxaz C-4), 65.2 (Oxaz C-5), 66.1 (Mor C-3, C-5), 115.4
(d, J= 20.7 Hz, FAr C-2), 119.1 (d, J= 3.1 Hz, FAr C-5), 124.1
(d, J = 3.1 Hz, FAr C-6), 126.7 (biphenyldicarbamide Ar C-3,
C-5, C-3′, C-5′), 127.9 (biphenyldicarbamide Ar C-2, C-6,
C-2′, C-6′), 131.0 (d, J= 6.2 Hz, FAr C-1), 133.4 (biphenyldicarbamide
Ar C-1, C-1′), 138.9 (d, J = 8.3 Hz, FAr C-4), 141.3
(biphenyldicarbamide Ar C-4, C-4′), 154.7 (d, J = 245.2 Hz,
FAr C-3), 157.6 (Oxaz C-2), 166.6 (biphenyldicarbamide
C═O). Anal. Calcd for C44H46N6O8 F2 ꢃ H2O: C, 62.70; H,
5.74; N, 9.97. Found: C, 62.68; H, 5.73; N, 9.75.
N1,N3-Bis((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
methyl)benzene-1,3-dicarbamide (12a). This compound was
obtained in 56.9% yield. Mp 107–122ꢁC. IR (KBr) cmꢂ1: 3390,
1733, 1662 cmꢂ1. FABMS (positive) m/z: 695 (M + H)+.
1H-NMR (DMSO-d6) d: 3.53–3.58 (4H, m, CONHCH2),
3.84–3.88 (2H, m, Oxaz H-4), 4.24–4.27 (2H, m, Oxaz H-
5), 4.32–4.38 (2H, m, Oxaz H-5), 4.39 (2H, d, J = 16.0 Hz, CHH-
Ph), 4.66 (2H, d, J = 16.0Hz, CHH-Ph), 7.35–7.40 (6H, m,
biphenyl Ar H), 7.44–7.47 (4H, m, biphenyl Ar H), 7.58–7.61
(1H, benzenedicarbamide Ar H-5), 7.64–7.66 (8H, m, biphenyl
Ar H), 7.96–7.97 (2H, benzenedicarbamide Ar H-4, H-6), 8.30
(1H, benzenedicarbamide Ar H-2), 8.75 (2H, t, J = 5.5 Hz,
NH). 13C-NMR (DMSO-d6) d: 39.7 (CONHCH2), 44.8
(PhCH2), 53.7 (Oxaz C-4), 65.2 (Oxaz C-5), 126.4
(benzenedicarbamide Ar C-2), 126.5, 126.9, 127.4 (biphenyl Ar
C), 128.3 (biphenyl Ar C + benzenedicarbamide Ar C-5), 128.8
(biphenyl Ar C), 129.8 (benzenedicarbamide Ar C-4, C-6),
134.3 (benzenedicarbamide Ar C-1), 135.7 (biphenyl Ar C-1),
139.4 (biphenyl Ar C-4 or C-1′), 139.7 (biphenyl Ar C-1′ or
C-4), 155.7 (Oxaz C-2), 166.6 (benzenedicarbamide C═O).
Anal. Calcd for C42H38N4O6 ꢃ H2O: C, 70.77; H, 5.66; N, 7.86.
Found: C, 70.78; H, 5.67; N, 7.59.
General procedure for the preparation of compounds
11–14.
The corresponding dicarbonyl dichloride (0.22 mmol)
was added to a solution of compound 9 (0.50 mmol) and NEt3
(0.50 mmol) in CH2Cl2 (10 mL), and the mixture was stirred for
20min at room temperature. The product was purified by column
chromatography to give compounds 11–14, respectively. Physical
and spectroscopic data are shown below.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
Synthesis and Antibacterial Activity of 3-(Substituted arylmethyl)-4-
423
acylaminomethyloxazolidin-2-ones and Derivatization to Symmetrical Twin-Drug Type Molecules
N1,N3-Bis((3-(3-fluoro-4-morpholinobenzyl)-2-oxooxazolidin-
4-yl)methyl)benzene-1,3-dicarbamide (12b). This compound
F2 ꢃ 0.5H2O: C, 58.57; H, 5.58; N, 12.92. Found: C, 58.48; H,
5.76; N, 12.78.
N1,N5-Bis((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
methyl)pentanediamide (14a). This compound was obtained in
67.6% yield. Mp 81–92ꢁC (with dec). IR (KBr) cmꢂ1: 3317, 1739,
1658 cmꢂ1. FABMS (positive) m/z: 661 (M + H)+. 1H-NMR
(DMSO-d6) d: 1.73 (2H, dd, J= 15.0, 7.5 Hz, pentanediamide H-3),
2.08–2.12 (4H, t-like, pentanediamide H-2, H-4), 3.30–3.39 (4H, m,
CONHCH2), 3.69–3.73 (2H, m, Oxaz H-4), 4.06–4.09 (2H,
m, Oxaz H-5), 4.28 (2H, d, J= 15.5 Hz, CHH-Ph), 4.31–4.33
(2H, m, Oxaz H-5), 4.62 (2H, d, J=15.5Hz, CHH-Ph), 7.34–7.39
(6H, m, biphenyl Ar H), 7.44–7.47 (4H, m, biphenyl Ar H),
7.64–7.67 (8H, m, biphenyl Ar H), 7.98 (2H, t-like, NH). 13C-
NMR (DMSO-d6) d: 21.3 (pentanediamide C-3), 34.6
(pentanediamide C-2), 38.3 (CONHCH2), 44.6 (PhCH2), 53.6
(Oxaz C-4), 65.0 (Oxaz C-5), 126.5, 126.9, 127.4, 128.3, 128.8
(biphenyl Ar C), 135.6 (biphenyl Ar C-1), 139.4 (biphenyl Ar
C-4 or C-1′), 139.7 (biphenyl Ar C-1′or C-4), 157.7 (Oxaz C-
2), 172.5 (pentanediamide C═O). Anal. Calcd for
C39H40N4O6 ꢃ 1.5H2O: C, 68.11; H, 6.30; N, 8.15. Found: C,
68.04; H, 6.14; N, 8.16.
was obtained in 40.1% yield as amorphous powder. IR (KBr)
cmꢂ1: 3431, 1739, 1660 cmꢂ1. FABMS (positive) m/z: 749
1
(M + H)+. H-NMR (DMSO-d6) d: 2.98 (8H, t, J = 4.5 Hz, Mor
H-2, H-6), 3.50–3.54 (4H, m, CONHCH2), 3.71–3.74 (8H, m,
Mor H-3, H-5), 3.80–3.83 (2H, m, Oxaz H-4), 4.20–4.23 (2H,
m, Oxaz H-5), 4.27 (2H, d, J = 15.5 Hz, CHH-Ph), 4.34 (2H, t,
J = 9.0 Hz, Oxaz H-5), 4.54 (2H, d, J = 15.5 Hz, CHH-Ph),
6.98–7.09 (6H, m, FAr H), 7.58–7.61 (1H, benzenedicarbamide
Ar H-5), 7.94–7.96 (2H, m, benzenedicarbamide Ar H-4, H-6),
8.27 (1H, br s, benzenedicarbamide Ar H-2), 8.70–8.73 (2H, br
s, NH). 13C-NMR (DMSO-d6) d: 39.8 (CONHCH2), 44.3
(PhCH2), 50.4 (Mor C-2, C-6), 53.6 (Oxaz C-4), 65.2 (Oxaz
C-5), 66.1 (Mor C-3, C-5), 115.4 (d, J = 20.7 Hz, FAr C-2),
119.0 (d, J= 3.1 Hz, FAr C-5), 124.1 (d, J= 3.1 Hz, FAr C-6), 126.4
(benzenedicarbamide Ar C-2), 128.3 (benzenedicarbamide Ar C-5),
129.8 (benzenedicarbamide Ar C-4, C-6), 131.0 (d, J=7.2Hz,
FAr C-1), 134.3 (benzenedicarbamide Ar C-1, C-3), 138.9
(d, J = 8.3 Hz, FAr C-4), 154.7 (d, J = 245.2 Hz, FAr C-3),
157.6 (Oxaz C-2), 166.5 (benzenedicarbamide C═O). Anal.
Calcd for C38H42N6O8 F2 ꢃ 0.6H2O: C, 60.09; H, 5.73; N,
11.06. Found: C, 60.03; H, 5.67; N, 10.98.
We confirmed that the diastereomeric mixture of compound
14a exhibited significant differences in the 1H and 13C-NMR
spectra in CDCl3. The data are shown below.
N2,N6-Bis((3-(biphenyl-4-ylmethyl)-2-oxooxazolidin-4-yl)
methyl)pyridine-2,6-dicarboxamide (13a).
This compound
1H-NMR (CDCl3) d: 2.09–2.12 (2H, m, Pentanediamide H-3),
2.16–2.30 (4H, m, Pentanediamide H-2, H-4), 3.39–3.50 (2H,
m, CONHCH2), 3.61–3.75 (4H, m, CONHCH2 + Oxaz H-4),
4.29–4.33 (2H, m, Oxaz H-5), 4.35 (1H, d, J= 15.5 Hz, CHH-Ph),
4.44 (1H, d, J= 15.5 Hz, CHH-Ph), 4.53 (1H, d, J=9.0Hz, Oxaz
H-5), 4.64 (1H, dd, J= 9.0, 2.5 Hz, Oxaz H-5), 4.92 (1H, d,
J = 15.5 Hz, CHH-Ph), 4.95 (1H, d, J = 15.5 Hz, CHH-Ph),
6.82–6.86 (2H, m, NH), 7.34–7.46 (10H, m, biphenyl Ar H),
7.56–7.61 (8H, m, biphenyl Ar H). 13C-NMR (CDCl3) d:
21.86, 21.99 (pentanediamide C-3), 34.37, 34.52 (pentanedia-
mide C-2), 38.64, 38.68 (CONHCH2), 45.64, 45.70 (PhCH2),
54.72, 54.77 (Oxaz C-4), 66.12, 66.17 (Oxaz C-5), 127.04,
127.04, 127.53, 127.69, 127.69, 128.58, 128.58, 128.62,
128.84, 128.84 (biphenyl Ar C), 134.67, 134.74 (biphenyl Ar
C-1), 140.40, 140.40 (biphenyl Ar C-4 or C-1′), 141.13,
141.13 (biphenyl Ar C-1′or C-4), 159.27, 159.27 (Oxaz C-2),
174.42, 174.44 (pentanediamide C═O).
was obtained in 87.6% yield. Mp 115–119ꢁC. IR (KBr) cmꢂ1
:
3345, 1747, 1676 cmꢂ1. FABMS (positive) m/z: 696 (M+ H)+.
1H-NMR (DMSO-d6) d: 3.55–3.72 (4H, m, CONHCH2),
3.92–3.96 (2H, m, Oxaz H-4), 4.26–4.29 (2H, m, Oxaz H-5),
4.39 (2H, d, J = 9.0 Hz, Oxaz H-5), 4.42–4.45 (2H, m, CHH-
Ph), 4.69 (2H, dd, J = 16.0, 3.0 Hz, CHH-Ph), 7.33–7.37 (6H,
m, biphenyl Ar H), 7.43–7.46 (4H, m, biphenyl Ar H), 7.58–
7.62 (8H, m, biphenyl Ar H), 8.16–8.22 (3H, m, pyridine H),
9.38 (2H, br s, NH). 13C-NMR (DMSO-d6) d: 39.8, 39.9
(CONHCH2), 45.11, 45.13 (PhCH2), 53.54, 53.62 (Oxaz C-4),
65.23, 65.28 (Oxaz C-5), 124.5 (pyridine C-3, C-5), 126.6,
126.9, 127.4, 128.20, 128.22, 128.9 (biphenyl Ar C), 135.57,
135.63 (biphenyl Ar C-1), 139.4 (biphenyl Ar C-4 or C-1′),
139.7 (pyridine C-4 and biphenyl Ar C-1′ or C-4), 148.2
(pyridine C-2, C-6), 157.8 (Oxaz C-2), 163.79, 163.82
(pyridinedicarbamide
C═O).
Anal.
Calcd
for
C41H37N5O6 ꢃ 0.5H2O: C, 69.87; H, 5.43; N, 9.94. Found:
N1,N5-Bis((3-(3-fluoro-4-morpholinobenzyl)-2-oxooxazolidin-
4yl)methyl)pentanediamide (14b). This compound was obtained
in 91.0% yield as amorphous powder. IR (KBr) cmꢂ1: 3418, 3328,
C, 69.84; H, 5.43; N, 9.94.
N1,N5-Bis((3-(3-fluoro-4-morpholinobenzyl)-2-oxooxazolidin-
4-yl)methyl)pyridine-2,6-dicarboxamide (13b).
This compound
1
1741, 1656 cmꢂ1. FABMS (positive) m/z: 715 (M + H)+. H-NMR
was obtained in 64.5% yield. Mp 128–133ꢁC. IR (KBr)
cmꢂ1: 3353, 1747, 1677 cmꢂ1. FABMS (positive) m/z: 749
(M + H)+. 1H-NMR (DMSO-d6) d: 2.94–2.96 (8H, m, Mor
H-2, H-6), 3.56–3.72 (12H, m, Mor H-3, H-5 and
CONHCH2), 3.88–3.92 (2H, m, Oxaz H-4), 4.21–4.25 (2H,
m, Oxaz H-5), 4.31 (2H, d, J = 15.5 Hz, CHH-Ph), 4.36–4.39
(2H, m, Oxaz H-5), 4.56 (2H, dd, J = 15.5, 2.5 Hz, CHH-Ph),
6.91–7.03 (6H, m, FAr H), 8.18–8.19 (3H, m, pyridine H),
9.32–9.37 (2H, m, NH). 13C-NMR (DMSO-d6) d: 39.93, 40.00
(CONHCH2), 44.6 (Ph-CH2), 50.32, 50.34 (Mor C-2, C-6),
53.42, 53.48 (Oxaz C-4), 65.15, 65.18 (Oxaz C-5), 66.0 (Mor
C-3, C-5), 115.3 (d, J = 20.7 Hz, FAr C-2), 118.9 (d, J = 3.1 Hz,
FAr C-5), 123.9 (d, J = 3.1 Hz, FAr C-6), 124.4 (pyridine C-3,
C-5), 130.8 (d, J = 7.2 Hz, FAr C-1), 138.8 (d, J = 8.3 Hz, FAr
C-4), 139.6 (pyridine C-4), 148.4 (pyridine C-2, C-6), 154.6 (d,
J = 245.2 Hz, FAr C-3), 157.6 (Oxaz C-2), 163.69, 163.71
(pyridinedicarbamide C═O). Anal. Calcd for C37H41N7O8
(DMSO-d6) d: 1.68–1.71 (2H, m, pentanediamide H-3), 2.06–3.00
(4H, t-like, pentanediamide H-2), 2.98–3.00 (8H, m, Mor H-2,
H-6), 3.24–3.34 (4H, m, CONHCH2), 3.65–3.68 (2H, m, Oxaz
H-4), 3.72–3.74 (8H, m, Mor H-3, H-5), 4.03 (2H, dd, J=9.0,
5.5 Hz, Oxaz H-5), 4.15 (2H, d, J=15.5Hz, CHH-Ph), 4.28
(2H, t, J= 9.0 Hz, Oxaz H-5), 4.49 (2H, d, J=15.5Hz, CHH-Ph),
6.99–7.07 (6H, m, FAr H), 7.92 (2 H, t-like, NH). 13C-NMR
(DMSO-d6) d: 21.3 (pentanediamide C-3), 34.6 (pentanediamide
C-2), 39.3 (CONHCH2), 44.1 (PhCH2), 50.4 (Mor C-2, C-6), 53.5
(Oxaz C-4), 65.0 (Oxaz C-5), 66.1 (Mor C-3, C-5), 115.4
(d, J= 20.7 Hz, FAr C-2), 119.0 (d, J= 3.1 Hz, FAr C-5), 124.1
(d, J= 3.1 Hz, FAr C-6), 130.9 (d, J= 7.2 Hz, FAr C-1), 138.9
(d, J= 8.3 Hz, FAr C-4), 154.7 (d, J= 245.2 Hz, FAr C-3), 157.7
(Oxaz C-2), 172.5 (pentanediamide C═O). Anal. Calcd for
C35H44N6O8 F2 ꢃ H2O: C, 57.37; H, 6.33; N, 11.47. Found: C,
57.50; H, 6.29; N, 11.48.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

424
F. Fujisaki, S Hiromatsu, Y Matsumura, A Fukami, N. Kashige, F. Miake, and K Sumoto
Vol 50
Acknowledgment. We thank Daicel Chemical Industries, Ltd.
for assisting us with the HPLC enantioseparation experiments by
a chiral stationary phase (CHIRALPAK IAW) for our compounds.
Saunders, M. R.; Singh, O.; Spitzfaden, C. E.; Shen, C.; Shillings, A.;
Theobald, A. J.; Wohlkonig, A.; Pearson, N. D.; Gwynn, M. N. Nature
2010, 466, 935.
[17] Camille, G. W. The Practice of Medicinal Chemistry, 3rd ed.;
Academic Press: San Diego, 2008.
[18] Krishnamurthy, V. M.; Estroff, L. A.; Whitesides, G. M.
Multivalency in ligand design. In Methods and Principles in Medicinal
Chemistry: Fragment-based Approaches in Drug Discovery, Mannhold,
R.; Kubinyi, H.; Folkers, G., Eds. WILEY-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2006, Vol 34, pp 11–53.
REFERENCES AND NOTES
[1] Oshovsky, G. V.; Reinhoudt, D. N.; Verboom, W. Angew
Chem Int Ed 2007, 46, 2366.
[2] Imberty, A.; Varrot A. Curr Opin Struct Biol 2008, 18, 567.
[3] Varki, A. Essentials of Glycobiology, 2nd ed.; Cold Spring
Harbor Laboratory Press: Cold Spring Harbor, N. Y., 2009; pp 719–732.
[4] Fujisaki, F.; Shoji, K.; Shimodouzono, M.; Kashige, N.;
Miake, F.; Sumoto, K. Chem Pharm Bull 2010, 58, 1123.
[5] Abe, N.; Fujisaki, F.; Sumoto, K. Chem Pharm Bull 1998, 46,
142.
[6] Fujisaki, F.; Abe, N.; Sumoto, K. Chem Pharm Bull 2004, 52,
1238.
[7] Fujisaki, F.; Abe, N.; Sumoto, K. Heterocycles 2008, 75, 1681.
[8] Fujisaki, F.; Shoji, K.; Sumoto, K. Chem Pharm Bull 2009, 57,
1415.
[9] Fujisaki, F.; Shoji, K.; Sumoto, K. Heterocycles 2009, 78, 213.
[10] These compounds (2) synthesized in this study showed weak
antibacterial activities (MIC = 0.286–0.465 mM/mL) against E. coli but
had no antibacterial activities against S. aureus (at the concentration of
>0.286–0.465 mM/mL).
[11] Compounds (3c and 3d) showed antibacterial activities (MIC =
0.293 and 0.280 mM/mL, respectively) against E. coli and antibacterial
activities (MIC > 0.293 and >0.280 mM/mL, respectively) against S.
aureus. Regarding compounds 3a and 3b, we could not determine the pre-
cise MIC values against both strains (>0.395 and > 0.365 mM/mL, respec-
tively). However, we confirmed antibacterial activity against both strains
by calculating the number of readily observable colonies for compounds
in agar culture medium. Compound 3a showed a higher level of bacterial
static activity at the concentration of 5 mM than that of 3b at the concentra-
tion of 10 mM. Therefore, we used the derivative (3a and 3b) as a template
for the scaffold of twin-drug type molecules.
[19] We used a racemic 4-aminomethyloxazolidin-2-one (9) as a
starting material in the synthesis of twin-drug type compounds. The
obtained twin-drug type products (10–14) can be considered to be a
mixture of three twin-drug type molecules, that is, a Cs-symmetrical meso
compound and two enantiomeric C2-symmetrical molecules that have the
same absolute configuration regarding two C-4-substituted oxazolidin-2-
one rings in each molecule. For instance, three components in product
14a were detected by HPLC enantioseparation with the use of CHIRAL-
PAK IAW as a chiral stationary phase. The obtained diastereomeric
mixture exhibited very simple symmetrical 13C-NMR in DMSO-d6,
showing little difference with respect to all of the signals assignable to
substituted oxazolidin-2-one rings and a linker group. However, we found
that the diastereomeric mixture of compound 14a exhibited significant
differences in the 1H and 13C-NMR spectra in CDCl3 (see Experimental
section). In the case of compounds 13a and 13b, 13C-NMR spectra
indicated unsymmetrical molecular features. It is likely that intramolecular
hydrogen bonding between pyridine ring nitrogen and one of the amide
functionalities [25] gave rise to a slightly different non-equivalent
magnetic resonance patterns.
[20] This result has considerable significance in comparison with
antibacterial activity of cephalothin. Thus, when the experiments with
E. coli NIHJ or S. aureus Terajima were carried out under similar conditions,
antibacterial activity of cephalothin (MIC = 12.5 mg/mL (0.032 mM/mL) or
0.20 mg/mL (0.001 mM/mL), respectively) had been reported [26].
[21] Japanese Society of Chemotherapy (1989). Chemotherapy
1990, 38, 102.
[22] Japanese Society of Chemotherapy (1992). Chemotherapy
1993, 41, 184.
[12] Leach, K. L.; Swaney, S. M.; Colca, J. R.; McDonald, W. G.;
Blinn, J. R.; Thomasco, L. M.; Gadwood, R. C.; Shinabarger, D.; Xiong,
L.; Mankin, A. S. Mol Cell 2007, 26, 393.
[13] Locke, J. B.; Finn, J.; Hilgers, M.; Morales, G.; Rahawi, S.;
Kedar, G. C.; Picazo, J. J.; Im, W.; Shaw, K. J.; Stein, J. L. Antimicrob
Agents Chemother 2010, 54, 5337 and related references cited therein.
[14] Lemaire, S.; Tulkens, P. M.; Bambeke, F. V. Antimicrob
Agents Chemother 2010, 54, 2540 and related references cited therein.
[15] Balzarini, J. Antiviral Res 2006, 71, 237 and related references
cited therein.
[23] This compound (8a) was easily obtained by the procedure
described in our previous paper [7]. Yield was 85.0%, mp 208–210ꢁC.
IR (KBr) cmꢂ1
: 1773, 1736, 1717. FABMS (positive) m/z: 413
(M + H)+. Anal. Calcd for C25H20N2O4: C, 72.80; H, 4.89; N, 6.79.
Found: C, 72.87; H, 4.94; N, 6.83.
[24] This compound (8b) was prepared by the procedure reported
previously [7]. Yield was 61.4%, mp 196–199ꢁC. IR (KBr) cmꢂ1: 1772,
1736, 1713. FABMS (positive) m/z: 439 (M+). Anal. Calcd for
C23H22N3O5F: C, 62.86; H, 5.05; N, 9.56. Found: C, 62.66; H, 5.26; N, 9.57.
[25] Affeld, A.; Hübner, G. M.; Seel, C.; Schalley, C. A. Eur J Org
Chem 2001, 2877.
[16] Bax, B. D.; Chan, P. F.; Eggleston, D. S.; Fosberry, A.; Gentry,
D. R.; Gorrec, F.; Giordano, I.; Hann, M. M.; Hennessy, A.; Hibbs, M.;
Huang, J.; Jones, E.; Jones, J.; Brown, K. K.; Lewis, C. J.; May, E. W.;
[26] Noto, T.; Nehashi, T.; Endo, H.; Saito, S.; Matsubara, S.;
Harada, S.; Ogawa, H.; Koyama, K. J Antibiot 1976, 19, 1058.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Featured Compounds
1
2
3
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
2a
2b
2c
Compound Details
Compound Details
Compound Details
4
4a
4b
Compound Details
Compound Details
Compound Details
FC-1

Featured Compounds
5
5a
5b
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
5c
6
6a
Compound Details
Compound Details
Compound Details
6b
6c
2d
Compound Details
Compound Details
Compound Details
FC-2

Featured Compounds
2e
3a
3b
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
3c
3d
7
Compound Details
Compound Details
Compound Details
8a
8b
9a
Compound Details
Compound Details
Compound Details
FC-3

Featured Compounds
9b
10
10a
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Structure Search
Structure Search
10b
11
11a
Compound Details
Compound Details
Compound Details
11b
12
12a
Compound Details
Compound Details
Compound Details
FC-4

Featured Compounds
12b
13
13a
Compound Details
Structure Search
Structure Search
Structure Search
Compound Details
Structure Search
Compound Details
Structure Search
13b
14
14a
Compound Details
Compound Details
Structure Search
Compound Details
Structure Search
14b
Compound Details
FC-5