A conventional route for the synthesis of new oxazolidin-2-one derivatives with β-aminoalanines

Article abstract of DOI:10.1248/cpb.52.1238

A conventional new route to the novel oxazolidin-2-one derivatives (3a - f) having two substituents on N-3 and C-4 in the oxazolidin-2-one ring was established with racemic β-aminoalanine derivatives (1) as the key starting materials.

Full text of DOI:10.1248/cpb.52.1238

1238
Notes
Chem. Pharm. Bull. 52(10) 1238—1241 (2004)
Vol. 52, No. 10
A Conventional Route for the Synthesis of New Oxazolidin-2-one
b
Derivatives with -Aminoalanines
Fumiko FUJISAKI, Nobuhiro ABE, and Kunihiro SUMOTO*
Faculty of Pharmaceutical Sciences, Fukuoka University; Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan.
Received March 10, 2004; accepted July 12, 2004
A conventional new route to the novel oxazolidin-2-one derivatives (3a—f) having two substituents on N-3
and C-4 in the oxazolidin-2-one ring was established with racemic b-aminoalanine derivatives (1) as the key
starting materials.
Key words oxazolidin-2-one; oxazolidinone; b-aminoalanine; cyclization; benzoylation; dehydration
The derivatives of oxazolidin-2-one have recently attracted Results and Discussion
much attention for showing an interesting new class of syn-
The starting compounds (1) and the N-benzoyl derivatives
thetic antibacterial activity.1) Many of the target compounds (5a—f) were prepared according to the procedure described
for investigations of new drug candidates have two sub- previously.3) Benzoylation of these amino acids (1) with sub-
stituents at the N-3 and C-5 positions of the oxazolidin-2-one stituted benzoyl chlorides under Schotten–Baumann reaction
ring.
conditions easily proceeded and gave the desired 5a—f in
We have recently developed a new synthetic method for good to excellent yields. The physical data of the compounds
synthesizing the racemic b-aminoalanine derivatives (1).2) (5a—f) are summarized in Table 1, and spectroscopic data
One of the applications of this unique amino acid for the syn- are given in the Experimental section. From these data, the
thesis of N-[2-(1-piperidinyl)ethyl]benzamides (2) has been structures of 5a—f were easily elucidated. Thus the intro-
reported recently.3) These b-aminoalanine derivatives (1) are duced substituted benzoyl group and a tert-amino group
also expected to be applicable for the ring formation of novel (–NR2R3) were confirmed in both 1H- and 13C-NMR spectra.
oxazolidin-2-one derivatives such as (3), which has two sub- Full assignments of these data for the structures of 5a—f
stituents on N-3 and C-4 of the oxazolidin-2-one ring and (represented in Chart 1) are recorded in the Experimental
1
this mimics the fundamental structural framework of Line- section. These assignments and correlations of H- and 13C-
zolid (4).4,5) These derivatives (3) are selected as the target NMR signals were supported by two-dimensional (2D) spec-
heterocycles for one of the synthetic applications of the troscopic analysis. Interestingly, IR spectra (KBr) showed
above unique amino acid b-aminoalanine derivatives (1) two typical strong absorption bands at 1647—1662 and
(Fig. 1). The molecular modification (4Æ3) is one of the 1570—1584 cmꢀ1 attributable to the amide CꢁO and
well-known procedures in the search for biologically active carboxylate (COOꢀ) groups, respectively. This apparently
compounds, the so-called disjunctive approach in medicinal indicates these compounds require the well-known twitterion
chemistry.6) In this paper, we report a new conventional route structure between the carboxy (COOH) and basic tert-amino
to the synthesis of the above novel oxazolidin-2-one deriva- groups in the solid state (see Table 1). The reductions of both
tives.
these two carbonyl groups (N-benzoyl amide and COOH) in
the derivatives (5a—f) were successfully achieved by treat-
ment with NaAlH2(OCH2CH2OCH3)2 in anhydrous benzene
to afford the corresponding amino alcohols 6a—f. These
compounds (6a—f) were relatively sensitive to exposure to
air and included trace amounts of unknown contaminants
upon TLC analysis. The purification of the products to re-
move these unknown contaminants resulted in a great loss of
the target compounds (6a—f). Therefore we used the above
obtained material for the next cyclization process without
further purification (see Experimental).
The procedure for the cyclization step with the treatment
of 6a—f with diethyl carbonate in the presence of sodium
methoxide in anhydrous benzene was effective, and resulted
in the formation of 3a—f in good yields (58—81%) (Chart
1), which were comparable with the results reported by
Homeyer.7) The physical data on the compounds (3a—f) are
summarized in Table 2, and 1H- and 13C-NMR spectroscopic
data are reported in the Experimental section.
The structures of the target oxazolidin-2-ones (3a—f)
were easily confirmed from the above elemental and spectro-
scopic analysis. Thus IR spectra of 3a—f showed a typical
Fig.
1
* To whom correspondence should be addressed. e-mail: kunihiro@cis.fukuoka-u.ac.jp
© 2004 Pharmaceutical Society of Japan

October 2004
1239
Table 1. Physical Data on Compounds 5a—f
IR (KBr) cmꢀ1
Analysis (%)
Calcd (found)
Compound
no.
R1
Yield
(%)
mp (°C)
(recryst. solvent)
FAB-MS
Formula
(MꢂH)ꢂ
Amide CꢁO
(COOꢀ)
C
H
N
139—141 (dec.)
(H2O)
1647
(1570)
61.21 7.53 9.52
(61.08 7.53 9.51)
5a
5b
5c
5d
5e
5f
H
3-OCH3
H
67
53
64
60
81
62
C15H20N2O3·H2O
C15H20N2O4S
C14H18N2O3S
C19H22N2O3
277
325
295
327
357
1651
(1578)
325.1222b)
(325.1220)
295.1116b)
(295.1115)
100—106 (dec.)a)
97—101a)
1662
(1578)
–N(CH2)2Ph
CH3
162—164 (dec.)
(H2O)
1655
(1578)
69.92 6.79 8.58
(70.06 6.80 8.61)
H
–N(CH2)2Ph
CH3
122—132 (dec.)
(AcOEt)
1647
(1584)
67.4
6.79 7.86
3-OCH3
H
C20H24N2O4
(67.12 6.80 7.91)
173—175 (dec.)
(EtOH)
1651
(1578)
62.39 7.03 10.39
(62.37 6.98 10.56)
C14H18N2O3·0.4H2O 263
a) Melting point of the material purified by silica gel column chromatography with EtOH/NH3 (25/1) as the solvent. b) Since the compound was hygroscopic, analysis was
carried out using HR-MS spectrometry. The correct (MꢂH)ꢂ ion peaks, C15H21N2O4S and C14H19N2O3S, were observed for compounds 5b and 5c, respectively.
Chart
1
absorption band at 1738—1757 cmꢀ1 attributable to the oxa-
To the best of our knowledge, no previous report has dealt
zolidin-2-one ring CꢁO group (see Table 2). In all 1H-NMR
spectra, a ring proton (C-4) was observed at d 4.06—
4.39 ppm as a multiplet, and two methylene protons on C-5
ring carbon at d 4.34—4.68 ppm were observed. Some of the
C-5 ring protons overlapped with other protons. The 13C-
NMR spectra are also in good agreement with the repre-
sented structures of oxazolidin-2-ones (3a—f). Regarding
the oxazolidin-2-one ring in 3a—f, two 13C signals were
observed at d 49.9—53.3 and d 66.6—70.0 ppm, ascribable
to the C-4 and C-5 of oxazolidin-2-one ring, respectively.
The NMR data are given in the Experimental section. These
with this class of oxazolidin-2-one derivatives (3). We em-
phasize that these easily obtainable b-aminoalanine deriva-
tives (1) can be used in the synthesis of novel N-3 and C-4
disubstituted oxazolidin-2-ones (3) as efficient starting mate-
rials. Further synthetic application of this method for related
derivatives8,9) is in progress.
Experimental
Melting points are uncorrected. IR spectra were measured with a Shi-
1
madzu FTIR-8100 spectrometer. H- and 13C-NMR spectra were obtained
with a JEOL JNM A-500 at 35 °C unless otherwise noted. Chemical shifts
are expressed as d ppm downfield from an internal tetramethylsilane (TMS)
or sodium salt of 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid (TSP) signal
1
assignments and correlations of H- and 13C-NMR signals
1
(0 ppm) (in D2O) for H-NMR, and the carbon signal of the corresponding
were supported by 2D spectroscopic methods.

1240
Vol. 52, No. 10
Table 2. Physical Data on 3,4-Disubstituted Oxazolidine-2-one Hydrochlorides 3a—f
Analysis (%)
Calcd (found)
Compound
no.
Yield
(%)
mp (°C)
(recryst. solvent)
FAB-MS
IR (KBr)
cmꢀ1
R1
Formula
(MꢂH)ꢂ
C
H
N
207 (dec.)
(CH3CN)
61.83 7.46 9.01
(61.93 7.49 9.09)
3a
3b
3c
3d
3e
3f
H
3-OCH3
H
67
71
81
61
58
74
C16H22N2O2·HCl
C16H22N2O3S·HCl
C15H20N2O2S·HCl
C20H24N2O2·HCl
C21H26N2O3·HCl
C15H20N2O2·HCl
275
323
293
325
355
261
1752
1757
1755
1736
1738
1740
185—189
(CH3CN)
53.55 6.46 7.81
(53.83 6.49 7.83)
198—203 (dec.)
(CH3CN)
54.78 6.44 8.52
(54.71 6.32 8.56)
–N(CH2)2Ph
CH3
142—144
(Acetone)
66.57 6.70 7.76
(66.50 6.98 7.80)
H
–N(CH2)2Ph
CH3
128—130
(Acetone/Et2O)
64.52 6.96 7.17
(64.38 7.06 7.14)
3-OCH3
H
182—184 (dec.)
(EtOH/acetone)
60.7
7.13 9.44
(60.87 7.37 9.53)
solvent [CDCl3 (77.0 ppm), DMSO-d6 (39.5 ppm), CD3OD (49.8 ppm)], and
C-3, C-5), 131.8 (Ar C-4), 133.6 (Ar C-1), 167.4 (CONH), 173.7 (COOH).
2-Benzoylamino-3-(N-methyl-N-phenethylamino)propionic Acid (5d)
TSP (0 ppm) (in D2O) for 13C-NMR, respectively. The signal assignments
1
1
were confirmed with H–1H correlation spectroscopy (COSY). H–13C het- 1H-NMR (DMSO-d6) d: 2.48 (3H, s, NCH3), 2.78—2.83 [2H, m, N(CH3)
1
eronuclear multiple-quantum coherence (HMQC), or H–13C heteronuclear CH2CH2Ph], 2.84—2.87 [2H, m, N(CH3)CH2CH2Ph], 2.99—3.01 [2H, m,
multiple-bond connectivity (HMBC) spectra. FAB-MS were obtained with a NHCH(COOH)CH2], 4.59 [1H, q, Jꢁ7.5 Hz, NHCH(COOH)CH2Nꢁ], 5.0
JEOL JMS-HX110 mass spectrometer. The preparation of racemic (1H, br, COOH), 7.16—7.19 [1H, m, Ar H-4 of PhCH2], 7.22—7.27 [4H, m,
b-aminoalnines (1) as starting materials has already been described in our
previous paper.2) The following abbreviation was used for the oxazolidin-2- PhCONH], 7.53—7.56 [1H, m, Ar H-4 of PhCONH], 7.84—7.86 [2H, m,
one ring (Oxzln) in NMR spectroscopic data.
Ar H-2, H-6 of PhCONH], 8.39 (1H, d, Jꢁ7.5 Hz, CONH). 13C-NMR
Ar H-2, H-3, H-5, H-6 of PhCH2], 7.46—7.49 [2H, m, Ar H-3, H-5 of
Preparation of 3-(N,N-Disubstituted amino)-2-benzoylaminopropi- (DMSO-d6) d: 31.8 (CH2CH2Ph), 41.0 (NCH3), 49.9 [CONHCH(COOH)-
onic Acids (5a—f) 3-(N,N-Disubstituted amino)-2-benzoylaminopropi- CH2], 56.7 [CH2N(CH3)CH2CH2], 57.8 (CH2CH2Ph), 126.0 [Ar C-4 of
onic acids (5a—f) were prepared by the same method as described previ-
ously.3) Yields and physical data (MS and analysis) for compounds 5a—f are
summarized in Table 1. Other spectroscopic data are reported below.
Ph(CH2CH2)], 127.2 [Ar C-2, C-6 of PH(CONH)], 128.2 [Ar C-2, C-3, C-5,
C-6 of Ph(CH2CH2)], 128.5 [Ar C-3, C-5 of Ph(CONH)], 131.3 [Ar C-4 of
Ph(CONH)], 133.9 [Ar C-1 of Ph(CONH)], 139.3 [Ar C-1 of Ph(CH2CH2)],
2-Benzoylamino-3-piperidinopropionic Acid (5a) 1H-NMR (D2O) 166.0 (CONH), 172.4 (COOH).
d: 1.55—2.10 (6H, br, piperidine ring H-3, H-4, H-5), 2.90—3.82
2-(3-Methoxybenzoylamino)-3-(N-methyl-N-phenethylamino)propi-
(4H, br, piperidine ring H-2, H-6), 3.47 [1H, dd, Jꢁ13.0, 8.0 Hz, onic Acid (5e) 1H-NMR (DMSO-d6) d: 2.46 (3H, s, NCH3), 2.78—2.80
NHCH(COOH)CHH], 3.61 [1H, dd, Jꢁ13.0, 6.0 Hz, NHCH(COOH)CHH], (2H, m, NCH2CH2Ph), 2.81—2.84 (2H, m, NCH2CH2Ph), 2.98 [2H, d,
4.84 [1H, dd, Jꢁ8.0, 6.0 Hz, NHCH(COOH)CH2], 7.55—7.58 (2H, m, Ar Jꢁ7.5 Hz, NHCH(COOH)CH2N(CH3)], 3.80 (3H, s, OCH3), 4.58 (1H, q,
H-3, H-5), 7.65—7.66 (1H, m, Ar H-4), 7.85—7.87 (2H, m, Ar H-2, H-6).
13C-NMR (D2O) d: 23.9 (piperidine ring C-4), 25.6 (piperidine ring C-3,
C-5), 52.8 [CH(COOH)CH2], 56.6 (piperidine ring C-2, C-6), 60.9
[CH(COOH)CH2], 130.2 (Ar C-2, C-6), 131.7 (Ar C-3, C-5), 135.5 (Ar C-1
or C-4), 135.6 (Ar C-4 or C-1), 173.4 (CONH), 176.8 (COOH).
Jꢁ7.5 Hz, NHCH(COOH)CH2N(CH3)], 7.10—7.12 (1H, m, Ph H-4),
7.17—7.18 (1H, m, m-methoxyphenyl H-4), 7.22—7.27 (4H, m, Ph H-2,
H-3, H-5, H-6), 7.37—7.43 (3H, m, m-methoxyphenyl H-2, H-5, H-6),
8.40 (1H, d, Jꢁ7.5 Hz, CONH). 13C-NMR (DMSO-d6) d: 31.9 (CH2CH2Ph),
41.0 (NCH3), 49.6 [NHCH(COOH)CH2], 55.2 (OCH3), 56.7 [NHCH
2-(3-Methoxybenzoylamino)-3-thiomorpholinopropionic Acid (5b) (COOH)CH2], 57.8 (CH2CH2Ph), 112.5 (m-methoxyphenyl group C-2),
1H-NMR (CDCl3) d: 2.82 (4H, m, thiomorpholine ring H-2, H-6), 3.07 [1H,
dd, Jꢁ13.0, 8.0 Hz, –CH(COOH)CHHNꢁ], 3.17—3.19 (2H, m, thiomor-
pholine ring H-3, H-5), 3.29 (2H, m, thiomorpholine ring H-3, H-5), 3.32
117.1 (m-methoxyphenyl group C-4), 119.4 (m-methoxyphenyl group C-6),
125.9 (Ph group C-4), 128.2 (Ph group C-2, C-6 or C-3, C-5), 128.5 (Ph
group C-3, C-5 or C-2, C-6), 129.4 (m-methoxyphenyl group C-5), 135.4
[1H, dd, Jꢁ13.0, 6.0 Hz, –CH(COOH)CHHNꢁ], 3.81 (3H, s, OCH3), 4.62 (m-methoxyphenyl group C-1), 139.4 (Ph group C-1), 159.1 (m-
[1H, dd, Jꢁ13.0, 6.0 Hz, –CONHCH(COOH)CH2], 6.7 (1H, br, COOH), methoxyphenyl group C-3), 165.7 (CONH), 172.3 (COOH).
6.99—7.02 (1H, m, Ar H-4), 7.28 (1H, t, Jꢁ8.0 Hz, Ar H-5), 7.37—7.41
2-Benzoylamino-3-(1-pyrrolidinyl)propionic Acid (5f) 1H-NMR
(2H, m, Ar H-2, H-6), 7.72 (1H, d, Jꢁ5.0 Hz, CONH). 13C-NMR (CDCl3) d: (D2O) d: 2.11 (4H, br, pyrrolidine ring H-3, H-4), 3.48 (4H, br, pyrrolidine
26.0 (thiomorpholine ring C-2, C-6), 50.1 [NHCH(COOH)CH2], 54.7 ring H-2, H-5), 3.57 [1H, dd, Jꢁ13.0, 8.0 Hz, NHCH(COOH)CHHNꢁ],
(thiomorpholine ring C-3, C-5), 55.4 (OCH3), 58.1 [NHCH(COOH)CH2], 3.72 [1H, dd, Jꢁ13.0, 6.0 Hz, NHCH(COOH)CHHNꢁ], 4.79 [1H, dd,
112.6 (Ar C-2), 117.9 (Ar C-4), 119.1 (Ar C-6), 129.6 (Ar C-5), 135.0 (Ar
C-1), 159.8 (Ar C-3), 167.3 (CONH), 173.7 (COOH).
Jꢁ8.0, 6.0 Hz, NHCH(COOH)CH2Nꢁ], 7.57 (2H, m, Ar H-3, H-5), 7.66
(1H, m, Ar H-4), 7.87 (2H, m, Ar H-2, H-5). 13C-NMR (D2O) d: 25.5
2-Benzoylamino-3-thiomorpholinopropionic Acid (5c) 1H-NMR (pyrrolidine ring C-3, C-4), 54.4 [NHCH(COOH)CH2], 57.7 (pyrrolidine
(CDCl3) d: 2.82 (4H, m, thiomorpholine ring H-2, H-6), 3.10 [1H, dd,
Jꢁ13.0, 8.0 Hz, CH(COOH)CHHN=], 3.18—3.20 (2H, m, thiomorpholine
ring H-3, H-5), 3.29 (2H, m, thiomorpholine ring H-3, H-5), 3.33 [1H, dd,
ring C-2, C-5), 59.2 [NHCH(COOH)CH2], 130.1 (Ar C-2, C-6), 131.7 (Ar
C-3, C-5), 135.4 (Ar C-4), 135.6 (Ar C-1), 173.3 (CONH), 176.8 (COOH).
General Procedure for the Preparation of Amino Alcohols (6) by Re-
Jꢁ13.0, 6.0 Hz, CH(COOH)CHHNꢁ], 4.63 [1H, dd, Jꢁ13.0, 6.0 Hz, CON- duction of 5 To a solution of sodium bis(2-methoxyethoxy)aluminum hy-
HCH(COOH)CH2], 7.38 (2H, t, Jꢁ7.5 Hz, Ar H-3, H-5), 7.40 (1H, br, dride (51 mmol) in anhydrous benzene was added 5 (10.2 mmol) with stir-
COOH), 7.47 (1H, t, Jꢁ6.0 Hz, Ar H-4), 7.75 (1H, d, Jꢁ5.0 Hz, CONH), ring at room temperature. The reaction mixture was allowed to stand for 2 h
7.84 (2H, d, Jꢁ7.0 Hz, Ar H-2, H-6). 13C-NMR (CDCl3) d: 22.8 (thiomor- and then refluxed for 2 h. After decomposition of the reaction mixture with
pholine ring C-2, C-6), 50.1 [CONHCH(COOH)CH2], 54.6 (thiomorpholine
ring C-3, C-5), 58.0 [CH(COOH)CH2Nꢁ], 127.2 (Ar C-2, C-6), 128.5 (Ar
water, the benzene layer was isolated and then the viscous residue was
washed with benzene. The combined benzene layer was shaken with 1 N-HCl

October 2004
1241
3-Phenylmethyl-4-(N-methyl-N-phenethylamino)methyloxazolidin-2-
one Hydrochloride (3d) 1H-NMR (CDCl3) d: 2.60 (3H, br s, NCH3),
2.99—3.36 (6H, m, CH2N(CH3)CH2CH2Ph), 4.31—4.39 (2H, m, a benzylic
proton of N-3 substituent and H-4 on Oxzln), 4.61—4.64 (2H, m, Oxzln H-
5), 4.66—4.72 (1H, m, a benzylic proton of N-3 substituent on Oxzln),
7.01—7.35 (10H, m, Ar-H), 12.49 (1H, br s, NHꢂ). 13C-NMR (CDCl3, as
free base) d: 33.6 (CH2CH2Ph), 42.6 (NCH3), 46.7 (Ph–CH2Nꢁ), 52.2
(Oxzln C-4), 60.0 (CH2–N(CH3)–CH2CH2), 66.8 (Oxzln C-5), 126.1, 127.8,
128.2, 128.4, 128.7 (two Ar C-2—C-6), 136.3 (Ar C-1 of PhCH2Nꢁ), 140.0
(Ar C-1 of PhCH2CH2Nꢁ), 158.6 (CꢁO).
3-(3-Methoxyphenylmethyl)-4-(N-methyl-N-phenethylamino)meth-
yloxazolidin-2-one Hydrochloride (3e) 1H-NMR (CD3OD) d: 2.87—2.92
(5H, m, N(CH3)CH2CH2Ph), 3.30—3.74 (4H, m, CH2N(CH3)CH2CH2Ph),
3.75 (3H, s, OCH3), 4.19—4.23 (1H, m, Oxzln H-4), 4.34 (1H, d,
Jꢁ16.0 Hz, Ph–CHH–Nꢁ), 4.43 (1H, dd, Jꢁ8.0, 5.0 Hz, Oxzln H-5),
4.60—4.68 (1H, m, Oxzln H-5), 4.70 (1H, d, Jꢁ16.0 Hz, Ph–CHH–Nꢁ),
6.87—6.89 (1H, m, Ar-H), 6.94—6.95 (2H, m, Ar-H), 7.24—7.34 (6H, m,
Ar-H). 13C-NMR (CD3OD) d: 31.0 (CH2CH2Ph), 41.9 (NCH3), 47.3
(PhCH2–Nꢁ), 51.9 (Oxzln C-4), 55.8 (OCH3), 57.6, 59.8 (CH2–N
(CH3)–CH2), 68.7 (Oxzln C-5), 114.8 (m-methoxyphenyl group C-2, C-4),
121.2 (m-methoxyphenyl group C-6), 128.4 (Ph group C-4), 129.9 (Ph
group C-3, C-5), 130.0 (Ph group C-2, C-6), 131.4 (m-methoxyphenyl group
C-5), 137.1 (Ph group C-1), 138.5 (m-methoxyphenyl group C-1), 159.9
(CꢁO), 161.8 (m-methoxyphenyl group C-3).
3-Phenylmethyl-4-(1-pyrrolidinylmethyl)oxazolidin-2-one Hydrochlo-
ride (3f) 1H-NMR (DMSO-d6) d: 1.88—1.97 (4H, m, pyrrolidine ring H-
3, H-4), 2.90—2.96 (2H, m, ꢁCH–CH2–Nꢁ), 3.42—3.49 (4H, m, pyrroli-
dine ring H-2, H-5), 4.06—4.08 (1H, m, Oxzln H-4), 4.32 (1H, d,
Jꢁ15.5 Hz, CHHPh), 4.46—4.50 (1H, m, Oxzln H-5), 4.54—4.58 (1H, m,
Oxzln H-5), 4.56 (1H, d, Jꢁ15.5 Hz, CHHPh), 7.31—7.42 (5H, m, Ar-H),
11.76 (1H, br s, NHꢂ). 13C-NMR (DMSO-d6) d: 22.4 (pyrrolidine ring C-3),
22.5 (pyrrolidine ring C-4), 45.1 (Ph–CH2–Nꢁ), 51.3 (Oxzln C-4), 52.8,
53.6, 54.0 (pyrrolidine ring C-2, C-5 and ꢁCH–CH2–Nꢁ), 66.6 (Oxzln C-
5), 127.6, 127.7, 128.5 (Ar C-2—C-6), 136.3 (Ar C-1), 157.2 (CꢁO).
(ꢃ3). The separated aqueous layer was washed with benzene, and then the
aqueous layer was made alkaline with K2CO3. The precipitate was extracted
with Et2O. The ethereal solution was dried over K2CO3 and concentrated in
vacuo to give a crude product of 6.10) As a typical example, the free base of
compound 6d was obtained in 86% yield. To obtain an analytical sample,
this material was converted to dihydrochloride with 20% ethanolic HCl. Re-
crystallization from ethanol gave 6d dihydrochloride in 41% yield, mp
1
172—174 °C. FAB-MS (positive) m/z: 299 (MꢂH)ꢂ. H-NMR (DMSO-d6)
d: 2.93 (3H, s, NCH3), 3.09—3.13 (2H, m, CH2CH2Ph), 3.41—3.63 [4H, m,
CH2N(CH3)CH2CH2], 3.80—3.95 [4H, m, NHCH(CH2OH)CH2], 4.26—
4.29 and 4.39—4.41 (2H, m, PhCH2), 7.24—7.44 (8H, m, Ar-H), 7.67—
7.69 (2H, m, Ar-H), 9.80—9.92 (2H, m, NH2ꢂ), 11.1 (1H, br s, NHꢂ). 13C-
NMR (DMSO-d6, 69 °C) d: 29.5 (CH2CH2Ph), 40.6 (NCH3), 48.4 (Ph-
CH2NH), 54.2 [NHCH(CH2OH)CH2], 54.4 [NHCH(CH2OH)CH2], 57.3
(CH2CH2Ph), 57.8 (CH2OH), 127.0, 128.7, 128.8, 129.2, 130.1, 131.5, 136.6
(Ar). Anal. Calcd for C19H26N2O·2HCl: C, 61.45; H, 7.60; N, 7.54. Found:
C, 61.55, H, 7.52; N, 7.55.
General Procedure for the Preparation of 3-Phenylmethyl-4-(N,N-di-
substituted aminomethyl)oxazolidin-2-one Hydrochloride (3a—f)
A
mixture of 6 (9.19 mmol) and diethyl carbonate (46 mmol) in anhydrous
benzene (100 ml) was subjected to azeotropic distillation. Sodium methoxide
(0.1 g) was added to the residue and then the resulting mixture was heated at
130 °C for 1 h. The excess diethyl carbonate was distilled off by raising the
bath temperature to 160 °C to give a viscous residue. After the addition of
Et2O, the resulting mixture was extracted with 1 N-HCl (ꢃ3). The acidic
aqueous layer was washed with Et2O, neutralized with K2CO3, and then re-
extracted with Et2O. The ethereal extract was dried over anhydrous MgSO4
and then evaporation of the solvent under reduced pressure afforded a solid
material. This was treated with 10% methanolic HCl and concentrated under
reduced pressure to give the crude product of 3. Recrystallization from an
appropriate solvent gave pure hydrochloride of 3a—f. Yields and physical
data are listed in Table 2. Other specroscopic data are reported below.
3-Phenylmethyl-4-piperidinomethyloxazolidin-2-one Hydrochloride
(3a) 1H-NMR (DMSO-d6) d: 1.32—1.35 (1H, m, piperidine ring H-4),
1.65—1.74 (3H, m, piperidine ring H-3, H-4, H-5), 1.77—1.88 (2H, m,
piperidine ring H-3, H-5), 2.80—2.91 (2H, m, piperidine ring H-2, H-6),
3.27—3.47 (4H, m, piperidine ring H-2, H-6 and ꢁCH–CH2–Nꢁ), 4.20—
4.25 (1H, m, Oxzln H-4), 4.34 (1H, d, Jꢁ16 Hz, CHHPh), 4.40—4.44 and
4.51—4.54 (2H, m, Oxzln H-5), 4.55 (1H, d, Jꢁ16.0 Hz, CHHPh), 7.37
(5H, m, Ar-H), 11.21 (1H, br s, NHꢂ). 13C-NMR (DMSO-d6) d: 21.0
(piperidine ring C-4), 21.9 (piperidine ring C-3), 22.0 (piperidine ring C-5),
45.1 (Ph–CH2), 50.2 (Oxzln C-4), 51.9, 52.9 (piperidine ring C-2, C-6), 56.0
(ꢁCH–CH2–Nꢁ), 67.4 (Oxzln C-5), 127.5, 127.8, 128.5 (Ar C-2—C-6),
136.5 (Ar C-1), 157.1 (CꢁO).
References and Notes
1) Bronson J. J., Barrett J. F., Annu. Rep. Med. Chem., 36, 89—98 (2001).
2) Abe N., Fujisaki F., Sumoto K., Chem. Pharm. Bull., 46, 142—144
(1998), and related references cited therein.
3) Fujisaki F., Abe N., Sumoto K., Chem. Pharm. Bull., 50, 129—132
(2002).
4) Park C.-H., Brittelli D. R., Wang C.-L. J., Marsh F. D., Gregory W. A.,
Wuonola M. A., McRipley R. J., Eberly V. S., Slee A. M., Forbes M.,
J. Med. Chem., 35, 1156—1165 (1992).
5) Brickner S. J., Hutchinson D. K., Barbachyn M. R., Manninen P. R.,
Ulanowicz D. A., Garmon S. A., Grega K. C., Hendges S. K., Toops
D. S., Ford C. W., Zurenko G. E., J. Med. Chem., 39, 673—679 (1996).
6) Camille G. W., “The Practice of Medicinal Chemistry,” 2nd ed., Acad-
emic Press, San Diego, 2003.
7) Homeyer A. H., U.S. Patent 2399118 (1946) [Chem. Abst., 40, 404084
(1946)].
8) Further modifications of two substituents on the oxazolidin-2-one ring
are under investigation to develop a lead compound for new antibacte-
rial agents.
9) The compound having –NHAc functionality as a part of the –NR1R2
group in the target molecule (3) can be obtained with a similar cycliza-
tion procedure with diethyl carbonate. However, the procedure for this
class of compounds consists of multistage reactions. We will describe
the synthesis of these analogues elsewhere.
10) Other amino alcohols (6) were obtained in good to moderate yields
(51—83%) using this procedure. However, these compounds con-
tained trace amounts of unknown contaminants. As mentioned in the
Discussion, the purifications of these amino alcohols (6) were attrib-
uted to a loss of materials, and therefore we used the materials for the
next stage without further purification.
3-(3-Methoxyphenylmethyl)-4-thiomorpholinomethyloxazolidin-2-one
Hydrochloride (3b) 1H-NMR (DMSO-d6ꢂD2O) d: 2.89 (4H, t, Jꢁ5.0
Hz, thiomorpholine ring H-2, H-6), 3.33—3.37 (6H, m, thiomorpholine ring
H-3, H-5 and ꢁCH–CH2–Nꢁ), 3.82 (3H, s, OCH3), 4.24—4.25 (1H, m,
Oxzln H-4), 4.34—4.40 (2H, m, CHHPh and Oxzln H-5), 4.58—4.63 (2H,
m, CHHPh and Oxzln H-5), 6.93—7.42 ( 4H, m, Ar-H). 13C-NMR (DMSO-
d6ꢂD2O) d: 26.7 (thiomorpholine ring C-2, C-6), 48.3 (Ph–CH2–Nꢁ), 53.3
(Oxzln C-4), 56.9 (thiomorpholine ring C-3, C-5), 57.8 (OCH3), 60.0
(ꢁCH–CH2–Nꢁ), 70.0 (Oxzln C-5), 115.8 (Ar C-4), 116.1 (Ar C-2), 122.6
(Ar C-6), 132.9 (Ar C-5), 139.5 (Ar C-1), 161.4 (CꢁO), 161.8 (Ar C-3).
3-Phenylmethyl-4-thiomorpholinomethyloxazolidin-2-one Hydrochlo-
ride (3c) 1H-NMR (DMSO-d6) d: 2.76 (2H, br, thiomorpholine ring H-2,
H-6), 3.08—3.15 (2H, m, thiomorpholine ring H-3, H-5), 3.35—3.45 (4H,
m, thiomorpholine ring H-2, H-6 and ꢁCH–CH2–Nꢁ), 3.61 (2H, br,
thiomorpholine ring H-3, H-5), 4.22—4.23 (1H, m, Oxzln H-4), 4.31 (1H, d,
Jꢁ16.0 Hz, CHHPh), 4.49—4.50 (2H, m, Oxzln H-5), 4.55 (1H, d,
Jꢁ16.0 Hz, CHHPh), 7.29—7.38 (5H, m, Ar-H), 11.76 (1H, br s, NHꢂ).
13C-NMR (DMSO-d6) d: 23.5 (thiomorpholine ring C-2, C-6), 45.1
(CH2Ph), 49.9 (Oxzln C-4), 52.8, 53.7 (thiomorpholine ring C-3, C-5), 56.5
(ꢁCH–CH2–Nꢁ), 67.3 (Oxzln C-5), 127.5, 127.8, 128.6 (Ar C-2—C-6),
136.4 (Ar C-1), 157.1 (CꢁO).