Identification of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A

Article abstract of DOI:10.1021/jm0400810

Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Many oxazolidinones, including linezolid (marketed as Zyvox),

Full text of DOI:10.1021/jm0400810

J. Med. Chem. 2005, 48, 499-506
499
Identification of 4-Substituted 1,2,3-Triazoles as Novel Oxazolidinone
Antibacterial Agents with Reduced Activity against Monoamine Oxidase A
Folkert Reck,*,† Fei Zhou,† Marc Girardot,† Gunther Kern,† Charles J. Eyermann,† Neil J. Hales,§
Rona R. Ramsay,‡ and Michael B. Gravestock†
AstraZeneca Discovery, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, and Centre for
Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews KY16 9ST, Scotland, U.K.
Received April 7, 2004
Oxazolidinones represent a new and promising class of antibacterial agents. Current research
in this area is mainly concentrated on improving the safety profile and the antibacterial
spectrum. Many oxazolidinones, including linezolid (marketed as Zyvox), are inhibitors of
monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found
that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found
in oxazolidinones. We now disclose the finding that 1,2,3-triazoles bearing a substituent like
methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position
(compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity,
within the detection limit of the assay, against MAO-A. The results are especially promising
for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can
be rationalized on the basis of docking studies to a MAO-A/MAO-B homology model.
Introduction
The development of bacterial resistance to existing
drugs is a major problem in antibacterial therapy and
necessitates continuing research into new classes of
antibacterials.1 Of particular concern are severe infec-
tions caused by multidrug-resistant Gram-positive patho-
gens, which cause high mortality rates especially in the
hospital setting. The individual organisms responsible
include methicillin-resistant Staphylococcus aureus (MR-
SA),2,3 vancomycin-resistant Enterococcus faecalis (VRE),4
and penicillin-resistant Streptococcus pneumoniae.5,6
Oxazolidinones are a new class of antibacterials that
are exemplified by linezolid (marketed as Zyvox)7-9 and
have resulted in important and new treatment options
for infections caused by Gram-positive bacteria. Oxazo-
lidinones target bacterial protein synthesis, probably by
binding at or near the peptidyltransferase center in
actively translating bacterial ribosomes.10-12 However,
resistance against linezolid has already started to
develop in Enterococcus faecium13-17 and, more alarm-
ingly, in S. aureus, giving rise to linezolid-resistant
MRSA strains.18 A concern with oxazolidinones as a
drug class has been inhibition of monoamine oxidase
(MAO), especially type A (MAO-A), due to structural
similarity to MAO inhibitors such as toloxatone.19
Inhibition of MAO-A could potentially lead to severe
hypertensive crises as a result of ingestion of tyramine-
containing food together with an oxazolidinone drug (the
“cheese effect”).20,21 It is therefore desirable to develop
novel oxazolidinone drugs, which not only have im-
proved activity against resistant Gram-positive bacteria
Figure 1. Thiapyran sulfone analogue of linezolid (1) and
corresponding AstraZeneca 1,2,3-triazole lead (2).
but also show an improved safety profile with regard
to MAO-A inhibition.
We have been interested for some time in oxazolidi-
nones bearing a thiapyran sulfone moiety because we
found that structures such as 122 (Figure 1) show
improved potency against both Gram-positive and fas-
tidious Gram-negative pathogens relative to linezolid.
We attempted to further improve the antibacterial
activity of the thiapyran sulfones by modifying the
acetamido functionality in 1. While looking for a new
way of introducing diversity at this position, we saw an
opportunity arising from our recent finding that the
1,2,3-triazole moiety is a good replacement for the
acetamide23 (compound 2, Figure 1). The 4 and 5
positions of the triazole in 2 allow diversification with
a different spatial arrangement compared to the con-
ventional acetamido functionality.24,25 Recently, Phillips
et al.26 reported a limited exploration into substituted
triazole analogues of linezolid, but these efforts failed
to identify new substituted triazole compounds with
potent antibacterial activity. We now report on our more
extensive study into the SAR in this area, which has
led to the identification of potent and novel antibacteri-
als with interesting properties.
* To whom correspondence should be addressed. Phone: 781-839-
4617. Fax: 781-839-4500. E-mail: folkert.reck@astrazeneca.com.
† AstraZeneca R&D Boston.
§ Present address: AstraZeneca, Mereside, Alderley Park, Maccles-
field, Cheshire, SK10 4TG, U.K.
‡ University of St. Andrews.
10.1021/jm0400810 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/04/2005

500 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Reck et al.
Scheme 1a
Scheme 2a
a Reagents: (a) P(Ph)3, CH3CN/H2O, room temp; (b) DIEA,
MeOH, 0 °C to room temp.
a Reagents: (a) MCPBA, CH2Cl2, 0 °C to room temp; (b) dioxane,
reflux.
Scheme 3a
Chemistry
The synthesis of substituted 1,2,3-triazoles via Huis-
gen 1,3-dipolar thermal cycloaddition is outlined in
Scheme 1. Cycloaddition of the azide 4 with tert-butyl
propiolate proceeded smoothly and selectively to 7.
When 5,6,7,8-tetrachloro-1,4-dihydro-2,9-dimethyl-1,4-
ethenonaphthalene27 was employed as an alkyne equiva-
lent, a mixture of the 4- and 5-methyl-substituted
triazoles 5 and 6 was obtained (after retro-Diels-Alder
reaction of the transient triazoline), which was chro-
matographically separated. The structural assignment
of the regioisomeric triazoles was based on nuclear
Overhauser effect (NOE) and heteronuclear multiple-
bond correlation (HMBC) NMR experiments. In cases
where both isomers were available, the proton reso-
nance for H-5 was lower than the one for H-4 in all
examples, confirming the rule by Alonso et al.28
Chromatographic separation of regioisomeric triazoles
was tedious, and selective routes into 4-substituted
triazoles were sought. Selective synthesis of the 4-meth-
yltriazole 5 was achieved by reacting amine 8 with R,R-
dichloroacetone tosylhydrazone 9a29 to give 5 in 64%
yield (Scheme 2). Similarly, we found that the novel
tosylhydrazone 9b reacted with 8 to give cleanly the
4-ethyltriazole 10 in 72% yield. The corresponding
5-alkylated triazole species were not observed.
a Reagents: (a) neat or toluene or NMP, 90 or 110 °C.
halogenated triazoles; thus, the R-bromosulfonyl chlo-
ride 11e32 gave selectively the 4-bromotriazole 16 in 76%
yield.33 In contrast, p-nitrophenyl-R-bromovinylsulfone
gave the p-nitrophenylsulfonyl triazole as the sole
product, resulting from elimination of HBr from the
triazoline intermediate (result not shown). We prepared
the novel R-chlorosulfonyl chloride 11d (Scheme 4) and
found that it is similarly very useful for the selective
preparation of 4-chlorotriazoles, giving 15 in 64% yield.
Interestingly, the regioselectivity of the addition was
reversed for phenyl R-fluorovinylsulfone 11c,34 which
gave a ∼1:7 mixture of the 4- and 5-fluorotriazoles 13
and 14 in 28% yield. The lower yield was a result of
Thermal cycloaddition of vinylsulfone 11a30 with
azide 4, followed by elimination of phenylsulfinic acid
gave the 4-isopropyltriazole 12 in 36% yield after
chromatography and crystallization (Scheme 3). The
corresponding 5-isopropyltriazole was not observed, and
the modest yield was due to the recovery of some
unreacted starting azide. Reaction of the less sterically
demanding hydroxymethylvinylsulfone 11b31 with azide
4 gave 17 in 50% yield after chromatography. In this
case the corresponding 5-hydroxymethyltriazole was
observed as a minor component. We found vinyl sulfonyl
reagents particularly useful for the preparation of

Substituted Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 501
Scheme 4a
a Reagents: (a) (1) 2,6-lutidine, Et2O, -60 °C to room temp, (2)
H2SO4, 0 °C.
Scheme 5a
Figure 2. Model of compound 2 docked into the MAO-A
homology model. Residue numbers correspond to those from
the MAO-B X-ray structure.40,41 A Connolly molecular surface
is displayed for oxazolidinone 2 to illustrate the “aromatic
cage” formed by Y398, Y435, and the flavin cofactor. F199 is
the gatekeeper residue identified by Binda40 that joins or
separates the entrance and substrate cavities.
a Reagents: (a) buta-1,3-diynyl(trimethyl)silane, 2,6-lutidine,
CuI, room temp; (b) KOH, room temp.
Scheme 6a
20, which was converted to the cyanide 21 with sodium
cyanide in good overall yield.
Molecular Modeling
A docking model for MAO-A was constructed on the
basis of homology of MAO-A to MAO-B. Crystal struc-
tures for human mitochondrial monoamine oxidase B
(MAO-B) have been reported recently.40-42 The 1.7 Å
structure of MAO-B with isatin40 was used to interpret
the interaction of covalent and noncovalent inhibitors
of MAO-B. Given the ∼70% sequence identity between
MAO-B and MAO-A, a simple homology model for
MAO-A was built by substituting the MAO-B substrate
cavity residues Leu 171, Cys 172, Ile 199, and Tyr 326
with the MAO-A residues Ile 180, Asn 181, Phe 208,
and Ile 335, respectively. As noted by Binda et al.,41 the
different binding cavity residues in MAO-A lead to a
fusion of the substrate binding cavity with the entrance
cavity, thereby allowing MAO-A to bind larger sub-
strates.
Flexible docking studies of oxazolidinones to the
homology model of MAO-A were performed using the
QXP/FLO software.43 Residues in the substrate and
entrance cavities were allowed full conformational flex-
ibility in the docking studies. Figure 2 illustrates the
most favorable binding mode for 2 identified by QXP.
The triazolo group binds in the substrate cavity and fits
exquisitely into the aromatic cage formed by Tyr 398,
Tyr 435, and the flavin ring. The fluorophenyl moiety
is positioned in the large hydrophobic pocket linking the
substrate and entrance cavities. The mainly hydropho-
bic entrance cavity is occupied by the thiapyran sulfone
group. Note that the gatekeeper residue F199 rotates
to accommodate the longer size of this series of inhibi-
tors (relative to small substrates such as benzylamine
and dopamine).
a Reagents: (a) diphenyl phosphorochoridate, CH2Cl2/pyridine,
0 °C; (b) NaCN, DMF, 60 °C; (c) (1) oxalyl chloride, DMSO, CH2Cl2,
-50 °C, (2) DIEA, -40 to -20 °C; (d) CBr4, P(Ph)3, CH2Cl2, 0 °C
to room temp; (e) HPO(OEt)2, NEt3, 90 °C.
unreacted starting azide; elimination of HF instead of
phenylsulfinic acid was not observed.
Copper(I)-catalyzed ligation35,36 of buta-1,3-diynyl-
(trimethyl)silane37 with 4 gave 18 in 80% yield, which
was cleanly desilylated to the 4-ethynyltriazole 19
(Scheme 5). The alcohol 17 served as starting material
for further modifications at the 4 position on the triazole
moiety (Scheme 6). Swern oxidation gave aldehyde 22,
which was reacted with carbon tetrabromide/tri-
phenylphosphine38 to give the 1,1-dibromoalkene 23 in
good overall yield. 23 was reduced to the E-bromoalkene
24 with diethyl phosphite.39 Treatment of alcohol 17
with diphenyl phosphorochloridate gave phosphate ester

502 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Reck et al.
Table 1. SAR of Substituted Triazolo Oxazolidinones,
Compared to Unsubstituted Triazole and Acetamide Lead
S.a.a
MIC
S.p.b
MIC
H.inf.c MAO-Ad
MIC Ki
compd
R′
R′′ (µg/mL) (µg/mL) (µg/mL) (µM)
1
2
5
6
7
1
1
1
0.25
0.5
1
2
5.9
3.4
H
CH3
H
H
H
0.5
2
25
CH3 >64
64
>64
>64
8
32
2
64
1
2
4
>64
2
64
2
4.5
3.5
>200
102
0.5
COOtBu
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
>64
4
8
1
32
1
2
32
>64
2
32
16
16
>64
8
>64
2
10 CH2CH3
12 CH(CH3)2
13
14
15 Cl
16 Br
17 CH2OH
18 CCSiMe3
19 CCH
20 CH2OPO(OPh)2
21 CH2CN
22 CHO
4
F
H
0.25
8
1.6
3.0
16
Figure 3. Close-up view on the triazole ring of 2 docked into
the MAO-A homology model. The triazole ring is in van der
Waals contact with the flavin, Y435, and Y398. Three putative
hydrogen bonds are shown between the triazole N3 and the
Y188 OH, between the N172 NH2 group and the oxazolidinone
carbonyl oxygen, and between the Y435 OH and the oxazoli-
dinone ether oxygen. Note that the Connolly molecular surface
indicates that substitution of the triazole ring is not sterically
favorable, especially at the 4 position.
0.25
0.5
2
47
>200
>200
>100
>200
3.2
>100
>200
1
0.5
4
1
2
16
>64
8
23 CHdCBr2
24 CHdCHBr(E)
4
2
the corresponding methyloxime show only weak anti-
bacterial activity. Presumably the binding site does not
readily accommodate nonlinear substituents that occupy
space within the plane defined by the triazole ring
moiety. Even though we were not able to improve the
microbiological activity of 4-substituted triazoles sig-
nificantly relative to the unsubstituted triazole lead,
except in the 4-chlorotriazolo compound 15, we were
pleased to find an interesting SAR against MAO-A
within this series (Table 1). Increasing the bulk of
substitution at the 4 position reduces MAO-A activity.
This seems to be mainly a steric effect, with rising Ki
values observed in the order F < Cl < Br and H < CH3
< isopropyl < ethyl. Moreover, there seems to exist a
window of opportunity in 4-substituted triazoles where
MAO-A activity is abolished within the detection limit
of our assay and where potent antibacterial activity is
retained (compounds 10, 19, and 21). The 4-methyl-,
4-bromo-, and 4-ethynyltriazoles (5, 16, and 19) show
essentially the same microbiological potency as the
parent triazole 2, while showing significantly higher
MAO-A Ki values (25, 16, and >200 µM compared to
3.4 µM for the parent). The rather potent inhibition by
the tert-butyl ester 7 is difficult to explain. This com-
pound cannot bind to the homology model without
significant changes and must use a different binding
mode in its interaction with MAO-A. The MAO-A SAR
of the oxazolidinones listed in Table 1 can be largely
rationalized on the basis of the docking model shown
in Figures 2 and 3. The Connolly surface in Figure 3
suggests that 4-substituted triazoles are sterically
forbidden and require the oxazolidinone to adopt a
different binding mode. Further docking studies on
these 4-substituted triazoles suggest that most of these
analogues can still bind in the substrate cavity in a
different, presumably less favorable binding mode, with
a Methicillin-susceptible Staphylococcus aureus AP601055. b Pen-
icillin-susceptible Streptococcus pneumoniae AP671401. c Haemo-
philius influenzae ATCC51907. Minimum inhibitory concentration
(MIC): lowest drug concentration that reduced growth by 80% or
more.48 d Monoamine oxidase A Ki expressed as a mean of three
experiments.44
Results and Discussion
Oxazolidinones bearing a substituted 1,2,3-triazole
moiety were submitted for evaluation for antibacterial
activity (Table 1). 5-Substituted triazoles as exemplified
by the 5-methyltriazole 6 were generally inactive or only
marginally active. Several other 5-substituted triazole
derivatives, including the hydroxymethyl, chloromethyl,
carboxymethyl, and cyclopropyl derivatives were syn-
thesized, and these were found to show a lack of activity
very similar to that of 6 (results not shown). The best
compound within the 5-substituted series was the
fluoride 14 with an S. pneumoniae MIC of 8 µg/mL.
These results indicate that the loss of activity upon
5-substitution may be due to a steric effect.
However, in the case of 4-substituted triazoles it was
found that many compounds showed good antibacterial
activity. The best compounds had a methyl, a small
substituted methyl group in the 4 position (compounds
5 and 21), a halogen (compounds 13, 15, and 16), or an
ethynyl group (compound 19). These results suggest
that the effect of 4-substitution on the triazole moiety
on antibacterial activity is mostly steric, with only small
or linear substituents (substituent linked via an sp3 or
sp center) coming from the 4-position on the triazole
moiety tolerated in the ribosomal binding site. Linking
a substitutent at the 4-position via an sp2 center
(compounds 7 and 22-24) was detrimental for activity.
Consistent with this observation Phillips et al.26 have
found that a 4-acetyltriazole analogue of linezolid and

Substituted Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 503
reaction mixture was allowed to warm to room temperature
overnight. Solvent was removed under reduced pressure and
the residue was taken up in dichloromethane and purified by
chromatography on silica gel with acetone/hexanes (1:1 to 2:1)
to give 5 (2.04 g, 64%) as a colorless solid: mp 185 °C; MS
(ESP) m/z 407.09 (MH+); 1H NMR (DMSO-d6) (500 MHz) δ
2.24 (s, 3H), 2.97 (m, 2H), 3.32-3.38 (m, 2H), 3.89-3.92 (m,
3H), 4.25 (dd, 1H, J 9.1, 9.1 Hz), 4.77 (d, 2H, J 5.2 Hz), 5.13
(m, 1H), 5.84 (m, 1H), 7.30 (dd, 1H, J 1.9, 8.6 Hz), 7.41 (dd,
1H, J 8.6, 8.7 Hz), 7.47 (dd, 1H, J 1.9, 13.6 Hz), 7.89 (s, 1H).
Anal. (C18H19FN4O4S) C, H, N.
the oxazolidinone oxygens making hydrogen bonds to
the Y435 OH group and to the N172 NH2 group.
Conclusions
We report the synthesis and biological evaluation of
novel oxazolidinones bearing a 4-substituted triazole
moiety instead of the conventional acetamide function-
ality. Vinylsulfones and tosylhydrazone reagents were
found to provide good selective access into this com-
pound class, in addition to the copper(I)-catalyzed
ligation of azides with alkynes. We found that com-
pounds bearing a small substituent linked via an sp or
sp3 center to the 4 position of the triazole moiety were
potent antibacterials with good Gram-positive activity.
Many of these compounds had significantly higher
MAO-A Ki values than the unsubstituted triazole parent
or the acetamide equivalent, giving these types of
compounds a potential advantage in the search for
oxazolidinone drugs with a better safety profile. The
MAO-A SAR can largely be rationalized by docking
studies using an MAO-A/MAO-B homology model.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-methyl)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (6). A solution of 4 (300 mg, 0.82 mmol) and
5,6,7,8-tetrachloro-1,4-dihydro-2,10-dimethyl-1,4-ethenonaphth-
alene (0.78 g, 2.44 mmol) in 1,4-dioxane (10 mL) was heated
to reflux for 48 h. The solvent was removed under reduced
pressure and the residue was purified by chromatography on
silca gel with CH2Cl2/DMF (25:1), followed by crystallization
from DMF/CH2Cl2/hexanes, to give 6 (75 mg, 23%) (TLC, Rf
0.29, dichloromethane/DMF ) 20:1) as a colorless solid: mp
243 °C (5 was formed as a minor product, Rf 0.27, not isolated);
1
MS (ESP) m/z 407.09 (MH+); H NMR (DMSO-d6) (300 MHz)
δ 2.32 (s, 3H), 2.94 (m, 2H), 3.23-3.38 (m, 2H), 3.87-4.00 (m,
3H), 4.25 (m, 1H), 4.72 (m, 2H), 5.13 (m, 1H), 5.80 (m, 1H),
7.22-7.55 (m, 4H). Anal. Calcd for C18H19FN4O4S‚0.6H2O: C,
51.82; H, 4.88; N, 13.43. Found: C, 51.72; H, 4.38; N, 13.23.
Experimental Section
MAO-A Assay. The assay was carried out adapting the
method of Flaherty.44 Specific conditions were 100 µM of
substrate 4-(1-methyl-2-pyrryl)-1 methyl-1,2,3,6-tetrahydro-
pyridine, 82 nM human liver monoamine oxidase A,45 and 100
mM potassium phosphate buffer at pH 7.4 and 25 °C; total
substrate turnover was ∼10%. Inhibition was reversible and
competitive to the amine substrate. Ki values were fitted using
the model for MAO-A previously described.46
General Chemical Methods. All commercially available
solvents and reagents were used without further purification.
All moisture-sensitive reactions were carried out under a
nitrogen atmosphere in commercially available anhydrous
solvents. Column chromatography was performed on 230-400
mesh silica gel 60. Aluminum-backed sheets of silica gel 60
F254 (EM Science) were used for TLC. Melting points were
obtained with a Mel-TempII melting point apparatus from
Laboratory Devices, Inc. and are uncorrected. 1H NMR spectra
were recorded at 300 or 500 MHz. Chemical shifts are reported
in ppm (δ) relative to solvent. Mass spectrometry was per-
formed using a Micromass Quattro Micro mass spectrometer
(for ESP) and an Agilent 1100 MSD instrument (for APCI).
Elemental analyses were carried out by Quantitative Technol-
ogy, Inc., Whitehouse NJ.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (4). A so-
lution of 323 (7 g, 20.9 mmol) in dichloromethane (200 mL) was
treated dropwise at 0 °C with a solution of 3-chloroperbenzoic
acid (15.4 g, 70%, 62.9 mmol) in dichloromethane (100 mL).
The temperature was allowed to reach room temperature over
2 h, and the reaction mixture was stirred for an additional 30
min at room temperature. It was diluted with ethyl acetate
and washed with aqueous sodium thiosulfate solution and then
with aqueous sodium hydrogencarbonate solution and with
water, and the organic phase was dried over sodium sulfate.
Chromatography on silica gel with hexanes/acetone (3:2) gave
4 (6.75 g, 88%) as a colorless solid: mp 120 °C; [R]D -119° (c
1, acetonitrile); MS (ESP) m/z 367.1 (MH+); 1H NMR (DMSO-
d6) (500 MHz) δ 2.98 (m, 2H), 3.35-3.40 (m, 2H), 3.71 (dd,
1H, J 5.6, 13.6 Hz), 3.79 (dd, 1H, J 3.3, 13.6 Hz), 3.82 (dd, 1H,
J 6.0, 9.3 Hz), 3.93 (m, 2H), 4.17 (dd, 1H, J 9.2, 9.3 Hz), 4.93
(m, 1H), 5.84 (m, 1H), 7.37 (dd, 1H, J 8.7, 2.2 Hz), 7.42 (dd,
1H, J 8.6, 8.7 Hz), 7.54 (dd, 1H, J 13.7, 2.2 Hz).
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-t-butylcarboxy)-1,2,3-triazol-1-yl)-
methyl]oxazolidin-2-one (7). A solution of 4 (6.9 g, 18.83
mmol) and tert-butyl propiolate (4.75 g, 37.67 mmol) in dry
1,4-dioxane (15 mL) was heated to reflux for 12 h under
vigorous stirring. Ethyl acetate (30 mL) was added and the
resulting precipitate was collected by filtration, washed with
ethyl acetate, and dried to give 7 (5 g, 54%) as a colorless
solid: mp 226 °C; MS (ESP) m/z 493.24 (MH+); 1H NMR
(DMSO-d6) (500 MHz) δ 1.53 (s, 9H), 2.95 (m, 2H), 3.31 (m,
2H), 3.92 (m, 3H), 4.25 (dd, 1H), 4.87 (d, 2H), 5.18 (m, 1H),
5.82 (m, 1H), 7.31 (m, 1H), 7.39 (m, 1H), 7.40 (m, 1H), 8.70 (s,
1H). Anal. (C22H25FN4O6S) C, H, N.
(5S)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-(aminomethyl)oxazolidin-2-one (8). A
solution of 4 (3 g, 8.2 mmol) and triphenylphosphine (2.6 g,
9.9 mmol) in acetonitrile/water (10:1, 50 mL) was stirred
overnight with evolution of nitrogen. The reaction mixture was
applied onto a silica gel column and eluted with acetonitrile/
water (15:1 to 5:1) to give 8 (2.67 g, 96%) as a colorless solid:
[R]D -31° (c 1, DMSO); MS (ESP) m/z 341 (MH+); 1H NMR
(DMSO-d6) (300 MHz) δ 1.81 (brs, 2H), 2.81 (dd, 1H), 2.87 (dd,
1H), 2.98 (m, 2H), 3.30-3.38 (m, 2H), 3.89 (dd, 1H), 3.93 (m,
2H), 4.09 (dd, 1H), 4.65 (m, 1H), 5.84 (m, 1H), 7.37 (dd, 1H),
7.41 (dd, 1H), 7.54 (dd, 1H).
N′-[(1E)-1-(Dichloromethyl)propylidene]-4-methylben-
zenesulfonohydrazide (9b). A mixture of 1,1-dichlorobutan-
2-one (210 mg, 1.49 mmol) and 4-methylbenzenesulfonohy-
drazide (268 mg, 1.49 mmol) was treated with propionic acid
(3 mL) at 80 °C for 5 h and was then allowed to cool to room
temperature overnight. Hexanes (20 mL) were added and the
precipitate was filtered under nitrogen to yield 9b (100 mg,
22%) as a colorless solid: 1H NMR (DMSO-d6) (300 MHz) δ
1.21 (m, 3H), 2.46 (m, 5H), 6.19 (s, 1H), 7.36 (m, 2H), 7.83 (m,
3H).
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-ethyl)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one(10).8(85.5mg,0.25mmol),N′-[(1E)-1-(dichloro-
methyl)propylidene]4-methylbenzenesulfonohydrazide (9b) (10
mg, 0.32 mmol), and diisopropylethylamine (0.13 mL, 0.7
mmol) were reacted as described for 5. Chromatography on
silica gel with 5% methanol in dichloromethane gave 10 (71
mg, 72%) as a colorless solid: mp 137 °C; MS (APCI) m/z
421.30 (MH+); 1H NMR (DMSO-d6) (500 MHz) δ 1.17 (m, 3H),
2.60 (m, 2H), 2.97 (m, 2H), 3.57 (m, 2H), 3.90 (m, 3H), 4.25
(m, 1H), 4.76 (d, 2H), 5.15 (m, 1H), 5.83 (s, 1H), 7.28 (d, 2H),
7.42 (m, 2H), 7.90 (s, 1H). Anal. (C19H21FN4O4S) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-methyl)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (5). A partial solution/suspension of 8 (2.67
g, 7.8 mmol) in dry methanol (100 mL) containing diisopro-
pylethylamine (5.4 mL, 31 mmol) was treated with R,R-
dichloroacetone tosylhydrazone29 (2.9 g, 9.8 mmol) at 0 °C. The

504 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2
Reck et al.
1-Chloro-1-ethenesulfonyl Chloride (11d). A stirred
solution of 1,2-dichloroethanesulfonyl chloride47 (14.54 g, 73.62
mmol) in dry ether (140 mL) was treated at -60 to -50 °C
under an atmosphere of nitrogen with 2,6-lutidine (10.30 mL,
88.34 mmol). The stirred reaction mixture was allowed to
warm to room temperature, cooled to 0 °C, and then treated
dropwise with dilute aqueous sulfuric acid (1%, 50 mL). The
ethereal phase was separated, washed with dilute aqueous
sulfuric acid (1%, 2 × 60 mL) and brine (3 × 60 mL), dried
over magnesium sulfate, and concentrated under reduced
pressure (60 mmHg) to give an oil that was purified by
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-bromo)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (16). 4 (1.5 g, 4.1 mmol) and 1-bromo-1-
ethenesulfonyl chloride32 (1.8 g, 8.8 mmol) were heated to 90
°C for 1 h under stirring in a pressure tube. The reaction
mixture was cooled to room temperature, diluted with dichlo-
romethane (10 mL), and applied onto a silica gel column.
Elution with hexanes/acetone (2:1 to 1:1) gave 16 (1.46 g, 76%),
as a colorless solid: mp 178 °C; MS (ESP) m/z 471/473 (MH+);
1H NMR (DMSO-d6) (500 MHz) δ 2.98 (m, 2H), 3.34-3.38 (m,
2H), 3.92-3.96 (m, 3H), 4.27 (dd, 1H, J 9.2, 9.2 Hz), 4.87 (d,
2H, J 5.2 Hz), 5.18 (m, 1H), 5.84 (m, 1H), 7.31 (dd, 1H, J 2.2,
8.6 Hz), 7.42 (dd, 1H, J 8.6, 8.8 Hz), 7.47 (dd, 1H, J 2.2, 13.7
Hz), 8.49 (s, 1H). Anal. (C17H16BrFN4O4S) C, H, N.
1
distillation to give 7.2 g (61%) of 11d: bp 26 °C/2 mmHg; H
NMR (CDCl3) (300 MHz) δ 6.22 (d, 1H, J 3.8 Hz), 6.70 (d, 1H,
J 3.8 Hz).
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-hydroxymethyl)-1,2,3-triazol-1-yl)-
methyl]oxazolidin-2-one (17). A suspension of 4 (15 g, 41
mmol) in 2-(phenylsulfonyl)-2-propene-1-ol31 (12 g, 61 mmol)
and N-methylpyrolidone (2 mL) was heated to 90 °C under
stirring. After 30 min, more NMP (2 mL) was added and the
mixture was stirred for another 3.5 h. The partially solidified
reaction mixture was taken up in DMF, filtered, and then
concentrated under reduced pressure. Chromatography on
silica gel with dichloromethane/methanol (16:1) gave 17 (TLC,
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-isopropyl)-1,2,3-triazol-1-yl)methyl]-
oxazolidin-2-one (12). 4 (0.5 g, 1.36 mmol) and (2-methyl-
1-methylenepropyl)phenylsulfane dioxide (0.72 g, 3.42 mmol)30
were heated in a pressure tube to 90 °C for 5 h. The reaction
mixture was diluted with dichloromethane, loaded onto a silica
gel column, and eluted with hexanes/acetone (1:1). Fractions
containing product were pooled, solvent was evaporated in
vacuo, and precipitation from dichloromethane with hexanes
gave 12 (214 mg, 36%) as a colorless solid: mp 191 °C; MS
(ESP) m/z 435.16 (MH+); 1H NMR (DMSO-d6) (500 MHz) δ
1.20 (d, 6H, J 6.9 Hz), 2.93-3.00 (m, 3H), 3.31-3.37(m, 2H),
3.89-3.94 (m, 3H), 4.26 (dd, 1H, J 9.1, 9.1 Hz), 4.76 (d, 2H, J
4.8 Hz), 5.16 (m, 1H), 5.83 (m, 1H), 7.27 (dd, 1H, J 1.9, 8.6
Hz), 7.40 (dd, 1H, J 8.6, 8.8 Hz), 7.43 (dd, 1H, J 1.9, 13.7 Hz),
7.89 (s, 1H). Anal. (C20H23FN4O4S) C, H, N.
Rf
0.3, chloroform/methanol ) 6:1) (8.64 g, 50%) as a colorless
solid: mp 168 °C (the corresponding 5-hydroxymethyl regioi-
somer was separated during chromatography and presented
a minor product, TLC, Rf 0.4); MS (ESP) m/z 422.94 (MH+);
1H NMR (DMSO-d6) (500 MHz) δ 2.98 (m, 2H), 3.28-3.36 (m,
2H), 3.91-3.94 (m, 3H), 4.27 (dd, 1H, J 9.1, 9.1 Hz), 4.54 (d,
2H, J 5.7 Hz), 4.82 (d, 2H, J 5.4 Hz), 5.16 (m, 1H), 5.23 (dd,
1H, J 5.7, 5.7 Hz), 5.84 (m, 1H), 7.30 (dd, 1H, J 8.6, 2.2 Hz),
7.41 (dd, 1H, J 8.6, 8.8 Hz), 7.50 (dd, 1H, J 13.7, 2.2 Hz), 8.03
(s, 1H). Anal. (C18H19FN4O5S) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-fluoro)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (13) and (5R)-3-[4-(1,1-Dioxo-3,6-dihydro-
2H-thiopyran-4-yl)-3-fluorophenyl]-5-[(5-fluoro)-1,2,3-
triazol-1-yl)methyl]oxazolidin-2-one (14). 4 (0.7 g, 1.9
mmol) and (1-fluoroethenyl)phenylsulfane dioxide (0.7 g, 3.8
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-((2-trimethylsilyl)ethynyl)-1,2,3-tria-
zol-1-yl)methyl]oxazolidin-2-one (18). A solution of 4 (11
g, 30 mmol), buta-1,3-diynyl(trimethyl)silane (5.8 g, 47.5
mmol),37 2,6-lutidine (3.53 g, 33 mmol), and copper iodide (571
mg, 10 mmol%) in dry acetonitrile (200 mL) was stirred at
room temperature for 12 h. The mixture was poured into water
(250 mL) and stirred for 10 min. The resulting precipitate was
collected by filtration, washed with water and diethyl ether
(3 × 50 mL), and dried in vacuo to give 18 (11.8 g, 80%) as a
34
mmol) were mixted in toluene (5 mL) and heated to reflux
under stirring for 2 days. The reaction mixture was cooled to
room temperature, diluted with dichloromethane, washed with
phosphate buffer (pH 7), and dried over sodium sulfate.
Chromatography on silica gel with hexanes/acetone (1:1) gave
13 (Rf ∼0.25, TLC, hexanes/acetone, 1:1) (28 mg, 4%) and 14
(Rf ∼0.18, TLC, hexanes/acetone, 1:1) (188 mg, 24%) as
colorless solids.
1
colorless solid: mp 198 °C; MS (ESP) m/z 489.24 (MH+); H
1
13: mp 139 °C; MS (ESP) m/z 409.19 (M - H-); H NMR
NMR (DMSO-d6) (500 MHz) δ 0.01 (s, 9H), 2.96 (m, 2H), 3.34
(m, 2H), 3.91 (m, 3H), 4.28 (dd, 1H), 4.85 (m, 2H), 5.20 (m,
1H), 5.81 (m, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 7.43 (m, 1H),
8.51 (s, 1H). Anal. (C22H25FN4O4SSi) C, H, N.
(DMSO-d6) (500 MHz) δ 2.98 (m, 2H), 3.32-3.39 (m, 2H),
3.91-3.95 (m, 3H), 4.27 (dd, 1H, J 9.2, 9.2 Hz), 4.81 (d, 2H, J
5.3 Hz), 5.17 (m, 1H), 5.84 (m, 1H), 7.32 (dd, 1H, J 2.1, 8.6
Hz), 7.42 (dd, 1H, J 8.6, 8.8 Hz), 7.48 (dd, 1H, J 2.1, 13.7 Hz),
8.22 (d, 1H, J 7.7 Hz). Anal. Calcd for C17H16F2N4O4S: C,
49.75; H, 3.93; N, 13.65. Found: C, 49.41; H, 3.58; N, 13.17.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-ethynyl)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (19). 18 (11.5 g, 23.5 mmol) was dissolved in
methanol (100 mL), potassium hydroxide (1 M, 36 mL) was
added, and the mixture was stirred at room temperature for
4 h. Aqueous HCl (2 M, 24 mL) was added, methanol was
evaporated, and the residue was extracted with dichlo-
romethane. The organic phase was collected and concentrated,
the residue was dissolved in a mixture of 10% methanol in
dichloromethane, followed by addition of hexanes, and the
resulting precipitate was collected by filtration to give 19 (8.8
g, 90%) as a colorless solid: mp 244 °C; MS (ESP) m/z 417.24
1
14: mp >210 °C (dec); MS (ESP) m/z 409.25 (M - H-); H
NMR (DMSO-d6) (500 MHz) δ 2.98 (m, 2H), 3.32-3.38 (m, 2H),
3.93 (m, 2H), 3.96 (dd, 1H, J 5.8, 9.5 Hz), 4.30 (dd, 1H, J 9.2,
9.5 Hz), 4.78 (m, 2H), 5.17 (m, 1H), 5.84 (m, 1H), 7.29 (dd,
1H, J 2.1, 8.6 Hz), 7.41 (dd, 1H, J 8.6, 8.8 Hz), 7.47 (dd, 1H,
J 2.1, 13.7 Hz), 7.71 (d, 1H, J 7.4 Hz). Anal. Calcd for
C17H16F2N4O4S: C, 49.75; H, 3.93; N, 13.65. Found: C, 49.57;
H, 3.64; N, 13.20.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-chloro)-1,2,3-triazol-1-yl)methyl]ox-
azolidin-2-one (15). 4 (1.0 g, 2.7 mmol) and 1-chloro-1-
ethenesulfonyl chloride (11d) (1.1 g, 6.8 mmol) were heated
to 90 °C for 1 h under stirring in a pressure tube. The reaction
mixture was cooled to room temperature, diluted with dichlo-
romethane (10 mL), and applied onto a silica gel column.
Elution with hexanes/acetone (1.5:1) gave 15 (0.745 g, 64%)
as a colorless solid: mp 180 °C; MS (ESP) m/z 427 (MH+); 1H
NMR (DMSO-d6) (300 MHz) δ 2.96 (m, 2H), 3.29-3.43 (m, 2H),
3.90-3.95 (m, 3H), 4.25 (dd, 1H, J 9.2, 9.2 Hz), 4.83 (d, 2H, J
5.3 Hz), 5.16 (m, 1H), 5.82 (m, 1H), 7.29 (dd, 1H, J 2.1, 8.6
Hz), 7.40 (dd, 1H, J 8.6, 8.7 Hz), 7.45 (dd, 1H, J 2.1, 13.8 Hz),
8.45 (s, 1H). Anal. (C17H16ClFN4O4S) C, H, N.
1
(MH+); H NMR (DMSO-d6) (500 MHz) δ 2.96 (m, 2H), 3.34
(m, 2H), 3.92 (m, 3H), 4.22 (dd, 1H), 4.38 (s, 1H), 4.82 (d, 2H),
5.18 (m, 1H), 5.81 (m, 1H), 7.22 (m, 1H), 7.38 (m, 1H) 7.42 (m,
1H), 8.51 (s, 1H). Anal. (C19H17FN4O4S‚0.6H2O) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-[[(diphenoxyphosphinyl)oxy]methyl]-
1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (20). A partial
solution/suspension of 17 (0.66 g, 1.6 mmol) in dichloromethane/
pyridine (10 mL, 2:1) was treated dropwise with a solution of
diphenyl phosphorochloridate (0.33 mL, 1.6 mmol) in dichlo-
romethane (2 mL) at 0 °C. After 30 min an additional 60 µL
(0.29 mmol) of diphenyl phophorochloridate was added via
syringe and the mixture was stirred for another hour. It was

Substituted Triazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 505
quenched with potassium phosphate buffer (pH 7) and diluted
with ethyl acetate. The organic phase was washed with water
and dried over sodium sulfate. Chromatography on silica gel
with acetone/hexanes (1:1) gave 20 (0.82 g (80%) as a hard
foam: MS (ESP) m/z 655.05 (MH+); 1H NMR (DMSO-d6) (500
MHz) δ 2.94 (m, 2H), 3.29-3.34 (m, 2H), 3.90 (m, 3H), 4.12 (s,
2H), 4.24 (dd, 1H, J 9.1, 9.1 Hz), 4.83 (m, 2H), 5.14 (m, 1H),
5.39 (m, 2H), 5.80 (m, 1H), 7.19-7.30 (m, 7H), 7.35-7.47 (m,
6H), 8.30 (s, 1H). Anal. (C30H28FN4O8PS) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-cyanomethyl)-1,2,3-triazol-1-ylmethyl]-
oxazolidin-2-one (21). Sodium cyanide (0.22 g, 4.5 mmol) was
added to a solution of 20 (0.5 g, 0.76 mmol) in DMF (10 mL),
and the mixture was heated to 60 °C for 1.5 h. It was diluted
with ethyl acetate, washed with potassium phosphate buffer
(pH 7) and with water, and dried over sodium sulfate.
Chromatography on silica gel with acetone/hexanes (1:1) gave
21 (236 mg, 72%) as a colorless solid: mp 184 °C; MS (ESP)
m/z 432.07 (MH+); 1H NMR (DMSO-d6) (500 MHz) δ 2.94 (m,
2H), 3.30-3.34 (m, 2H), 3.88-3.90 (m, 3H), 4.12 (s, 2H), 4.24
(dd, 1H, J 9.1, 9.1 Hz), 4.82 (d, 2H, J 5.3 Hz), 5.14 (m, 1H).
Anal. (C19H18FN5O4S) C, H, N.
3.04 (m, 2H), 3.23-3.28 (m, 2H), 3.81 (brs, 2H), 3.87 (dd, 1H,
J 5.7, 9.6 Hz), 4.22 (dd, 1H, J 9.3, 9.6 Hz), 4.72 (dd, 1H, J 6.2,
15.0 Hz), 4.78 (dd, 1H, J 3.7, 15.0 Hz), 5.10 (m, 1H), 5.82 (m,
1H), 7.09 (d, 1H, J 14.5 Hz), 7.15 (d, 1H, J 14.5 Hz), 7.20 (dd,
1H, J 2.2, 8.5 Hz), 7.33 (dd, 1H, J 8.5, 8.6 Hz), 7.37 (dd, 1H,
J 2.2, 13.4 Hz), 7.97 (s, 1H). Anal. (C19H18BrFN4O4S) C, H, N.
Acknowledgment. The authors thank Dr. Camil
Joubran, Analytical Chemistry Department of Astra-
Zeneca R&D Boston, for performing NOE NMR experi-
ments; Organix, Inc., Woburn, MA, for the synthesis of
some intermediates and vinylsulfone reagents; Adam
Mondello and Jeanette Jones, Microbiology Department,
AstraZeneca R&D Boston, for the determination of
MICs; and Tory Nash, Biochemistry Department, As-
traZeneca R&D Boston, for the determination of MAO-A
Ki values.
Supporting Information Available: Elemental analysis
results. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-carboxaldehyde-1,2,3-triazol-1-yl)-
methyl]oxazolidin-2-one (22). A solution of oxalyl chloride
(1.36 mL, 15.6 mmol) in dichloromethane (30 mL) was treated
dropwise with a solution of DMSO (1.42 mL, 20 mmol) in
dichloromethane (30 mL) at -50 °C. After 10 min, a solution
of 17 (5 g, 11.8 mmol) in N-methylpyrolidone (25 mL) was
diluted with dichloromethane (25 mL) and added dropwise.
The mixture was stirred vigorously for 1 h, then treated
dropwise with N,N-diisopropylethylamine (10 mL, 57.4 mmol),
warmed to -40 °C, and stirred for another hour. The reaction
mixture allowed to warm to -20 °C slowly and held at this
temperature overnight. The resulting homogeneous solution
was directly applied onto a silica gel column and eluted with
hexanes/acetone (1:1 to 1:2). Fractions containing product were
pooled and concentrated under reduced pressure. The product
was further purified by precipitation from acetone (100 mL)
with hexanes (700 mL) to give 22 (4.2 g, 84%) as a colorless
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solid: mp 146 °C; MS (ESP) m/z 419.29 (M - H-); H NMR
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(DMSO-d6) (500 MHz) δ 2.98 (m, 2H), 3.29-3.38 (m, 2H), 3.93
(s, 2H), 3.97 (dd, 1H, J 5.8, 9.5 Hz), 4.29 (dd, 1H, J 9.2, 9.5
Hz), 4.94 (d, 2H, J 5.4 Hz), 5.22 (m, 1H), 5.84 (m, 1H), 7.32
(dd, 1H, J 2.2, 8.6 Hz), 7.42 (dd, 1H, J 8.6, 8.8 Hz), 7.48 (dd,
1H, J 2.2, 13.7), 8.95 (s, 1H), 10.05 (s, 1H). Anal. (C18H17-
FN4O5S) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-(2,2-dibromoethenyl)-1,2,3-triazol-1-
yl)methyl]oxazolidin-2-one (23). To a mixture of 22 (5 g,
11.9 mmol) and carbon tetrabromide (4.34 g, 13.1 mmol) in
dichloromethane (100 mL) was added triphenylphosphine (6.55
g, 25 mmol) at 0 °C. The reaction mixture was stirred for 30
min at 0 °C and then for 1 h at room temperature. Chroma-
tography on silica gel with toluene/ethanol (10:1 to 7:1) gave
23 (6.1 g, 89%) as an off-white solid: mp 188 °C; MS (ESP)
m/z 575, 577, 579 (MH+); 1H NMR (DMSO-d6) (500 MHz) δ
2.98 (m, 2H), 3.31-3.40 (m, 2H), 3.93-3.96 (m, 3H), 4.28 (dd,
1H, J 9.1, 9.1 Hz), 4.90 (d, 2H, J 5.2 Hz), 5.21 (m, 1H), 5.85
(m, 1H), 7.31 (dd, 1H, J 2.2, 8.6 Hz), 7.42 (dd, 1H, J 8.6, 8.8
Hz), 7.47 (dd, 1H, J 2.2, 13.7 Hz), 7.80 (s, 1H), 8.68 (s, 1H).
Anal. (C19H17Br2FN4O4S) C, H, N.
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-
fluorophenyl]-5-[(4-((E)-2-bromoethenyl)-1,2,3-triazol-1-
yl)methyl]oxazolidin-2-one (24). A mixture of 23 (0.4 g, 0.69
mmol), diethyl phosphite (0.36 mL, 2.79 mmol), and triethyl-
amine (0.195 mL, 1.39 mmol) in ethanol (2 mL) was heated at
90 °C for 5 h under vigorous stirring. The reaction mixture
was cooled to room temperature, diluted with dichloromethane,
washed with potassium phosphate buffer (pH 7), and dried
over sodium sulfate. Chromatography on silica gel with
dichloromethane/DMF (50:1 to 40:1) gave 24 (151 mg, 44%)
as a colorless amorphous solid: MS (ESP) m/z 537.7/539.9
(16) Jones, R. N.; Della-Latta, P.; Lee, L. V.; Biedenbach, D. J.
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