Substituent effects on the antibacterial activity of nitrogen-carbon- linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis

Article abstract of DOI:10.1021/jm990373e

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram- negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 μg/mL and M. catarrhalis = 2 μg/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3- triazole congeners 28, 50, and 90 had S. aureus MICs ≤ 0.5-1 μg/mL and H. influenzae and M. catarrhalis MICs = 2-4 μg/mL. These analogues are also very effective versus S. aureus and S. pneumoniae in mouse models of human infection with ED₅₀s in the range of 1.2-1.9 mg/kg versus 2.8-4.0 mg/kg for the eperezolid (1) control.

Full text of DOI:10.1021/jm990373e

J . Med. Chem. 2000, 43, 953-970
953
Su bstitu en t Effects on th e An tiba cter ia l Activity of Nitr ogen -Ca r bon -Lin k ed
(Azolylp h en yl)oxa zolid in on es w ith Exp a n d ed Activity Aga in st th e F a stid iou s
Gr a m -Nega tive Or ga n ism s Ha em oph ilu s in flu en za e a n d Mor a xella ca ta r r h a lis
Michael J . Genin,*,† Debra A. Allwine,† David J . Anderson,† Michael R. Barbachyn,† D. Edward Emmert,†
Stuart A. Garmon,† David R. Graber,† Kevin C. Grega,† J ackson B. Hester,† Douglas K. Hutchinson,§
J oel Morris,† Robert J . Reischer,† Charles W. Ford,‡ Gary E. Zurenko,‡ J udith C. Hamel,‡ Ronda D. Schaadt,‡
Douglas Stapert,‡ and Betty H. Yagi‡
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001
Received J uly 19, 1999
A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has
been prepared in an effort to expand the spectrum of activity of this class of antibiotics to
include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties
have been used to replace the morpholine ring of linezolid (2). These changes resulted in the
preparation of compounds with good activity against the fastidious Gram-negative organisms
Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and
the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae ) 4 µg/mL and M. catarr-
halis ) 2 µg/mL. Various substituents were also placed on the azole moieties in order to study
their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity
were observed for many analogues that cannot be rationalized solely on the basis of sterics
and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly
on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime,
and cyano azoles generally led to dramatic improvements in activity against both Gram-positive
and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester,
amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in
antibacterial activity. The placement of a cyano moiety on the azole often generates analogues
with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole,
4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus
MICs e 0.5-1 µg/mL and H. influenzae and M. catarrhalis MICs ) 2-4 µg/mL. These analogues
are also very effective versus S. aureus and S. pneumoniae in mouse models of human infection
with ED50s in the range of 1.2-1.9 mg/kg versus 2.8-4.0 mg/kg for the eperezolid (1) control.
In tr od u ction
positive organisms including MRSA, MRSE, and VRE.13
They have been shown to selectively and uniquely bind
to the 50S ribosomal subunit and inhibit bacterial
translation at the initiation phase of protein synthe-
sis.14,15 In addition, single-step selection studies dem-
onstrated that eperezolid- and linezolid-resistant mu-
tants develop with a very low spontaneous mutation
frequency of <10-9 among selected staphylococcal bac-
teria.16 Furthermore, evidence for the rapid develop-
ment of bacterial resistance to both compounds could
not be found via serial passage studies using spiral drug
concentration gradient plates.17 Recently, phase III
clinical trials with linezolid (PNU-100766) for the treat-
ment of Gram-positive infections have been successfully
completed.
Multi-drug-resistant Gram-positive bacterial patho-
gens1-3 including methicillin-resistant Staphylococ-
cus aureus (MRSA)4 and Staphylococcus epidermidis
(MRSE),4 vancomycin-resistant enterococci (VRE),5,6
and penicillin- and cephalosporin-resistant streptococci7
have become a serious problem in hospitals and the
community. Particularly alarming is the emergence of
staphylococcal strains with reduced susceptibility to
vancomycin, the so-called vancomycin/glycopeptide in-
termediate strains (VISA or GISA).8-11 More recently,
a multinational team reported high rates of resistance
among aerobic Gram-negative bacilli in European in-
tensive care units.14 Thus, the search for novel potent
broad-spectrum antibacterial agents is being fervently
pursued by pharmaceutical houses worldwide.
We have been interested in expanding the spectrum
of activity of the oxazolidinones to include the fastidious
Gram-negative bacteria Haemophilus influenzae and
Moraxella catarrhalis, which are key organisms in cases
of community acquired pneumonia (CAP) and otitis
media. Linezolid exhibits only modest in vitro activity
against these organisms (MIC90 ) 16 µg/mL). In our
efforts to improve the spectrum of activity, the (azolyl-
phenyl)oxazolidinone subclass has been discovered
wherein the morpholine ring of linezolid has been
The totally synthetic oxazolidinones typified by ep-
erezolid (1) and linezolid (2) are one such class of
antibacterial agents with potent activity against Gram-
* To whom correspondence should be addressed. Tel: 616-833-9869
or 4000. Fax: 616-833-2516. E-mail: michael.j.genin@am.pnu.com.
† Combinatorial and Medicinal Chemistry Research.
‡ Infectious Diseases Research.
§ Current address: Abbott Laboratories, One Abbott Park Rd.,
Abbott Park, IL 60064.
10.1021/jm990373e CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/17/2000

954 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
Sch em e 1a
a
Reagents: (a) pyrrole, NaH, THF, 66%; or pyrazole, K2CO3, DMSO, 90 °C, 87%; or imidazole, K2CO3, DMSO, 90 °C, 92%; or 1,2,3-
triazole, K2HPO4, DMSO, 90 °C, 50% 1H-isomer + 43% 2H-isomer; or 1,2,4-triazole, K2HPO4, DMSO, 90 °C, 72% 1H-isomer; or tetrazole,
NEt3, CH3CN, 10% 2H-isomer + 4% 1H-isomer; (b) H2, 5% Pt/S/C, THF; or H2, RaNi, EtOAc/MeOH; or H2, 10% Pd/C, THF; (c) benzyl
chloroformate, NaHCO3, THF, rt, 37-92% for steps b + c; (d) (i) LiHMDS, THF -78 °C, (ii) R-(-)-glycidyl butyrate, -78 °C-rt, 48-85%;
(e) MsCl, NEt3, CH2Cl2; (f) NaN3, DMF, 65 °C; (g) H2, Pd/C, THF/MeOH; (h) Ac2O, pyridine, 0 °C-rt, 47-66% for steps e-h.
replaced with various five-membered nitrogen-contain-
ing heterocycles (azoles). Some of these analogues have
interesting levels of antibacterial activity. In particular,
the pyrrole 3 and the 1H-1,2,3-triazole 6 analogues have
excellent Gram-positive activity (MICs < 0.5-1 µg/mL),
vide infra. More interesting, however, was their good
activity against H. influenzae and M. catarrhalis
(MICs ) 2-4 µg/mL). In an effort to further increase
the activity of the azolylphenyl class of oxazolidinones,
we have explored the effects of various substituents on
the azole rings. Previously we reported the discovery of
the 3-cyanopyrrole and 4-cyanopyrazole analogues
(PNU-171933 and PNU-172576) which have S. aureus
MICs e 0.5 µg/mL and H. influenzae and M. catarrhalis
MICs ) 2-4 µg/mL.18 These analogues also exhibit
excellent pharmacokinetics and in vivo activity.18 We
now wish to report a more extensive survey of this class
in which numerous pyrrole, pyrazole, imidazole, triazole,
and tetrazole analogues have been synthesized and
tested for antibacterial activity.
the resulting aniline gave intermediates 14a -g. Depro-
tonation with base followed by treatment with (R)-(-)-
glycidyl butyrate afforded oxazolidinones 15a -g.19 The
hydroxymethyl side chain was then elaborated to the
final acetamide analogues 3-10 via standard transfor-
mations. The synthesis of the pyrrole, pyrazole, imida-
zole, and 1H-1,2,4-triazole derivatives 3-5 and 9 pro-
ceeded smoothly. Preparation of the 1H-1,2,3-triazole
analogue 6 and the 2H-1,2,3-triazole analogue 7 was
made possible by the formation of both 1H- and 2H-
regioisomers in the reaction between 1,2,3-triazole and
3,4-difluoronitrobenzene.
Also shown in Scheme 1, treatment of an acetonitrile
solution of 3,4-difluoronitrobenzene with tetrazole in the
presence of triethylamine afforded in low yield a mixture
of regioisomers, which were separable. The major 2H-
isomer 13g was taken on to the target 2H-tetrazole
analogue 10. The minor 1H-isomer adduct was not
available in sufficient quantity for preparation of the
1H-tetrazole analogue 11 via this route. Thus an
alternate approach was used to prepare this compound
(Scheme 2). This route involved the preparation of the
aniline 20, which served as a key intermediate in the
synthesis of 11 and numerous other derivatives. Reac-
tion of 12 with benzylamine followed by bis-protection
afforded 17. Oxazolidinone ring formation and side
chain elaboration gave the bis-protected aniline 19,
which was deprotected to afford 20. Reaction of 20 with
triethyl orthoformate and sodium azide afforded the
desired tetrazole analogue 11 directly.20,21
The synthesis of the 4H-1,2,4-triazole analogue 9 is
also shown in Scheme 2. Reaction of 20 with 1,1-
thiocarbonyldi-2(1H)-pyridone22 gave an excellent yield
of the isothiocyanate 21 which was treated with formic
hydrazide to give the thiosemicarbazide 22.23 Cycliza-
tion of 22 in aqueous base gave the 2-mercaptotriazole
intermediate 23.23 Treatment of this material with nitric
acid afforded the desired analogue 9.24
Su bstitu ted Azole An a logu es. 3-Su bstitu ted P yr -
r ole An a logu es: Substituted pyrrole analogues were
synthesized as shown in Scheme 3. The aniline 20 was
condensed with dimethoxytetrahydrofurancarboxalde-
hyde25 24 to yield the 3-formylpyrrole 25 which was
exploited for the preparation of 26, 27, 29, and 31-35
via standard transformations. Dehydration of the oxime
26 with triphenylphosphine in a mixture of acetonitrile/
Ch em istr y
Un su bstitu ted Azole An a logu es. The synthesis of
the unsubstituted azole analogues 3-8 and 10 is
outlined in Scheme 1. The general preparation involved
nucleophilic aromatic substitution reaction between the
requisite azole and 3,4-difluoronitrobenzene (12) to give
the 3-fluoro-4-azolylnitrobenzene intermediates 13a -
g. Reduction of the nitro group and Cbz protection of

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 955
Sch em e 2a
Sch em e 3a
a
Reagents: (a) 20, HOAc, reflux, 85%; (b) NH2OH or NH2OMe,
MeOH/CH2Cl2, K2CO3, 63-94% E/ Z mixture; (c) NaBH4, CH2Cl2/
MeOH, 84%; (d) NaCN, MnO2, HOAc, MeCN/MeOH, 71%; (e)
PPh3, CH3CN/CCl4, 72%; (f) NH3/MeOH, KCN, 50 °C, 20%; (g) (i-
PrO)2POCH2CO2Et, t-BuOK, -78 °C-rt, 83%; (h) CuCl, NaBH4,
0 °C-rt, 99%; (i) LiBH4, THF, 39%; (j) (i) MsCl, NEt3, CH2Cl2, (ii)
CH3SO2NH2, NaH, DMF, 26%; (k) K2CO3, DMSO, 50 °C, 98%; (l)
same steps as in Scheme 1, 19%; (m) NaBH4, MeOH, 72%.
a
Reagents: (a) BnNH2, DIEA, CH3CN, 90 °C, 84%; (b) H2, 5%
Pt/C, THF; (c) N,N-dimethylaniline, benzyl chloroformate, THF,
0 °C-rt, 72% for steps b + c; (d) (i) n-BuLi, THF, -78 °C, (ii) R-
(-)-glycidyl butyrate, -78 °C-rt, 77%; (e) MsCl, NEt3, CH2Cl2;
(f) potassium phthalimide, CH3CN, 95 °C, 93% for steps e + f; (g)
hydrazine hydrate, MeOH, 80 °C, 99%; (h) Ac2O, pyridine, 0 °C-
rt, 89%; (i) H2, 10% Pd/C, EtOH, 78%; (j) HC(OEt)3, NaN3, HOAc,
reflux, 47%; (k) 1,1-thiocarbonyldi-2(1H)-pyridone, CH2Cl2, 0 °C,
94%; (l) formic hydrazide, THF, 70 °C, 91%; (m) KOH, H2O, 98%;
(n) 20% HNO3, steam bath, NH4OH, 77%.
3-Su bstitu ted P yr a zole An a logu es: The (3-ami-
nopyrazolylphenyl)oxazolidinone 66 was targeted as a
key intermediate in this series. In addition to the usual
N-acylation, N-sulfonylation, and N-alkylation chemis-
try, we anticipated that the 3-amino derivative would
allow access to the 3-cyano analogue 71 via Sandmeyer
chemistry.31 Thus, the Boc-protected (3-aminopyra-
zolylphenyl)oxazolidinone 65 was prepared as outlined
in Scheme 5. Removal of the Boc group and functional
group manipulation gave the analogues 66-71. The
trifluoromethyl congener 64 was synthesized in a simi-
lar fashion (Scheme 5).
CCl4 yielded the 3-cyano analogue 28.26 The aldehyde
25 was oxidized to the ester 30 with manganese(IV)
oxide according to the method of Corey and co-workers.27
Analogues 38-41 were synthesized from 3-acetylpyrrole
36 and 12 as shown.
It was anticipated that the arylhydrazine 72 would
be a useful intermediate in azole synthesis. This mate-
rial was prepared from the aniline 20 as shown in
Scheme 6. Diazotization followed by reduction of the
diazonium species afforded the arylhydrazine 72.32
Condensation of 72 with acetylacetaldehyde dimethyl
acetal proceeded to give the 3- and 5-methylpyrazole
analogues 73 and 74 as a 2:1 mixture (Scheme 6).33 The
hydrazine 72 was also utilized in the regiochemical
synthesis of the (3-hydroxypyrazolylphenyl)oxazol-
idinone analogue 77. The known ethoxyacryloyl chloride
(75)34 was reacted with 73 to yield the key acylhydra-
zine intermediate 76. This material was cyclized in HCl
to afford the desired analogue 77,35 which was converted
to the acetoxy and methoxy analogues 78 and 79.
4-Su bstitu ted P yr a zole An a logu es: Several 4-sub-
stituted pyrazole analogues were synthesized utilizing
the ethyl 4-pyrazolecarboxylate analogue 47. This mate-
rial was prepared in a regioselective manner as outlined
in Scheme 4. The arylhydrazine 42 was synthesized and
condensed with the known (ethoxycarbonyl)malondial-
dehyde (43)28 to give the ethyl 4-pyrazolecarboxylate
44.29 This material was then converted to 47 employing
the azide intermediate 46 for the introduction of the
acetylaminomethyl side chain. Ester 47 was further
converted to 48-50.
Another approach to 4-substituted pyrazoles wherein
the 4-iodopyrazole 54 serves as a key intermediate was
investigated. Thus, 54 was prepared in several steps as
outlined in Scheme 4. Palladium-mediated carboxyl-
ation of 54 yielded an intermediate acid, which was
converted to 55 via Curtius rearrangement.30 This
material was then deprotected and acylated to give 56.
The intermediate 52 was also used to prepare the
terminal acetylene derivative 58 as shown.
Im id a zole An a logu es: The synthesis of the imida-
zole analogues of interest is outlined in Scheme 7. The
2-hydroxymethylimidazole (80) was converted to the
oxazolidinone derivative 83 as described above for the
preparation of 3-8. Removal of the silyl group yielded

956 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
Sch em e 4a
Sch em e 6a
a
Reagents: (a) NaNO2, HCl then SnCl2, 85%; (b) HCl, EtOH,
reflux, 80%; (c) NEt3, THF, reflux; (d) cond HCl, reflux, 65% for
steps c + d; (e) Ac2O, 89%; (f) MeI, K2CO3, acetone, reflux, 74%.
Sch em e 7a
a
Reagents: (a) hydrazine hydrate, K2CO3, CH3CN, 94%; (b)
NaOAc, EtOH, reflux, 65%; (c) H2, 10% Pd/C, MeOH, 96%; (d)
benzyl chloroformate, NaHCO3, THF, 98%; (e) (i) n-BuLi, THF,
-78 °C, (ii) R-(-)-glycidyl butyrate, -78 °C-rt, 79%; (f) MsCl,
NEt3, CH2Cl2, 98%; (g) NaN3, DMF, 65 °C, 93%; (h) (i) PPh3, THF,
(ii) H2O, 65 °C, 77%; (i) Ac2O, pyridine, CH2Cl2, 99%; (j) NH3/
MeOH, KCN, 70 °C, 34%; or MeNH2/H2O/MeOH, 70 °C, 53%; (k)
SOCl2, DMF, 0 °C, 71%; (l) 12, DMSO, 95 °C, 95%; (m) SnCl2,
EtOH, reflux, 88%; (n) Pd(PPh3)2Cl2, CuI, 85%; (o) (i) PdOAc, dppp,
CO, NEt3, H2O/DMF, 60%, (ii) DPPA, NEt3, t-BuOH, reflux, 23%;
(p) (i) TFA, CH2Cl2, (ii) Ac2O, pyridine, 91%; (q) K2CO3, MeOH,
98%.
a
Reagents: (a) K2CO3, DMSO, 90 °C, 47%; (b) TBDMSCl,
imidazole, DMF, 64%; (c) same as in Scheme 1; (d) AcOH/THF/
MeOH (98%); (e) (i) (PhO)2PON3, DBU, (ii) 2,5-dimethyl-3-hexyne-
2,5-diol, 10% Pd/C, EtOH, reflux, 25%.
Sch em e 5a
the hydroxymethyl congener 84 which was treated with
diphenyl phosphorazidate and DBU according to the
method of Mizuno and Shiori generating an intermedi-
ate azide.36 The azide was then subjected to palladium-
catalyzed decomposition to the nitrile 85 according to
the method of Hayashi and co-workers.37
1H-1,2,3- a n d 2H-1,2,3-Tr ia zole An a logu es: 1H-
1,2,3- and 2H-1,2,3-triazole analogues were synthesized
from the aniline derivative 20 (Scheme 8). Formation
of the azide 86 followed by 1,3-dipolar cycloaddition in
refluxing toluene with various commercially available
alkynes gave 1H-1,2,3-triazoles 87 and 89-91.38 These
materials were converted to other analogues of interest
as shown.
The primary analogue of interest in the 2H-1,2,3-
triazole series was the cyano derivative 99. Diazotiza-
tion of aniline 20 followed by reaction of the diazonium
salt with malononitrile afforded the dicyano intermedi-
ate 97.39 Treatment of this material with hydrazine
a
Reagents: (a) 12, 3-trifluoromethylpyrazole, DMSO, 90 °C,
94%; or 3-aminopyrazole, K2CO3, CH3CN, 43%; (b) Boc2O, THF,
77%; (c) same steps as in Scheme 6; (d) TFA, CH2Cl2, 83%; (e)
benzyloxyacetyl chloride, NEt3, 97%; (f) Ac2O, NEt3, CH2Cl2, 78%;
(g) MeSO2Cl, pyridine, 73%; (h) HCl, NaNO2 then CuCN, KCN,
38%; (i) H2, 10% Pd/C, 99%.

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 957
Sch em e 8a
a
Reagents: (a) (i) NaNO2, HCl, (ii) NaN3, NaOAc, >90%; (b) PhCH3, reflux, 33-56%; (c) NH2OH-HCl, K2CO3, MeOH, 20%; (d) NH3/
MeOH, KCN, 70 °C; or MeNH2/MeOH 70 °C, 65-67%; (e) MeOH, NaBH4, 88%; (f) NH2OH or NH2OMe, K2CO3, MeOH/THF, 72%; (g) (i)
HNO2, (ii) CH2(CN)2, 88%; (h) N2H4-H2O, EtOH, reflux, 97%; (i) Cu(OAc)2, pyridine, 100 °C, 7%; (j) (i) NaNO2, HCl, (ii) CNCH2CO2CH3,
NaHCO3, 78%; (k) LiBH4, i-PrOH, 78%; (l) Swern, 17%; (m) NH4OH, CH3CN, 82%; (n) TFAA, pyridine, 83%.
Sch em e 9a
afforded the diaminopyrazolylhydrazone intermediate
98 which was cyclized with cupric acetate40 to give the
targeted cyanotriazole 99.
1H-1,2,4-Tr ia zole An a logu es: Several 1H-1,2,4-tria-
zoles were also prepared from the advanced aniline
intermediate 20 (Scheme 8). Diazotization and conden-
sation with methyl isocyanoacetate afforded the ester
analogue 100.41 This material was converted to com-
pounds 101-104 under standard conditions. The 3-meth-
yl-1,2,4-triazole congener was prepared as shown in eq
1. Treatment of ethyl acetimidate with the arylhydra-
a
Reagents: (a) HC(OEt)3, reflux, 92%; (b) 20, THF/EtOH,
zine 72 in ethanol followed by addition of methanolic
HCl gave an intermediate imidohydrazide, which upon
refluxing in triethyl orthoformate according to the
procedure of Westermann and co-workers afforded the
methyltriazole 106.42
reflux, 82%; (c) 10% NaOH, EtOH, 89%; (d) triphosgene, CH2Cl2,
74%; (e) EtOH, HCl, reflux, 92%; (f) (i) NaNO2, 2 N HCl, 0 °C, (ii)
CuCl, rt, 22%.
2H-Tetr a zole An a logu es: Once again, the advanced
aniline intermediate 20 was used for the preparation
of the tetrazole analogues of interest (Scheme 10).
Cycloaddition of the phenylsulfonylhydrazone 11446
with the diazonium salt of 20 in pyridine afforded the
cinnamyltetrazole 115.46 Ozonolysis with reductive
workup gave the aldehyde 116 that was further con-
verted to 117 and 118.
Additional 1H-1,2,4-triazole analogues were synthe-
sized as depicted in Scheme 9. The known aminooxa-
diazole 10743 was prepared and converted to the imino-
formate intermediate 108 with triethyl orthoformate.44
Condensation of this ethoxyformylamino derivative 108
with the aniline 20 afforded the formamidine 109 which
was then cyclized to the phenylacetylaminotriazole
110.44 This process however cleaved the base-sensitive
oxazolidinone ring to the amino alcohol. Reformation of
the oxazolidinone with triphosgene yielded the protected
analogue 111. Removal of the phenylacetyl protecting
group gave the amino analogue 112 which was con-
verted to the chloro derivative 113 via diazotization and
Sandmeyer reaction with copper(I) chloride.45
Resu lts a n d Discu ssion
The oxazolidinone analogues prepared above were
tested in vitro versus a panel of Gram-positive and
Gram-negative bacterial isolates.19 Minimum inhibitory
concentration (MIC) values were determined using
standard agar dilution methods and are shown in Tables

958 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
Sch em e 10a
was not extensively explored, again due to significant
losses in activity.
The pyrrole analogues were studied initially due to
the excellent activity of the lead compound 3 in this
series. Several 3-substituted pyrrole analogues were
prepared which retain good broad-spectrum activity
such as the formyl, oxime, nitrile, and hydroxymethyl
derivatives 25-28. Other modifications resulted in a
decrease in activity across the panel of isolates. Activity
against H. influenzae was especially sensitive to struc-
tural changes. Upon testing in vivo, the methoxime,
cyano, and acetyl congeners 27, 28, and 38 all displayed
an increase in efficacy vis-a-vis the parent pyrrole, with
the cyano analogue 28 being the most efficacious
(ED50 ) 1.9 mg/kg).
a
Reagents: (a) (i) 20, NaNO2, HCl, H2O, EtOH, (ii) 114,
pyridine, 35%; (b) O3, CH2Cl2, -78 °C then DMS, rt, >90%; (c)
NH2OH, K2CO3, CH2Cl2, 44%; (d) PPh3, CCl4, CH3CN, 69%.
In the pyrazole series substitution at the 3- or
4-position of the ring often led to a decrease in activity.
The noted exceptions to this are both the 3- and 4-cyano
analogues 50 and 71 which show an increase in activity
against all organisms. It is interesting to note the
change in activity when moving the cyano group from
the 3-position to the 4-position of the pyrazole ring. The
4-cyano congener 50 is 2-4 times more potent than the
3-cyano analogue 71. In particular, the 4-cyano analogue
has very good Gram-negative activity whereas the
3-cyano analogue has only moderate activity versus
these bacteria. Furthermore, although the parent pyra-
zole 4 was devoid of in vivo activity, the 4-cyano-
substituted compound 50 is very potent (ED50 ) 1.2 mg/
kg). The acetylene moiety was incorporated at the
4-position for a comparison to the 4-cyano congener.
Although this change resulted in a reasonably active
Gram-positive compound 58, the Gram-negative activity
dropped dramatically (58 vs 50). Because the cyano
moiety imparted such interesting activity, the corre-
sponding analogue was targeted in the imidazole series.
Unfortunately, the 4-cyanoimidazole analogue 85 did
not show an improvement in antibacterial activity.
Due to the very potent in vitro and in vivo activity of
the unsubstituted 1H-1,2,3-triazole analogue 6, a more
in-depth survey of substituent effects on the various
triazoles was investigated (Table 2). Several analogues
in the 1H-1,2,3-triazole series have excellent broad-
spectrum activity. Analogues 87, 90, 91, and 94 are
potent antibacterial agents versus both Gram-positive
and Gram-negative organisms. Once again the cyano
and formyl derivatives were the most active in this
series, and the cyano analogue 90 maintains excellent
in vivo efficacy with an ED50 ) 1.9 mg/kg.
1-3. Many of the analogues tested had excellent in vitro
antibacterial activity several times more potent than
that of linezolid, eperezolid, and vancomycin. Notably,
several analogues were very potent against the fastidi-
ous Gram-negative bacteria H. influenzae and M. ca-
tarrhalis. Also, included in Tables 1-3 is in vivo efficacy
data for selected analogues tested in a lethal systemic
S. aureus infection model in mice (po administration).19
Considering the unsubstituted azole analogues, the
pyrrolyl and 1H-1,2,3-triazolyl derivatives 3 and 6
emerge as the most interesting followed by the imida-
zolyl analogue 5. All three have very good activity
against Gram-positive and Gram-negative bacteria. It
is interesting to note the profound effect on Gram-
negative activity exerted by the number and location
of the nitrogens of the azole rings. For example, whereas
the pyrrole congener 3 is very active against H. influ-
enzae and M. catarrhalis, the pyrazole analogue 4, with
a nitrogen in the 2-position, is not. However, moving
the 2-nitrogen of the pyrazole to the 3-position to give
the imidazole variant 5 results in a significant increase
in the Gram-negative activity. Interestingly, replacing
the 2-CH of the imidazole with a nitrogen to give the
1H-1,2,3-triazole 6 results in one of the most potent
analogues. Thus, one can conclude that a nitrogen at
the 2-position is not deleterious to activity in and of
itself. Likewise, the absence of a nitrogen at the 2-posi-
tion does not explain the improved activity of the
imidazole 5. It appears that the overall electronics of
the azole ring play a subtle, yet important, role in the
antibacterial activity of these compounds, especially
when one considers the Gram-negative activity.
Several of the parent azole analogues were also tested
in vivo versus a lethal systemic S. aureus infection in a
mouse model of human infection.19 The analogues were
dosed orally and compared to either orally administered
eperezolid or linezolid or subcutaneously dosed vanco-
mycin as controls. Of the unsubstituted azoles, the 1H-
1,2,3-triazole analogue 6 was the most efficacious with
an ED50 ) 4.7 mg/kg.
The 4-cyano analogue 99 was also prepared in the 2H-
1,2,3-triazole series, and a significant increase in in vitro
antibacterial activity was seen. Good broad-spectrum
activity was attained, with the exception of H. influen-
zae where an MIC ) 8 µg/mL was observed. This
analogue is also active in vivo with an ED50 ) 3.2 mg/
kg.
With these results in hand an extensive survey of
substituted derivatives within each class was under-
taken in order to increase the antibacterial activity as
well as to attain and/or improve in vivo potency. This
discussion will be limited to monosubstituted analogues
at the 3- or 4-position of the azole rings since disubsti-
tution generally led to decreases in activity. In addition,
substitution at the 2-position (i.e. R to the phenyl ring)
The 1H-1,2,4-triazole series was not as interesting.
Although the parent analogue 8 has good in vivo
activity, it lacks Gram-negative activity. Unfortunately,
the incorporation of the cyano moiety, analogue 104, in
this series did not significantly increase the Gram-
negative activity. Furthermore, all other substituents
explored were not beneficial. One interesting exception
is the chloro derivative 113 that is equipotent with

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 959
Ta ble 1. Antibacterial Activity (MIC, µg/mL) of (Pyrrolylphenyl)-, (Pyrazolylphenyl)-, and (Imidazolylphenyl)oxazolidinones
h
i
compd
R
S.a.a
S.a.b
S.e.c
S.p.d
E.f.e
H.inf.f M.cat.g
ED50
control ED50
2.7 (NDj)v
Pyrrolyl
e0.5
3
H
CHO
1
0.25
1
1
0.5
1
2
16
4
4
4
8
2
16
2
1
0.25
0.5
1
e0.5
0.125 e0.06
0.25
0.5
1
0.25
0.5
1
0.25
1
1
4
2
2
2
2
1
8
1
2
4
2
2
1
13.2 (7.9-32.5)
25
26
27
28
29
30
31
32
33
34
35
38
39
40
41
>20
1.7 (0.9-2.6)v
2.6 (2.2-2.9)e
3.5 (2.2-6.1)e
4.0 (0.1-6.6)e
0.9 (0.5-1.5)v
2.9 (1.8-4.4)e
CHdNOH
CHdNOCH3
CN
e0.125
0.25
4
1
5.5 (3.5-9.1)
7.3 (4.3-13.3)
1.9 (1.1-2.7)
16
4
16
1
0.25 e0.125 e0.125
1
2
8
4
4
4
4
1
CH2OH
0.25
0.5
1
2
1
1
2
0.5
4
0.5
1
0.25
0.25
0.25
0.5
0.5
0.5
0.5
0.25
2
0.25
0.5
4
2
>20
>20
CO2CH3
>16
>16
32
16
>16
4
CONH2
CHdCHCO2Et
(CH2)2CO2Et
(CH2)3OH
(CH2)3NHSO2Me
COCH3
CH(OH)CH3
C(NOH)CH3
C(NOCH3)CH3
>20
2.1 (1.3-3.7)e
>16
>16
>16
16
2
8
8
4
>20
1.8 (0.8-2.3)e
6.5 (ND)
10 (ND)e
16
1
2
>16
>16
8
2
15 (ND)
10 (ND)e
4
>16
8
Pyrazolyl
4
H
2
4
>16
>16
2
4
>16
>16
0.5
2
4
16
4
2
4
2
4
16
8
1
2
4
2
0.25
1
2
2
2
1
2
2
1
4
2
4
0.5
1
1
1
0.5
0.5
e0.125
0.5
1
1
2
0.5
1
0.5
0.5
1
0.5
4
0.5
1
1
2
4
>16
16
0.5
2
8
16
8
32
>16
>16
>16
4
>16
>16
>16
>16
>16
>16
>16
16
>16
>16
>16
16
>16
16
16
>16
16
16
2
>20
1.8 (1.1-2.8)v
47
48
49
50
54
55
56
57
58
64
65
66
68
69
70
71
73
77
78
79
CO2Et
CONH2
CONHMe
CN
0.5
2
8
1.2 (0.8-2.0)
3.3 (1.8-7.0)e
I
8
NHBoc
NHAc
CC-TMS
CCH
CF3
NH-Boc
NH2
NHCOCH2OH
NHAc
NHSO2Me
CN
CH3
OH
>16
>16
>16
8
>16
4
2
4
4
2
8
2
4
8
>16
8
2
16
8
16
>16
>16
>16
8
16
8
4
>16
>16
>16
1
4
8
8
1
4
8
8
2
4
1
2
2
8
16
8
OAc
OCH3
2
2
16
>16
16
>16
4
4
Imidazolyl
e0.5
0.25
5
85
H
CN
2
4
1
4
e0.5
0.5
2
2
8
8
4
4
9.5 (5.5-22.1)
2.2 (1.43-3.5)v
linezolid
eperezolid
vancomycin
4
4
1
2
1
1
1
0.5
2
1
0.5
0.5
4
2
4
16
16
>32
8
8
>32
5.6 (2.9-8.5)
1.9 (1.4-3.8)
3.9 (2.5-6.4)
3.9 (2.5-6.4)v
3.9 (2.5-6.4)v
a
b
Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. c Methicillin-resistant S. epidermidis UC12084.
Str. pneumoniae UC9912. e E. faecalis UC9217. f H. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration
(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED50 is the amount of drug required after oral
administration (mg/kg/day) to cure 50% of infected mice subjected to a lethal systemic infection of S. aureus. Numbers in parentheses are
95% confidence ranges. Data shown is from one experiment (n ) 36 mice/drug). v ) vancomycin, e ) eperezolid, l ) linezolid as controls.
ND ) not determined.
d
g
h
i
j
linezolid against Gram-positive bacteria and has excel-
lent activity against M. catharralis.
In the tetrazole series, the 5-cyano-2H-tetrazole de-
rivative 118 has good Gram-positive activity, but it is
only moderately active against the Gram-negative or-
ganisms and shows no appreciable benefit over linezolid.
(azolylphenyl)oxazolidinone subclass. Certain members
of this class have very potent activity versus both Gram-
positive and Gram-negative organisms. Interesting dif-
ferences in antibacterial activity were seen in many
analogues that cannot be rationalized solely on the basis
of sterics and position/number of nitrogen atoms in the
azole ring. It seems that differences in activity rely
strongly on subtle changes in the electronic character
of the overall azole system. Electronic differences or
changes in dipole may effect such characteristics as
partitioning through the bacterial cell wall and/or efflux
Con clu sion
In conclusion, an effort to expand the spectrum of
antibacterial activity of the oxazolidinones to include
Gram-negative organisms has led to the discovery of the

960 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
Ta ble 2. Antibacterial Activity (MIC, µg/mL) of (Triazolylphenyl)oxazolidinones
h
i
compd
R
S.a.a
S.a.b
S.e.c
S.p.d
1H-1,2,3
e0.5
0.5
0.5
E.f.e
H.inf.f M.cat.g
ED50
control ED50
6
H
1
1
4
4
1
0.5
4
8
4
1
1
4
4
0.5
0.25
4
4
4
2
2
e0.5
1
2
2
0.25
e0.125
1
2
1
2
8
4
1
4
8
2
8
4.7 (3.1-7.8)
8.8 (5.7-14.5)
2.0 (NDj)v
87
88
89
90
91
92
93
94
95
96
COCH3
4.4 (2.9-7.1)e
C(NOH)Me
CO2CH3
CN
16
4
1
>16
16
2
>20
1.9 (1.1-3.3)
>20
15.3 (ND)e
e0.125
0.25
0.5
1
0.25
0.5
2
2.8 (1.7-4.5)e
1.1 (0.5-1.5)e
CHO
0.5
4
2
CONH2
CONHCH3
CH2OH
HCdNOH
HCdNOMe
8
8
2
8
4
>16
>16
4
8
>16
0.5
1
1
2
8
4
>16
>16
8
16
0.5
8.6 (ND)
3.8 (1.9-6.6)e
2H-1,2,3
7
99
H
CN
4
0.5
2
0.5
1
1
4
0.5
>16
>16
e0.125
e0.125
8
2
3.2 (2.0-4.9)
5.7 (3.1-13.1)
3.8 (1.9-6.6)e
2.4 (1.0-3.2)v
1H-1,2,4
1
8
H
4
>16
16
4
4
1
4
2
0.5
16
2
4
32
>16
16
8
>16
16
>16
>16
>16
16
16
>16
8
100
101
102
103
104
106
111
112
113
CO2CH3
CH2OH
CHO
CONH2
CN
CH3
NHCOBn
NH2
>16
16
2
4
1
>16
16
4
0.5
8
>16
>16
2
1
>16
16
16
16
>16
16
2
4
8
2
4
4
8
2
>16
1
>16
>16
2
1
>16
16
2
8
4
4
2
2
0.5
Cl
e0.125
9.4 (6.2-16.5)
5.0 (ND)
4H-1,2,4
9
na
16
8
4
1
8
>16
8
>20
2.0 (1.1-2.8)e
linezolid
eperezolid
vancomycin
4
4
1
2
1
1
1
0.5
2
1
0.5
0.5
4
2
4
16
16
>32
8
8
>32
5.6 (2.9-8.5)
1.9 (1.4-3.8)
3.9 (2.5-6.4)
3.9 (2.5-6.4)v
3.9 (2.5-6.4)v
a
b
Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. c Methicillin-resistant S. epidermidis UC12084.
Str. pneumoniae UC9912. e E. faecalis UC9217. f H. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration
(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED50 is the amount of drug required after oral
administration (mg/kg/day) to cure 50% of infected mice subjected to a lethal systemic infection of S. aureus. Numbers in parentheses are
95% confidence ranges. Data shown is from one experiment (n ) 36 mice/drug). v ) vancomycin, e ) eperezolid, l ) linezolid as controls.
ND ) not determined.
d
g
h
i
j
a nitrogen atmosphere in oven- or flame-dried glassware.
Chromatography was carried out on EM Science 230-400
mesh ASTM silica gel. Elemental analyses were within (0.4%
of calculated values. Biological assays were performed as
described previously in ref 19.
mechanisms which have been shown to be responsible
for the lack of activity of the oxazolidinones against
Gram-negative bacteria.47,48 The placement of a cyano
moiety on the azole often leads to a significant increase
in antibacterial activity in vitro and in vivo. In particu-
lar, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-
1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus
MICs e 0.5-1 mg/mL and H. influenzae and M. ca-
tarrhalis MICs ) 2-4 mg/mL. Furthermore, these
analogues are very effective versus S. aureus and S.
pneumoniae18 in mouse models of human infection.
3-F lu or o-1-n itr o-4-(1H-p yr r ol-1-yl)ben zen e (13a ). So-
dium hydride (630 mg of 60% in oil, 15.75 mmol) was
suspended in THF (85 mL) and treated with pyrrole (1.0 g, 15
mmol), followed by warming at 50 °C for 15min. The solution
was then treated with 3,4-difluoronitrobenzene (2.51 g, 15.75
mmol) and refluxed for 18 h. The mixture was cooled and
treated with saturated ammonium chloride solution (10 mL).
The mixture was diluted with ethyl acetate and washed with
water (2×). Drying (Na2SO4) and concentration in vacuo
afforded a dark brown solid, which was chromatographed over
75 g silica gel, eluting with 30% CH2Cl2/hexane. These
procedures afforded 2.05 g (66%) of 13a as a light yellow
solid: mp 101-102 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (m,
2 H), 7.56 (t, J ) 8.7 Hz, 1 H), 7.16 (m, 2 H), 6.44 (m, 2 H);
HRMS (EI) calcd for C10H7FN2O2 206.0492, found 206.0504.
Exp er im en ta l Section
Gen er a l. Melting points were determined on a Fisher-J ohns
or a Thomas-Hoover apparatus and are uncorrected. 1H NMR
spectra were recorded on either a Bruker AM-300 or ARX-
400 spectrometer. Chemical shifts are reported in δ units
(ppm) relative to TMS as internal standard. Mass spectra and
combustion analyses were obtained by the Structural, Analyti-
cal and Medicinal Chemistry Department of Pharmacia &
Upjohn, Inc. Unless otherwise indicated all reactions were
conducted in commercially available anhydrous solvents under
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-F lu or o-
1-n itr o-4-(a zolyl)ben zen es 13b-f, 37, 61, 62, a n d 81. The
azole (1 equiv), K2CO3 or dibasic potassium phosphate (2 equiv)
and 3,4-difluoronitrobenzene (1 equiv) were heated to 90 °C

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 961
Ta ble 3. Antibacterial Activity (MIC, µg/mL) of (Tetrazolylphenyl)oxazolidinones
S.a.a
S.a.b
S.e.c
S.p.d E.f.e
2H-Tetrazolyl
H.inf.f
M.cat.g
ED50
control ED50
h
i
compd
R
10
H
CHO
CHdNOH
CN
2
8
4
2
2
4
4
1
1
2
1
0.5
0.5
1
0.5
0.5
1
16
4
8
16
16
16
8
16
8
116
117
118
2
4
1H-Tetrazolyl
11
na
4
2
2
1
2
16
16
>20
7.8 (4.0-26.7)e
linezolid
eperezolid
vancomycin
4
4
1
2
1
1
1
0.5
2
1
0.5
0.5
4
2
4
16
16
>32
8
8
>32
5.6 (2.9-8.5)
1.9 (1.4-3.8)
3.9 (2.5-6.4)
3.9 (2.5-6.4)v
3.9 (2.5-6.4)v
a
b
Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. c Methicillin-resistant S. epidermidis UC12084.
Str. pneumoniae UC9912. e E. faecalis UC9217. f H. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration
(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED50 is the amount of drug required after oral
administration (mg/kg/day) to cure 50% of infected mice subjected to a lethal systemic infection of S. aureus. Numbers in parentheses are
d
g
h
i
95% confidence ranges. Data shown is from one experiment (n ) 36 mice/drug). v ) vancomycin, e ) eperezolid, l ) linezolid as controls.
in DMSO for 18 h. The reaction was cooled diluted with water
(100 mL) and extracted with ethyl acetate (2 × 100 mL). The
organic layers were washed with water (5 × 100 mL) and brine
(75 mL). Drying (Na2SO4) and concentration in vacuo afforded
crude products.
of 14a as a brown solid: mp 124-126 °C; 1H NMR (400 MHz,
CDCl3) δ 7.40 (m, 7 H), 7.08 (d, J ) 8.7 Hz, 1 H), 6.98 (m, 2
H), 6.79 (bs, 1 H), 6.35 (m, 2 H), 5.23 (s, 2 H); HRMS (EI) calcd
for C18H15FN2O2 310.1117, found 310.1132. Anal. Calcd for
C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.32; H,
4.89; N, 9.07.
3-Flu or o-1-n itr o-4-(1H-pyr azol-1-yl)ben zen e (13b). Work-
up afforded an off-white solid which was crystallized from hot
hexanes to afford 5.3 g (87%) of an off-white solid: mp 128-
Gen er a l P r oced u r e for Oxa zolid in on e Rin g F or m a -
tion fr om Cbz-P r otected An ilin es 14a -g To Give Com -
p ou n d s 15a -g a n d 18. A solution of Cbz derivative 14a -g
(1 equiv) THF at -78 °C was treated with 1.0 M lithium bis-
(trimethylsilyl)amide (1.1 equiv) followed by stirring at -78
°C for 30 min. The solution was treated with (R)-(-)-glycidiyl
butyrate (1 equiv) followed by gradual warming to ambient
temperature for 24 h. The mixture was diluted with EtOAc
and washed with H2O and brine. Drying (Na2SO4) and
concentration in vacuo afforded crude products 15a -g.
1
129 °C; H NMR (400 MHz, CDCl3) δ 8.28 (m, 1 H), 8.17 (m,
3 H), 7.82 (d, J ) 1.4 Hz, 1 H), 6.58 (m, 1 H); MS (EI) m/z 207
(M + H); HRMS (EI) calcd for C9H6FN3O2 207.0444, found
207.0454. Anal. Calcd for C9H6FN3O2: C, 52.18; H, 2.92; N,
20.28. Found: C, 52.01; H, 2.75; N, 20.22.
3-Flu or o-1-n itr o-4-(2H-1,2,3,4-tetr azol-1-yl)ben zen e (13g).
Tetrazole (15.83 g, 0.23 mol), 3,4-difluoronitrobenzene (7.19
g, 45.16 mmol) and NEt3 (31.5 mL, 0.23 mol) in 90 mL
acetonitrile was heated at reflux for 18 h, followed by cooling
and concentration in vacuo. The residue was dissolved in
EtOAc (250 mL) and washed with water (2 × 100 mL) and
brine (100 mL). Drying (Na2SO4) and concentration in vacuo
afforded a black oil that was chromatographed over 360 g silica
gel, eluting with 3% acetone/CH2Cl2. These procedures afforded
0.93 g (10%) of the less polar 2H-regioisomer 13g as a yellow
solid and 0.38 g (4%) of the more polar 1H-regioisomer as a
yellow-brown solid. 13g: mp 111-115 °C; 1H NMR (400 MHz,
DMSO) δ 9.71 (s, 1 H), 8.57 (dd, J ) 9.6, 1.6 Hz, 1 H), 8.32 (m,
2 H); HRMS (FAB) calcd for C7H4FN5O2 + H 210.0427, found
210.0424. Anal. Calcd for C7H4FN5O2: C, 40.20; H, 1.93; N,
33.49. Found: C, 40.28; H, 1.87; N, 33.26.
(S)-[3-[3-F lu or o-4-(1H -p yr r ol-1-yl)p h en yl]-2-oxo-5-ox-
a zolid in yl]m eth a n ol (15a ). Workup gave a red-brown oil
which was subjected to radial chromatography on a 2 mm
plate, eluting with 2-5% CH3OH/CH2Cl2 gradient. These
procedures afforded 157 mg (59%) of 15a as a light tan solid:
mp 112-113 °C; [R]25 ) -46° (c 0.84, DMSO); 1H NMR (400
D
MHz, CDCl3) δ 7.63 (dd, J ) 13.2, 2.5 Hz, 1 H), 7.37 (m, 3 H),
7.00 (m, 2 H), 6.36 (m, 2 H), 4.79 (m, 1 H), 4.05 (m, 3 H), 3.79
(dd, J ) 12.7, 3.7 Hz, 1 H); HRMS (EI) calcd for C14H13FN2O3
276.0910, found 276.0918. Anal. Calcd for C14H13FN2O3: C,
60.87; H, 4.74; N, 10.14. Found: C, 60.97; H, 4.77; N, 9.84.
Gen er a l P r oced u r e for Con ver sion of Alcoh ols 15a -g
to F in a l Aceta m id e An a logu es 3-8 a n d 10. The alcohols
15a -g (1 equiv) and NEt3 (1.75 equiv) were cooled to 0 °C in
CH2Cl2 and treated with methanesulfonyl chloride (1.25 equiv)
followed by stirring at 0 °C for 30 min. The solution was
warmed to ambient temperature, diluted with CH2Cl2, and
washed with water (3×) and brine. Drying (Na2SO4) and
concentration in vacuo afforded intermediate mesylates that
were dissolved in DMF and treated with sodium azide (10
equiv) at 60 °C for 18 h. The mixture was cooled, diluted with
EtOAc and washed with water (6×) and brine. Drying (Na2-
SO4) and concentration in vacuo afforded intermediate azides
sufficiently pure for use. Then, a solution of the azide (1 equiv)
in CH3OH/THF was treated with an appropriate catalyst and
hydrogenated at 1 atm for 24 h. The solution was filtered
through Celite and concentrated in vacuo and the residue was
dissolved in pyridine and treated with acetic anydride (1.1
equiv) followed by stirring at ambient temperature for 12 h.
The solution was concentrated under high vacuum to yield
crude products 3-8 and 10.
1H-isom er : 1H NMR (DMSO) δ 10.04 (s, 1 H), 8.57 (dd,
J ) 10.4, 2.0 Hz, 1 H), 8.34 (d, J ) 8.9 Hz, 1 H), 8.23 (t, J )
8.1 Hz, 1 H).
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-F lu or o-
1-(p h en ylm et h oxyca r b on yla m in o)-4-(a zolyl)b en zen es
14a -g. Compounds 13a -g (1 equiv) and the indicated catalyst
in THF were hydrogenated for 18 h. The mixture was filtered
through Celite treated with saturated NaHCO3 solution and
cooled to -20 °C. Benzyl chloroformate (1.2 equiv) was added
followed by warming to ambient temperature for 48 h. The
mixture concentrated to ca. half the original volume diluted
with EtOAc and washed with water (4×) and brine. Drying
(Na2SO4) and concentration in vacuo afforded crude products
14a -g which were purified as indicated.
3-F lu or o-1-(p h en ylm eth oxyca r bon yla m in o)-4-(1H-p yr -
r ol-1-yl)ben zen e (14a ). 5% Pt on sulfide carbon was used as
catalyst and workup afforded a brown solid, which was
chromatographed over 35 g silica gel, eluting with 1:3:32 to
1:3:16 CH3OH/CH2Cl2/hexane gradient to yield 581 mg (77%)

962 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
(S)-N-[[3-[3-F lu r o-4-(1H-p yr r ol-1-yl)p h en yl]-2-oxo-5-ox-
a zolid in yl]m eth yl]a ceta m id e (3). Workup afforded a brown
solid which was chromatographed over 50 g of silica gel,
eluting with 1-2% CH3OH/CH2Cl2 gradient to yield 582 mg
anhydride (2.8 mL) was added dropwise and the reaction was
stirred for 18 h at room temperature and partitioned between
water and EtOAc. The mixture was extracted with EtOAc (3×)
and the combined extracts were dried over MgSO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel with 1% MeOH/0.1% NH4OH/CH2Cl2 followed by 2%
MeOH/0.2% NH4OH/CH2Cl2 to yield 0.36 g of pure product 19
followed by 0.25 g of product mixed with a small amount of
(56%) of 3 as an off-white solid: mp 198-199.5 °C; [R]25
)
D
-26° (c 0.93, DMSO); 1H NMR (400 MHz, CD3OD) δ 7.70 (dd,
J ) 18.3, 3.3 Hz, 1 H), 7.47 (t, J ) 11.7 Hz, 1 H), 7.37 (dd,
J ) 11.8, 3.2 Hz, 1 H), 7.01 (m, 2 H), 6.27 (m, 2 H), 4.84 (m,
1 H), 4.18 (t, J ) 12.1 Hz, 1 H), 3.85 (dd, J ) 12.3, 8.5 Hz, 1
H), 3.57 (d, J ) 6.6 Hz, 2 H), 1.97 (s, 3 H); HRMS (EI) calcd
for C16H16FN3O3 317.1176, found 317.1183. Anal. Calcd for
1
polar impurity: mp 64-66 °C; [R]D -13° (c 0.93, EtOH); H
NMR (300 MHz, CDCl3) δ 2.00 (s, 3 H), 3.64 (m, 2 H), 3.71 (m,
1 H), 3.98 (t, 1 H), 4.74 (m, 1 H), 4.81 (s, 2 H), 5.15, 5.23 (s,s,
2 H), 6.15 (broad s, 1 H), 6.95-7.52 (m, 13 H); HRMS calcd
for C27H26FN3O5 491.1856, found 491.1860. Anal. Calcd for
C
16H16FN3O3: C, 60.56; H, 5.08; N, 13.24. Found: C, 60.28;
H, 5.10; N, 13.14.
C
27H26FN3O5: C, 65.98; H, 5.33; N, 8.55. Found: C, 65.29; H,
N-(4-Am in o-2-flu or op h en yl)-N-ben zyla m in e (16). To a
solution of 3,4-difluoronitrobenzene (0.7 mL, 6.29 mmol) in
acetonitrile (12 mL) was added N,N-diisopropylethylamine
(1.64 mL, 9.43 mmol) followed by benzylamine (0.82 mL, 7.54
mmol). After heating at 90 °C in an oil bath for 6 h the reaction
was allowed to cool and stand at room temperature for 16 h
and then concentrated in vacuo. The residue was treated with
EtOAc and the suspended solid was removed by filtration and
washed with additional EtOAc. The combined filtrates were
concentrated in vacuo and the residue was chromatographed
over silica gel with 5% EtOAc/hexane to yield after recrystal-
lization from EtOAc/hexane 1.19 g (77%) of intermediate
N-benzylnitroaniline. A solution of this material (0.50 g, 2.03
mmol) in THF (150 mL) containing of 5% platinum-on-carbon
(0.1 g) was shaken with H2 on a Parr hydrogenator for 6 h.
The catalyst was removed by filtration through Celite and the
filtrate was concentrated in vacuo to yield 0.54 g of 16 as a
dark oil that was used as is in the next step: 1H NMR (300
MHz, CDCl3) δ 3.91 (broad s, 3 H), 4.29 (s, 2 H), 6.52 (m, 3 H),
7.35 (m, 5 H).
Ben zyl Ben zyl(4-{[(ben zyloxy)ca r bon yl]a m in o}-2-flu o-
r op h en yl)ca r ba m a te (17). To a solution of 16 (0.54 g, 4.47
mmol) in THF (36 mL) was added N,N-dimethylaniline (0.58
mL, 4.57 mmol) followed by benzyl chloroformate (0.64 mL,
4.47 mmol). After 40 min the ice bath was removed and then
after stirring at room temperature for 17 h the reaction
mixture was concentrated in vacuo. A solution of the residue
in CH2Cl2 (100 mL) was washed in turn with cold 1 N HCl
(3×), water, and aqueous NaHCO3, dried over MgSO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel with 10-15% EtOAc/hexane gradient to yield 0.74 g
(72%) of 17: mp 105-106.5 °C. An analytical sample was
recrystallized from methyl tert-butyl ether: mp 107-108 °C;
1H NMR (300 MHz, CHCl3) δ 4.77 (broad s, 2 H), 5.16 (m, 4
H), 6.85-7.36 (m, 19 H); MS m/z 484 (M + H). Anal. Calcd for
C29H25FN2O4: C, 71.89; H, 5.20; N, 5.78. Found: C, 71.86; H,
5.27; N, 5.74.
Ben zyl 4-{(5S)-5-[(Acetyla m in o)m eth yl]-2-oxo-1,3-ox-
a zolid in -3-yl}-2-flu or op h en yl(b en zyl)ca r b a m a t e (19).
Methanesulfonyl chloride (0.16 mL, 2.05 mmol) was added
dropwise to a solution of 18 (0.71 g, 1.58 mmol) and NEt3 (0.48
mL, 3.47 mmol) in CH2Cl2 (25 mL) at 0 °C. After stirring in
the cold for 45 min the reaction was washed with water,
aqueous NaHCO3, and brine, dried over MgSO4 and concen-
trated in vacuo to yield 0.86 g of the mesylate as a gummy
residue. This material was placed in acetonitrile (25 mL) and
potassium phthalimide (0.875 g, 4.73 mmol) was added. The
reaction was heated at 95 °C for 48 h and allowed to cool. A
suspended solid was collected on a filter and washed well with
acetonitrile. The combined filtrates were concentrated in
vacuo. The residue was chromatographed over silica gel with
0.5% MeOH/CH2Cl2 to yield 0.85 g (93%, two steps) of the
phthalimide. This phthalimide (0.85 g, 1.47 mmol) was sus-
pended in MeOH and hydrazine monohydrate (0.075 g, 0.073
mL) was added. The mixture was heated at 80 °C for 5 h and
then allowed to cool and stand at room temperature. After
standing for 16 h the reaction mixture was poured into 3%
aqueous sodium carbonate (25 mL) and extracted with EtOAc.
The combined extracts were dried over MgSO4 and concen-
trated in vacuo to give 0.65 g of the free amine as a gummy
residue which was placed in pyridine (8.5 mL) at 0 °C. Acetic
5.41; N, 8.44.
N-{[(5S)-3-(4-Am in o-3-flu or op h en yl)-2-oxo-1,3-oxa zoli-
d in -5-yl]m eth yl}a ceta m id e (20). To a solution of 19 (2.381
g, 4.84 mmol) in absolute ethanol (150 mL) was added 0.5 g of
10% Pd/C catalyst. The mixture was placed on a Parr hydro-
genator for 7.5 h. There was then added an additional 0.1 g of
10% Pd/C catalyst and the reaction was allowed to continue.
After an additional 15.5 h the catalyst was removed by
filtration through Celite. The filtrate was concentrated in
vacuo and the residue was recrystallized from MeOH to yield
20: 1.0 g (77%); mp 168-169 °C; [R]D -24° (c 0.70, DMSO);
1H NMR (300 MHz, DMSO-d6) δ 1.83 (s, 3 H), 3.38 (m, 2 H),
3.63 (d,d, 1 H), 4.01 (t, 1 H), 4.65 (m, 1 H), 5.04 (s, 2 H), 6.76
(t, 1 H), 6.96 (d,d, 1 H), 7.30 (d,d, 1 H), 8.25 (t, 1 H); MS (EI)
m/z 267 (M + H). Anal. Calcd for C12H14N3F1O3: C, 53.93; H,
5.28; N, 15.72. Found: C, 53.90; H, 5.36; N, 15.66.
(S)-N-[[3-[3-F lu or o-4-(1H-1,2,3,4-tetr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (11). A slurry of
20 (500 mg, 1.87 mmol), sodium azide (182 mg, 2.81 mmol),
and triethyl orthoformate (450 mg, 3.02 mmol) in acetic acid
(10 mL) was refluxed for 4 h. The mixture was cooled and
added to ice water (20 mL). After setting at ambient temper-
ature for 48 h, the precipitated product was collected by
filtration and washed with cold CH3OH to yield 172 mg (29%)
1
of 11: mp 167-169 °C; H NMR (400 MHz, DMSO) δ 9.96 (s,
1 H), 8.25 (t, J ) 5.76 Hz, 1 H), 7.89 (t, J ) 8.7 Hz, 1 H), 7.85
(dd, J ) 13.2, 2.4 Hz, 1 H), 4.79 (m, 1 H), 4.20 (t, J ) 9.1 Hz,
1 H), 3.81 (dd, J ) 9.2, 6.5 Hz, 1 H), 3.44 (t, J ) 5.4 Hz, 1 H);
HRMS (FAB) calcd for C13H13FN6O3 + H 321.1111, found
321.1118. Anal. Calcd for C13H13FN6O3‚1/3CH3OH: C, 48.39;
H, 4.37; N, 25.39. Found: C, 48.72; H, 4.29; N, 24.71.
N-{[(5S)-3-(3-F lu or o-4-isot h iocya n a t op h en yl)-2-oxo-
1,3-oxa zolid in -5-yl]m eth yl}a ceta m id e (21). To a solution
of 1,1-thiocarbonyldi-2(1H)-pyridone (0.96 g, 4.12 mmol) in
CH2Cl2 (30 mL) at 0 °C was added 20 (1.0 g, 3.74 mmol) in
one portion. Over the course of 1 h 20 slowly went into solution
as a second material came out. After stirring in the cold for
2.5 h and then at room temperature for 2 h, the reaction
mixture was concentrated in vacuo. The residue was treated
with water (15 mL) and the solid was finely divided with a
spatula and collected on a filter, washed with a small amount
of water and dried overnight under vacuum at 55 °C to yield
1.09 g (94%) of 21: mp 173-176 °C; MS m/z 309 (M + H).
N-{[(5S)-3-(3-Flu or o-4-{[(2-for m ylh yd r a zin o)ca r both io-
yl]a m in o}p h en yl)-2-oxo-1,3-oxa zolid in -5-yl]m eth yl}a cet-
a m id e (22). Formic hydrazide (0.23 g) was added to a
mechanically stirred mixture of 21 (1.11 g, 3.6 mmol) in THF
(25 mL). The mixture was heated at 70 °C and over 3.5 h a
heavy precipitate came out of solution. The mixture was then
allowed to cool and stir at room temperature for 1 h. The
suspended solid was collected and washed well with EtOAc.
The resulting solid was dried under vacuum at 60 °C to yield
1.2 g (91%) of 22 that was carried on to the next reaction
without further purification.
(S)-N -[[3-[4-[3-Me r ca p t o-4-[1,2,4]t r ia zolyl]-3-flu or o-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (23). To
a mechanically stirred suspension of 22 (1.10 g, 3.0 mmol) in
water (22 mL) was added 1 N KOH (3.1 mL). Over 30 min the
solid gradually became a finely divided suspension. After
stirring for 1 h at room temperature the reaction mixture was

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 963
acidified with 1 N HCl (3 mL). The resulting precipitate was
collected, washed with a little 0.1 N HCl and dried under
vacuum at 60 °C to yield 1.03 g (98%) of 23: mp 266.5-268
°C. An analytical sample was recrystallized from DMF:H2O:
and partitioned between water and CH2Cl2. The combined
organic layer was washed (H2O), dried (MgSO4), and concen-
trated in vacuo to give 0.254 g of crude material. This material
was purified on a 2.5 × 23 cm medium-pressure silica column
with 5% MeOH/CH2Cl2 to give 0.047 g (72%) of 28: mp 167-
1
mp 272-273 °C; H NMR (300 MHz, DMSO-d6) δ 1.84 (s, 3
H), 3.44 (m, 2 H), 3.78 (m, 1 H), 4.19 (t, 1 H), 4.78 (m, 1 H),
7.48 (d, 1 H), 7.66 (t, 1 H), 7.75 (d, 1 H), 8.29 (t, 1 H), 8.70 (s,
1 H), 14.02 (broad s, 1 H); MS m/z 351 (M + H). Anal. Calcd
for C14H14FN5O3S: C, 47.86; H, 4.02; N, 19.93. Found: C,
48.01; H, 4.29; N, 19.70.
168 °C; [R]25 ) -26° (c 0.49, DMSO); 1H NMR (400 MHz,
D
CDCl3) δ 7.68 (dd, J ) 13.2 Hz, J ′ ) 2.4 Hz, 1 H), 7.41 (d,
J ) 1.6 Hz, 1 H), 7.35 (t, J ) 8.4 Hz, 1 H), 7.28 (dd, J ) 9.6
Hz, J ′ ) 2.4 Hz, 1 H), 6.92 (t, J ) 3.2 Hz, 1 H), 6.58 (dd, J )
2.8 Hz, J ′ ) 1.6 Hz, 1 H), 6.40 (t, J ) 6.0 Hz, 1 H), 4.84 (m,
8 lines, 1 H), 4.09 (t, J ) 8.8 Hz, 1 H), 3.87 (dd, J ) 8.8 Hz,
J ′ ) 6.8 Hz, 1 H), 3.69 (dd, J ) 6.0 Hz, J ′ ) 4.8 Hz, 2 H),
2.03 (s, 3 H); HRMS calcd for C17H15FN4O3 342.1128, found
342.1140. Anal. Calcd for C17H15FN4O3: C, 59.65; H, 4.42; N,
16.37. Found: C, 59.58; H, 4.57; N, 16.07.
N-[((5S)-3-{3-F lu or o-4-[3-(h yd r oxym eth yl)-1H-p yr r ol-
1-yl]p h en yl}-2-oxo-1,3-oxa zola n -5-yl)m et h yl]a cet a m id e
(29). A solution of aldehyde 25 (125 mg, 0.36 mmol) in 2:1
CH3OH/CH2Cl2 (6 mL) at 0 °C was treated with sodium
borohydride (7 mg, 0.18 mmol) followed by warming to ambient
temperature for 4 h. The solution was diluted with CH2Cl2,
treated with saturated ammonium chloride solution, and
washed. Drying (Na2SO4) and concentration in vacuo afforded
a white solid which was crystallized from boiling EtOAc/
hexane (with a few drops of methanol) to afford 29 as a white
solid 106 mg (84%): mp 155-157 °C.
(S)-N-[[3-[4-[4-[1,2,4]Tr ia zolyl]-3-flu or op h en yl]-2-oxo-
5-oxa zolid in yl]m eth yl]a ceta m id e (9). A mixture of 23 (0.33
g, 0.94 mmol) and 20% HNO3 (0.6 mL) were heated on a steam
bath in a test tube with vigorous efforvescing. After 1 min the
sides of the tube were rinsed down with an additional 0.6 mL
of 20% HNO3. Heating was continued for 7 min until the solid
dissolved and then the reaction was cooled in an ice bath. The
pH was adjusted to 9.5 with 1 N NH4OH (5.7 mL) and the
solution was concentrated in vacuo. The residue was chro-
matographed over silica gel with 5% MeOH/0.5% NH4OH/CH2-
Cl2 to yield 0.23 g (77%) of 9: mp 204-206 °C; [R]25 ) -26°
D
(c 0.92, DMSO); 1H NMR (300 MHz, DMSO-d6) δ 1.82 (s, 3
H), 3.42 (t, 2 H), 3.78 (m, 1 H), 4.16 (t, 1 H), 4.75 (m, 1 H),
7.46 (dd, 1 H), 7.72 (t, 1 H), 7.77 (dd, 1 H), 8.24, (t, 1 H), 8.90
(s, 1 H), 8.91 (s, 1 H); HRMS (FAB) calcd for C14H14FN5O3 +
H1 320.1159, found 320.1159. Anal. Calcd for C14H14FN5O3:
C, 52.67; H, 4.42; N, 21.93. Found: C, 52.42; H, 4.56; N, 21.68.
(S)-N-[[3-[3-F lu or o-4-(3-ca r bom eth oxy-1H-p yr r ol-1-yl)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (30). A
solution of 25 (220 mg, 0.64 mmol) in 1:1 acetonitrile-CH3-
OH (10 mL) was treated with NaCN (164 mg, 0.64 mmol),
activated manganese dioxide (1.15 g, 13.2 mmol), and HOAc
(58 µL, 1.0 mmol). The mixture was stirred at ambient
temperature for 36 h, at which point additional activated
manganese dioxide (550 mg, 6.32 mmol) and HOAc (58 µL,
1.0 mmol) were added. The solution was stirred for an
additional 24 h, and was filtered through Celite. The filtrate
was concentrated in vacuo, diluted with EtOAc and washed
with water. The organic layer was dried (Na2SO4) and con-
centrated in vacuo to afford a pink solid. This material was
subjected to radial chromatography on a 2 mm plate, eluting
with a 0-2% CH3OH/CH2Cl2 gradient to afford 170 mg (71%)
of 30 as a white solid: mp 134-135 °C.
Gen er a l P r oced u r e for th e Am on olysis of Ester s 30,
47, 89, a n d 100 To Give Am id es 31, 48, 49, 92, a n d 93. A
solution of the ester (1 equiv) and KCN (0.25 equiv) in
saturated methanolic ammonia or 2 N MeNH2/CH3OH was
heated in a sealed tube at 50 °C. The solvent was evaporated
and the residue was purified as indicated.
(S)-N-[[3-[3-F lu or o-4-(3-a m id op yr r ol-1-yl)p h en yl]-2-
oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (31). The residue
was purified on a 2.5 × 25 cm medium-pressure silica column
with 5-10% MeOH/CH2Cl2 to give 0.029 g (20%) of 31 as a
light yellow solid: mp 119-121 °C; 1H NMR (400 MHz, CDCl3)
δ 7.61 (dd, J ) 13.2 Hz, J ′ ) 2.4 Hz, 1 H), 7.51 (s, 1 H), 7.35
(t, J ) 8.4 Hz, 1 H), 7.22 (d, J ) 9.2 Hz, 1 H), 6.90 (m, 1 H),
6.57 (m, 1 H), 4.75 (m, 1 H), 4.04 (t, J ) 9.2 Hz, 1 H), 3.77 (dd,
J ) 9.2 Hz, J ′ ) 6.8 Hz, 1 H), 3.58 (m, 1 H), 3.56 (m, 1 H),
3.01 (s, 3 H), 1.96 (s, 3 H); HRMS calcd for C17H17FN4O4 + H
(S)-N-[[3-[3-Flu or o-4-(1H-pyr r ol-1-yl-3-car boxaldeh yde)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (25). A
solution of 20 (2.0 g, 7.5 mmol) and 2,5-dimethoxy-3-tetrahy-
drofurancarboxaldehyde (1.68 g, 10.5 mmol) in acetic acid (55
mL) was refluxed for 2 h. The solution was cooled and the
solvent removed under high vacuum, azeotroping the residue
with toluene to remove the last traces of acetic acid. The
residue was chromatographed over 300 g of silica gel with
0-3% CH3OH/CH2Cl2 to yield 2.21 g (85%) of 25 as a light
yellow amorphous solid: mp 165-168 °C; [R]D -24° (c 0.38,
1
DMSO); H NMR (400 MHz, CDCl3) δ 9.86 (s, 1 H), 7.70 (dd,
J ) 13.0, 2.4 Hz, 1 H), 7.59 (q, J ) 1.9 Hz, 1 H), 7.41 (t, J )
8.7 Hz, 1 H), 7.27 (d, J ) 6.9 Hz, 1 H), 7.0 (m, 1 H), 6.80 (dd,
J ) 3.1, 1.6 Hz, 1 H), 6.07 (m, 1 H), 4.83 (m, 1 H), 4.10 (t, J )
9.0 Hz, 1 H), 3.85 (dd, J ) 9.1, 6.8 Hz, 1 H), 3.70 (m, 2 H),
2.04 (s, 3 H); HRMS (EI) calcd for C17H16FN3O4 345.1125,
found 345.1129. Anal. Calcd for C17H16FN3O4‚0.1H2O: C,
58.82; H, 4.70; N, 12.10. Found: C, 58.71; H, 4.77; N, 12.01.
Gen er a l P r oced u r e for th e P r ep a r a tion of Oxyim in o
An a logu es 26, 27, 40, 41, 88, 95, 96, a n d 117. The aldehyde
or ketone (1 equiv), hydroxyl- or methyoxylamine hydrochlo-
ride (1.5 equiv) and K2CO3 (1 equiv) were stirred in CH3OH/
CH2Cl2 (1:1). Water and EtOAc were added, the phases were
separated, and the aqueous portion was extracted with EtOAc
and CH2Cl2. The combined organics were dried (MgSO4) and
concentrated to give crude materials which were purified as
indicated.
(S)-N-[[3-[3-F lu or o-4-(3-((h yd r oxyim in o)m et h yl)-1H -
p yr r ol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m et h yl]a cet a -
m id e (26). The residue was purified on a 2.3 × 28 cm medium-
pressure silica column with 5% MeOH/CH2Cl2 to give 0.116 g
(72%) of 26 as a mixture of E and Z isomers: mp 216-218 °C;
[R]D -23° (c 0.47, DMSO); 1H NMR (400 MHz, DMSO) δ 11.08
(s, 1 H), 10.56 (s, 1 H), 8.24 (m, 1 H), 8.01 (s, 1 H), 7.75 (m, 1
H), 7.70 (m, 1 H), 7.62 (m, 1 H), 7.40 (m, 1 H), 7.30 (m, 1 H),
7.14 (bs, 1 H), 6.63 (m, 1 H), 6.49 (m, 1 H), 4.76 (m, 1 H), 4.16
(t, J ) 9.1 Hz, 1 H), 3.78 (dd, J ) 9.0, 6.6 Hz, 1 H), 3.42 (t,
J ) 5.5 Hz, 2 H), 1.83 (s, 3 H); MS (EI) m/z 360 (M + H); HRMS
(EI) calcd for C17H17FN4O4 360.1234, found 360.1237. Anal.
Calcd for C17H17FN4O4: C, 56.66; H, 4.75; N, 15.55. Found:
C, 56.26; H, 4.85; N, 15.17.
(S)-[[3-[3-F lu or o-4-(3-cya n op yr r ol-1-yl)p h en yl]-2-oxo-
5-oxa zolid in yl]m eth yl]a ceta m id e (28). An acetonitrile (15
mL) solution of 26 (0.068 g, 0.19 mmol), triphenylphosphine
(0.198 g, 0.75 mmol), and CHCl4 (0.04 mL, 0.41 mmol) was
stirred overnight. More carbon tetrachloride (2.5 mL, 25.9
mmol) was added, the reaction mixture was stirred for 4 h
361.1312, found 361.1314. Anal. Calcd for
1.6H2O: C, 52.47; H, 5.23; N, 14.39. Found: C, 52.78; H, 5.22;
N, 13.69.
C17H17FN4O4‚
(S)-N-[[3-[3-F lu or o-4-[3-(2-ca r beth oxyvin yl)-1H-p yr r ol-
1-yl]p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (32).
A solution of diisopropyl ethoxycarbonylmethylphosphonate
(805 mg, 3.19 mmol) in THF (7 mL) at 0 °C was treated with
potassium tert-butoxide (3.19 mL 1.0 M/THF, 3.19 mmol) and
warmed to ambient temperature for 1 h. The solution was
cooled to -78 °C and treated via cannula with a solution of
25 (500 mg, 1.45 mmol) in THF (4 mL). The reaction was
stirred at -78 °C for 30 min, followed by warming to ambient
temperature for 2 h. The solution was quenched by addition
of 1 mL saturated ammonium chloride solution, diluted with
EtOAc and washed with water. Drying (Na2SO4) and concen-
tration in vacuo afforded a yellow solid, which was chromato-

964 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
graphed over 100 g of silica gel with 1-2% CH3OH/CH2Cl2 to
yield 497 mg (83%) of 32 as a light yellow solid: mp 161-163
°C.
g, 45 mmol) and 42 (8.5 g,49.6 mmol) were placed in absolute
EtOH and stirred at room temperature for 30 min. The
reaction was then heated to reflux until complete by TLC,
cooled and the solvent removed in vacuo. The residue was
partitioned between EtOAc/H2O. The organic layer was washed
with brine and dried (Na2SO4). Removal of solvent gave 44 as
a brown solid which was crystallized from EtOAc/hexane as
orange needles 11.5 g (65%): mp 127-127 °C.
(S)-N-[[3-[3-F lu or o-4-[3-(2-ca r beth oxyeth yl)-1H-p yr r ol-
1-yl]p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (33).
A solution of 32 (150 mg, 0.36 mmol) and copper[I] chloride
(54 mg, 0.54 mmol) in 1:1 CH3OH-THF (15 mL) at 0 °C was
treated with NaBH4 (136 mg, 3.6 mmol). The solution was
stirred at 0 °C for 30 min and then warmed to ambient
temperature for 1 h. The solution was treated with 2 mL
saturated ammonium chloride solution and filtered through
Celite. The filtrate was concentrated in vacuo and the residue
was diluted with EtOAc and washed with water. Drying (Na2-
SO4) and concentration in vacuo afforded 33 150 mg (99%) as
a white solid.
(S)-N-[[3-[3-F lu or o-4-[3-(3-h yd r oxyp r op yl)-1H-p yr r ol-
1-yl]p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (34).
A solution of the ester 33 (275 mg, 0.66 mmol) in THF (15
mL) was treated with lithium borohydride (287 mg, 13.2 mmol)
and stirred at ambient temperature for 18 h. The solution was
treated with 1 mL of saturated ammonium chloride solution,
diluted with EtOAc, and washed with water. Drying (Na2SO4)
and concentration in vacuo afforded an oil, which was chro-
matographed over 20 g silica gel eluting with 2-4% CH3OH/
CH2Cl2 to yield 96 mg (39%) of 34 as a white solid.
(S)-N-[[3-[3-F lu or o-4-[3-(3-m eth a n esu lfon yla m in op r o-
p yl)-1H-p yr r ol-1-yl]p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]-
a ceta m id e (35). A solution of the alcohol 34 (100 mg, 0.266
mmol) and NEt3 (0.12 mL, 0.87 mmol) CH2Cl2 (2 mL) at 0 °C
was treated with methanesulfonyl chloride (58 mL, 0.73 mmol)
for 30 min. The solution was diluted with CH2Cl2 and washed
with water and saturated sodium bicarbonate solution. Drying
(Na2SO4) and concentration in vacuo afforded the mesylate as
a solid. This was dissolved in DMF (2 mL) and added via
cannula to a 0 °C solution of methanesulfonamide (38 mg, 0.40
mmol) in DMF (2 mL) that had been previously treated with
NaH (17 mg of 60% in oil, 0.43 mmol). The reaction was then
warmed at 60 °C for 18 h and cooled and the DMF removed in
vacuo. The residue was dissolved in EtOAc and washed with
water. Drying (Na2SO4) and concentration in vacuo afforded
a solid which was subjected to radial chromatography on a 2
mm plate, eluting with 1-4% CH3OH/CH2Cl2 to yield 31 mg
(26%) of 35 as a white solid.
(S)-[[3-[3-F lu or o-4-(3-a cetylp yr r ol-1-yl)p h en yl]-2-oxo-
5-oxa zolid in yl]m eth yl]a ceta m id e (38). The same proce-
dures were used as described for the preparation of 3-8 above.
Starting with 37 (11.612 g, 42.38 mmol) and making noncriti-
cal variations 38, 1.12 g (19%), was isolated as a pink solid:
mp 145-148 °C.
(S)-[[3-[3-Flu or o-4-[3-(1-h ydr oxyeth yl)pyr r ol-1-yl]ph en -
yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (39). Sodium
borohydride (0.046 g, 1.21 mmol) was added to a CH2Cl2 (2.5
mL) and CH3OH (2.5 mL) solution of 38 (0.101 g, 0.28 mmol).
After stirring overnight, the reaction was quenched with 1 mL
saturated ammonium chloride and the mixture was partitioned
between water and CH2Cl2. The aqueous portion was extracted
with CH2Cl2. The combined organic portions were dried
(MgSO4) and concentrated in vacuo to give of crude material
that was purified on a preparative TLC plate (1000 µm, eluted
with 5% MeOH/CH2Cl2 2×) to give 0.073 g (72%) of the 39 as
a white solid: mp 169-171 °C.
(S)-[3-[3-Flu or o-4-(1H-4-car beth oxypyr azol-1-yl)ph en yl]-
2-oxo-5-oxa zolid in yl]m eth a n ol (45). The nitro compound
44 (10 g, 35.8 mmol) was hydrogenated in MeOH with 10%
Pd/C (1 g) at 20 psi on a Parr shaker for 3 h. The reaction was
filtered through Celite and the solvent removed in vacuo to
give pure aniline as an orangish solid 8.63 g (97%). This aniline
(8.36 g, 33.5 mmol) and NaHCO3 (5.6 g, 67 mmol) were placed
in dry THF (200 mL) and cooled to 0 °C. Benzyl chloroformate
(5.3 mL, 36.9 mmol) was added and the reaction was allowed
to warm to room temperature. It was partitioned between
EtOAc/H2O and the organic layer was washed with brine and
dried (Na2SO4). Removal of solvent gave pure Cbz-aniline as
an orange solid. 12.7 g (98%). The Cbz-aniline (1.23 g, 3.2
mmol) was place in dry THF at 78 °C under N2. BuLi was
added dropwise and the reaction was stirred 45 min. The R-
(-)-glycidyl butyrate (0.48 mL, 3.4 mmol) was added dropwise
and stirring was continued at -78 °C for 1 h then at room
temperature overnight. The mixture was quenched with
saturated NaHCO3 and partitioned between H2O and EtOAc.
The organic layer was washed with brine and dried (Na2SO4).
Removal of solvent gave an orange residue which was passed
through a 4 × 5 cm silica gel plug with 50%EtOAc/hexane to
100% EtOAc gradient. Product 45 was isolated as a white
solid: 0.885 g (79%); mp 133-134 °C; [R]D -39° (c 0.93,
1
DMSO); H NMR (400 MHz, CDCl3) δ 1.38 (t, J ) 7.1 Hz, 3
H), 2.35-2.45 (br m, 1 H), 3.77-3.83 (m, 1 H), 4.02-4.10 (m,
3 H), 4.34 (q, J ) 7.1 Hz, 2 H), 4.78-4.82 (m, 1 H), 7.28 (d,
J ) 10.7 Hz, 1 H), 7.77 (dd, J ) 2.4, 11.4 Hz, 1 H), 7.88 (t,
J ) 8.8 Hz, 1 H), 8.11 (s, 1 H), 8.43 (d, J ) 2.4 Hz, 1 H); HRMS
calcd for C16H16FN3O5 + H 350.1152, found 350.1153. Anal.
Calcd for C16H16FN3O5: C, 55.01; H, 4.62; N, 12.03. Found:
C, 55.68; H, 4.74; N, 11.66.
(S)-[3-[3-Flu or o-4-(1H-4-car beth oxypyr azol-1-yl)ph en yl]-
2-oxo-5-oxa zolid in yl]m eth yl Azid e (46). The alcohol 45
(0.76 g, 2.2 mmol) and NEt3 (0.46 mL, 3.3 mmol) were placed
in dry CH2Cl2 at 0 °C under N2. Methanesulfonyl (0.185 mL,
2.4 mmol) was added dropwise. The reaction was allowed to
stir at room temperature for 4 h at which time it was
partitioned between saturated NaHCO3 and CH2Cl2. The
organic layer was washed with brine and dried (Na2SO4).
Removal of solvent gave the mesylate as an off white solid
which was pure by TLC and NMR: 0.925 g (98%). The
mesylate (0.74 g, 1.73 mmol) and NaN3 (0.84 g, 13 mmol) were
placed in dry DMF and heated to 65 °C overnight. The reaction
was cooled, diluted with EtOAc, washed with water (2×) and
brine, and dried (Na2SO4). Removal of solvent gave 46 as an
off white solid: 0.6 g (93%); mp 128-130 °C; [R]D -105° (c
1
0.96, DMSO); H NMR (400 MHz, CDCl3) δ 1.38 (t, J ) 7.1
Hz, 3 H), 3.63 (dd, J ) 4.2, 13.3 Hz, 1 H), 3.76 (dd, J ) 4.4,
13.2 Hz, 1 H), 3.91 (dd, J ) 6.2, 8.9 Hz, 1 H), 4.13 (t, J ) 8.9
Hz, 1 H), 4.34 (q, J ) 7.1 Hz, 2 H), 4.82-4.87 (m, 1 H), 7.28
(d, J ) 7.3 Hz, 1 H), 7.79 (dd, J ) 2.4, 13.7 Hz, 1 H), 7.91 (t,
J ) 8.8 Hz, 1 H), 8.12 (s, 1 H), 8.45 (d, J ) 2.4 Hz, 1 H); HRMS
calcd for C16H15FN6O4 374.1139, found 374.1143.
3-F lu or o-4-h yd r a zin on itr oben zen e (42). K2CO3 (35 g,
251 mmol) and 3,4-difluoronitrobenzene (20 g, 126 mmol) were
stirred in CH3CN (200 mL) overnight. The solvent was
removed in vacuo and the residue was partitioned between
EtOAc/H2O. The organic layer was washed with brine and
dried (Na2SO4). Removal of solvent in vacuo gave pure 42 as
(S)-N-[[3-[3-F lu or o-4-(1H -4-ca r b et h oxyp yr a zol-1-yl)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (47). The
azide 46 (0.59 g, 1.58 mmol) was placed in dry THF and a
solution of triphenylphosphine (0.5 g, 1.89 mmol) in THF was
added dropwise. The reaction was stirred at room temperature
for 1.5 h at which time water (3 mL) was added and the
temperature raised to 65 °C overnight. The reaction was cooled
and the solvent removed in vacuo. The residue was partitioned
between CH2Cl2 and water. The aqueous was extracted with
CH2Cl2 and the combined extracts were dried (Na2SO4).
Removal of solvent in vacuo gave a residue which was
chromatographed on a 2 × 30 cm column with 5-10% MeOH/
1
a yellow solid: 20.2 g (94%); mp 144-145 °C; H NMR (400
MHz, CDCl3) δ 3.75 (br s, 2 H), 5.97 (br s, 1 H), 7.25 (t, J )
8.7 Hz), 7.89 (dd, J ) 2.3, 9.4 Hz, 1 H), 8.05 (d, J ) 9.1 Hz, 1
H); MS (+ESI) m/z 172 (M + H). Anal. Calcd for C6H6FN3O2:
C, 42.11; H, 3.53; N, 24.55. Found: C, 42.49; H, 3.52; N, 24.13.
3-F lu or o-1-n itr o-4-(1H-4-ca r beth oxyp yr a zol-1-yl)ben -
zen e (44). The dialdehyde 4328 (6.5 g, 45 mmol), NaOAc (3.7

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 965
CHCl3 gradient. The intermediate amine was isolated as a
white solid: 0.43 g (77%). The amine (0.35 g, 1 mmol) and
pyridine (0.243 mL, 3 mmol) were placed in CH2Cl2. Acetic
anhydride (0.132 mL, 1.4 mmol) was added and the reaction
was stirred at room temperature until complete as determined
by TLC. The reaction was then diluted with CH2Cl2, washed
with 1 N HCl (2×), saturated NaHCO3, and brine, and dried
(Na2SO4). Removal of solvent gave a residue which was
chromatographed on a 2 × 35 cm column with 5% MeOH/CH2-
Cl2. Product 47 was isolated as a white solid: 0.39 g (99%);
mp 160-161 °C; [R]D -23° (c 0.47, DMSO); 1H NMR (400 MHz,
CDCl3) δ 1.39 (t, J ) 7.1 Hz, 3 H), 2.04 (s, 3 H), 3.61-3.69 (m,
1 H), 3.70-3.79 (m, 1 H), 3.84 (dd, J ) 6.8, 15.8 Hz, 1 H), 4.10
(t, J ) 9.0 Hz, 1 H), 4.35 (q, J ) 7.1 Hz, 2 H), 4.81-4.90 (m,
1 H), 5.95 (br t, 1 H), 7.28 (d, J ) 8.8 Hz, 1 H), 7.75 (dd, J )
2.4, 13.7 Hz, 1 H), 7.91 (t, J ) 8.9 Hz, 1 H), 8.12 (s, 1 H), 8.45
(d, J ) 2.4 Hz, 1 H); HRMS calcd for C18H19FN4O5 + H
tected aniline 52 (3.17 g, 7.25 mmol) was reacted as above for
the preparation of compound 47 making noncritical variations.
The procedures afforded 54 as a white solid: 0.88 g (27%); mp
199-201 °C.
(S)-N-[[3-[3-Flu or o-4-(1H-4-N-(ter t-bu toxyca r bon yla m i-
n o)p yr a zol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a c-
eta m id e (55). The aryl iodide 54 (0.265 g, 0.6 mmol), PdOAc2
(13.3 mg, 0.06 mmol), dppp (29.7 mg, 0.072 mmol), and Et3N
(0.1 mL, 0.72 mmol) were heated in 1:10 H2O/DMF (10 mL)
at 100 °C an atmosphere of CO with vigorous stirring for 2
days. The reaction was cooled, filtered and the solvent
removed. The residue was triturated in hot acetone and the
solid acid filtered off to give 0.2 g (92%): HRMS (FAB) calcd
for C16H15FN4O5 362.1104, found 362.1265. This acid (0.15 g,
0.4 mmol), DPPA (0.09 mL, 0.4 mmol), and NEt3 (0.057 mL,
0.4 mmol) were refluxed in t-BuOH for 3 days. The solvent
was removed and the residue was chromatographed on a 2 ×
30 cm column with 5% MeOH/CH2Cl2 to give pure 55 as an
ivory solid: 110 mg (58%); mp 177-179 °C.
391.1418, found 391.1421. Anal. Calcd for
C18H19FN4O5‚
0.25H2O: C, 54.75; H, 4.98; N, 14.19. Found: C, 54.67; H, 4.98;
N, 14.11.
(S)-N-[[3-[3-F lu or o-4-(1H-4-N-(a cetyla m in o)p yr a zol-1-
yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (56).
The Boc-amine 55 (20 mg, 0.05 mmol) was deprotected in 1:1
TFA/CH2Cl2 (4 mL) at room temperature under N2 for 4 h.
The solvent and excess TFA were removed in vacuo and the
residue was triturated in Et2O. The solvent was removed again
and the solid product was placed in CH2Cl2 (5 mL) and NEt3
(0.5 mL) was added followed by Ac2O (0.5 mL). The reaction
was stirred at room temperature for 2 h and evaporated to
dryness in vacuo. The residue was taken up in CH2Cl2 and
washed with saturated NaHCO3. The organic layer was dried
(Na2SO4) and the solvent removed. The product 56 was
purified on a 2 × 25 cm column with 10% MeOH/CH2Cl2 and
isolated as a white solid: 15 mg (80%); mp 229-230 °C dec.
(S)-N-[[3-[3-F lu or o-4-(1H -4-t r im et h ylsilyla cet ylen yl-
p yr a zol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta -
m id e (57). The acetylene derivative 53 (1.2 g, 3 mmol) was
reacted as described above for the preparation of compound
47 making noncritical variations. The procedures afforded 57
as a white solid: 0.35 g (28%); mp 197-199 °C.
(S )-N -[[3-[3-F lu or o-4-(1H -4-a ce t yle n ylp yr a zol-1-yl)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (58). The
TMS-acetylide 57 (0.31 g, 0.75 mmol) was treated with K2-
CO3 (0.1 g) in MeOH (20 mL) at room temperature for 1 h.
The solvent was removed in vacuo and the residue was
partitioned between CH2Cl2 and water. The organic layer was
dried (Na2SO4) and the solvent removed to give pure product
as a white solid: 0.25 g (98%); mp 180-182 °C.
3-F lu or o-1-n it r o-4-(1H -3-ter t-b u t oxyca r b on yla m in o-
p yr a zol-1-yl)ben zen e (63). The aminopyrazole derivative
62 (3 g, 13.5 mmol), di-tert-butyl dicarbonate (2.95 g, 13.5
mmol), NEt3 (1.88 mL, 13.5 mmol) and (dimethylamino)-
pyridine (20 mg) were placed in dry DMF and stirred under
nitrogen overnight. The reaction was partitioned between
water and Et2O and the organic layer was washed with water,
brine and dried (Na2SO4). Removal of solvent gave a residue
that was purified on a 3 × 30 cm column to give 63: 2.2 g
(51%); 1H NMR (400 MHz, CDCl3) δ 1.55 (s, 9 H), 5.97 (d, J )
2.6 Hz, 1 H), 7.12 (br s, 1 H), 8.07-8.14 (m, 4 H); MS (+ESI)
m/z 322 (M + H); MS (-ESI) m/z 321 (M - H).
(S)-N-[[3-[3-F lu or o-4-(1H-4-cya n op yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (50). The carboxa-
mide 48 (0.23 g, 0.64 mmol) was placed in dry DMF (7.5 mL)
and cooled to 0 °C under N2. SOCl2 (0.07 mL, 0.95 mmol) was
added dropwise and the reaction was stirred at room temper-
ature for 30 min. More SOCl2 (0.07 mL, 0.95 mmol) was added
and stirring was continued another 30 min. Saturated NaH-
CO3 was added and the reaction was extracted with CH2Cl2.
The extracts were dried (Na2SO4) and the solvent removed.
The residue was chromatographed on a 2 × 30 cm column with
5% MeOH/CH2Cl2. Product 50 was isolated as a white solid:
155 mg (71%); mp 194-196 °C; [R]D -27° (c 0.57, DMSO); 1H
NMR (400 MHz, CDCl3) δ 2.04 (s, 3 H), 3.65-3.76 (m, 2 H),
3.86 (dd, J ) 6.9, 8.9 Hz, 1 H), 4.10 (t, J ) 8.9 Hz, 1 H), 4.81-
4.90 (m, 1 H), 6.07 (br t, 1 H), 7.29 (d, J ) 7.6 Hz, 1 H), 7.78
(dd, J ) 1.9, 13.8 Hz, 1 H), 7.89 (t, J ) 8.8 Hz, 1 H), 8.00 (s,
1 H), 8.38 (s, 1 H); HRMS calcd for C16H14FN5O3 + H 344.1159,
found 344.1153. Anal. Calcd for C16H14FN5O3‚0.5H2O: C,
54.55; H, 4.29; N, 19.87. Found: C, 54.66; H, 4.24; N, 19.46.
3-Flu or o-1-(p h en ylm eth oxyca r bon yla m in o)-4-(1H-4-io-
d op yr a zol-1-yl)ben zen e (52). 4-Iodopyrazole (10 g, 52 mmol),
3,4-difluoronitrobenzene (8.3 g, 52 mmol) and K2CO3 (7.2 g,
52 mmol) were placed in dry DMSO (100 mL) and heated to
90 °C under N2 for 24 h. The reaction was cooled and
partitioned between EtOAc and water. The aqueous layer was
extracted with EtOAc and the combined extracts were dried
(Na2SO4). Removal of solvent gave a residue which was taken
up in Et2O, washed with H2O (3×) and dried (Na2SO4).
Removal of solvent again gave pure pyrazolylnitrobenzene
intermediate as a yellow solid, 16.5 g (95%). This pyrazolylni-
trobenzene (2.6 g, 7.8 mmol) and SnCl2 (8.8 g, 39 mmol) were
placed in absolute EtOH and heated to 75 °C for 1 h. The
reaction was cooled and poured into ice. The mixture was made
basic with saturated NaHCO3 and filtered. The filtrate was
extracted with EtOAc (3×). The combined extracts were
washed with brine and dried (Na2SO4). Removal of solvent
gave the aniline as a yellow oil 2.1 g (88%). This aniline (9.41
g, 31.05 mmol) and NaHCO3 (5.2 g, 62 mmol) were placed in
dry THF and benzyl chloroformate was added. The reaction
was stirred at room temperature overnight, diluted with water
and extracted with EtOAc (3×). The extracts were dried (Na2-
SO4) and the solvent was removed in vacuo to give 52 as a
yellow solid: 13.72 g (99% from the aniline).
(S)-[[3-[3-F lu or o-4-(1H-3-tr iflu or om eth ylp yr a zol-1-yl)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (64). The
nitro compound 61 (6.5 g, 23.6 mmol) was reacted as described
above for the preparation of compound 47 making noncritical
variations. The procedures afforded 64 as a white solid: 1.32
3-F lu or o-1-(p h en ylm et h oxyca r b on yla m in o)-4-(1H -4-
tr im eth ylsilyla cetylen ylp yr a zol-1-yl)ben zen e (53). The
Cbz intermediate 52 (2.0 g, 4.6 mmol), TMS-acetylene (0.78
mL, 5.5 mmol) and diethylamine (20 mL) were place under
N2. Pd(PPh3)2Cl2 (0.1 mmol, 70 mg) and CuI (0.005 g) were
added. The reaction was stirred at room temperature under
N2 for 8 h. The reaction was evaporated to dryness and the
residue was purified on a 2 × 40 cm column. Product 53 was
isolated as a solid 1.6 g (85%): mp 133-136 °C.
g (14%); mp 180-181 °C; [R]25 ) -23 °C (c 0.95, DMSO); 1H
D
NMR (400 MHz, CDCl3) δ 2.04 (s, 3 H), 3.65-3.78 (m, 2 H),
3.85 (dd, J ) 6.9, 9.0 Hz, 1 H), 4.10 (t, J ) 8.9 Hz, 1 H), 4.79-
4.85 (m, 1 H), 6.09 (br t, 1 H), 6.73 (d, J ) 2.4 Hz, 1 H), 7.24
(d, J ) 10.4 Hz, 1 H), 7.77 (dd, J ) 2.5, 13.7 Hz, 1 H), 7.90 (t,
J ) 8.8 Hz, 1 H), 8.00 (s, 1 H); MS (+ESI) m/z 387 (M + H).
Anal. Calcd for C16H14F4N4O3: C, 49.75; H, 3.65; N, 14.50.
Found: C, 50.01; H, 3.70; N, 14.10.
(S)-N-[[3-[3-F lu or o-4-(1H-4-iod op yr a zol-1-yl)p h en yl]-2-
oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (54). The Cbz-pro-
(S)-N-[[3-[3-F lu or o-4-(1H -3-ter t-b u t oxyca r b on yla m i-
n op yr a zol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a c-

966 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
eta m id e (65). The Boc intermediate 63 (1.8 g, 5.6 mmol) was
reacted as described above for the preparation of compound
47. The main variation was that 2 equiv of n-BuLi were used
in the oxazolidinone ring forming reaction. The procedures
afforded 65 as a pale yellow solid: 300 mg (12%); mp 193-
194 °C.
(S)-N-[[3-[3-F lu or o-4-(1H-3-a m in op yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m et h yl]a cet a m id e (66). The Boc-
protected material 65 (0.25 g, 0.58 mmol) was dissolved in
CH2Cl2 (7 mL) and cooled to 0 °C under nitrogen. Trifluoro-
acetic acid (5 mL) was added and the reaction was allowed to
warm to room temperature and stirred 3 h. The solvent and
excess TFA were removed in vacuo and the residue was
partitioned between 1 M NaHCO3 and CH2Cl2. The aqueous
layer was extracted with 5%MeOH/CH2Cl2 and the extracts
were combined and dried (Na2SO4). Removal of solvent gave
pure 66 as a pale yellow solid: 0.16 g (83%).
(S)-N-[[3-[3-Flu or o-4-(1H-3-ben zyloxym eth yla cetyla m i-
n op yr a zol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a c-
eta m id e (67). The arylamine 66 (25 mg, 0.075 mmol) and
NEt3 (0.012 mL, 0.082 mmol) were placed in dry methylene
chloride. Benzyloxyacetyl chloride (0.013 mL, 0.082 mmol) was
added and the reaction was stirred under nitrogen for 4 h and
then partitioned between saturated NaHCO3 solution and CH2-
Cl2. The organic layer was dried (Na2SO4) and the solvent
removed to give a residue which was chromatographed on a
2 × 30 cm column with 7% MeOH/CHCl3. The product 67 was
isolated as a tan solid: 35 mg (97%).
Anal. Calcd for C16H14FN5O3‚1.25CH3OH: C, 54.04; H, 4.99;
N, 18.27. Found: C, 53.65; H, 4.35; N, 18.10.
N-{[(5S)-3-(3-F lu or o-4-h yd r a zin op h en yl)-2-oxo-1,3-ox-
a zolid in -5-yl]m eth yl}a ceta m id e (72). A solution of the
aniline 20 (5.34 g, 20.0 mmol) in 8 mL of methanol, 20 mL of
water plus 6 mL of 37% HCl at -10 °C was treated dropwise
with a solution of NaNO2 (1.40 g, 20.2 mmol) in 4 mL of water
over a 2 min period. After stirring for 8 min at -10° C, the
contents were transferred to a dropping funnel and added over
a 2 min period to a vigorously stirred solution of SnCl2‚2H2O
(10.80 g, 47.8 mmol) in 52 mL of 37% HCl at -10 °C. After
stirring for an additional 40 min, the pH of the reaction
mixture was adjusted to 7-8 by the dropwise addition of 10
N NaOH (80 mL) with cooling in an ice/acetone bath. The
milky white aqueous suspension was concentrated and the
gelatinous residue triturated (5 × 150 mL) with chloroform-
methanol (9:1). The combined organic extracts were dried with
anhydrous Na2SO4 and concentrated in vacuo to obtain 5.2 g
of crude product. Recrystallization from a methanol, methylene
chloride, diethyl ether mixture afforded 4.26 g (75.5%) of
analytically pure 72 as a white solid: mp 173-175 °C; [R]25
D
1
-26° (c 0.79, DMSO); H NMR (400 MHz, DMSO-d6) δ 8.22
(t, J ) 5.77 Hz, 1 H), 7.32 (dd, J ) 2.34, 14.14 Hz, 1 H), 7.11
(q, J ) 8.95 Hz, 1 H), 7.04 (dd, J ) 2.27, 8.87 Hz, 1 H), 6.53 (s,
1 H), 4.64 (m, 1 H), 4.01 (m, 3 H), 3.63 (m, 1 H), 3.37 (t, J )
5.54 Hz, 2 H), 1.81 (s, 3 H); MS (EI) m/z 282 (M + H). Anal.
Calcd for C12H15FN4O3: C, 51.06; H, 5.36; N, 19.85. Found:
C, 51.07; H, 5.34; N, 19.76.
(S)-N-[[3-[3-Flu or o-4-(1H-3-m eth ylpyr azol-1-yl)ph en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (73). Acetaldehyde
dimethyl acetal (0.105 mL, 0.71 mmol) and the arylhydrazine
72 (0.2 g, 0.71 mmol) were heated at reflux in ethanol for 2 h.
The solvent was removed in vacuo and the residue was
partitioned between CH2Cl2 and saturated NaHCO3. The
organic layer was dried (Na2SO4) and the solvent removed in
vacuo. The residue was purified on a 2 × 35 cm column with
5% MeOH/CH2Cl2 to give the desired product 73 (high Rf) as
(S)-N-[[3-[3-F lu or o-4-(1H-3-h yd r oxym eth yla cetyla m i-
n op yr a zol-1-yl)p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a c-
eta m id e (68). The intermediate 67 (30 mg, 0.062 mmol) was
hydrogenated in MeOH on a Parr shaker at 30 psi with 10%
Pd/C for 6 h. The reaction was filtered through Celite and
evaporated to dryness. The residue was purified on a 2 × 35
cm column with 10% MeOH/CHCl3 to give the product as a
tan solid: 22 mg (99%); mp 129-132 °C.
(S)-N-[[3-[3-F lu or o-4-(1H -3-a cet yla m in op yr a zol-1-yl)-
p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (69). In-
termediate 66 (26 mg, 0.078 mmol) and NEt3 (0.012 mL, 0.085
mmol) were placed in dry CH2Cl2. Acetic anhydride (2 mL) was
added and the reaction was stirred at room temperature for 2
h and evaporated to dryness. The residue was purified on a
2 × 30 cm column with 10% MeOH/CHCl2 to give product as
a white solid: 25 mg (78%); mp 212-214 °C.
(S)-N-[[3-[3-F lu or o-4-(1H-3-m eth a n esu lfon yla m in op yr -
a zol-1-yl)p h e n yl]-2-oxo-5-oxa zolid in yl]m e t h yl]a ce t a -
m id e (70). Intermediate 66 (20 mg, 0.06 mmol) was placed in
pyridine (3 mL) and cooled to 0 °C. Methanesulfonyl chloride
(0.005 mL, 0.066 mmol) was added and the reaction was
stirred at room temperature overnight. The reaction was
diluted with CH2Cl2, washed with saturated NaHCO3 and
dried (Na2SO4). Removal of solvent in vacuo gave the product
as a pale yellow foam: 18 mg (73%); mp 145-146 °C.
a solid 110 mg (47%): mp 129-131 °C; [R]25 ) -29° (c 0.74,
D
1
DMSO); H NMR (400 MHz, CDCl3) δ 2.01 (s, 3 H), 2.35 (s, 3
H), 3.66 (dd, J ) 4.6, 6.0 Hz, 2 H), 3.81 (dd, J ) 6.7, 9.1 Hz,
1 H), 4.06 (t, J ) 9.0 Hz, 1 H), 4.76-4.83 (m, 1 H), 6.23 (d,
J ) 2.4 Hz, 1 H), 6.71 (br t, J ) 6.0 Hz, 1 H), 7.17 (dd, J ) 1.7,
8.9 Hz, 1 H), 7.63 (dd, J ) 2.4, 13.9 Hz, 1 H), 7.82 (d, J ) 1.7
Hz, 1 H); HRMS (FAB) calcd for C16H17FN4O3 + H1 333.1363,
found 333.1349. Anal. Calcd for C16H17FN4O3‚0.25H2O: C,
57.05; H, 5.24; N, 16.63. Found: C, 57.05; H, 5.10; N, 16.44.
(S)-N-[[3-[3-Flu or o-4-(1H-5-m eth ylpyr azol-1-yl)ph en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (74). In addition
to the above material a lower Rf product was isolated which
was found to be the 5-regioisomer by 2D NMR: 60 mg (25%);
1
mp 139-141 °C; H NMR (400 MHz, CDCl3) δ 2.01 (s, 3 H),
2.20 (s, 3 H), 3.59-3.71 (m, 2 H), 3.84 (dd, J ) 6.8, 9.1 Hz, 1
H), 4.08 (t, J ) 9.0 Hz, 1 H), 4.76-4.83 (m, 1 H), 6.19 (s, 1 H),
6.63 (br t, J ) 6.0 Hz, 1 H), 7.27 (dd, J ) 1.8, 8.7 Hz, 1 H),
7.44 (t, J ) 8.5 Hz, 1 H), 7.60 (d, J ) 1.5 Hz, 1 H), 7.67 (dd,
J ) 2.4, 12.2 Hz, 1 H); HRMS (FAB) calcd for C16H17FN4O3 +
H 333.1363, found 333.1349. Anal. Calcd for C16H17FN4O3‚
0.75H2O: C, 55.57; H, 5.39; N, 16.20. Found: C, 55.71; H, 5.10;
N, 16.00.
(S)-N-[[3-[3-F lu or o-4-(1H-3-cya n op yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (71). The amino
derivative 67 (36 mg, 0.108 mmol) was placed in 2 N HCl (3
mL) at 0 °C. A solution of NaNO2 in water (1 mL) was added
and the mixture was stirred 30 min at 0 °C before being
neutralized with solid NaHCO3. In a separate flask CuCN
(12.6 mg, 0.14 mmol), KCN (10.5 mg, 0.162 mmol), water (2
mL) and EtOAc (3 mL) were cooled to 0 °C. The diazonium
salt was added to this mixture with a pipet. The reaction was
stirred at 0 °C for 30 min and then at room temperature for 2
h. It was partitioned between saturated NaHCO3 and CHCl3
and extracted with CHCl3. The extracts were dried (Na2SO4)
and evaporated to dryness. The residue obtained was purified
on a 2 × 35 cm column with 5% MeOH/CHCl3. Product was
isolated as a yellow free flowing powder: 14 mg (38%); mp
N-{[(5S)-3-(4-{2-[(E)-3-eth oxy-2-p r op en oyl]h yd r a zin o}-
3-flu or op h en yl)-2-oxo-1,3-oxa zolid in -5-yl]m et h yl}a cet -
a m id e (76). The arylhydrazine 72 (1.3 g, 4.6 mmol), the
acryloyl chloride 7534 (0.42 g, 3 mmol) and triethylamine (0.42
mL, 3 mmol) were heated to reflux in dry THF for 5 h. The
reaction was cooled and diluted with a large volume of Et2O.
The precipitated product was isolated as an orange solid and
used without further purification: 1H NMR (400 MHz, DMSO-
d6) δ 1.25 (t, J ) 7.0 Hz, 3 H), 1.82 (s, 3 H), 3.38 (t, 2 H), 3.65-
3.70 (m, 1 H), 3.91 (q, J ) 7.0 Hz, 2 H), 4.03 (t, 1 H), 4.62-
4.70 (m, 1 H), 5.41 (d, 1 H), 6.72 (t, 1 H), 7.05 (d, 1 H), 7.39 (d,
1 H), 7.42 (br s, 1 H), 7.53 (br s, 1 H), 8.21 (br t, 1 H); MS
(+ESI) m/z 381 (M + H); MS (-ESI) m/z 379 (M - H).
1
190-192 °C dec; H NMR (400 MHz, CDCl3) δ 2.04 (s, 3 H),
3.62-3.73 (m, 2 H), 3.86 (dd, J ) 6.7, 9.1 Hz, 1 H), 4.11 (t,
J ) 8.9 Hz, 1 H), 4.80-4.88 (m, 1 H), 5.98 (br t, 1 H), 6.88 (d,
J ) 2.6 Hz, 1 H), 7.27 (d, J ) 6.1 Hz, 1 H), 7.80 (dd, J ) 2.4,
13.8 Hz, 1 H), 7.89 (t, J ) 8.8 Hz, 1 H), 8.04 (t, J ) 2.5 Hz, 1
H); HRMS calcd for C16H14FN5O3 343.1081, found 343.1078.
(S)-[[3-[3-F lu or o-4-(1H-3-h yd r oxyp yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (77). The acylhy-

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 967
drazine 76 was stirred in concentrated HCl for 4 h at room
temperature. An equal volume of water was added and the
reaction was evaporated to dryness under Hi-vac. The residue
was chromatographed on a 2 × 30 cm column with 5%MeOH/
CH2Cl2. The product 77 was isolated as a yellow solid: 0.65 g
(65% for 2 steps); mp 234-235 °C; 1H NMR (400 MHz, DMSO-
d6) δ 1.83 (s, 3 H), 3.42 (t, J ) 5.5 Hz, 2 H), 3.76 (dd, J ) 6.5,
9.1 Hz, 1 H), 4.12 (t, J ) 9.0 Hz, 1 H), 4.70-4.78 (m, 1 H),
5.82 (d, J ) 2.5 Hz, 1 H), 7.39 (d, J ) 9.0 Hz, 1 H), 7.65 (dd,
J ) 2.4, 13.2 Hz, 1 H), 7.70 (t, J ) 9.1 Hz, 1 H), 7.86 (t, J )
2.6 Hz, 1 H), 8.23 (br t, 1 H); MS (+ESI) m/z 335 (M + H); MS
(-ESI) m/z 333 (M - H). Anal. Calcd for C15H15FN4O4‚1/
3H2O: C, 53.20; H, 4.64; N, 16.46. Found: C, 53.20; H, 4.73;
N, 16.02.
Hz, 1 H), 4.84 (br m, 1 H), 6.01 (br t, 1 H), 7.34-7.43 (m, 2 H),
7.75-7.80 (m, 3 H); MS (ESI+) m/z 344 (M + H); MS (ESI-)
m/z 342 (M - H). Anal. Calcd for C16H14FN5O3: C, 55.98; H,
4.11; N, 20.40. Found: C, 55.86; H, 3.99; N, 20.31.
N-{[(5S)-3-(4-Azid o-3-flu or op h en yl)-2-oxo-1,3-oxa zoli-
d in -5-yl]m et h yl}a cet a m id e (86). The aniline 20 (2 g, 7.5
mmol) was dissolved in concentrated HCl (10 mL) and water
(10 mL) and cooled to 0 °C. Sodium nitrite was added and the
yellow solution was stirred at 0 °C for 2 h. A solution of NaN3
(0.97 g, 15 mmol) and NaOAc (12.3 g, 150 mmol) was added
dropwise. The mixture was extracted with EtOAc and the
combined extracts were washed with brine and dried (Na2SO4).
Removal of solvent gave product as a tan solid, 2.1 g (96%),
that was used without further purification.
(S)-[[3-[3-F lu or o-4-(1H-3-a cetoxyp yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (78). The alcohol
77 (20 mg, 0.06 mmol) was placed in acetic anhydride (3 mL)
and pyridine (0.03 mL) was added. The reaction was stirred
at room temperature for 3 h and then evaporated to dryness.
The residue was purified on a 2 × 30 cm column with 3%
MeOH/CH2Cl2 to give the product as an oil. This was crystal-
lized from CH2Cl2/hexane to give 20 mg (89%): mp 125-128
°C.
(S)-[[3-[3-F lu or o-4-(1H-3-m eth oxyp yr a zol-1-yl)p h en yl]-
2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e (79). The alcohol
77 (0.11 g, 0.33 mmol), methyl iodide (3.3 mmol) and K2CO3
were heated to reflux in acetone for 3 h. The reaction was
cooled, filtered and evaporated to dryness. The residue was
purified on a 2 × 30 cm column with 5% MeOH/CH2Cl2 to give
the product as a gum which was solidified in CH2Cl2/hexane
to yield a tan solid: 85 mg (74%); mp 132-133 °C.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2,3-tr ia -
zoles 87 a n d 89-91 fr om Azid e 86 a n d Alk yn es. The azide
86 (1 equiv) was suspended in benzene and the alkyne (3
equiv) was added and the mixture was refluxed. The reaction
was cooled and the precipitated products were isolated.
N-({(5S)-3-[4-(4-Acet yl-1H -1,2,3-t r ia zol-1-yl)-3-flu or o-
p h e n yl]-2-oxo-1,3-oxa zolid in -5-yl}m e t h yl)a ce t a m id e
(87): yield 0.41 g (66%); mp 183-186 °C; [R]25D ) -29° (c 0.73,
1
DMSO); H NMR (400 MHz, CDCl3) δ 2.05 (s, 3 H), 2.77 (s, 3
H), 3.67-3.80 (m, 2 H), 3.88 (dd, J ) 9, 7 Hz, 1 H), 4.12 (t,
J ) 9 Hz, 1 H), 4.81-4.90 (m, 1 H), 6.05 (br t, 1 H), 7.35 (d,
J ) 11 Hz, 1 H), 7.82 (dd, J ) 2, 13 Hz, 1 H), 7.97 (t, J ) 9 Hz,
1 H), 8.55 (d, J ) 2 Hz, 1 H); MS (EI) m/z 361 (M); HRMS (EI)
calcd for C16H16FN5O4 361.1186, found 361.1183. Anal. Calcd
for C16H16FN5O4: C, 53.19; H, 4.46; N, 19.38. Found: C, 53.03;
H, 4.54; N, 19.13.
N-[((5S)-3-{3-F lu or o-4-[4-(h yd r oxym eth yl)-1H-1,2,3-tr i-
a zol-1-yl]p h en yl}-2-oxo-1,3-oxa zolid in -5-yl)m eth yl]a ceta -
m id e (94). The aldehyde 91 (100 mg, 0.29 mmol) was
suspended in MeOH, NaBH4 (11 mg, 0.29 mmol) was added
and the mixture became homogeneous. The reaction was
stirred at room temperature overnight, and a few drops of
water was added and the solvent removed in vacuo. The
residue was purified on silica gel with 10% MeOH/CH2Cl2.
Product was isolated as a white solid: mp 186-188 °C.
4-({[ter t-Bu tyld im eth ylsilyl]oxy}m eth yl)-1-(2-flu or o-4-
n itr op h en yl)-1H-im id a zole (82). Compound 81 (5.8 g, 24.5
mmol) and imidazole (3.32 g, 48.8 mmol) were dissolved in dry
DMF (40 mL) and cooled to 0 °C. TBDMSCl (5.5 g, 36.5 mmol)
was added and the reaction was stirred at room temperature
overnight. The solvent was removed in vacuo and the residue
was chromatographed with a 30-50% EtOAc/hexane gradient.
Product was isolated as a yellow solid: 5.53 g (64%); 1H NMR
(400 MHz, CDCl3) δ 0.15 (s, 6 H), 0.94 (s, 9 H), 4.78 (s, 2 H),
7.26 (d, J ) 3 Hz, 1 H), 7.34 (t, J ) 8 Hz, 1 H), 7.96 (s, 1 H),
8.17 (s, 1 H), 8.20 (s, 1 H); MS (ESI+) m/z 352 (M + H); MS
(ESI-) 350 (M - H).
N-[((5S)-3-{4-[4-({[ter t-Bu tyld im eth ylsilyl]oxy}m eth yl)-
1H-im id a zol-1-yl]-3-flu or op h en yl}-2-oxo-1,3-oxa zolid in -
5-yl)m eth yl]a ceta m id e (83). Compound 82 (5.53 g, 15.6
mmol) was reacted as described above for the preparation of
compounds 3-8 making noncritical variations. The procedures
afforded 83 as an amber solid: 1.67 g (23%).
N-[((5S)-3-{4-[4-(Hyd r oxym eth ylm eth yl)-1H-im id a zol-
1-yl]-3-flu or op h en yl}-2-oxo-1,3-oxa zolid in -5-yl)m eth yl]-
a ceta m id e (84). Compound 83 (1.67 g, 3.6 mmol) was
dissolved in 3:1:1 AcOH/THF/H2O (50 mL) and stirred at room
temperature for 16 h. The solvent was removed in vacuo and
the residue was dissolved in CH2Cl2 and diluted with Et2O.
The resulting precipitate was collected as a white solid and
used as is: 1.27 g.
N-[((5S)-3-{4-[2-(1-Cya n o-2-n itr iloeth ylid en e)h yd r a zi-
n o]-3-flu or op h en yl}-2-oxo-1,3-oxa zolid in -5-yl)m eth yl]a c-
eta m id e (97). A mixture of concentrated HCl (100 mL) and
water (100 mL) was stirred at 25 °C and aniline 20 (20.0 g,
74.9 mmol) was added. The solution was cooled in ice and
sodium nitrite (5.5 g, 79.7 mmol) added over 5 min. After 1 h
of vigorous mechanical stirring, a solution of sodium acetate
(12.5 g, 1.52 mole) in water (200 mL) was added. The mixture
became very thick and a solution of malononitrile (5.0 g, 75.8
mmol) in ethanol (50 mL) was added. The reaction was allowed
to come to room temperature then filtered. The precipitate was
washed with NaHCO3 solution (150 mL) and water (200 mL)
and dried. The filter cake was ground up and dried in vacuo,
25 °C for 3 days, to afford a bright yellow solid (22.7 g, 88%):
1
mp 235 °C dec; H NMR δ (DMSO-d6) δ 1.81 (s, 3 H), 3.40 (t,
J ) 5.5 Hz, 2 H), 3.73 (dd, J ) 6.5, 9.1 Hz, 1 H), 4.11 (t, J )
9.0 Hz, 1 H), 4.66-4.78 (m, 1 H), 7.34 (d, J ) 9.0 Hz, 1 H),
7.50 (t, J ) 9.0 Hz, 1 H), 7.60 (dd, J ) 2.3, 13.8 Hz, 1 H), 8.22
(t, J ) 5.8 Hz, NH); MS (ESI+) m/z 345 (M + H). Anal. Calcd
for C15H13FN6O3: C, 52.33; H, 3.81; N, 24.41. Found: C, 52.32;
H, 3.84; N, 24.41.
N-({(5S)-3-[4-(4-Cya n o-1H-im id a zol-1-yl)-3-flu or op h en -
yl]-2-oxo-1,3-oxa zolid in -5-yl}m eth yl)a ceta m id e (85). A
slurry of 84 (1.27 g, 3.65 mmol) in CH2Cl2 (10 mL) was treated
with DBU (1.33 mL, 8.9 mmol) followed by diphenyl phosphor-
azidate (1.8 mL, 8.4 mmol). The mixture was stirred at room
temperature for 2 days. The solvent was removed in vacuo and
the residue was purified on silica gel with 0.5-2%MeOH/CH2-
Cl2 gradient. The intermediate azide was isolated as an amber
syrup: 1.17 g (86%). The azide (1.17 g, 3.14 mmol) was
suspended in EtOH (80 mL). 2,5-dimethyl-3-hexyne-2,5-diol
(0.58 g, 4.12 mmol) and 10% Pd/C (0.58 g) were added. The
mixture was heated to reflux for 3 h. The reaction was filtered
and the solvent removed in vacuo. The residue was purified
on silica gel with 0.5-2%MeOH/CH2Cl2 gradient to give 85
as a white solid: 308 mg (28%); mp 204-205 °C; [R]25D ) -25°
N-[((5S)-3-{4-[2-(3,5-Dia m in o-4H-p yr a zol-4-ylid en e)h y-
dr azin o]-3-flu or oph en yl}-2-oxo-1,3-oxazolidin -5-yl)m eth yl]-
a ceta m id e (98). To the dinitrile 97 (1.0 g, 2.90 mmol)
suspended in ethanol (15 mL) was added hydrazine hydrate
(1.0 mL). A yellow solution resulted which was heated to reflux
for 2 h. After cooling, filtration afforded 98 as a caked golden
solid (1.065 g, 97%): mp 256 °C dec; 1H NMR δ (400 MHz,
DMSO) δ 1.82 (s, 3 H), 3.40 (t, J ) 5.1 Hz, 2 H), 3.75 (t, J )
7.7 Hz, 1 H), 4.14 (t, J ) 9.0, Hz, 1 H), 4.64-4.78 (m, 1 H),
6.13 (bd, 3 H), 7.28 (d, J ) 9.0 Hz, 1 H), 7.55 (d, J ) 13.6 Hz,
1 H), 7.81 (t, J ) 9.0 Hz, 1 H), 8.23 (t, J ) 5.4 Hz, NH); MS
(ESI+) m/z 375 (M + H). Anal. Calcd for C15H17FN8O3: C,
47.87; H, 4.56; N, 29.77. Found: C, 47.49; H, 4.61; N, 29.52.
1
(c 0.79, DMSO); H NMR (400 MHz, CDCl3) δ 2.04 (s, 3 H),
3.65-3.78 (m, 2 H), 3.88 (dd, J ) 7, 9 Hz, 1 H), 4.10 (t, J ) 9

968 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
N-({(5S)-3-[4-(4-Cya n o-2H -1,2,3-t r ia zol-2-yl)-3-flu or o-
p h en yl]-2-oxo-1,3-oxa zolid in -5-yl}m eth yl)a ceta m id e (99).
Cupric acetate monohydrate (4.0 g, 20 mmol) was stirred in
pyridine (20 mL) to give a brilliant blue mixture. Diamino-
pyrazole 98 (1.88 g, 5.0 mmol) was added and the mixture
heated at 100 °C for 1 h. After cooling, the solvent was removed
at 40 °C/1 mm and the dark residue partitioned between
chloroform (150 mL) and 1 N HCl (100 mL). The acid layer
was washed with chloroform (2 × 100 mL) and the combined
organics dried (MgSO4), filtered and evaporated. The chloro-
form was evaporated and the residue chromatographed over
silica gel (50 g) eluting with a 0-3% methanol-chloroform
gradient. The product was obtained as a creamy yellow powder
(128 mg, 7%): mp 164-5 °C; 1H NMR (400 MHz, CDCl3) δ
2.04 (s, 3 H), 3.60-3.78 (m, 2 H), 3.87 (dd, J ) 6.8, 9.1 Hz, 1
H), 4.11 (t, J ) 9.0 Hz, 1 H), 4.80-4.90 (m, 1 H), 5.99 (t, J )
6 Hz, NH), 7.37 (d, J ) 9.0 Hz, 1 H), 7.76 (dd, J ) 2.4, 12.9
Hz, 1 H), 7.83 (t, J ) 8.5 Hz, 1 H), 8.20 (s, 1 H); HRMS (EI)
calcd for C15H13FN6O3 344.1033, found 344.1022. Anal. Calcd
for C15H13FN6O3‚0.2H2O: C, 51.79; H, 3.88; N, 24.15. Found:
C, 51.87; H, 3.99; N, 23.78.
acetone-methylene chloride (2:1) afforded 0.058 g (17%) of 102
as a white solid: mp 186.5-188.5 °C.
1-(4-{(5S)-5-[(Acetylam in o)m eth yl]-2-oxo-1,3-oxazolidin -
3-yl}-2-flu or op h en yl)-1H -1,2,4-t r ia zole-3-ca r b oxa m id e
(103). To a solution of 20 mL of 29% NH4OH in 40 mL of CH3-
CN at 50 °C was added 100 (0.500 g, 0.133 mmol). After 3.5
h, the reaction mixture was cooled to 0-5 °C for 25 min, and
the white solid was collected and dried in a vacuum oven at
50 °C overnight to yield 375 mg (78%) of 103: mp 269-270
°C dec.
N-({(5S)-3-[4-(3-Cya n o-1H -1,2,4-t r ia zol-1-yl)-3-flu or o-
ph en yl]-2-oxo-1,3-oxazolidin -5-yl}m eth yl)acetam ide (104).
A suspension of 103 (1.20 g, 3.31 mmol) in 45 mL of CH2Cl2
at 0-5 °C in an ice bath was treated with pyridine (0.916 g,
11.60 mmol) followed by the dropwise addition of trifluoroacetic
anhydride (2.44 g, 11.60 mmol) in 5 mL of CH2Cl2 over a 3
min period. The cooling bath was removed after 20 min and
the contents allowed to stir overnight at room temperature.
The mixture was poured into 110 mL of saturated NaHCO3
and stirred to decompose the excess reagent. The contents were
extracted three times with CH2Cl2, dried with anhydrous Na2-
SO4 and concentrated in vacuo with 6 g of silica gel. Chroma-
tography over 55 g of silica gel, packed and eluted with
acetone-methylene chloride (1:3), afforded 0.952 g (83.5%) of
Meth yl 1-(4-{(5S)-5-[(Acetyla m in o)m eth yl]-2-oxo-1,3-
oxa zolid in -3-yl}-2-flu or op h en yl)-1H-1,2,4-tr ia zole-3-ca r -
boxyla te (100). A mixture of 20 (5.00 g, 18.73 mmol) and 3 N
HCl (26.25 mL, 78.75 mmol) at 0 °C was treated dropwise with
a solution of NaNO2 (1.31 g, 18.91 mmol) in 6 mL of water
over a 4 min period. After stirring for 8 min, the mixture was
added to an ice cooled, mechanically stirred solution of
NaHCO3 (20.45 g, 243.5 mmol) in 200 mL of water over a 1
min period. After stirring for an additional 5 min, a solution
of methyl isocyanoacetate (2.04 g, 20.60 mmol) in 25 mL of
CH3OH was added dropwise over a 5 min period at 0-5 °C.
The reation was stirred at 0-5 °C for 5 h. The mixture was
diluted with CHCl3-CH3OH (9:1) and 200 mL of water, and
the aqueous layer was extracted six times with CHCl3-CH3-
OH (9:1). The combined organics were dried with Na2SO4 and
concentrated with 26 g of silica gel. The material was chro-
matographed over 350 g of silica gel, packed and eluted with
EtOAc-CH3OH (95:5) with increasing polarity gradient to 8%
CH3OH to obtain 5.50 g as an off-white solid. Trituration with
200 mL of Et2O at room temperature gave 5.50 g (78%) of 100
104 as a white solid: mp 202-203 °C; [R]25 -26 (c 0.51,
D
DMSO); 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 8.23 (t,
J ) 6 Hz, 1 H), 7.85 (t, J ) 9 Hz, 1 H), 7.80 (dd, J ) 2, 13 Hz,
1 H), 7.54 (dd, J ) 2, 9 Hz, 1 H), 4.77 (m, 1 H), 4.18 (t, J ) 9
Hz, 1 H), 3.79 (m, 1 H), 3.43 (t, J ) 5 Hz, 2 H), 1.82 (s, 3 H);
HRMS (FAB) calcd for C15H13FN6O3 + H 345.1111, found
345.1117. Anal. Calcd for C15H13FN6O3: C, 52.33; H, 3.81; N,
24.41. Found: C, 52.22; H, 3.89; N, 24.35.
N-({(5S)-3-[3-F lu or o-4-(3-m eth yl-1H-1,2,4-tr ia zol-1-yl)-
ph en yl]-2-oxo-1,3-oxazolidin -5-yl}m eth yl)acetam ide (106).
To a stirred suspension of ethyl acetimidate hydrochloride
(105) (0.492 g, 4.00 mmol) in 10 mL of absolute ethanol at
room temperature under N2 was added triethylamine (0.424
g, 4.20 mmol) and the mixture stirred for 13 min. A sample of
hydrazine 72 (1.13 g, 4.00 mmol) was added with 2 mL of an
additional absolute ethanol rinse. In a separate flask acetyl
chloride (0.343 g, 4.40 mmol) was added to 3 mL of CH3OH to
prepare HCl in situ. After cooling to 0 °C, the methanolic HCl
was added at once to the reaction mixture at 0 °C. The cooling
bath was removed after addition, and the contents were stirred
at ambient temperature for 10 min and concentrated in vacuo.
The dry solid was treated with 15 mL of triethyl orthoformate
and heated for 25 min at 100 °C, allowing the ethanol to distill
off. Absolute ethanol (3 mL) was added to dissolve some
insoluble material and the mixture was heated at 85 °C. The
mixture was diluted with CHCl3-CH3OH (95:5) and washed
successively with saturated NaHCO3 (25 mL) and 50% satu-
rated brine (30 mL) and the combined aqueous washings were
back-extracted with CHCl3-CH3OH (95:5) (4 × 30 mL). The
combined organics were dried with Na2SO4, concentrated at
reduced pressure with 10 g of silica gel and chromatographed
over 100 g of silica gel packed and eluted with CHCl3-CH3-
OH (97:3 to 96:4) to obtain 478 mg (36%) of 106 as a white
solid: mp 206-208 °C; [R]25D -27 (c 0.41, methanol); 1H NMR
(400 MHz, DMSO-d6) δ 8.80 (brs, 1 H), 8.25 (m, 1 H), 7.76 (m,
2 H), 7.46 (d, J ) 9 Hz, 1 H), 4.75 (m, 1 H), 4.16 (t, J ) 9 Hz,
1 H), 3.77 (t, J ) 9 Hz, 1 H), 3.42 (t, J ) 5 Hz, 2 H), 2.34 (s,
3 H), 1.82 (s, 3 H); MS (EI) m/z 333 (M + H). Anal. Calcd for
as a white solid: mp 165-166.5 °C; [R]25 -27° (c 0.27,
D
methanol); 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1 H), 7.84
(t, J ) 9 Hz, 1 H), 7.79 (dd, J ) 2, 13 Hz, 1 H), 7.53 (dd, J )
2, 11 Hz, 1 H), 4.77 (m, 1 H), 4.17 (t, J ) 9 Hz, 1 H), 3.88 (s,
3 H), 3.79 (m, 1 H), 3.43 (t, J ) 5 Hz, 2 H), 1.82 (s, 3 H); MS
(EI) m/z 377 (M + H). Anal. Calcd for C16H16FN5O5: C, 50.93;
H, 4.27; N, 18.56. Found: C, 50.86; H, 4.34; N, 18.34.
N-[((5S)-3-{3-F lu or o-4-[3-(h yd r oxym eth yl)-1H-1,2,4-tr i-
a zol-1-yl]p h en yl}-2-oxo-1,3-oxa zolid in -5-yl)m eth yl]a ceta -
m id e (101). A mixture of lithium borohydride (0.880 g, 95%
assay, 0.040 mol) in 160 mL of 2-propanol under N2 was
treated with 100 (7.54 g, 0.020 mol) at room temperature. The
reaction was stirred at room temperature overnight. The
mixture was treated with 30 mL of water and stirred to
decompose the excess LiBH4. The residuals were suspended
in CH3OH/H2O and adsorbed onto 35 g of silica get at reduced
pressure. The material was chromatographed with 400 g of
silica gel packed with CHCl3-CH3OH (92:8) and eluted with
increasing CH3OH gradient to 12% to obtain 5.07 g (73%) of
product. Recrystallization from EtOAc, CH3OH and Et2O
mixture gave analytically pure 101 as white crystals: mp 180-
183 °C.
N-({(5S)-3-[3-F lu or o-4-(3-for m yl-1H-1,2,4-tr ia zol-1-yl)-
ph en yl]-2-oxo-1,3-oxazolidin -5-yl}m eth yl)acetam ide (102).
A mixture of 101 (0.349 g, 1.00 mmol), 4-methylmorpholine
N-oxide (0.176 g, 1.50 mmol), tetrapropylammonium perru-
thenate (TPAP) (0.018 g, 0.05 mmol) and 0.50 g of flame-dried
4 Å molecular sieves in 8 mL of acetonitrile was heated at 60-
65 °C for 10 h. The mixture was diluted with EtOAc and
washed with 50% saturated brine (40 mL). The aqueous layer
was backed extracted two times with EtOAc and the combined
organics were dried over Na2SO4 and concentrated in vacuo.
Chromatography over 50 g of silica gel, packed and eluted with
C
15H16FN5O3: C, 54.05; H, 4.84; N, 21.01. Found: C, 54.01;
H, 4.81; N, 20.92.
Eth yl 5-Ben zyl-1,2,4-oxa d ia zol-3-ylim in ofor m a te (108).
3-Amino-5-benzyl-1,2,4-oxadiazol (107)43 (12 g, 68.5 mmol) was
suspended in triethyl orthoformate and refluxed overnight.
The reaction was evaporated to dryness under Hi-vac to give
1
108 as a yellow oil which was used as is: 14.51 g (92%); H
NMR (400 MHz, CDCl3) δ 1.38 (t, J ) 7 Hz, 3 H), 4.17 (s, 2
H), 4.43 (q, J ) 7 Hz, 2 H), 7.28-7.37 (m, 5 H), 8.48 (s, 1 H).
N-({(5S)-3-[4-({[(5-Ben zyl-1,2,4-oxa d ia zol-3-yl)im in o]-
m et h yl}a m in o)-3-flu or op h en yl]-2-oxo-1,3-oxa zolid in -5-
yl}m eth yl)a ceta m id e (109). Compound 108 (13.9 g, 60

N-C-Linked (Azolylphenyl)oxazolidinone Antibacterials
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5 969
mmol) and 20 (16 g, 60 mmol) were placed in THF (100 mL)
and absolute EtOH (50 mL) and refluxed overnight. The
reaction was cooled to room temperature and the precipitated
product 109 was isolated as a white solid: 22 g (82%); mp 233-
235 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.83 (s, 3 H), 3.43 (t,
J ) 5 Hz, 1 H), 3.68 (br s, 1 H), 3.78 (dd, J ) 7, 9 Hz, 1 H),
4.17 (t, J ) 9 Hz, 1 H), 4.99 (br m, 1 H), 7.23-7.32 (m, 6 H),
7.48 (dd, J ) 2, 9 Hz, 1 H), 7.72-7.78 (m, 2 H), 8.23 (t, J ) 6
Hz, 1 H), 8.81 (d, J ) 2 Hz, 1 H), 10.8 (br s, 1 H).
°C. The resulting yellow solid was filtered and recrystallized
from boiling ethanol and water to give 7.101 g (88%) of the
desired material as white needles: mp 162-163 °C; 1H NMR
(400 MHz, CDCl3) δ 1.62 (bs, 1H), 2.43 (s, 3 H), 6.81-6.88 (m,
2 H), 7.30-7.37 (m, 5 H), 7.40-7.42 (m, 2 H), 7.57 (d, J ) 8
Hz, 1 H), 7.88 (d, J ) 14 Hz, 2 H); HRMS (EI) calcd for
C
C
16H16N2O2S 300.0932, found 300.0938. Anal. Calcd for
16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C, 63.91; H,
5.42; N, 9.32.
N -{[(5S )-3-(3-F lu or o-4-{5-[(E )-2-p h e n yle t h e n yl]-2H -
1,2,3,4-tetr aazol-2-yl}ph en yl)-2-oxo-1,3-oxazolan -5-yl]m eth -
yl}a ceta m id e (115). A precooled (0 °C) aqueous (0.7 mL)
solution of sodium nitrite (0.071 g, 1.03 mmol) was added to a
solution of 20 (0.274 g, 1.03 mmol) in water (1 mL), hydro-
chloric acid (0.37 mL), and ethanol (1 mL). This reaction
mixture was stirred at 0 °C for 10 min. Then it was added,
via cannula, over 30 min, to a pyridine (8 mL) solution of 114
(0.303 g, 1.01 mmol) which had been cooled in an ice/salt bath.
After stirring 2 h, chloroform and water were added to the
reaction mixture. The phases were separated, and the organic
portion was washed with water and brine, dried with MgSO4,
and evaporated. The residue was chromatographed on a 2.3
× 25 cm medium-pressure silica column with 2% MeOH/CH2-
Cl2 to give 115 (0.150 g, 35%) as a brown solid: mp 180-182
°C; 1H NMR (400 MHz, CDCl3 + MeOD) δ 1.99 (s, 3 H), 3.60-
3.64 (m, 2 H), 3.84 (dd, J ) 9, 7 Hz, 1 H), 4.10 (t, J ) 9 Hz, 1
H), 4.77-4.84 (m, 1 H), 7.19 (d, J ) 16 Hz, 1 H), 7.31-7.39
(m, 5 H), 7.56 (d, J ) 7 Hz, 2 H), 7.76 (dd, J ) 13, 2 Hz, 1 H),
7.81 (d, J ) 17 Hz, 1 H), 7.83 (dd, J ) 12, 9 Hz, 1 H); HRMS
(FAB) calcd for C21H19FN6O3 + H 423.1581, found 423.1585.
Anal. Calcd for C21H19FN6O3: C, 59.71; H, 4.53; N, 19.90.
Found: C, 59.45; H, 4.56; N, 19.77.
N-({(5S)-3-[3-F lu or o-4-(5-for m yl-2H -1,2,3,4-t et r a a zol-
2-yl)p h en yl]-2-oxo-1,3-oxa zola n -5-yl}m et h yl)a cet a m id e
(116). A suspension of 115 (1.355 g, 3.21 mmol) in CH2Cl2 (100
mL) was cooled to -78 °C. Ozone was bubbled through the
solution until it turned blue. After stirring for 20 min, nitrogen
was then bubbled through the reaction mixture for about 5
min. Then dimethyl sulfide (6 mL) was added, and the mixture
was stirred at -78 °C for 5 min then warmed to room
temperature. The solvent was evaporated, and the crude
material, a cream solid, was used in the next reaction as is:
mp 230 °C dec.
N-[1-(4-{[(2R)-3-(Acetylam in o)-2-h ydr oxypr opyl]am in o}-
2-flu or op h e n yl)-1H -1,2,4-t r ia zol-3-yl]-2-p h e n yla ce t a -
m id e (110). The intermediate 109 (5 g, 11 mmol) was
dissolved in EtOH (80 mL) and 10% NaOH (12 mL) and stirred
at room temperature overnight. AcOH (11 mL) was added and
the reaction was concentrated in vacuo at which time the solid
product formed and was isolated, washed with cold EtOH and
dried: 4.2 g (89%); mp 191-193 °C; HRMS (FAB) calcd for
C
21H23FN6O3 + H 427.1894, found 427.1886. Anal. Calcd for
C21H23FN6O3: C, 59.15; H, 5.44; N, 19.71. Found: C, 56.13;
H, 5.58; N, 18.38.
N-[1-(4-{(5S)-5-[(Acetyla m in o)m eth yl]-2-oxo-1,3-oxa zo-
lid in -3-yl}-2-flu or op h en yl)-1H-1,2,4-tr ia zol-3-yl]-2-p h en -
yla ceta m id e (111). The amino alcohol 110 (2.3 g, 5.4 mmol)
was suspended in CH2Cl2 (125 mL) and triphosgene (2.4 g,
8.1 mmol) was added. The reaction was stirred overnight at
room temperature and concentrated and saturated NaHCO3
was added. The aqueous was decanted to leave a sticky gum
that was dissolved in acetone. Precipitated starting material
was filtered off and the filtrate was evaporated. The residue
was dissolved in MeOH and the desired product precipitated
as a white solid: 0.81 g (59%); mp 204-206 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.82 (s, 3 H), 3.42 (t, J ) 5 Hz, 1 H), 3.68
(br s, 1 H), 3.79 (dd, J ) 7, 9 Hz, 1 H), 4.17 (t, J ) 9 Hz, t H),
4.77 (br m, 1 H), 7.25 (br m, 1 H), 7.3-7.33 (m, 5 H), 7.48 (d,
J ) 11 Hz, 1 H), 7.72-7.78 (m, 2 H), 8.23 (br t, 1 H), 8.81 (d,
J ) 2 Hz, 1 H), 10.85 (br s, 1 H). Anal. Calcd for C22H21FN6O4:
C, 58.40; H, 4.68; N, 18.58. Found C, 58.09; H, 4.77; N, 18.38.
N-({(5S)-3-[4-(3-Am in o-1H -1,2,4-t r ia zol-1-yl)-3-flu or o-
ph en yl]-2-oxo-1,3-oxazolidin -5-yl}m eth yl)acetam ide (112).
The benzoyl derivative 111 (1 g, 2.2 mmol) was suspended in
EtOH and concentrated HCl (20 drops) was added. The
mixture was refluxed for 3 h and the solvent was removed in
vacuo. Saturated NaHCO3 was added to the residue and the
mixture was diluted with water. The precipitated product was
isolated and dried to give a white solid: 0.68 g (92%); mp 222-
224 °C; 1H NMR (400 MHz, DMSO-d6) δ 1.83 (s, 3 H), 3.42 (t,
J ) 5 Hz, 2 H), 3.77 (dd, J ) 7, 9 Hz, 1 H), 4.15 (t, J ) 9 Hz,
1 H), 4.75 (br m, 1 H), 5.69 (s, 2 H), 7.43 (d, J ) 9 Hz, 1 H),
7.68-7.73 (m, 2 H), 8.23 (br t, 1 H), 8.44 (d, J ) 2 Hz, 1 H);
HRMS (EI) calcd for C14H15FN6O3 334.1190, found 334.1192.
Anal. Calcd for C14H15FN6O3‚1/3H2O: C, 49.41; H, 4.64; N,
24.69. Found: C, 49.62; H, 4.76; N, 24.37.
N-({(5S)-3-[4-(5-Cya n o-2H-1,2,3,4-tetr a a zol-2-yl)-3-flu o-
r oph en yl]-2-oxo-1,3-oxazolan -5-yl}m eth yl)acetam ide (118).
Acetonitrile (7.5 mL) and carbon tetrachloride (1 mL) were
added to a flask containing 117 (0.052 g, 0.14 mmol) and
triphenylphosphine (0.070 g, 0.27 mmol). The reaction mixture
was heated at 85 °C overnight under nitrogen atmosphere.
Water and CH2Cl2 were added to the reaction mixture. The
phases were separated, and the aqueous portion was extracted
with CH2Cl2, the combined organic portions were dried (Mg-
SO4) and evaporated. The crude material was chromato-
graphed on a 2.3 × 26 cm medium-pressure silica column with
2-5% MeOH/CH2Cl2 to give 0.034 g (69%) of the desired
compound 118 as a white solid: mp 199-200 °C; [R]25D ) -18°
N-({(5S)-3-[4-(3-Ch lor o-1H -1,2,4-t r ia zol-1-yl)-3-flu or o-
ph en yl]-2-oxo-1,3-oxazolidin -5-yl}m eth yl)acetam ide (113).
The amino analogue 112 (1 g, 3 mmol) was placed in 2 N HCl
(30 mL) at 0 °C and NaNO2 (0.23 g, 3.2 mmol) in water was
added. The yellow mixture was stirred at 0 °C for 30 min and
CuCl (34 mg, 3.4 mmol) was added. The reaction was warmed
to room temperature and stirred overnight. Saturated NH4Cl
was added and the mixture was extracted with EtOAc and
dried (Na2SO4). Removal of solvent gave a residue that was
purified on a silica gel column with 2% MeOH/CH2Cl2 to give
245 mg (22%): mp 182-183 °C; 1H NMR (400 MHz, CDCl3) δ
2.04 (s, 3 H), 3.67-3.74 (m, 2 H), 3.86 (dd, J ) 7, 9 Hz, 1 H),
4.11 (t, J ) 9 Hz, 1 H), 4.84 (br m, 1 H), 6.07 (br t, 1 H), 7.28
(d, J ) 9 Hz, 1 H), 7.81 (dd, J ) 2, 14 Hz, 1 H), 7.85 (t, J ) 9
1
(c 0.93, DMSO); H NMR (400 MHz, CDCl3) δ 1.98 (s, 3 H),
3.63 (d, J ) 4 Hz, 2 H), 3.86 (dd, J ) 9, 7 Hz, 1 H), 4.11 (t,
J ) 9 Hz, 1 H), 4.79-4.85 (m, 1 H), 7.20 (bt, 1 H), 7.42 (dt,
J ) 9, 1 Hz, 1 H), 7.82 (m, 1 H), 7.84 (t, J ) 9 Hz, 1 H); HRMS
(FAB) calcd for C14H12FN7O3 + H 346.1064, found 346.1078.
Anal. Calcd for C14H12FN7O3: C, 48.70; H, 3.50; N, 28.40.
Found: C, 48.68; H, 3.54; N, 28.05.
Ack n ow led gm en t. We thank the Structural, Ana-
lytical and Medicinal Chemistry Department of Phar-
macia & Upjohn for mass spectral and combustion
analysis data and the Oxazolidinone Program Team for
many helpful discussions.
Hz, 1 H), 8.52 (d, J ) 2 Hz, 1 H). Anal. Calcd for C14H13
-
ClFN5O3: C, 47.54; H, 3.70; N, 19.80. Found: C, 47.46; H, 3.63;
N, 19.63.
Cin n a m a ld eh yd e Tosylh yd r a zon e (114). Cinnamalde-
hyde (3.4 mL, 26.96 mmol) was added to an ethanol (50 mL)
solution of p-toluenesulfonyl hydrazide (5.008 g, 26.89 mmol).
The reaction mixture was stirred for 1 h, then was cooled to 0
Su p p or tin g In for m a tion Ava ila ble: Full experimental
descriptions and analytical data for compounds 13c,d -f, 14b-
g, 15b-g, 18, 4-8, 10, 27, 37, 40, 41, 48, 49, 61, 62, 81, 88-
93, 95, 96, and 117 and complete analytical data for com-

970 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5
Genin et al.
(23) Wikel, J . H.; Paget, C. J . Synthesis of s-triazolo[4,3-b]benzothia-
zoles. J . Org. Chem. 1974, 39, 3506-3508.
(24) Aulaskari, P.; Ahlgren, M.; Rouvinen, J .; Vainiotalo, P. Prepara-
tion and Structure Determination of 1-Benzyl-, 1-Methyl- and
1H-5-[(2-Nitro-2-phenyl)ethenyl]imidazoles. J . Heterocycl. Chem.
1996, 33, 1345-1354.
pounds 29, 30, 32-35, 38, 39, 44, 52-58, 65-70, 78, 79, 83,
94, 101-103, and 116. This material is available free of charge
via the Internet at http://pubs.acs.org.
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