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

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.^14,15In addition, single-step selection studies dem-

onstrated that eperezolid- and linezolid-resistant mu-

tants develop with a very low spontaneous mutation

frequency of <10^-9among selected staphylococcal bac-

teria.¹⁶Furthermore, 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.¹⁷Recently, 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-

gens^1-3including methicillin-resistant Staphylococ-

cus aureus (MRSA)⁴and Staphylococcus epidermidis

(MRSE),⁴vancomycin-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).^8-11More recently,

a multinational team reported high rates of resistance

among aerobic Gram-negative bacilli in European in-

tensive care units.¹⁴Thus, 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.

Published on Web 02/17/2000

954 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 5

Genin et al.

Sch em e 1^a

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.¹⁸These analogues also exhibit

excellent pharmacokinetics and in vivo activity.¹⁸We

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.¹⁹The

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)-pyridone²²gave an excellent yield

of the isothiocyanate 21 which was treated with formic

hydrazide to give the thiosemicarbazide 22.²³Cycliza-

tion of 22 in aqueous base gave the 2-mercaptotriazole

intermediate 23.²³Treatment 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-

hyde²⁵24 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 2^a

Sch em e 3^a

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.³¹Thus, 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).

CCl₄yielded the 3-cyano analogue 28.²⁶The 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).³³The

hydrazine 72 was also utilized in the regiochemical

synthesis of the (3-hydroxypyrazolylphenyl)oxazol-

idinone analogue 77. The known ethoxyacryloyl chloride

(75)³⁴was reacted with 73 to yield the key acylhydra-

zine intermediate 76. This material was cyclized in HCl

to afford the desired analogue 77,³⁵which 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)²⁸to give the ethyl 4-pyrazolecarboxylate

44.²⁹This 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.³⁰This

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 4^a

Sch em e 6^a

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 7^a

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 5^a

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.³⁶The 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 89-91.³⁸These

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 97.³⁹Treatment 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, NaNO₂then 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 8^a

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 9^a

afforded the diaminopyrazolylhydrazone intermediate

98 which was cyclized with cupric acetate⁴⁰to 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 100.⁴¹This 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 115.⁴⁶Ozonolysis 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 107⁴³was 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

110.⁴⁴This 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.¹⁹Minimum 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 10^a

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.¹⁹The 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.^fM.cat.^g

ED₅₀

control ED₅₀

2.7 (ND^j)v

Pyrrolyl

e0.5

3

H

CHO

1

0.25

1

0.5

1

2

16

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

4

2

1

8

1

2

4

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

1

CH₂OH

0.25

0.5

1

2

1

2

0.5

4

0.5

1

0.25

0.5

0.25

2

0.25

0.5

4

2

>20

CO₂CH₃

>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

2

8

4

>20

1.8 (0.8-2.3)e

6.5 (ND)

10 (ND)e

16

1

2

>16

8

2

15 (ND)

10 (ND)e

4

>16

8

Pyrazolyl

4

H

2

4

>16

2

4

>16

0.5

2

4

16

4

2

4

2

4

16

8

1

2

4

2

0.25

1

2

1

2

1

4

2

4

0.5

1

0.5

e0.125

0.5

1

2

0.5

1

0.5

1

0.5

4

0.5

1

2

4

>16

16

0.5

2

8

16

8

32

>16

4

>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

8

>16

4

2

4

2

8

2

4

8

>16

8

2

16

8

16

>16

8

16

8

4

>16

1

4

8

1

4

8

2

4

1

2

8

16

8

OAc

OCH₃

2

16

>16

16

>16

4

Imidazolyl

e0.5

0.25

5

85

H

CN

2

4

1

4

e0.5

0.5

2

8

4

9.5 (5.5-22.1)

2.2 (1.43-3.5)v

linezolid

eperezolid

vancomycin

4

1

2

1

0.5

2

1

0.5

4

2

4

16

>32

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

a

b

Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. ^cMethicillin-resistant S. epidermidis UC12084.

Str. pneumoniae UC9912. ^eE. faecalis UC9217. ^fH. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration

(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED₅₀is 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

E.f.^e

H.inf.^fM.cat.^g

ED₅₀

control ED₅₀

6

H

1

4

1

0.5

4

8

4

1

4

0.5

0.25

4

2

e0.5

1

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 (ND^j)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

2

8

4

>16

4

8

>16

0.5

1

2

8

4

>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

4

0.5

>16

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

1

4

2

0.5

16

2

4

32

>16

16

8

>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

2

1

>16

16

>16

16

2

4

8

2

4

8

2

>16

1

>16

2

1

>16

16

2

8

4

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

1

2

1

0.5

2

1

0.5

4

2

4

16

>32

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

a

b

Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. ^cMethicillin-resistant S. epidermidis UC12084.

Str. pneumoniae UC9912. ^eE. faecalis UC9217. ^fH. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration

(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED₅₀is 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.^47,48The 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.

pneumoniae¹⁸in 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 C₁₀H₇FN₂O₂206.0492, 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), K₂CO₃or 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.^dE.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

4

1

2

1

0.5

1

0.5

1

16

4

8

16

8

16

8

116

117

118

2

4

1H-Tetrazolyl

11

na

4

2

1

2

16

>20

7.8 (4.0-26.7)e

linezolid

eperezolid

vancomycin

4

1

2

1

0.5

2

1

0.5

4

2

4

16

>32

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

a

b

Methicillin-susceptible S. aureus UC9213. Methicillin-resistant S. aureus UC6685. ^cMethicillin-resistant S. epidermidis UC12084.

Str. pneumoniae UC9912. ^eE. faecalis UC9217. ^fH. influenzae UC30063. M. catarrhalis UC30610. Minimum inhibitory concentration

(MIC): lowest concentration of drug (µg/mL) that inhibits visible growth of the organism. ED₅₀is 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 C₁₈H₁₅FN₂O₂310.1117, 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 C₉H₆FN₃O₂207.0444, 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/CH₂Cl₂gradient. 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

CH₂Cl₂and 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 NaHCO₃solution 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/CH₂Cl₂gradient 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 MgSO₄and

concentrated in vacuo. The residue was chromatographed over

silica gel with 1% MeOH/0.1% NH₄OH/CH₂Cl₂followed by 2%

MeOH/0.2% NH₄OH/CH₂Cl₂to 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 C₁₆H₁₆FN₃O₃317.1176, 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 C₂₇H₂₆FN₃O₅491.1856, 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 H₂on 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 MgSO₄and

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 MgSO₄and 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/CH₂Cl₂to 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 MgSO₄and 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/CH₂Cl₂to 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 C₁₇H₁₅FN₄O₃342.1128, 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-

Cl₂to 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+

H₁320.1159, 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/CH₂Cl₂gradient 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/CH₂Cl₂to 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/CH₂Cl₂to 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 C₁₇H₁₆FN₃O₄345.1125,

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/CH₂Cl₂to 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 C₁₇H₁₇FN₄O₄360.1234, 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/CH₂Cl₂to

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/

CH₂Cl₂to 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 CH₂Cl₂and 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/CH₂Cl₂to 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/CH₂Cl₂2×) 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 NaHCO₃and 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 CH₂Cl₂at 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 NaHCO₃and 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 C₁₆H₁₅FN₆O₄374.1139, 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 CH₂Cl₂and water. The aqueous was extracted with

CH₂Cl₂and 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

CHCl₃gradient. 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 C₁₆H₁₅FN₄O₅362.1104, 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/CH₂Cl₂to 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 N₂for 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 CH₂Cl₂and

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/CH₂Cl₂and

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 CH₂Cl₂and 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-

CO₃was 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 N₂for 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 NaHCO₃and 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

N₂for 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 NaHCO₃and CH₂Cl₂. The aqueous

layer was extracted with 5%MeOH/CH₂Cl₂and 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 NaHCO₃solution 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 Na₂SO₄and 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 CH₂Cl₂and 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/CH₂Cl₂to give the desired product 73 (high R_f) 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/CHCl₃to 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/CHCl₂to 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 NaHCO₃and

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+ H₁333.1363,

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 R_fproduct 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 NaNO₂in 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 NaHCO₃and 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 C₁₆H₁₄FN₅O₃343.1081, 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/CH₂Cl₂to 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/CH₂Cl₂to 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]²⁵_D) -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 C₁₆H₁₆FN₅O₄361.1186, 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 CH₂Cl₂and 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 NaHCO₃solution (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-

Cl₂gradient. 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/CH₂Cl₂gradient to give 85

as a white solid: 308 mg (28%); mp 204-205 °C; [R]²⁵_D) -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 C₁₅H₁₃FN₆O₃344.1033, 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 CH₂Cl₂over 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-

SO₄and 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 Na₂SO₄and

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 N₂was 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]²⁵_D-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 N₂was

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 Na₂SO₄and 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

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-

Cl₂to 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 NaHCO₃was 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 C₁₄H₁₅FN₆O₃334.1190, 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 CH₂Cl₂were 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/CH₂Cl₂to give 0.034 g (69%) of the desired

compound 118 as a white solid: mp 199-200 °C; [R]²⁵_D) -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/CH₂Cl₂to 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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J M990373E

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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

DOI: 10.1021/jm990373e

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