Synthesis of pyrazole, isoxazole, and aminopyrimidine ring-fused benzothiocycloheptane-derived oxazolidinones and their corresponding sulfone derivatives

Article abstract of DOI:10.1055/s-2007-990890

The synthesis of a series of pyrazole, isoxazole, and aminopyrimidine ring-fused benzothiocycloheptane-derived oxazolidinones and their corresponding sulfone derivatives is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990890

3858
PAPER
Synthesis of Pyrazole, Isoxazole, and Aminopyrimidine Ring-Fused
Benzothiocycloheptane-Derived Oxazolidinones and Their Corresponding
Sulfone Derivatives
S
ynthesis of
Oxazo
l
lidino
a
D
erivativ
d
e
s
imir Khlebnikov,a Samarendra N. Maiti,*a J. V. N. Vara Prasad,b Frederick E. Boyer,b Mike Stier b
a
Naeja Pharmaceutical Inc., #2 4290-91A Street, Edmonton, AB, T6E 5V2, Canada
Fax +1(780)4610196; E-mail: smaiti@naeja.com
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
b
Received 1 June 2007; revised 6 August 2007
analogue of compound 2. In the course of our research we
also investigated the influence of the oxidation state of
sulfur by oxidizing to the corresponding sulfone. As fur-
ther extension of the program, using compounds 9 and 10
as building blocks, we also became interested in building
several heterocyclic rings such as pyrazole, isoxazole, and
aminopyrimidine on the backbone of the benzothiocyclo-
heptanone ring of compound 9 and on its sulfone analogue
10. In this paper, we wish to report the synthesis of a series
of heterocyclic-ring-fused bezothiocycloheptane derived
oxazolidinones 12, 13 and the sulfone derivatives 15, 16,
and 17. (S)-N-[2-Oxo-3-(1-oxo-1,2,4,5-tetrahydroben-
zo[d]thiepin-7-yl)oxazolidin-5-ylmethyl]acetamide (9)
and the corresponding sulfone (S)-N-[2-oxo-3-(1,3,3-tri-
oxo-2,3,4,5-tetrahydro-1H-3l6-benzo[d]thiepin-7-yl)ox-
azolidin-5-ylmethyl]acetamide (10) were synthesized as
shown in the reaction sequence reported in Scheme 1.5
Abstract: The synthesis of a series of pyrazole, isoxazole, and ami-
nopyrimidine ring-fused benzothiocycloheptane-derived oxazolidi-
nones and their corresponding sulfone derivatives is described.
Key words: antibiotics, heterocycles, fused-ring systems, oxazoli-
dinones, bezothiocycloheptanone
There is an ongoing need to synthesize new and improved
antibiotics since bacteria develop fascinating mechanisms
of resistance for the existing antibiotics. Many common
Gram-positive pathogens (e.g., Staphylococcus aureus,
Enterococcus spp., and Streptococcus pneumoniae) have
become increasingly resistant to antimicrobial agents, and
new drugs with activity against Gram-positive bacteria
are urgently needed.1 Oxazolidinones are synthetic anti-
bacterial agents having a novel mechanism of action that
involves inhibition of bacterial protein synthesis at a very
early stage, prior to chain initiation. Oxazolidinones, as
exemplified by linezolid (1) possess excellent activity
against Gram-positive organisms including methicillin-
resistant Staphylococcus aureus (MRSA), Staphylococ-
cus epidermidis (MRSE), and Vancomycin-resistant en-
terococci (VRE).2 Strong interest in this quickly evolving
area is expressed in recent publications from several
research groups.3 In our previous report,4 we described
benzocycloheptanone-derived oxazolidinone 2, which
displayed activity against Gram-positive organisms
(Figure 1).
Reaction of 3-aminophenylacetic acid (3) with ethyl chlo-
roformate in the presence of aqueous NaOH gave the de-
sired carbamate 4 in 96% yield. Subsequent reduction of
the carboxylic acid with sodium borohydride in the pres-
ence of iodine in anhydrous THF furnished intermediate
alcohol 5 in good yield.6 The preparation of the mesylate
6 was carried out by stirring 5 in ethyl acetate with mesyl
chloride and triethylamine as base in 90% yield, and sub-
sequent displacement of mesylate with mercaptoacetic
acid was performed in DMF in the presence of triethyl-
amine and a stoichiometric amount of sodium iodide at
60 °C to give 7. Alternative procedure for the preparation
of 7 via the corresponding bromide instead of the mesyl-
ate 6 can also be done, but we found the mesylate route
to be more convenient. Several attempts of direct cycliza-
tion of 7 to 8 in the presence of the Eaton’s reagent were
unsuccessful. However, the preparation of compound 8
was accomplished in good yield via a two-step and one-
pot procedure. Thus, the compound 7 on treatment with
thionyl chloride in dichloromethane and a catalytic
amount of DMF furnished the acid chloride intermediate.
After evaporation of the volatiles, the acid chloride on
treatment with two molar equivalents of anhydrous alumi-
num chloride in dichloromethane furnished compound 8.
Next, the oxazolidinone ring formation was accomplished
in a single step from compound 8 using the procedure re-
ported by Perrault et al.7 The carbamate 8 on treatment
with (S)-N-(2-acetoxy-3-chloropropyl)acetamide in a
mixture of anhydrous methanol and DMF in the presence
O
F
O
F
N
O
O
N
N
O
O
1
2
NHAc
NHAc
Figure 1 Antibacterial oxazolidinones 1 and 2
In our continued search for an oxazolidinone with broad
spectrum of activity, our initial focus was to incorporate a
sulfur (–S–) atom in the cycloheptanone ring of desfluoro
SYNTHESIS 2007, No. 24, pp 3858–3862
x
x.
x
x
.
2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990890; Art ID: M04007SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Oxazolidinone Derivatives
3859
NaBH4, I2
EtOCOCl
CO2H
HN
CO2Et
OH
CO2H
THF, r.t., 16 h
HN
CO2Et
aq NaOH,
r.t., 16 h
H2N
5
3
4
i) SOCl2, cat. DMF,
CH2Cl2, r.t., 1.5 h
HSCH2CO2H,
Et3N, NaI
MsCl, Et3N
ii) AlCl3, CH2Cl2,
0 °C to r.t., 2.5 h
DMF,
60 °C, 16 h
EtOAc,
r.t., 30 min
HN
CO2Et
S
CO2H
HN
CO2Et
OMs
7
6
O
O
OAc
O
Cl
NHAc
MCPBA
Me2CO,
O
O
S
O2S
S
t-BuOLi, MeOH
DMF, r.t., 20 h
N
N
O
NH
O
r.t., 2 h
10
9
8
CO2Et
NHAc
NHAc
Scheme 1
of lithium tert-butoxide gave the desired oxazolidinone 9 excellent yields. The synthesis of aminopyrimidine-
in 17% yield (not optimized). Although the reasons for the derived oxazolidinones 13 and 17 started from the same
low yield in construction of oxazolidinone ring in 9 have dimethylaminomethylene precursors 11 and 14, which
not been carefully investigated, one can speculate that the were treated with guanidine hydrochloride in the presence
presence of a relatively acidic proton between carbonyl of potassium carbonate in refluxing ethanol. Finally, the
group and sulfur atom could be a factor. The sulfide 9 was isoxazole derivative 16 was synthesized in 53% yield
oxidized with MCPBA in acetone to the corresponding from 14 by heating with hydroxylamine-O-sulfonic acid
sulfone 10.
in methanol (Scheme 3). On the contrary, the similar isox-
azole derivative from sulfide 11 appeared to be quite un-
stable, and even at room temperature the isoxazole ring
underwent ring opening with formation of the correspond-
ing cyano ketone. Therefore, we were unable to isolate the
desired isoxazole ring-fused benzothiocycloheptane-de-
rived oxazolidinone in pure form. It should also be noted
that all the prepared oxazolidinones had poor solubility in
common organic solvents, which made their purification
very difficult.
The dimethylaminomethylene precursor 11 required for
the synthesis of the target oxazolidinones 12 and 13
(Scheme 2) was obtained from the condensation of 9 with
dimethylformamide dimethylacetal in 57% yield by re-
fluxing in n-propanol. By applying the same reaction con-
ditions as for the synthesis of compound 11, compound 14
was obtained (Scheme 3) in almost quantitative yield,
which was not surprising considering the much higher
acidity of the methylene protons in 10. Compounds 11 and
14 were then refluxed with hydrazine hydrate in ethanol to In conclusion, (S)-N-[2-oxo-3-(1-oxo-1,2,4,5-tetrahydro-
achieve the desired pyrazole-fused benzothiocyclohep- benzo[d]thiepin-7-yl)oxazolidin-5-ylmethyl]acetamide
tane-derived oxazolidinones 12 and 15, respectively, in (9) has been synthesized in six steps and its sulfone ana-
N
NH
NH2NH2·H2O
O
EtOH
reflux, 2 h
S
N
O
O
O
Me2N
Me2NCH(OMe)2
PrOH, reflux, 2 h
12
O
NHAc
O
S
S
NH2
N
N
O
O
N
9
N
11
NHAc
guanidine
hydrochloride,
K2CO3
NHAc
O
S
N
EtOH
reflux, 4 h
O
13
NHAc
Scheme 2
Synthesis 2007, No. 24, 3858–3862 © Thieme Stuttgart · New York

3860
V. Khlebnikov et al.
PAPER
N
NH
O
NH2NH2·H2O
O2S
EtOH
reflux, 2 h
N
O
15
NHAc
N
O
O
O
Me2N
O
Me2NCH(OMe)2
PrOH, reflux, 2 h
NH2OSO3H
O
O
O2S
O2S
O2S
MeOH,
reflux, 4 h
N
N
O
N
O
O
16
10
14
NHAc
NHAc
NHAc
NH2
N
N
guanidine
hydrochloride,
K2CO3
O
O2S
EtOH
reflux, 4 h
N
O
17
NHAc
Scheme 3
THF (30 mL) at r.t. The stirring was continued for 5 min at r.t. and
a solution of I2 (2.84 g, 11.2 mmol) in anhyd THF (30 mL) was then
added dropwise. The mixture was stirred at r.t. for 6 h, then cooled
in an ice bath, and quenched with aq 2 N HCl (20 mL). The mixture
was extracted with EtOAc (2 × 150 mL), the combined organic lay-
ers were washed with H2O (2 × 50 mL), aq 2 N NaOH (50 mL),
brine (50 mL), dried (Na2SO4), and concentrated under vacuum. Pu-
rification by flash chromatography on silica gel (hexane–EtOAc,
1:1) gave 5; pale yellow oil; yield: 3.49 g (74%).
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H), 1.63 (br
s, 1 H), 2.84 (t, J = 6.5 Hz, 2 H), 3.84 (t, J = 6.5 Hz, 2 H), 4.21 (q,
J = 7.1 Hz, 2 H), 6.69 (br s, 1 H), 6.92 (d, J = 6.4 Hz, 1 H), 7.19–
7.32 (m, 3 H).
logue (S)-N-[2-Oxo-3-(1,3,3-trioxo-2,3,4,5-tetrahydro-
1H-3l6-benzo[d]thiepin-7-yl)oxazolidin-5-ylmethyl]acet-
amide (10) in seven steps. Using these oxazolidinones 9
and 10 as key building blocks, the desired pyrazole-fused,
isoxazole-fused, and aminopyrimidine-fused benzothio-
cycloheptane-derived oxazolidinones and their corre-
sponding sulfone analogues have been synthesized in two
steps. The biological evaluation of these oxazolidinone
derivatives will be described elsewhere.
The melting points were measured on Electrothermal digital melt-
ing point apparatus and are not corrected. The 1H NMR spectra were
determined using SiMe4 as an internal reference in CDCl3 or
DMSO-d6 with Varian Mercury 400 MHz NMR spectrometer.
Mass spectra were determined using Waters Micromass ZQ with
electrospray ionization sources. Combustion analyses were per-
formed on Costech ECS 4010 elemental analyzer. Column chroma-
tography was performed using Merck Kieselgel 60 (230–400
mesh). THF was dried and distilled under N2 prior to use.
Methanesulfonic Acid 2-(3-Ethoxycarbonylaminophenyl)ethyl
Ester (6)
To a stirred solution of 5 (10.5 g, 50 mmol) and Et3N (6.10 g, 60
mmol) in anhyd EtOAc (100 mL), cooled to 0 °C was added drop-
wise a solution of MeSO2Cl (6.30 g, 55 mmol) in EtOAc (15 mL)
via a syringe. The stirring was continued at 0 °C for 30 min, then the
mixture was diluted with EtOAc (50 mL). The EtOAc solution was
washed with aq 2 N HCl (2 × 30 mL), sat. aq NaHCO3 (50 mL),
brine (50 mL), dried (Na2SO4), and concentrated under vacuum to
give 6; colorless solid; yield: 12.97 g (90%).
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H), 2.88 (s,
3 H), 3.02 (t, J = 6.8 Hz, 2 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.41 (t,
J = 6.8 Hz, 2 H), 6.65 (s, 1 H), 6.93 (d, J = 7.1 Hz, 1 H), 7.18–7.28
(m, 2 H), 7.36 (s, 1 H).
(3-Ethoxycarbonylaminophenyl)acetic Acid (4)
To a solution of (3-aminophenyl)acetic acid (3; 10.6 g, 70.1 mmol)
in aq 2 N NaOH (80 mL), cooled in an ice bath was added dropwise
ethyl chloroformate (8.37 g, 77.1 mmol). The cooling bath was re-
moved and the stirring was continued for 16 h at r.t. The mixture
was washed with Et2O (2 × 50 mL), the aqueous layer was separat-
ed, acidified with HCl, and the mixture was extracted with EtOAc
(3 × 50 mL). The EtOAc extracts were washed with brine (50 mL),
dried (Na2SO4), and evaporated to give 4; pale yellow oil, which
crystallized on standing to give a low-melting waxy solid; yield:
15.1 g (96%).
[2-(3-Ethoxycarbonylaminophenyl)ethylsulfanyl]acetic Acid
(7)
To a stirred solution of 6 (10.0 g, 34.8 mmol) in anhyd DMF (80
mL) were added mercaptoacetic acid (3.53 g, 38.3 mmol), Et3N
(7.75 g, 76.6 mmol), and NaI (5.21 g, 34.8 mmol), and the mixture
was stirred for 16 h at 60 °C . The DMF was removed under vacuum
and the residue was dissolved in EtOAc (150 mL). The EtOAc so-
lution was washed with aq 2 N HCl (2 × 30 mL) and extracted with
aq 5% NaOH (3 × 30 mL). The combined basic aqueous extracts
were cooled, acidified with aq 6 N HCl, and the mixture was ex-
tracted with CH2Cl2 (3 × 50 mL). The combined CH2Cl2 extracts
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.1 Hz, 3 H), 3.62 (s,
2 H), 4.22 (q, J = 7.1 Hz, 2 H), 6.71 (br s, 1 H), 6.97 (d, J = 7.1 Hz,
1 H), 7.22–7.36 (m, 3 H), 11.35 (br s, 1 H).
[3-(2-Hydroxyethyl)phenyl]carbamic Acid Ethyl Ester (5)
To a stirred suspension of NaBH4 (1.27 g, 33.6 mmol) in anhyd
THF (30 mL) was added a solution of 4 (5.0 g, 22.4 mmol) in anhyd
Synthesis 2007, No. 24, 3858–3862 © Thieme Stuttgart · New York

PAPER
Synthesis of Oxazolidinone Derivatives
ESMS: m/z = 367 (M + 1).
3861
were washed with brine (50 mL), dried (Na2SO4), and concentrated
under vacuum to give acid 7; pale yellow oil, which crystallized on
standing to give a low-melting waxy solid; yield: 4.90 g (48%).
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.1 Hz, 3 H), 2.90 (m,
4 H), 3.24 (s, 2 H), 4.22 (q, J = 7.1 Hz, 2 H), 6.71 (br s, 1 H), 6.90
(d, J = 6.6 Hz, 1 H), 7.17–7.30 (m, 3 H), 10.34 (br s, 1 H).
Anal. Calcd for C16H18N2O6S: C, 52.45; H, 4.95; N, 7.64. Found: C,
52.72; H, 5.16; N, 7.44.
(S)-N-[3-(2-Dimethylaminomethylene-1-oxo-1,2,4,5-tetrahy-
drobenzo[d]thiepin-7-yl)-2-oxooxazolidin-5-ylmethyl]acet-
amide (11)
(1-Oxo-1,2,4,5-tetrahydrobenzo[d]thiepin-7-yl)carbamic Acid
Ethyl Ester (8)
To a stirred solution of 9 (0.45 g, 1.3 mmol) in n-propanol (15 mL)
was added dropwise dimethylformamide dimethylacetal (0.62 g,
5.2 mmol) at r.t. and the stirring was continued under reflux for 2 h.
Upon cooling to r.t., a precipitate appeared, which was collected by
filtration, washed with n-propanol (5 mL), and dried to provide a
first crop of 11 (0.20 g). The mother liquor was concentrated and
purified by flash chromatography on silica gel (EtOAc–MeOH,
10:1 to 5:1) to give an additional amount of 11 (0.09 g); yellow crys-
tals; combined yield: 0.29 g (57%); mp 221–222 °C.
1H NMR (400 MHz, CDCl3): d = 2.03 (s, 3 H), 2.83 (br s, 2 H), 2.96
(t, J = 6.4 Hz, 2 H), 3.35 (br s, 6 H), 3.56–3.64 (m, 1 H), 3.68–3.75
(m, 1 H), 3.79 (dd, J = 9.2, 7.0 Hz, 1 H), 4.08 (t, J = 9.0 Hz, 1 H),
4.78 (m, 1 H), 5.96 (t, J = 6.0 Hz, 1 H), 7.33 (dd, J = 8.4, 2.2 Hz, 1
H), 7.51 (d, J = 2.2 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 8.13 (s, 1 H).
To a stirred solution of acid 7 (4.90 g, 17.2 mmol) in anhyd CH2Cl2
(50 mL) was added SOCl2 (4.1 g, 34.4 mmol) at r.t., followed by
DMF (5 drops) and the stirring was continued for 1.5 h at r.t. The
volatile components were removed under vacuum, the residue was
dissolved in anhyd CH2Cl2 (20 mL), and added dropwise to a vigor-
ously stirred suspension of AlCl3 (4.60 g, 34.4 mmol) in anhyd
CH2Cl2 (50 mL) cooled to 0 °C. The stirring was continued at r.t. for
2.5 h, the mixture was then quenched with ice and extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were washed
with brine (50 mL), dried (Na2SO4), and concentrated under vacu-
um. Purification by flash chromatography on silica gel (hexane–
EtOAc, 3:1 to 1:1) gave 8; colorless crystals; yield: 3.02 g (66%);
mp 145–146 °C.
ESMS: m/z = 390 (M + 1).
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H), 2.99 (t,
J = 6.5 Hz, 2 H), 3.18 (t, J = 6.5 Hz, 2 H), 3.53 (s, 2 H), 4.25 (q,
J = 7.1 Hz, 2 H), 6.77 (s, 1 H), 7.22 (dd, J = 8.5, 2.3 Hz, 1 H), 7.51
(s, 1 H), 7.93 (d, J = 8.5 Hz, 1 H).
(S)-N-[3-(5,6-Dihydro-1H-4-thia-1,2-diazabenzo[e]azulen-8-
yl)-2-oxooxazolidin-5-ylmethyl]acetamide (12)
To a stirred suspension of 11 (0.20 g, 0.51 mmol) in EtOH (6.0 mL)
was added hydrazine hydrate (0.20 g, 4.0 mmol) and the stirring was
continued for 20 h at r.t. The mixture was purified directly by flash
chromatography on silica gel (EtOAc–MeOH, 10:1 to 5:1) to give
12; colorless crystals; yield: 0.17 g (94%); mp 186–187 °C.
ESMS: m/z = 266 (M + 1).
(S)-N-[2-Oxo-3-(1-oxo-1,2,4,5-tetrahydrobenzo[d]thiepin-7-
yl)oxazolidin-5-ylmethyl]acetamide (9)
To a stirred solution of 8 (1.50 g, 5.65 mmol) and anhyd MeOH
(0.36 g, 11.3 mmol) in anhyd DMF (6.0 mL) was added dropwise a
solution of t-BuOLi (17.0 mL of 1 M hexane solution, 17.0 mmol)
during 1 h at r.t. The mixture was cooled to 0 °C and (S)-N-(2-acet-
oxy-3-chloropropyl)acetamide (2.19 g, 11.5 mmol) was added as a
solid in one portion. The stirring was continued at r.t. for 20 h, the
mixture was then quenched with sat. aq NH4Cl (20 mL) and extract-
ed with a large amount of EtOAc (ca. 350 mL). The combined or-
ganic extracts were washed with brine (50 mL), dried (Na2SO4), and
concentrated under vacuum. Purification by flash chromatography
on silica gel (EtOAc–MeOH, 10:1 to 3:1), followed by recrystalli-
zation from EtOAc–MeOH gave 9; colorless crystals; yield: 0.16 g
(17%); mp 232–233 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.82 (s, 3 H), 2.90 (t, J = 6.5
Hz, 2 H), 3.23 (t, J = 6.5 Hz, 2 H), 3.41 (t, J = 5.5 Hz, 2 H), 3.62 (s,
2 H), 3.77 (dd, J = 9.3, 6.7 Hz, 1 H), 4.16 (t, J = 9.0 Hz, 1 H), 4.74
(m, 1 H), 7.49 (d, J = 2.3 Hz, 1 H), 7.63 (dd, J = 8.7, 2.3 Hz, 1 H),
7.83 (d, J = 8.7 Hz, 1 H), 8.25 (t, J = 5.8 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 1.83 (s, 3 H), 2.77–2.91 (m, 2
H), 3.27 (m, 2 H), 3.41 (t, J = 5.2 Hz, 2 H), 3.77 (t, J = 7.7 Hz, 1 H),
4.15 (t, J = 8.9 Hz, 1 H), 4.73 (m, 1 H), 7.47–7.56 (m, 3 H), 7.58 and
7.86 (s each, 1 H), 8.26 (t, J = 5.1 Hz, 1 H), 13.06 and 13.32 (s each,
1 H).
ESMS: m/z = 359 (M + 1).
Anal. Calcd for C17H18N4O3S: C, 56.97; H, 5.06; N, 15.63. Found:
C, 56.59; H, 4.80; N, 15.33.
(S)-N-[3-(2-Amino-6,7-dihydro-5-thia-1,3-diazadibenzo[a,c]cy-
clohepten-9-yl)-2-oxooxazolidin-5-ylmethyl]acetamide (13)
To a stirred suspension of 11 (111 mg, 0.28 mmol) in EtOH (6.0
mL) was added guanidine hydrochloride (267 mg 2.8 mmol), fol-
lowed by K2CO3 (387 mg, 2.8 mmol), and the stirring was contin-
ued under reflux for 2 h. Upon cooling to r.t., the mixture solidified.
Small amount of H2O (0.5–1.0 mL) was added and the mixture was
purified directly by flash chromatography on silica gel (EtOAc–
MeOH, 10:1 to 4:1) to give 13; pale yellow crystals; yield: 85 mg
(79%); mp 190–191 °C (dec.).
ESMS: m/z = 335 (M + 1).
Anal. Calcd for C16H18N2O4S: C, 57.47; H, 5.42; N, 8.38. Found:
C, 57.41; H, 5.37; N, 8.25.
1H NMR (400 MHz, DMSO-d6): d = 1.83 (s, 3 H), 2.75 (t, J = 6.2
Hz, 2 H), 3.28 (t, J = 6.6 Hz, 2 H), 3.42 (t, J = 5.5 Hz, 2 H), 3.79
(dd, J = 9.1, 6.7 Hz, 1 H), 4.16 (t, J = 8.9 Hz, 1 H), 4.73 (m, 1 H),
6.94 (s, 2 H), 7.50 (d, J = 2.1 Hz, 1 H), 7.58 (d, J = 8.5 Hz, 1 H),
7.65 (dd, J = 8.5, 2.1 Hz, 1 H), 8.23 (s, 1 H), 8.25 (t, J = 5.8 Hz, 1
H).
(S)-N-[2-Oxo-3-(1,3,3-trioxo-2,3,4,5-tetrahydro-1H-3l6-ben-
zo[d]thiepin-7-yl)oxazolidin-5-ylmethyl]acetamide (10)
To a stirred suspension of 9 (0.30 g, 0.9 mmol) in acetone (10.0
mL), cooled in an ice bath was added a solution of MCPBA (0.65 g
of ~60% reagent, ~2.25 mmol) in acetone (2.0 mL). The cooling
bath was removed and the stirring was continued for 3 h at r.t. The
mixture was purified directly by flash chromatography on silica gel
(EtOAc–MeOH, 10:1 to 6:1) to give 10; colorless crystals; yield:
0.26 g (79%); mp 225–226 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.82 (s, 3 H), 3.42 (t, J = 4.9
Hz, 2 H), 3.56 (m, 4 H), 3.77 (t, J = 7.8 Hz, 1 H), 4.15 (t, J = 8.8 Hz,
1 H), 4.76 (m, 1 H), 4.88 (s, 2 H), 7.54 (s, 1 H), 7.66 (d, J = 8.7 Hz,
1 H), 7.79 (d, J = 8.7 Hz, 1 H), 8.25 (t, J = 4.9 Hz, 1 H).
ESMS: m/z = 386 (M + 1).
Anal. Calcd for C18H19N5O3S: C, 56.09; H, 4.97; N, 18.17. Found:
C, 55.72; H, 5.20; N, 17.83.
(S)-N-[3-(2-Dimethylaminomethylene-1,3,3-trioxo-2,3,4,5-tet-
rahydro-1H-3l6-benzo[d]thiepin-7-yl)-2-oxooxazolidin-5-yl-
methyl]acetamide (14)
To a stirred solution of 10 (0.52 g, 1.4 mmol) in n-propanol (20 mL)
was added dropwise dimethylformamide dimethylacetal (0.67 g,
Synthesis 2007, No. 24, 3858–3862 © Thieme Stuttgart · New York

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V. Khlebnikov et al.
PAPER
(S)-N-[3-(2-Amino-5,5-dioxo-6,7-dihydro-5H-5l6-thia-1,3-di-
azadibenzo[a,c]cyclohepten-9-yl)-2-oxooxazolidin-5-ylmeth-
yl]acetamide (17)
To a stirred suspension of 14 (250 mg, 0.59 mmol) in EtOH (10.0
mL) was added guanidine hydrochloride (564 mg 5.9 mmol), fol-
lowed by K2CO3 (815 mg, 5.9 mmol), and the stirring was contin-
ued under reflux for 4 h. Upon cooling to r.t., the solids were
collected by filtration and suspended in H2O (10.0 mL). After stir-
ring for 1 h at r.t., the precipitate was filtered, washed with H2O
(2 × 2 mL), and dried under vacuum to give 16; colorless crystals;
yield: 215 mg (87%); mp 211–213 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 1.83 (s, 3 H), 3.05 (t, J = 6.3
Hz, 2 H), 3.43 (t, J = 5.2 Hz, 2 H), 3.78 (m, 3 H), 4.15 (t, J = 8.9 Hz,
1 H), 4.75 (m, 1 H), 7.54–7.70 (m, 3 H), 7.79 (m, 2 H), 8.25 (t,
J = 5.3 Hz, 1 H), 8.56 (s, 1 H).
5.6 mmol) at r.t. and the stirring was continued under reflux for 2 h.
Upon cooling to r.t., a precipitate appeared, which was collected by
filtration, washed with n-propanol (5 mL), and dried to give 14; yel-
low crystals; yield: 0.56 g (95%); mp 261–263 °C.
1H NMR (400 MHz, CDCl3): d = 2.02 (s, 3 H), 3.02 (s, 3 H), 3.30
(t, J = 6.4 Hz, 2 H), 3.37 (s, 3 H), 3.48 (t, J = 6.4 Hz, 2 H), 3.54–
3.71 (m, 2 H), 3.80 (dd, J = 9.1, 7.1 Hz, 1 H), 4.06 (t, J = 9.0 Hz, 1
H), 4.76 (m, 1 H), 6.16 (t, J = 5.9 Hz, 1 H), 7.36 (dd, J = 8.6, 2.2 Hz,
1 H), 7.62 (d, J = 2.1 Hz, 1 H), 7.80 (s, 1 H), 7.84 (d, J = 8.6 Hz, 1
H).
ESMS: m/z = 422 (M + 1).
(S)-N-[3-(4,4-Dioxo-1,4,5,6-tetrahydro-4l6-thia-1,2-diazaben-
zo[e]azulen-8-yl)-2-oxooxazolidin-5-ylmethyl]acetamide (15)
To a stirred suspension of 14 (200 mg, 0.47 mmol) in EtOH (6.0
mL) was added hydrazine hydrate (0.20 g, 4.0 mmol) at r.t. and the
stirring was continued under reflux for 2 h. Upon cooling to r.t., a
precipitate appeared, which was collected by filtration, washed with
EtOH (3 mL), and dried under vacuum to give 15; colorless crystals;
yield: 159 mg (87%); mp 292–293 °C.
ESMS: m/z = 418 (M + 1).
Anal. Calcd for C18H19N5O5S·H2O: C, 49.64; H, 4.86; N, 16.08.
Found: C, 49.27; H, 4.81; N, 15.92.
1H NMR (400 MHz, DMSO-d6): d = 1.83 (s, 3 H), 3.12 (m, 2 H),
3.42 (t, J = 5.4 Hz, 2 H), 3.70 (m, 2 H), 3.77 (dd, J = 9.0, 6.7 Hz, 1
H), 4.15 (t, J = 8.9 Hz, 1 H), 4.74 (m, 1 H), 7.56–7.65 (m, 2 H), 7.73
(d, J = 8.4 Hz, 1 H), 8.25 (t, J = 5.7 Hz, 1 H), 8.44 (br s, 1 H), 13.88
(br s, 1 H).
References
(1) Payne, D. J.; Gwynn, M. N.; Holmes, D. J.; Pompliano, D.
L. Nat. Rev. Drug Discovery 2007, 6, 29.
(2) Hutchinson, D. K. Expert Opin. Ther. Pat. 2004, 14, 1309.
(3) (a) Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt,
R. D.; Yagi, B. H.; Ford, C. W.; Hamel, J. C.; Stapert, D.;
Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13, 4197.
(b) Renslo, A. R.; Jaishankar, P.; Venkatachalam, R.;
Hackbarth, C.; Lopez, S.; Patel, D. V.; Gordeev, M. F. J.
Med. Chem. 2005, 48, 5009. (c) Renslo, A. R.; Gao, H.;
Jaishankar, P.; Venkatachalam, R.; Gordeev, M. F. Org.
Lett. 2005, 7, 2627.
(4) Vara Prasad, J. V. N.; Boyer, F. E.; Chupak, L.; Dermyer,
M.; Ding, Q.; Gavardinas, K.; Hagen, S. E.; Huband, M. D.;
Jiao, W.; Kaneko, T.; Maiti, S. N.; Melnick, M.; Romero, K.;
Patterson, M.; Wu, X. Bioorg. Med. Chem. Lett. 2006, 16,
5392.
ESMS: m/z = 391 (M + 1).
Anal. Calcd for C17H18N4O5S: C, 52.30; H, 4.65; N, 14.35. Found:
C, 52.39; H, 4.55; N, 14.36.
(S)-N-[3-(4,4-Dioxo-5,6-dihydro-4H-1-oxa-4l6-thia-2-azaben-
zo[e]azulen-8-yl)-2-oxooxazolidin-5-ylmethyl]acetamide (16)
To a stirred suspension of 14 (200 mg, 0.47 mmol) in MeOH (8.0
mL) was added a solution of hydroxylamine O-sulfonic acid (70
mg, 0.62 mmol) in MeOH (1.0 mL) at r.t. and the stirring was con-
tinued under reflux for 4 h. Upon cooling to r.t., a precipitate ap-
peared, which was collected by filtration, dried, and purified by
chromatography on silica gel (EtOAc–MeOH, 10:1) to give 17; col-
orless crystals; yield: 84 mg (53%); mp 211–212 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.82 (s, 3 H), 3.42 (m, 4 H),
3.80 (m, 3 H), 4.17 (t, J = 9.1 Hz, 1 H), 4.77 (m, 1 H), 7.65 (d,
J = 2.1 Hz, 1 H), 7.77 (dd, J = 8.8, 2.1 Hz, 1 H), 8.03 (d, J = 8.8 Hz,
1 H), 8.25 (t, J = 5.7 Hz, 1 H), 9.39 (s, 1 H).
(5) Chupak, L.; Kaneko, T.; Vara Prasad, J. V. N.; Jiao, W.
PC Pat Appl WO 2004/069245 A1, 2004; Chem. Abstr.
2004, 141, 207197.
(6) Kanth, J. V. B.; Periasamy, M. J. Org. Chem. 1991, 56,
5964.
(7) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan,
A.; Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.;
Gadwood, R. C.; Chan, L.; Lyster, M. A.; Maloney, M. T.;
Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org.
Process Res. Dev. 2003, 7, 533.
ESMS: m/z = 392 (M + 1).
Anal. Calcd for C17H17N3O6S: C, 52.17; H, 4.38; N, 10.47. Found:
C, 52.33; H, 4.51; N, 10.55.
Synthesis 2007, No. 24, 3858–3862 © Thieme Stuttgart · New York