Synthesis of naphthyridone derivatives containing 8-alkoxyimino-1,6- dizaspiro[3.4]octane scaffolds

Article abstract of DOI:10.1016/j.tet.2011.08.089

The synthesis of naphthyridone derivatives containing 8-alkoxyimino-1,6- dizaspiro[3.4]octane scaffolds, the position isomers of the side chain at the C-7 position of Zabofloxacin, has been achieved in eight steps from tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate. The possible reaction mechanisms were also proposed. The key spirocyclic carbamate esters, which could be prepared using a modified Hofmann rearrangement strategy, were condensed with naphthyridone nuclei, and the resulting condensates were easily cleaved by TMSI and subsequently cyclized in the presence of K₂CO₃. Moreover, additional N-methylation derivatives were also obtained using the synthetic sequence.

Full text of DOI:10.1016/j.tet.2011.08.089

Tetrahedron 67 (2011) 8264e8270
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Tetrahedron
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Synthesis of naphthyridone derivatives containing 8-alkoxyimino-1,
6-dizaspiro[3.4]octane scaffolds
*
Lian-Shun Feng, Ming-Liang Liu , Shuo Wang, Yun Chai, Kai Lv, Guang-Zhi Shan, Jue Cao, Su-Jie Li,
Hui-Yuan Guo
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanwei road, No. 2, Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Received in revised form 23 August 2011
Accepted 30 August 2011
Available online 3 September 2011
The synthesis of naphthyridone derivatives containing 8-alkoxyimino-1,6-dizaspiro[3.4]octane scaffolds,
the position isomers of the side chain at the C-7 position of Zabofloxacin, has been achieved in eight
steps from tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate. The possible reaction mechanisms were
also proposed. The key spirocyclic carbamate esters, which could be prepared using a modified Hofmann
rearrangement strategy, were condensed with naphthyridone nuclei, and the resulting condensates were
easily cleaved by TMSI and subsequently cyclized in the presence of K2CO3. Moreover, additional N-
methylation derivatives were also obtained using the synthetic sequence.
Keywords:
Naphthyridone derivatives
8-Alkoxyimino-1,6-dizaspiro[3.4]octane
scaffolds
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Synthesis
1. Introduction
important class of naturally occurring substances characterized by
their highly pronounced biological properties,12 to the C-7 position
Since the discovery of nalidixic acid in 1962 by Lesher et al.,1
quinolone antibacterial agents, one of the few classes that are
synthetic in an area where natural products have dominated, are
important weapons in our antibacterial arsenal.2,3 As privileged
structures, the 4-quinolone/naphthyridone-3-carboxylic acids
containing a good number of points for functionalization have also
been proven useful in other therapeutic areas where they have, for
example, demonstrated activity as antitumor agents (mammalian
topoisomerase II inhibition), anxiolytics, anti-ischemic agents, an-
tivirals (e.g., anti-HIV and anti-herpes simplex virus), cannabinoid
type 2 receptor agonists, and antimalarials.4,5
Structureeactivity relationship (SAR) studies of quinolone an-
tibacterial agents have indicated that the basic group at the C-7
position is the most adaptable site for chemical change and is an
area that greatly influences potency, spectrum and safety.6,7 In fact,
almost all the quinolones currently on the market or under de-
velopment have a nitrogen heterocycle at this position. Among
them, five- and six-membered nitrogen heterocycles including
piperazinyl, pyrrolidinyl and piperidinyl type side chains have
proven to be optimal substituents.8,9 There is general recognition of
the need for the development of both new heterocyclic scaffolds10
and approaches to modify existing scaffolds in novel ways to confer
desirable biological and pharmacological properties.11 As a result,
introduction of nitrogen spirocyclic scaffolds, which are an
of quinolone/naphthyridone cores have led to the discovery of
sitafloxacin13 and DC-159a,14,15 and both of them generally exhibit
good antibacterial activity. However, the goal of modifying existing
heterocyclic scaffolds is particularly challenging, because most
modifications add molecular weight, which often results in con-
comitant undesirable changes in physicochemical and ADMET be-
havior.16 We are very interested in Zabofloxacin (DW224a, Fig. 1),
a
novel naphthyridone antibacterial containing an oxime-
functionalized spirocycle scaffold as the C-7 substituent. It was
reported that Zabofloxacin showed excellent activity against Gram-
positive resistant bacteria, associated with very low toxicity and
favorable pharmacokinetic profiles.17 Therefore, it was decided to
introduce 8-alkoxyimino-1,6-dizaspiro[3.4]octane scaffolds, the
position isomers of the side chain at the C-7 position of Zabo-
floxacin, to naphthyridone cores, and obtain a series of novel
naphthyridone derivatives. The synthetic methods were in-
vestigated and the possible mechanisms were proposed.
O
3
F
COOH
4
5
8
6
7
1
2
N
N
N
MeON
HN
* Corresponding author. E-mail address: lmllyx@yahoo.com.cn (M.-L. Liu).
Fig. 1. Chemical structure of Zabofloxacin.
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.089

L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
8265
It is well known that naphthyridone antibacterials, such as
Tosufloxacin and Gemifloxacin, are usually synthesized by direct
condensation of naphthyridone nuclei and the side-chain com-
pounds.18,19 Accordingly, 8-alkoxyimino-1,6-dizaspiro[3.4]octane
scaffolds are key intermediates for the manufacture of these
naphthyridone derivatives. Several potential strategies could be
envisioned to access the target derivatives from pyrrolidin-3-ones
and the corresponding retrosynthesis is described in Fig. 2.
was prepared by reaction of 2-bromoethanol and acetyl chloride in
a yield of 87%. Nucleophilic substitution of the nitriles 6a,b and 2-
bromoethyl acetate in the presence of NaH gave 12a,b, which
could be successfully converted to the desired amides 13a,b in
DMSOeH2O2 system. However, Hofmann degradation of the am-
ides 13a,b, used freshly prepared aqueous NaBrO,23 did not produce
the primary amines 14a,b but the spirocyclic carbamate esters
15a,b, unexpectedly (Scheme 3).
O
O
Bzl
X
N
CO2H
Bzl
X
N
CO2H
Bzl
N
N
N
H
N
RON
RON
N
N
R1
N
N
R1
N
p
N
H
RON
RON
Bzl
O
Z
NH2
Z
NH
O
RON
Z
RON
RON
G
RON
G
G
N
P
N
p
N
p
N
p
N
p
P = Boc, Z = CN
R = Me, Et
G = Br, OH, OAc
or P = Cbz, Z = CO2Et
Fig. 2. Retrosynthesis of naphthyridone derivatives.
2. Results and discussion
The possible mechanism of 13a,b/15a,b is described in Fig. 4.
When treated with Br2eNaOH, the amides 13a,b were first con-
verted to the isocyanates (eN]C]O), and the ester group was
hydrolyzed simultaneously. The resulting 16a,b were cyclized by
intramolecular addition, and subsequently proton transfer to give
the spirocyclic compounds 15a,b.
In fact, the carbamate ester is usually using to protect the amino
group in synthetic chemistry, and the protecting group is easily re-
moved with trimethyl silane iodine (TMSI) in neutral condition.24e26
However, the Boc-protectinggroup of15a,b can be also cleaved when
treated with TMSI.27 In this way, both of the protecting groups of
15a,b are removed simultaneously by TMSI to produce the primary
amino iodides 17a,b, and the latter will be cyclized in the presence of
a base (such as K2CO3) to give the more stable compounds 18a,b,
rather than the desired spirocyclic compounds 19a,b (Fig. 5).
On the basis of these considerations, we decided to synthesize
naphthyridone derivatives by direct condensation of the naph-
To the best of our knowledge, naphthyridone derivatives con-
taining 8-alkoxyimino-1,6-dizaspiro[3.4]octane scaffolds at the C-7
position are not described so far in the literature. We planned to
prepare the spirocyclic scaffolds from 1-benzyl 3-ethyl 4-
oxopyrrolidine-1,3-dicarboxylate (1) or tert-butyl 3-cyano-4-oxo-
pyrrolidine-1-carboxylate (5)20 at hand. The first synthetic route
designed, using compound 1 as starting material, is outlined in
Scheme 1. Alkylation of 1 with the strong nucleophilic reagent 2-
iodoethanol gave 2-hydroxyethyl pyrrolidone 2 in the presence of
K2CO3. Surprisingly, O-alkylated product rather than C-alkylated
product was obtained under the same condition when 2-chloro/
bromoethanol instead of 2-iodoethanol as the reagent. However,
the oxime ester 3, which was obtained easily by coupling 2 with
methoxylamine,21,22 was not converted to the desired amide 4 even
though various attempts were made.
CO2Et
CO2Et
CO2Et
CONH2
O
O
MeON
MeON
NH3 H2O
.
OH MeONH2
I(CH2)2OH
K2CO3
HCl
OH
OH
.
Pyridine
N
N
N
N
Me2CO
39%
MeOH
88%
Cbz
Cbz
Cbz
Cbz
1
2
4
3
Scheme 1.
Subsequently, we designed the second synthetic pathway to the
spirocyclic scaffolds from Boc-protected cyano ketone 5 (Scheme
2). Introduction of methoxyimino/ethoxyimino group to 5 to yield
oximes 6a,b, which then reacted with 1,2-dibromoethane in the
presence of NaH to give compounds 7a,b. Hydrolysis of the nitriles
7a,b in NaOHeH2O2 system produced the spirocyclic compounds
9a,b, instead of the desired amides 8a,b.
The mechanism of 7a,b/9a,b may be described in Fig. 3. As
a strong nucleophilic reagent, HOOꢀ attacked the cyano group of
7a,b, and the resulting adducts 10a,b were subsequently cyclized to
11a,b. Finally, the transition states 11a,b accepted a proton from
H2O2 molecule to provide 9a,b.
thyridone nuclei 21aee19 with the spirocyclic compounds 20a,b,
which were obtained easily from 15a,b by treatment with MeSO3H,
and subsequently cleavage of the carbamate ester with TMSI and
cyclization in the presence of K2CO3. Finally, we successfully pre-
pared the target compounds 24aei based on the synthetic route
depicted in Scheme 4.
In this investigation, the condensates 22aeh reacted with TMSI
and MeOH, respectively, to provide the amino iodides 23aeh. In-
terestingly, naphthyridone derivatives 24a,b,eeg were only the
target products when the corresponding amino iodides 23a,b,def,
if isolated (in 32e68% yields), were cyclized in the presence of
K2CO3. However, in the same reaction condition, cyclization of 23c,
if not purified by column chromatography, could yield both of the
desired compound 24c and the corresponding N-methylation
To avoid the above undesired cyclization in Scheme 2, 1,2-
dibromoethane was replaced with 2-bromoethyl acetate, which

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L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
CONH2
RON
Br
CN
CN
RON
N
.
CN
O
HCl
RONH2
RON
Br(CH2)2Br
NaH
Br
Boc
Pyridine
NaOH
H2O2
8a,b
N
N
MeOH
MeCN
N
Boc
O
Boc
Boc
RON
NH
6a,b
5
7a,b
a: R = Me
b: R = Et
Yield: 7a: 84%;
7b: 80%.
Yield: 6a: 91%;
6b: 87%.
N
Boc
9a,b
Yield: 7a: 97%;
7b: 96%.
Scheme 2.
OH
N
OOH
C
N-
O
O
C
RON
C N
RON
HOO-
RON
RON
NH
H
O O H
Br
N
Br
N
N
N
Boc
9a,b
Boc
Boc
Boc
7a,b
10a,b
11a,b
Fig. 3. Possible mechanism of 7a,b/9a,b.
RON
NH2
OAc
N
RON
RON
CONH2
OAc
Boc
13a,b
RON
CN
CN
Br(CH2)2OAc
NaH
Boc
14a,b
H2O2
NaBrO
MeCN
N
N
O
C
OAc DMSO
36%
N
MeCN
Boc
12a,b
Boc
O
HN
RON
6a,b
Yield: 12a: 58%;
12b: 56%.
Yield: 13a: 33%;
13b: 34%.
a: R = Me
b: R = Et
N
Boc 15a,b
Yield: 15a: 62%;
15b: 57%.
Scheme 3.
HO
O
C
C
O
O
.
RON
RON
.N
HN
N
C
O
CONH2
OAc
RON
RON
Br2
NaOH
OH
N
N
N
N
Boc
Boc
Boc
Boc
13a,b
16a,b
15a,b
Fig. 4. Possible mechanism of 13a,b/15a,b.
derivative 24d simultaneously. This may be due to the existence of
MeI in the reaction system resulted from reaction of the excess
TMSI with MeOH when 23c was treated with MeOH (Fig. 6). Sur-
prisingly, only the N-methylation derivatives 24h,i, rather than the
corresponding N-hydrogen compounds with low percentage, were
obtained by isolation techniques from 23g,h although using a sim-
ilar manner as for the preparation of 24c,d.
position isomers of the side chain at the C-7 position of Zabo-
floxacin, has been achieved through a modified Hofmann rear-
rangement strategy, in eight steps from tert-butyl 3-cyano-4-
oxopyrrolidine-1-carboxylate. The possible reaction mechanisms
were also proposed. Although the synthetic sequence is in-
consistent with the initial design, it has some advantages in syn-
thetic chemistry. First, the spirocyclic compounds 20a,b were
reacted with the naphthyridone nuclei 21aee to yield only con-
densates 22aeh because there is only one secondary amino group
in 20a,b. On the contrary, the designed spirocyclic compounds
19a,b contain two secondary amino groups, so they have no che-
moselectivity in condensation with 21aee, unless the amino group
3. Conclusion
In summary, the synthesis of naphthyridone derivatives con-
taining 8-alkoxyimino-1,6-dizaspiro[3.4]octane scaffolds, the

L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
8267
HN
RON
O
O
N
NH2
C
C
OSiMe3
MeOH
RON
O
NHCO2H
I
H
RON
HN
HN
RON
19a,b
NH2
RON
K2CO3
I
TMSI
N
I
N
H
N
RON
H
N
H
17a,b
Boc
N
15a,b
18a,b
Fig. 5. Possible mechanism of 15a,b/18a,b.
Scheme 4.
T100CS (JEOL) mass spectrometer, respectively. Unless otherwise
noted, the reagents were obtained from commercial supplier and
used without further purification. TLC was performed on silica gel
plates (Merck, ART5554 60 F254).
Fig. 6. Possible mechanism of MeI formation.
4.1.1. N-tert-Butoxycarbonyl-3-cyano-4-(methoxyimino/ethox-
yimino)pyrrolidine (6a,b). To a solution of methoxylamine/ethox-
ylamine hydrochloride (1.2 mol) and pyridine (80 mL, 1.0 mol)
dissolved in MeOH (1000 mL) was added N-tert-butoxycarbonyl-3-
cyano-4-oxopyrrolidine (5, 210 g, 1.0 mol) at room temperature.
The reaction mixture was stirred at the same temperature over-
night and concentrated under reduced pressure. The residue was
diluted with CH2Cl2 and washed with water, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give the title
compounds 6a,b as light yellow oils. The crude products were used
directly without further purification. Compound 6a: yield: 91%. 1H
at the N-1 position of 19a,b was previously protected. Second, be-
sides the desired target compounds 24a,b,eeg, three N-methyla-
tion derivatives 24d,h,i were also obtained using the synthetic
sequence, and this may be important in SAR studies of these
naphthyridone derivatives. Further improvement on the reaction
conditions of the new sequence is currently in progress.
4. Experimental section
4.1. General
NMR (400 MHz, CDCl3) d: 1.46 (9H, s, Boc-9H), 3.68e3.90 (3H, m,
Melting points were determined in open capillaries and un-
corrected. 1H NMR spectra were determined on a Varian Mercury-
400 spectrometer in DMSO-d6 or CDCl3 using tetramethylsilane
(TMS) as an internal standard. Electrospray ionization (ESI) mass
spectra and high resolution mass spectra (HRMS) were obtained on
an MDSSCIEX Q-Tap mass spectrometer and AccuTOF CS JMS-
pyrrolidine), 3.97 (3H, s, OCH3), 4.06e4.18 (2H, m, pyrrolidine). ESI-
MS (m/z): 262 (MþNa)þ. Compound 6b: yield: 87%. ESI-MS (m/z):
276 (MþNa)þ, 292 (MþK)þ.
4.1.2. N-tert-Butoxycarbonyl-3-(2-acetoxyethyl)-3-cyano-4-(me-
thoxyimino/ethoxyimino)pyrrolidine (12a,b). To a solution of 6a,b

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L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
(0.9 mol) and 2-bromoethyl acetate28 (200 g, 1.2 mol) dissolved in
MeCN (1000 mL) was added 60% NaH (40 g, 1.0 mol) in batches at
0 ꢁC over 1 h. The reaction mixture was stirred for 4 h at the same
temperature, and then adjusted to pH 6.5 with HOAc and filtered.
The filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel) eluted with
petroleum ether and ethyl acetate to give the title compounds
12a,b as colorless oils. Compound 12a: yield: 58%. 1H NMR (DMSO-
pyrrolidineeH), 3.99e4.26 (7H, m, pyrrolidineeH, NOCH2CH3 and
OCH2), 7.65 (1H, s, D2O exchangeable, CONH). ESI-MS (m/z): 314
(MþH)þ, 336 (MþNa)þ. HRMS-ESI (m/z): C14H24N3O5 calcd:
314.17160; found 314.17148.
4.1.5. 4-Methoxyimino/ethoxyimino-7-oxo-8-oxa-2,6-diazaspiro[4.5]
decane mesylate (20a,b). To a solution of 15a,b (60 mmol) dissolved
in EtOH (100 mL) was added methanesulfonic acid (7.8 mL,
120 mmol) at room temperature. The reaction mixture was stirred
at 50 ꢁC overnight and then concentrated under reduced pressure
to afford the crude title compounds 20a,b (60 mmol, 100%) as light
yellow oils, which were used directly without further purification.
A mixture of the above crude 20a and CH2Cl2 (100 mL) was
stirred for 1 h at room temperature. The resulting precipitate was
filtered and dried to give off-white solid (30 mmol, 50%), mp:
d6, 400 MHz) d: 1.47 (9H, s, Boc-9H), 2.08 (3H, s, COCH3), 2.10e2.35
(2H, m, CH2), 3.93 (1H, d, J¼10.0 Hz, pyrrolidineeH), 3.94 (3H, s,
NOCH3), 4.01e4.41 (5H, m, pyrrolidineeH and OCH2). ESI-MS (m/z):
348 (MþNa)þ, 364 (MþK)þ. Compound 12b: yield: 56%. 1H NMR
(DMSO-d6, 400 MHz)
d
: 1.21 (3H, t, J¼9.6 Hz, NOCH2CH3), 1.41 (9H,
s, Boc-9H), 2.00 (3H, s, COCH3), 2.20e2.49 (2H, m, CH2), 3.72e4.27
(8H, m, pyrrolidineeH, NOCH2CH3 and OCH2). ESI-MS (m/z): 362
(MþNa)þ, 378 (MþK)þ.
155e157 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 2.06e2.17 (2H, m,
CH2), 2.34 (3H, s, CH3SO3), 3.34e4.32 (9H, m, pyrrolidineeH,
NOCH3 and OCH2), 7.62 (1H, s, D2O exchangeable, CONH), 9.39 (2H,
s, D2O exchangeable, CH3SO3H2N). ESI-MS (m/z): 200 (MþH)þ.
HRMS-ESI (m/z): C8H14N3O3 calcd: 200.10352; found 200.10381.
4.1.3. N-tert-Butoxycarbonyl-3-(2-acetoxyethyl)-3-carbamoyl-4-
(methoxyimino/ethoxyimino)pyrrolidine (13a,b). To a stirring solu-
tion of 12a,b (0.36 mol) dissolved in DMSO (200 mL) was added
K2CO3 (40 g, 0.29 mol) at 0 ꢁC, and then added dropwise 30% H2O2
(180 mL, 1.6 mol) over 1 h. The reaction mixture was stirred at the
same temperature for 3 h, and then overnight at room temperature.
The mixture was extracted with ethyl acetate (2ꢂ200 mL), and the
combined extracts were washed with saturated brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel) eluted
with petroleum ether and ethyl acetate to afford the title com-
pounds 13a,b as off-white solids. Compound 13a: yield: 33%, mp:
4.1.6. 1-Cyclopropyl-7-[8-(methoxyimino)-1,6-diazospiro[3.4]oct-6-
yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (24a). To
a solution of the above crude 20a (2.9 g, 9.8 mmol) dissolved in
MeCN (50 mL) was added Et3N (14.1 mL, 98 mmol) and 7-chloro-1-
cyclopropyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (21a, 1.8 g, 7.3 mmol) at room temperature. The reaction
mixture was stirred at 50 ꢁC overnight. The resulting precipitate
was filtered, washed with H2O and CH3CN, dried to give 22a (1.5 g,
35%) as an off-white solid, which was used directly without further
purification.
To a solution of the above solid 22a dissolved in MeCN (50 mL)
was added TMSI (22.5 mmol) at 50 ꢁC, and stirred at the same
temperature for 1 h. After cooled to room temperature, to the re-
action mixture was added MeOH (10 mL) and continued to stir at
the same temperature for 10 min, and then concentrated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel) eluted with CH2Cl2 and MeOH to provide 23a
(0.74 g, 42%) as a yellow solid, which was used directly without
further purification.
105e107 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 1.39 (9H, s, Boc-9H),
1.96 (3H, s, COCH3), 2.04e2.16 (2H, m, CH2), 3.30e3.33 (1H, m,
pyrrolidineeH), 3.83 (3H, s, NOCH3), 3.90e4.14 (5H, m,
pyrrolidineeH and OCH2), 7.12, 7.36 (2H, s, D2O exchangeable,
CONH2). ESI-MS (m/z): 366 (MþNa)þ, 382 (MþK)þ. HRMS-ESI (m/
z): C15H26N3O6 calcd: 344.18216; found 344.18233. Compound 13b:
yield: 34%, mp: 115e116 ꢁC. 1H NMR (CDCl3, 400 MHz)
d: 1.19 (3H, t,
J¼7.2 Hz, NOCH2CH3), 1.39 (9H, s, Boc-9H), 1.96 (3H, s, COCH3),
2.05e2.16 (2H, m, CH2), 3.30e4.15 (8H, m, pyrrolidineeH,
NOCH2CH3 and OCH2), 7.09, 7.35 (2H, s, D2O exchangeable, CONH2).
ESI-MS (m/z): 380 (MþNa)þ, 396 (MþK)þ. HRMS-ESI (m/z):
C16H28N3O6 calcd: 358.19781; found 358.19747.
To a solution of the above solid 23a dissolved in MeCN (100 mL)
was added K2CO3 (4.4 g, 32 mmol). The reaction mixture was
heated to reflux and stirred at the same temperature for 5 h, and
then concentrated under reduced pressure. The residue was diluted
with H2O (50 mL), adjusted to pH 6.0 with 20% HOAc, and then
extracted with CH2Cl2 (3ꢂ100 mL). The combined extracts were
washed with saturated brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel) eluted with CH2Cl2 and MeOH
to afford the title compound 24a (58.5 mg, 10.6%) as a light yellow
4.1.4. 2-(N-tert-Butoxycarbonyl)-4-methoxyimino/ethoxyimino-7-
oxo-8-oxa-2,6-diazaspiro[4.5]decane (15a,b). To a solution of 13a,b
(0.10 mol) dissolved in MeCN (200 mL) was added dropwise freshly
prepared 8% NaBrO (281 mL, 0.20 mol) at 0 ꢁC over 1 h. The reaction
mixture was stirred at room temperature overnight. The organic
layer was separated, adjusted to pH 6.5 with HOAc, and then con-
centrated under reduced pressure. The residue was diluted with
H2O (200 mL), and combined with the above water layer. The
combined water layers were adjusted to pH 3.0 with 6 N HCl and
washed with ethyl acetate (2ꢂ100 mL), and then adjusted to pH 9.0
with 6 N NaOH and extracted with ethyl acetate (6ꢂ200 mL). The
combined extracts were washed with saturated brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel) eluted
with petroleum ether and ethyl acetate to afford the title com-
pounds 15a,b as off-white solids. Compound 15a: yield: 62%, mp:
solid, mp: 236 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 1.03e1.19 (4H, m,
2ꢂ cyclopropyl CH2), 2.46e2.52 (2H, m, CH2), 3.24e3.74 (3H, m,
pyrrolidineeH and cyclopropyleH), 3.93e4.38 (7H, m,
pyrrolidineeH, NOCH3 and CH2N), 6.95 (1H, s, C6eH), 8.28 (1H, d,
J¼8.8 Hz, C5eH), 8.58 (1H, s, C2eH), 15.40 (1H, br s, D2O ex-
changeable, COOH). ESI-MS (m/z): 384 (MþH)þ. HRMS-ESI (m/z):
C19H22N5O4 calcd: 384.16663; found 384.16621.
184e186 ꢁC. 1H NMR (CDCl3, 400 MHz)
d: 1.40 (9H, s, Boc-9H),
4.1.7. 1-Cyclopropyl-6-fluoro-7-[8-(methoxyimino)-1,6-diazospiro
[3.4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
(24b). The title compound 24b was obtained from 20a and 7-
chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-
2.06e2.11 (2H, m, CH2), 3.36e3.66 (2H, m, pyrrolidineeH), 3.84
(3H, s, NOCH3), 4.01e4.25 (4H, m, pyrrolidineeH and OCH2), 7.66
(1H, s, D2O exchangeable, CONH). ESI-MS (m/z): 300 (MþH)þ, 322
(MþNa)þ. HRMS-ESI (m/z): C13H22N3O5 calcd: 300.15595; found
300.15621. Compound 15b: yield: 57%, mp: 114e116 ꢁC. 1H NMR
naphthyridine-3-carboxylic acid (21b) in a similar manner as for
the preparation of 24a. Yield: 7.6%, mp: 227e228 ꢁC. 1H NMR
(CDCl3, 400 MHz)
Boc-9H), 2.01e2.04 (2H, m, CH2), 3.30e3.66 (2H, m,
d
: 1.19 (3H, t, J¼7.2 Hz, NOCH2CH3), 1.40 (9H, s,
(DMSO-d6, 400 MHz)
1.28e1.33 (2H, m, cyclopropyl CH2), 2.62e2.69 (2H, m, CH2),
d: 1.04e1.08 (2H, m, cyclopropyl CH2),

L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
8269
3.44e3.49 (1H, m, pyrrolidineeH), 3.64e3.67 (1H, m, cyclo-
propyleH), 3.85 (1H, d, J¼8.0 Hz, pyrrolidineeH), 4.00 (3H, s,
NOCH3), 4.04e4.60 (4H, m, pyrrolidineeH and CH2N), 8.01 (1H, d,
J¼12.4 Hz, C5eH), 8.67 (1H, s, C2eH). ESI-MS (m/z): 402 (MþH)þ.
HRMS-ESI (m/z): C19H21FN5O4 calcd: 402.15721; found 402.15745.
(MþH)þ. HRMS-ESI (m/z): C23H21F3N5O4 calcd: 488.15402; found
488.15384.
4.1.11. 1-Ethyl-6-fluoro-7-[8-(methoxyimino)-1,6-diazospiro[3.4]oct-
6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
(24g). The title compound 24g was obtained from 20a and 7-
chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid (21d) in a similar manner as for the preparation of
4.1.8. 1-Cyclopropyl-6-fluoro-7-[8-(ethoxyimino)-1,6-diazospiro[3.4]
oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid
(24c). To a solution of 22c (1.5 g, 3.3 mmol), which was obtained
from 20b and 21b in a similar manner as for the preparation of 22a,
in MeCN (50 mL) was added TMSI (22.5 mmol) at 50 ꢁC, and stirred
at the same temperature for 1 h. After cooled to room temperature,
MeOH (10 mL) was added and continued to stir at the same tem-
perature for 10 min. To the reaction mixture was added K2CO3
(4.4 g, 32 mmol), stirred at reflex for 5 h and then concentrated
under reduced pressure. To the residue was diluted with H2O
(50 mL), adjusted to pH 6.0 with 20% HOAc, and then extracted with
CH2Cl2 (3ꢂ100 mL). The combined extracts were washed with
saturated brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by column
chromatography (silica gel) eluted with CH2Cl2 and CH3OH to afford
The title compound 24c, and its N-methylation compound 1-
cyclopropyl-6-fluoro-7-[1-methyl-8-(ethoxyimino)-1,6-diazospiro
[3.4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic
acid (24d).
24a. Yield: 10.5%, mp: 197 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 1.41
(3H, t, J¼7.2 Hz, NCH2CH3), 3.22e3.57 (4H, m, pyrrolidineeH and
CH2N), 3.92 (3H, s, NOCH3), 4.05e4.55 (6H, m, pyrrolidineeH and
NCH2CH3), 8.06 (1H, d, J¼12.8 Hz, C5eH), 8.96 (1H, s, C2eH). ESI-MS
(m/z): 390 (MþH)þ. HRMS-ESI (m/z): C18H21FN5O4 calcd:
390.15721; found 390.15718.
4.1.12. 1-(Pyridin-3-yl)-6-fluoro-7-[1-methyl-8-(methoxyimino)-1,6-
diazospiro[3.4] oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid (24h). The title compound 24h was obtained from
20a
and
7-chloroethyl-6-fluoro-1-(pyridin-3-yl)-4-oxo-1,4-
dihydro-1,8-naphthyridine-3-carboxylic acid (21e) in a similar
manner as for the preparation of 24d. Yield: 19.6%, mp:
235e236 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 2.06 (3H, s, NCH3),
2.07e2.28 (2H, m, CH2), 2.98e4.28 (9H, m, pyrrolidineeH, NOCH3
and CH2N), 7.63e8.82 (6H, m, AreH), 15.09 (1H, br s, D2O ex-
changeable, COOH). ESI-MS (m/z): 453 (MþH)þ. HRMS-ESI (m/z):
C22H21FN4O6 calcd: 453.16811; found 453.16788.
Compound 24c: yield: 14.5%, mp: 192e193 ꢁC. 1H NMR (DMSO-
d6, 400 MHz) d: 1.04e1.09 (2H, m, cyclopropyl CH2), 1.30e1.36 (5H,
m, NOCH2CH3 and cyclopropyl CH2), 1.45e2.00 (1H, br s, D2O ex-
changeable, NH), 2.68e2.74 (2H, m, CH2), 3.56e3.57 (1H, m,
pyrrolidineeH), 3.66e3.68 (1H, m, cyclopropyleH), 3.90 (1H, d,
J¼8.0 Hz, pyrrolidineeH), 4.18e4.71 (6H, m, pyrrolidineeH,
NOCH2CH3 and CH2N), 8.02 (1H, d, J¼12.0 Hz, C5eH), 8.69 (1H, s,
C2eH), 15.30 (1H, br s, D2O exchangeable, COOH). ESI-MS (m/z): 416
(MþH)þ. HRMS-ESI (m/z): C20H23FN5O4 calcd: 416.17286; found
416.17349.
4.1.13. 1-(Pyridin-3-yl)-6-fluoro-7-[1-methyl-8-(ethoxyimino)-1,6-
diazospiro[3.4] oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
carboxylic acid (24i). The title compound 24i was obtained from
20b and 21e in a similar manner as for the preparation of 24d.
Yield: 24.3%, mp: 237e238 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d:
1.18e1.26 (3H, m, NOCH2CH3), 2.06 (3H, s, NCH3), 2.09e2.25 (2H, m,
CH2), 3.00e4.25 (8H, m, pyrrolidineeH, NOCH2CH3 and CH2N),
7.63e8.82 (6H, m, AreH),15.08 (1H, br s, D2O exchangeable, COOH).
ESI-MS (m/z): 467 (MþH)þ. HRMS-ESI (m/z): C23H23FN4O6 calcd:
467.18376; found 467.18414.
Compound 24d: yield: 32.1%, mp: 235e236 ꢁC. 1H NMR (DMSO-
d6, 400 MHz) d: 1.10e1.12 (2H, m, cyclopropyl CH2), 1.19e1.21 (2H,
m, cyclopropyl CH2), 1.28 (3H, t, J¼6.8 Hz, NOCH2CH3), 2.16 (3H, s,
NCH3), 2.34e2.37 (2H, m, CH2), 3.07e3.30 (2H, m, pyrrolidineeH),
3.73e3.77 (1H, m, cyclopropyleH), 3.95 (1H, d, J¼12.4 Hz,
pyrrolidineeH), 4.18e4.58 (5H, m, pyrrolidineeH, NOCH2CH3 and
CH2N), 8.05 (1H, d, J¼12.8 Hz, C5eH), 8.60 (1H, s, C2eH). ESI-MS (m/
z): 430 (MþH)þ. HRMS-ESI (m/z): C21H25FN5O4 calcd: 430.18851;
found 430.18855.
Acknowledgements
This work was supported by National S&T Major Special Project
on Major New Drug Innovation (No. 2009ZX09301-003).
References and notes
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diazospiro[3.4]oct-6-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-
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(4H, m, pyrrolidineeH and CH2N), 3.94 (3H, s, NOCH3), 4.20e4.45
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10.6%, mp: 193 ꢁC. 1H NMR (DMSO-d6, 400 MHz)
d: 1.22 (3H, t,
J¼7.2 Hz, NOCH2CH3), 2.32e2.54 (2H, m, CH2), 3.15e4.14 (8H, m,
pyrrolidineeH, NOCH2CH3 and CH2N), 7.33e7.84 (3H, m, AreH),
8.12 (1H, d, J¼12.8 Hz, C5eH), 8.86 (1H, s, C2eH). ESI-MS (m/z): 488

8270
L.-S. Feng et al. / Tetrahedron 67 (2011) 8264e8270
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d
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Med. Chem. 2011, 46, 2421e2426.
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