Amination of quinolones with morpholine derivatives

Article abstract of DOI:10.1016/j.tet.2012.09.082

The aromatic nucleophilic substitution reaction of 7-chloroquinolone carboxylic acid and its ethyl ester with cyclic amines under microwave irradiation conditions was investigated. ¹H NMR spectroscopy was used to monitor the progress of the substitution reaction. The reaction proceeded in high yield with simple cyclic amines and was less efficient for sterically more demanding bimorpholine derivatives. A Pd-catalyzed amination of quinolone carboxylic acid ethyl ester with bimorpholine derivatives provided new C-7 bimorpholino-substituted quinolone derivatives.

Full text of DOI:10.1016/j.tet.2012.09.082

Tetrahedron 68 (2012) 9550e9555
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Amination of quinolones with morpholine derivatives
*
~
€
~
Kristin Lippur, Tonis Tiirik, Marina Kudrjashova, Ivar Jarving, Margus Lopp, Tonis Kanger
Department of Chemistry, Faculty of Science, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 May 2012
Received in revised form 31 August 2012
Accepted 17 September 2012
Available online 23 September 2012
The aromatic nucleophilic substitution reaction of 7-chloroquinolone carboxylic acid and its ethyl ester
with cyclic amines under microwave irradiation conditions was investigated. 1H NMR spectroscopy was
used to monitor the progress of the substitution reaction. The reaction proceeded in high yield with
simple cyclic amines and was less efficient for sterically more demanding bimorpholine derivatives. A
Pd-catalyzed amination of quinolone carboxylic acid ethyl ester with bimorpholine derivatives provided
new C-7 bimorpholino-substituted quinolone derivatives.
Keywords:
Fluoroquinolone
Bimorpholine
Ó 2012 Elsevier Ltd. All rights reserved.
Microwave-assisted synthesis
1. Introduction
side-product that can be difficult to separate from the target
compound.8 Microwave (MW) irradiation has been used to accel-
Quinolones form an important class of compounds, which are
widely used in medicine, mainly as antibacterial agents, but, also as
anti-tumour or anti-viral agents.1,2 They are targeted to the pro-
karyotic type II topoisomerases, DNA gyrase and topoisomerase IV.3
A five- or six-membered heterocyclic ring in the quinolones C-7
position, which is one of the most influential positions on the
molecule, increases the bioactivity of compounds and improves
their pharmacokinetic profile. The combination of a cyclic amino
group at C-7 with a fluorine atom at the C-6 position provides
broad-spectrum activity (e.g., ciprofloxacin).
erate organic reactions for over two decades,9 since it can enhance
the reaction rate, improve yield and give a cleaner reaction profile.
A
microwave-assisted synthesis of quinolones has been
reported.10e12 There are only a few reports for the preparation of 7-
morpholinoquinolones by this method.13,14 No bimorpholinoqui-
nolones have been synthesized so far.
2. Results and discussion
We report herein the results of a thorough investigation of the
nucleophilic substitution reaction of 7-chloroquinolone carboxylic
acid 1a (QA) and its ethyl ester 1b (QE) with morpholine, to find
optimal conditions for the introduction of bimorpholines and other
cyclic amines into the quinolone scaffold. The preparation of 7-
morpholinoquinolone derivatives from 6,7-difluoroquinolone de-
rivatives15 and 6-fluoro-7-chloroquinolone derivatives by using
a large excess of amine has been reported in the literature.16,17
Because a multi-step synthetic scheme is required to obtain
bimorpholine, it is highly impractical to apply the described
methods for the synthesis of quinolone derivatives (Fig. 1).
On the other hand, substituted morpholine subunits are found
in various biologically and therapeutically active compounds.4 The
morpholine moiety has been utilized extensively by the pharma-
ceutical industry in drug design, often because of the improve-
ments in pharmacokinetic properties it can confer. We have
previously been engaged with the synthesis of several unsub-
stituted and substituted bimorpholines5,6 whose biological activity
has also been tested on HIV and HCV.7
The most straightforward way to introduce an amine group into
the quinolone ring is an aromatic nucleophilic substitution of 7-
chloro- or 7-fluoroquinolone. The direct amination of quinolones
usually requires a large excess of the amine and thereby suffers
from low atom economy. Also, for the less reactive amines very long
reaction times are needed. Previously reported methods also in-
duce amination at the C-6 position, which produces an undesirable
O
O
F
HN
*
NH
*
OH
3
6
R
R
7
1
N
* *
O
O
R'
R
* Corresponding author. Tel.: þ372 6204372; fax: þ372 6202828; e-mail address:
tonis.kanger@ttu.ee (T. Kanger).
Fig. 1. General structure of fluoroquinolone carboxylic acid and 2,20-bimorpholine.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.082

K. Lippur et al. / Tetrahedron 68 (2012) 9550e9555
9551
In order to find more efficient synthetic conditions for the re-
action between morpholine and quinolone carboxylic acid 1a, we
applied MW irradiation to the reaction (Scheme 1).
proceeded well in DMF, DMSO and DMPU. An apolar solvent, such
as toluene or protic solvents, such as water and morpholine, were
not suitable for the reaction (Table 1). Formation of side-product
was observed when the reaction was run in DMF. At an elevated
temperature dimethylamine was formed from DMF. That com-
All reactions were carried out using a CEM DiscoverÒ MW re-
actor and monitored by 1H NMR spectroscopy. The 1H NMR spec-
O
O
F
COOR
F
COOR
O
MW irradiation
+
Cl
N
N
H
N
N
1a: R = H
1b: R = Et
O
2a-b
Scheme 1. Amination of quinolone carboxylic acid 1a and ester 1b with morpholine.
trum of the starting 7-chloroquinolone acid 1a, 7-
morpholinoquinolone acid 2a and the 1H NMR spectrum of the
reaction medium after 1.5 h reaction in MW conditions in DMPU
are shown in Fig. 2. The integral of the proton at C-2 makes it
possible to unambiguously determine the conversion of the
reactants.
pound also reacted with quinolone carboxylic acid, affording 7-
dimethylaminoquinolone as a side-product (in a ratio of 2:1 of
the desired product 2a and the side-product). Therefore, it was
found that DMSO and DMPU were the solvents of choice for the
reaction. The experiments showed that the amination of quinolone
1a with morpholine was much quicker in DMSO than in DMPU.
Fig. 2. 1H NMR spectrum (400 MHz, CDCl3) of (A) 7-chloroquinolone acid 1a, (B) 7-morpholinoquinolone acid 2a and of (C) the reaction medium after 1.5 h reaction in MW
conditions in DMPU.
First, to find the most suitable solvent for the reaction, various
solvents were screened. The reactions were carried out in the mi-
crowave reactor at a constant temperature using a 1:5 M ratio of 7-
chloroquinolone 1a and morpholine. As expected, the amination
reaction required an aprotic polar solvent and the reaction
However, almost full conversion was obtained in both solvents
within 1.5 h: compound 2a was isolated from DMPU in 87% yield
and from DMSO in 86% yield.
Morpholine (5 equiv) was needed to get an acceptable yield of
the products. While the morpholine excess was reduced to 1.1 equiv

9552
K. Lippur et al. / Tetrahedron 68 (2012) 9550e9555
Table 1
The higher ratio of products 8a and 9a (74:26) allowed us to
isolate the dimeric product 8a in 37% yield via crystallization.
However, no product was detected in the reaction with sterically
more demanding benzyl- or methyl-substituted bimorpholines 7b
and 7c under typical conditions.
It is known that the BuchwaldeHartwig amination reaction has
been used for the regioselective attachment of the 2,5-diazabicyclo
[4.1.0]heptane ring to the fluoroquinolone core.19 This method is
selective for chlorinated sites, so side-products resulting from
fluoro-substitution should not form. Furthermore, there is no need
to use a large excess of amine. Thus, a Pd-catalyzed cross-coupling
reaction of the bimorpholines 7a and 7b with quinolone carboxylic
acid ethyl ester 1b was investigated (Scheme 3).
Solvent screening on the MW-assisted amination of quinolone carboxylic acid 1aa
Entry
Solvent
Temp (ꢀC)
NMR ratio
Product 2a:QA 1a
1
2
3
4
5
6
DMF
115
115
115
110
100
80
93:7b
100:0
91:9
No reaction
17:83
1:99
DMSO
DMPU
Toluene
H2O
Morpholine
a
Reaction conditions: 1 equiv QA 1a, 5 equiv morpholine, 0.5 M, MW, 1.5 h.
Formation of the side product with Me2NH in 2:1 ratio (desired product 2a:side
b
product).
(in the following reaction conditions: DMPU 0.5 M, MW, 1.5 h), the
amount of unreacted starting quinolone acid 1a increased consid-
erably (a ratio of 1a and 2a 64:36). The reaction with quinolone
carboxylic acid ethyl ester 1b in DMPU under MW conditions was
very slow even with 5 equiv of morpholine. After 1.5 h of reaction
time only 11% of product 2b was formed compared to 89% of the
unreacted starting compound 1b left by NMR spectroscopy.
The scope of the method was broadened by using other cyclic
amines. Under the same reaction conditions (1 equiv QA, 5 equiv
amine, DMPU 0.5 M, MW irradiation, 115 ꢀC, 1.5 h), piperidine,
pyrrolidine N-Boc-piperazine and piperazine reacted smoothly
with quinolone carboxylic acid 1a (the yields and structures of the
products are presented in Fig. 3). In the case of pyrrolidine and
piperazine a considerable amount (up to 25%) of unidentified side-
products was also formed.
The reaction with unsubstituted bimorpholine 7a was run under
various reaction conditions. The use of bis(tri-tert-butylphosphine)
palladium(0) or (2-biphenyl)di-tert-butylphosphine (JohnPhos) as
a ligand gave an inseparable mixture of starting compounds and
several products. When a Pd2(dba)3/BINAP catalyst system was
used with Cs2CO3 as a base in DMF (48 h at 100 ꢀC) the ratio of 10a
and 11a, according to the 1H NMR spectrum, was 45:55. The iso-
lated yield of the mono-arylated product 11a was 35% and that of
the diarylated product 10a was 27%. Using the same conditions
with benzyl-substituted bimorpholine 7b, a mono-arylated prod-
uct 11a was obtained in 33% yield. Changing the solvent from DMF
to DMSO did not improve the results of the reaction with any of the
amines, always resulting in a mixture of several products. The ob-
tained products were hydrolyzed with 2 M hydrochloric acid in 3 h
at reflux, affording dimeric product 8a in a quantitative yield,
monomeric product 9a in 95% yield and benzyl-substituted mo-
nomeric product 9b in 68% yield.
O
N
O
N
F
COOH
F
COOH
3. Conclusions
3
4
N
N
Two alternative ways to obtain 7-morpholino-substituted qui-
nolone carboxylic acids were investigated: an aromatic nucleo-
philic substitution reaction of 7-chloroquinolone carboxylic acid
under MW irradiation conditions, and a Pd-catalyzed reaction of its
ethyl ester. Simple five- and six-membered cyclic amines (pyrroli-
dine, piperidine etc.) were efficient under MW conditions, affording
products in moderate to high yields (57e74%). The N-arylation of
unsubstituted bimorpholine under the same conditions was less
efficient and substituted bimorpholines gave no product. Alterna-
tively, the target compounds were formed in the Pd-catalyzed
BuchwaldeHartwig reaction. Evaluation of the biological proper-
ties of the new quinolone derivatives is in progress.
62%
61%
O
N
O
N
F
COOH
F
COOH
N
N
5
6
N
HN
Boc
57%
74%
Fig. 3. Amination products with cyclic amines.
It has been reported that dimeric products of quinolone also
possess biological activity.18 So, we examined the amination of 1a
with bimorpholine 7a under the optimized conditions (2 equiv
QA 1a, 1 equiv amine, 6 equiv base, DMSO 0.5 M, MW, 115 ꢀC)
(Scheme 2). To achieve the arylation of both bimorpholine sec-
ondary amino groups, the molar ratio for QA 1a and bimorpholine
7a was taken 2:1. The reaction without any additives proceeded to
give a ratio of product:starting quinoline 17:83 (in favour of the
starting material) (Table 2, entries 1 and 2). In order to facilitate the
reaction and to increase the low nucleophilicity of the amino group
in the morpholine ring, a base additive was needed. The addition of
the strong base DBU or NaOtBu (entries 8 and 9) resulted in the
decomposition of the starting quinolone. Chemical shifts in the
double bond region indicated that decarboxylation of the quino-
lone carboxylic acid had occurred. In the presence of DIPEA and
triethylamine, reactions afforded quite similar results (entries 7 and
4). The ratio of mono- and diarylated products 8a and 9a was ap-
proximately 1:1 in all cases. The reaction with triethylamine was
slightly faster, a 6-h reaction was run affording approximately 3:2
ratio of aminated quinolones and starting QA.
4. Experimental
4.1. General
Full assignment of 1H and 13C chemical shifts is based on the 1D
and 2D FT NMR spectra measured on a Bruker Avance III 400 MHz
instrument. TMS (
d
¼0.00) or DMSO (
d
¼2.50, ¼39.52) peaks were
d
used as chemical shift reference. Mass spectra were recorded by
using Agilent Technologies 6540 UHD Accurate-Mass Q-TOF LC/MS
spectrometer by using AJ-ESI ionization or on LTQ Orbitrap
(Thermo Electron). Optical rotations were obtained using an Anton
Paar GWB Polarimeter MCP 500. Precoated silica gel 60 F254 plates
from Merck were used for TLC, whereas for column chromatogra-
phy silica gel KSK40-100 m
m was used. A CEM DiscoverÒ microwave
reactor was used for the microwave assisted reactions. Chemicals
were purchased from Aldrich Chemical Co or Apollo Scientific Ltd
and were used as received. Reactions sensitive to oxygen or mois-
ture were conducted under an Ar atmosphere in flame-dried
glassware.

K. Lippur et al. / Tetrahedron 68 (2012) 9550e9555
9553
O
N
F
COOH
R
N
O
N
O
F
COOH
HN
NH
MW
8a-c
O
+
R
R
O
O
N
O
N
F
Cl
1a
7a: R = H (2S,2'S)
7b: R = Bn (2 ,2' ,5 ,5'
R
R
)
S
S
R
R
HOOC
+
7c: R = Me (2 ,2' ,5 ,5' )
S S S S
O
N
F
COOH
N
O
9a-c
O
HN
R
Scheme 2. Amination of quinolone carboxylic acid 1a with bimorpholines.
Table 2
MW-assisted amination of quinolone carboxylic acid 1a with bimorpholine 7aa
4H), 1.73e1.65 (m, 2H), 1.42e1.35 (m, 2H), 1.23e1.17 (m, 2H). (NMR
spectroscopic data were in agreement with the literature data.)21
Entry
Base
Time (h)
NMR ratio
8aþ9ab:QA 1a
4.2.3. 1-Cyclopropyl-6-fluoro-4-oxo-7-(pyrrolidin-1-yl)-1,4-dihydroqu-
inoline-3-carboxylic acid 4. Yield 61%, mp 318e322 ꢀC. 1H NMR
1
2
3
4
5
6
7
8
9
d
1.5
3.5
1
2
6
1
2
1
1
17:83
17:83
44:56
50:50
61:39
29:71
43:57
Decomposed
Decomposed
d
(400 MHz, DMSO)
d
15.55 (br s, 1H), 8.58 (s, 1H), 7.81 (d, J¼14.3 Hz,
Et3N
Et3N
Et3N
DIPEA
DIPEA
DBU
NaOtBu
1H), 7.08 (d, J¼7.7 Hz, 1H), 3.78e3.71 (m, 1H), 3.65e3.56 (m, 4H),
2.02e1.96 (m, 4H), 1.33e1.27 (m, 2H), 1.18e1.12 (m, 2H). (NMR
spectroscopic data were in agreement with the literature NMR data of
compound 4 hydrochloride salt.)20
4.2.4. 7-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-1-cyclopropyl-6-
a
Reaction conditions: 2 equiv QA 1a, 1 equiv bimorpholine 7a, 6 equiv base,
fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5. Yield 57%,
DMSO 0.5 M, MW, 115 ꢀC.
mp 240e245 ꢀC. 1H NMR (400 MHz, CDCl3)
d 14.96 (s, 1H), 8.77 (s,
b
The sum of the integral values for the mixture of mono- and dimeric product 8a
1H), 8.04 (d, J¼12.7 Hz, 1H), 7.37 (d, J¼6.9 Hz, 1H), 3.70e3.64 (m,
4H), 3.57e3.50 (m, 1H), 3.33e3.25 (m, 4H), 1.50 (s, 9H), 1.44e1.37
(m, 2H), 1.24e1.18 (m, 2H). (NMR spectroscopic data were in
agreement with the literature data.)22
and 9a.
4.2. General procedure for MW-assisted amination of quino-
lone carboxylic acid 1a
4.2.5. 1-Cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroqu-
inoline-3-carboxylic acid 6. Yield 74%, mp 185e188 ꢀC. 1H NMR
A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic
amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed
temperature, at 115 ꢀC (power value ranging from 7 to 10 W) in the
CEM DiscoverÒ microwave reactor for 1.5 h. The reaction mixture
was cooled to room temperature and EtOAc (1 mL) was added. The
precipitate was filtered and dried at reduced pressure affording the
aminated quinolone as an off-white solid.
(400 MHz, CDCl3)
d
8.76 (s, 1H), 8.01 (d, J¼13.1 Hz, 1H), 7.36 (d,
J¼7.1 Hz, 1H), 3.58e3.51 (m, 1H), 3.34e3.28 (m, 4H), 3.14e3.09 (m,
4H), 1.43e1.36 (m, 2H), 1.23e1.17 (m, 2H). (NMR spectroscopic data
were in agreement with the literature data.)23
4.3. 7,70-((2S,20S)-[2,20-Bimorpholine]-4,40-diyl)bis(1-cyclopro-
pyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) 8a
4.2.1. Cyclopropyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid 2a. Yield 87%, mp 293e295 ꢀC. 1H NMR (CDCl3,
A mixture of quinolone carboxylic acid 1a (334 mg, 1.184 mmol),
(2S,20S)-bimorpholine 7a (102 mg, 0.592 mmol), triethylamine
400 MHz)
d
14.96 (br s, 1H), 8.76 (s, 1H), 8.01 (d, J¼12.8 Hz, 1H), 7.38
(d, J¼7.1 Hz, 1H), 3.97e3.91 (m, 4H), 3.60e3.53 (m,1H), 3.37e3.31 (m,
4H), 1.45e1.36 (m, 2H), 1.25e1.18 (m, 2H). (NMR spectroscopic data
were in agreement with the literature NMR data of compound 2a
hydrochloride salt.)20
(496 m
L, 3.553 mmol) and DMSO (0.5 mL) was heated at 115 ꢀC in
the CEM DiscoverÒ microwave reactor for 6 h. The reaction mixture
was cooled to room temperature and MeOH (1 mL) was added. The
precipitate was filtered and dried at reduced pressure, affording the
product 8a as off-white solid (yield 146 mg, 37%), mp 317e323 ꢀC.
4.2.2. 1-Cyclopropyl-6-fluoro-4-oxo-7-(piperidin-1-yl)-1,4-dihydroqui-
noline-3-carboxylic acid 3. Yield 62%, mp 243e249 ꢀC. 1H NMR
1H NMR (400 MHz, DMSO)
d 15.18 (br s, 2H), 8.69 (s, 2H), 7.96 (d,
J¼13.3 Hz, 2H), 7.61 (d, J¼7.4 Hz, 2H), 4.10e4.02 (m, 2H), 3.94e3.74
(m, 6H), 3.72e3.66 (m, 2H), 3.61e3.55 (m, 2H), 3.17e3.06 (m, 4H),
1.36e1.30 (m, 4H), 1.23e1.18 (m, 4H); 13C NMR (101 MHz, DMSO)
(400 MHz, CDCl3)
J¼7.2 Hz, 1H), 3.56e3.49 (m, 1H), 3.33e3.27 (m, 4H), 1.84e1.76 (m,
d
8.76 (s, 1H), 8.00 (d, J¼13.2 Hz, 1H), 7.34 (d,

9554
K. Lippur et al. / Tetrahedron 68 (2012) 9550e9555
O
N
F
COOEt
R
O
N
N
F
COOEt
Pd-catalyst
N
HN
NH
O
+
R
R
O
N
O
O
Cl
F
COOEt
R
1b
10a
O
7a: R = H
7b: R = Bn
N
F
N
O
R
EtOOC
O
O
11a-b
HN
2 M HCl
R
2 M HCl
O
N
F
COOH
R
O
N
O
N
F
COOH
R
8a
O
N
O
N
N
O
R
F
HOOC
O
9a-b
HN
.
HCl
R
Scheme 3. Pd-catalyzed amination of quinolone ester 1b.
d
176.4, 165.9, 153.4 (d, 1JCF¼248.8 Hz), 148.1, 145.0 (d, 2JCF¼10.3 Hz),
1687, 1622, 1493, 1344, 1260, 1169, 1080, 800 cmꢁ1; HRMS
2
139.2, 118.8, 111.1 (d, JCF¼25.5 Hz), 109.1, 106.5, 75.1, 65.9, 50.2,
C38H41F2N4O8: calcd [MþH]þ 719.2887, found 719.2886; Rf (10%
48.9, 35.8, 7.6, 7.2; IR (KBr)
n
¼2857, 1721, 1627, 1470, 1387, 1335,
MeOH/NH3 in CH2Cl2) 0.7; [
a
]
25 ꢁ69 (c 0.02, CHCl3).
D
1258, 1087, 953, 807 cmꢁ1; HRMS C34H33F2N4O8: calcd [MþH]þ
Compound 11a: 1H NMR (400 MHz, CDCl3)
d
8.53 (s, 1H), 8.05 (d,
25
663.2261, found 663.2254; [
MeOH).
a]
ꢁ42 (c 0.048, 18 mass% HCl in
J¼13.3 Hz, 1H), 7.27 (d, J¼7.0 Hz, 1H), 4.39 (q, J¼7.1 Hz, 2H),
4.12e4.07 (m, 1H), 3.97 (dd, J¼11.4, 2.3 Hz, 1H), 3.90e3.82 (m, 1H),
3.77e3.58 (m, 3H), 3.49e3.40 (m, 3H), 3.11e2.82 (m, 6H), 1.41 (t,
D
J¼7.1 Hz, 3H), 1.37e1.29 (m, 2H), 1.17e1.10 (m, 2H); 13C NMR
4.4. Diethyl 7,70-((2S,20S)-[2,20-bimorpholine]-4,40-diyl)bis(1-
cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxy-
late) 10a and ethyl 7-((2S,20S)-2,20-bimorpholino)-1-cyclopro-
pyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate 11a
4
(101 MHz, CDCl3)
d
173.2 (d, JCF¼2.4 Hz), 165.8, 154.1 (d,
1JCF¼248 Hz), 148.2, 144.4 (d, JCF¼10.2 Hz), 138.1 (d, JCF¼1.2 Hz),
2
4
3
2
123.4 (d, JCF¼7.0 Hz), 113.5 (d, JCF¼23.1 Hz), 110.5, 104.8 (d,
3JCF¼2.8 Hz), 76.8, 76.2, 68.1, 66.7, 60.9, 51.2 (d, 4JCF¼4.8 Hz), 49.7 (d,
4JCF¼4.0 Hz), 47.1, 45.6, 34.5, 14.5, 8.2, 8.1; IR (KBr)
n
¼2856, 1722,
HRMS
A mixture of quinolone carboxylic acid ethyl ester 1b (240 mg,
0.774 mmol), Cs2CO3 (505 mg, 1.548 mmol), Pd2(dba)3 (35 mg,
0.039 mmol), BINAP (29 mg, 0.046 mmol) and (2S,20S)-bimor-
pholine 7a (160 mg, 0.929 mmol) in DMF (7.7 mL) was placed in
a sealable microreactor under Ar. After heating the reaction mix-
ture at 100 ꢀC for 48 h, the mixture was cooled to room temper-
ature and DMF was removed at reduced pressure. The residue was
dissolved in CH2Cl2 and filtered through Celite. After evaporation
of the solvent, the crude mixture was purified by column chro-
matography on silica gel (2e7% MeOH/NH3 in CH2Cl2), affording
compounds 10a as off-white solid (yield 150 mg, 27%), mp
313e318 ꢀC and 11a as off-white solid (yield 120 mg, 35%), mp
123e129 ꢀC.
1622, 1493, 1345, 1315, 1260, 1172, 1081, 802 cmꢁ1
;
C23H29FN3O5: calcd [MþH]þ 446.2086, found 446.2087; Rf (10%
25
MeOH/NH3 in CH2Cl2) 0.55; [
a
]
ꢁ36 (c 0.02, CHCl3).
D
4.5. Ethyl 1-cyclopropyl-7-((2S,20S,5R,50R)-5,50-dibenzyl-2,20-
bimorpholino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbo-
xylate 11b
A mixture of quinolone carboxylic acid ethyl ester 1b (42 mg,
0.136 mmol), Cs2CO3 (88 mg, 0.271 mmol), Pd2(dba)3 (6 mg,
0.0067 mmol), BINAP (5 mg, 0.0081 mmol) and (2S,20S,5R,50R)-5,50-
dibenzyl-2,20-bimorpholine 7b (57 mg, 0.163 mmol) in DMF
(1.3 mL) was placed in a sealable microreactor under Ar. After
heating the reaction mixture at 100 ꢀC for 48 h, the mixture was
cooled to room temperature and DMF was removed at reduced
pressure. The residue was dissolved in CH2Cl2 and filtered through
Celite. After evaporation of the solvent, the crude mixture was
purified by column chromatography on silica gel (1e3% MeOH/NH3
in CH2Cl2), affording 11b as off-white solid (yield 28 mg, 33%), mp
99e103 ꢀC.
Compound 10a: 1H NMR (400 MHz, CDCl3)
d 8.54 (s, 2H), 8.07 (d,
J¼13.3 Hz, 2H), 7.29 (d, J¼7.0 Hz, 2H), 4.39 (q, J¼7.1 Hz, 4H), 4.14 (dd,
J¼11.4,1.9 Hz, 2H), 3.97e3.85 (m, 4H), 3.55e3.50 (m, 2H), 3.49e3.41
(m, 4H), 3.16e3.02 (m, 4H), 1.41 (t, J¼7.1 Hz, 6H), 1.38e1.31 (m, 4H),
1.17e1.12 (m, 4H); 13C NMR (101 MHz, CDCl3)
d
173.1,165.9,153.4 (d,
1JCF¼248 Hz), 148.2, 144.2 (d, JCF¼10.6 Hz), 138.1, 123.6 (d,
2
3JCF¼7.4 Hz), 113.6 (d, JCF¼23.2 Hz), 110.7, 104.8 (d, JCF¼2.1 Hz),
2
3
75.8, 66.8, 60.9, 51.4, 49.6, 34.5, 14.4, 8.2, 8.1; IR (KBr)
n
¼2870, 1721,

K. Lippur et al. / Tetrahedron 68 (2012) 9550e9555
9555
1H NMR (400 MHz, CDCl3)
d
8.50 (s, 1H), 8.04 (d, J¼13.8 Hz, 1H),
was dried under reduced pressure, affording 9a as an off-white
solid (5 mg, 24%), mp 246e253 ꢀC.
7.36e7.07 (m, 11H), 4.38 (q, J¼7.1 Hz, 2H), 4.09e3.96 (m, 2H),
3.96e3.74 (m, 5H), 3.45 (t, J¼11.3 Hz, 1H), 3.40e3.32 (m, 1H),
3.21e3.11 (m, 3H), 3.11e2.96 (m, 2H), 2.89 (dd, J¼13.1, 5.7 Hz, 1H),
2.84e2.73 (m, 2H), 1.41 (t, J¼7.1 Hz, 3H), 1.30e1.23 (m, 2H),
1H NMR (400 MHz, CDCl3)
d
8.78 (s, 1H), 8.03 (d, J¼13.0 Hz, 1H),
7.36 (d, J¼7.1 Hz, 1H), 4.15e4.09 (m, 1H), 4.01e3.95 (m, 1H),
3.91e3.83 (m, 1H), 3.79e3.73 (m, 1H), 3.72e3.46 (m, 5H), 3.15e3.05
(m, 2H), 3.05e2.82 (m, 4H), 1.44e1.36 (m, 2H), 1.24e1.16 (m, 2H);
1.13e1.07 (m, 2H); 13C NMR (101 MHz, CDCl3)
d 173.0, 165.9, 152.9
1
2
(d, JCF¼247 Hz), 148.1, 143.2 (d, JCF¼10.1 Hz), 138.8, 138.2, 138.1,
13C NMR (101 MHz, CDCl3)
d
177.1, 166.9, 153.6 (d, 1JCF¼250.6 Hz),
3
129.4, 129.2, 128.7, 128.5, 126.5, 122.7 (d, JCF¼6.9 Hz), 113.6 (d,
147.5, 145.7 (d, 2JCF¼10.4 Hz), 139.1, 120.2 (d, 3JCF¼7.8 Hz), 112.6 (d,
2JCF¼23.9 Hz), 110.4, 105.3 (d, JCF¼2.8 Hz), 76.0, 75.9, 69.3, 67.8,
2JCF¼23.5 Hz), 108.3, 104.8 (d, 3JCF¼3.1 Hz), 76.7, 76.1, 68.2, 66.6, 51.0
4
60.9, 58.2 (d, 4JCF¼9.4 Hz), 53.9, 45.1, 42.4, 36.6, 34.4, 33.1, 14.4, 8.2,
(d, JCF¼4.3 Hz), 49.5 (d, JCF¼4.4 Hz), 47.0, 45.6, 35.3, 8.3, 8.2; IR
4
4
8.1; IR (KBr)
n
¼2858, 1725, 1621, 1494, 1313, 1245, 1166, 1101, 803,
(KBr)
n
¼2867, 1726, 1629, 1494, 1470, 1389, 1338, 1262, 1090, 952,
745, 701 cmꢁ1; HRMS C37H41FN3O5: calcd [MþH]þ 626.30248,
894, 805 cmꢁ1; HRMS C21H25FN3O5: calcd [MþH]þ 418.1773, found
found 626.30286; Rf (10% MeOH/NH3 in CH2Cl2) 0.75; [
a
]
25 þ127 (c
418.1775.
D
0.14, CHCl3).
Acknowledgements
4.6. General procedure for hydrolysis of 7-substituted quino-
lone carboxylic acid esters
The authors thank the Estonian Ministry of Education and Re-
search (Grant No: SF0140060s12), the Centre of Excellence in
Chemical Biology, the EU European Regional Development Fund
3.2.0101.08-0017 and Estonian Science Foundation (Grant No
8289).
A 2 M aq HCl solution (1 mL) was added to diethyl 7-substituted
quinolone carboxylic acid ester (0.04 mmol) and the solution was
heated at reflux for 3 h under an Ar atmosphere. The mixture was
cooled to room temperature. For compounds 8a and 9b, H2O was
added and the crude mixture was extracted with CH2Cl2 (3ꢂ). The
organic layer was dried under reduced pressure, affording the 7-
substituted quinolone carboxylic acid as off-white solid. For com-
pound 9a, the mixture was dried under reduced pressure. The
residue was washed with MeOH and the precipitate was dried
under reduced pressure, affording compound 9a as off-white solid.
References and notes
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4.6.1. 7,70-((2S,20S)-[2,20-Bimorpholine]-4,40-diyl)bis(1-cyclopropyl-
6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) 8a. Yield
100%.
€€
5. Lippur, K.; Kanger, T.; Kriis, K.; Kailas, T.; Muurisepp, A.-M.; Pehk, T.; Lopp, M.
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ꢀ
€
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4.6.2. 7-((2S,20S)-2,20-Bimorpholino)-1-cyclopropyl-6-fluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid hydrochloride salt 9a. Yield
25
9. Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry; Wiley-
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95%. [
a
]
þ16 (c 0.01, H2O).
D
€
10. Albrecht, M.; Osetska, O.; Rantanen, T.; Frohlich, R.; Bolm, C. Synlett 2010,
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1H NMR (CDCl3, 400 MHz)
d
8.73 (s, 1H), 8.00 (d, J¼13.7 Hz, 1H),
7.36e7.05 (m, 11H), 4.21e4.10 (m, 1H), 4.07e3.77 (m, 6H),
3.61e3.39 (m, 2H), 3.27e3.10 (m, 4H), 3.10e2.82 (m, 4H), 1.30e1.23
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(m, 2H), 1.13e1.07 (m, 2H); 13C NMR (CDCl3, 101 MHz)
d 177.1, 167.1,
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1
2
153.0 (d, JCF¼250 Hz), 147.4, 143.3 (d, JCF¼10.9 Hz), 139.1, 138.4,
137.9, 129.3, 129.2, 128.8, 128.6, 126.6, 120.3, 112.8 (d, 2JCF¼23.1 Hz),
4
108.2, 105.0, 75.8, 75.5, 68.8, 68.0, 58.2 (d, JCF¼9.5 Hz), 53.7, 45.0,
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]
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D
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1 M aq NaOH solution (51 mL, 0.051 mmol) was added to 7-
((2S,20S)-2,20-bimorpholino)-1-cyclopropyl-6-fluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid hydrochloride salt 9a (23 mg,
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