Synthesis of norfloxacin analogues catalyzed by Lewis and Br?nsted acids: An alternative pathway

Article abstract of DOI:10.1016/j.jfluchem.2010.07.002

An alternative synthetic pathway to prepare norfloxacin analogues is presented. Three Lewis acids (CeCl₃·7H₂O, AlCl ₃·6H₂O, ZnCl₂) and one Bro?nsted acid (TsOH) were tested as catalysts in the prepara

Full text of DOI:10.1016/j.jfluchem.2010.07.002

Journal of Fluorine Chemistry 131 (2010) 982–988
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of norfloxacin analogues catalyzed by Lewis and Br o¨ nsted acids:
An alternative pathway
Socorro Leyva, Hiram Hern a´ ndez *
Facultad de Ciencias Qu ı´ micas. Universidad Aut o´ noma de San Luis Potos ı´ , Av. Manuel Nava No. 6, Zona Universitaria, C.P. 78210, San Luis Potos ı´ , S.L.P., M e´ xico
A R T I C L E I N F O
A B S T R A C T
Article history:
An alternative synthetic pathway to prepare norfloxacin analogues is presented. Three Lewis acids
Received 30 April 2010
Received in revised form 29 June 2010
Accepted 6 July 2010
(
CeCl
of 3,4-difluoroacrylate. Cyclization of this acrylate at 55 8C was achieved with the use of Eaton’s reagent
/MeSO
H) a known Br o¨ nsted acid. The fluoroquinolone–boron complex presented high yields on C-
nucleophilic substitution of the fluorine atom by different heterocyclic amines with low, medium and
strong nucleophilic character.
3
Á7H
2
O, AlCl
3
Á6H
2 2
O, ZnCl
) and one Br o¨ nsted acid (TsOH) were tested as catalysts in the preparation
(
P
2
O
5
3
Available online 14 July 2010
7
Keywords:
ß 2010 Elsevier B.V. All rights reserved.
Fluoroquinolone
Lewis acid
Br o¨ nsted acid
Hydroxyquinoline
Antibacterial
1
. Introduction
Fluoroquinolones are a group of compounds with a broad
reaction [12,13], little has been established concerning the use of
Eaton’s reagent [14–16]. This reagent is easily prepared by
dissolving phosphorus pentoxide in methanesulfonic acid
antibacterial spectrum [1–3]. Ciprofloxacin, norfloxacin and
sparfloxacin have gained a wide acceptance for their use in the
treatment of numerous diseases [1]. The synthesis of norfloxacin
and its derivatives, starting from 3-chloro-4-fluoroaniline and
followed by a limited number of reactions already reported [4,5],
presented certain disadvantages such as a long time in the
condensation reaction, extreme conditions for acrylate cyclization
3 3
(CH SO H) [12]. It provides the advantages of a solution with less
viscosity and a better solubility of certain organic molecules [13].
Furthermore, it is a convenient alternative to achieve good yields in
the cyclization reaction.
On the other hand, the methodology for introducing different
N
heterocyclic amines by nucleophilic aromatic substitution (S Ar)
at C-7 of 7-chloro-6-fluoroquinolone has not been satisfactory in
terms of yield. An alternative reaction has been proposed, which
uses the quinolone–boron complex derivative of the fluoroquino-
lone-3-carboxylic acid [17,18]. The complex obtained, opens the
possibility of introducing a heterocyclic amine, as pyrrolidine or
piperidine, obtaining the fluoroquinolone-7-substituted in good
yields. However, its efficiency against different kinds of nucleo-
philes has been poorly explored. This strategy is evaluated by
introducing different heterocyclic amines as nucleophiles, such as
piperazine, morpholine, pyrrolidine, 2-methyl-piperazine, 2-ami-
no-pyrimidine, 3,5-diamino-1,2,4-triazole and 5-amino-uracil.
(250 8C) and non-specific fluorine substitution with moderate
yields at C-7 only when strong nucleophiles are used.
Recently, evidence of quinolone interaction with several metals
2+
2+ 3+
2+
2+
2+
2+
2+
2+
such as Mg , Ca , B , Fe , Co , Zn , Ag , Cd and Bi has been
presented by other authors [6,7]. Covalent, coordinative or ionic
interactions with ketone and carboxylic acid moieties of fluoro-
quinolone molecule, allowed us to introduce Lewis and Br o¨ nsted
acids in a catalytic amount in order to promote the Michael
addition reaction under mild conditions. CeCl
3
Á7H
2
O [8],
AlCl O [9,10] and ZnCl [11] have been described as Lewis
3
Á6H
2
2
acids with great affinity for the electron pair of oxygen, these
interactions are useful for the synthesis of intermediate molecules
of norfloxacin analogues.
2. Results and discussion
In spite of the large number of publications, regarding the
synthetic applications of polyphosphoric acid (PPA) for cyclization
In the first reaction, the conjugate addition of an amine to
a
,
b-unsaturated esters (Michael reaction) catalyzed by Lewis
(
CeCl O, AlCl O, ZnCl
3
Á7H
2
3
Á6H
2
2
) or Br o¨ nsted (TsOH) acids, could be
carried out in a solvent-free environment without employing
poisonous condensations solvents such as benzene or toluene. The
liquid malonate 1 allowed a good interaction at room temperature
*
Corresponding author. Tel.: +52 444 826 2440; fax: +52 444 826 2372.
E-mail address: sleyva@uaslp.mx (H. Hern a´ ndez).
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.07.002

S. Leyva, H. Hern a´ ndez / Journal of Fluorine Chemistry 131 (2010) 982–988
983
Table 1
Preparation of 3,4-difluoroacrylate 3 using Lewis and Br o¨ nsted acids as catalyst.
[TD$INLINE]
a
Sample
Catalyst (mmol)
Yield (%)
mp (8C)
Time (min)
b
c
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
[19]
[20]
None
None
74
81
54
67
52
55
46
37
60
70
61
60
45
43
43
76–77
80–81
76–77
76–77
76–77
76–77
72–73
72–73
68–69
73–74
74–75
72–73
68–69
68–69
66–67
80
120
d
CeCl
CeCl
CeCl
CeCl
3
3
3
3
1:100
1:100
1:100
1:150
1:200
1:150
1:100
1:100
1:150
1:200
1:100
1:150
1:100
120
3
e
f
7
e
e
e
e
e
e
e
e
e
f
1
33
39
28
23
25
27
20
10
TsOH
TsOH
TsOH
0
AlCl
AlCl
AlCl
3
3
3
1
2
3
4
5
ZnCl
ZnCl
ZnCl
2
2
2
41
a
b
c
d
e
f
Relationship catalyst:feedstock.
00 8C.
10–120 8C.
0 8C.
rt.
8C.
1
1
8
0
between oxygen-carbonyl group and the catalyst, forming the
complex malonate-Lewis acid that reacted with the liquid 3,4-
difluoroaniline 2 in order to obtain a pink solid. This interaction
lower force of attraction over the electronic density in a malonate
molecule than aluminum or cerium salts, presenting a lower
oxophilicity and reacting over a long time. In a similar way,
protonation of malonate carbonyl groups by TsOH, resulted in a
poor electronic density movement, a longer time of reaction and
the lowest yields [22]. Moreover, because of the shortest reaction
time and highest purity, according to the melting data, the best
catalyst to use in this Michael addition reaction could be Ce ion.
Cyclization of acrylate 3 was achieved with the use of Eaton’s
reagent decreasing the reported temperature from 250 8C to 55 8C,
obtaining the hydroxyquinoline 4 in a 50% yield (Table 2). The
reaction probably followed a 2+2+2 electrocyclization upon
was more efficient with CeCl
TsOH and ZnCl . A further re-crystallization produced a white solid
in fairly good yields (Table 1).
The ionic bonding contributions of Ce ion combined with the
3
Á7H
2
O than AlCl
3
Á6H
2
O followed by
2
3
3+
3+
high Lewis acidity cause the strong oxophilicity shown in the
lanthanide cations [21], catalyzing Michael addition reaction in
3+
less time over the Al ion that possesses a strong affinity toward
various heteroatoms due to its low polarizability and small ionic
2+
radii. In contrast, the high polarizability of the Zn ion exerts a
Table 2
Preparation of ethyl 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 4 using Eaton’s reagent.
[TD$INLINE]
a
b
Sample
Molar ratio (mmol)
Time (h)
Yield (%)
sp (8C)
Temp (8C)
1
2
3
4
5
6
[20]
None
5.1:1
3:1
6
168
22
87
8
241–242
229–230
229–230
–
250
63
55
rt
17
0
3:1
168
168
336
2:1
41
50
220–221
218–219
55
55
2.5:1
a
Molar ratio (Eaton:acrylate).
sp: sublimation point.
b

9
84
S. Leyva, H. Hern a´ ndez / Journal of Fluorine Chemistry 131 (2010) 982–988
Scheme 1. Nucleophilic aromatic substitution at C-7 of difluoroquinolone ester, carboxylic acid and boron complex rings. (i) CH
BF , (C O, 200 8C, 30 min. (iii) CH SOCH , N(C , rt, 24 h. (iv) CH CN, reflux, 4 h for piperazine, or NaH 95%, C
ÁOEt
NaOH (2N), 110–120 8C, 2 h, (b) HCl (1:1) or H SO 2N, 80–90 8C, 2 h. (vi) morpholine or 2-methylpiperazine/N-methyl-2-pyrrolidinone, rt, 2 h for R
29a] or excess of pyrrolidine/pyridine, 95 8C, 4 h for R = C [28].
3
CH
2 2 3 3 2
I, K CO , (CH ) NCHO, 80–90 8C, 10 h. (ii)
3
2
6
H
5
)
2
3
3
2
H
5
)
3
3
5 5
H N, reflux, 24 h for 2-aminopyrimidine. (v) (a)
2
4
1
6 4 3 5
= p-FC H [27], c-C H
[
1
2 5
H
protonation and then the hemiketal intermediate decomposed to
form the hydroxyquinoline 4. Variations on the molar ratio
Eaton:acrylate influenced the reaction yield. An excess of polypho-
sphoric acid and temperatures for over 55 8C resulted in a drop
boron chelated 6 was achieved with BF
CH CH
HF. The electron pair on the tertiary amine allows better
conjugation with the ketone group on the pyridone ring, this
electronic movement promotes the formation of an oxygen
3
ÁOEt
2
. In this case, the
F is generated as a sub-product, avoiding the formation of
3
2
2 3
regarding yields. Better results could be obtained using Na SO as a
saturated basic solution instead of water to stop cyclization
reaction with moderate yields [23].
anion. Then the oxygen with negative charge can attack the BF
3
molecule, and the adduct is formed. High temperature induced
the production of fluoroethane molecule and the corresponding
complex 6.
In this latter intermediate 6 [18] a more positive charge at C-7 is
generated. Introduction of a heterocyclic amine (Table 3), classified
as a poor nucleophile such as 5-amino-uracil into a fluoroquino-
A further N-alkylation was carried out for obtaining ethyl 1-
ethyl-6,7-difluoroquinolone-3-carboxylate 5 (Scheme 1). Syn-
thesis of fluoroquinolone–boron complex has been performed
with excellent results [24], but this method did not prove to be a
good choice due to formation of HF as a sub-product when
fluoroboric acid is used to convert ester 5 into boron complex 6
lone ring by S
N
Ar reaction, was performed at room temperature in
[
25,26]. In our experimental procedure, the production of the
24 h of reaction time and a 69% yield.

S. Leyva, H. Hern a´ ndez / Journal of Fluorine Chemistry 131 (2010) 982–988
985
Table 3
Different heterocyclic amines used as nucleophiles in S
N
Ar on C-7 of fluoroquinolone–boron complex.
Entry
Nucleophile
Product
Yield (%)
mp (8C)
Product
Yield (%)
mp (8C)
[
D
I
L
N
]
[TD$INLE]
a
1
2
Piperazine
7a
7b
82
93
268–269
269–270
8a
46
56
172–173
b
Morpholine
10b
None
c
51
281–283
d
e
e
e
3
2-Methyl-piperazine
7c
74
286–287
10c
10d
50
168–169
235–237
225–227
277–280
5
3
3
2
3
0
d
f
4
Pyrrolidine
7d
75
285–286
52
222–223
233–234
56
a
5
6
7
2-Amino-pyrimidine
3,5-Diamino-1,2,4-triazole
5-Amino-uracil
7e
7f
69
54
69
336–338
>400
8e
41
266–267
None
None
None
None
None
7g
>400
None
a
R
1
= C
= p-FC
= C
= c-C
= c-C
= c-C
2
H
5
, R
3
= C
, R
= H, R
, R and R
, R = H
, R = H, R
2
H
5
, R
and R
and R
= H, R
= F, R
= NH
8
= H [20].
b
c
d
e
f
R
1
6
H
4
3
, R
5
8
= H [27].
= F [28].
R
1
2
H
5
, R
3
5
8
R
1
3
H
5
3
5
8
= OEt [29a].
= F, Cl, OH [29b].
, R = F [29c].
R
1
3
H
5
3
,
R
8
5
R
1
3
H
5
3
5
2
8
Pyrrolidine, morpholine, piperazine and 2-methylpiperazine
internal standard. Mass spectrometry was done on a JEOL
apparatus using FAB technique.
3
+
rings are expected to be good nucleophiles because of their sp -
hybridized nitrogen. On the other hand, in the 3,5-diamino-1,2,4-
triazole, 2-amino-pyrimidine and 5-amino-uracil compounds,
the electron pair on the nitrogen is delocalized into the ring atom,
4.2. Diethyl 2-(3,4-difluoro)-phenyl-aminomethylenemalonate (3)
2
since the neighbor carbon is sp -hybridized. Therefore, these
A measured amount of Lewis acid: CeCl
3
Á7H
2
O, AlCl
3
Á6H
2
O,
heterocyclic amines are poor nucleophiles and they reacted
under mild conditions giving good substitution yields on C-7
when the fluoroquinolone–boron complex is used. Fluoroquino-
lone antibacterials are commonly prepared by direct amination
of 1-ethyl-6,7-difluoroquinolone-3-carboxylic acid 9 [27,28,29a–
c] or ester 5 [20] with heterocyclic amines having low to
moderate yields with longer reaction times and higher tem-
peratures.
ZnCl mol) was added to diethyl
2
or Br o¨ nsted acid: TsOH (33.4
m
ethoxymethylenemalonate 1 (3.34 mmol) and allowed it to react
for 15 min at a room temperature (25 8C). Then, 3,4-difluoroaniline
2 (3.34 mmol) was added. After 3 min of reaction, a pink solid was
obtained and poured into warm n-hexane (5 mL) until achieving its
complete dissolution. The formation of two phases was observed
when the temperature of suspension decreased. The upper phase
was removed and the lower one was left to cool down to allow
crystallization. The 3,4-difluoroacrylate 3 was obtained as white
3
. Conclusions
needles and separated by vacuum filtration in 67% yield, m.p. 76–
À1
77 8C. IR (KBr, cm ): 3263 (N–H, secondary amine), 3175 (N–H,
We have synthesized various 7-substituted-6-fluoroquinono-
overtone), 1686 and 1645 (C 55 O, ester), 1629 (C 55 C, alkene), 1594
and 1522 (C 55 C, aromatic), 1381 (CH ), 1300–1200 (C–O), 1250 and
3
1100 (C–F), 1076 (C–N, secondary amine). H NMR (CDCl ) d ppm:
10.97 (1H, d, J = 13.50 Hz, amine H), 8.36 (1H, d, J = 13.50 Hz, vinyl
H), 7.17 (1H, dd, J = 9.00, 6.50 Hz, aromatic H), 6.98 (1H, m,
aromatic H), 6.85 (1H, dd, J = 9.00, 2.50 Hz, aromatic H), 4.31 (2H, q,
lone–boron complexes in moderate yields. The Michael condensa-
tion (between 3,4-difluoroaniline and malonate) was catalyzed by
Lewis and Br o¨ nsted acids in a solvent-free environment in a very
short time. Cyclization was performed decreasing the temperature
3
1
N
from 250 8C to 55 8C with Eaton’s reagent. Then, the S Ar
substitutions in C-7 were realized with poor nucleophiles in a
more reactive fluoroquinolone–boron complex to produce nor-
floxacin analogues. A further treatment with a basic solution
J = 7.00 Hz, CH
J = 7.00 Hz, CH
ppm: 168.94 and 165.41 (C 55 O ester), 151.67 and 94.67 (vinyl C),
106.64, 149.92, 146.58, 136.18, 118.38 and 113.06 (aromatic C),
60.59 and 60.28 (CH ), 14.39 and 14.24 (CH ). The exact mass was
22.0861 amu, the mass observed was 322.0873 amu for
2 2
), 4.25 (2H, q, J = 7.00 Hz, CH ), 1.38 (3H, t,
1
3
3
3 3
), 1.33 (3H, t, J = 7.00 Hz, CH ). C NMR (CDCl )
d
(NaOH 2N) could be used to generate the corresponding
fluoroquinolone-3-carboxylic acid [30,31]
2
3
3
C
+
4
. Experimental
14 15 2 4
H F NO Na .
4.1. Instruments
4.3. Ethyl 6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4)
The melting points were obtained by using a Fisher-Johns
The Eaton’s reagent (2.5 mmol) was added to diethyl 2-(3,4-
difluoro)-phenyl-aminomethylenemalonate 3 (1.66 mmol) and
allowed to react under stirring for 2 weeks at 55 8C. After then,
the reacting mixture was poured into water to yield a yellow solid.
melting point apparatus. The IR spectra were recorded on a Fourier
Perkin Elmer, FTIR-1600 spectrophotometer. The NMR spectra
were recorded on a Varian 300 MHz spectrometer using TMS as the

9
86
S. Leyva, H. Hern a´ ndez / Journal of Fluorine Chemistry 131 (2010) 982–988
It was filtered, washed twice with ethanol/acetone (1:1) and
refluxed with ethanol for 30 min. The hydroxyquinoline 4 was
4.6.1. Difluoroboranyl 1-ethyl-6-fluoro-7-(piperazin-1-yl)-
quinolone-3-carboxylate (7a)
filtered and dried to give a white powder (50% yield) with s.p. 218–
It was obtained as a yellow solid in 82% yield and m.p. 268–
269 8C. IR (KBr, cm ): 3347 (N–H, secondary amine), 2967–2763
À1
À1
2
19 8C. IR (KBr, cm ): 1697 (C 55 O, ester), 1621 (C 55 C, alkene), 1565
and 1533 (C 55 C, aromatic), 1495 (CH
2
), 1381 (CH
C–O), 1250 and 1100 (C–F), 1082 (C–N, secondary amine). H NMR
DMSO-d ppm: 8.59 (1H, s, vinyl H), 7.99 (1H, dd, J = 8.96,
.44 Hz, aromatic H), 7.64 (1H, dd, J = 8.96, 7.44 Hz, aromatic H),
.21 (2H, q, J = 7.00 Hz, CH ), 1.27 (3H, t, J = 7.00 Hz, CH ). The exact
3
), 1292 and 1263
(CH
alkene), 1529 and 1490 (C 55 C, aromatic), 1453 (CH
1137 (C–O), 1105 and 1038 (C–N, tertiary amine), 1105 (C–F). H
NMR (DMSO-d ppm: 9.62 (1H, s, vinyl H), 8.27 (1H, d,
J = 13.93 Hz, aromatic H), 7.70 (1H, d, J = 7.32 Hz, aromatic H) 3.64
(4H, t, J = 5.12 Hz, piperazine CH ), 3.15 (4H, t, J = 5.12 Hz,
piperazine CH ), 3.48 (1H, br s, amine H), 5.20 (2H, q,
J = 7.32 Hz, CH
2
), 1704 (C 55 O, pyridone), 1638 (C 55 O, ester), 1574 (C 55 C,
1
(
(
2
), 1256 and
1
6
) d
7
4
6
) d
2
3
mass was 276.0442 amu and the mass observed was
2
+
2
76.0440 amu for C12
H
9
F
2
NO
3
Na .
2
+
2
3
), 1.83 (3H, t, J = 7.32 Hz, CH ). MS FAB (probe)
+
+
4.4. Ethyl 1-ethyl-6,7-difluoroquinolone-3-carboxylate (5)
70 eV, m/z (rel. int.): 368 [M+1] (48), 348 [M–F] (7), 320
+
+
[
M+H
BF –H
155 [M–OBF
2
–BF
2
]
(8), 307 [M–F+H
]
2
–CH
(21), 220 [M+H
–CO–C NO+3H
3
–CO] (41), 289 [M+2H
2
–
+
+
The hydroxyquinoline 4 (10 mmol) was added into a flask with
2
2
O–CH
3
2
–BF
2
Á
–CO
2
–CO–C
2
H
4
]
(10),
+
K
2
CO
3
(24.96 mmol), EtI (50 mmol) and dimethylformamide
produced
2
–C
NO+2H
2
H
4
5
+
H
7
2
]
(39), 154 [M–OBF
+H] (100), 136 [M+H
2
–
(20 mL), and refluxed at 80–90 8C for 10 h. The KHCO
3
C
C
2
H
H
4
3
–CO–C
2 4 9
–N C H ] (95).
5
H
7
+
2
2
–BF –CO –CO–
2
2
was removed by hot filtration and washed with ethanol. After
cooling the liquid phase at room temperature, the formation of
white rectangular needles was observed. The solid was washed
with hot ethanol to give the compound 5, m.p. 154–155 8C and 85%
2
4.6.2. Difluoroboranyl 1-ethyl-6-fluoro-7-(morpholin-1-yl)-
quinolone-3-carboxylate (7b)
À1
yield. IR (KBr, cm ): 1717 (C 55 O, pyridone), 1686 (C 55 O, ester),
It was obtained as a beige solid in 93% yield and m.p. 269–
À1
1
618 (C 55 C, alkene), 1565 and 1497 (C 55 C, aromatic), 1388 (CH
3
),
270 8C. IR (KBr, cm ): 1726 (C 55 O, pyridone), 1637 (C 55 O, ester),
1
290 and 1230 (C–O), 1184 and 1080 (C–F), 1080 (C–N, tertiary
1613 (C 55 C, alkene), 1581 and 1490 (C 55 C, aromatic), 1449 and
1
amine). H NMR (DMSO-d
m, aromatic H), 4.37 (2H, q, J = 7.28 Hz, CH
J = 7.28 Hz, CH ), 1.33 (3H, t, J = 7.28 Hz, CH
6
)
d
ppm: 8.69 (1H, s, vinyl H), 8.06 (2H,
), 4.22 (2H, q,
), 1.27 (3H, t,
ppm: 171.30 (C 55 O ketone),
64.29 (C 55 O ester), 149.42 and 110.05 (vinyl C), 153.54, 146.42,
36.04, 125.71, 113.85 and 106.90 (aromatic C), 59.86 and 48.42
), 14.25 (CH ). The exact mass was 304.0755 amu and the
mass observed for C14
1414 (CH
2
), 1284–1245 (C–O), 1126 (C–N, tertiary amine), 1064
(C–F). H NMR (DMF-d ppm: 9.62 (1H, s, vinyl H), 8.31 (1H, d,
J = 14.08 Hz, aromatic H), 7.76 (1H, d, J = 7.31 Hz, aromatic H), 5.21
(2H, q, J = 7.32 Hz, CH ), 4.04 (4H, t, J = 5.12 Hz, morpholine CH ),
3.72 (4H, t, J = 5.12 Hz, morpholine CH
1
2
7
) d
2
3
13
J = 7.28 Hz, CH
3
). C NMR (DMSO-d
6
)
d
2
2
1
1
2
), 1.83 (3H, t, J = 7.32 Hz,
+
+
CH
3
). MS FAB (probe) 70 eV, m/z (rel. int.): 369 [M+1] (48), 349
+
+
+
(CH
2
3
[M–F] (7), 321 [M+H
2
+
–BF
2
] (17), 307 [M–BF
2
–CH
3
+H
2
+H] (60),
+
+
H
13
F
2
NO
3
Na was 304.0752 amu.
289 [M–OBF
54 [M–OBF
CO–C –C
NO+H] (100).
2
–CH
–CO–C
NO+H
3
+H] (29), 220 [M–BF
2
–CO
2
–CO–C
2
H
3
]
(11),
+Á
1
2
5
H
7
+
NO–C
2
H
4
+2H
2
]
(100), 137 [M–BF
2
–CO –CO–C H
2
–CO
2
–
–
4.5. Difluoroboranyl 1-ethyl-6,7-difluoroquinolone-3-carboxylate (6)
2
H
2
4
+
H
8
2
]
(100), 136 [M–BF
2
2
2
4 8
C H
The ethyl 1-ethly-6,7-difluoroquinolone-3-carboxylate
5
(
2.29 mmol) and BF (2.72 mmol) were added into diphenyl-
3
ÁOEt
2
4.6.3. Difluoroboranyl 1-ethyl-6-fluoro-7-(3-methyl-piperazin-1-yl)-
quinolone-3-carboxylate (7c)
ether (10 mL) at 200 8C and refluxed for 30 min. The solid obtained
was separated by filtration and washed with ethyl acetate to
afford compound 6 as a white solid in 93% yield and m.p. 292–
It was obtained as a yellow solid in 74% yield and m.p. 286–
287 8C. IR (KBr, cm ): 3267 (N–H, secondary amine), 3055 (C–H,
À1
À1
2
1
1
93 8C. IR (KBr, cm ): 1715 (C 55 O, pyridone), 1637 (C 55 O, ester),
alkene and aromatic), 2963 and 2845 (CH
1636 (C 55 O, ester), 1582 (C 55 C, alkene), 1530 and 1489 (C 55 C,
aromatic), 1450 (CH ), 1395 (CH ), 1268 and 1125 (C–O), 1125 and
1082 (C–N, tertiary amine), 1081 (C–F). H NMR (DMF-d
9.58 (1H, s, vinyl H), 8.27 (1H, d, J = 13.96 Hz, aromatic H), 7.07 (1H,
d, J = 7.31 Hz, aromatic H), 5.20 (2H, q, J = 7.32 Hz, CH ), 3.98 (4H, t,
J = 7.97 Hz, piperazine CH ), 3.22 (2H, td, J = 10.97, 1.63 Hz,
piperazine CH ), 3.13 (2H, m, piperazine CH and amine H), 1.82
(3H, t, J = 7.32 Hz, CH ), 1.25 (3H, d, J = 6.59 Hz, piperazine CH ). MS
2
), 1722 (C 55 O, pyridone),
583 (C 55 C, alkene), 1554 and 1487 (C 55 C, aromatic), 1388 (CH
308 and 1268 (C–O, ester), 1140 and 1040 (C–F), 1075 (C–N,
3
),
2
3
1
1
tertiary amine). H NMR (DMSO-d
6
)
d
ppm: 9.61 (1H, s, vinyl H),
.69 (1H, dd, J = 12.44, 6.59 Hz, aromatic H), 8.55 (1H, dd, J = 12.44,
.59 Hz, aromatic H), 4.88 (2H, q, J = 7.32 Hz, CH ), 1.48 (3H, t,
ppm: 167.50 (C 55 O
7
) d ppm:
8
6
2
2
1
3
J = 7.32 Hz, CH
3
).
C NMR (DMSO-d
6
)
d
2
ketone), 159.52 (C 55 O ester), 154.70 and 108.64 (vinyl C), 151.01,
49.60, 137.64, 119.43, 112.71 and 107.13 (aromatic C), 51.73
2
1
3
3
+
+
+
+
(
[
CH
2
), 14.61 (CH
3
). MS FAB (probe) 70 eV, m/z (rel. int.): 302
FAB (probe) 70 eV, m/z (rel. int.): 382 [M+1] (74), 362 [M–F]
(34), 361 [M–HF] (11), 334 [M–BF
+
+
+
+
+
M+1] (16), 289 [M+1–CH
3
+H
–H] (7), 220 [M–CH
2
]
(39), 282 [M–F] (9), 236 [M–
2
+H
2
]
(7), 316 [M–BF
(43), 289 [M–BF –H
2
–CO] (6), 220 [M–OBF –
2
+H
2
–
+
+
+
+
CH
BF
M+2H
3
–BF
+H –F–CH
–BF –CO
2
3
–BF
(16), 167 [M–BF
2
+H
2
–F] (41), 205 [M–CH
3
–
H
2
O] (29), 307 [M–BF
2
+H–C
] (22), 279 [M–BF –C
2
H
4
+H
2
]
2
2
O–
+
+
+
+
2
2
3
]
2
–2CO–C
–CO–F] (100), 136 [M+H
(98), 107 [M+H –BF –CO –C
2
H
5
]
(25), 137
–BF –CO
–CO+H–F–
C
2
H
5
+2H
2CO–C
(16), 154 [M–OBF
OBF –C –CO–C
2
2
2
H
5
+2H
2
+
Á
+
+
[
2
2
2
–C
2
H
4
2
2
2
–
2
H
4
–CH
3
+H
2
+H] (41), 205 [M–OBF
–C –CO–C –C NO+2H
NO+2H –F+H] (100).
2
–2CO–C
2
H
4
–C
2 5 2
H +H ]
+
Á
+
C
C
2
2
H
H
4
5
–CO+H–F]
2
2
2
2
H
4
2
2
H
3
3
H
6
3
H
3
2
] (100), 136 [M–
+
+
] (51).
2
2
H
3
3
H
6
–C
3
H
3
2
4
.6. General procedure for difluoroboranyl 1-ethyl-6-fluoro-7-
4.6.4. Difluoroboranyl 1-ethyl-6-fluoro-7-(pyrrolidin-1-yl)-
quinolone-3-carboxylate (7d)
(substituent)-quinolone-3-carboxylate (7a–g)
It was obtained as a yellow solid in 75% yield and m.p. 285–
À1
The corresponding amine (1 mmol) was added into a flask
286 8C. IR (KBr, cm ): 1700 (C 55 O, pyridone), 1640 (C 55 O, ester),
with dimethylsulfoxide (3 mL), triethylamine (138.83
difluoroboranyl 1-ethyl-6,7-difluoroquinolone-3-carboxylate 6
665.70 mol) stirring for 24 h at room temperature. After that,
ethanol was added and a solid was formed. The solvent was
removed by filtration and the solid was dried under vacuum.
m
L) and
1571 (C 55 C, alkene), 1540 and 1497 (C 55 C, aromatic), 1431 (CH
1355 and 1248 (C–O), 1121 and 1100 (C–N, tertiary amine), 1047
2
),
1
(
m
(C–F). H NMR (DMF-d
J = 10.25 Hz, aromatic H), 7.16 (1H, d, J = 7.32 Hz, aromatic H), 5.09
(2H, q, J = 7.32 Hz, CH ), 3.94 (4H, m, J = 3.66 Hz, pyrrolidine CH ),
7
) d ppm: 9.44 (1H, s, vinyl H), 8.15 (1H, d,
2
2

S. Leyva, H. Hern a´ ndez / Journal of Fluorine Chemistry 131 (2010) 982–988
987
2
CH
.22 (4H, m, J = 3.66 Hz, pyrrolidine CH
2
), 1.80 (3H, t, J = 7.32 Hz,
8.49 (1H, s, vinyl H), 8.15 (1H, d, J = 10.26 Hz, aromatic H), 6.82 (1H,
d, J = 7.47 Hz, aromatic H), 4.48 (2H, q, J = 7.32 Hz, CH ), 4.29 (2H, q,
J = 7.32 Hz, CH ), 3.31 (4H, br s, piperazine CH ), 3.19 (4H, br s,
piperazine CH ), 2.02 (1H, br s, amine H), 1.63 (3H, t, J = 7.32 Hz,
3 3 3
CH ), 1.50 (3H, t, J = 7.32 Hz, CH ). C NMR (CD COCD ) d ppm:
+
+
3
). MS FAB (probe) 70 eV, m/z (rel. int.): 353 [M+1] (31), 333
2
+
+
+
[
M–F] (16), 307 [M–BF
20 [M–BF
CH
2
+2H
–CO–CH
(19), 154 [M–OBF –CO–C
37 [M–OBF –CO–C –C –C
–CO–C –C O+2H
2
]
(82), 287 [M–BF
2
+H–OH] (14),
+2H –CO –CO–
O+2H
(100), 136 [M–
2
2
+
2
2
1
2
+2H
2
–CO
2
3
] (49), 205 [M–BF
–C –C
O–F+3H
2
2
2
2
+
+
13
3
]
2
2
H
4
2
H
3
3
+
H
2
2
]
(100),
3
2
2
H
4
2
H
3
3
H
2
2
]
175.73 (C 55 O ketone), 168.58 (C 55 O ester), 150.58 and 106.39 (vinyl
C), 147.85, 138.81, 126.47, 116.50, 116.22 and 113.27 (aromatic C),
+
OBF
2
2
H
4
2
H
3
–C
3
H
2
2
–F+H] (100).
+
6
3.46, 53.96, 51.59 and 48.68 (CH
2
), 17.07 (CH
3
). MS FAB (probe)
+
+
4.6.5. Difluoroboranyl 1-ethyl-6-fluoro-7-(pyrimidin-2-yl-amino)-
2 5
70 eV, m/z (rel. int.): 348 [M+1] (100), 303 [M–C H O+H] (13),
+
+
quinolone-3-carboxylate (7e)
302 [M–C
2 5 3 3
H OH+H] (99). The mass exact of C18H22FN O Na was
It was obtained as a brown solid in 69% yield and m.p. 336–
38 8C. IR (KBr, cm ): 1715 (C 55 O, pyridone), 1636 (C 55 O, ester),
370.1543 amu, the observed mass was 370.1535 amu.
À1
3
1
583 (C 55 C, alkene), 1553 and 1509 (C 55 C, aromatic), 1267–1133
4.8. Ethyl 1-ethyl-6-fluoro-7-(pyrimidin-2-yl-amino)-quinolone-3-
1
(C–O), 1042 (C–F). H NMR (DMF-d
7
)
d
ppm: 9.88 (1H, s, vinyl H),
carboxylate (8e)
9
.00 (3H, dd, J = 12.48, 6.59 Hz, aromatic H, pyrimidine 2H), 8.76
(
2H, dd, J = 10.25, 8.05 Hz, aromatic H, pyrimidine H), 8.18 (1H, br s,
amine H), 5.27 (2H, q, J = 7.32 Hz, CH ), 1.84 (3H, t, J = 7.32 Hz,
). MS FAB (probe) 70 eV, m/z (rel. int.): 307 [M–BF +H–OH–
] (8), 154 [M–OBF –CO–
The difluoroquinolone ester 5 (1.28 mmol) was added to a
suspension of 2-amino-pyrimidine (3.84 mmol), 95% NaH
(4.44 mmol) and pyridine (15 mL). The reaction mixture was
refluxed for 24 h under nitrogen atmosphere, cooled, and
concentrated. The residue was dissolved in 30 mL of ethanol,
boiled for 5 min, and concentrated to a yellow solid. It was
2
+
CH
H
3
+
2
+
2
] (32), 238 [M–OBF
2
–CO–C
2
H
4
–F+H
2
2
+
3 2 4 3 2 2
C H O–C H N +2H ] (100).
4.6.6. Difluoroboranyl 1-ethyl-6-fluoro-7-(5-amino-1H-[1,2,4]-
3 2 2 3 3
chromatographed on silica gel with 95:5 CH CO CH CH /CHCl
triazol-3-yl-amino)-quinolone-3-carboxylate (7f)
to give yellow crystals in 41% yield and mp 266–267 8C. IR (KBr,
cm ): 3400 (N–H, secondary amine), 1715 (C 55 O, ester), 1662
À1
It was obtained as an orange needles in 54% yield and m.p.
À1
>
400 8C. IR (KBr, cm ): 3316 and 3133 (N–H, primary amine),
(C 55 O, pyridone), 1581, 1560 and 1491 (pyrimidine), 1309 and
1
1
709 (C 55 O, pyridone), 1656 (C 55 N–C, heterocycle), 1625 (C 55 O,
1225 (C–O, ester). H NMR (CD
2
Cl
2
)
d
ppm: 9.47 (2H, br s,
ester), 1540 (C 55 C, alkene), 1581, 1485 and 1412 (C 55 N, heterocy-
pyrimidine H), 8.68 (2H, br s, vinyl H, pyrimidine H), 8.10 (2H, br
s, aromatic H), 4.96 (2H, q, J = 7.32 Hz, CH ), 4.75 (2H, q,
J = 7.32 Hz, CH ), 1.83 (3H, t, J = 7.32 Hz, CH ), 1.62 (3H, t,
J = 7.32 Hz, CH ppm: 174.06 (C 55 O
ketone), 165.04 (C 55 O ester), 140.31 and 110.21 (vinyl C), 169.42,
151.73 and 111.40 (pyrimidine C), 122.74, 121.53, 118.96,
1
cle), 1288–1258 (C–O), 1048 (C–F). H NMR (DMF-d
1H, s, vinyl H), 8.80 (1H, d, J = 10.25 Hz, aromatic H), 8.59 (1H, d,
J = 6.59 Hz, aromatic H), 8.18 (1H, s, amine H), 6.99 (2H, s, amine H),
.67 (1H, s, amine H), 5.31 (2H, q, J = 7.32 Hz, CH ), 1.87 (3H, t,
7
)
d
ppm: 9.86
2
(
2
3
1
3
3
3 3
). C NMR (CD COCD ) d
5
2
+
+
J = 7.32 Hz, CH
3
). MS FAB (probe) 70 eV, m/z (rel. int.): 381 [M+1]
+
+
(32), 361 [M–F] (18), 307 [M–CH
3
N
3
–CH
3
–H] (23), 289 [M–
116.55, 115.18 and 108.42 (aromatic C), 67.97 and 56.43
+
+
+
CH
3
N
3
–CH
3
–F] (21), 254 [M–BF
–CO–C –C
–C O–C
2
–C
O–C
+2H
2
H
5
+2H
2
–OH–NH
2
–F+H
2
]
(CH
int.): 305 [M–C
236 [M–C –CO
2
), 17.05 and 16.15 (CH
3
). MS FAB (probe) 70 eV, m/z (rel.
+
+
+
(
[
10), 154 [M–OBF
M–OBF –CO–C
2
2
H
5
3
H
2
2
H
2
N
4
+2H
2
]
(100), 136
2
H
5
–F–2H
2 2 5 2
+H] (32), 304 [M–C H –F–2H ] (100),
+
+
2
2
H
5
3
H
2
2
H
2
N
4
2
–F+H] (81).
2
H
5
2
–C –F] (85).
2 4
H
4.6.7. Difluoroboranyl 1-ethyl-6-fluoro-7-(2,4-dioxo-1,2,3,4-
Acknowledgments
tetrahydro-pyrimidin-5-yl-amino)-quinolone-3-carboxylate (7g)
It was obtained as a dark goldenrod solid in 69% yield and m.p.
400 8C. IR (KBr, cm ): 3374 and 3200 (N–H, amide), 1710 (C 55 O,
pyridone and amide), 1639 (C 55 O, ester), 1583 (C 55 C, alkene), 1553
We wish to thank CONACYT (SEP-82585) and UASLP (C09-FRC-
09-23.53) for their financial support. We also wish to express our
gratitude to Dr. Jes u´ s Sandoval Ram ı´ rez and M.Sc. V ı´ ctor G o´ mez
Calvario from BUAP for their technical assistance in the spectral
studies.
À1
>
and 1485 (C 55 C, aromatic) 1480 (C–N, heterocycle), 1318 and 1279
1
(
C–O), 1047 (C–F). H NMR (DMF-d
7
)
d
ppm: 9.53 (1H, s, amine H),
9
.48 (1H, s, amine H) 9.36 (1H, s, vinyl H), 8.48 (1H, d, J = 10.25 Hz,
aromatic H), 7.63 (1H, d, J = 8.05 Hz, aromatic H), 6.83 (1H, s, amine
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+
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