Mechanism and synthesis of pharmacologically active quinolones from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tet.2010.04.018

The synthesis of quinolones from Morita-Baylis-Hillman (MBH) adducts is reported. The quinolone skeleton is formed via a TFA-mediated cyclization of the MBH adduct, and a mechanism study using ESI(+)-MS(/MS) has indicated the role played by TFA in this key reaction step. The total syntheses of Norfloxacin and a benzyl quinolone carboxylic acid (BQCA) derivative are described. Norfloxacin is a fluoroquinolonic antibacterial drug whereas BQCA is M₁ receptor positive allosteric modulator and seem to provide access to new potential drugs for Alzheimer disease, pain, and sleep disorders. The syntheses of these two important quinolones exemplify the versatility and potentiality of the approach.

Full text of DOI:10.1016/j.tet.2010.04.018

Tetrahedron 66 (2010) 4370e4376
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Mechanism and synthesis of pharmacologically active quinolones
from MoritaeBayliseHillman adducts
,
a,
*
Giovanni W. Amarante a, Mario Benassi b, Robert N. Pascoal a, Marcos N. Eberlin b , Fernando Coelho
*
a Laboratory of Natural Products and Drug Synthesis, University of Campinas, Institute of Chemistry, 13083-970, Campinas, São Paulo, Brazil
b ThoMSon Mass Spectrometry Laboratory, University of Campinas, Institute of Chemistry, 13083-970, Campinas, São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of quinolones from MoritaeBayliseHillman (MBH) adducts is reported. The quinolone
skeleton is formed via a TFA-mediated cyclization of the MBH adduct, and a mechanism study using ESI
(þ)-MS(/MS) has indicated the role played by TFA in this key reaction step. The total syntheses of
Norfloxacin and a benzyl quinolone carboxylic acid (BQCA) derivative are described. Norfloxacin is
a fluoroquinolonic antibacterial drug whereas BQCA is M1 receptor positive allosteric modulator and
seem to provide access to new potential drugs for Alzheimer disease, pain, and sleep disorders. The
syntheses of these two important quinolones exemplify the versatility and potentiality of the approach.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 March 2010
Received in revised form 1 April 2010
Accepted 2 April 2010
Available online 14 April 2010
Keywords:
MoritaeBayliseHillman
4-Quinolones
N-Oxides
Antibiotics
Alzheimer disease
1. Introduction
Quinolones are highly biologically active. They display anti-
bacterial and anti-tumoral activities and its heterocyclic unit is also
seen in drugs used to treat neurodegenerative diseases, sleep dis-
orders or pain. Nalidixic acid (1, Fig. 1) was the first therapeutically
important quinolonic drug,1,2 whereas the fluoroquinolones 2e8
(Fig. 1) are the most important result of the SAR (StructureeActivity
Relationship) study based on 1.
Flumequine (2) was the first to indicate that modifications of the
basicquinolinestructurecouldimproveGram-positiveactivity,2 since
earlier modifications had offered no significant improvements over 1.
Norfloxacin (3) has been used in genitourinary infections.3
Ciprofloxacin (4) is the most potent of the currently available
fluoroquinolones against Gram-negative bacteria. Fleroxacin (5) is
distinguished from its predecessors by its excellent bioavailability,
high concentrations in plasma and other body fluids, good tissue
penetration and long half-life (10e12 h),4 but 5 has displayed some
severe side effects.5
Moxifloxacin (6), gemifloxacin (7), and grepafloxacin (8) are
new antibacterials fluoroquinolones active against all the primary
pathogens of typical respiratory diseases.6,7
Figure 1. Representative examples of fluoroquinolone antibacterials (2e8) derived
from 1.
Quinolones 9 and 10 (Fig. 2) have also shown tubuline poly-
merization inhibition effects and potential as anti-cancer agents.8,9
Quinolone 11 has been shown to be useful to prevent tumor cell
proliferation, tumor formation, metastasis, inflammatory diseases,
* Corresponding authors. E-mail addresses: eberlin@iqm.unicamp.br (M.N. Eber-
lin), coelho@iqm.unicamp.br (F. Coelho).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.018

G.W. Amarante et al. / Tetrahedron 66 (2010) 4370e4376
4371
Scheme 1. Retrosynthetic analysis for Norfloxacin (3) and BQCA (12).
commercially available aldehydes with ethyl or methyl acrylates,
would afford the key N-oxide quinolines 15 and 16.
Herein we describe the total synthesis of the fluoroquinolone
Norfloxacin (3) and BQCA (12) using this new method designed
from o-substituted MBH adducts. To probe the crucial role played
by TFA in the cyclization step, a mechanistic study via ESI-MS(/MS)
monitoring was also performed.
Figure 2. New biologically active quinolones.
treatment of HIV infectivity, stem cell differentiation, and mobili-
zation disorders.10,11
Recently, a benzyl quinolone carboxylic acid (BQCA) 12 has been
synthesized and considered as promising drug to the Alzheimer
disease (AD) owing the development of selective M1 activators.12e14
The vast biological relevance of quinolones has therefore stim-
ulated the development of more general and efficient methods for
quinolinone synthesis. The current methods (Fig. 3) can be divided
into five major groups depending on the bond (iev) used to close
the quinoline ring.15,16
2. Results and discussion
In order to prepare some allylic derivatives, Kim et al.22 treated
o-nitrophenyl MBH adducts derived from o-nitrobenzaldehyde
with TFA. Surprisingly, instead of the desired product 20 from an
allylic rearrangement, the N-oxide hydroxyquinoline 21 was
formed via intramolecular cyclization accompanied by water
elimination (Scheme 2).
Scheme 2. Kim’s TFA-mediated cyclization from MBH adducts.
This synthetically useful reaction seems to work only with TFA,
and attempts to use acetic or formic acids failed.22 This unique
feature of TFA catalysis intrigued us since, judging from the reaction
mechanism proposed by Kim et al.22 (Scheme 2), TFA should work
solely as a source of protons.
Electrospray ionization mass spectrometry (ESI(þ)-MS) as well
as its tandem version (ESI-MS/MS) has been established as a pow-
erful tool to probe mechanisms of major organic reactions 23,24 such
as the MBH reaction18a,b,h via the interception and characterization
of their key intermediates. To elucidate therefore this key TFA
catalysis, we monitored the reaction outlined in Scheme 2 by ESI
(þ)-MS(/MS) hoping to intercept and characterize key inter-
mediates that would reveal mechanistic details.18a,b,h,25
Figure 3. Current approaches to the synthesis of quinolones.
The MoritaeBayliseHillman (MBH) reaction is an atom-efficient
condensation methodology that provides easy access to highly
functionalized carbonyl derivatives.17,18 MBH adducts are exten-
sively used in synthesis as versatile starting material for many
natural products and drugs,19 and to prepare heterocycles,20 in-
cluding quinolones.21
In a research program focused to develop new biologically active
quinolones, particularly those active against human cancers, we
were first interested in developing a synthetic strategy to prepare
quinolones with great structural diversity. MBH adducts seemed
appropriate to this goal owing to the diversity offered by structural
variation in the reacting aldehydes and acrylates. We were also
interested in developing a method using less expensive reagents
than those used by Hong et al.21 The use of MBH adducts seemed
appropriate considering that Kim et al. have reported the synthesis
of N-oxide quinoline derivatives from ortho-substituted MBH
adducts,22 and this method served therefore as the key starting step
for our synthetic planning (Scheme 1).
The MBH adduct 17 was prepared in 8 h with 98% yield
according to a methodology developed in our laboratory.26 Using
experimental conditions reported by Kim et al.22,27 we treated 17
with TFA at 60e70 ꢀC and monitored the reaction by ESI(þ)-MS for
10 h in 1 h intervals (Scheme 3). Aliquots of 10 mL of the reaction
solution were taken and diluted with methanol, and directly
infused to the ESI source of a tandem mass spectrometer. The mass
spectrometer used was a Qtrap (Applied Biosystems, Concord,
Ontario, Canada) with a QqQ (linear ion trap) configuration.
As the reaction starts, the ESI-MS (Fig. 4a) showed mainly ions
associated with the reactant MBH adduct, that is: [17þH]þ of m/z
238, [17þNa]þ of m/z 260 and [(17)2þNa]þ of m/z 497. After 150 min
(Fig. 4b), however, the ESI-MS was dominated by product ions of
m/z 334 and m/z 220. The ion of m/z 334 is a key intermediate and
corresponds to the O-trifluoroacetylated MBH adduct 22 in its
We rationalized that reduction of N-Oxide quinolines 15 and 16
should give the corresponding 4-quinolone-esters 13 and 14, which
could be used as substrate for an N-alkylation reaction. Ester
hydrolysis should provide BQCA (12) and Norfloxacin (3) could be
made, for instance, by using piperazine in a regioselective SNAr
reaction after hydrolysis of 16. A TFA-mediated cyclization using the
MBH adducts 17 and 18, which could be easily prepared from

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G.W. Amarante et al. / Tetrahedron 66 (2010) 4370e4376
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
m/z 220
m/z 238
m/z 334
0.1
0.0
Scheme 3. Synthesis of N-Oxide-hydroxyquinolines from MBH adducts. Reagents and
conditions: (a) methyl acrylate, DABCO, ultrasound, 8 h, 98%; (b) TFA, 60e70 ꢀC, 10 h,
80%; (c) (CF3CO)2O, NEt3, 0 ꢀC, 30 min., 80%; (d) CH3CN, AcOH (cat.), 8 h, 62%.
0
2
4
6
8
10
Reaction Time (h)
Figure 5. Relative abundances of the ions of m/z 220, m/z 238, and m/z 334 as
a function of reaction time.
indicates that, as the reaction progresses, most of the ions of m/z
220 correspond to detection of the final product 15 in its pro-
tonated form [15þH]þ.
Note also that, as the abundance of [17þH]þ of m/z 238 de-
creases, that of [22þH]þ of m/z 334 (Fig. 4c) initially raises and then
after ca. 3 h falls down slowly.
Based on these ESI-MS data, it seems that the O-trifluoro-
acetylated MBH adduct 22 is a key reaction intermediate, and that its
formation is the main factor inducing the reaction deviation from 20
to form instead the N-oxide hydroxyquinoline 21 (Scheme 2). We
rationalize this role by assuming that, after TFA acetylation, a good
leaving group is formed facilitating intramolecular substitutionwith
the participation of the nucleophilic oxygen atom of the nitro group.
We have also monitorated the same reaction replacing TFA by
acid acetic as solvent and catalyst. Even after 6 h at 60e70 ꢀC we
were unable to see by ESI-MS monitoring any changes in the re-
action solution. The predominant ion was that of m/z 238 attributed
as the starting MBH adduct. Therefore, only TFA (used in excess)
seems to be able to auto-catalyze acylation of 17.
We have also prepared an authentic sample of trifluoroacetate 22
to investigatewhetherit could bedirectlyconverted into 15. The MBH
adduct 17 was treated at 0 ꢀC with trifluoroacetic anhydride
(1.5 equiv) and triethylamine (1.5 equiv) in anhydrous dichloro-
methane.28 After 30 min, the solvent was evaporated and the residue
was quickly purified by flash silica gel column chromatography to
afford the corresponding trifluoroacetate 22 in 80% yield (Scheme 3).
Two different experimental conditions were tested: 22 was dis-
solved and refluxed in acetonitrile (i) without or (ii) with the addi-
tion of a catalytic amount (few drops) of acetic acid. After 8 h, we
observed for condition (ii) that 22/15 conversion was almost
complete and all the spectral data were identical to 15 produced
from 17 by direct TFA treatment. This result constitutes therefore
evidence of the key role played by the trifluoroacetate MBH adduct
22 in the formation of 15, as revealed by the ESI-MS(/MS) experi-
ments. It is also clear that the presence of an acid is crucial for cy-
clization of 22.25
Based on these experimental evidences, we propose in Scheme 4
a mechanism to rationalize the formation of N-oxidehydroxyquinoline.
Differently from Kim et al.22, no aromaticity loss occurs in our
mechanistic view, since TFA is acid enough to promote a auto-
catalytic trifluoroacetylation to 22. An intramolecular SN2 reaction
resulting from the attack of ionic oxygen of the nitro group forms
intermediate 23, since now the trifluoroacetate is a very good
leaving group. The free trifluoracetate anion is assumed to abstract
the acidic benzylic proton to initiate the rearrangement leading to
the nitroso derivative 24.29 An intramolecular Michael addition
gives the cyclic intermediate 25, which re-aromatizes to afford
Figure 4. ESI(þ)-MS for (a) the reaction solution at the beginning; (b) after 150 min
and (c) after 360 min of reaction and (d) ESI(þ)-MS/MS for CID of the ion of m/z 334.
protonated form. This structural assignment was corroborated by
collision induced dissociation (CID) performed via an ESI-MS/MS
experiment in which [22þH]þ dissociated mainly by the sequential
losses of neutral TFA, methanol, and CO (Fig. 4d).
The ion of m/z 220 (Fig. 4a) was trickier to assign. At first glance,
it was attributed to a fragment of [17þH]þ of m/z 238 from water
loss. Indeed, at the beginning of the reaction, most of the low
abundance ions of m/z 220 are likely to arise from such loss.
However, as Figure 4c and most particularly Figure 5 shows, the
abundance of the ion of m/z 220 increases steadily as the reaction
progresses, even after 17 is totally consumed, as monitored by the
abundance of [17þH]þ of m/z 238 (Fig. 5). This steady increase

G.W. Amarante et al. / Tetrahedron 66 (2010) 4370e4376
4373
Scheme 6. Synthesis of Norfloxacin from MoritaeBayliseHillman adduct. (a) HNO3,
H2SO4, 80 ꢀC, 1 h, 93%; (b) methyl acrylate, DABCO, ultrasound, 8 h, 98%; (c) TFA, 70 ꢀC,
30 h, 60%; (d) Mo(CO)6, EtOH, reflux, 30 min.; (e) EtI, K2CO3, DMF, 95 ꢀC, 10 h, 45% (for
two steps); (f) LiOH, CH3CN/H2O (1:1), 50e60 ꢀC, 10 h, 80%; (g) Piperazine, EtOH,
microwaves, 35 min, 80%.
Scheme 4. Mechanistic proposition for the formation of N-oxide hydroxyquinoline 15
from 17 catalyzed by TFA.
N-oxide hydroxyquinoline 15. This sequence rationalizes the role of
TFA and corroborates the importance of the trifluoroacetylated
species in the reaction mechanism.
the N-alkylation reaction was carried out directly over quinolone 14
without purification, that is, 16 was reduced in the presence of
molybdeniumhexacarbonyl and the crude product was N-alkylated
in the presence of ethyl iodide and K2CO3 in DMF to provide the
N-ethyl quinolone 30 in an two steps overall 45% yield. Simulta-
neously, transesterification also occurred (Scheme 6). Quinolone 30
was then hydrolysed to give the corresponding quinolonic acid
derivative 31 in 80%. To complete the synthesis, an ethanolic
solution of acid 31 was treated with piperazyne under microwave
radiation to afford norfloxacin 3 in 85% (Scheme 6).
The N-oxide quinoline 15 was therefore prepared in 80%. The next
step of our sequence was the reduction of the N-oxide group. We
tested classical methodologies, such as PPh3 (in different
concentrations and temperatures), POCl3, and Zn(0), but all attempts
failed or gave 13 in low yield. Recently, Yoo et al. reported a method to
reduce N-oxide derivatives using molibdeniumhexacarbonyl.30 In
the presence of a stoichiometric amount of this reagent in ethanol,15
was smoothly reduced to 13, after 45 min, in 77% yield. Trans-
esterification has likely occurred due to the use of an excess of
ethanol. To finish the synthesis of BQCA (12), alkylation of the
nitrogen atom of 4-quinolone 13 was required. For that, commercial
p-anisyl alcohol was treated with CBr4/PPh3 to afford the corre-
sponding bromide 26 in 80% yield after 3 h. Quinolone 13 was then
treated with K2CO3 in the presence of a catalytic amount of KI and
aslightexcessofbromide26togivetheN-alkylatedproduct27 in65%
yield (Scheme 5). The total synthesis of BQCA (12) was accomplished
through basic hydrolysis of the ethyl ester group, in 85% yield.
Fluoroquinolonic antimicrobial Norfloxacin (3) was therefore
synthesized in seven steps from commercially available 4-fluoro-5-
chlorobenzaldehyde with an overall yield of 16%.
3. Conclusion
A synthetic method to prepare quinolines from MBH adducts is
described. As proof-of-principle cases, the total synthesis of two
pharmacologically active quinolones has been accomplished. The
synthetic sequence is relatively simple, uses rather inexpensive
reagents, can be easily scalable, and seems to provide access to
quinolones with great structural diversity. The MBH adducts used
as substrate can be prepared from commercially available and
inexpensive starting materials. Via ESI-MS(/MS), a new mecha-
nistic proposition has also been disclosed rationalizing the key
role of TFA in the Kim’s TFA-mediated method to prepare N-oxide
hydroxyquinolines.
Scheme 5. Total synthesis of the selective allosteric M1 muscarinic acetylcholine
receptor potentiator (12). (a) Mo(CO)6, EtOH, reflux, 45 min., 77%; (b) K2CO3, KI, DMF,
bromide 26, 27 h, 65%; (c) LiOH, CH3CN/H2O (1:1), rt, 3 h, 85%.
4. Experimental section
4.1. General
In summary, benzyl quinolone carboxylic acid (BQCA) 12 was
synthesized in five steps using a relatively simple, efficient and
easily scalable synthetic sequence from commercially available
2-nitrobenzaldehyde with an overall yield of 33%. To further dem-
onstrate the synthetic feasibility of this approach, we also synthe-
sized norfloxacin 3. Initially, 4-chloro-3-fluorobenzaldehyde 28 was
nitrated in a mixture of H2SO4 and HNO3 to give solely and regio-
selectively the nitro-aldehyde 29 in 93% yield. The fluorine atom
guided efficiently the nitration reaction toward the para-position by
The 1H and 13C spectra were recorded on a Brucker at 250 MHz
and 62.5 MHz, respectively. The 1H and 13C spectra were also
recorded on an Inova instrument at 500 MHz and 125 MHz,
respectively. The high resolution mass spectra were recorded using
a Q-TOF Micromass equipment (Waters, UK). Manipulations and
reactions were not performed under dry atmospheres or employing
dry solvents, unless otherwise specified. In those cases CH2Cl2,
DMF, and triethylamine were dried over CaH2 and distilled. Puri-
fication and separations by column chromatography were per-
formed on silica gel, using normal or flash chromatography. TLC
visualization was achieved by spraying with 5% ethanolic phos-
phomolybdic acid and heating. All the reactions the Moritae
BayliseHillman reactions were sonicated in an ultrasonic cleaner
(81 W, 40 MHz). Compounds prepared in this manuscript that were
stabilizing the
s
complex formed in the reaction TS (Scheme 6).31
Aldehyde 29 was then immediately used to prepare the MBH
adduct 18 in 85% after 8 h of reaction. We applied to 18 the same
synthetic sequence as described for 13. That is, 18 was warmed at
70 ꢀC in TFA for 30 h to afford the N-oxide hydroxyquinoline 16 in
60% yield. Quinolone 14 resulting from the reduction of N-oxide
quinoline 16 has proved to be unstable. To circumvent this problem,

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G.W. Amarante et al. / Tetrahedron 66 (2010) 4370e4376
previously known gave spectral data consistent with those
reported.
133.4, 132, 127.4, 126.5, 125.7, 124.9, 114.7, 114.6, 107.5, 79.9, 60.1,
54.4, 13.2; HRMS (ESI m/z) calcd for C20H19NO4K [MþK]þ 376.0945.
Found 376.0951.
4.1.1. Synthesis of methyl 4-hydroxyquinoline-3-carboxylate 1-oxide
(15). A solution of the MBH adduct 17 (0.3 g, 1.26 mmol) in TFA
(2 mL) was stirred for 10 h at 70e75 ꢀC. The reaction medium was
then dropped in cold water. The mixture was extracted with CHCl3
(3ꢁ10 mL). The combined organic phases were dried over Na2SO4
and the solvent was removed under reduced pressure. The crude
product was purified by silica gel column chromatography to pro-
vide 0.22 g (80% yield) of N-oxide 15 as a white amorphous solid. Mp
187e189 ꢀC; IR (film, nmax): 3417, 2924, 1702, 1613, 1541, 1454, 1356,
4.1.5. Synthesis of 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroisoquino-
line-3-carboxylic acid (12). To a solution of quinolonic ester 27
(0.1 g, 0.3 mmol) in a mixture of CH3CN/H2O (1:1, 4 mL) was added
lithium hydroxide (0.078 g, 0.25 mmol). The resulting mixture was
stirred at room temperature for 3 h. The solvents were removed
under reduced pressure. The residue was neutralized with a 10%
solution of HCl and extracted with ethyl acetate (2ꢁ10 mL). The
mixture was extracted with ethyl acetate (2ꢁ10 mL) and the organic
phase was washed with brine (10 mL), dried over Na2SO4, and
concentrated at reduced pressure. No purification was necessary.
BQCA 12 was obtained as an amorphous solid (0.079 g), in 85% yield.
Mp: 210e212 ꢀC; IR (KBr, nmax): 3438, 3043, 2961, 2839, 1709, 1611,
1229, 1143, 1068, 767 cmꢂ1. 1H NMR (250 MHz, DMSO-d6),
12.8 (s, 1H), 8.70 (s, 1H), 8.19 (d, J¼7.8 Hz, 1H), 7.81 (m, 2H), 7.49 (m,
1H), 3.73 (s, 3H).13C NMR (62.5 MHz, DMSO-d6),
ppm: 171.9,164.6,
d ppm:
d
145,139.0,133.0,127.4,126.1,125.5,115.3,107.3, 51.3. HRMS (ESI TOF)
calcd for C11H10NO4 [MþH]þ 220.0673. Found 220.0610.
1557,1516,1458,1387,1304 cmꢂ1. 1H NMR (250 MHz, CDCl3)
d ppm:
14.8 (br s, 1H, exchangeable with D2O), 8.74 (s, 1H), 8.50 (dt, J¼0.7,
8.0 Hz, 1H), 7.91e7.80 (m, 2H), 7.73e7.57 (m, 1H), 7.30 (d, J¼8.7 Hz,
2H), 6.93 (d, J¼8.7 Hz, 2H), 5.25 (s, 2H), 3.83 (s, 3H). 13C NMR
4.1.2. Synthesis of methyl-2{(2-nitrophenyl)[(trifluoroacetyl)oxy]-
methyl}acrylate (22). To a stirred solution of 17 (0.53 g, 2.24 mmol)
in 10 mL of dry dichloromethane at 0 ꢀC under argon was added
anhydrous triethylamine (0.48 mL, 0.339 g, 3.36 mmol) followed by
the careful addition of distilled trifluoroacetic anhydride (0.47 mL,
0.705 g, 3.36 mmol). The reaction was stirred at 0 ꢀC for 30 min. The
solvent was evaporated and the residue was quickly purified over
a pad of flash silica gel to afford 0.59 g of 22 (80% yield), as a col-
orless oil. The product proved to be unstable and was kept in dry
dichloromethane at 0 ꢀC. IR (nmax, film); 2958, 1789, 1723, 1634,
(62.5 MHz, CDCl3) d ppm: 177.7,166.0,161.3,144.1,137.9,134.4,131.8,
127.0, 126.8, 125.9, 123.5, 114.8, 114.7, 114.6, 107.3, 81.0, 55.3; HRMS
(ESI m/z) calcd for C18H15NO4K [MþK]þ 348.0838. Found 348.0744.
4.1.6. Synthesis of (ꢃ)-4-chloro-5-fluoro-2-nitro-benzaldehyde (29).
To a stirred mixture of 4-chloro-3-fluoro-benzaldehyde 28 (0.5 g,
3.16 mol) in concentrated sulfuric acid (2 mL) at 0 ꢀC, concentrated
nitric acid (2 mL) was added dropwise. The resulting mixture was
stirred at 80 ꢀC for 1 h. The reaction mixture was then dropped into
distilled cold water and the mixture was extracted with ethyl ac-
etate (2ꢁ25 mL). The combined organic phases were dried over
Na2SO4 and the solvent was removed under reduced pressure. The
crude residue was purified by silica gel column chromatography
(ethyl acetate/hexanesd65:35) to give 0.6 g (93% yield) of 29, as
a yellow tinged viscous oil. IR (film, nmax): 3072, 1683, 1528,
1527, 1433, 1348, 1221, 1135 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d 8.12
(d, 1H, J¼8.4 Hz, 1H), 7.73 (m, 1H), 7.59 (m, 2H), 7.52 (broad s, 1H),
6.53 (s, 1H), 5.59 (s, 1H), 3.78 (s, 3H). 13C NMR (75.4 MHz, CDCl3):
d
164.2, 155.6 (q, J¼42.7 Hz, COCF3), 147.5, 136.7, 133.9, 130.7, 130.0,
129.4, 128.2, 125.3, 114.2 (q, J¼285.6 Hz, CF3), 72.0, 52.4; HRMS (ESI,
m/z) calcd for C13H10F3NO6 (MþꢂCOCF3) 333.2168. Found 333.2167.
4.1.3. Synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate
(13). To a solution of 15 (0.4 g, 1.83 mmol) under inert gas atmo-
sphere in anydrous ethanol (10 mL) was added molybdeniumhexa-
carbonyl (0.484 g, 1.83 mmol). The resulting mixture was stirred for
45 min under reflux. The mixture was then cooled to room temper-
ature, filtered, and the solvent removed under reduced pressure to
give 0.31 g of 13 (77% yield) as a white solid. The product was pure
enough to be use in the next step without purification. Mp
1340 cmꢂ1
.
1H NMR (300 MHz, CDCl3),
d
ppm: 10.41 (d, J¼2.1 Hz,
1H), 8.29 (d, J¼5.7 Hz, 1H), 7.75 (d, J¼8.1 Hz, 1H). 13C NMR
(75.4 MHz, CDCl3),
d
ppm: 185.5, 162.9, 159.4, 132.0 (d, J¼6.5 Hz),
128.0, 127.2 (d, J¼19.7 Hz), 117.4 (d, J¼24.4 Hz). HRMS (ESI m/z)
calcd for C7H3O3ClFNNa [MþNa]þ: 225.9683. Found: 225.9678.
4.1.7. Synthesis of (ꢃ)-methyl-2-[(4-chloro-5-fluoro-2-nitrophenyl)
(hydroxy)methyl] acrylate (18). To a solution of nitro-aldehyde 29
(0.37 g, 1.82 mmol) in methyl acrylate (10 mL) was added DABCO
(0.13 g,1.17 mmol). The resulting mixture was kept in an ultrasound
bath (ultrasonic cleaner UNIQUE model GA 1000e1000 W) for 8 h.
Methyl acrylate was then removed under reduced pressure (92%
recovery). The residue was dissolved in ethyl acetate (15 ml) and
the organic phase was washed with distilled water (10 mL), brine
(2ꢁ10 mL), dried over anhydrous Na2SO4, and the solvent was re-
moved under reduced pressure. The crude residue was purified by
silica gel column chromatography (ethyl acetate/hexanesd1:1) to
afford 0.45 g (85% yield) of 18, as a tinged yellow viscous oil. IR
(film, nmax): 3477, 1716, 1630, 1531, 1348 cmꢂ1. 1H NMR (300 MHz,
285e287 ꢀC (lit.32 285e287 ꢀC).1HNMR(500 MHz,CF3CO2D),
d ppm:
9.84 (s, 1H), 9.23 (d, J¼8.5 Hz, 1H), 8.75 (t, J¼7.0 Hz, 1H), 8.67 (d,
J¼8.5 Hz, 1H), 8.53 (t, J¼7.0 Hz, 1H), 5.22 (q, J¼7.0 Hz, 2H), 2.08 (t,
J¼7.0 Hz, 3H). 13C NMR (125 MHz, CF3CO2D),
d ppm: 176.3, 170.2,
147.6, 142, 140.6, 132.9, 127.5, 122.7, 122.5, 107.5, 67.3, 14.8.
4.1.4. Synthesis of ethyl 1-(4-methoxybenzyl)-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (27). To
a
solution of 13 (0.125 g,
0.58 mmol) in DMF (4 ml) was added K2CO3 (0.16 g, 1.2 mmol), KI
(0.015 g, 0.09 mmol), and 4-methoxybenzyl bromide (26) (0.17 g,
0.84 mmol). The resulting mixture was warmed at 95 ꢀC for 27 h.
The mixture was then filtered and the cake was washed with ethyl
acetate (2ꢁ10 mL). The combined organic phase were washed
with distilled water (4ꢁ5 mL), brine (4ꢁ5 mL), dried over Na2SO4,
and the solvent was removed under reduced pressure. The crude
product was purified by silica gel column chromatography (ethyl
acetate/hexanesd30:70) to provide 0.13 g of 27 (65% yield), as
a tinged yellow viscous oil. IR (film, nmax): 3062, 2979, 2838, 1726,
1688, 1628, 1607, 1515, 1487, 1460, 1416 cmꢂ1. 1H NMR (250 MHZ,
CDCl3),
1H), 6.24 (s, 1H), 5.67 (s, 1H), 3.78 (s, 3H). 13C NMR (75.4 MHz,
CDCl3),
d
ppm: 8.13 (d, J¼6.6 Hz, 1H), 7.62 (d, J¼9.6 Hz, 1H), 6.35 (s,
d
ppm: 166.3, 160.9 (d, J¼258.6 Hz), 140.4, 138.5 (d,
J¼7.4 Hz), 127.9 (d, J¼1.5 Hz), 126.9, 121.5 (d, J¼19.5 Hz), 117.2 (d,
J¼24.6 Hz), 67.5, 52.6. HRMS (ESI m/z) calcd for C11H9O5ClFNNa
[MþNa]þ: 312.0051. Found: 311.9922.
4.1.8. Synthesis of methyl 7-chloro-6-fluoro-4-hydroxyquinoline-3-
carboxylate 1-oxide (16). A stirred mixture of the MBH adduct 18
(0.2 g, 0.69 mmol) in TFA (2 mL) was warmed at 70e75 ꢀC for 48 h.
The reaction medium was then dropped over cold distilled water
(10 mL). The precipitated solid was filtered under reduced pressure,
CD3OD)
d
ppm: 8.42 (s, 1H), 8.35 (dt, J¼0.95 and 8 Hz, 1H), 7.84 (m,
2H), 7.5 (m, 1H), 7.34 (d, J¼8.7 Hz, 2H), 6.94 (d, J¼8.7 Hz, 2H), 5.28
(s, 2H), 4.23 (q, J¼7.1 Hz, 2H), 3.79 (s, 3H), 1.29 (t, J¼7.1 Hz, 3H). 13C
NMR (62.5 MHz, CD3OD)
d ppm: 174.3, 163.7, 161.1, 145.5, 137.6,

G.W. Amarante et al. / Tetrahedron 66 (2010) 4370e4376
4375
dried, and use for the next step without purification. N-Oxide 16
was obtained in 60% yield (0.11 g). Mp 252e253 ꢀC. IR (film, nmax):
mounted under the reaction vessel. The mixture was then cooled to
room temperature and the white precipitate was filtered and dried
and purified by crystallisation (methanol/dichloromethane) to
furnish 0.025 g (80% yield) of Norfloxacin (3), as a white solid. Mp:
220e221 ꢀC (lit.33 221 ꢀC); 3600e3250, 2950, 2830, 2500,
1720, 1605, 1556, 1458, 1356, 1164, 1025, 796 cmꢂ1 1H NMR
.
(250 MHz, CF3CO2D),
d
ppm: 9.40 (s,1H), 8.59 (d, J¼6.0 Hz,1H), 8.32
(d, J¼9.0 Hz, 1H), 4.16 (s, 3H). 13C NMR (125 MHz, CF3CO2D),
d ppm:
172.5, 169.6, 161.5 (d, J¼260.7 Hz), 146.6, 139.2, 138.5 (d, J¼21.4 Hz),
123.6, 122.7, 113.2 (d, J¼25.3 Hz), 106.8, 56.4. HRMS (ESI m/z) calcd
for C11H7O4ClFN [MþH]þ: 272.0126. Found: 272.0057.
1725e1700, 1628, 1619, 1484, 1250 cmꢂ1
.
1H NMR (500 MHz,
ppm: 9.16 (d, J¼12.2 Hz, 1H), 8.66 (br s, 1H), 8.32 (d,
CF3CO2D),
d
J¼6.5 Hz,1H), 5.69 (q, J¼7.0 Hz, 2H), 4.80 (s, 4H), 4.62 (s, 4H), 2.61 (t,
J¼7.0 Hz, 3H). 13C NMR (125 MHz, CF3CO2D),
d ppm: 171.5 (d,
4.1.9. Synthesis of ethyl 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihy-
droquinoline-3-carboxylate (30). A stirred mixture of N-oxide
hydroxyquinoline 16 (0.3 g, 1.1 mmol) in anhydrous methanol
(10 mL) and molybdeniumhexacarbonyl (0.29 g, 1.83 mmol), under
an inert gas atmosphere, was warmed at reflux for 30 min. The
resulting mixture was then cooled to room temperature and the
solvent was removed under reduced pressure to afford 0.2 g (68%
yield) of 4-quinolone 14. This product revealed to be unstable and
was used for the next step without purification. To a solution of
quinolone 14 (0.2 g, 0.75 mmol) in anhydrous DMF (1.5 mL) was
added K2CO3 (0.45 g, 2.91 mmol) and ethyl iodide (0.45 mL,
4.85 mmol). The resulting stirred mixture was warmed at 95 ꢀC
under argon atmosphere for 7 h. The reaction was then cooled and
filtered. The cake was washed with ethyl acetate (3ꢁ7 mL) and the
organic phases were combined, washed with distilled water
(4ꢁ10 mL), brine (10 mL), dried over Na2SO4, and the solvent was
removed under vacuum. The residue was purified by silica gel
column chromatography (ethyl acetate/hexanesd30:70) to afford
0.213 g of quinolone 30 (65% overall yield), as a white solid. Mp:
139e141 ꢀC. IR (film, nmax): 2985, 2928, 1718, 1689, 1613, 1527, 1487,
J¼3.8 Hz), 170.6, 157.1, 155.0, 149.3, 149.1 (d, J¼10.4 Hz), 139.9, 117.1
(d, J¼10 Hz), 112.9 (d, J¼26 Hz), 105.8 (d, J¼2.9 Hz), 104.6, 53.7, 47.1,
47.0, 45.4, 13.8; HRMS (ESI TOF) calcd for C16H19FN3O3 [MþH]þ
320.1411. Found 320.1453.
Acknowledgements
GWA and MB thanks São Paulo Foundation for Science (Fapesp)
for fellowship. FC and MNE thanks Fapesp and CNPq for research
financial support and research fellowships.
Supplementary data
The 1H, 13C NMR, and HRMS spectra are available for all com-
pounds. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2010.04.018. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
References and notes
1312, 1218, 1174 cmꢂ1 1H NMR (250 MHz, CDCl3),
. d ppm: 8.47 (s,
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