Advantageous Use of Ionic Liquids for the Synthesis of Pharmaceutically Relevant Quinolones

Article abstract of DOI:10.1002/ejoc.201800415

The advantageous use of ionic liquids (ILs) as alternatives to common DMF as solvent in the Grohe cycloaracylation for the synthesis of pharmaceutically relevant quinolones is reported. ILs showed in many cases shorter reaction times and higher yields, complete conversions of the reactants and easy work-up procedures compared with DMF. Of the ILs screened, tributylmethylammonium methanesulfonate ([TBMA][MsO]) was selected as the most suitable for further studies. Interestingly, a wide substrate scope was observed and the IL was recycled by a green process. A further step forward in the use of [TBMA][MsO] for quinolone synthesis was the preparation by a one-pot/three-step procedure of the representative 3-carboxy-4-quinolone acid 16, which was obtained in high yield in a short time. The greener properties of ILs in comparison with DMF and their non-volatility appoint this method as a potentially efficient and alternative approach to the industrial production of quinolones.

Full text of DOI:10.1002/ejoc.201800415

A Journal of
Accepted Article
Title: Advantageous use of ionic liquids for the synthesis of
pharmaceutically relevant quinolones
Authors: Rolando Cannalire, Matteo Tiecco, Violetta Cecchetti,
Raimondo Germani, and Giuseppe Manfroni
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800415
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10.1002/ejoc.201800415
European Journal of Organic Chemistry
Advantageous use of ionic liquids for the synthesis of
pharmaceutically relevant quinolones
Rolando Cannalire,¥,a Matteo Tiecco,¥,b Violetta Cecchetti,a Raimondo Germani,b Giuseppe
Manfroni. b,*
aDipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Via del Liceo, 1-06123-
Perugia, Italy. bDipartimento di Chimica, Biologia e Biotecnologie, Università degli Studi di Perugia,
Via Elce di Sotto, 8-06123-Perugia, Italy.
¥These authors contributed equally to this work
*Corresponding author: giuseppe.manfroni@unipg.it; Università degli Studi di Perugia,
Dipartimento di Science Farmaceutiche, Via del Liceo,1.
Abstract
The advantageous use of Ionic Liquids (ILs), as alternatives to common DMF as solvent in the
Grohe cycloaracylation, for the synthesis of pharmaceutically relevant quinolones is reported. ILs
showed in many cases lower reaction times and higher yields, complete conversions of the
reactants, easy workup procedures compared to DMF. Among the ILs, tributylmethylammonium
methanesulfonate [TBMA][MsO] was selected as the most suitable for additional studies.
Interestingly, a wide substrates scope was observed and a green re-cycling process of the IL was
realized. A further step forward in the use of [TBMA][MsO] for quinolone synthesis, was the
preparation in a one-pot/three-steps procedure of the representative 3-carboxy-4-quinolone acid
16, which was obtained in high yields and short time. The greener properties of ILs in comparison
to DMF and their non-volatility appoint this method as potentially efficient and an alternative way
for the industrial production of quinolones.
1
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Introduction
Ionic Liquids (ILs) are a remarkable class of organic solvents composed by organic and/or
inorganic ions.[1] Due to their molecular structures, ILs have peculiar properties such as high
thermal stability, high electric conductivity, low vapour pressure.[2–4] One of the most relevant topics
where ILs have been finding fruitful application is their use as solvents and/or catalysts for
chemical reactions.[5–8] There are many different advantages on the use of ILs in chemical
synthesis such as milder reaction conditions, higher yields, easier reaction workups that anyhow
represent a non-exhaustive list of them. Moreover, in some cases the synthesis in ILs permitted to
obtain products otherwise non-obtainable in other common organic liquids.[9] There is also an
ecological advantage that must be considered regarding these salts: the non-volatility of ILs is a
key-factor for their use as environmental-friendly alternatives of organic solvents.[10–12]
In the last 15 years, many research groups have reported the use of ILs in different chemical
processes related to the production of pharmaceuticals including precursors or intermediates and
in most cases ILs are used as reaction media. So far, the synthesis of several non-steroidal anti-
inflammatory drugs, antiviral, antimicrobial, anti-malarial, and anti-tumor agents, as well as
cholinesterase inhibitors and radiolabelled molecular imaging and therapy agents, have been
described.[13]
Although the numerous advantages associated with the use of ILs, in recent years, some critical
aspects emerged with regards to toxicity, biodegradability and their potential role as persistent
environmental pollutants.[14–18] In particular, ILs have been considered similar to poly chlorinated
biphenyls because they produce similar effects on aquatic environment.[19] However, no exhaustive
studies have been reported so far and this means that aspects related to toxicity and
biodegradability of ILs deserve further investigations. In order to reduce the potential
environmental impact of ILs, a recent review reported some recommended guidelines to produce
greener ILs and to choose the suitable IL for a desired application.[20]
3-Carboxy-4-quinolone nucleus has been extensively developed to obtain anti-bacterial drugs
targeting DNA gyrase,[21] prokaryotic counterpart of topoisomerse II, and besides the canonical
anti-bacterial activity, several studies have highlighted the versatile nature of this chemical class.
2
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Indeed, suitable functionalization of the quinolone scaffold has allowed the shifting from bacterial
uses towards other therapeutic areas such as viral infections and cancer.[22,23] Eviltegravir is a
quinolone able to inhibit the HIV integrase approved in 2012 by the FDA as antiretroviral drug;[24]
furthermore, we and other groups reported anti-HIV[25] and anti HCV quinolones.[26–28] Vosaroxin
(also called voreloxin) is a mammalian topoisomerase II inhibitor currently in phase III of clinical
development for cancer therapy.[29] More recently, the old antibacterial drug enoxacin has been
described as new antitumor agent endowed with a novel epigenetic mode of cell differentiation
regulation.[30]
Due to the wide therapeutic employment of quinolones and the great value in pharmaceutical and
biological chemistry, the development of general and more efficient methods for the construction of
4-quinolone nucleus and its functionalization has attracted considerable interest. One of the typical
synthetic routes to these heterocycles is the Grohe method, known also as cycloaracylation
procedure,[31] applied for the preparation of ciprofloxacin, one of the most employed antibacterial
agents. The Grohe’s procedure is based on the intramolecular nucleophilic aromatic substitution of
an ethyl N-monosubstituted 3-amino-2-benzoyl acrylate intermediate (e.g. 1[31]) that cyclizes to
afford the quinolone nucleus (intermediate 2[31]) (Scheme 1 – synthesis of ciprofloxacin as
representative example). Classic reaction conditions are i) the use of a base such as K2CO3 in
high-boiling dipolar aprotic solvents (e.g. DMF, DMSO) at 80-100 °C or ii) NaH in apolar solvents
(THF or toluene) at 40-60 °C. The subsequent functionalization at C-7 position usually employs a
cyclic amine (e.g. piperazine) which provides intermediate 3 through intermolecular nucleophilic
displacement in dipolar aprotic solvents (e.g. DMF, DMSO, NMP) at 80-100 °C. The intermediate 3
is then hydrolized by basic or acid conditions into the corresponding carboxylic acid ciprofloxacin
(Scheme 1).[32]
To the best of our knowledge no publications has been reported on the use of ILs for the synthesis
of pharmaceutically relevant quinolones although ILs have been used in previous works for the
synthesis of similar compounds,[33] or as extracting agents of quinolone molecules from biological
matrixes.[34]. In this work we aimed to explore the synthesis 3-carboxy-4-quinolones using ILs as
3
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reaction media in place of DMF usually employed during the synthetic procedures. More
precsisely,
Scheme 1. Classic example of synthesis of the antibacterial ciprofloxacin based on the Grohe
method.
At first we explored the use of ILs as reaction media in place of DMF for the cyclization step of the
Grohe’s procedure. A set of differently structured ILs have been analysed and studied as reaction
media: 1-butyl-3-methylimidazolium methanesulfonate ([BMIM][MsO]), 1-butyl-3-methylimidazolium
tetrafluoroborate ([BMIM][BF4]), tributylmethylammonium methanesulfonate ([TBMA][MsO]), and
tributylmethylammonium bromide ([TBEA][Br]).[35][36] They were selected because they are all
water-soluble quaternary ammonium/imidazolium salts having inert anions thus permitting to
evaluate the effects of different cations and anions.
Furthermore, we proposed the synthesis of a representative 3-carboxy-4-quinolone acid carrying
out the entire process in a selected IL medium.
Results and Discussion
The first step of the work was to explore the cyclization of acrylate intermediate 1[31] into the
corresponding quinolone 2[31] using the aforementioned ILs in absence/presence of K2CO3 at 80 °C
(Table 1 – entries 1-4 and 6-9). The screening of the ILs was carried out in parallel and in
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comparison to the same reaction performed in DMF (Table 1 – entries 5 and 10). In absence of the
base, no reaction was detected both using ILs and DMF, as reaction media (entries 1-5). Adding
K2CO3, regardless of the reaction medium, total conversion of acrylate 1 into the desired quinolone
2 was observed (entries 6-10). Aqueous work-up afforded pure powders of compound 2 from all
the reaction mixtures with the different ILs. The use of [BMIM][MsO] (entry 6) or [TBMA][MsO]
(entry 8) gave similar results, affording derivative 2 in high yields (78 and 80%, respectively) and
shorter reaction time (2 h) in comparison to DMF (65%, 6 h - entry 10), the classic solvent for this
reaction. Lower yields were observed carrying out the reaction in [BMIM][BF4] (50% - entry 7) or in
[TBEA][Br] (50% - entry 9), in the last case coupled with longer reaction time (6h – entry 9).
The higher yields and the shorter reaction times obtained using the ILs with mesylate anion could
be explained with a better solubility of the base in such media with respect to tetrafluoroborate or
bromide ILs, as already observed in a previous study.[37]
Table 1. Screening of ILs as reaction media for cycloaracylation.
Entry
Reaction medium
Base
Time (h)
Yield (%)
1
2
[BMIM][MsO]
[BMIM][BF4]
[TBMA][MsO]
[TBEA][Br]
DMF
No base
No base
NDb
NDb
NDb
NDb
NDb
2
NDb
NDb
NDb
NDb
NDb
78
3
No base
4
No base
5
No base
6
[BMIM][MsO]
[BMIM][BF4]
[TBMA][MsO]
[TBEA][Br]
DMF
K2CO3 (2 eq.)
K2CO3 (2 eq.)
K2CO3 (2 eq.)
K2CO3 (2 eq.)
K2CO3 (2 eq.)
7
2
50
8
2
80
9
6
50
10
6
65
a solvent (0.5 mL), 80 °C. b ND = not determined because no reaction was observed
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This first survey indicated [BMIM][MsO] and [TBMA][MsO] as suitable replacer of DMF for the
cyclization of acrylate into quinolone for the high yields and the short reaction times observed.
However, [TBMA][MsO] was chosen between these two ILs to proceed in the next steps of our
studies for different reasons: (i) the cost of the reagents for the preparation of [TBMA][MsO] is
lower than the one of [BMIM][MsO] and the former was prepared by nucleophilic substitution
between tributylamine and methylmethanesulfonate in acetonitrile considered as a usable solvent
concerning the environmental impact;[36] (ii) the stability of [TBMA][MsO] is higher than
[BMIM][MsO] under the employed conditions since the C-2 hydrogen in imidazolium cation could
lead to unwanted side-reactions with K2CO3 at high temperatures in longer reaction times as
observed in precedent work;[37] (iii) [TBMA][MsO] partially fits the general guidelines proposed by
Bubalo et al.[20] In fact, the core differs from an imidazolium which is not recommended for both
toxicity and biodegradability, while the mesylate anion is tolerated and in addition the medium size
of alkyl chain appears more advantageous in terms of biodegradability although not suitable for
toxicity.
Then, in order to explore the scope of the reaction, a set of acrylate intermediates differently
functionalized at the arene ring (3,[38] 4,[39] 5,[40] and 6[41] – entries 1-4 – [TBMA][MsO] – Table 2) or
at the acrylic nitrogen (7[42] and 8[43] – entries 5 and 6 – [TBMA][MsO] – Table 2) were cyclized in
[TBMA][MsO] as reaction medium, in presence of K2CO3 at 80 °C (Table 2). Also in this case, the
results were compared to those derived from parallel reactions conducted in DMF (entry 1-6 –
DMF – Table 2). Overall, [TBMA][MsO] resulted a good choice for the cyclization of all the
acrylates 3-8 into the corresponding quinolones 9,[38] 10,[39] 11,[40] 12,[41] 13,[42] and 14[43] (entries 1-
6 – [TBMA][MsO]), obtained in good yields (68-80%) and in short reaction times (2-5 h). In
comparison to the cyclization reactions in DMF (entries 1-6 – DMF), in general the use of the IL
gave slightly higher yields. Regarding intermediates 3-6 differently substituted at the arene ring,
the activated substrates 4 and 5 (entries 2 and 3 – [TBMA][MsO] vs. DMF), as expected, afforded
the corresponding quinolones 10 and 11 in the shorter reaction times and with the highest yields.
Worthy of note, the use of [TBMA][MsO] as medium afforded compound 9 from the unsubstituted
and less activated acrylate 3 after 5 h in 68% yields (entry 1 – [TBMA][MsO]). On the contrary,
6
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using DMF, only partial conversion of starting material 3 into the desired quinolone 9 was observed
after 4 days (entry 1 – [TBMA][MsO]), as checked by TLC (eluent: CHCl3/MeOH 98:2; Rf of
compounds 3 and 9 of 0.7 and 0.4, respectively). Regarding intermediate 6, no significant
differences were observed between the IL and DMF. The cyclization of N-phenyl 7 and N-benzyl 8
acrylates in [TBMA][MsO] (entries 5 and 6 – [TBMA][MsO]) provided comparable results to the
reaction carried out in DMF (entries 5 and 6 – DMF) in terms of time and yield.
The results obtained in this second reactions set strongly indicated [TBMA][MsO] as suitable
replacer of the classic DMF as medium for the construction of a variety of different functionalized
quinolone scaffolds exploiting the cycloaracylation method.
Table 2. Cyclization step of acrylate intermediates 3-8 into quinolones 9-14 using [TBMA][MsO].
Time
(h)
Yield
(%)
Entry
Cmpd
R
X
Solvent
[TBMA][MsO]
DMF
5
68
3, 9
1
a
a
-
-
[TBMA][MsO]
DMF
2
3
2
2
77
77
80
53
4, 10
5, 11
2
3
[TBMA][MsO]
DMF
[TBMA][MsO]
DMF
4
2
71
66
6, 12
4
[TBMA][MsO]
DMF
4.5
5
75
73
80
80
7, 13
8, 14
5
6
[TBMA][MsO]
5.0
DMF
5
a After 4 days only partial conversion of starting acrylate 3 was observed by TLC
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In order to investigate the re-usability of [TBMA][MsO] as solvent, three cycles of cycloaracylation
were realized using intermediate 1 as representative starting compound. At first, a method as
greener as possible was designed to recover the IL after the first reaction cycle entailing the use of
EtOH as washing solvent of the evaporated aqueous mixture of [TBMA][MsO] and inorganic salts
which was obtained after the aqueous work-up, before mentioned. In particular, after precipitation
of quinolone intermediate 2 in aqueous medium, water was evaporated to dryness to give a slurry
containing the IL, the excess of K2CO3, and the formed KCl. EtOH was then used to separate the
soluble [TBMA][MsO] from the large part of inorganics and the IL was recovered by EtOH
evaporation. Through this procedure, [TBMA][MsO] was used for additional two cycles and for a
total of three cyclizations. Interestingly, quinolone 2 was obtained with a total conversion,
comparable reaction times and yields, and no side products were observed by TLC employing re-
cycled IL in comparison to the first reaction using fresh IL (Table 3, see also Table 1, entry 8 for
comparison). This result showed that the re-usability of [TBMA][MsO] for cycloaracylation can be
realized with low costs and reduced environmental impact.
Table 3. Re-cycling of [TBMA][MsO] in the cyclization of acrylate 1 into quinolone intermediate 2
Entry
Cycle
1st
2nd
Time (h)
Yield (%)a
1
2
3
2
2
2
80
81
77
3rd
a Total conversion no side products were observed by TLC
Finally, the entire process (i.e., ring closure, aromatic nucleophilic substitution, and saponification
of the 4-carboxylic ester), performed in [TBMA][MsO] as solvent, was applied to synthesize
compound 16.[31] This latter is also known as UB-8902 and is an old fluoroquinolone recently
explored against multiresistant bacteria such as Acinetobacter baumannii.[44,45] First, starting
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acrylate 1 was cyclized into the corresponding quinolone intermediate 2, in presence of K2CO3 at
80°C for 2 h. After total conversion of starting material, methylpiperazine was added to give, after 3
h, the C-7 functionalized derivative 15, which was obtained after aqueous work-up and filtration in
good yield (overall yield = 72%). For comparison, these first two steps were carried out also in
DMF and resulted in longer reaction time (24 h) and lower yield (40%). Therefore, the use of
[TBMA][MsO] resulted advantageous in comparison to DMF.
The hydrolysis of the ethyl ester was explored in the same reaction medium without isolation of
derivative 15. Obviously, this attempt was performed only in the IL while it is not possible using
DMF. Therefore, the first two steps of this procedure in [TBMA][MsO] were replicated and when
ethyl ester intermediate 15 was obtained, aq. 10% NaOH was added to the mixture to provide
target acid 16, after 2.5 h. Worthy of note the desired acid 16 was obtained, after simply aqueous
work-up and filtration, in 65% overall yield (over 3 steps) and short time (7.5 h for the entire
process).
Scheme 2. Synthesis of target quinolone 16 performed in the same medium, using [TBMA][MsO],
in a one-pot/three steps procedure.
Worth noting, all the procedure described have been realized avoiding the use of highly toxic
organic solvents and work-up of reactions as well as IL recycling have been carried out by green
procedures thus allowing the synthesis of desired quinolones outside the fume hood.
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Conclusions
In this work we explored the use of ILs instead of the classic DMF as reaction medium in the
Grohe cycloaracylation procedure for the synthesis of representative compounds based on the
pharmaceutically relevant 4-quinolone scaffold. In particular, ILs demonstrated to be suitable
replacers of DMF in the cyclization step to build the quinolone nucleus, demonstrating in most
cases higher yields and shorter reaction times; among the ILs screened, [TBMA][MsO] was
selected for further applications because of its favourable balance between results (times and
yields) and environmental impact. Importantly, we demonstrated that [TBMA][MsO] can be
recycled several times during the cyclization step increasing the “greenness” of the procedure.
Furthermore, we advantageously carried out the entire synthetic process using [TBMA][MsO] as
medium to obtain a 3-carboxy quinolone in the same reaction mixture in a one-pot/three steps
procedure.
The greener properties of ILs compared to DMF and their non-volatility, promote this method as an
efficient and green way to synthesise quinolones from benzoylacrylate intermediate via Grohe
reaction. The developed procedure can be used as an alternative way for the industrial production
of quinolones and it also meets several principles of green chemistry, such as: a) atom economy;
b) less hazardous chemical synthesis; c) safer solvents and auxiliaries; d) reduction of derivatives;
e) inherently safer chemistry for accident prevention; f) use of renewable feedstocks, g) prevention
of waste.[46]
Materials and Methods
General chemistry. ILs were synthesized and purified following a previous procedure.[35,36]The
other reagents and solvents were purchased from common commercial suppliers and were used
as such. All reactions were routinely checked by TLC on silica gel 60F254 (Merck) and visualized
by using UV or iodine. Melting points were determined in capillary tubes (Büchi Electrotermal
1
model 9100) and are uncorrected. Yields were of pure products and were not optimized. H NMR
spectra were recorded at 400 MHz (BrukerAvance DRX 400) while 13C NMR spectra were
recorded at 100 MHz (BrukerAvance DRX-400). Chemical shifts are given in ppm (δ) relative to
10
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TMS. Spectra were acquired at 298 K. Data processing was performed with standard Bruker
software XwinNMR and the spectral data are consistent with the assigned structures. The purity of
the compounds was assesed by UHPLC using an Agilent 1290 series machine equipped with DAD
detector from 190 to 640 nm and the purity was estimated by peaks integration at 254 nm. A
Phenomenex Luna C18 polar (2.1 mm × 100 mm, 1.7 µm particle size) column was used with
gradient of 0-100% acetonitrile with 0.1% formic acid (channel B) in water with 0.1% formic acid
(channel A) for 15 min (time 0 min A = 99.5%, time 6 min A=80%, time 12 min A=0%, time 15 min
stop run) at 0.3 mL/min. Injection volume was of 1.0 µL and column temperature of 40 °C. Peaks
retention time are given in minutes.
General procedure of cyclization of compound 1 employing ILs. A mixture of the starting
acrylate intermediate 1 (100 mg, 0.3 mmol) and K2CO3 (83.5 mg, 0.6 mmol) in the opportune hot IL
(0.5 mL) was heated at 80 °C until the disappearance of the starting material. After cooling, the
reaction mixture was poured into ice/water to give a precipitate that was filtered under vacuum and
crystallized by EtOH to afford the desired quinolone as white solid. In particular, by using: i)
[BMIM][MsO], the reaction time was of 2h and the yield was of 78% (entry 6, Table 1); ii)
[BMIM][BF4], the reaction time was of 2h and the yield was of 50% (entry 7, Table 1); iii)
[TBMA][MsO], the reaction time was of 2h and the yield was of 80%; and iv) [TBEA][Br], the
reaction time was of 6h and the yield was of 50%.
Ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (2). m.p.: 225-226
°C (litt.:[31] 227 °C). 1H NMR (400 MHz, [D6]DMSO): δ=8.43 (s, 1H, H-2), 8.08 (dd, J = 12.1, 6.8 Hz,
1H, H-5), 8.00 (dd, J = 10.7, 8.9 Hz, 1H, H-8), 4.19 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.62-3.53 (m,
1H, cyclopropyl-CH), 1.26-1. (m, 5H, cyclopropyl-CH2, and OCH2CH3), 1.10-1.04 ppm (m, 2H,
cyclopropyl-CH2). 13C NMR (100 MHz, [D6]DMSO): δ=171.74, 164.52, 152.62 (dd, JC-F = 250.0,
15.0 Hz, C-7), 149.17, 148.03 (dd, JC-F = 247.0, 14.0 Hz, C-6), 138.20 (d, JC-F = 8 Hz, C4a), 125.41
(d, JC-F = 4 Hz, C8a), 113.99 (d, JC-F = 17 Hz, C-5), 110.38, 107.40 (d, JC-F = 22 Hz, C-8), 60.32,
35.54, 14.62, 7.98 ppm. HPLC ret. time: 8.95; purity: 97.3%.
11
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Melting point values and the spectral data for the compound obtained from all the reactions are
identical and in agreement with those reported in literature.[31]
General procedure of cyclization of acrylate intermediates employing [TBMA][MsO] as
suitable IL. A mixture of the starting acrylate intermediate (3,4,5,6,7, and 8) (0.3 mmol) and K2CO3
(0.6 mmol) in hot [TBMA][MsO] (0.5 mL) was heated at 80 °C until the disappearance of the
starting material. After cooling, the reaction mixture was poured into ice/water to give a precipitate
that was filtered under vacuum and crystallized by EtOH to afford the desired quinolone as solid.
Ethyl 1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (9). White solid, reaction time:
1
5h; yield: 68%; m.p.: 165-167 °C (litt.:[38] 167-168 °C). H NMR (400 MHz, [D6]DMSO): δ=8.46, (s,
1H, H-2), 8.18 (dd, J = 8.0, 1.4 Hz, 1H, H-5), 8.04 (d, J = 8.2, 1H, H-8), 7.80 (dt, J = 8.2, 1.5 Hz,
1H, H-7), 7.24 (dt, J = 8.0, 0.7 Hz, 1H, H-6), 4.18 (q, J = 7.2 Hz, 2H, OCH2CH3), 3.64-3.59 (m, 1H,
cyclopropyl-CH), 1.28-1.19 (m, 5H, cyclopropyl-CH2, and OCH2CH3), 1.07-1.03 ppm (m, 2H,
cyclopropyl-CH2). 13C NMR (100 MHz, [D6]DMSO): δ=173.26, 164.88, 148.80, 140.83, 132.96,
128.09, 126.50, 125.37, 117.90, 110.22, 61.15, 35.05, 14.69, 7.95 ppm. HPLC ret. time: 8.45;
purity: 95.9%.
The spectral data are in agreement with those reported in literature.[38]
Ethyl 7-chloro-1-cyclopropyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (10). Yellow
1
solid, reaction time: 2h; yield: 77%; m.p.: >280 °C (litt.:[39] >280 °C). H NMR (400 MHz,
[D6]DMSO): δ=8.67 (s, 1H, H-5), 8.48 (s, 1H, H-2), 8.25 (s, 1H, H-8), 4.19 (q, J = 4.03 Hz, 2H,
OCH2CH3), 3.69-3.65 (m, 1H, cyclopropyl-CH), 1.26-1.18 (m, 5H, cyclopropyl-CH2, and OCH2CH3),
1.12-1.08 ppm (m, 2H, cyclopropyl-CH2). 13C NMR (100 MHz, [D6]DMSO): δ=171.99, 164.14,
150.61, 143.97, 143.60, 129.54, 126.55, 125.03, 121.51, 112.05, 60.72, 35.68, 14.67, 8.17 ppm.
HPLC ret. time: 9.38; purity: 96.8%.
The spectral data are in agreement with those reported in literature.[39]
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Ethyl
7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate
1
(11). Whitish solid, reaction time: 2h; yield: 80%; m.p.: 216-217 °C. H NMR (400 MHz,
[D6]DMSO): δ=8.54 (s, 1H, H-2), 8.41 (d, J = 7.8 Hz, 1H, H-5), 4.20 (q, J = 7.2 Hz, 2H, OCH2CH3),
3.64-3.58 (m, cyclopropyl-CH), 1.17 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.13-1.00 ppm (m, 4H,
13
cyclopropyl-CH2). C NMR (100 MHz, [D6]DMSO): δ=172.66, 164.14, 152.08 (d, JC-F = 256.0 Hz,
C-6), 149.71, 146.43, 140.86 (d, JC-F = 22.0 Hz, C-7), 123.75, 123.37 (d, JC-F = 20.3 Hz, C-5),
111.56, 60.58, 34.78, 14.60, 7.45 ppm. HPLC ret. time: 9.40; purity: 94.7%.
The spectral data are in agreement with those reported in literature.[40]
Ethyl 1-cyclopropyl-7-fluoro-8-methyl-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (12).
1
Yellow solid, reaction time: 4h; yield: 71%; m.p.: 197-199 °C (litt.:[41] 198-200 °C). H NMR (400
MHz, [D6]DMSO): δ=8.63-8.57 (m, 2H, H-2, and H-5), 4.23-4.17 (m, 3H, OCH2CH3, and
cyclopropyl-CH), 2.72 (d, J = 3.2 Hz, 3H, CH3), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.20-1.10 (m,
2H, cyclopropyl-CH2), 1.00-0.92 ppm (m, 2H, cyclopropyl-CH2). 13C NMR (100 MHz, [D6]DMSO):
δ=171.97, 163.79, 155.40 (d, JC-F = 257.1 Hz, C-7), 153.81, 146.18 (d, JC-F = 7.0 Hz, C-8a), 134.48
(d, JC-F = 12.0Hz, C-6), 125.05 (brs, C4a), 122.84 (brs, C5), 119.96 (d, JC-F = 19.0 Hz, C8), 111.71,
60.62, 40.56, 14.58, 13.88, 13.56, 6.53 ppm. HPLC ret. time: 9.35; purity: 90.0%.
The 1H NMR spectral data are in agreement with those reported in literature.[41]
Ethyl 6,7-difluoro-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate (13). White solid,
1
reaction time: 4.5h; yield: 75%; m.p.: 252-254 °C. H NMR (400 MHz, [D6]DMSO): δ=8.43 (s, 1H,
H-3), 8.12-8.07 (m, 1H, H-5), 7.70-7.60 (m, 5H, phenyl-H), 6.9 (dd, J = 11.6, 6.6 Hz, 1H, H-8), 4.17
(q, J = 7.1 Hz, 2H, OCH2CH3), 1.21 ppm (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR (100 MHz,
[D6]DMSO): δ=171.92, 164.23, 152.50 (dd, JC-F = 251.0, 14.0 Hz, C-7), 149.45, 148.00 (dd, JC-F
=
246.4, 13.7 Hz, C-6), 140.40, 138.10 (d, JC-F = 9.0 Hz, C-8a), 130.91, 130.66, 127.86, 125.09 (brs,
C-4a), 114.20 (d, JC-F = 19.0 Hz, C-5), 110.80, 107.56 (d, JC-F = 23.3 Hz, C-5), 60.49, 14.57 ppm.
HPLC ret. time: 9.34; purity: 93.7%.
The spectral data are in agreement with those reported in literature.[38]
13
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10.1002/ejoc.201800415
European Journal of Organic Chemistry
Ethyl 1-benzyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (14). White solid,
1
reaction time: 5h; yield: 80%; m.p.: 208-210 °C (litt.:[43] 208-209 °C). H NMR (400 MHz,
[D6]DMSO): δ=8.89 (s, 1H, H-2), 8.08-8.03 (m, 1H, H-5), 7.80 (dd, J = 12.09, 6.51 Hz, 1H, H-8),
7.35-7.21 (m, 5H, benzyl-H), 5.63 (s, 2H, benzyl-CH2), 4.19 (q, J = 6.9 Hz, 2H, OCH2CH3), 1.24
ppm (t, J = 6.9 Hz, 2H, OCH2CH3). 13C NMR (100 MHz, [D6]DMSO): δ=171.78, 164.65, 152.66 (dd,
JC-F = 250.0, 15.0 Hz, C-7), 150.83, 147.86 (dd, JC-F = 246.6, 13.8 Hz, C-6), 136.86 (d, JC-F = 10.4
Hz, C-8a), 135.76, 129.36, 128.41, 126.98, 126.22 (brs, C-4a), 114.35 (d, JC-F = 19.0 Hz, C-5),
110.62, 107.62 (JC-F = 246.6, 22.0 Hz, C-8), 60.40, 56.09, 14.64 ppm. HPLC ret. time: 9.33; purity:
90.0%.
The spectral data are in agreement with those reported in literature.[43]
Procedure for [TBMA][MsO] recycling. A mixture of the starting acrylate 1 (100 mg, 0.3 mmol)
and K2CO3 (83.5 mg, 0.6 mmol) in hot [TBMA][MsO] (0.5 mL) was heated at 80 °C for 2h. After
cooling, aqueous work-up and filtration afforded quinolone 2 as above described. The water was
evaporated to dryness to give a slurry constituted by the [TBMA][MsO], the excess of K2CO3 and
the formed KCl. EtOH (5 mL) was added to the slurry to dissolve [TBMA][MsO] and to precipitate
the inorganics that were removed by filtration. Then, EtOH was evaporated to give the
[TBMA][MsO] which was used for additional two reaction cycles. Yields, reaction time, conversion
and quality of reaction checked by TLC were perfectly comparable to the same reaction conducted
with fresh [TBMA][MsO].
Procedure for the preparation of ethyl 1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-
oxo-1,4-dihydroquinoline-3-carboxylate (15) using [TBMA][MsO] trough subsequent
cyclization and nucleophilic substitution. A mixture of the starting acrylate 1 (100.0 mg, 0.3
mmol) and K2CO3 (83.5 mg, 0.6 mmol) in hot [TBMA][MsO] (0.5 mL) was heated at 80 °C for 2h
until total conversion into quinolone 2. Then, methylpiperazine (0.05 mL, 0.46 mmol) dissolved in
hot [TBMA][MsO] (0.2 mL) was added and the resulting mixture was heated for additional 3h. After
cooling, the reaction mixture was poured into ice/water to give a precipitate that was filtered under
14
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10.1002/ejoc.201800415
European Journal of Organic Chemistry
1
vacuum to afford the title compound 15 as a white solid (81 mg, 72%); m.p. 202-204 °C. H NMR
(400 MHz, [D6]DMSO): δ=8.37 (s, 1H, H-2), 7.69 (d, J = 13.6 Hz, 1H, H-5), 7.38 (d, J = 7.4 Hz, 1H,
H-8), 4.16 (q, J = 7.0 Hz, 2H, OCH2CH3), 3.63-3.58 (m, 1H, cyclopropyl-CH), 3.20-3.15 and 2.53-
2.49 (m, each 4H, piperazine-CH2), (s, 3H, piperazine-CH3), 1.24-1.18 (m, 5H, OCH2CH3, and
cyclopropyl-CH2), 1.07-1.00 ppm (m, 2H, cyclopropyl-CH2). 13C NMR (100 MHz, [D6]DMSO):
δ=171.95, 164.85, 152.95 (d, JC-F = 245.0 Hz, C-6), 148.40, 144.24 (d, JC-F = 10.2 Hz, C-8a),
138.45, 121.12 (d, JC-F = 6.4 Hz, C-4a), 111.85 (d, JC-F = 23 Hz, C-5), 109.62, 106.56, 60.12,
54.74, 49.81, 46.11, 35.07, 14.68, 7.90 ppm. HPLC ret. time: 9.33; purity: 90.0%.
The spectral data are in agreement with those reported in literature.[31]
One-pot/three steps procedure conducted in [TBMA][MSO] for the synthesis of 1-
Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (16). Starting acrylate 1 (200.0 mg, 0.6 mmol) and K2CO3 (167.0 mg, 1.2 mmol) were added
while stirring at 80 °C to the preheated [TBMA][MsO] (1.0 mL) and the resulting reaction mixture
was kept under stirring at 80 °C for 2h until total conversion into quinolone 2, as observed by TLC
(CHCl3/MeOH 99:1, Rf = 0.3). Then, a preheated solution of methylpiperazine (0.1 mL, 0.9 mmol)
in [TBMA][MsO] (0.4 mL) was added and the reaction mixture was maintained at 80 °C for
additional 3h. After conversion of intermediate 2 into 15, as observed by TLC (CHCl3/MeOH 90:10,
Rf = 0.5), aq. 10% NaOH (2 mL) was added and the resulting mixture was heated at 80-90 °C for
3h. After cooling, the reaction mixture was poured into ice/water and neutralized with HCl 2N to
give a precipitate that was filtered under vacuum to afford the title compound 16 as white solid
1
(134 mg, 65%); m.p. 246-248 °C (litt,[31] 248-250 °C). H NMR (400 MHz, [D6]DMSO): δ=15.08
(brs, 1H, CO2H), 8.61 (s, 1H, H-2), 7.84 (d, J = 13.3 Hz, 1H, H-5), 7.51 (d, J = 7.4 Hz, 1H, H-8),
3.80-3.75 (m, 1H, cyclopropyl-CH), 3.30-3.25 and 2.53-2.49 (m, each 4H, piperazine-CH2), 2.21 (s,
13
3H, piperazine-CH3), 1.30-1.25 and 1.13-1.10 ppm (m, each 2H, cyclopropyl-CH2). C NMR (100
MHz, [D6]DMSO): δ=176.71, 166.27, 153.38 (d, JC-F = 250.0 Hz, C-6), 148.29, 145.50 (d, JC-F = 10
Hz, C-8a), 139.59, 118.96 (d, JC-F = 10 Hz, C-4a), 111.32 (d, JC-F = 23 Hz, C-5), 106.65 (d, JC-F = 4
Hz, C-8), 54.66, 49.66, 46.06, 36.19, 7.93 ppm. HPLC ret. time: 6.11; purity: 92.8%.
15
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10.1002/ejoc.201800415
European Journal of Organic Chemistry
The spectral data are in agreement with those reported in literature.[31]
Keywords
Quinolones; heterocycles; ionic liquids; green chemistry
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Table of Contents
Several advantages were observed using ILs instead of common DMF in the Grohe
cycloaracylation for synthesis of pharmaceutically relevant quinolones. [TBMA][MsO]
resulted the most favourable IL due to good balance between performance/green
properties and was used in a one-pot/3-steps procedure for the preparation of
quinolone acid 16 by using a totally green procedure. Our procedures can represent an
alternative way for the industrial production of quinolones.
18
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