Synthesis of 6-aryl substituted 4-quinolones via Suzuki cross coupling

Article abstract of DOI:10.1039/c3ra45056b

A convenient way to introduce aryl functionalization in the 6-position of 4-quinolones is developed via selective bromination and subsequent arylation by Suzuki cross-coupling. Ethyl 4-quinolone 3-carboxylates were subjected to selective bromination at C-6 followed by arylation under microwave irradiation that yielded the desired cross-coupling products within 5 minutes. This approach can expediently be used for library synthesis of the aryl functionalized 4-quinolone derivative, an important class of biologically active compounds.

Full text of DOI:10.1039/c3ra45056b

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Synthesis of 6-aryl substituted 4-quinolones via
Suzuki cross coupling†
Cite this: RSC Adv., 2014, 4, 6254
*
Sumanta Gupta, Prasanjit Ghosh, Seema Dwivedi and Sajal Das
A convenient way to introduce aryl functionalization in the 6-position of 4-quinolones is developed via
selective bromination and subsequent arylation by Suzuki cross-coupling. Ethyl 4-quinolone 3-
carboxylates were subjected to selective bromination at C-6 followed by arylation under microwave
irradiation that yielded the desired cross-coupling products within 5 minutes. This approach can
expediently be used for library synthesis of the aryl functionalized 4-quinolone derivative, an important
class of biologically active compounds.
Received 12th September 2013
Accepted 15th November 2013
DOI: 10.1039/c3ra45056b
www.rsc.org/advances
allied with the drawback that the substituents required on the
quinolone moiety can only be introduced during the synthesis
of the main skeleton.10 This connes the scope of ne tuning of
Introduction
4-Quinolones are the most privileged scaffolds found in both
natural products and biologically active molecules. They have
experienced prolic development aer the accidental discovery
of the rst synthetic antibiotic i.e.; nalidixic acid in 1962.1
Further, SAR (structure activity relationship) studies have
facilitated the development of quinolones with better pharma-
cokinetic properties and good tolerability.2 These potent qui-
nolone derivatives now serve as active components in diverse
families of drugs such as antibacterial,3 antiviral,4 antimalarial,5
anticancer,6 antitumor7 and anti-HIV4a,8 agents. A few important
biologically active moieties based on the quinolone scaffold are
shown in Fig. 1. In spite of the wide applicability of quinolone
based drugs, they are oen associated with limitations like poor
absorption, side effects etc.9 Hence, efforts are still required to
synthesize highly efficient drugs with good oral absorption,
selective binding ability and minimal secondary effects.
the structure activity relationships. As substituents play a
crucial role in deciding drug efficacy, for an effective library
synthesis of 4-quinolones, it is desirable to develop new strat-
egies that permit the introduction of substituents at later stage
or as per the requirements. So, we endeavored to create a way to
undertake sequential functionalization of quinolones. Many
research works in the recent past have reported quinolone
derivatives bearing diverse C-6 substituents that exhibit highly
active therapeutic capabilities.10f,11,12 This fostered our interest
to execute selective functionalization at the C-6 atom of the
quinolone skeleton. In this context, herein, we disclose a simple
and convenient route for the selective bromination of
compound 2 which effectively yields 6-bromo-4-quinolones.
These bromoquinolones can then participate in various kinds
of organic transformations, and the access of structurally
diverse 6-substituted quinolones is prevailed. Here we have
studied only the Suzuki coupling reactions for the synthesis of
6-aryl substituted 4-quinolones.
Many reliable and well established methods are available for
the library synthesis of 4-quinolones, but majority of them are
Results and discussion
We began by synthesising the starting scaffolds [ethyl-4-quino-
lone-3-carboxylate] compound 1 via the classic Gould–Jacobs
approach10a (Scheme 1). It is reported that the presence of the
substituent at the C-8 position of 4-quinolone enhances the
Fig. 1 Structures of several biologically active quinolones.
Department of Chemistry, University of North Bengal, Darjeeling, 734013, India.
E-mail: sajal.das@hotmail.com; Fax: +91-0353-2699-001; Tel: +91-0353-2776-381
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR of all compounds. See DOI: 10.1039/c3ra45056b
Scheme 1 General synthesis of 4-quinolones 1.
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in acetic acid medium at room temperature resulted in the
corresponding 6-bromo derivatives selectively in satisfactory
yields (65–75%, Scheme 3).
Aryl substituted 4-quinolones are known to be effective drugs
as Plasmodium falciparum Type II NADH,16 M1 positive allosteric
modulators with reduced plasma protein binding,17 selective
agonists of somatostatin receptor subtype 2,12a antimitotic and
antitumor agents.7b Earlier studies include aryl substitution
mostly at the 1 and 2 positions of the quinolone moiety.
Scientists are now investigating the inuence of 6-aryl substi-
tution on the therapeutic applications of quinolones which are
yet to be well explored. Recent work by Chen and co-workers
reported C-6 aryl substituted 4-quinolone derivatives as inhib-
itors of the hepatitis C virus (HCV).12b 6-Substituted 4-quino-
lone-3-carboxamides having high selective affinity for the
human CB2 (cannabinoid-2) receptor over CB1 are also repor-
ted.12c Such promising perspectives of 6-arylated-4-quinolones
inspired us to synthesize such entities via Suzuki cross coupling
of compounds 3. This method offered the opportunity to enrich
the library of 6-aryl substituted quinolone scaffolds.
Scheme 2 Synthesis of N-methylated derivatives 2 from compound 1.
Reaction conditions: compound 1 (1 mmol), NaH (0.036 mg, 1.5
mmol), MeI (0.284 g, 2 mmol) in DMF at 60 ꢀC. Stirring under N2
atmosphere, 4 h. Isolated yields after column chromatography.
antibacterial activity.9b Again, the uoro group at C-8 owes
better oral absorption of the drug.13 So, we considered different
substituents at the C-8 position that can be isosteres or
analogues and accordingly synthesized compounds (1a–1c) as
the starting materials (8-substituted-4-quinolones) for this
present work.
In the search for suitable conditions for the Suzuki coupling
reaction, we rst examined the coupling of phenylboronic acid
with 3d using different solvents and catalysts (common palla-
dium salts) in the presence of potassium carbonate. The results
are shown in Table 1. Notably, the combination of DMF as
solvent and K2CO3 (potassium carbonate) as base was best
suited for this coupling reaction in presence of our newly
developed Pd-NHC catalyst.18 The desired coupled product 4g
was formed within 5 minutes under microwave irradiation at
110 ꢀC. Suzuki cross-coupling reaction of compound 3 with
different aryl boronic acids under this optimized condition
furnished the corresponding cross-coupled products in excel-
lent yields (Scheme 4). Compounds 3a and 3b were successfully
coupled with phenylboronic acid and correspondingly
produced 4a and 4c in 90% and 87% yield. With 4-uo-
rophenylboronic acid they provided coupled products 4b and 4d
It is known that the protection of the N–H of compound 1
with alkyl group (preferable smaller alkyl groups like methyl,
ethyl and cyclopropyl) is essential to enhance drug potency and
efficiency.14 Therefore we have replaced the N–H of compound 1
with a methyl substituent. Synthetic procedures of N-alkylation
are well documented in literature.15 Aer screening of standard
techniques, use of NaH (sodium hydride) as base was found to
be best suited in our system. Hence, to carry out N-methylation,
compound 1 was treated with NaH in dry DMF (N,N-dimethyl
formamide) followed by the addition of methyliodide under
inert atmosphere at 60 ꢀC. The desired N-methylated product 2
was obtained in good yields (Scheme 2) without formation of
the possible side product (O-methylated). Presence of electron
donating or withdrawing group at C-8 position literally has no
signicant role in this reaction. Selective bromination followed
by the Suzuki coupling was studied next to access the struc-
turally diverse 4-quinolones.
Table 1 Standardization of Suzuki couplinga
Initially, we attempted the bromination of compound 2 with
NBS (N-bromosuccinimide) in chloroform at room temperature.
Here the rate of the reaction as well as the yield of desired
product was not satisfactory. Conducting the reaction at higher
temperature (50 ꢀC) which also resulted poor yield (yield < 50%)
of the desired compound even aer continuing the reaction up
to 24 hours. Finally, the treatment of compound 2 with bromine
Entry
Pd-catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
Pd(OAc)2
PdCl2
Pd(OAc)2
Pd2(dba)3
Pd-NHCc
Pd-NHCc
DMF
DMF
Toluene
DMF
DMF
73
NR
63
64
91
55
DMF + H2O (1 : 1)
a
Reaction conditions: compound 3d (310 mg, 1 mmol), phenylboronic
acid (146 mg, 1.2 mmol), K2CO3 (276 mg, 2 mmol), Pd-catalyst (19.2
mg, 2 mol%), 110 ꢀC (microwave). b Isolated yield aer purication.
Scheme 3 Synthesis of 6-bromo-4-quinolone derivatives. Reaction
conditions: 2 (1 mmol), bromine (1.2 equiv., 0.1 mL), AcOH (4 mL), stir rt
(8 h). Isolated yields after column chromatography.
c
Structure of Pd-NHC ¼
.
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heteroarylboronic acids on the reaction performance and
employed similar reaction conditions to couple thienyl and
pyridinyl boronic acid derivatives with 6-bromoquinolones 3.
The corresponding coupling products with the general struc-
ture 5 were achieved in high yields. Compound 3a coupled with
5-methyl thienylboronic acid and thienylboronic acid and fur-
nished compounds 5a and 5b in 84% and 80% yields respec-
tively. 6-Methoxy-3-pyridinylboronicacid also coupled to provide
5c and 5d in 83% and 81% yields respectively. Hence, our
reaction system was found compatible with variety of
substituted aryl and heteroarylboronic acids. A family of 6-aryl
and heteroaryl substituted quinolones have successfully been
synthesized utilizing the 6-bromoquinolones 3 (Scheme 5).
Conclusions
Scheme 4 Synthesis of 6-aryl-4-quinolones. Reaction conditions:
compound 3 (1 mmol), aryl boronic acid (1.2 mmol), K2CO3 (2 mmol),
Pd-NHC (0.0192 g, 2 mol%), dry DMF (3 mL), Microwave, 110 ꢀC, 5 min.
Isolated yields after column chromatography purification.
In summary, we have demonstrated a suitable synthetic
approach to obtain bromo and aryl substitution at 6-position of
4-quinolones. The bromo group may easily be substituted by
different functional groups using various common synthetic
reactions, thus opening opportunity to access variety of
substituted quinolones. For instance we employed these bro-
moquinolones to Suzuki cross coupling reaction and produced
a set of arylated quinolones. Both electron donating and with-
drawing groups are well tolerated to provide excellent yields.
Heterocyclic groups (thiophene and pyridine derivatives) were
also successfully coupled in high yields. The 6-bromo and 6-
arylated entities synthesized (3 / 5) are all new compounds
which are anticipated to be valuable components for drug
design. Exploring antimicrobial activities of these compounds
in future may also add to the current knowledge about their
structural activity relationships.
in 95% and 89% yields respectively. The compound 3c coupled
with 4-uoroboronic acid to afford 4e in 85% yield. The
compound 3d underwent smooth coupling with phenylboronic
acid and 3-methyl phenylboronic acid to yield the desired cross-
couple products in 91% and 95% respectively. Highly active, 4-
formyl phenylboronic acid was also successfully coupled with 3c
to furnish the cross-coupling product 4f in high yield (85%).
Hence, our potential catalytic system allowed the smooth
coupling of compound 3 with different aryl boronic acids under
optimized conditions. Substrates having both electron-
donating and withdrawing groups easily participated in the
reaction to afford the desired couple products within a short
time (5 minutes).
It is reported that the presence of heterocyclic ring substit-
uents in many quinolone derivatives attribute enhanced anti-
bacterial activity,13 increased activity in in vitro cytotoxicity and
tubulin based assays,19 and xanthine oxidase inhibition.20
Therefore, we further explored the inuence of
Experimental
General methods
Unless stated otherwise, all reagents such as aromatic anilines,
EMME, palladium acetate, boronic acids and solvents were used
as received from commercial suppliers. NMR spectra were
recorded on a 300 MHz spectrometer at 298 K with calibration
on the basis of the solvent residual peak. Mass spectra were
performed using an ion trap mode. Products were puried
using column chromatography on silica gel (60–120 mesh).
Ethyl acetate and petroleum ether (60–80 ꢀC) were used as
eluents. Progress of the reaction was monitored using silica gel
TLC.
Preparation of compound 1
A mixture of aniline (10 mmol), EMME (11 mmol) and toluene
(30 mL) was reuxed in a 250 mL round bottom ask for 5
hours. It was then cooled and washed with 3(N) 100 mL H2SO4.
Toluene was distilled out aerwards. The mixture was scratched
vigorously to get solid aniline product. This product (5g) was
reuxed with biphenyloxide (50 mL) for 2 hours at 280 ꢀC. It was
then cooled and stirred for an hour aer the addition of a small
Scheme 5 Suzuki cross coupling with heteroarylboronic acids forming
products 5. Reaction conditions: compound 3 (1 mmol), hetero-
arylboronic acid (1.2 mmol), K2CO3 (2 mmol), Pd-NHC (0.0192 g, 2 mol%),
DMF (3 mL), microwave, 110 ꢀC, 5 min. Isolated yields after column
chromatography purification.
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amount (100 mL) of petroleum ether. Crude compound 1 was
obtained by ltration on a Buchner funnel.
C
13H13NO4: C, 63.15; H, 5.30; N, 5.67, found C, 63.11; H, 5.34; N,
5.64.
Ethyl 1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (1c).
White solid, yield 70% (1.617 g); m.p. 249–251 ꢀC; 1H NMR
(300 MHz, DMSO-d6, 25 ꢀC, TMS): d ¼ 1.28 (t, J ¼ 7.2 Hz, 3H), 4.22
(q, J ¼ 7.2 Hz, 2H), 7.31 (t, J ¼ 7.8 Hz, 1H), 7.55 (d, J ¼ 6.9 Hz, 1H),
8.03 (d, J ¼ 7.8 Hz, 1H), 8.39 (s, 1H), 11.63 (s, 1H); 13C NMR
(75 MHz, DMSO-d6, 25 ꢀC, TMS): d ¼ 14.8, 17.4, 60.1, 110.1, 124.0,
124.8, 127.4, 127.9, 133.7, 137.9, 145.0, 165.2, 174.1; HRMS (EI+):
[M]+, found 231.0891. C13H13NO3 requires 231.0895.
Ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate (1d).21 White
solid, yield 50% (1.085 g); m.p. 251–253 ꢀC; 1H NMR (300 MHz,
DMSO-d6, 25 ꢀC, TMS): d ¼ 1.27 (t, J ¼ 7.2 Hz, 3H), 4.21 (q, J ¼
7.2 Hz, 2H), 7.41 (t, J ¼ 6.9 Hz, 1H), 7.68 (m, 2H), 8.16 (dd, J ¼
6.9 Hz, 0.9 Hz, 1H), 8.55 (s, 1H), 12.3 (s, 1H); 13C NMR (75 MHz,
DMSO-d6, 25 ꢀC, TMS): d ¼ 14.8, 60.0, 110.2, 119.2, 125.2, 126.1,
127.7, 132.4, 139.4, 145.4, 165.3, 173.9.
Preparation of N-methylated derivatives (2)
Compound 1 (1 mmol) and DMF (5 mL) were placed in a round
bottom ask tted with a guard tube. NaH (36 mg, 1.5 mmol)
was added and the reaction mixture was stirred at room
temperature until H2 gas ceased to evolve. Methyliodide (284
mg, 2 mmol) was then introduced drop-wise into the reaction
mixture and it was further stirred at 60 ꢀC for 4 hours. The
mixture was diluted with water and the product was extracted
with DCM (3 ꢁ 20 mL). The organic layer was dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The
crude product was then puried using column
chromatography.
Ethyl 8-uoro 1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxy-
Preparation of bromo derivatives (3)
1
ꢀ
late (2a). White solid, yield 76% (0.189 g); m.p. 121–124 C; H
NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.40 (t, J ¼ 7.2 Hz, 3H),
4.10 (d, J ¼ 8.1 Hz, 3H), 4.38 (q, J ¼ 7.2 Hz, 2H), 7.37 (m, 2H), 8.31
(m, 1H), 8.36 (s, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼
14.33, 46.1, 46.3, 61.1, 109.5, 120.3, 120.6, 122.47, 122.51, 126.3,
126.4, 129.2, 129.3, 130.4, 150.8, 152.5, 154.2, 165.1, 173.3; MS
(ESI+) m/z 271.95 [M + Na]+, elemental analysis calcd (%) for
C13H12FNO3: C, 62.65; H, 4.85; N, 5.62, found C, 62.51; H, 4.88; N,
5.64.
The N-Methylated product (compound 2) was dissolved in a
minimum amount of acetic acid and an equivalent quantity of
bromine was added drop-wise. The resulting mixture was stir-
red at room temperature for 8 hours. Then it was poured into
water and the organic layer was extracted with DCM and
concentrated under reduced pressure. The crude material was
further puried using column chromatography.
Preparation of 6-arylated derivatives (4 and 5)
Ethyl
1,4-dihydro-8-methoxy-1-methyl-4-oxoquinoline-3-
carboxylate (2b). Light brown solid, yield 75% (0.196 g); m.p.
113–116 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.23 (t,
J ¼ 7.2 Hz, 3H), 3.75 (s, 3H), 3.98 (s, 3H), 4.20 (q, J ¼ 7.2 Hz, 2H),
6.96 (d, J ¼ 7.8 Hz, 1H), 7.14 (m, 1H), 7.96 (d, J ¼ 8.1 Hz, 1H),
Compound 3 (1 mmol), aryl boronic acid (1.2 mmol), K2CO3
(276 mg, 2 mmol), Pd-NHC (0.0096 g, 1 mol %) and DMF (2 mL)
were p[laced in a microwave reaction vessel. The mixture was
ꢀ
placed in the focused microwave reactor and heated at 110 C
13
ꢀ
8.16 (s, 1H); C NMR (75 MHz, CDCl3, 25 C, TMS): d ¼ 14.8,
47.6, 57.2, 60.1, 109.6, 115.9, 118.6, 125.9, 131.0, 131.1, 151.1,
152.4, 165.0, 172.5; MS (ESI+) m/z 284.31 [M + Na]+, elemental
analysis calcd (%) for C14H15NO4: C, 64.36; H, 5.79; N, 5.36,
found C, 64.40; H, 5.75; N, 5.39.
for 5 minutes. Then the solution was diluted with water and
extracted with DCM (3 ꢁ 10 mL). The combined organic layer
was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude residue was puried by silica gel
column chromatography.
Ethyl 1,4-dihydro-1,8-dimethyl-4-oxoquinoline-3-carboxylate
1
ꢀ
(2c). White solid, yield 70% (0.171 g); m.p. 91–93 C; H NMR
(300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.41 (t, J ¼ 7.2 Hz, 3H), 2.80
Spectral analysis
Ethyl 8-uoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1a). (s, 3H), 4.11 (s, 3H), 4.38 (q, J ¼ 7.2 Hz, 2H), 7.29 (m, 1H), 7.43
White solid, yield 52% (1.220 g); m.p. 217–219 ꢀC; 1H NMR (300 (m, 1H), 8.37 (s, 1H), 8.42 (d, J ¼ 8.1 Hz, 1H); 13C NMR (75 MHz,
MHz, DMSO-d6, 25 ꢀC, TMS): d ¼ 1.28 (t, J ¼ 6.9 Hz, 3H), 4.22 (q, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 24.2, 47.0, 60.9, 110.2, 125.3,
J ¼ 6.9 Hz, 2H), 7.40 (m, 1H), 7.65 (t, J ¼ 9 Hz, 1H), 7.96 (d, J ¼ 126.38, 126.43, 130.7, 137.4, 140.4, 152.5, 165.8, 174.2; MS (ESI+)
7.8 Hz, 1H), 8.39 (s, 1H), 12.5 (bs, 1H); 13C NMR (75 MHz, m/z 268.32 [M + Na]+, elemental analysis calcd (%) for
DMSO-d6, 25 ꢀC, TMS): d ¼ 14.2, 59.8, 110.5, 117.17, 117.4,
C14H15NO3: C, 68.56; H, 6.16; N, 5.71, found C, 68.40; H, 6.05; N,
121.3, 121.3, 124.5, 124.6, 128.1, 128.3, 129.1, 144.7, 150.1, 5.74.
153.4, 164.4, 172.5; HRMS (EI+): [M]+, found 235.0634.
12H10FNO3 requires 235.0645.
Ethyl
1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylate
C
(2d).21 Brown solid, yield 78% (0.180 g); m.p.102–105 ꢀC; 1H
Ethyl 1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.44 (t, J ¼ 7.2 Hz, 3H),
1
(1b). Greyish white, yield 55% (1.358 g); m.p. 243–245 ꢀC; H 4.00 (s, 3H), 4.43 (q, J ¼ 7.2 Hz, 2H), 7.53 (m, 2H), 7.78 (m, 1H),
NMR (300 MHz, DMSO-d6, 25 ꢀC, TMS): d ¼ 1.26 (t, J ¼ 7.2 Hz, 8.55 (m, 1H), 8.80 (s, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC,
3H), 3.99 (s, 3H), 4.20 (q, J ¼ 7.2 Hz, 2H), 7.29–7.37 (m, 2H), 7.70 TMS): d ¼ 14.4, 41.4, 60.8, 110.7, 115.7, 125.2, 127.7, 128.8,
(dd, J ¼ 7.2 Hz, 1.2 Hz, 1H), 8.34 (s, 1H), 11.9 (s, 1H); 13C NMR 132.7, 139.7, 149.7, 165.6, 174.4.
(75 MHz, DMSO-d6, 25 ꢀC, TMS): d ¼ 14.8, 56.8, 60.1, 110.4,
Ethyl
6-bromo-8-uoro-1,4-dihydro-1-methyl-4-oxoquino-
117.3, 125.1, 128.6, 129.8, 144.3, 144.7, 149.2, 165.1, 173.7; MS line-3-carboxylate (3a). White solid, yield 70% (0.229 g); m.p.
(ESI+) m/z 270.31[M + Na]+, elemental analysis calcd (%) for 150–153 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.27 (t,
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J ¼ 7.2 Hz, 3H), 4.02 (d, J ¼ 8.7 Hz, 3H), 4.20 (q, J ¼ 7.2 Hz, 2H),
7.91 (dd, J ¼ 13.5 Hz, 2.4 Hz, 1H), 8.03 (d, J ¼ 1.2 Hz, 1H), 8.52 (s,
1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.7, 45.6, 60.4,
110.4, 117.2, 117.4, 122.7, 123.2, 124.9, 125.1, 129.1, 129.2,
131.9, 151.1, 152.3, 152.6, 154.5, 164.4, 170.5; HRMS (ESI-TOF)
Ethyl 1,4-dihydro-8-methoxy-1-methyl-4-oxo-6-phenylquino-
line-3-carboxylate (4c). White solid, yield 87% (0.293 g); m.p.
182–185 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.38 (t,
J ¼ 7.2 Hz, 3H), 3.78 (s, 3H), 4.05 (s, 3H), 4.35 (q, J ¼ 7.2 Hz, 2H),
7.21 (d, J ¼ 1.8 Hz, 1H), 7.39 (m, 3H), 7.62 (d, J ¼ 7.2 Hz, 2H),
8.17 (s, 1H) 8.31 (d, J ¼ 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d
14.4, 47.8, 56.4, 60.7, 109.9, 112.9, 116.9, 126.9, 127.9, 128.9,
129.9, 131.3, 137.9, 139.2, 150.8, 151.5, 165.5, 173.5; MS (ESI+):
m/z 337.95 [M]+, elemental analysis calcd (%) for C20H19NO4: C,
71.20; H, 5.68; N, 4.15, found C, 71.13; H, 5.60; N, 4.16.
Ethyl-6-(4-uorophenyl)-1,4-dihydro-8-methoxy-1-methyl-4-
oxoquinoline-3-carboxylate (4d). White solid, yield 89% (0.316
g); m.p. 178–180 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼
1.44 (t, J ¼ 7.2 Hz, 3H), 4.03 (s, 3H), 4.22 (s, 3H), 4.42 (q, J ¼ 7.2
Hz, 2H), 7.17 (m, 2H), 7.32 (d, J ¼ 2.1 Hz, 1H), 7.65 (m, 2H), 8.35
(d, J ¼ 2.1 Hz, 1H), 8.40 (s, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC,
TMS): d ¼ 14.4, 47.9, 56.5, 60.9, 110.2, 113.1, 115.7, 116.0, 117.3,
128.7, 128.8, 130.0, 131.6, 135.56, 135.60, 137.4, 150.9, 151.7,
161.2, 164.4, 165.8, 173.6; MS(ESI+): m/z 355.89 [M]+, elemental
analysis calcd (%) for C20H18FNO4: C, 67.60; H, 5.11; N, 3.94,
found C, 67.49; H, 5.01; N, 3.98.
m/z: [M
327.9985.
+
H]+, found 327.9902. C13H12BrFNO3 requires
Ethyl 6-bromo-1,4-dihydro-8-methoxy-1-methyl-4-oxoquino-
line-3-carboxylate (3b). Yellowish white solid, yield 65% (0.221
g); m.p. 155–157 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼
1.40 (t, J ¼ 7.2 Hz, 3H), 3.93 (s, 3H), 4.17 (s, 3H), 4.38 (q, J ¼ 7.2
Hz, 2H), 7.18 (d, J ¼ 2.1 Hz, 1H), 8.20 (d, J ¼ 2.1 Hz, 1H), 8.43 (s,
1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.5, 48.3, 56.8,
61.3, 110.1, 117.7, 119.6, 122.0, 130.0, 131.7, 151.2, 152.1, 165.6,
172.1; HRMS (ESI-TOF) m/z: [M + H]+, found 340.0119.
C
14H15BrNO4 requires 340.0184.
Ethyl 6-bromo-1,4-dihydro-1,8-dimethyl-4-oxoquinoline-3-
carboxylate (3c). Yellowish white solid, yield 72% (0.232 g); m.p.
205–208 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.40 (t,
J ¼ 7.2 Hz, 3H), 2.76 (s, 3H), 4.09 (s, 3H), 4.37 (q, J ¼ 7.2 Hz, 2H),
7.49 (d, J ¼ 2.4 Hz, 1H), 8.30 (s, 1H), 8.43 (d, J ¼ 2.4 Hz, 1H); 13
C
ꢀ
NMR (75 MHz, CDCl3, 25 C, TMS): d ¼ 14.4, 23.9, 47.1, 61.0,
110.4, 119.0, 128.5, 129.1, 131.7, 139.2, 139.6, 152.4, 165.1,
172.7; HRMS (ESI-TOF) m/z: [M + H]+, found 324.0129.
Ethyl-6-(4-uorophenyl)-1,4-dihydro-1,8-dimethyl-4-oxoqui-
noline-3-carboxylate (4e). Light yellow solid, yield 85% (0.288 g);
1
ꢀ
ꢀ
m.p. 217–220 C; H NMR (300 MHz, CDCl3, 25 C, TMS): d ¼
1.41 (t, J ¼ 7.2 Hz, 3H), 2.83 (s, 3H), 4.11 (s, 3H), 4.38 (q, J ¼ 7.2
Hz, 2H), 7.13 (t, J ¼ 8.7 Hz, 2H), 7.60 (m, 3H), 8.34 (s, 1H), 8.56
(d, J ¼ 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼
14.4, 24.3, 47.0, 60.9, 110.1, 115.7, 116.0, 123.6, 127.3, 128.5,
128.6, 130.9, 135.0, 135.8, 136.5, 139.4, 152.2, 161.1, 164.4,
165.5, 174.2; MS(ESI+): m/z 361.92 [M + Na]+, elemental analysis
calcd (%) for C20H18FNO3: C, 70.78; H, 5.35; N, 4.13, found C,
70.75; H, 5.08; N, 4.11.
C
14H15BrNO3 requires 324.0235.
Ethyl 6-bromo-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxy-
late (3d). White solid, yield 75% (0.232 g); m.p. 108–111 ꢀC; 1H
NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.39 (t, J ¼ 7.2 Hz, 3H),
3.85 (s, 3H), 4.36 (q, J ¼ 7.2 Hz, 2H), 7.28 (d, J ¼ 2.1 Hz, 1H), 7.70
(dd, J ¼ 9.0 Hz, 2.4 Hz, 1H), 8.36 (s, 1H), 8.49 (d, J ¼ 2.4 Hz, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 41.5, 60.9,
111.0, 117.7, 119.2, 129.9, 130.1, 135.6, 138.4, 149.7, 165.0,
172.9; MS (ESI+) m/z 332.05 ([M + Na]+, 79Br), 334.04 ([M + Na]+,
81Br), elemental analysis calcd (%) for C13H12BrNO3: C, 50.34; H,
3.90; N, 4.52, found C, 50.31; H, 3.94; N, 4.48.
Ethyl 6-(4-formylphenyl)-1,4-dihydro-1,8-dimethyl-4-oxoqui-
noline-3-carboxylate (4f). White solid, yield 85% (0.296 g); m.p.
230–233 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.39 (t,
J ¼ 7.2 Hz, 3H), 2.87 (s, 3H), 4.14 (s, 3H), 4.38 (q, J ¼ 7.2 Hz, 2H),
7.70 (s, 1H), 7.80 (d, J ¼ 8.1 Hz, 2H), 7.95 (d, J ¼ 8.1 Hz, 2H), 8.38
(s, 1H), 8.68 (s, 1H), 10.04 (s, 1H); 13C NMR (75 MHz, CDCl3,
25 ꢀC, TMS): d ¼ 14.4, 24.4, 47.0, 61.0, 110.6, 124.7, 127.5, 130.4,
131.0, 135.5, 135.9, 136.0, 140.3, 144.8, 152.5, 165.5, 174.1,
191.8; MS(ESI+) m/z 372.23 [M + Na]+, elemental analysis calcd
(%) for C21H19NO4: C, 72.19; H, 5.48; N, 4.01, found C, 72.11; H,
5.40; N, 3.98.
Ethyl
8-uoro-1,4-dihydro-1-methyl-4-oxo-6-phenylquino-
line-3-carboxylate (4a). Light brown solid, yield 90% (0.292 g);
1
ꢀ
ꢀ
m.p. 168–170 C; H NMR (300 MHz, CDCl3, 25 C, TMS): d ¼
1.43 (t, J ¼ 7.2 Hz, 3H), 4.14 (d, J ¼ 8.1 Hz, 3H), 4.41 (q, J ¼ 7.2
Hz, 2H), 7.47 (m, 3H), 7.67 (m, 3H), 8.40 (s, 1H), 8.59 (d, J ¼ 2.4
Hz, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 45.9,
46.1, 61.2, 110.8, 118.0, 118.3, 121.2, 127.0, 128.5, 129.2, 129.3,
131.7, 138.0, 138.7, 138.8, 151.0, 151.5, 165.6, 166.5, 173.0; MS
(ESI+) m/z 347.91 [M + Na]+, C19H16FNO3, elemental analysis
calcd (%) for C19H16FNO3: C, 70.14; H, 4.96; N, 4.31, found C,
70.07; H, 5.01; N, 4.33.
Ethyl 1,4-dihydro-1-methyl-4-oxo-6-phenylquinoline-3-carboxy-
1
late (4g). White solid, yield 91% (0.279 g); m.p. 137–140 ꢀC; H
NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.31 (t, J ¼ 7.2 Hz, 3H),
3.77 (s, 3H), 4.27 (q, J ¼ 7.2 Hz, 2H), 7.35 (m, 4H), 7.55 (m, 2H),
7.76 (dd, J ¼ 8.7 Hz, 2.1 Hz, 1H), 8.29 (s, 1H), 8.58 (d, J ¼ 2.1 Hz,
1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 13.3, 40.4, 59.8,
109.4, 115.4, 124.0, 125.9, 126.8, 127.6, 127.9, 130.4, 136.8,
137.7, 137.9, 148.3, 164.4, 173.3; MS (ESI+): m/z 329.94 [M +
Na]+, elemental analysis calcd (%) for C19H17NO3: C, 74.25; H,
5.58; N, 4.56, found C, 74.21; H, 5.62; N, 4.60.
Ethyl 8-uoro-6-(4-uorophenyl)-1,4-dihydro-1-methyl-4-
oxoquinoline-3-carboxylate (4b). White solid, yield 95% (0.326
1
ꢀ
ꢀ
g); m.p. 184–187 C; H NMR (300 MHz, CDCl3, 25 C, TMS):
d ¼ 1.41 (t, J ¼ 7.2 Hz, 3H), 4.10 (d, J ¼ 8.1 Hz, 3H), 4.39 (q, J ¼
7.2 Hz, 2H), 7.15 (m, 2H), 7.58 (m, 3H), 8.33 (s, 1H), 8.48 (d, J ¼
13
ꢀ
1.5 Hz 1H); C NMR (75 MHz, CDCl3, 25 C, TMS): d ¼ 14.5,
46.0, 46.2, 61.2, 111.0, 116.0, 116.3, 116.5, 117.8, 118.1, 121.0,
128.1, 128.2, 128.7, 128.8, 129.0, 131.8, 134.2, 137.7, 137.8,
151.0, 151.6, 154.3, 161.5, 164.8, 165.5, 166.4, 172.9; HRMS
(ESI+): [M + Na]+, found 366.0868. C19H15F2NO3Na requires
366.0918.
Ethyl 1, 4-dihydro-1-methyl-4-oxo-6-m-tolylquinoline-3-
carboxylate (4h). Light yellow solid, yield 95% (0.305 g); m.p.
98–101 ꢀC; 1H NMR (300 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 1.41 (t,
6258 | RSC Adv., 2014, 4, 6254–6260
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J ¼ 7.2 Hz, 3H), 2.44 (s, 3H), 3.97 (s, 3H), 4.42 (q, J ¼ 7.2 Hz, 2H), North Bengal, for his valuable suggestion during manuscript
7.21 (d, J ¼ 7.5 Hz, 1H), 7.36 (t, J ¼ 7.8 Hz, 1H), 7.51 (m, 3H), 7.97 preparation.
(dd, J ¼ 8.7 Hz, 2.1 Hz, 1H), 8.61 (s, 1H), 8.75 (d, J ¼ 2.4 Hz, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 21.6, 41.6, 61.0,
Notes and references
110.5, 116.5, 125.1, 125.4, 127.8, 128.0, 128.7, 138.3, 138.7,
138.8, 139.0, 149.4, 149.7, 165.8, 174.3; HRMS (EI+): [M]+, found
321.1366. C20H19NO3 requires 321.1365.
1 G. Lesher, E. Froelich, M. Gruett, J. Bailey and R. Brundage,
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Ethyl 8-uoro-1, 4-dihydro-1-methyl-6-(5-methylthiophen-2-
yl)-4-oxoquinolone-3-carboxylate (5a). Light yellow solid, yield
84% (0.290 g); m.p. 158–161 ꢀC; 1H NMR (300 MHz, CDCl3,
25 C, TMS): d ¼ 1.37 (t, J ¼ 6.9 Hz, 3H), 2.49 (s, 3H), 4.03 (m,
2 (a) O. M. Cociorva, B. Li, T. Nomanbhoy, Q. Li, A. Nakamura,
K. Nakamura, M. Nomura, K. Okada, S. Seto, K. Yumoto,
M. Liyanage, M. C. Zhang, A. Aban, B. Leen,
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C. Mugnaini, A. Brizzi, N. P. Caradonna, M. G. Cascio,
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2756–2766.
3 Y. M. Al-Hiari, I. S. Al-Mazari, A. K. Shakya, R. M. Darwish
and R. Abu-Dahab, Molecules, 2007, 12, 1240–1258.
4 (a) V. Cecchetti, C. Parolin, S. Moro, T. Pecere, E. Filipponi,
A. Calistri, O. Tabarrini, B. Gatto, M. Palumbo, A. Fravolini
and G. Palu, J. Med. Chem., 2000, 43, 3799–3802; (b)
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J. Med. Chem., 2004, 47, 6584–6594; (c) B. A. Lucero,
C. R. B. Gomes, I. C. P. P. Frugulhetti, L. V. Faro,
L. Alvarenga, M. C. B. V. de-Souza, T. M. L. de-Souza and
V. F. Ferreiraa, Bioorg. Med. Chem. Lett., 2006, 16, 1010–1013.
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D. E. Kyle and R. Manetsch, J. Med. Chem., 2010, 53, 7076–
7094.
ꢀ
3H), 4.36 (q, J ¼ 6.9 Hz, 2H), 6.72 (m, 1H), 7.16 (d, J ¼ 3.6 Hz,
1H), 7.44 (dd, J ¼ 15 Hz, 2.4 Hz, 1H), 8.23 (s, 1H), 8.36 (m, 1H);
13C NMR (75 MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 15.5, 45.9, 46.1,
61.1, 110.6, 116.2, 116.6, 119.0, 124.7, 126.7, 127.54, 127.6,
131.6, 132.6, 132.7, 138.9, 141.6, 150.9, 151.2, 154.2, 165.6,
172.7; HRMS (EI+): [M]+, found 345.0832. C18H16FNO3S requires
345.0835.
Ethyl 8-uoro-1,4-dihydro-1-methyl-4-oxo-6-(thiophen-2-yl)-
quinolone-3-carboxylate (5b). Light yellow solid, yield 80%
1
ꢀ
ꢀ
(0.265 g); m.p. 185–188 C; H NMR (300 MHz, CDCl3, 25 C,
TMS): d ¼ 1.42 (t, J ¼ 7.2 Hz, 3H), 4.10 (d, J ¼ 8.1 Hz, 3H), 4.40 (q,
J ¼ 7.20 Hz, 2H), 7.10–7.13 (m, 1H), 7.36 (dd, J ¼ 5.1 Hz, 0.9 Hz,
1H), 7.44 (dd, J ¼ 3.6 Hz, 1.2 Hz, 1H), 7.61 (dd, J ¼ 15 Hz, 2.1 Hz,
1H), 8.34 (s, 1H), 8.54 (m, 1H); 13C NMR (75 MHz, CDCl3, 25 ꢀC,
TMS): d ¼ 14.4, 45.9, 46.1, 61.1, 110.8, 116.6, 116.9, 119.6, 119.7,
124.7, 126.5, 128.0, 128.5, 131.8, 132.2, 132.3, 141.4, 150.9,
151.3, 154.2, 165.5, 172.7; HRMS (EI+): [M]+, found 331.0676.
C
17H14FNO3S requires 331.0678.
Ethyl 1,4-dihydro-8-methoxy-6-(6-methoxypyridin-3-yl)-1-
methyl-4-oxoquinoline-3-carboxylate (5c). White solid, yield
83% (0.305 g); m.p. 181–184 ꢀC; 1H NMR (300 MHz, CDCl3,
25 ꢀC, TMS): d ¼ 1.42 (t, J ¼ 7.2 Hz, 3H), 4.00 (s, 6H), 4.18 (s, 3H),
4.40 (q, J ¼ 7.2 Hz, 2H), 6.85 (d, J ¼ 8.4 Hz, 1H), 7.27 (s, 1H), 7.90
(dd, J ¼ 5.4, 2.1 Hz, 1H), 8.31 (m, 2H), 8.46 (s, 1H); 13C NMR (75
MHz, CDCl3, 25 ꢀC, TMS): d ¼ 14.4, 47.9, 53.8, 56.5, 60.9, 110.3,
111.1, 112.5, 117.0, 128.5, 130.1, 131.8, 135.1, 137.5, 144.9,
151.0, 151.7, 163.9, 165.8, 173.6; MS (ESI+): m/z 391.20 [M +
Na]+, elemental analysis calcd (%) for C20H20N2O5: C, 65.21; H,
5.47; N, 7.60, found C, 65.23; H, 5.45; N, 7.62.
6 (a) M. Hadjeri, E.-L. Peiller, C. Beney, N. Deka, M. A. Lawson,
C. Dumontet and A. Boumendjel, J. Med. Chem., 2004, 47,
4964–4970; (b) S. Nakamura, M. Kozuka, K. F. Bastow,
H. Tokuda, H. Nishino, M. Suzuki, J. Tatsuzaki,
S. M. Natschke, S.-C. Kuo and K.-H. Lee, Bioorg. Med.
Chem., 2005, 13, 4396–4401.
Ethyl 1,4-dihydro-6-(6-methoxypyridin-3-yl)-1-methyl-4-oxo-
quinoline-3-carboxylate (5d). White solid, yield 81% (0.274 g);
7 (a) Y. Xia, Z.-Y. Yang, P. Xia, K. Bastow, Y. Nakanishi,
P. Nampoothiri, E. Hamel, A. Brossia and K.-H. Lee, Bioorg.
Med. Chem. Lett., 2003, 13, 2891–2893; (b) Y. Xia,
Z.-Y. Yang, P. Xia, T. Hackl, E. Hamel, A. Mauger, J.-H. Wu
and K.-H. Lee, J. Med. Chem., 2001, 44, 3932–3936.
8 M. Sato, T. Motomura, H. Aramaki, T. Matsuda,
M. Yamashita, Y. Ito, H. Kawakami, Y. Matsuzaki,
W. Watanabe, K. Yamataka, S. Ikeda, E. Kodama,
M. Matsuoka and H. Shinkai, J. Med. Chem., 2006, 49,
1506–1508.
1
ꢀ
ꢀ
m.p. 169–171 C; H NMR (300 MHz, CDCl3, 25 C, TMS): d ¼
1.40 (t, J ¼ 7.2 Hz, 3H), 3.88 (s, 3H), 3.99 (s, 3H), 4.37 (q, J ¼ 7.2
Hz, 2H), 6.82 (d, J ¼ 8.7 Hz, 1H), 7.46 (d, J ¼ 8.7 Hz, 1H), 7.82 (m,
2H), 8.39 (d, J ¼ 10.8 Hz, 2H), 8.56 (d, J ¼ 1.5 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) d: 14.4, 41.4, 53.7, 60.8, 110.7, 116.7, 124.6,
128.1, 129.0, 130.6, 134.6, 138.7, 145.0, 149.9, 163.9, 165.4,
174.2; MS (ESI+): m/z 361.24 [M + Na]+, elemental analysis calcd
(%) for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28, found C, 67.48; H,
5.32; N, 8.22.
9 (a) J. Blondeau, Antimicrob. Agents Chemother., 1999, 43, 1–
11; (b) S. Emami, A. Shaee and A. Foroumadi, Iran.
J. Pharm. Res., 2005, 3, 123–136.
Acknowledgements
We thank the DST, New Delhi for nancial support (SR/FT/CS- 10 (a) R. Gould and W. Jacobs, J. Am. Chem. Soc., 1939, 61, 2890–
017/2010). S. G. and P. G. are grateful to UGC for the award of
fellowship. We also acknowledge Prof. B. Basu, University of
2895; (b) D. Zewge, C.-Y. Chen, C. Deer, P. G. Dormer and
D. L. Hughes, J. Org. Chem., 2007, 72, 4276–4279; (c)
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6260 | RSC Adv., 2014, 4, 6254–6260
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