Copper-Catalyzed Synthesis of Substituted 4-Quinolones using Water as a Benign Reaction Media: Application for the Construction of Oxolinic Acid and BQCA

Article abstract of DOI:10.1002/adsc.201900286

A copper-catalyzed three-component synthetic method has been developed for the synthesis of substituted 4-quinolone derivatives from substituted 3-(2-halophenyl)-3-oxopropane, aldehydes and aq. NH₃ using water as an environmentally benign reaction media. Moreover, the synthetic utility of the obtained products has been successfully applied for the synthesis of available oxolinic acid and BQCA drugs. The key features of this approach include commercially available starting materials, broad scope, and moderate to good reaction yields. Reaction with formaldehyde, and other functionalities such as ?CN, ?NO₂, ?SO₂Ar, and ?COAr were also successful. In addition, reaction with heterocyclic compounds such as 3-(3-bromothiophen-2-yl)-3-oxopropanenitrile proceeded smoothly to afford tetrahydrothieno[3,2-b]pyridine-6-carbonitrile analogues. The practicality of the designed protocol was confirmed by gram scale synthesis of two derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201900286

Title: Copper-Catalyzed Synthesis of Substituted 4-Quinolones
using Water as a Benign Reaction Media: Application for the
Construction of Oxolinic Acid and BQCA
Authors: Babasaheb Sopan Gore, Chein Chung Lee, Jessica Lee, and
Jeh-Jeng Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900286
Link to VoR: http://dx.doi.org/10.1002/adsc.201900286

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Synthesis of Substituted 4-Quinolones using
Water as a Benign Reaction Media: Application for the
Construction of Oxolinic Acid and BQCA
Babasaheb Sopan Gore,[a] Chein Chung Lee,[a] Jessica Lee,[a] and Jeh-Jeng Wang*[a,b]
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd, Sanmin
district, Kaohsiung City, 807 (Taiwan). Tel: (886)-7-3121101, Fax: (886)-7-3125339, email: jjwang@kmu.edu.tw
b
Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Rd, Sanmin District,
Kaohsiung City, 807 (Taiwan).
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A copper-catalyzed three-component synthetic Reaction with formaldehyde, and other functionalities such
method has been developed for the synthesis of substituted as CN, -NO2, -SO2Ar, and -COAr were also successful. In
4-quinolone derivatives from substituted 3-(2-halophenyl)-3- addition, reaction with heterocyclic compounds such as 3-
oxopropane, aldehydes and aq. NH3 using water as an (3-bromothiophen-2-yl)-3-oxopropanenitrile
proceeded
environmentally benign reaction media. Moreover, the smoothly to afford tetrahydrothieno[3,2-b]pyridine-6-
synthetic utility of the obtained products has been carbonitrile analogues. The practicality of the designed
successfully applied for the synthesis of available oxolinic protocol was confirmed by gram scale synthesis of two
acid and BQCA drugs. The key features of this approach derivatives.
include commercially available starting materials, broad Keywords: Water; formaldehyde; oxolinic acid; BQCA.
scope, and moderate to good reaction yields.
oxidase, cathepsin inhibitory[9] and anti-HIV
activities.[10] In 1899, Camp et al, developed an
Introduction
elegant method for the base-promoted cyclization of
Quinolone and its derivatives are important structural
motifs due to their widespread occurrence in a variety
of natural products,[1] commercially-available
drugs,[2] and biological and medicinal fields.[3] In
particular, the acid functionality at the C3 position of
quinolones such as oxolinic acid, ciprofloxacin,
besifloxacin, ozenoxacin, norfloxacin, BQCA,
Ivacftor[4] can allow these derivatives to act as
potential drug candidates[5] (Figure 1). In addition,
these compounds exhibit are also used as
antimitotic,[6] antiviral,[7] antimalarial,[8] xanthine
N-(o-ketoarylamides), which further evolved into
Camps cyclization.[11] Due to the limited access of o-
ketoamides as well as the required strong base, the
synthetic utility of this method is limited. However, a
well-known classical method for the synthesis of
quinolone involves the condensation of aniline with
Meldrum’s acid[12] in the presence of trimethyl
orthoformate to generate the enamine intermediate
followed by heating at higher temperature (300 °C)
under microwave irradiation. This transformation
suffers from harsh reaction conditions and a narrow
substrate scope. Therefore, several researchers have
recently devoted significant efforts towards the
synthesis of quinolone derivatives. For example, Faul
and coworkers (2008) developed a two-step [Pd]-
catalyzed amidation followed by a base-promoted
cyclization to afford 4-quinolone analogues (Scheme
1a).[13a] In addition, Xu et al, (2010) reported a Pd(0)-
catalyzed intermolecular reaction between o-haloaryl
acetylenic ketones and primary amines to synthesize
4-quinolone derivatives, Zhu and coworkers (2016)
synthesized
sulfone
containing
4-quinolones
analogous via a metal-free pathway. Recently, Li et al
(2018) reported the aminoacylation of ynones with
amides to construct the 2-substituted-3-aroylquinolin-
4(1H)-one scaffolds (Scheme 1b).[13b,d,e] Helaja et al
(2014) developed the gold-catalyzed cyclization of
Figure 1. Representative Popular Drugs Containing
Quinolone Scaffolds
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
alkyl- or aryl-substituted 1-(o-aminophenyl)-2-
propyn-1-ones to various 2-substituted 4- quinolones
(Scheme 1b).[13c] Similarly, Larhed et al (2015) and
Lee et al (2018) independently established the ortho-
functionalization of anilines with alkynes or alkenes
and Aza-Michael addition alternative approaches to
Additives
(Y mmol)
Catalyst
Base (Z Yield
Entry
(X mmol)
equiv)
(%)[b]
K2CO3
(2.0)
1
2
CuI (20)
-
22
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(1.0)
K2CO3
(3.0)
K2CO3
(4.0)
K2CO3
(2.0)
K2CO3
(2.0)
CuCl (20)
-
29
33
13
20
38
73
76
65
84
87
81
70
75
52
49
68
82
79
43
CuBr
(20)
Cu(OAc)2
(20)
Cu(OTf)2
(20)
CuCl2
(20)
CuCl2
(20)
CuCl2
(20)
CuCl2
(20)
CuCl2
(10)
3
-
4
-
5
-
6
-
7
L-Proline (20)
L-Proline (10)
L-Proline (5)
L-Proline (10)
8
9
10
11
12
13
14
15
16[c]
17[d]
18[e]
19
20
CuCl2 (5) L-Proline (10)
CuCl2
L-Proline (10)
(2.5)
Scheme 1. Previous and current approaches
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Prolinol (10)
afford 4-quinolones (Scheme 1c).[13f,g] Long and
coworkers (2015) developed a transition metal-free
intramolecular oxidative C(sp3)-H/C(sp3)-H protocol
to synthesize 2-aryl-4-quinolones (Scheme 1d).[13h]
Xu et al (1991) (Scheme 1e)[13i] developed a
carbonylative coupling of o-iodoaniline with terminal
acetylene and carbon monoxide in presence of a
palladium catalyst, and Lei et al (2017) developed an
elegant method for the synthesis of 4-quinolone
derivatives that overcame the previously reported
protocol (aryl halogen substituted compounds) via
[Pd]-catalyzed carbonylation with amines-, ketones
and CO in a one-pot strategy (Scheme 1e).[13j] Xu et
al (2017) reported Cu(I)/TfOH- catalyzed cyclization
of anilines with electron deficient alkynes to afford
quinolones (Scheme 1f).[13k] Although, several fruitful
synthetic routes exist in the literature for the synthesis
of quinolone and its analogues,[14] the development of
an alternative and eco-friendly strategy remains a
fundamental area of research. Moreover, to the best
of our knowledge, no reports of preparation of 3-
cyano quinolones exist in the literature except for the
K2CO3
(2.0)
K2CO3
(2.0)
K2CO3
(2.0)
CuCl2 (5) Piperidine (10)
2-
K2CO3
(2.0)
21
22
CuCl2 (5)
pyrrolidinone
(10)
47
75
Cs2CO3
(2.0)
CuCl2 (5) L-Proline (10)
CuCl2 (5) L-Proline (10)
Na2CO3
(2.0)
23
24
65
19
40
CuCl2 (5) L-Proline (10) DBU (2)
K2CO3
CuCl2 (5) L-Proline (10)
(2.0)
25[f]
K2CO3
CuCl2 (5) L-Proline (10)
(2.0)
K2CO3
CuCl2 (5) L-Proline (10)
(2.0)
26[g]
27[h]
55
41
Results and Discussion
Table 1. Optimization of the reaction conditions[a]
K2CO3
CuCl2 (5) L-Proline (10)
(2.0)
28[i]
29
trace
-
CuCl2 (5) L-Proline (10)
-
K2CO3
(2.0)
30
-
L-Proline (10)
<9
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
[a]
Reaction Conditions: 1a (0.2 mmol), 2a (1.2 equiv), aq.
use of various nitrogen source such as from aq.NH3
to ammonium formate and ammonium acetate did not
improve the reaction yield of 4aa (Table 1, entries
25-26). In the absence of water, the reaction yield
decreased to 41% (Table 1, entry 27) and when the
reaction was performed at room temperature, a trace
amount of product was observed (Table 1, entry 28).
In the absence of base (Table 1, entry 29) and catalyst
(Table 1, entry 30), the reaction yielded a trace
amount of product or no product. Therefore, among
the screened parameters in Table 1, entry 11 was
chosen as the optimized reaction conditions.
NH3 (3, 5.0 equiv), Cu (X mol%), additives (Y mol%),
base (Z equiv) H2O 0.5 mL reflux. [b] Isolated yields. [c] 1.0
[d]
equiv of aq. NH3 was used,
3.0 equiv of equiv of aq.
NH3 was used, [e] 7.0 equiv of aq. NH3 was used, [f] Instead
[g]
of aq. NH3 ammonium formate was used, Instead of aq.
NH3 ammonium acetate was used, reaction was carried
out in absence of water. All reactions were carried out in
presence of water under at reflux for 20 to 24 h until the
completion of starting materials [i] reaction carried out at
room temperature at 48 h.
[h]
Table 2. Substrate scope of 3-(2-halophenyl)-
3-step process reported by Wentrup and coworkers
over three steps at 600 °C.[15] In continuation of our
study of nitrile and β-ketonitriles[16], we report a
simple and eco-friendly route for the synthesis of
unexpected bioactive 3-substituted 4-quinolone
scaffolds rather than the expected substituted 4-
hydroxy quinoline 4aa’ in a one-pot fashion from
aldehyde, aqueous ammonia and substituted 3-(2-
halophenyl)-3-oxopropane in the presence of 5 mol%
Cu(II) and 10 mol% of L-proline using water as a
benign solvent (Scheme 1g). The Ullman coupling
reaction[17] using water as a solvent is particularly
attractive and has “green features” due to its harmless
conditions. Moreover, the obtained nitrile
functionality can be further transformed into other
functional groups depending on the nature of the
reagents used.[18,16b] The initial investigation of this
methodology began with the use of 3-(2-
3oxopropanenitrile derivatives with aldehydes[a,b]
[a]
bromophenyl)-3-oxopropanenitrile
(1a)
and
benzaldehyde (2a) as model substrates by varying
parameters such as catalyst, base, additives and
nitrogen source in the presence of water as a green
and eco-friendly reaction media to synthesize 3-
cyano-4-quinolone (4aa), as shown in Table 1.
Reaction screening with various copper I & II salts
(Table 1, entries 1-6) in the presence of K2CO3 (2.0
equiv) and aq. NH3 (3, 5.0 equiv) indicated that 20
mol% of CuCl2 resulted in 38% yield of 3-cyano
quinolone 4aa (Table 1, entry 6). Interestingly, the
reaction yield was drastically improved to 73% using
20 mol% of L-proline as a ligand[19] (Table 1, entry 7).
The yield of compound 4aa slightly increased to 76%
using 10 mol% of L-proline (Table 1, entry 8), and a
lower yield was obtained by reducing this amount to
5 mol% (Table 1, entry 9). A lower catalyst loading
(Table 1, entries 10-12) indicated that 5 mol% of
CuCl2 is sufficient to obtain a maximum 4aa yield of
87% (Table 1, entry 11). The results from an
equivalent study with K2CO3 (Table 1, entries 13-15)
indicated that 2.0 equiv of base is necessary for
achieving a better 4aa yield (Table 1, entry 11). By
increasing or decreasing the stoichiometric quantity
of aq. NH3 failed to improve the yield of 4aa (Table 1,
entries 16-18). Replacing L-proline with other
additives such as L-prolinol, piperidine and 2-
pyrrolidinone resluted in low yields (Table 1, entries
19-21). Changing the reaction base from K2CO3 to
other bases such as Cs2CO3, Na2CO3 and DBU
resulted in low yields (Table 1, entries 22-24). The
Reaction conditions: 1a, g (0.2 mmol), 2a-v (1.2 equiv.),
CuCl2 (5 mol%), L-proline (10 mol%), aq. NH3 (3) (5.0
[b]
equiv.), 0.5 mL of water, reflux at mentioned time,
[c]
Isolated yields, Instead of bromo starting material, an
[d]
iodo starting material was used and
material was used.
a chloro starting
With the optimized reaction condition in hand, the
scope and limitations of this three-component
reaction was investigated as shown in Table 2. The
electron-donating groups present on aromatic
aldehydes such as o-Me-Ph (2b), o-OMe-Ph (2c), m-
Me-Ph (2d), m-OMe-Ph (2e), p-Me-Ph (2f) and p-
OMe-Ph (2g) afforded the desired compounds 4ab-
4ag 82-87% yields. Replacing the mono-substituted
aldehyde with trisubstituted derivatives such as 2,3,4-
tri-OMe-Ph (2h) and 3,4,5-tri-OMe-Ph (2i) also
afforded the desired product 4ah-4ai in 78-83%
yields. In addition, the reaction proceeded smoothly
with electron-withdrawing groups present on the
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
aromatic aldehyde (i.e., m-Cl-Ph (2j), m-Br-Ph (2k),
m-CN-Ph (2l), p-F-Ph (2m), p-Cl-Ph (2n), p-NO2-Ph
(2o)) to afford the desired compounds 4aj-4ao in 53-
79% yields. Interestingly, the reaction also worked
well with biphenyl (2p), naphthyl (2q) and heteroaryl
(2r & 2s) to afford the desired products 4ap-4as in
62-80% yields.
formaldehyde solution (36% aqueous) under the
optimized conditions as shown in Table 2.
Surprisingly, the reaction underwent smooth
conversion with electron-donating and electron-
withdrawing groups to afford the desired products
(6aa-6ga) in 47-85% yields. When the reaction was
performed with iodo/chloro derivatives, the required
product was obtained in only 53% and 39% yield
(6aa), respectively. However, the reaction failed to
produce the desired product (6ha) using the naphthyl
Table 3. Substrate scope of 3-(2-halophenyl)-3-
oxopropanenitrile derivatives with formalin (aq. 36%) [a,b]
Table 4. Substrate scope for 4-quinolone synthesis with
different electronic groups and heteroaromatic derivatives
with aldehydes[a,b]
[a] Reaction conditions: 1a-h (0.2 mmol), 5a (1.2 equiv, aq.
36%), CuCl2 (5 mol%), L-proline (10 mol%), aq. NH3 (3,
[b]
5.0 equiv), 0.5 mL of water,
mentioned time,
Isolated yields, reflux at
[c]
Instead of bromo starting material, an
iodo starting material was used and
material was used.
[d]
a chloro starting
[a]
Reaction conditions: 7a-d, 8a (0.2 mmol), 2a (1.2
equiv.), CuCl2 (5 mol%), L-proline (10 mol%), aq. NH3 (3,
[b]
5.0 equiv.), 0.5 mL of water,
mentioned time.
Isolated yields, reflux at
Unfortunately, the reaction failed to work with
aliphatic (2t & 2u) and benzyl (2v) aldehyde
derivatives. Changing from 3-(2-bromophenyl)-3-
derivative. The gram-scale synthesis of 4aa and 6ga
under the standard conditions resulted in moderate
yields of 63% and 57% respectively, compared to the
0.2 mmol scale (Scheme 2). Due to the successful
transformation with cyanide derivatives, we have
demonstrated the potential utility of the developed
methodology for other functionalities such as -NO2, -
Ts, and –COAr, and the corresponding quinolone
derivatives (9aa, af, ba, bm, and cm) were obtained
in 27-46% yields (Table 4). The previous 3-nitro 4-
quinolone derivatives were synthesized with o-
oxopropanenitrile
(1a)
to
3-(6
bromobenzo[d][1,3]dioxol-5-yl)-3-oxopropanenitrile
(1g) with aldehydes (2a) and (2f) also resulted in the
desired product 4ga-4gf in 76-78% yields. Moreover,
we have carried out the reactions with iodo and
chloro derivatives of compound 1a rather than the
bromo derivative, and the desired product was
obtained in 72% and 58% yield (4aa),
Scheme 2. Gram scale synthesis
respectively. The structure of compounds 4aa, 4ap
and 4gf were unambiguously confirmed by X-ray
analyses.[20a,b] In general, the reaction underwent
smooth conversion with aromatic aldehydes
Scheme 3. Synthetic applications of 3-cyano-4-quinolone
containing
electron-donating
and
electron-
aminobenzoic acids under acidic condition at low
yields.[21] The 2-substituted-3-aroylquinolin-4(1H)-
one is known to be an inhibitor of the Hedgehog
Signaling Pathway that was recently studied by
Goggiamani et al.[22] Moreover, sulfur-containing
withdrawing functionalities irrespective of steric
factors. After the successful outcome of the reaction
with aromatic and heteroaromatic aldehydes, we
investigated the scope of the reaction using a
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
compounds have unique chemical and biological
activites and play an important role in drug design in
agrochemicals and material chemistry.[13d] However,
our reaction did not work with the simple
acetophenone derivative 9dm. These results indicate
that the electron withdrawing groups are crucial to
product generation. Surprisingly, the reaction with
heterocyclic compounds worked well to afford the 7-
oxo-5-phenyl-4,7-dihydrothieno [3,2-b]pyridine-6-
carbonitrile derivatives 10aa, am and as in 74-79%
yields. These compounds are known as protein kinase
inhibitor and were synthesized by Harris et al.[23] We
believe that this reported protocol could allow for the
development in this type of chemistry. However the
of aq. ammonia (Scheme 4, eq. 2). Interestingly, the
desired product 4aa was obtained in 82% yield by
reacting the aldol adduct with aq. NH3 under the
standard condition (Scheme 4, eq. 3). In addition, the
reaction in absence of 2a did not afford the 1aa'
intermediate (Scheme 4, eq. 4). These results suggest
that the reaction proceeds via an aldol condensation.
Based on the control experiments and previous
studies,[27] a plausible reaction
Scheme 5. Plausible mechanism
mechanism has been proposed in Scheme 5. The
reaction of compound 1 with 2 or 5 under the
standard conditions generated aldol intermediate
19aa. Then, oxidative addition of in situ generated
Cu(0) afforded the reactive Cu(II) species A.
Nucleophilic addition of ammonia to intermediate A
followed by reductive elimination yielded compound
C with the catalytic generation of Cu(0) for the next
catalytic cycle. An intramolecular Michael addition
followed by protonation afforded compound D.
Finally, aerobic oxidation of compound D yielded the
desired products 4/6/9/10.
Scheme 4. Control experiments
methods for their synthesis, which contain the 4-
quinolone scaffolds bearing nitro, benzoyl, and
sulfonyl functionalities are rarely reported. Therefore,
the development of an eco-friendly protocol to
construct these scaffolds is urgently needed. We
observed that compounds 6aa and 6ga are the
precursors of BQCA and oxolinic acid, respectively.
Surprisingly, the reactions successfully to afforded
BQCA 13 and oxolinic acid 15 in good yields, as
shown in Scheme 3.[24a,b] In general, oxolinic acid
plays a role in dopamine reuptake, and is a first
generation quinolone antimicrobial drug, known for
its antibacterial activity and useful for urinary tract
infections.[24] In addition, Scammells et al reported
that benzyl quinolone carboxylic acid exihibits
allosteric activity for acetylcholine binding, with
inherent agonist activity at the M1 muscarinic
receptor.[25] In addition, we have successfully treated
4ad under reported condition[26] to afford
pyrano[2,3,4-de]quinoline-3-carbonitrile 17 in 81%
yield.
Conclusion
In conclusion, we have developed an efficient and
green protocol for the synthesis of 3-cyano, nitro,
sulfones, and benzoyl 4-quinolone derivatives in the
presence of water as the reaction medium and aq.
ammonia as a cheap N1-synthon. A late-stage
modification for the synthesis of oxolinic acid and
BQCA has been performed. This greener and more
economical approach may provide an alternative
strategy to the previously reported methodology for
the construction of substituted quinolone analogues
and can be widely applied in the synthetic community.
In addition, we have demonstrated the potential
utility of heterocyclic compounds to afford 7-oxo-5-
phenyl-4,7-dihydrothieno[3,2-b]pyridine-6
carbonitrile derivatives. Further, the utility of this
methodology for the construction of valuable
heterocyclic compounds is underway in our
laboratory.
To better understand the reaction mechanism,
several control experiments were performed as shown
in Scheme 4. The reaction of compound 1a with
benzamide 18 under the standard conditions in
absence of aq. ammonia afforded the desired
compound 4aa in 7% yield (Scheme 4, eq. 1). An
aldol condensation adduct was observed 19aa in 86%
yield when the reaction was performed in the absence
Experimental Section
Synthesis of 2-Bromobenzoylacetonitrile Derivatives
(1b,c,f, and g)
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
4-oxo-2-phenyl-1,4-dihydroquinoline-3-carbonitrile
In a 25 mL of round bottom flask o-bromobenzaldehyde
(1b,c,f, and g) derivatives (2.0 mmol, 1.0 equiv), CuCl (10
mol%), KOH (3.0 equiv) in dimethylacetamide (DMA, 20
mL) and acetonitrile (10.0 equiv) were stirred at room
temperature under oxygen for 24 h. The reaction progress
was monitored by TLC and upon completion, the reaction
was quenched by water and extracted with ethyl acetate (4
× 25 mL). The obtained residue was dried over sodium
sulfate, filtered and concentrated under vacuum. Finally
the residue was purified by column chromatography with
hexane-ethyl acetate (9:2) as eluent to afford the
corresponding 2-bromocyanoacetophenone derivatives
1b,c,f, and g.
(4aa): Off White Solid; Yield= 87% (42 mg); Mp 349-351
1
°C; H NMR (400 MHz, CDCl3+DMSO-d6) δ 12.30 (s,
1H), 8.30 (dd, J = 8.4, 1.2 Hz, 1H), 7.79 – 7.71 (m, 2H),
7.74 – 7.68 (m, 2H), 7.64 – 7.58 (m, 3H), 7.44 (ddd, J =
8.0, 6.8, 1.2 Hz, 1H); 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 175.59, 156.29, 138.83, 132.61,
131.87, 130.90, 128.32, 128.28, 125.02, 124.89, 123.82,
118.69, 116.16, 93.76; HRMS (ESI) calcd. for C16H10N2O
(M+H)+ 246.07931 found 246.08568. .
4-oxo-2-(o-tolyl)-1,4-dihydroquinoline-3-carbonitrile
(4ab): Pale Yellow; Yield= 82% (42.64 mg); Mp 297-298
1
°C; H NMR (400 MHz, CDCl3+DMSO-d6) δ 12.45 (s,
1H), 8.31 – 8.28 (m, 1H), 7.69 – 7.65 (m, 2H), 7.53 – 7.43
(m, 3H), 7.43 – 7.36 (m, 2H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3+DMSO-d6) δ 175.24, 156.60, 138.73, 135.74,
132.62, 132.00, 130.27, 130.25, 128.29, 125.63, 124.99,
124.93, 124.00, 118.69, 115.56, 95.22, 18.79; HRMS (ESI)
calcd. for C17H12N2O (M+H)+ 261.10224, found 261.10250.
3-(2-bromo-4-methylphenyl)-3-oxopropanenitrile (1b):
1
Brown Solid; Yield= 73% (344.5 mg) Mp 72-74 °C; H
NMR (400 MHz, CDCl3) δ 7.52 – 7.49 (m, 1H), 7.47 (d, J
= 7.9 Hz, 1H), 7.24 (ddd, J = 7.9, 1.6, 0.7 Hz, 1H), 4.12 (s,
2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 189.60,
144.92, 134.86, 134.79, 130.22, 128.62, 119.67, 113.44,
32.29, 21.14; HRMS (ESI) calcd. for C10H8BrNO (M+H)+
236.97893, found 236.9783.
2-(2-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ac): Yellow Solid; Yield= 87% (48.02 mg);
Mp 290-292 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
12.41 (s, 1H), 8.28 – 8.26 (m, 1H), 7.69 – 7.66 (m, 2H),
7.59 (m, 1H), 7.50 (dd, J = 7.6, 1.6 Hz, 1H), 7.44 (ddd, J
= 8.4, 6.0, 2.4 Hz, 1H), 7.19 – 7.13 (m, 2H), 3.90 (s, 3H);
13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.24, 156.29,
154.07, 138.89, 132.43, 132.17, 129.81, 124.84, 124.70,
123.92, 121.03, 120.10, 118.68, 115.99, 111.29, 95.32,
55.37; HRMS (ESI) calcd. for C17H12N2O2 (M+H)+
277.09715, found 277.09735.
3-(2-bromo-5-methoxyphenyl)-3-oxopropanenitrile (1c):
Yellow Solid; Yield= 70% (352.8 mg) Mp 132-134 °C; 1H
NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.8 Hz, 1H), 7.03
(d, J = 2.8 Hz, 1H), 6.95 (dd, J = 8.8, 2.8 Hz, 1H), 4.15 (s,
2H), 3.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.38,
159.00, 134.89, 119.57, 114.87, 109.19, 55.73, 32.38;
HRMS (ESI) calcd. for C10H8BrNO2 (M+H)+ 252.97384,
found 252.9734.
4-oxo-2-(m-tolyl)-1,4-dihydroquinoline-3-carbonitrile
(4ad): Dark Yellow Solid; Yield= 84% (43.68 mg); Mp
>247 decomposed °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.27 (s, 1H), 8.19 (dd, J = 8.0, 1.2
Hz, 1H), 7.66 – 7.55 (m, 2H), 7.49 (m, 2H), 7.48 – 7.32 (m,
3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 175.46, 156.45, 138.82, 138.10, 132.58, 131.80, 131.59,
128.69, 128.23, 125.42, 124.85, 124.82, 123.75, 118.75,
116.20, 93.56, 20.84; HRMS (ESI) calcd. for C17H12N2O
(M+H)+ 260.09496, found 261.10249.
3-(2-bromo-4,5-dimethoxyphenyl)-3-oxopropanenitrile
(1f): Yellow Solid; Yield= 75% (423 mg) Mp 146-148 °C;
1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.07 (s, 1H),
4.23 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 188.36, 152.96, 148.48, 129.32, 116.49,
113.67, 113.25, 112.52, 56.46, 56.22, 32.58; HRMS (ESI)
calcd. for C11H10BrNO3 (M+H)+ 282.98441, found
282.9840.
2-(3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ae): Pale yellow Solid; Yield= 82% (45.28
mg); Mp 248-250 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.26 (s, 1H), 8.25 (dd, J = 8.0, 1.2
Hz, 1H), 7.77 – 7.73 (m, 3H), 7.70 – 7.65 (m, 1H), 7.44 –
7.40 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 7.12 – 7.09 (m, 2H),
3.91 (s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ
175.23, 161.15, 155.68, 138.50, 132.16, 129.64, 124.44,
124.33, 123.43, 123.26, 118.31, 116.18, 113.26, 92.79,
54.66; HRMS (ESI) calcd. for C17H12N2O2 (M+H)+
277.09715, found 277.09733.
3-(6-bromobenzo[d][1,3]dioxol-5-yl)-3-
oxopropanenitrile (1g): Yellow Solid; Yield= 67% (327.6
1
mg) Mp 124-126 °C; H NMR (400 MHz, CDCl3) δ 7.08
(d, J = 3.6 Hz, 2H), 6.10 (s, 2H), 4.13 (s, 2H); 13C NMR
(101 MHz, CDCl3) δ 188.46, 151.80, 147.82, 130.79,
114.10, 113.51, 113.09, 109.94, 109.93, 109.89, 102.90,
32.43; HRMS (ESI) calcd. for C10H6BrNO3 (M+H)+
266.95311, found 266.9538.
General Procedure for (B) the Synthesis of substituted
4-quinolone Analogous (4aa-av, 4ga, 4gf;, 9aa, af, ba,
bm, cm, dm;,10aa, am, as)
4-oxo-2-(p-tolyl)-1,4-dihydroquinoline-3-carbonitrile
(4af): Dark Yellow Solid; Yield= 85% (44.2 mg); Mp 292-
294 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ 12.30 (s,
1H), 8.26 (dd, J = 8.0, 1.2 Hz, 1H), 7.79 – 7.61 (m, 4H),
7.44 – 7.39 (m, 3H), 2.48 (s, 3H); 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 175.58, 156.41, 141.42, 138.88,
132.58, 128.92, 128.23, 124.88, 124.80, 123.74, 118.74,
116.38, 93.47, 20.97; HRMS (ESI) calcd. for C17H12N2O
(M+H)+ 261.10224, found 261.10249.
A reaction tube was charged with 2-halo substituted
electronic withdrawing groups and heteroaromatic
derivatives (1a,g,9a,b,c,d,10a 0.2 mmol) respective
aldehydes (2a-v, 1.2 equiv.), CuCl2 (5 mol%), L-proline
(10 mol%), K2CO3 (2.0 equiv.), and aqueous ammonia (3,
5.0 equiv.) in 0.5 mL of water. The reaction suspension
was stirred under reflux conditions and the reaction
progress was monitored by TLC. Upon completion water
was added to quench the reaction. Then, the mixture was
extracted with a 10% ethyl acetate-methanol solution (3 ×
20 mL) and the combined organic layer were dried over
sodium sulfate, filtered and concentrated under vacuum.
The residue was purified by column chromatography on
silica gel to afford the corresponding 3-cyano nitro,
sulfones, and benzoyl 4-quinolone derivatives (4aa-av,
4ga, 4gf;, 9aa, af, ba, bm, cm, dm, 10aa, am, as).
2-(4-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ag): Brown Solid; Yield= 83% (45.81 mg);
Mp 273-275 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
12.22 (s, 1H), 8.16 (dd, J = 8.0, 1.2 Hz, 1H), 7.69 – 7.64
(m, 3H), 7.60 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.35 (ddd, J
= 8.0, 6.8, 1.2 Hz, 1H), 7.06 – 7.02 (m, 2H), 3.82 (s, 3H);
13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.51, 161.52,
156.06, 138.89, 132.53, 130.04, 124.76, 124.70, 123.80,
123.63, 118.73, 116.57, 113.63, 93.12, 55.04; HRMS (ESI)
calcd. forC17H12N2O2 (M+H)+ 277.09715, found
277.09737.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
4-oxo-2-(2,3,4-trimethoxyphenyl)-1,4-dihydroquinoline-
3-carbonitrile (4ah): Off White Solid; Yield= 78% (52.41
mg); Mp 272-274 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.29 (s, 1H), 8.29 (d, J = 8.0 Hz,
1H), 7.74 – 7.61 (m, 2H), 7.51 – 7.37 (m, 1H), 7.22 (d, J =
8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H), 3.93 (s,
3H), 3.90 (s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 175.10, 155.36, 153.65, 150.51, 141.10, 138.51, 132.21,
124.66, 124.45, 124.11, 123.63, 118.41, 118.35, 115.85,
106.40, 95.03, 60.92, 60.22, 55.41; HRMS (ESI) calcd. for
C19H16N2O4 (M+H)+ 337.11828, found 337.11844.
δ 175.29, 155.06, 138.78, 136.97, 132.71, 130.18, 129.86,
128.49, 125.01, 124.89, 123.80, 118.74, 116.02, 93.69;
HRMS (ESI) calcd. for C16H9ClN2O (M+H)+ 281.04762,
found 281.04780.
2-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ao): Dark Brown Solid; Yield= 54% (31.42
mg); Mp 342-344 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 8.31 (d, J = 8.4 Hz, 2H), 8.25 (d, J =
7.6 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz,
1H), 7.64 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H); 13C
NMR (101 MHz, CDCl3+DMSO-d6) δ 176.15, 156.29,
147.85, 143.42, 141.79, 131.60, 129.63, 124.30, 124.25,
123.28, 122.92, 118.49, 92.50; HRMS (ESI) calcd. for
C16H9N3O3 (M+H)+ 291.06439, found 291.0641.
4-oxo-2-(3,4,5-trimethoxyphenyl)-1,4-dihydroquinoline-
3-carbonitrile (4ai): Off White Solid; Yield= 77% (51.74
mg); Mp 277-279 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.17 (s, 1H), 8.29 (qd, J = 8.4, 8.0,
1.2, 0.4 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.70 – 7.67 (m, 1H),
7.42 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.03 (s, 2H), 3.96 (s,
6H), 3.92 (s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 176.04, 156.19, 152.89, 140.09, 138.96, 132.87, 126.89,
125.35, 125.14, 123.99, 118.80, 116.53, 106.12, 93.73,
60.62, 56.16; HRMS (ESI) calcd. for C19H16N2O4 (M+H)+
337.11828, found 337.11811.
2-([1,1'-biphenyl]-3-yl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ap): Pale Brown Solid; Yield= 72% (46.36
mg); Mp 316-318 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.42 (s, 1H), 8.30 (dd, J = 8.0, 1.2
Hz, 1H), 8.00 (t, J = 1.6 Hz, 1H), 7.91 – 7.83 (m, 1H), 7.80
– 7.67 (m, 6H), 7.52 – 7.39 (m, 4H); 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 175.55, 156.20, 141.11, 138.94,
138.90, 132.68, 132.30, 129.35, 128.91, 128.59, 127.63,
127.17, 126.98, 126.57, 124.97, 123.86, 118.79, 116.33,
93.70; HRMS (ESI) calcd. for C22H14N2O (M+H)+
323.11061, found 323.11772.
2-(3-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4aj): Yellow Solid; Yield= 77% (43.12 mg);
Mp 283-285 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
12.38 (s, 1H), 8.30 – 8.28 (m, 1H), 7.75 – 7.67 (m, 4H),
7.63 – 7.54 (m, 2H), 7.45 (ddd, J = 8.4, 6.4, 2.0 Hz, 1H);
13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.32, 154.57,
138.74, 133.97, 133.40, 132.70, 130.81, 129.77, 128.07,
126.82, 125.04, 124.98, 123.83, 118.69, 115.78, 93.84;
HRMS (ESI) calcd. for C16H9ClN2O (M+H)+ 281.04762,
found 281.04780.
2-(naphthalen-2-yl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4aq): Dark Brown Solid; Yield= 80% (47.36
mg); Mp 288-290 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.52 (s, 1H), 8.31 – 8.29 (m, 2H),
8.08 (d, J = 8.8 Hz, 1H), 8.05 – 7.97 (m, 2H), 7.85 (dd, J =
8.4, 1.6 Hz, 1H), 7.78 – 7.64 (m, 4H), 7.48 (ddd, J = 8.0,
6.8, 1.6 Hz, 1H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 175.52, 156.36, 138.96, 133.66, 132.69, 131.85, 129.10,
128.71, 128.14, 127.72, 127.37, 126.87, 124.97, 124.94,
124.71, 123.86, 118.80, 116.31, 93.90; HRMS (ESI) calcd.
for C20H12N2O (M+H)+ 297.10224, found 297.10230.
2-(3-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ak): Pale Yellow Solid; Yield= 53% (34.23
mg); Mp 283-285 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 8.26 (dd, J = 8.0, 0.8 Hz, 1H), 7.91 (t,
J = 1.6 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 2H), 7.73 – 7.67
(m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.45 (ddd, J = 8.0, 6.4,
1.6 Hz, 1H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ
175.30, 154.66, 138.94, 133.76, 132.77, 130.93, 130.07,
127.37, 125.10, 124.88, 123.87, 121.94, 118.99, 115.96,
93.73; HRMS (ESI) calcd. for C16H9BrN2O (M+H)+
323.11789, found 323.11772.
2-(furan-2-yl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4ar): Brown Solid; Yield= 65% (30.68 mg);
Mp 217-219 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
11.93 (s, 1H), 8.16 (dd, J = 8.4, 1.2 Hz, 1H), 7.82 (d, J =
8.0 Hz, 1H), 7.74 (dd, J = 1.6, 0.8 Hz, 1H), 7.71 (dd, J =
4.0, 1.2 Hz, 1H), 7.58 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.31
(ddd, J = 8.4, 7.6, 1.2 Hz, 1H), 6.66 (dd, J = 3.6, 1.6 Hz,
1H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.46,
145.25, 143.69, 143.33, 138.62, 132.70, 124.79, 124.76,
123.61, 118.83, 116.83, 116.43, 112.81, 89.10; HRMS
(ESI) calcd. for C14H8N2O2 (M+H)+ 237.06585, found
237.06608.
2-(3-cyanophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4al): Brown Solid; Yield= 79% (42.81 mg);
Mp 323-325 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
12.53 (s, 1H), 8.29 (dt, J = 8.0, 0.8 Hz, 1H), 8.14 – 8.1 (m,
2H), 7.98 (dt, 8.0, 1.2 Hz, 1H), 7.80 (td, J = 7.8, 0.6 Hz,
1H), 7.74 – 7.71 (m, 2H), 7.48 (ddd, J = 8.4, 5.2, 3.2 Hz,
1H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.16,
153.89, 138.81, 134.13, 132.98, 132.94, 131.85, 129.50,
125.30, 124.99, 123.93, 118.84, 117.13, 115.77, 112.43,
109.45, 93.82; HRMS (ESI) calcd. for C17H9N3O (M+H)+
272.08184, found 272.08204.
4-oxo-2-(thiophen-2-yl)-1,4-dihydroquinoline-3-
carbonitrile (4as): Brown Solid; Yield= 62% (31.24 mg);
1
Mp 333-334 °C; Mp 333-334 °C; H NMR (400 MHz,
CDCl3+DMSO-d6) δ 8.22 (dd, J = 8.0, 1.2 Hz, 1H), 7.88
(dd, J = 3.6, 0.8 Hz, 1H), 7.80 – 7.78 (m, 2H), 7.68 (ddd,
8.4, 6.8, 1.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.30 (dd, J =
4.0, 3.6 Hz, 1H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 175.46, 149.41, 139.55, 132.57, 130.94, 130.16, 127.40,
124.75, 124.69, 123.75, 119.42, 116.65, 92.69; HRMS
(ESI) calcd. for C14H8N2OS (M+H)+ 252.03573, found
252.0354.
2-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4am): Off White Solid; Yield= 72% (38.01
mg); Mp 327-3329 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.47 (s, 1H), 8.27 (dd, J = 8.0, 3.2
Hz, 1H), 7.84 – 7.81 (m, 2H), 7. 74 – 7.63 (m, 2H), 7.45
(ddd, J = 8.0, 6.4, 1.2 Hz, 1H), 7.34 – 7.30 (m, 2H); 13C
NMR (101 MHz, CDCl3+DMSO-d6) δ 175.40, 163.75, (d,
JF = 250.9 Hz), 155.27, 138.82, 132.71, 130.75 (d, J = 8.7
Hz), 127.93 (d, JF = 3.2 Hz), 124.94 (d, JF = 7.7 Hz),
123.78, 118.76, 116.17, 115.50, (d, JF = 21.8 Hz), 93.72;
HRMS (ESI) calcd. for C16H9FN2O (M+H)+ 265.07717,
found 265.07732.
8-oxo-6-phenyl-5,8-dihydro-[1,3]dioxolo[4,5-
g]quinoline-7-carbonitrile (4ga): Brown Solid; Yield=
1
76% (44.08 mg); Mp >303 °C decomposed; H NMR (400
MHz, CDCl3+DMSO-d6) δ 12.35 (s, 1H), 7.76 – 7.73 (m,
2H), 7.67 – 7.58 (m, 3H), 7.55 (s, 1H), 7.16 (s, 1H), 6.15 (s,
2H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 174.24,
154.79, 152.08, 146.40, 136.16, 131.88, 130.86, 128.40,
128.35, 119.67, 116.44, 101.93, 101.71, 97.74, 93.04;
HRMS (ESI) calcd. for C17H10N2O3 (M+H)+ 290.069146.
2-(4-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (4an): Dark Brown Solid; Yield= 75% (42
mg); Mp 130-132 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.33 (s, 1H), 8.18 (d, J = 7.6 Hz,
1H), 7.69 – 7.61 (m, 4H), 7.51 (m, 2H), 7.36 (ddd, J = 8.0,
6.4, 1.6 Hz, 1H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
8-oxo-6-(p-tolyl)-5,8-dihydro-[1,3]dioxolo[4,5-
g]quinoline-7-carbonitrile (4gf): Brown Solid; Yield=
1
78% (47.42 mg); Mp 188-190 °C; H NMR (400 MHz,
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
CDCl3+DMSO-d6) δ 12.19 (s, 1H), 7.67 – 7.63 (m, 2H),
7.56 (s, 1H), 7.39 (d, J = 7.6 Hz, 2H), 7.16 (s, 1H), 6.13 (s,
2H), 2.47 (s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 174.40, 154.83, 151.98, 146.26, 141.26, 136.13, 128.95,
128.21, 119.61, 116.56, 101.81, 97.65, 92.93, 20.99;
HRMS (ESI) calcd. for C18H12N2O3 (M+H)+ 304.08479.
7-oxo-5-(thiophen-2-yl)-4,7-dihydrothieno[3,2-
b]pyridine-6-carbonitrile (10as): Orange Solid; Yield=
1
76%; H NMR (400 MHz, CDCl3+DMSO-d6) δ 8.12 (d, J
= 5.2 Hz, 1H), 7.97 (dd, J = 4.8, 0.8 Hz, 1H), 7.85 (dd, J =
3.6, 1.2 Hz, 1H), 7.37 – 7.30 (m, 2H). 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 170.92, 149.13, 145.69, 134.55,
133.49, 131.29, 128.17, 126.53, 120.25, 117.38, 93.20;
HRMS (ESI) calcd. for C12H5N2OS2 (M - H+) 256.98488,
found 256.98520.
3-nitro-2-phenylquinolin-4(1H)-one (9aa): Off White
Solid; Yield= 41%; 1H NMR (400 MHz, CDCl3+DMSO-d6)
δ 8.25 – 8.22 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.71 (ddd,
J = 8.4, 6.8, 1.2 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.55 (m,
3H), 7.42 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H). 13C NMR (101
MHz, CDCl3+DMSO-d6) δ 167.35, 147.82, 135.29, 132.12,
130.14, 128.52, 127.73, 126.11, 125.05, 124.20, 121.30;
HRMS (ESI) calcd. for C15H11N2O3 (M + H+) 267.07642,
found 267.07624.
General Procedure for (C) the Synthesis of 3-Cyano-
Quinolone Analogous (6aa-ga)
A
reaction tube was charged with substituted 2-
halobenzoylacetonitrile (1a-h, 0.2 mmol), 36% aqueous
formaldehyde (5a, 1.2 equiv.), CuCl2 (5 mol%), L-proline
(10 mol%), K2CO3 (2.0 equiv.) and aqueous ammonia (3,
5.0 equiv.) in 0.5 mL of water. The reaction suspension
was stirred under reflux conditions and the reaction
progress was monitored by TLC. Upon completion, water
was added to quench the reaction. Then, the mixture was
extracted with a 10% ethyl acetate-methanol solution (3 ×
20 mL) and the combined organic layer were dried over
sodium sulfate, filtered and concentrated under vacuum.
The residue was purified by column chromatography on
silica gel to afford the corresponding 3-cyano 4-quinolone
derivatives (6aa-ha)
3-nitro-2-(p-tolyl)quinolin-4(1H)-one (9af): Light Brown
Solid; Yield= 46%; 1H NMR (400 MHz, CDCl3+DMSO-d6)
δ 12.10 (s, 1H), 8.41 – 8.34 (m, 1H), 7.74 – 7.65 (m, 2H),
7.51 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.43
(ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.36 (dd, J = 8.4, 0.7 Hz,
2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3+DMSO-d6)
δ 168.04, 145.92, 141.01, 138.61, 132.42, 129.12, 127.40,
125.54, 125.32, 124.36, 118.73, 20.92; HRMS (ESI) calcd.
for C16H13N2O3 (M + H+) 281.09207, found 281.09205.
2-phenyl-3-tosylquinolin-4(1H)-one (9ba): White Solid;
1
Yield= 38% H NMR (400 MHz, CDCl3+DMSO-d6) δ
12.12 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.4 Hz,
2H), 7.73 – 7.61 (m, 4H), 7.61 – 7.51 (m, 5H), 7.36 (ddd, J
= 8.0, 6.4, 1.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 2.39 (s,
3H). 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 173.14,
153.98, 142.51, 139.46, 138.47, 134.14, 132.38, 129.14,
128.26, 127.85, 127.51, 127.29, 125.71, 125.00, 124.53,
118.60, 118.47, 20.99.
4-oxo-1,4-dihydroquinoline-3-carbonitrile (6aa): Dark
Yellow Solid; Yield= 73% (24.82 mg); Mp 255-257 °C; 1H
NMR (400 MHz, CDCl3+DMSO-d6) δ 12.41 (s, 1H), 8.31
(dd, J = 8.0, 1.6 Hz, 1H), 8.21 (s, 1H), 7.68 (ddd, J = 8.4,
6.8, 1.6 Hz, 1H), 7.56 (m, 1H), 7.44 (ddd, J = 8.0, 7.2, 1.2
Hz, 1H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 174.92,
144.51, 138.71, 132.53, 125.28, 125.22, 125.02, 118.46,
115.96, 94.36; HRMS (ESI) calcd. for C10H6N2O (M+H)+
170.04801.
2-(4-fluorophenyl)-3-tosylquinolin-4(1H)-one
(9bm):
White Solid; Yield= 42%; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.19 (s, 1H), 8.15 (d, J = 8.0 Hz,
1H), 7.86 (d, J = 8.0 Hz, 2H), 7.67 – 7.56 (m, 4H), 7.36 (m,
1H), 7.27 (m, 4H), 2.39 (s, 3H). 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 173.08, 164.08, 161.61, 153.07,
142.64, 139.41, 138.48, 132.53, 130.14, 130.06, 128.34,
127.52, 125.73, 125.00, 124.69, 118.75, 118.54, 114.52,
114.30, 21.03.
7-methyl-4-oxo-1,4-dihydroquinoline-3-carbonitrile
(6ba): Brown Solid; Yield= 81% (29.80 mg); Mp
decomposed
>270 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.25 (s, 1H), 8.16 (s, 1H), 8.05 (d, J
= 8.4 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 2.40
(s, 3H); 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 174.60,
144.55, 143.46, 138.85, 126.66, 124.95, 123.06, 117.97,
116.10, 93.98, 21.24; HRMS (ESI) calcd. for C11H8N2O
(M+H)+ 185.07094, found 185.07081.
2-(4-fluorophenyl)-3-(4-methylbenzoyl)quinolin-4(1H)-
one (9cm): Brown Solid; Yield= 27%; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 11.80 (s, 1H), 8.23 (d, J = 8.1, 0.8 Hz,
1H), 7.73 – 7.62 (m, 4H), 7.51 – 7.46 (m, 2H), 7.38 – 7.34
(m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H),
2.36 (s, 3H). 13C NMR (101 MHz, CDCl3+DMSO-d6) δ
195.24, 175.58, 164.06, 161.58, 156.44, 148.18, 143.22,
141.44, 139.51, 135.23, 132.59, 131.76, 130.47, 130.38,
129.63, 129.59, 128.95, 128.81, 128.66, 128.25, 125.00,
124.77, 123.50, 120.48, 118.76, 118.22, 116.42, 115.14,
114.92, 21.14; HRMS (ESI) calcd. for C23H17FNO2 (M +
H+) 358.12378, found 358.12385.
6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile
(6ca): Dark Yellow Solid; Yield= 82% (32.8 mg); Mp
decomposed >223 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.39 (s, 1H), 8.12 (s, 1H), 7.54 (d, J
= 3.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H) 7.20 (dd, J = 9.2,
3.2 Hz, 1H), 3.81 (s, 3H); 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 174.34, 156.91, 143.14, 133.18,
126.37, 122.95, 120.20, 116.29, 104.29, 92.96, 55.18;
HRMS (ESI) calcd. for C11H8N2O2 (M+H)+ 201.06585,
found 201.06569.
7-oxo-5-phenyl-4,7-dihydrothieno[3,2-b]pyridine-6-
1
carbonitrile (10aa): Orange Solid; Yield= 74%; H NMR
(400 MHz, CDCl3+DMSO-d6) δ 7.86 (d, J = 5.6 Hz, 1H),
7.78 – 7.72 (m, 2H), 7.67 – 7.57 (m, 3H), 7.33 (d, J = 5.6
Hz, 1H). 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 175.92,
171.10, 155.03, 143.68, 133.37, 131.73, 130.86, 128.43,
128.37, 127.10, 118.70, 116.11, 109.46, 94.75; HRMS
(ESI) calcd. for C14H8N2OS (M + H+) 253.04301, found
253.04287.
6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile
(6da): Brown Solid; Yield= 56% (21.05 mg); Mp 337-339
1
°C; H NMR (400 MHz, CDCl3+DMSO-d6) δ 12.15 (s,
1H), 8.27 (s, 1H), 7.91 (dd, J = 8.8, 2.8 Hz, 1H), 7.64 (dd,
J = 9.2, 4.4 Hz, 1H), 7.49 – 7.41 (m, 1H); 13C NMR (101
MHz, CDCl3+DMSO-d6) δ 174.19, 159.38 (d, JF = 245.8
Hz), 144.43, 135.34, 126.70, 121.31, 121.12, 121.05,
115.75, 109.86 (d, JF = 23.0 Hz), 93.56; HRMS (ESI)
calcd. for C10H5FN2O (M+H)+ 188.03859, found 188.0388.
5-(4-fluorophenyl)-7-oxo-4,7-dihydrothieno[3,2-
b]pyridine-6-carbonitrile (10am): Orange Solid; Yield=
1
79%; H NMR (400 MHz, CDCl3+DMSO-d6) δ 7.86 (d, J
= 5.2 Hz, 1H), 7.82 – 7.78 (m, 2H), 7.35 (d, J = 5.6 Hz,
1H), 7.33 – 7.27 (m, 2H). 13C NMR (101 MHz,
CDCl3+DMSO-d6) δ 171.17, 163.51 (d, J = 250 Hz),
154.62, 144.92, 133.04, 130.83, 130.74, 127.82 (d, J = 180
Hz), 119.43, 116.61, 115.57, 115.35 (d, J = 21.8 Hz),
94.39; HRMS (ESI) calcd. for C14H7FN2OS (M + H+)
271.03359, found 271.03346.
6-chloro-3-nitroquinolin-4(1H)-one (6ea): Off White
Solid; Yield= 47%; 1H NMR (400 MHz, CDCl3+DMSO-d6)
δ 8.46 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 2.0 Hz,
2H). 13C NMR (101 MHz, CDCl3+DMSO-d6) δ 173.92,
145.68, 137.50, 133.10, 130.85, 126.28, 124.43, 121.07,
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
172.88, 152.67, 146.94, 146.32, 135.64, 122.27, 115.70,
103.23, 102.27, 95.67, 94.17, 49.16, 14.04.
116.04, 94.39; HRMS (ESI) calcd. for C10H6ClN2O (M +)
205.01632, found 205.01629.
5,6-diphenyl-2-(m-tolyl)pyrano[2,3,4-de]quinoline-3-
6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-
1
carbonitrile (17)[26]: Brown Solid; Yield=81%; H NMR
carbonitrile (6fa): Brown Solid; Yield= 85% (39.10 mg);
Mp decomposed >208 °C; 1H NMR (400 MHz,
CDCl3+DMSO-d6) δ 12.32 (s, 1H), 8.16 (s, 1H), 7.59 (s,
1H), 6.99 (s, 1H), 3.98 (s, 3H), 3.98 (s, 3H); 13C NMR
(101 MHz, CDCl3+DMSO-d6) δ 173.74, 153.51, 147.73,
142.96, 134.56, 119.44, 116.39, 104.23, 99.43, 93.44,
55.77, 55.68; HRMS (ESI) calcd. for C12H10N2O3 (M+H)+
230.06914, found 230.0685.
(600 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 0.8 Hz, 1H), 7.79 –
7.74 (m, 2H), 7.70 (dd, J = 8.0, 7.6 Hz, 1H), 7.48 – 7.40
(m, 5H), 7.34 (d, J = 7.6 Hz, 1H), 7.32 – 7.22 (m, 6H),
6.85 (dd, J = 7.5, 0.7 Hz, 1H), 2.48 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 163.80, 161.51, 149.58, 149.36, 138.41,
137.98, 134.47, 133.81, 131.98, 131.38, 130.90, 130.39,
129.50, 129.46, 129.41, 128.94, 128.50, 128.47, 128.12,
126.02, 125.68, 120.18, 117.86, 115.09, 114.91, 87.87,
21.51; HRMS (ESI) calcd. for C31H20N2O (M + H+),
437.16484, found 437.16472.
8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-7-
carbonitrile (6ga): Brown Solid; Yield= 79% (33.81 mg);
Mp 381-382 °C; 1H NMR (400 MHz, CDCl3+DMSO-d6) δ
8.22 (s, 1H), 7.54 (s, 1H), 7.01 (s, 1H), 6.14 (s, 2H); 13C
NMR (101 MHz, CDCl3+DMSO-d6) δ 173.52, 151.91,
146.39, 143.27, 136.06, 120.97, 116.26, 101.90, 101.79,
97.45, 93.45; HRMS (ESI) calcd. for C11H6N2O3 (M+H)+
215.04512, found 215.04493.
Acknowledgements
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for
Research and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyses.
General Procedure for the synthesis of BQCA 13 and
Oxolinic Acid 15
A reaction tube was charged with 6aa/6ga (0.1882/0.1401
mmol), 4-methoxybenzylbromide (11) or ethyl iodide (4.0
equiv), respectively, and NaH (1.4 equiv) in 2.0 mL of
THF. The reaction suspension was stirred under reflux
conditions and the reaction progress was monitored by
TLC. Upon completion, water was added to quench the
reaction. Then, the mixture was extracted an ethyl acetate
solution (3 × 20 mL) and the combined organic layers were
dried over sodium sulfate, filtered and concentrated under
vacuum. The residue was purified by column
chromatography on silica gel to afford the corresponding
alkylated derivatives (12/14) in 79% and 82% yields,
respectively.
References
[1] a) H. Huse, M. Whiteley, Chem. Rev. 2011, 111, 152; b)
M. Fryknas, J. Gullbo, X. Wang, L. Rickardson, M.
Jarvius, M. Wickstrom, S. Hassan, C. Andersson, M.
Gustafsson, G. Westman, P. Nygren, S. Linder, R.
Larsson, BMC Cancer 2013, 13; c) C. Mugnaini, S.
Pasquini, F. Corelli, Curr. Med. Chem. 2009, 16, 1746;
d) Y. Zhi, L. X. Gao, Y. Jin, C. L. Tang, J. Y. Li, J. Li,
Y. Q. Long, Bioorg. Med. Chem. 2014, 22, 3670; e) J.
A. Joule, K. Mills, G. F. Smith, Heterocyclic Chemistry,
3rd ed; Chapman & Hall: Chel Tenham, 1995; Chapter
6; f) J. Wiesner, R. Ortmann, H. Jomaa, M. Schlitzer,
Angew. Chem. Int. Ed. 2003, 43, 5274; g) J. P. Michael,
Nat. Prod. Rep. 1997, 14, 605; h) D. M. Fort, J. Litvak,
J. L. Chen, Q. Lu, P.-W. Phuan, R. Cooper, D. E.
Bierer, J. Nat. Prod. 1998, 61, 1528.
The obtained alkylated derivatives (12 0.15 mmol /14
0.12 mmol) were subsequently subjected to hydrolysis in
the presence of a 1:1 mixture of AcOH+H2SO4 (1.0 mL).
The reaction suspension was stirred under reflux
conditions, and the reaction progress was monitored by
TLC. Upon completion, water was added to quench the
reaction. Then, the mixture was extracted with a 25% ethyl
acetate-methanol solution (3 × 20 mL) and the combined
organic layer were dried over sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by
column chromatography on silica gel to afford the
corresponding BQCA 13 and Oxolinic acid 15 in 64% and
69% yields, respectively.
[2] a) J. A. Wiles, B. J. Bradbury, M. J. Pucci, Expert
Opin. Ther. Patent 2010, 20, 1295; b) G. L. McPhail, J.
P. Clancy, Drugs Today 2013, 49, 253; c) K. Kuk, J. L.
Taylor-Cousar, Ther. Adv. Respir. Dis. 2015, 9, 313.
[3] G. Manfroni, R. Cannalire, M. L. Barreca, N. Kaushik-
Basu, P. Leyssen, J. Winquist, N. Iraci, D. Manvar, J.
Paeshuyse, R. Guhamazumder, A. Basu, S. Sabatini, O.
Tabarrini, U. H. Danielson, J. Neyts, V. Cecchetti, J.
Med. Chem. 2014, 57, 1952.
1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-
carbonitrile (12): Pale Yellow Solid; Yield= 64%; H
[4] a) A. M. Jones, J. M. Helm, Drugs 2009, 69, 1903; b) F.
Van Goor, S. Hadida, P. D. rootenhuis, B. Burton, D.
Cao, T. Neuberger, A. Turnbull, A. Singh, J. Joubran,
A. Hazlewood, J. Zhou, J. McCartney, V. Arumugam,
C. Decker, J. Yang, C. Young, E. R. Olson, J. J. Wine,
R. A. Frizzell, M. Ashlock, P. Negulescu, Proc. Natl.
Acad. Sci. USA 2009, 106, 18825.
1
NMR (600 MHz, CDCl3) δ 8.47 (m, 1H), 8.03 (s, 1H),
7.67 (ddd, J = 9.0, 7.2, 1.8 Hz, 1H), 7.48 (m, 2H), 7.14 (d,
J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 5.31 (s, 2H),
3.82 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 174.50,
160.21, 148.27, 139.41, 133.51, 129.87, 128.38, 127.49,
126.98, 125.99, 124.62, 116.62, 115.51, 115.06, 113.87,
111.06, 96.20, 56.92, 55.39, 34.68.
[5] a) A. Ahmed, M. Daneshtalab, J. Pharm. Pharmaceut.
Sci. 2012, 15, 52; b) S. Richter, C. Parolin, M. Palumbo,
G. Palo, Curr. Drug Targets: Infect. Disord. 2004, 4,
111; c) C. Sissi, M. Palumbo, Curr. Med. Chem.: Anti-
Cancer Agents 2003, 3, 439; d) G. Cheng, H. Hao, M.
Dai, Z. Liu, Z. Yuan, Eur. J. Med. Chem. 2013, 66, 555;
5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-
1
7-carbonitrile (14)4: White Solid; Yield= 69%; H NMR
(400 MHz, CDCl3+DMSO-d6) δ 8.35 (s, 1H), 7.67 (s, 1H),
7.09 (s, 1H), 6.18 (s, 2H), 4.28 (t, J = 7.2 Hz, 2H), 1.52 (t,
J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3+DMSO-d6) δ
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
e) J. A. Wiles, B. J. Bradbury, M. J. Pucci, Exp. Opin.
[11] R. Camps, Chem. Ber. 1899, 32, 3228.
Ther. Pat. 2010, 20, 1295.
[12] P. B. Madrid, J. Sherrill, A. P. Liou, J. L. Weisman, J.
L. DeRisi, R. K. Guy, Bioorg. Med. Chem. Lett. 2005,
15, 1015.
[6] a) Y. H. Chang, M. H. Hsu, S. H. Wang, L. J. Huang, K.
Qian, S. L. Morris-Natschke, E. Hamel, S. C. Kuo, K.
H. Lee, J. Med. Chem. 2009, 52, 4883; b) C. T. Chen,
M. H. Hsu, Y. Y. Cheng, C. Y. Liu, L. C. Chou, L. J.
Huang, T. S. Wu, X. M. Yang, K. H. Lee, S. C. Kuo,
Eur. J. Med. Chem. 2011, 46, 6046; c) L. C. Chou, M.
T. Tsai, M. H. Hsu, S. H. Wang, T. D. Way, C. H.
Huang, H. Y. Lin, K. D. Qian, Y. Z. Dong, K. H. Lee,
L. J. Huang, S. C. Kuo, J. Med. Chem. 2010, 53, 8047;
d) S.-C. Kuo, H.-Z. Lee, J.-P. Juang, Y.-T. Lin, T.-S.
Wu, J.-J. Chang, D. Lednicer, K. D. Paull, C. M. Lin, E.
Hamel, K.-H. Lee, J. Med. Chem. 1993, 36, 1146; e) L.
Li, H.-K. Wang, S.-C. Kuo, T.-S. Wu, D. Lednicer, C.
M. Lin, E. Hamel, K.-H. Lee, J. Med. Chem. 1994, 37,
1126; f) Y. Xia, Z.-Y. Yang, P. Xia, T. Hackl, E.
Hamel, A. Mauger, J.-H. Wu, K.-H. Lee, J. Med. Chem.
2001, 44, 3932; (g) M. Hadjeri, E. L. Peiller, C. Beney,
N. Deka, M. A. Lawson, C. Dumontet, A. Boumendjel,
J. Med. Chem. 2004, 47, 4964.
[13] a) J. Huang, Y. Chen, A. O. King, M. Dilmeghani, R.
D. Larsen, M. M. Faul Org. Lett., 2008, 10, 2609; b) T.
Zhao, B. Xu, Org. Lett., 2010, 12, 212; c) O. Seppänen,
M. Muuronen, J. Helaja, Eur. J. Org. Chem., 2014,
4044; d) N. Zhou, Z. Yan, H. Zhang, Z. Wu, C. Zhu J.
Org. Chem. 2016, 81, 12181; e) Z. Zheng, Q. Tao, Y.
Ao, M. Xu, Y. Li, Org. Lett. 2018, 20, 3907; f) L.
Åkerbladh, P. Nordeman, M. Wejdemar, L. R. Odell,
M. Larhed, J. Org. Chem., 2015, 80, 1464; g) S. Kang,
S. Park, K.-S. Kim, C. Song, Y. Lee, J. Org. Chem.,
2018, 83, 2694; h) W. Hu, J.-P. Lin, L.-R. Song, Y.-Q.
Long, Org. Lett., 2015, 17, 1268; i) S. Torii, H.
Okumoto, L. H. Xu, Tetrahedron Lett., 1991, 32, 237; j)
J. Wu, Y. Zhou, T. Wu, Y. Zhou, C.-W. Chiang, A. Lei,
Org. Lett., 2017, 19, 6432; k) X. Xu, Zhang, X. Org.
Lett., 2017, 19, 4984.
[14] a) D. Cheng, J. Zhou, E. Saiah, G. Beaton, Org. Lett.
2002, 4, 4411; b) P. Shi, L. Wang, K. Chen, J. Wang, J.
Zhu, Org. Lett. 2017, 19, 2418; c) N. Haddad, J. Tan, V.
Farina, J. Org. Chem. 2006, 71, 5031; d) S.
Chandrasekhar, K. Vijeender, C. Sridhar, Tetrahedron
Lett. 2007, 48, 4935; e) R. P. Pandit, K. Sharma and Y.
R. Lee, Synthesis, 2015, 47, 3881.
[7] a) M. Llinas-Brunet, M. D. Bailey, E. Ghiro, V. Gorys,
T. Halmos, M. Poirier, J. Rancourt, N. Goudreau, J.
Med. Chem. 2004, 47, 6584; b) A. Baxter, M.
Chambers, F. Edfeldt, K. Edman, A. Freeman, C.
Johansson, S. King, A. Morley, J. Petersen, P. Rawlins,
L. Spadola, B. Thong, H. Van de Poel, N. Williams,
Bioorg. Med. Chem. Lett. 2011, 21, 777; c) S. F. Wang,
J. P. Lin, P. L. He, J. P. Zuo, Y. Q. Long, Acta Chim.
Sin. 2014, 72, 906; d) B. d’A. Lucero, C. R. B. Gomes,
I. C. de P. P. Frugulhetti, L. V. Faro, L. Alvarenga, M.
C. B. V. Souza, T. M. L. de Souza, V. F. Ferreira,
Bioorg. Med. Chem. Lett. 2006, 16, 1010.
[15] V. V. Ramana Rao, C. Wentrup, J. Chem. Soc., Perkin
Trans. 2002, 1, 1232.
[16] a) G. C. Senadi, B. S. Gore, W.-P. Hu, J.-J. Wang,
Org. Lett. 2016, 18, 2890; b) B. S. Gore, G. C. Senadi,
A. M. Garkhedkar, J.-J. Wang, Adv. Synth. Catal. 2017,
359, 3014.
[8] a) A. Nilsen, G. P. Miley, I. P. Forquer, M. W. Mather,
K. Katneni, Y. X. Li, S. Pou, A. M. Pershing, A. M.
Stickles, E. Ryan, J. X. Kelly, J. S. Doggett, K. L.
White, D. J. Hinrichs, R. W. Winter, S. A. Charman, L.
N. Zakharov, I. Bathurst, J. N. Burrows, A. B. Vaidya,
M. K. Riscoe, J. Med. Chem. 2014, 57, 3818; b) Y. Q.
Zhang, J. A. Clark, M. C. Connelly, F. Y. Zhu, J. K.
Min, W. A. Guiguemde, A. Pradhan, L. Iyer, A.
Furimsky, J. Gow, T. Parman, F. El Mazouni, M. A.
Phillips, D. E. Kyle, J. Mirsalis, R. K. Guy, J. Med.
Chem. 2012, 55, 4205; c) P. L. Olliaro, W. R. J. J.
Taylor, Exp. Biol. 2003, 206, 3753.
[17] F. Ullmann, J. Bielecki, Chemische Berichte 1901, 2,
2174.
[18] a) Z. Rappoport, The Chemistry of the Cyano Group,
Wiley, New York, 1971; b) R. C. Larock,
Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, 2nd ed., VCH: New
York, USA, 1999; c) M.-X. Wang, Top. Catal. 2005, 35,
117; d) K. Hu, Q. Zhen, J. Gong, T. Cheng, L. Qi, Y.
Shao, J. Chen, Org. Lett. 2018, 20, 3083; e) S. Yu, L.
Qi, K. Hu, J. Gong, T. Cheng, Q. Wang, J. Chen, H.
Wu, J. Org. Chem. 2017, 82, 3631; f) M. C. Reddy, R.
Manikandan, M. Jeganmohan, Chem. Commun. 2013,
49, 6060.
[9] a) J. Greeff, J. Joubert, S. F. Malan and S. van Dyk,
Bioorg. Med. Chem. 2012, 20, 809; b) R. Dhiman,; S.
Sharma, G. Singh, K. Nepali, P. M. Singh Bedi, Archiv
der Pharmazie 2013, 346, 7.
[19] a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39,
1615; b) B. List, P. Pojarliev, C. Castello, Org. Lett.
2001, 3, 573.
[10] a) M. P. Moyer, F. H. Weber, J. L. Gross, J. Med.
Chem. 1992, 35, 4595; b) R. D. Santo, R. Costi, A.
Roux, M. Artico, A. Lavecchia, L. Marinelli, E.
Novellino, L. Palmisano, M. Andreotti, R. Amici, C. M.
Galluzzo, L. Nencioni, A. T. Palamara, Y. Pommier, C.
Marchand, J. Med. Chem. 2006, 49, 1939; c) 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, H.
Shinkai, J. Med. Chem. 2006, 49, 1506.
[20] a) CCDC number for compounds 4aa, 4ap and 4gf are
CCDC (1869598), CCDC (1896689) and CCDC
(1896691); b) See ESI for X-ray structures of 4ap and
4gf.
[21] M. M. Maslova, N. B. Marchenko, V. I. Polshakov, R.
G. Glushkov, Khimiko-Farmatsevticheskii Zhurnal
1993, 27, 57.
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
[22] R. Alfonsi, B. Botta, S. Cacchi, L. D. Marcotullio, G.
Fabrizi, R. Faedda, A. Goggiamani, A. Iazzetti, M.
Mori, J. Med. Chem., 2017, 60, 1469.
[23] a) B. D. Harris, Z. Nan, B. Sosa, A. Carolina, D. Haris,
W. Biqi, US 2002-60428862; b) D. H. Boschelli F. Ye,
J. Heterocyclic Chem., 2002, 39, 783.
[24] The compound synthesized is matching with literature;
a) S. K. Gadakh, A. Sudalai, WO 2015198349; b) G. W.
Amarante, M. Benassi, R. N.Pascoal, M. N.Eberlin, F.
Coelho,Tetrahedron 2010, 66, 4370; c) S. K. Gadakh, S.
Dey, A. Sudalai, Org. Biomol. Chem., 2016, 14, 2969;
d) L. A. Mitscher, E. Gracey, G. W. Clark, T. Suzuki J.
Med. Chem., 1978, 21, 485; e) S. Egetenmeyer, C.
Richert, Chemistry - A European Journal, 2011, 17,
11813.
[25] S. N. Mistry, C. Valant, P. M. Sexton, B. Capuano, A.
Christopoulos, P. J. Scammells, J. Med. Chem., 2013,
56, 5151.
[26] A. Banerjee, S. K. Santra, P. R. Mohanta, B. K. Patel
Org. Lett. 2015, 17, 5678.
[27] a) G. R. Potuganti, D. R. Indukuri, M. Alla, Synlett,
2018, 29, 1717; b) A. K. Pandey, R. Mishra, A. Jana, T.
Parvin, L. H. Choudhury, J. Org. Chem., 2018, 83,
3624; c) A. T. Manojkumar Janni, S. Peruncheralathan,
J. Org. Chem., 2018, 83, 8668; and references cited
therein; d) B. Li, B. Zhang, X. Zhang, X. Fan, J. Org.
Chem., 2016, 81, 9530; e) L. Chen, C. Li, X. Bi, H. Liu
and R. Qiao, Adv. Synth. Catal. 2012, 354, 1773; f) Z.-
B. Lou, X.-L. Pang, C. Chen, L.-R. Wen, M. Li, Chin.
Chem. Lett., 2015, 26, 1231; g) Z. Lou, S. Zhang, C.
Chen, X. Pang, M. Li, L. Wen, Adv. Synth. Catal. 2014,
356,
153.
11
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900286
Advanced Synthesis & Catalysis
FULL PAPER
Copper-Catalyzed Synthesis of Substituted 4-
Quinolones using Water as a Benign Reaction
Media: Application for the Construction of
Oxolinic Acid and BQCA
Adv. Synth. Catal. Year, Volume, Page – Page
B. S. Gore, C. C. Lee, J. Lee and J.-J. Wang*
12
This article is protected by copyright. All rights reserved.