DABCO-mediated decarboxylative cyclization of isatoic anhydride with aroyl/heteroaroyl/alkoylacetonitriles under microwave conditions: Strategy for the synthesis of substituted 4-quinolones

Article abstract of DOI:10.1016/j.tetlet.2021.153187

An efficient, 1,4-diazabicyclo[2.2.2]octane(DABCO)-mediated decarboxylative cyclization of isatoic anhydrides with active methylene groups namely aroyl/heteroaroyl/alkoylacetonitriles under microwave condition was developed for the synthesis of substituted 4-quinolones. This method utilizes commercially available substrates, occurs under mild conditions, short reaction time, good to excellent yields, easy scale-up, and is compatible with a wide substrate scope. 4-Quinolones (3) obtained by this DABCO-mediated approach were further explored in order to evaluate their synthetic applicability. Initially, 4-quinolone derivatives were efficiently transformed into corresponding 4-Chloro-2-phenyl-quinoline-3-carbonitriles. Further, 2,4-Diphenyl-quinoline-3-carbonitriles were prepared by palladium catalyzed Suzuki-Miyaura cross-coupling of 4-Chloro-2-phenyl-quinoline-3-carbonitrile with aryl boronic acids.

Full text of DOI:10.1016/j.tetlet.2021.153187

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DABCO-mediated decarboxylative cyclization of isatoic anhydride with
aroyl/heteroaroyl/alkoylacetonitriles under microwave conditions:
Strategy for the synthesis of substituted 4-quinolones
⇑
Mugada Sugunakara Rao, Sahid Hussain
Department of Chemistry, Indian Institute of Technology Patna, Bihta, Patna 801106, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, 1,4-diazabicyclo[2.2.2]octane(DABCO)-mediated decarboxylative cyclization of isatoic anhy-
drides with active methylene groups namely aroyl/heteroaroyl/alkoylacetonitriles under microwave con-
dition was developed for the synthesis of substituted 4-quinolones. This method utilizes commercially
available substrates, occurs under mild conditions, short reaction time, good to excellent yields, easy
scale-up, and is compatible with a wide substrate scope. 4-Quinolones (3) obtained by this DABCO-medi-
ated approach were further explored in order to evaluate their synthetic applicability. Initially, 4-quino-
lone derivatives were efficiently transformed into corresponding 4-Chloro-2-phenyl-quinoline-3-
carbonitriles. Further, 2,4-Diphenyl-quinoline-3-carbonitriles were prepared by palladium catalyzed
Suzuki-Miyaura cross-coupling of 4-Chloro-2-phenyl-quinoline-3-carbonitrile with aryl boronic acids.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 7 April 2021
Revised 17 May 2021
Accepted 18 May 2021
Available online xxxx
Keywords:
4-Quinolone
DABCO
Isatoic anhydride
Microwave
Quinolines
Introduction
and tedious multistep synthesis and purification. Accordingly,
extensive synthetic methods have been developed to access 4-qui-
Among the synthetic arena of nitrogen heterocycles, 4-quino-
lones are arguably the most significant class molecules in pharma-
ceutical chemistry as they are biologically active and found in
many natural products [1,2]. The quinolone core is commonly
found in antibiotics and an antitumor agent like ciprofloxacin,
ofloxacin, nalidixic acid, and NSC 6561588 respectively (Fig. 1)
[3]. The core and its structural features are attracting medicinal
chemists because of their immense applications in several drugs
like antibacterial [4], antimalarial [5], anti-HIV [6], antimitotic
[7], antiplatelet [8], antiviral [9], xanthine oxidase [10], and inhibi-
tory activities of cathepsin [11]. As a result, they became well-
known precursors for many important synthetic intermediates
that lead to the development of a variety of biologically active
compounds [12].
Because of their unique intriguing structures and the broad
spectrum of activity, they have attracted the attention of several
chemists. Notable synthetic methods are the Conrad-Limpach
[13] and Niementowski [14] reaction from amines and carboxyl
derivatives, and the base promoted cyclization of N-(ketoaryl)
amides known as the Camps cyclization [15]. These processes are
low-yielding and require more or less harsh reaction conditions,
nolones including the functionalization of existing core from suit-
able precursors [16–18].
Commercially available isatoic anhydrides are considered as
privileged structural motifs because of their impressive synthetic
utility in the construction of different heterocyclic compounds
[19]. For instance, Matsubara et al. reported the synthesis of 4-qui-
nolone derivatives from isatoic anhydrides and alkynes using
nickel-catalyzed decarboxylative cyclization [20] whereas Sun
et al., reported the same synthesis via decarboxylative cyclization
of isatoic anhydrides with 1,3-dicarbonyl compounds in the pres-
ence of potassium carbonate (Scheme 1a) [21]. Surprisingly, there
are only a few literature reports of the preparation of 3-cyano qui-
nolones. In 2002, Wentrup et al. demonstrated a three-step process
for making 3-cyano quinolones at 600 °C (Scheme 1b) [22]. More
than one and a half-decade later, Wang et al., demonstrated the
synthesis of 3-cyano, nitro, sulfone, and benzoyl quinolone deriva-
tives through a three-component reaction of substituted 3-(2-halo-
phenyl)-3-oxopropane, aldehyde, and aqueous ammonia under the
catalytic influence of copper (Scheme 1c) [23]. Other than these
studies, there are no reports on the preparation of 3-cyano quino-
lones to the best of our knowledge. Both the strategies suffer from
long reaction time and multistep synthesis of starting materials.
On the other hand, microwave-assisted synthesis has become pop-
ular because of the speed of the reaction and convenience
⇑
Corresponding author.
E-mail address: sahid@iitp.ac.in (S. Hussain).
https://doi.org/10.1016/j.tetlet.2021.153187
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Mugada Sugunakara Rao and S. Hussain, DABCO-mediated decarboxylative cyclization of isatoic anhydride with aroyl/heteroaroyl/alkoylacetoni-
triles under microwave conditions: Strategy for the synthesis of substituted 4-quinolones, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153187

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Biologically active molecules containing quinolone derivatives.
Previous work:
ried out under the same condition with inorganic bases like K2CO3
and Na2CO3 as well as organic bases Et3N, DBU, and DABCO, the
desired product 3a was noted at moderate to fair yields (Table 1,
entries 6–10). DABCO was chosen as the base for further reaction
as it gave the highest yield. To optimize the amount of DABCO,
reactions were carried out with the different amount of base, the
yield of 3a decreases substantially in case of one equivalent of base
whereas no substantial change in yield was in case of 3 equivalent
(Table 1, entries 11 and 12). Next, we turned to screen exposure
time and the power of the microwave. The yield of the reaction
decreases with a decrease of exposure time and power whereas,
no significant increase in the yield of the desired product was seen
with an increase in power to 400 W (Table 1, entries 13–16). When
the reaction was performed in 1, 4-dioxane and water (Table 1,
entries 17 and18), 72% and 80% yields were observed, and low
yields were noted when the reaction was performed in EtOH and
MeOH (Table 1, entries 19 and 20). Finally, the results conclude
that the reaction between 1a (0.5 mmol) and 2a (0.56 mmol) with
1.0 mmol of DABCO in acetonitrile (3 mL) at 300 W microwave
power for 30 min gave good yields.
With the optimized protocol in hand, we expanded the sub-
strate scope by examining the reaction of various substituted isa-
toic anhydride (1a) and benzoylacetonitrile (2a), and the results
are summarized in Table 2. At first, the reaction of 1a with substi-
tuted benzoylacetonitrile having different electron-withdrawing
groups like Cl, F, and electron-donating groups like methyl and
methoxy were employed. The reactions went on well and provided
the corresponding products in good to excellent yields 87–93%
(3b–3e). Next, substituted 5-chloro and 5-bromo isatoic anhy-
drides also gave good yields with benzoylacetonitrile (85–92%,
3f–3i). Further, N-methyl substituted isatoic anhydride produces
good yields when subjected to a variety of substituted benzoylace-
tonitrile (83–86%, 3j–3l). Furthermore, heterocyclic aroylacetoni-
triles also resulted in the desired product (Table 2).
2-Furoylacetonitrlie and 2-Thionylacetonitrile react with N-methyl
substituted isatoic anhydride/isatoic anhydride and produce
product in good yields respectively (81–89%, 3m–3p). In the case
of 5-bromo isatoic anhydride, the desired products were obtained
in excellent yields (91–92%, 3q, and 3r). Interestingly, when the
aliphatic 4,4-dimethyl-3-oxo-pentanenitrile was employed for this
transformation, it also gave the desired product 3s in 80% yield.
However, our reaction did not yield the desired product with the
1,3-Diphenyl-propane-1,3-dione and acetophenone (Table 23t,
and 3u).
(a)
O
O
O
R2
R1
K2CO3
O
+
R1
R2
H2O, 80 °C
N
H
N
H
O
R1 = Alkyl, Aryl
(b)
(c)
R
2 = COR, COOR
O
O
CN
3 steps
+
Wentrup' work
NH2
O
R
CN
N
R
H
O
R1
R1
R2
CuCl2, L-Proline, K2CO3
aq.NH3, Reflux
R2-CHO
+
X
N
H
X = Br, Cl, I
R1 = CN, NO2, SO2Ar, COAr
This work:
(d)
O
O
O
CN
DABCO (2 equiv)
O
+
R2
CH3CN, 80 °C
MW, 30 Min
CN
N
R1
R2
N
R1
O
R2 = Aromatic/heteroaromatic/aliphatic
R1 = H, CH3
Scheme 1. Scheme for the reactions.
compared to classic traditional heating [24]. Therefore, substantial
interest in the reaction under microwave was put forward by syn-
thetic organic chemists. DABCO, being an organic base, has found
its advantages in carrying out organic transformations because of
its availability, low-cost, non-toxic, and non-polluting nature
[25]. Herein, we propose a one-pot DABCO-mediated protocol for
the construction of 3-cyano quinolones by efficient decarboxyla-
tive cyclization of isatoic anhydrides with aroyl or heteroaroyl or
alkoyl acetonitriles in CH3CN solvent under microwave irradiation
(Scheme 1d).
Results and discussion
The reaction was carried out by choosing isatoic anhydride (1a)
and benzoylacetonitrile (2a) as model substrates in the presence of
a base and solvent under microwave for 30 min. To test our
hypothesis, we did a reaction at 80 °C under conventional heating
and room temperature in the presence of 2.0 equivalent of differ-
ent bases. The reactions furnished the desired product 4-oxo-2-
phenyl-1,4-dihydro-quinoline-3-carbonitrile (3a) in 45–71% yields
(Table 1, entries 1–4). Encouraged by the positive results, further
investigation of the reaction was carried out to find the optimal
reaction conditions. To begin with, isatoic anhydride (1a) and ben-
zoylacetonitrile (2a) in CH3CN without base were subjected under
the microwave (300 W) for 30 min. The target product was formed
in a 10% yield (Table 1, entry 5). When, further reactions were car-
The structures of 2-(4-chlorophenyl)-1-methyl-4-oxo-1,4-dihy-
droquinoline-3-carbonitrile (3k) and 1-methyl-4-oxo-2-(p-tolyl)-1,
4-dihydroquinoline-3-carbonitrile (3l) were unambiguously
proved by X-ray single-crystal studies (Fig. 2).
A feasible mechanistic route for the formation of substituted 4-
quinolone (3a) is proposed in Scheme 2 based on the observations
and literature studies. A carbanion 4 was initially produced in the
presence of DABCO from the corresponding reactant 2a and react
with isatoic anhydride (1a) to form 5, which undergo decarboxyla-
2

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of reaction parameters for the synthesis of 4-quinolones.a
O
O
O
CN
Reagent
O
+
Solvent, MW, Time
CN
N
H
N
H
O
3a
1a
2a
Entry
Base
Watt (W)
Solvent
Temp. (°C)
Time
Yield (%)b
1
2
3
4
5
6
7
8
K2CO3 (2 equiv)
Na2CO3 (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
–
K2CO3 (2 equiv)
Na2CO3 (2 equiv)
Et3N (2 equiv)
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1,4 dioxane
H2O
80
80
80
rt
8 h
8 h
8 h
8 h
71
67
76
45
10
83
81
62
47
89
72
90
69
50
89
82
72
80
20
22
300
300
300
300
300
300
300
300
300
300
400
200
300
300
300
300
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
20 min
10 min
30 min
30 min
30 min
30 min
30 min
30 min
9
DBU (2 equiv)
10
11
12
13
14
15
16
17
18
19
20
DABCO (2 equiv)
DABCO (1 equiv)
DABCO (3 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
DABCO (2 equiv)
EtOH
MeOH
a
Reaction conditions: 1a (0.5 mmol), 2a (0.56 mmol), base (X equiv.), solvent (3 mL).
Isolated yield.
b
tion followed by intramolecular cyclization to form 6 and 7 respec-
tively. Finally, the intermediate 7 releases H2O to produce the tar-
get product 3a.
To demonstrate the generality of this scale-up synthesis, we
performed reactions on the 5 mmol scale and obtained 78% yield
of the product (Scheme 3).
isatoic anhydrides with active methylene groups namely aroyl/het-
eroaroyl/alkoylacetonitriles using DABCO as an eco-friendly, inex-
pensive, and non-toxic reagent under microwave condition. This
approach provides one of the easiest pathways for making this
class of compounds in good to high yield from easily available
starting materials in short reaction times. Besides, we have demon-
strated the potential utility of quinolones with a late-stage modifi-
cation to access highly substituted quinolines.
We attempted to assess the synthetic applicability of the 4-qui-
nolone derivatives after exploring the scope of this protocol. For
that, we have chosen 4-oxo-2-phenyl-1,4-dihydro-quinoline-3-
carbonitriles that are used as starting materials for the preparation
of diverse 4-chloro-2-phenyl-quinoline-3-carbonitrile using POCl3
followed by palladium-catalyzed Suzuki-Miyaura cross-coupling
with aryl boronic acids to yield 2,4-diphenyl-quinoline-3-carboni-
trile heterocycles. In general, polysubstituted quinoline-based
compounds are widely known for their biological, pharmacologi-
cal, and optoelectronic properties [26,27].
To pursue this goal, we transformed the 4-quinolone ring into
quinoline rings. Initially, 4-oxo-2-phenyl-1,4-dihydro-quinoline-
3-carbonitrile derivatives (3a–3d) were efficiently converted into
the corresponding 4-chloro-2-phenyl-quinoline-3-carbonitrile
derivatives (4a–4d) in 85–92% yields by following the previously
reported procedure using POCl3 at reflux condition (Table 3) [28].
Further, we opted to use 4a–4d as versatile synthetic intermedi-
ates for generating 2,4-diphenyl-quinoline-3-carbonitriles (6a–e)
in 54–74% yields via palladium-catalyzed cross-coupling with
phenylboronic acid (Table 3) [29]. Unambiguously, the structure
of the compound 6e was confirmed by single-crystal X-ray analysis
(Fig. 3). All compounds are stable solids and their structures were
established by IR, 1H NMR, 13C NMR, and mass spectroscopy.
Experimental section
General procedure for the synthesis of 4-quinolones (3a–s)
Isatoic anhydride (0.5 mmol), benzoylacetonitrile (0.56 mmol),
DABCO (1.0 mmol), and acetonitrile (3 mL) were taken in a 50 mL
round bottom flask equipped with a condenser. The resulting mix-
ture was placed in the microwave reactor (NlTeCH) at 300 W and
the temperature was set to 80 °C for 30 min. The progress of the
reaction was monitored by TLC. After completion of the reaction,
the reaction mixture was cooled to room temperature, and water
was added, and extracted with EtOAc. The combined organic layers
were then dried with anhydrous Na2SO4. The organic layer was
concentrated under reduced pressure and the residue was purified
by column chromatography on silica gel (Hexane/EtOAc) to get a
final product.
General procedure for the preparation of 4-Chloro-3-cyano-2-phenyl-
4-quinolines 4a–d
Conclusions
4-Quinolone (0.5 mmol) in 2.5 mL phosphorus oxychloride is
heated to 100 °C for 4 h. Whereupon TLC indicated that the reac-
tion was complete. The mixture is cooled to room temperature
and then diluted under stirring with ice water and the pH is
In conclusion, we have developed an efficient method to access
3-cyano 4-quinolone derivatives via decarboxylative cyclization of
3

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Table 2
Substrate scope.a
Entry
1
Isatioc anhydride
Nitrile
Product
Yield [%]b
89
2
3
87
84
O
O
CN
CN
N
H
3c
F
F
4
92
O
CN
N
H
3d
Me
5
6
93
85
O
CN
N
H
3e
OMe
O
O
Cl
CN
Cl
O
O
N
H
N
H
O
O
3f
7
8
86
87
O
Br
CN
Br
N
H
3g
N
H
O
O
O
Br
Br
CN
O
N
H
3h
N
H
O
Cl
9
92
O
O
CN
O
N
H
3i
N
H
O
Me
4

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Table 2 (continued)
Entry
10
Isatioc anhydride
Nitrile
Product
Yield [%]b
86
O
N
O
CN
CN
O
N
CH3
O
O
CH3
3j
O
11
83
O
O
N
N
CH3
CH3
3k
O
Cl
12
84
O
O
CN
N
N
CH3
O
O
O
CH3
3l
Me
13
83
O
CN
O
N
CH3
N
CH3
O
3m
O
14
81
O
O
CN
N
CH3
O
N
CH3
3n
S
15
88
O
O
O
CN
N
H
O
O
N
H
O
3o
16
89
O
O
O
CN
N
H
3p
N
H
S
17
92
O
O
Br
CN
Br
O
N
H
3q
N
H
O
O
(continued on next page)
5

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Table 2 (continued)
Entry
18
Isatioc anhydride
Nitrile
Product
Yield [%]b
91
O
O
Br
CN
S
Br
O
N
H
3r
N
H
O
19
80
O
O
O
CN
H3C
H3C
O
CH3
CH3
CH3
CH3 CN
N
H
3s
N
H
O
20
–
O
O
O
O
O
O
N
H
O
O
O
N
H
3t
21
–
O
O
O
CH3
N
H
3u
N
H
a
Reaction conditions: 1 (0.5 mmol), 2 (0.56 mmol), DABCO (2 equiv), 3 mL of CH3CN.
Isolated yield.
b
Table 3
Substrate scope for the synthesis of Quinoline derivatives.a,b
a
Reaction conditions: Step-1: 3a–d (0.5 mmol), POCl3 (2.5 mL), stirred at 100 °C for 4 h. Step-2: 4a–d (0.3 mmol), 5 (0.36 mmol), Pd(OAc)2 (5 mol%), PPh3 (15 mol%), K3PO4
(2.0 equiv), and EtOH (0.5 mL), H2O (1 mL), Toluene (2 mL) stirred at 100 °C for 18 h.
b
Isolated yield.
adjusted to 10 by the slow addition of saturated aqueous sodium
bicarbonate solution. The aqueous solution is extracted with EtOAc
and the combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated. The crude residue was
purified by column chromatography on silica gel (Hexane/EtOAc)
to get a final product.
General procedure for the synthesis of 2,4-diphenyl-quinoline-3-
carbonitriles (6a–e)
A sealed-tube was charged with 4-chloro-3-cyano-2-phenyl-4-
quinolines (0.3 mmol), phenylboronic acid (0.36 mmol), K3PO4
(2 equiv), PPh3 (15 mol%), and Pd(OAc)2 (5 mol%) in EtOH
6

Mugada Sugunakara Rao and S. Hussain
Tetrahedron Letters xxx (xxxx) xxx
Fig. 2. Single-Crystal XRD of 3k (CCDC 2075057), and 3l (CCDC 2075312).
by TLC analysis, the reactions were allowed to reach room temper-
ature. The reaction mixture was extracted with EtOAc. The com-
bined organic layers were then dried with anhydrous Na2SO4.
The organic layer was concentrated under reduced pressure and
the residue was purified by column chromatography on silica gel
(Hexane/EtOAc) to get a final product.
O
O
O
CN
O
O
N
H
O
CN
NH
DABCO
1a
NH
O
CN
O
O
4
2a
N
NH
N
5
-CO2
Declaration of Competing Interest
O
O
O
H
CN
CN
CN
OH
-H2O
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
N
H
N
H
NH
NH
O
N
3a
7
6
Acknowledgment
Scheme 2. The proposed mechanism for the synthesis of 4-quinolones.
M.S. Rao is thankful to IIT Patna for his research fellowship and
research support. Authors are thankful to SAIF (IIT Patna) for HRMS
and Single Crystal-XRD facility.
O
O
O
CN
DABCO (2 equiv)
O
+
CN
CH3CN, 80 °C
MW, 30 Min
N
H
N
H
O
Appendix A. Supplementary data
1a
5 mmol
2a
5.6 mmol
3a
78%
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153187.
Scheme 3. Gram scale synthesis.
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