Aqueous NH3-mediated syntheses of 2-styrylquinoline-4-carboxamides by domino ring opening cyclization strategy

Article abstract of DOI:10.1080/00397911.2020.1822409

A straightforward and efficient protocol for the synthesis of medicinally relevant 2-styrylquinoline-4-carboxamide has been developed by aqueous ammonia-mediated domino ring-opening and cyclization strategy of 3-hydroxyoxindole. The starting precursors 3-hydroxyoxindoles were easily prepared through organocatalytic “on water” reaction of isatin and benzalacetone in high yields. The wide substrate scope with operationally simple experimental procedures provides an opportunity to create library of 2-styrylquinoline-4-carboxamide derivatives.

Full text of DOI:10.1080/00397911.2020.1822409

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Aqueous NH3-mediated syntheses of 2-
styrylquinoline-4-carboxamides by domino ring
opening cyclization strategy
Chandran R. , Ashwini Pise , Suraj Kumar Shah , Rahul D. , Anirudh Baluni &
Keshri Nath Tiwari
To cite this article: Chandran R. , Ashwini Pise , Suraj Kumar Shah , Rahul D. , Anirudh
Baluni & Keshri Nath Tiwari (2020): Aqueous NH3-mediated syntheses of 2-styrylquinoline-4-
carboxamides by domino ring opening cyclization strategy, Synthetic Communications, DOI:
10.1080/00397911.2020.1822409
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1822409
Aqueous NH3-mediated syntheses of 2-styrylquinoline-4-
carboxamides by domino ring opening cyclization strategy
Chandran R., Ashwini Pise, Suraj Kumar Shah, Rahul D., Anirudh Baluni, and
Keshri Nath Tiwari
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Raebareli, Transit Campus, Lucknow, India
ABSTRACT
ARTICLE HISTORY
Received 17 April 2020
A straightforward and efficient protocol for the synthesis of medicin-
ally relevant 2-styrylquinoline-4-carboxamide has been developed by
aqueous ammonia-mediated domino ring-opening and cyclization
strategy of 3-hydroxyoxindole. The starting precursors 3-hydroxyoxin-
doles were easily prepared through organocatalytic “on water” reac-
tion of isatin and benzalacetone in high yields. The wide substrate
scope with operationally simple experimental procedures provides
an opportunity to create library of 2-styrylquinoline-4-carboxamide
derivatives.
KEYWORDS
Ammonia; cyclization; 3-
hydroxyoxindole; isatin;
quinoline-4-carboxamide
GRAPHICAL ABSTRACT
Introduction
The broad-spectrum biological profile of quinoline derivatives enlists them as one of the
most sought after chemical entities in medicinal chemistry for the development of new
clinical candidates.[1] The widespread occurrence of this privileged scaffold in natural
products,[2] pharmaceuticals[3] and agrochemicals has garnered great interest among
synthetic as and medicinal chemists. Particularly, quinoline-4-carboxamide with aryl
substitution at 2-position has been predominantly discovered with diverse chemothera-
peutic activities such as antimalarial,[4] antibacterial,[5] antiviral[6] and anticancer.[7]
DD107498, a quinoline-4-carboxamide derivative, demonstrates potent antimalarial
activity against multiple life-cycle stages of the Plasmodium parasite with acceptable
safety profile and good pharmacokinetic properties (Figure 1).[8] The molecular target
CONTACT Keshri Nath Tiwari
keshri.tiwari@niperraebareli.edu.in
Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Transit Campus, Lucknow, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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Figure 1. Selected biologically active quinoline-4-carboxamide derivatives.
for DD107498 is Translation elongation factor 2 (eEF2) which is responsible for the
GTP-dependent translocation of the ribosome along with messenger RNA. Similarly, a
novel series of quinoline-4-carboxamide derivatives have been shown to interact with
Cytochrome P450 enzymes which plays a key role in metabolic reactions of endogenous
and exogenous substrates (Figure 1).[9] Very recently, the quinoline-4-carboxamide ana-
logs were discovered as potent antiviral agents against Enterovirus D68 against respira-
tory as well as neuronal infections (Figure 1).[10]
Many efforts have taken center stage for the synthesis of 4-functionalized quinolines
over the decades with conventional and frequently used name reactions like
Pfitzinger, Skraup, Doebner-von Miller, Conrad-Limpach-Knorr.[11] However, many of
these reactions encounter severe limitations like harsh reaction conditions and low yield
compelling researchers to discover an alternative synthetic strategy for quinoline-4-car-
boxamides. Very recently, O-acyl oxime has been employed as a starting precursor for
direct access to quinoline-4-carboxamide. For example, the copper-catalyzed coupling of
O-acyl oxime with isatin yielded quinoline derivatives in excellent yield (Scheme
1A).[12] Along a similar line, the coupling of isatin with iodine-triggered N-centered
radical of oxime acetate provided straightforward quinoline-4-carboxamide
(Scheme 1B).[13] The multi-substituted quinoline-4-carboxamides were efficiently
obtained in good to excellent yields utilizing 1,1-enediamine in a reaction with
isatin (Scheme 1C).[14] Owing to widespread biological significance, the development of
synthetic methods for the direct access of quinoline-4-carboxamide is
urgently warranted.
The 3-hydroxyoxindole derivatives have found wide application in medicinal chemis-
try due to their diverse biological activities with many derivatives currently under pre-
clinical evaluation.[15] Our research program is primarily focused on the design and
development of synthetic methods leading to oxindole based heterocyclic scaffold of
medicinal relevance.[16] We have recently demonstrated the synthesis of 3-hydroxyoxin-
dole derivatives and their synthetic transformation to quinoline-4-carboxamide.[17] In
continuation, we planned to explore the synthetic utility of 3-hydroxyoxindole as a tem-
plate for direct access to quinoline-4-carboxamides. Herein, we wish to report a straight
forward domino ring-opening cyclization strategy of 3-hydroxyoxindoline leading to
direct access of quinoline-4-carboxamides (Scheme 1D).

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Scheme 1. Synthetic approaches for quinoline-4-carboxamide derivatives.
Results and discussion
To implement our strategy, the reaction of isatin 1a was attempted with benzalacetone
2a in aqueous media similar to our previous observation.[17] With DABCO as a base,
the desired product 3a was isolated in 75% yield after 1.5 h of reaction (Table 1, entry
1). Further to obtain the optimal conditions, the reaction was performed with isatin 1a
and benzalacetone 2a as a model substrate with varying solvent and base. The reaction
in aprotic organic solvents like CH3CN, DCE, DMF, Toluene, THF resulted in poor
yield (32–15%) of desired product 3a (Table 1, entries 2–6). However, the good yield of
product 3a (65–70%) was obtained in protic solvents like MeOH and EtOH (Table 1,
entries 7–8). Advantageously, no chromatographic purification was required for product
3a as it precipitated out in the reaction mixture. The attempt of reaction with organic
bases like DMAP, DBU, Et3N, pyridine, piperidine furnished desired product 5a in low
yields (Table 1, entries 9–13). The use of inorganic bases like K2CO3 and NaOH was
also not fruitful and resulted into a lower conversion (Table 1, entries 14–15).
With the optimized reaction conditions in hand, we next turned our attention toward
exploring the generality and scope of the synthetic protocol. Isatin containing both elec-
tron-donating (5-Me and 5-OMe) and electron-withdrawing (5-F, 5-Cl, and 5-Br)
groups on the oxindole afforded 3-substituted-3-hydroxyoxindole derivatives 3a–l in
good to the excellent yield of 60–80% (Figure 2). The spectral data of known 3-hydrox-
yoxindole derivatives (3a, 3c, 3f, 3j) were found in complete agreement with litera-
ture data.[18]

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Table 1. Optimization of reaction conditionsa for 3a.
Entry
Solvent
Base
Temp (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
H2O
CH3CN
DCE
DMF
Toluene
THF
MeOH
EtOH
H2O
H2O
H2O
H2O
H2O
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
DBU
Et3N
Pyridine
Piperidine
K2CO3
80
80
80
120
100
60
65
75
80
80
80
80
80
80
80
1.5
5
5
5
5
5
2
2
5
3
5
5
5
3
3
75
32
25
30
15
26
65
70
30
60
20
35
35
20
15
9
10
11
12
13
14
15
H2O
H2O
NaOH
aReaction conditions: 1a (1.36 mmol) 2a (1.36 mmol), DABCO (1.36 mmol) water (10 mL); bIsolated yield
With 3-hydroxyoxindole derivatives in hands, we next planned to perform a reaction
of 3a with aqueous NH3. Like our previous observation,[15] the reaction of 3a with
NH4OAc in boiling EtOH didn’t work out for this reaction as only traces of product 4a
were observed. As aqueous ammonia is used as source of nitrogen, we turned our atten-
tion toward use of ammonia. Accordingly, 3a was treated with an excess of 25% (v/v)
aqueous NH3 as nitrogen source in EtOH at 80oC which provided product 4a in 69%
yield (Table 1, entry 1). Further, the attempt was made to enhance the yield of reaction
by performing reactions in several solvents (Table 2). The reaction of 3a in MeOH and
CH3CN yielded 4a with moderate yield of 55 and 45%, respectively (Table 2, entries
2–3) whereas the use of water and THF as solvent was unfruitful and no desired prod-
uct was obtained (Table 2, entries 4–5).
Next, the scope and limitation of the substrate were investigated with optimized reac-
tion conditions. The reaction demonstrated a wide range of substrate scope as isatin
containing both electron-withdrawing (5-F, 5-Cl, and 5-Br) and electron-donating (5-
Me and 5-OMe) groups on the oxindole successfully yielded 2-styrylquinoline-4-carbox-
amides 4a–i in good yield (Figure 3). The unsubstituted isatin derivative 4a was
obtained with 69% yield. In general, the yield of desired product was found more in
case of electron-withdrawing group (5-Cl and 5-Br) than electron-donating group (5-
Me and 5-OMe). Probably, electron-withdrawing group helps in cleavage of N–CO
bond (mentioned in reaction mechanism). the The spectral data of 4a was found in
complete agreement with literature data.[10] Further, the reaction of 3a with hydrazine
and hydrazide as a source of amide nitrogen failed to provide expected product leading

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Figure 2. Substrate scope for 3-substituted-3-hydroxyoxindole derivatives.
Table 2. Optimization of reaction conditionsa for 4a.
Entry
Solvent
Temp. (oc)
Time (h)
Yield (%)b (4a)
1
2
3
4
5
EtOH
MeOH
CH3CN
H2O
75
65
80
80
60
6
8
10
10
10
69
55
45
No product
No product
THF
aReaction conditions: 3a (0.68 mmol), 1.0 mL of aq. NH3 (25% v/v), EtOH (10 mL); bIsolated yield

6
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Figure 3. Substrate scope for 2-styrylquinoline-4-carboxamides.
Scheme 2. The plausible reaction mechanism
to the complex reaction mixture. The reason of this failure is not very clear but possibly
ammonia being small in size may be able to perform the required transformation.
For the reaction mechanism, we observed a similar reactivity pattern as our previous
observation with ammonium acetate.[15] Based on the outcome of the product and our
earlier findings, a plausible mechanism for the formation of 4a from 3a is proposed in

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Scheme 3. Reaction of 3-hydroxyindole with I2
Scheme 2. The ammonia attacks on carbonyl of enone of 3a leading to the formation of
enamine 6. The amine of 6 then cyclizes with amide carbonyl of oxindole to produce
pyrrole-2-one 7. The further attack of NH2 of aniline on imine of pyrrole-2-one 7 pos-
sibly yields benzodiazepinone 8 which after ring-opening and release of amide group
provides 4-hydroxydihydroquinoline 9. Finally, the elimination of water leads to the for-
mation of product 4a.
To transform 3-hydroxyindole 3a into spirooxindole pyran skeleton, the iodocycliza-
tion strategy was attempted with I2 in EtOH as solvent (Scheme 3). To our surprise, the
dehydrated product 5a was obtained as a red solid in 80% yield. Under similar condi-
tions, the compound 3 b was also transformed to product 5a in 75% yield. This could
be a utilized as a practical and simple method to dehydrate 3-hydroxyoxindole to conju-
gated indoline-2-one derivatives which otherwise requires harsh conditions. The possible
mechanism could be activation of hydroxyl group by iodine that triggers elimination of
water to provide conjugated product. The application of other reagents like Eaton’s
reagent and FeCl3 with 3a in CH3CN also led to the formation of dehydrated product
5a in 60 and 70% yield respectively. The reason behind formation of product 5a could
be thermodynamic stability of conjugated enone system.
Conclusions
In summary, we have developed a direct and efficient method for synthesis of 2-styryl-
quinoline-4-carboxamides through domino ring-opening and cyclization strategy of
3-hydroxyoxindoles. Utilizing this method, a library of quinoline-4-carboxamide deriva-
tives was rapidly generated with good to a very good yield of products. The primary
amide functionality of quinoline ring provides ample opportunity for further transform-
ation into medicinally relevant therapeutic agents and work along this line is currently
in progress.
Experimental part
General
All the chemicals and reagents such as isatin, benzalacetone, 25% aqueous ammonia
solution, DABCO, etc. were purchased from commercial suppliers unless otherwise
1
stated. All the NMR spectra were recorded in DMSO-d6, 500 MHz for H and 125 MHz

8
C. R ET AL.
for 13C on JEOL 500 MHz instrument or 300 MHz for 1H and 75 MHz for 13C
BrukerAvance DPX-300. The chemical shifts are reported in ppm relative to DMSO-d6
as internal standards. Integrals are in accordance with assignments and coupling con-
stants are given in Hz. The HRMS data were recorded on Agilent-6530 QTOF/LCMS
instrument using electrospray ionization (ESI). All the infrared spectra were recorded
using Alpha-Bruker IR spectrometer in ATR mode and wavelengths (ꢀ) are reported in
cmꢁ1. Melting points were recorded using melting point apparatus by LABINDIA and
are uncorrected. All the reactions were performed in heating conditions and progress of
reaction was monitored by use of thin layer chromatography (TLC) performed on plates
coated with Silicagel 60 F254 with 0.2 mm thickness. Visualization was achieved by a
combination of ultraviolet light (254 nm), potassium permanganate and iodine chamber.
Column chromatography was performed using silica gel 100–200 mesh (Merck). The
yields refer to quantities obtained after purification by column chromatography.
General procedure for synthesis of (E)-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-
yl)indolin-2-one (3a)
To a stirred mixture of isatin (1a) (200 mg, 1.36 mmol) in 10 mL of water, benzalacetone
(2a) (198 mg, 1.36 mmol) and DABCO (152 mg, 1.36 mmol) were added and reaction
mixture allowed to stir vigorously at 80 ꢀC for 1.5 hours. After the TLC indicated com-
plete consumption of starting material, the reaction mixture was filtered and product 3a
was collected as white solid.
Spectroscopic data for product 3a (E)-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-
yl)indolin-2-one (3a):
Yield (75%) white solid, mp 160–162oC (dec.). IR (solid) ~v ¼ 3261, 3058, 1705, 1646,
1
1471, 1336, 1186, 1057, 976, 745, 687 cmꢁ1. H NMR (300 MHz, DMSO-d6) d ¼ 10.23
(s, 1H, NH), 7.70–7.62 (m, 2H, Ar-H), 7.54 (d, J ¼ 16.3 Hz, 1H, ¼CH), 7.46–7.38 (m,
3H, Ar-H), 7.26 (d, J ¼ 1.3 Hz, 1H, Ar-H), 7.15 (td, J ¼ 7.6, 1.3 Hz, 1H, Ar-H), 6.88 (td,
J ¼ 7.5, 1.0 Hz, 1H, Ar-H), 6.80–6.71 (m, 2H, 1 Ar-H, 1 ¼ CH), 6.04 (s, 1H, OH), 3.64
(d, J ¼ 16.4 Hz, 1H, CH2), 3.22 (d, J ¼ 16.4 Hz, 1H, CH2). 13C NMR (75 MHz, DMSO-
d6) d ¼ 196.2, 178.1, 142.6, 142.4, 134.2, 131.4, 130.5, 128.9, 128.4, 126.3, 123.7, 121.1,
109.3, 73.1, 47.6. DEPT-135 (75 MHz, DMSO-d6) d ¼ 142.5, 130.5, 128.9, 128.4, 126.3,
123.7, 121.1, 109.3, 47.6 (CH2). HRMS (ESI-TOF) m/z: [M þ H]þ Calcd for C18H16NO3
294.1130; found 294.1126.[18]
General procedure for synthesis of (E)-2-styrylquinoline-4-carboxamide (4a)
To a stirred mixture of (E)-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one
(3a) (200 mg, 0.68 mmol) in 10 mL of ethanol, 1 mL of aqueous ammonia solution (25%
v/v) was added and allowed to stir vigorously at 75 ꢀC. After the TLC indicated the
complete consumption of starting material after 6 hours of reaction, the solution was
concentrated under reduced pressure to get brown solid. The crude mixture was

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9
purified by column chromatography using ethyl acetate:hexane (4:6) as an eluent to
afford to get 4a as white solid.
Spectroscopic data for product 4a (E)-2-styrylquinoline-4-carboxamide (4a):
Yield (69%) white solid. mp 214–216ꢀC (dec.). IR (solid) ~v ¼ 3622, 3045, 2684, 1666,
1
1584, 1392, 1042 cmꢁ1. H NMR (300 MHz, DMSO-d6) d ¼ 8.28 (s, 1H), 8.18 (dd,
J ¼ 8.4, 1.4 Hz, 1H), 8.05 (d, J ¼ 8.3 Hz, 1H), 7.94 (d, J ¼ 2.6 Hz, 2H), 7.88 (s, 1H),
7.83–7.71 (m, 3H), 7.61 (ddd, J ¼ 8.3, 6.8, 1.3 Hz, 1H), 7.55 (s, 1H), 7.51–7.41 (m, 2H),
7.37 (t, J ¼ 7.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) d ¼ 168.6, 155.2, 148.0, 142.7,
136.1, 134.6, 129.9, 129.0, 128.8, 128.8, 128.3, 127.3, 126.7, 125.4, 123.2, 117.3. DEPT-
135 NMR (75 MHz, DMSO-d6) d 134.6, 129.9, 129.0, 128.8, 128.8, 128.3, 127.3, 126.7,
125.4, 117.3. HRMS (ESI-TOF) m/z: [M þ H]þ Calcd for C18H15N2O 275.1184;
found 275.1190.[10]
General synthesis of (Z)-3-((E)-2-oxo-4-phenylbut-3-en-1-ylidene)indolin-2-one (5a)
To a stirred mixture of (E)-3-hydroxy-3-(2-oxo-4-phenylbut-3-en-1-yl)indolin-2-one
(3a) (200 mg, 0.68 mmol) in 10 mL of ethanol, and 2.0 equivalent of iodine was added
and allowed to stir vigorously at 75 ꢀC for 5 hours. The reaction mixture was washed
with aqueous sodium thiosulfate solution and extracted with EtOAc three times. The
combined organic layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to get crude reaction mixture as red solid. The solid was purified by
column chromatography using ethyl acetate:hexane (3:7) as an eluent to afford to get 5a
as a red solid.
Spectroscopic data for product 5a (Z)-3-((E)-2-oxo-4-phenylbut-3-en-1-
ylidene)indolin-2-one (5a)
1
Yield (80%) red solid. mp 175–176 ꢀC (dec.). H NMR (500 MHz, DMSO-d6) d 10.76 (s,
1H, NH), 8.36 (d, J ¼ 7.7 Hz, 1H), 7.85 ꢁ 7.75 (m, 3H), 7.50 ꢁ 7.44 (m, 3H), 7.43 ꢁ 7.32
(m, 3H), 6.99 (t, J ¼ 7.7 Hz, 1H), 6.88 (d, J ¼ 7.8 Hz, 1H).13C NMR (125 MHz, DMSO-
d6) d 190.5, 169.0, 145.6, 145.0, 136.7, 134.9, 133.6, 131.6, 129.6, 129.5, 128.4, 128.3,
127.9, 122.3, 120.8, 110.8. DEPT-135 NMR (DMSO-d6) d 145.0, 133.6, 131.6, 129.6,
129.5, 128.4, 128.3, 127.9, 122.3, 110.8. HRMS (ESI-TOF) m/z: [M þ H]þ Calcd for
C18H14NO2 276.1025; found 276.1031.
Acknowledgements
The authors are thankful to Dr. S. J. S. Flora, Director, NIPER, Raebareli for his support and
encouragement in carrying out this research work. C. R., A. P., S. K. S., R, D.; and A. B. are
thankful to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of
India for providing fellowship. The authors are thankful to Central Instrumentation Facility
(CIF), NIPER, Raebareli and SAIF, CSIR-CDRI, Lucknow for providing spectral data. NIPER,
Raebareli communication no. NIPER-R/104.

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Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
The manuscript was prepared by the contribution of all authors.
References
[1] (a) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchal, S. N.; Patel, H. D. RSC.
Adv. 2014, 4, 24463–24476. DOI: 10.1039/C4RA01814A. (b) Kumar, S.; Bawa, S.;
Gupta, H. Mini. Rev. Med. Chem. 2009, 9, 1648–1653. DOI: 10.2174/
138955709791012247.(c) Liu, B.; Li, F.; Zhou, T.; Tang, X.-Q.; Hu, G.-W. J.
Heterocyclic. Chem. 2018, 55, 1863–1873. DOI: 10.1002/jhet.3241.
[2] Michael, J. P. Nat. Prod. Rep. 2008, 25, 166–187. DOI: 10.1039/b612168n.
[3] (a) Kundu, B.; Das, S. K.; Chowdhuri, S. P.; Pal, S.; Sarkar, D.; Ghosh, A.;
Mukherjee, A.; Bhattacharya, D.; Das, B. B.; Talukdar, A. J. Med. Chem. 2019, 62,
3428–3446. DOI: 10.1021/acs.jmedchem.8b01938. (b) Pinheiro, L. C. S.; Feitosa, L. M.;
Gandi, M. O.; Silveira, F. F.; Boechat, N. Molecules. 2019, 24, 4095. DOI: 10.3390/
molecules24224095.(c) Upadhyay, A.; Kushwaha, P.; Gupta, S.; Dodda, R. P.;
Ramalingam, K.; Kant, R.; Goyal, N.; Sashidhara, K. V. Eur. J. Med. Chem. 2018,
154, 172–181. DOI: 10.1016/j.ejmech.2018.05.014.(d) Afzal, O.; Kumar, S.; Haider, M.
R.; Ali, M. R.; Kumar, R.; Jaggi, M.; Bawa, S. Eur. J. Med. Chem. 2015, 97, 871–910.
DOI: 10.1016/j.ejmech.2014.07.044.(e) Gorka, A. P.; de Dios, A.; Roepe, P. D. J. Med.
Chem. 2013, 56, 5231–5246. DOI: 10.1021/jm400282d.
[4] (a) Kumar, A.; Srivastava, K.; Kumar, R.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med.
€
Chem. Lett. 2010, 20, 7059–7063. DOI: 10.1016/j.bmcl.2010.09.107. (b) Frohlich, T.;
Tsogoeva, S. B. J. Med. Chem. 2016, 59, 9668–9671. DOI: 10.1021/acs.jmedchem.6b01486.
[5] (a) Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P. J.
Med. Chem. 2009, 52, 2109–2118. DOI: 10.1021/jm900003c. (b) Hu, Y.-Q.; Gao, C.;
Zhang, S.; Xu, L.; Xu, Z.; Feng, L.-S.; Wu, X.; Zhao, F. Eur. J. Med. Chem. 2017, 139,
22–47. DOI: 10.1016/j.ejmech.2017.07.061.
[6] (a) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R. L.; Janda, L.; Strekowski, L.;
Schinazi, R. F. Med. Chem. Res. 1992, 2, 102–110. (b) Strekowski, L.; Mokrosz, J. L.;
Honkan, V. A.; Czarny, A.; Cegla, M. T.; Wydra, R. L.; Patterson, S. E.; Schinazi, R. F. J.
Med. Chem. 1991, 34, 1739–1746. DOI: 10.1021/jm00109a031.(c) Meanwell, N. A. J. Med.
Chem. 2016, 59, 7311–7351. DOI: 10.1021/acs.jmedchem.6b00915.
[7] Solomon, V. R.; Hu, C.; Lee, H. Bioorg. Med. Chem. 2010, 18, 1563–1572. DOI: 10.1016/j.
bmc.2010.01.001.
~
[8] Baragana, B.; Norcross, N. R.; Wilson, C.; Porzelle, A.; Hallyburton, I.; Grimaldi, R.;
Osuna-Cabello, M.; Norval, S.; Riley, J.; Stojanovski, L.; et al. J. Med. Chem. 2016, 59,
9672–9685. DOI: 10.1021/acs.jmedchem.6b00723.
[9] (a) Peng, C. C.; Cape, J. L.; Rushmore, T.; Crouch, G. J.; Jones, J. P. J. Med. Chem. 2008,
51, 8000–8011. DOI: 10.1021/jm8011257. (b) Dahal, U. P.; Jones, C. J.; Jones, J. P. J. Med.
Chem. 2012, 55, 280–1290. DOI: 10.1021/jm201207h.
[10] Musharrafieh, R.; Zhang, J.; Tuohy, P.; Kitamura, N.; Bellampalli, S. S.; Hu, Y.; Khanna,
R.; Wang, J. J. Med. Chem. 2019, 62, 4074–4090. DOI: 10.1021/acs.jmedchem.9b00115.
[11] Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M. Coc. 2005, 9, 141–161. DOI: 10.
2174/1385272053369196.
[12] Ramaraju, A.; Chouhan, N. K.; Ravi, O.; Sridhar, B.; Bathula, S. R. Eur. J. Org. Chem.
2018, 2018, 2963–2971. DOI: 10.1002/ejoc.201800501.

R
SYNTHETIC COMMUNICATIONSV
11
[13] Gao, Q.; Liu, Z.; Wang, Y.; Wu, X.; Zhang, J.; Wu, A. Adv. Synth. Catal. 2018, 360,
1364–1369. DOI: 10.1002/adsc.201701610.
[14] Wang, B.-Q.; Zhang, C.-H.; Tian, X.-X.; Lin, J.; Yan, S.-Y. Org. Lett. 2018, 20, 660–663.
DOI: 10.1021/acs.orglett.7b03803.
[15] Yu, B.; Xing, H.; Yu De, Q.; Liu, H.-M. Beilstein J Org Chem. 2016, 12, 1000–1039. DOI:
10.3762/bjoc.12.98.
[16] (a) Tiwari, K. N.; Pandurang, T. P.; Pant, S.; Kumar, R. Tetrahedron. Lett. 2016, 57,
2286–2289. DOI: 10.1016/j.tetlet.2016.04.047. (b) Tiwari, K. N.; Taur, P. P.; Pant, S.;
Sreelekha, P. Synth. Commun. 2018, 48, 802–808. DOI: 10.1080/00397911.2018.
1425726.(c) Tiwari, K. N.; Prabhakaran, S. M.; Kumar, V.; Thakar, S. R.; Mathew, S.
Tetrahedron. 2018, 74, 3596–3601. DOI: 10.1016/j.tet.2018.05.020.(d) Tiwari, K. N.;
Thakar, S. R.; Kumar, V.; Prabhakaran, S. M. Synth. Commun. 2018, 48, 2965–2972.
DOI: 10.1080/00397911.2018.1525740.(e) Chandran, R.; Prabhakaran, S. M.; Kumar, V.;
Thakar, S. R.; Tiwari, K. N. ChemistrySELECT 2019, 4, 12757–12761. DOI: 10.1002/
slct.201903301.(f) Chandran, R.; Prabhakaran, S. M.; Tiwari, K. N. J. Heterocyclic.
Chem. 2020, 57, 2628–2633;(g) Chandran, R.; Tiwari, K. N. Synthesis. 2020, 52,
2233–2240. DOI: 10.1055/s-0040-1707816.
[17] Tiwari, K. N.; Choubey, R.; Shukla, S.; Gautam, P. ARKIVOC. 2018, 2018, 165–173. part
iii, DOI: 10.24820/ark.5550190.p009.760.
[18] Yan, T.; Wang, X.; Sun, H.; Liu, J.; Xie, Y. Molecules. 2013, 18, 14505–14518. DOI: 10.
3390/molecules181214505.