Electrocatalytic one pot synthesis of medicinally relevant 4H-benzo[g]chromene and pyrano[2,3-g]chromene scaffold via multicomponent-domino approach

Article abstract of DOI:10.1016/j.tetlet.2017.09.048

A highly efficient one pot, multicomponent synthesis of 4H-benzo[g]chromene and pyrano[2,3-g]chromene derivatives are reported by electrochemically stimulated condensation of an aromatic aldehyde, malononitrile and some enolizable acidic compounds in etha

Full text of DOI:10.1016/j.tetlet.2017.09.048

Accepted Manuscript
Electrocatalytic one pot synthesis of medicinally relevant 4H-benzo[g]chro-
mene and pyrano[2,3-g]chromene scaffold via multicomponent-domino ap-
proach
Abhishek Upadhyay, Vinay K. Singh, Rahul Dubey, Narendra Kumar, L.K.
Sharma, Rana Krishna Pal Singh
PII:
S0040-4039(17)31175-9
https://doi.org/10.1016/j.tetlet.2017.09.048
TETL 49318
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 August 2017
15 September 2017
16 September 2017
Please cite this article as: Upadhyay, A., Singh, V.K., Dubey, R., Kumar, N., Sharma, L.K., Singh, R.K.P.,
Electrocatalytic one pot synthesis of medicinally relevant 4H-benzo[g]chromene and pyrano[2,3-g]chromene
scaffold via multicomponent-domino approach, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.09.048
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Graphical Abstract
Leave this area blank for abstract info.
Electrocatalytic one pot synthesis of medicinally
relevant 4H-benzo[g]chromene and pyrano[2,3-
g]chromene scaffold via multicomponent-domino
approach
Abhishek Upadhyay, Vinay K. Singh, Rahul Dubey,
Narendra Kumar, L. K. Sharma, Rana Krishna Pal Singh*
O
O
HO
OH
O
O
O
CHO
NC
O
NH2
CN
HO
O
NH2
CN
CN
CN
O
O
H2N
O
Electrolysis
EtOH, NaBr
Electrolysis
EtOH, NaBr
O

1
Tetrahedron Letters
journal homepage: www.els evier.com
Electrocatalytic one pot synthesis of medicinally relevant 4H-benzo[g]chromene
and pyrano[2,3-g]chromene scaffold via multicomponent-domino approach
Abhishek Upadhyay, Vinay K. Singh, Rahul Dubey, Narendra Kumar, L. K. Sharma, Rana Krishna Pal
Singh*
Electrochemical laboratory of green synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
∗ Corresponding author. Tel.: +91 532 2465287; fax: +91 532 2460533; E-mail address: rkp.singh@rediffmail.com (R.K.P.Singh)
ARTICLE INFO
ABSTRACT
A highly efficient one pot, multicomponent synthesis of 4H-benzo[g]chromene and pyrano[2,3-
g]chromene derivatives are reported by electrochemically stimulated condensation of an aromatic
aldehyde, malononitrile and some enolizable acidic compounds in ethanol at room temperature
under constant current density. By utilizing common electrode materials and a simple constant
current protocol, this method is a new alternative to conventional methods.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
2-amino-4H-benzo[g]chromene
Multicomponent reaction
Electrolysis
Atom economy
One pot
Electrochemical reaction is one of the most dynamic fields in
organic synthesis and achieved considerable attention in recent
years.1 In the same way, multicomponent reactions are also
attractive and greener synthetic tool to access diverse molecular
scaffolds.2 By merging both concepts, electrocatalyzed
multicomponent reactions (EMCRs) has appeared as a very
useful approach in organic synthesis. Multicomponent reactions
allowing access to compounds with structural complexity and
diversity in a single operation, with improved atom economy,
synthetic efficiency and a minimum number of reactions and
purification steps.3 While in an electrochemical reaction, electric
current serves as an economical and potentially renewable
reagent that avoids the need of harmful and expensive reagent. It
minimizes the waste produced in the reaction, reduced the energy
requirements and reaction times, in addition electrochemical
method can be considered as inherently safe. These features
make electrocatalyzed multicomponent reactions (EMCRs) well
suited for the construction of heterocyclic compound from
readily available starting materials.
is a demanding task for organic chemists. Various methodologies
for the synthesis of 2-amino-4H-benzo[g]chromene scafold has
been reported such as by using different catalysts including
NEt3,12 DBU,13 potassium phthalimide-Noxyl,14 Fe3O4
nanoparticles under ultrasonic irradiations,15 [bmim]OH ionic
liquid,16 Zn(L-proline)2,17 lipase,18 urea,19 and microwave
irradiation.20 However, some of these methods suffer from certain
restrictions and disadvantage such as multistep synthesis, use of
toxic organic solvents, tedious work-up procedure, high catalyst
loading, low yields, poor availability of the catalysts,
incompatibility with the environment and long reaction time.
Owing to the importance of 2-amino-4H-benzo[g]chromene
nucleus from a pharmaceutical and biological point of view, there
is still the need to develop efficient, mild and environmentally
benign procedure for the synthesis of 2-amino-4H-
benzo[g]chromene derivatives.
O
O
HO
O
HO
O
Chromenes has received overwhelming attention in the
pharmaceutical industry as well as in the diversified field of
O
O
4
organic synthesis due to their potential biological activities .
Pyranokunthone B
Pyranokunthone A
This moiety occurs in different natural products, including β-
lapachone , WS-5995A , pyranokunthone B and pyranokunthone
A (Fig. 1).5 The literature reveals that benzochromenes are
significant pharmacophores related with a wide range of
pharmacological activities, such as anticancer,6 antimalarial,7
anti-inflammatory8 and pesticides activities.9 In addition
chromene moieties are used as fluorescence markers 10 as well as
laser dyes11 in pharmacy and biology.
Due to the aforementioned properties and wide spectrum of
applications, synthesis of benzo[g]chromene derivatives has been
a domain of intense interest and the development of novel
strategies to access the 2-amino-4H-benzo[g] chromene scaffold
O
O
O
O
O
O
O
O
β
-lapachone
WS-5995A
Figure 1. Some examples of biologically significant compounds
having chromene core.

2
Tetrahedron
Recently, we have reported the synthesis of a series of
substituents efficiently reacted to afford the corresponding
products in excellent yields, demonstrating that there was no
considerable effect of substituent on yields of reaction. Further
we carried out the same reaction with non-aromatic aldehyde but
unfortunately reaction is not working under similar condition.
heterocycles using MCRs or domino reactions catalyzed by
electricity.21In the current paper, we report a an efficient domino
protocol for the synthesis of 2-amino-5,10-dioxo-4-phenyl-5,10-
dihydro-4H-benzo[g]chromene-3-carbonitrile derivatives 4 and
2,7-diamino-5,10-dioxo-4,9-diphenyl-4,9-dihydropyrano[2,3-
g]chromene -3,8-dicarbonitrile derivative 5 from one-pot, three-
component domino reactions of aromatic aldehyde, malononitrile
and 2-hydroxynaphthalene-1,4-dione or 2,5-dihydroxycyclohexa-
2,5-diene-1,4-dione in an undivided cell at room temperature
under a constant current density and catalyst-free conditions
(Scheme 1).
Table 1a Optimization of reaction conditions for synthesis of
2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H
benzo[g]chromene-3-carbonitrile.a
O
CHO
O
O
NH2
CN
Electrolysis
HO
CN
CN
50mA, ROH or MeCN
NaBr
O
O
O
CHO
O
O
NH2
CN
R = EtOH, MeOH, n-Pr
Electrolysis
HO
1
2
3
4
CN
CN
50mA, EtOH, NaBr
O
Electricity Yieldb
O
Current
Entry
Solvent
I
Time
(min)
density
(mA/cm2)
Passed
(%)
(mA)
1
2
3
4
(F / mol)
Scheme 1. Synthesis of 2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-
4H-benzo[g]chromene-3-carbonitrile.
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
n-PrOH
MeCN
5
1
180
120
60
0.56
0.74
0.74
0.62
0.70
0.62
0.62
0.62
58
70
80
90
78
76
80
78
10
20
50
75
50
50
50
3
4
O
10
15
10
10
10
20
CHO
O
O
NC
O
NH2
CN
Electrolysis
OH
CN
CN
15
H2N
O
2
2
50mA, EtOH, NaBr
HO
O
20
20
1
2
3'
5
20
Scheme 2. Synthesis of 2,7-diamino-5,10-dioxo-4,9-diphenyl-4,9-
dihydropyrano[2,3-g]chromene-3,8-dicarbonitrile.
aGeneral procedure: aromatic aldehydes (1 mmol), malononitrile (1 mmol),
and 2-hydroxynaphthalene-1,4-dione (1 mmol) electrolyte(0.5 mmol), EtOH
(25 mL), iron cathode (5 cm2), graphite anode (5 cm2).
bYield of isolated product.
At present time, organic reactions in green solvents such as
water, ethanol and their mixtures in the presence of green catalyst
have attracted much attention, because these solvents are safe,
economical, and environmentally benign. For this reason, we
concentrated our study to developing green novel synthetic
methods for the preparation of benzo[g]chromene-3-carbonitrile
derivatives. This is a one-pot electrocatalytic reaction which is
not only operationally simple, efficient, safe and clean but also
continually furnishes the corresponding products in good to
excellent yields. Thus, to find the suitable reaction media, the
reaction was carried out in various solvents (Table 1) under
constant current at room temperature and found that ethanol was
best solvent in term of yield and desired product.
Next to evaluate the synthetic potential of the proposed
method and to optimize the electrolysis conditions for the
synthesis of 2-amino-5,10-dioxo-4-phenyl-5,10-dihydro-4H-
benzo[g]chromene-3-carbonitrile 4 from aromatic aldehyde,
malononitrile and 2-hydroxynaphthalene-1,4-dione, we carried
out the reaction at different amount of current in ethanol solvent
in the presence of sodium bromide as an electrolyte. Excellent
conversions of the starting materials were obtained under 10
mA/cm2 current densities after 0.62 F/mol of electricity had been
passed. The current density 10 mA/cm2 (I = 50 mA, electrodes
surface 5 cm2) was found to be optimal for the electrochemical
reaction and allowed for the highest yield of 4 (Table 1). The
yield of reaction was reduced on further increase of the current
density from 10 mA/cm2 (I = 50 mA) which may be due to
acceleration of undesired direct electrochemical processes.
2EtO
H2
2EtOH
2e
At cathode :
OH
O
O
EtOH
In solution
EtO
N
N
C
C
N
N
C
C
N
N
C
N
N
C
C
CH
H
CH
CH
C
R
R
R
1
2
-H2O
O
3
OH
O
O
N
O
O
N
OH
NH
N
A
C
C
C
C
R
N
O
C
N
H
O
B
R
R
3'
O
O
OH
O
O
NH2
CN
R
HO
O
O
N
C
O
OH
C
R
N
HO
4
R
R
O
O
H
O
O
NC
HN
O
NH2
NC
H2
O
NH2
CN
O
NH
C
C
O
CN
R
N
O
N
HO
O
O
H
B'
R
R
5
R
C
R
O
O
N
O
NH2
CN
O
NH2
CN
N
C
C
C
To evaluate the scope and limitations of this electrocatalytic
protocol, we investigated a range of aromatic aldehydes (Table 2
and Table 3). As shown in Table 2, the aromatic aldehydes
having different electron-withdrawing and electron-donating
N
HO
HO
N
O
O
R
R

3
O
Scheme 3. A plausible mechanism for the formation of 4a-4h and
5a-5d compounds.
265-267
CHO
O
NH2
CN
7
28
88
A possible mechanism for the formation of products 4 and 5 is
shown in Scheme 3. The reaction initiates with the formation of
alkoxide anion from alcohol at cathode, which abstract hydrogen
from malanonitrile and form malononitrile anion. Then
Knoevenagel condensation of malononitrile anion and Aromatic
aldehyde takes place in the solution with the elimination of
OMe
O
OMe
1g
4g
OMe
OMe
O
O
NH2
CN
90
241-243
CHO
25
8
hydroxide
anion
and
formation
of
corresponding
benzylidenemalononitrile A. Subsequently the enolizable
compound 3 and 3’ condensed with the Knoevenagel adduct A
via 1,4-addition to give intermediate B and B’. Intermediate B
and B’ by intramolecular cyclization transformed into final
product 4 and 5.
O
4h
1h
a For the experimental procedure, see supporting information..
bAll compounds are known and were characterized by comparison of their
spectral data with those reported in the literature.11, 14, 17
cYields of isolated pure compounds 4a – 4h.
Table 2 Electrochemical synthesis of 2-amino-5,10-dioxo-4-
phenyl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile
Table 3 Electrochemical synthesis of 2,7-diamino-5,10-
dioxo-4,9-diphenyl-4,9-dihydropyrano[2,3-g]chromene-3,8-
derivatives a b
O
derivatives a b
CHO
O
O
O
NH2
CN
Electrolysis
EtOH, NaBr
HO
R
CN
CN
R
O
O
O
O
CHO
Electrolysis
EtOH, NaBr
NC
O
NH2
CN
OH
R
CN
CN
2
2
1a-1h
2
3
4a-4h
H2N
O
HO
R
O
1a-1d
2
3'
5a-5d
R
Entry
Aryl
Product
Time
(min.)
Yieldc
(%)
Mp
(0C)
Entry
Aryl
Product
Time
(min.)
25
Yieldc
(%)
90
Mp
(0C)
O
O
NH2
CHO
262-264
20
90
1
288-290
CHO
1
CN
O
O
NC
O
NH2
1a
4a
O
1a
H2N
O
CN
O
O
NH2
CN
92
250-252
CHO
20
2
5a
O
Cl
Cl
25
90
272-274
CHO
2
4b
1b
O
O
Cl
O
NC
O
NH2
CN
O
Cl
H2N
O
254-255
20
92
NH2
CN
3
CHO
1b
5b
O
Cl
Br
1c
4c
Br
Br
O
25
90
262-264
CHO
3
O
O
O
NH2
CN
96
240-242
CHO
18
4
NC
O
NH2
CN
Br
1c
H2N
O
O
5c
NO2
1d
4d
NO2
O
Br
NO2
O
248-250
CHO
NH2
CN
5
18
94
20
90
293-295
CHO
4
O
O
NC
O
NH2
CN
NO2
O
1e
NO2
1d
4e
H2N
O
NO2
5d
O
NO2
O
NH2
CN
90
244-246
CHO
25
6
a For the experimental procedure, see supporting information..
bAll compounds are known and were characterized by comparison of their
spectral data with those reported in the literature.11
cYields of isolated pure compounds 5a – 5d.
O
4f
OMe
1f
OMe

4
Tetrahedron
14. Dekamin MG, Eslami M, Maleki A. Tetrahedron. 2013;69:
1074.
In conclusion, we have developed a facile and efficient
electrocatalytic procedure for the synthesis 2-amino-5,10-dioxo-
4-phenyl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile
15. Safaei-Ghomi J, Eshteghal F, Shahbazi-Alavi H. Ultrasonics
Sonochem. 2016;33:99.
16. Yu Y, Gu H, Li X. J. Heterocycl. Chem. 2011;48:1264.
17. Maleki B, Babaee S, Tayebee R. Appl. Organomet. Chem.
2015;29:408.
derivatives
and
2,7-diamino-5,10-dioxo-4,9-diphenyl-4,9-
dihydropyrano[2,3-g]chromene-3,8-derivatives with excellent
yields by applying inexpensive and readily available electrode
materials such as Iron and graphite. This method is appropriate
for a wide range of substrates under constant current and ambient
conditions. In addition, this electrocatalytic protocol represents a
novel synthetic concept for multicomponent reactions, and allows
for the combination of the synthetic qualities of conventional
MCR with ecological benefits and convenience of simple
electrocatalytic method.
18. Yang F, Wang H, Jiang L, Yue H, Zhang H, Wang Z, Wang
L. RSC Adv. 2015;5,5213.
19. Brahmachari G, Banerjee B. ACS Sustainable Chem. Eng.
2014;2:411.
20. Wang XH, Zhang XH, Tu SJ, Shi F, Zou X, Yan S, Han ZG,
Hao WJ, Cao XD, Wu SS. J Heterocycl Chem. 2009;46:832.
21. (a) Singh S, Sharma LK, Saraswat A, Siddiqui IR, Kehri HK,
Singh RKP. RSC Adv. 2013;3:4237; (b) Upadhyay A, Sharma
LK, Singh VK, Singh RKP. Tetrahedron Lett. 2016;57:5599;
(c) Upadhyay A, Sharma LK, Singh VK, Dubey R, Kumar N,
Singh RKP. Tetrahedron Lett. 2017;58:1245. (d) Dubey R,
Singh VK., Sharma LK, Upadhyay A, Kumar N, Singh RKP.
New J. Chem. 2017;4:7836.
Acknowledgments
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. A. Upadhyay is grateful to
UGC–India for financial support and Vinay K. Singh for the
award of a DS Kothari postdoctoral fellowship award No. F.4-
2/2006 (BSR)/CH/14-15/0020.
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5
Highlights
ꢀ One pot four-component electro-synthesis
of 1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile derivatives
ꢀ Electro-induced condensation of ethyl
acetoacetate, hydrazine hydrate,
malononitrile and
aromatic aldehydes.
ꢀ EGB promotes reaction in presence of NaBr
as supporting electrolyte and ethanol as
solvent.
ꢀ Small amount of current was used as energy
source in the place of conventional heating.