Electrochemically induced one pot synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives via a four component-tandem strategy

Article abstract of DOI:10.1016/j.tetlet.2017.01.049

An efficient one pot, multicomponent-tandem synthesis of highly functionalized 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile is reported by electrochemically induced condensation of ethyl acetoacetate, hydrazine hydrate, malononitrile and various aroma

Full text of DOI:10.1016/j.tetlet.2017.01.049

Accepted Manuscript
Electrochemically induced one pot synthesis of 1,4-dihydropyrano[2,3-c]-pyr-
azole-5-carbonitrile derivatives via a four component-tandem strategy
Abhishek Upadhyay, Laxmi Kant Sharma, Vinay K. Singh, Rahul Dubey,
Narendra Kumar, Rana Krishna Pal Singh
PII:
S0040-4039(17)30071-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.049
TETL 48552
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 December 2016
12 January 2017
14 January 2017
Please cite this article as: Upadhyay, A., Kant Sharma, L., Singh, V.K., Dubey, R., Kumar, N., Krishna Pal Singh,
R., Electrochemically induced one pot synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile derivatives
via a four component-tandem strategy, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.01.049
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Electrochemically induced one pot synthesis
of 1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile derivatives via a four
component-tandem strategy
Leave this area blank for abstract info.
Abhishek Upadhyay, Laxmi Kant Sharma, Vinay K. Singh, Rahul Dubey, Narendra Kumar, Rana
Krishna Pal Singh*
O
O
NH2
NH2
.H2O
O
H
1
2
CN
O
N
CN
CN
N
O
NH2
H
EtOH, NaBr

1
Tetrahedron Letters
Electrochemically induced one pot synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile derivatives via a four component-tandem strategy
Abhishek Upadhyay, Laxmi Kant Sharma, Vinay K. Singh, Rahul Dubey, Narendra Kumar, 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
An efficient one pot, multicomponent-tandem synthesis of highly functionalized 1,4-
dihydropyrano[2,3-c]-pyrazole-5-carbonitrile is reported by electrochemically induced
condensation of ethyl acetoacetate, hydrazine hydrate, malononitrile and various aromatic
aldehydes. The reaction is carried out in an undivided cell, at a constant current in the presence of
NaBr as a supporting electrolyte and ethanol as solvent.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
1,4-Dihydropyrano[2,3-c]-pyrazole-5-carbonitrile
Multicomponent reaction,
Electrosynthesis
Atom economy
In recent decades, the multicomponent reactions (MCRs) have
been used extensively to prepare biologically active compounds
and have become an important field of research in organic,
combinatorial, and medicinal chemistry.1 MCR strategy offers
significant advantages over conventional linear-type synthesis
due to its soft, convergent and atom efficient nature.2 In recent
years, the synthesis of combinatorial small-molecule heterocyclic
libraries has emerged as a valuable tool in the searching of novel
drugs or biologically active molecules. Thus, the success of
combinatorial chemistry in drug discovery is considerably
dependent on further advances in MCR methodology and,
according to current synthetic demands, ecologically pure
multicomponent procedures are particularly welcome.
The electrochemical procedure is advantageous for a
multicomponent reaction in utilizing simple equipment, an
undivided cell that would be of value for a large-scale process
due to its catalytic nature, and the use of cheap and
environmentally friendly chemical reagent electricity. In
electrochemistry electro-generated base (EGB) promotes
reactions in good yields without use of acid, base or catalyst.
Electrosynthesis have many advantages which include high atom
economy, the use of mild reaction conditions, decreased energy
requirements and reduced reaction times. These advantages
prompted us to developed MCR strategy for synthesis of 1,4-
dihydropyrano[2,3-c]-pyrazole.
In continuation of our ongoing efforts towards synthesis of
medicinally important compound,23 we developed a convenient
and environmentally friendly method for multicomponent
synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile
derivatives by the electrochemical transformation using
acetoacetate, hydrazine hydrate, malononitrile and various
aromatic aldehydes as starting material in an undivided cell
(Scheme 1) at 40oC under a constant current density.
1,4-dihydropyrano[2,3-c]-pyrazole moiety (Fig. 1) often
appears as an important structural motif in biologically active
compounds and show broad range of biological and
pharmacological properties such as anticancer,3 anti-HIV,4
antimicrobial,5 antiviral,6
anti-inflammatory,7 insecticidal,
molluscicidal,8 anticoagulant, diuretic, antianaphylactic,9
antimalarial,10 and anti-proliferative11 agents. The biological
properties of 1,4-dihydropyrano[2,3-c]-pyrazole have attracted
many synthetic chemists to explore different methods suitable for
their synthesis, though there are several methods reported in the
literature for the formation of four component reaction such as by
using nano TiO2,12 nano-CuI,13 Fe3O4 nanoparticles,14 DABCO,15
DBU,16 isonicotinic acid,17 disulfonic acid imidazolium
OH
OH
O
H3C
HN
CH3
O
H3C
HN
CN
CN
chloroaluminate,18 piperidine and pyridine,19 pyrrolidine,20 iodine
HN
N
O
NH2
N
N
O
21
cerium ammonium nitrate (CAN).22 However, many of these
O
NH2
,
antiinflammatory agents
Molluscicidal agent
Chk1 kinase inhibitors
protocols require long reaction times, multi-step reactions and
complex synthetic pathways and afford products with only
modest yields. Therefore, the introduction of milder, faster and
more ecofriendly methods, accompanied with higher yields, are
needed.
Figure 1. biologically active compounds bearing
a
1,4-
dihydropyrano[2,3-c]-pyrazole core.

2
Tetrahedron
mA/cm2 (I = 50 mA, electrode surface = 5 cm2) promote the
O
O
NH2
NH
2 .H2O
reaction. Ethyl acetoacetate, hydrazine hydrate, malononitrile and
aromatic aldehydes yields 1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile efficiently at 40oC. We applied different amount of
current for the same reaction and found that at 10 mA/cm2
current densities (when 0.93 F/mol of electricity had been
passed), the yield of reaction was excellent (Table 2, entry 7).
Finally, to explore the scope and generality of the reaction, we
extended our work under optimized reaction conditions to
various substituted aryl aldehyde and notice that there was no
considerable effect of substituent (electron withdrawing group or
electron donating groups) on yields of reaction. In all cases, rapid
synthesis of the products occurred in good yields under optimum
reaction condition and the results are summarized in Table 3.
H3C
O
1
2
Electrolysis
CN
N
O
50 mA, EtOH, NaBr
N
CN
O
NH2
H
CN
H
3
4
5
Scheme 1. Synthesis of 1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile.
The synthesis of
1,4-dihydropyrano[2,3-c]-pyrazole-5-
carbonitrile generally requires large amounts of oxidants,
expensive catalyst and in situ purification along with produce
large amounts of undesired waste so developing greener and
efficient procedure is still an important need. Our study is based
on the electrochemically induced transformation of ethyl
acetoacetate, hydrazine hydrate, malononitrile and aromatic
aldehydes to 1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile
under optimum reaction conditions (current density 10 mA/cm2,
0.93 F/mol passed electricity, 40oC, EtOH) by electrolysis in an
undivided cell. The synthetic pathway is shown in Scheme 1.
In the present protocol product formed in good yield at room
temperature in short time using small amount of electricity as
energy, electro-generated base (EGB) induces the reaction. While
conventional heating method18 requires more energy and time
with expensive catalyst in harsh reaction condition.
Table 2a Optimization of reaction conditions for synthesis of
1, 4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile.a
O
O
NH2
NH2
.H2O
H3C
O
Electrolysis
2
1
CN
50 mA, ROH or MeCN,
NaBr
N
O
CN
CN
N
O
NH2
H
H
R = Et, Me, n-Pr
3
4
5
Current
density
(mA/cm2)
Electricity
Time
Temp
Yieldb
(%)
Solvent
I
(oC)
Table 1a Electrode optimization for the synthesis of 1,4-
dihydropyrano[2,3-c]-pyrazole-5-carbonitrile.
Passed
(mA)
(min)
(F/mol)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
15
50
100
05
15
25
50
50
03
10
20
01
03
05
10
10
10
10
240
240
240
120
120
90
02.23
07.46
14.92
00.37
01.11
01.39
00.93
01.08
01.24
01.39
25
25
25
40
40
40
40
40
40
40
15
25
36
45
65
80
90
80
65
60
Current density
(mA/cm )
Ent Anode/
Solvent/
Electrolyte
EtOH/NaBr
Yieldb
(%)
2
ry
1
Cathode
graphite/iron
1.0
45
2
3
4
5
6
7
8
graphite/iron
EtOH/NaBr
EtOH/NaBr
EtOH/NaBr
EtOH/NaBr
EtOH/NaBr
EtOH/NaBr
EtOH/NaBr
5.0
80
90
40
45
20
25
30
graphite/iron
10.0
10.0
10.0
5.0
graphite/graphite
Platinum/graphite
Platinum/graphite
RVC/graphite
RVC/graphite
30
35
N/A
N/A
n-PrOH 50
MeCN
40
aGeneral procedure: Ethyl acetoacetate (1 mmol), hydrazine hydrate (1.5
mmol), aromatic aldehydes (1 mmol), and malononitrile (1 mmol) electrolyte
(0.5 mmol), EtOH (25 mL).
50
45
aGeneral procedure: Ethyl acetoacetate (1 mmol), hydrazine hydrate (1.5
mmol), aromatic aldehydes (1 mmol), and malononitrile (1 mmol) electrolyte
(0.5 mmol), EtOH (25 mL), iron cathode (5 cm2), graphite anode (5 cm2).
bYield of isolated product.
bYield of isolated product.
The nature of the electrode system was the most important
factor in MCR reactions. To study the effect of electrode, we
performed the reaction using various electrode combinations
such as graphite-iron, graphite-graphite, platinum-graphite, RVC-
graphite respectively as anode and cathode at constant current
density. Current density proved to be the most important
characteristic of the electrode. This refers to the amount of
current applied per unit area of electrode surface. As the current
density increased for a given electrode, the yield of the product
increases significantly (Table 1, entries 1-3). Surprisingly,
electrodes that have a high surface area and a low current density
such as reticulated vitreous carbon24 (RVC) were inferior to
typical graphite electrodes. On screening different electrode
combination at constant current density, we find that the yield
was excellent with graphite-iron electrode combination. Hence
graphite-iron electrode was chosen as preferred electrode
combination.
At cathode :
In solution :
2EtOH
2e
H2
2EtO
EtOH
CH(CN)2
EtO
CH2(CN)2
Scheme 2. Synthesis of malanonitrile anion in alcohol.
A possible mechanism is outlined in Scheme 3. In initiation
step, the deprotonation of alcohol at cathode leads to the
formation of alkoxide anion. The reaction between alkoxide
anion and malononitrile in solution gives rise to malononitrile
anion (Scheme 2).
The Knoevenagel condensation of malononitrile anion 4 with
aromatic aldehyde 3 gives corresponding arylidenemalononitrile
C with elimination of hydroxide anion. On the other hand
For solvent optimization, the reaction performed under various
solvents and found that ethanol solvent at current density of 10
compound
A was synthesized by the reaction of ethyl
acetoacetate 1 and hydrazine hydrate 2, which enolised in the

3
CHO
OMe
OMe
3
4
35
35
85
86
208-210
presence of ethoxide ion to form compound B. Subsequently, the
enolizable compound B condensed with the Knoevenagel adducts
C via Michael addition to give intermediate D. Intermediate
product D by intramolecular cyclization converted in to final
product 5.
MeO
N
OMe
MeO
OMe
CN
3c
N
O
NH2
H
5c
CHO
168–170
N
4
CN
N
O
CN
CN
CN
-OH
3d
CN
N
H
O
N
H
O
NH2
5d
NO2
CHO
NO2
3
5
25
90
251–252
CN
O
CN
3e
H2N
EtO
CN
-H2O
NH2
C
N
N
N
N
H
O
O
-EtOH
O
5e
NH2
N
N
H
H
EtO
O
CHO
B
2
A
NO2
1
6
7
25
25
88
90
194–196
234–236
NO2
CN
3f
N
N
H
O
NH2
5f
CHO
Cl
CN
CN
CN
C
CN
NH2
N
N
Cl
3g
N
CN
O
N
O
N
N
H
N
OH
H
N
N
H
O
NH2
H
D
5g
5
CHO
8
9
30
35
90
76
146-148
Scheme 3. A plausible mechanism for the formation of 1,4-
dihydropyrano[2,3-c]-pyrazole-5-carbonitrile 5 compounds.
Cl
Cl
CN
3h
N
N
H
O
NH2
In the present studies we conducted a four component
reaction using hydrazine hydrate (1.5 mmol), ethyl acetoacetate
(1 mmol), malononitrile (1 mmol) and aromatic aldehydes (1
mmol) in solution of NaBr (0.5 M) in ethanol (25 mL). The
electrolysis was carried out in an undivided cell equipped with
graphite rods (5 cm2) as anode and Fe (5 cm2) as cathode at 40 °C
under constant current density 10 mA/cm2 (I = 50 mA). The
progress of the reaction was monitored by thin-layer
chromatography. After the electrolysis was complete (30 min),
the mixture was filtered and the solvent was evaporated under
vacuum. The residue was purified by recrystallization from EtOH
to furnish the desired product.
5h
OH
CHO
224–226
OH
3i
CN
N
N
H
O
NH2
5i
OH
CHO
10
35
76
232-234
OMe
N
OH
OMe
3j
N
N
H
O
5j
NH2
CHO
OH
11
12
35
30
80
90
198–200
196–198
MeO
OMe
Table 3 Electrochemical synthesis of 1,4-dihydropyrano[2,3-
c]-pyrazole-5-carbonitrile derivatives a b
MeO
OMe
OH
Ar
CN
3k
O
N
CN
Electrolysis
EtOH, NaBr
O
O
NH2
CN
CN
N
H
O
NH2
N
Ar
H
NH2 .H2O
O
N
5k
CN
O
NH2
CHO
R2
1
2
4
3a- 3n
5a - 5n
CN
CN
3l
Entry
1
Aryl
Product
Time
(min.)
30
Yieldc (%)
90
mp (0C)
243-246
N
N
H
O
5l
NH2
CHO
13
14
25
30
80
86
200-201
244-246
CN
3a
CHO
N
CN
N
H
O
NH2
N
N
H
O
NH2
5a
OMe
3m
CHO
5m
2
30
85
210–212
S
CHO
S
OMe
CN
CN
3b
N
N
N
H
O
NH2
N
H
3n
O
5b
NH2
5n
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.17,
25, 26
cYields of isolated pure compounds 5a–5n.

4
Tetrahedron
23. (a) Singh, S.; Sharma, L. K.; Saraswat, A.; Siddiqui, I. R.;
Kehri, H. K.; Singh, R. K. P. RSC Adv. 2013, 3, 4237; (b)
Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.;
Shireen; Waseem, M. A.; Singh, R. K. P. Synlett 2013, 2586;
(c) Siddiqui, I. R.; Srivastava, A.; Shamim, S.; Srivastava, A.;
Shireen; Waseem, M. A.; Abumhdi, A. A. H.; Srivastava, A.;
Pragati, Rai; Singh, R. K. P. Asian J. Org. Chem. 2013, 2,
519. (d) Singh, V. K.; Sharma, L. K.; Singh, R. K. P.
Tetrahedron Lett. 2016, 57, 407; (e) Upadhyay, A.; Sharma,
L. K.; Singh, V. K.; Singh, R. K. P. Tetrahedron Lett. 2016,
57, 5599.
In summary, we have developed
a simple, efficient,
economical, method for the synthesis of 1,4 -dihydropyrano[2,3-
c]-pyrazole carbonitrile derivatives, by one-pot four-component
reaction in ethanol in an undivided cell, in the presence of NaBr
as an electrolyte. The use of cheap and environmental friendly
chemical reagent electricity, low cast starting materials, non-
hazardous reaction conditions, high yields and ease of separation
of products through simple filtration thereby avoiding the need of
column chromatography are some significance of proposed
protocol.
24. Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996,
37, 8317.
25. Vekariya, R. H.; Patel, K. D.; Patel, H. D. Res. Chem.
Intermed. 2016, 42, 4683.
26. Mecadon; H.; Rohman, M. R.; Rajbangshi, M.; Myrboh, B.
Tetrahedron Lett. 2011, 52, 2523.
Acknowledgments
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. A. Upadhyay and V.K.S.
are grateful to the UGC-India for financial support and DS
Kothari postdoctoral fellowship.
References
1.
2.
3.
Elinson, M. N.; Merkulova, V. M.; Ilovaiskya, A. I.; Barba,
F.; Batanero, B. Electrochim. Acta 2011, 56, 8219.
(a) Orru, R. V. A.; Greef, M. de.; Synthesis 2003, 1471; (b)
Weber, L.; Drug Disc. Today 2002, 7, 143.
Wu, J. Y. C.; Fong, W. F.; Zhang, J. X.; Leung, C. H.;
Kwong, H. L.; Yang, M. S.; Li, D.; Cheung, H. Y. Eur. J.
Pharmacol. 2003, 9, 473.
4.
5.
6.
7.
Rueping, M.; Sugiono, V.; Merino, E. Chem. Eur. J. 2008, 14,
6329.
Shaabani, A.; Sarvary, A.; Rezayan, A. H.; Keshipour, S.;
Tetrahedron 2009, 65, 3492.
Martı´nez-Grau, A.; Marco, J. Bioorg. Med. Chem. Lett.
1997, 7, 3165.
Moon, D. O.; Kim, K. C.; Jin, C. Y.; Han, M. H.; Park, C.;
Lee, K. J.; Park, Y. M.; Choi, Y. H.; Kim, G. Y. Int.
Immunopharmacol. 2007, 7, 222.
8.
9.
Balaskar, R. S.; Gavade, S. N.; Mane, M. S. Chin. Chem. Lett.
2010, 21, 1175.
Albadi, J.; Mansournezhad, A.; Derakhshandeh, Z. Chin.
Chem. Lett. 2013, 24, 821.
10. De Andrade-Neto, V. F. ; Goulart, M. L. O.; Da Silva Filho, J.
F.; Da Silva, M. J.; Maria do Carmo, F.; Pinto, A. V.; Zalis,
M. G.; Carvalho, L. H.; Krettli, A. U. Bioorg. Med. Chem.
Lett. 2004, 14, 1145.
11. Venkatesham, A.; Rao, R. S.; Nagaiah, K.; Yadav, J.;
RoopaJones, G.; Basha, S.; Sridhar, B.; Addlagatta, A. Med.
Chem. Comm. 2012, 3, 652.
12. Shaterian, H. R.; Azizi, K. Res. Chem. Intermed. 2014, 40,
661.
13. Safaei-Ghomi, J.; Ziarati, A.; Tamimi, M. Acta Chim. Slov.
2013, 60, 403.
14. ElAleem, M. A.; El-Remaily, A. A. Tetrahedron 2014, 70,
2971.
15. Keyume, A.; Esmayil, Z.; Wang, L.; Jun, F. Tetrahedron
2014, 70, 3976.
16. Bhavanarushi, S.; Kanakaiah, V.; Yakaiah, E.; Saddanapu, V.;
Addlagatta, A.; VatsalaRani, J. Med. Chem. Res. 2013, 22,
2446.
17. Zolfigol, M. A.; Tavasoli, M.; Moosavi-Zare, A. R.; Moosavi,
P.; Kruger, H. G.; Shiri, M. V. Khakyzadeh, RSC Adv. 2013,
3, 25681.
18. Moosavi-Zare, A. R.; Zolfigol, M. A.; Noroozizadeh, E.;
Tavasoli, M.; Khakyzadeh, V.; Zare, A. New J. Chem. 2013,
37, 4089.
19. Katariya, L. K.; Kharadi, G. J. Int. J. Pharm. Res. Sch. 2014,
3, 627.
20. Liju, W.; Ablajan, K. Curr. Org. Synth. 2014, 11, 310.
21. Parshad, M.; Verma, V.; Kumar, D. Monatsh. Chem. 2014,
145, 1857.
22. Ablajan, K.; Liju, W.; Kelimu, Y.; Jun, F. Mol. Divers. 2013,
17, 693.

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.