Catalyst-free, visible light irradiation promoted synthesis of spiroacenaphthylenes and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones in aqueous ethyl lactate

Article abstract of DOI:10.1016/j.jphotochem.2020.113041

Catalyst-free three-component tandem approach can synthesize spiroacenaphthylenes and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones by Knoevenagel-Michael cyclocondensation via visible light irradiation in aqueous ethyl lactate at room temperature. The signif

Full text of DOI:10.1016/j.jphotochem.2020.113041

Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
Contents lists available at ScienceDirect
Journal of Photochemistry & Photobiology, A: Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Catalyst-free, visible light irradiation promoted synthesis of
spiroacenaphthylenes and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones in
aqueous ethyl lactate
Farzaneh Mohamadpour
School of Engineering, Apadana Institute of Higher Education, Shiraz, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords:
Catalyst-free three-component tandem approach can synthesize spiroacenaphthylenes and 1H-pyrazolo[1,2-b]
phthalazine-5,10-diones by Knoevenagel-Michael cyclocondensation via visible light irradiation in aqueous ethyl
lactate at room temperature. The significant advantages of the present protocol include energy-effectiveness,
catalyst-free, excellent yields, operational simplicity, high atom-economy, commercially accessible, inexpen-
sive preliminary substances, so it meets some features of sustainablility and green chemistry.
Catalyst-free
Visible light irradiation
Spiroacenaphthylenes
1H-pyrazolo[1,2-b]phthalazine-5,10-diones
1. Introduction
synthetic policies include restrictions regarding metal catalyst, the
expensive reagents, intense reaction conditions, uniform training pro-
Given the increased requests for influential, sustainable, and eco-
friendly synthesis methods in catalyst-free, green chemistry use was
very useful for preparing the organic mixtures over the last years due to
low expense, easy workup, low pollution, and precluding the catalyst
effect on substrates. Also, visible light irradiation has been a reliable
approach for green chemists because of its plentiful reserves of the en-
ergy, low cost and its renewable source of energy in the eco-friendly
synthesis of organic compounds [1,2]. In general, we employed light
emitting diodes and compact fluorescent lights as the sources of visible
light for various transformations.
cess, environmental hazard, long reaction time.
Searching for simple, effective, and eco-safe strategies, which, under
green circumstances, can increase organic reactions have fascinated
many researchers due to the mentioned difficulties and our consider-
ations for an environmentally benign protocols [41]. Therefore, we
report the catalyst-free synthesis of spiroacenaphthylenes and 1H-pyr-
azolo[1,2-b]phthalazine-5,10-diones with the CFL irradiation at room
temperature as green endorsing media in aqueous ethyl lactate via
tandem Knoevenagel-Michael cyclocondensation which can provide
short reaction times and the anticipated products in excellent yields to
overcome some expense problems in industry.
We report spiropyrans and pyrazolophthalazines with various
pharmacological features as (Fig. 1) anticancer [3], fungicidal [4], anti
HIV [5], antimalarial [6], antitubercular [7], in addition these spiro-
cycles are MDM2 inhibitor [8] and progesterone receptor modulator [9],
anti-inflammatory [10], anti micrbiological [11], vasorelaxant [12],
cardiotonic [13] and anticonvulsant [14].
2. Experimental
2.1. General
Many approaches are accessible such as Et3N [15], [BDDMA]Cl [16],
DABCO [17], DBU [18], Fe2O3 [19], NiFe2O4@SiO2@Melamine [20],
Isinglass [21], SBA-Pr-SO3H [22], InCl3 [23], NiCl2.6H2O [24], [Bmim]
OH [25], Ultrasound-assisted [26], P-TSA [27], STA [28], CuI nano-
particles [29], PTSA/[Bmim]Br [30], TBBAD [31], Cu(OAc)2.H2O [32],
K2CO3 [33], β-cyclodextrin [34], [Bu3NH][HSO4] [35], CuO nano-
particles [36], NZF@HAP-Cs [37], theophylline [38], carboxymethyl
cellulose [39] and STA-Amine-Si-Magnetite [40].
Using a 9100 electro-thermal device, the melting points of all com-
pounds were found. In addition, the nuclear magnetic resonance
recording, the spectrum (1H NMR) was performed on a Bruker (DRX-
400) instruments using DMSO-d6 as solvent. All reagents were pur-
chased from the chemical companies called Fluka, Merck, and Acros and
used without additional treatment.
The reported procedures may result in several cases. Some of
E-mail address: mohamadpour.f.7@gmail.com.
https://doi.org/10.1016/j.jphotochem.2020.113041
Received 25 September 2020; Received in revised form 8 November 2020; Accepted 11 November 2020
Available online 16 November 2020
1010-6030/© 2020 Elsevier B.V. All rights reserved.

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
N
H
O
O
N
N
N
MeO
O
O
O
N
HO
H
N
H
Elacomine
Horsifiline
Spirotryprostatin B
O
OH
O
O
CH3
OH
O
O
N
N
N
N
N
N
Nigellicine
Cinnopentazone
Nigellidine
Fig. 1. Some alkaloids containing biologically active compounds and heterocyclic spirooxindoles unit with two ring junction nitrogen atoms.
O
O
O
O
O
NH2
CN
Catalyst free, CFL (23 W)
EL/H2O (2:1) , rt
NC
CN
+
+
2
4a-i
1
3a-i
O
O
OEt
O
O
O
O
O
HN
O
NH
O
O
O
O
O
3a
3f
3b
3d
3e
3c
O
O
O
O
N
N
O
O
OH
3g
3h
3i
Scheme 1. Synthesis of spiroacenaphthylenes.
2.2. The overall process of preparing (4a-i)
acetate/n-hexane (1:3)). Afterwards, the filtering of the acquired solid
was conducted, then the solid was rinsed water (2 × 3 mL) and ethanol
(2 × 3 mL) and solid composition became recrystallized by EtOH. The
products were classified after the comparison of spectroscopic infor-
mation (1H NMR). Support for this manuscript can be found in the online
version.
Multifarious reagents including acenaphthequinone (1, 1.0 mmol),
malononitrile (2, 1.0 mmol) and various reagents including a-methyl-
encarbonylcompounds/enols (3a-i, 1.0 mmol) were reacted opposed to
CFL (23 W) irradiation at room temperature in aqueous ethyl lactate
(2:1, 3 mL) (Scheme 1). This was observed by TLC that employed (ethyl
2

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
O
O
NH2
O
R
H
N
NH
NH
CN
Catalyst free, CFL (23 W)
EL/H2O (2:1) , rt
N
+
NC
CN
+
O
O
2
5
6a-r
7 a-r
R
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
Me
OMe
Cl
MeO
OMe
Br
OMe
OH
6e
NO2
F
6a
6b
6c
6f
6d
6g
6h
6i
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
NO2
H
O
H
F
OMe
NO2
Cl
Me
Br
Cl
OMe
Me
6j
6k
6l
6m
6n
6o
6p
6q
6r
Scheme 2. Synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.
3

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
Table 1
Solvent optimization in synthesis of 4ca.
Isolated Yields (%)
Time (h)
Solvent (3 mL)
Entry
trace
43
14
10
10
10
14
8
H2O
1
EL
2
31
EtOH
3
22
H2O/EtOH (1:1)
EtOAc
4
trace
trace
74
5
Solvent free
EL/H2O (1:1)
EL/H2O (2:1)
EL/H2O (3:1)
CH3CN
6
5.5
5
7
91
8
91
5
9
24
14
14
14
14
12
14
14
10
11
12
13
14
15
16
45
DMSO
60
DMF
63
THF
38
MeOH
trace
trace
CHCl3
DCM
a
Reaction conditions: acenaphthequinone (1 mmol), malononitrile (1 mmol) and dimedone (1 mmol) in the presence of CFL (23 W) irradiation under catalyst-free
circumstances at rt.
Table 2
CFL optimization in synthesis of 4ca.
Isolated Yields (%)
Time (h)
Reaction conditions
Entry
76
81
84
91
91
5
5
5
5
5
CFL (18 W)
CFL (20 W)
CFL (22 W)
CFL (23 W)
CFL (32 W)
1
2
3
4
5
a
Reaction conditions: acenaphthequinone (1 mmol), malononitrile (1 mmol) and dimedone (1 mmol) in the presence of CFL irradiation under catalyst-free con-
ditions in EL/H2O (2:1) at rt.
2.3. The overall process of preparing (7a-r)
3. Results and discussion
Multifarious reagents including phthalhydrazide (5, 1.0 mmol),
malononitrile (2, 1.0 mmol) and aromatic aldehydes (6a-r, 1.0 mmol)
were reacted opposed to CFL (23 W) irradiation at room temperature in
aqueous ethyl lactate (2:1, 3 mL) (Scheme 2). This was observed by TLC
that employed (ethyl acetate/n-hexane (1:3)). Afterwards, the filtering
of the acquired solid was conducted, then the solid was rinsed water (2 ×
3 mL) and ethanol (2 × 3 mL) and solid composition became recrys-
tallized by EtOH. The products were classified after the comparison of
spectroscopic information (1H NMR). Support for this manuscript can be
found in the online version.
At first, Table 1 shows the results of the reaction between acenaph-
thequinone (1.0 mmol), malononitrile (1.0 mmol) and dimedone (1
mmol) (4c) in different solvents under catalyst-free conditions opposite
compact floating lamp radiation (CFL (23 W)) at room temperature.
Accordingly, a small amount of H2O, EL, EtOH, H2O/EtOH (1:1), EtOAc,
CH3CN, DMSO, DMF, THF, MeOH, CHCl3, DCM and solvent-free prod-
ucts were found. Extraordinary improvements were clear under EL/H2O
as a solvent (Table 1, entries 7–9). Using CFL (23 W) irradiation without
further catalyst, an ultra-91 % yield was established under EL/H2O (2:1)
as a solvent (Table 1, entry 8). Also, by changing the intensity of CFL (18
W, 20 W, 22 W, 23 W and 32 W) irradiation, the optimized conditions
were defined. According to Table 2, the best results were opposite the
compact fluorescent lamp (CFL) (23 W) irradiation (Table 2, entry 4).
4

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
Table 3
Catalyst-free synthesis of spiroacenaphthylenes.
5

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
Table 4
Solvent optimization in synthesis of 7da.
Isolated Yields (%)
Time (h)
Solvent (3 mL)
Entry
trace
52
10
8
H2O
1
EL
2
44
8
EtOH
3
35
8
H2O/EtOH (1:1)
EtOAc
4
trace
trace
78
10
8
5
Solvent free
EL/H2O (1:1)
EL/H2O (2:1)
EL/H2O (3:1)
CH3CN
6
4
7
93
4
8
94
4
9
29
10
12
10
10
8
10
11
12
13
14
15
16
51
DMSO
64
DMF
59
THF
41
MeOH
trace
trace
10
10
CHCl3
DCM
a
Reaction conditions: phthalhydrazide (1 mmol), benzaldehyde (1 mmol) and malononitrile (1 mmol) in the presence of CFL (23 W) irradiation under catalyst-free
circumstances at rt.
Table 5
CFL optimization in synthesis of 7da.
Isolated Yields (%)
Time (h)
Reaction conditions
Entry
73
82
89
93
93
4
4
4
4
4
CFL (18 W)
CFL (20 W)
CFL (22 W)
CFL (23 W)
CFL (32 W)
1
2
3
4
5
a
Reaction conditions: phthalhydrazide (1 mmol), benzaldehyde (1 mmol) and malononitrile (1 mmol) in the presence of CFL irradiation under catalyst-free in EL/
H2O (2:1) conditions at rt.
Table 3 and Scheme 1, shows that its functionality with different
substrates.
tautomering malononitrile irradiated with visible light in EL/H2O. The
combination of activated methylene 2 and acenaphthequinone 1 was
subjected to a Knoevenagel condensation in solution to give a cyanoo-
lefin A by removing water. Then, visible light activated the cyanoolefin
to form a free radical B. The intermediate B abstracted a methylene
hydrogen from malononitrile, and produced a malononitrile radical,
which in turn summarizes a hydrogen from dimedone 3 to form the
intermediate E. Therefore, intermediate B also becomes intermediate C.
Subsequently, the intermediate E reacted further with the intermediate
C by Michael’s additive, resulting in the intermediate F of shape, fol-
lowed by the intra-molecular cycle to produce the desired product 4c.
The proposed mechanism for the synthesis of (7a-r) is indicated by
the Scheme 4. The intermediate ylidenemalononitrile (cyano olefin) H
was willingly formed at the site of Knoevenagel concentration between
arylaldehyde 6 and active methylene compound 2 opposite the visible
light irradiation in the solvent (EL/H2O) which can be responded to by
the sterile effects of arylaldehydes on efficacy (Table 6). Then, visible
light could activate the mediator to form a free radical Intermediate I.
Intermediate I absorbs a hydrogen from methylene malononitrile 2, and
Also in continuation, Table 4 shows the results of the reaction be-
tween phthalhydrazide (1 mmol), benzaldehyde (1 mmol) and malo-
nonitrile (1 mmol) (7d) in different solvents under catalyst-free
conditions opposite compact floating lamp radiation (CFL (23 W)) at
room temperature. Accordingly, a small amount of H2O, EL, EtOH, H2O/
EtOH (1:1), EtOAc, CH3CN, DMSO, DMF, THF, MeOH, CHCl3, DCM and
solvent-free products were found. Extraordinary improvements were
clear under EL/H2O as a solvent (Table 4, entries 7–9). Using CFL (23 W)
irradiation without further catalyst, an ultra-93 % yield was established
under EL/H2O (2:1) as a solvent (Table 4, entry 8). Also, by changing the
intensity of CFL (18 W, 20 W, 22 W, 23 W and 32 W) irradiation, the
optimized conditions were defined. According to Table 5, the best results
were opposite the compact fluorescent lamp (CFL) (23 W) irradiation
(Table 5, entry 4). Table 6 and Scheme 2, shows that its functionality
with different substrates.
The scheme 3 indicates the proposed procedure for the synthesis of
4c. At first, the active methylene compound 2 was formed by
6

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
Table 6
Catalyst-free synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.
7

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
N
C
N
O
HN
C
N
H
C
C
-H2O
O
Knoevenagel condensation
photochemical
activation
CN
NC
O
2
A
1
photochemical
activation
N
.
NH
.
C
C
N
O
N
C
O
O
C
.
O
NH
H
O
C
CN
B
NC
CN
C
NC
H
CN
Michael addition
.
F
.
O
O
O
O
O
O
Tautomerization
3
D
E
O
O
O
O
H
O
O
NH2
NH2
H
CN
CN
N
C
N
O
C
4c
G
A
Ylidenemalononitrile
(Cyano olefin)
Scheme 3. Recommended mechanistic path for synthesizing spiroacenaphthylenes.
8

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
O
O
NH2
N
N
CN
R
HN
C
N
H
7
C
R
photochemical
activation
CN
NC
Cyclization and Tautomerization
H
O
2
6
Knoevenagel condensation
NH
O
O
O
O
NH
..
C
N
N
C
NH
N
CN
CN
H
C
R
N
N
..
H
K
L
R
R
photochemical
activation
. .
C
N
.
C
NH
N
C
N
R
C
R
I
Michael addition
NC
CN
NC
CN
J
.
NC
O
CN
..
NH
NH
R
O
H
5
Ylidenemalononitrile
(Cyano olefin)
Scheme 4. Recommended mechanistic path for synthesizing 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives.
thus converts malononitrile to radical malononitrile, thus, it is
composed of intermediate J which suffers from Michael addition of
Acknowledgments
–
phthalhydrazide 5 to the C C bond of J forms iminomethylene deriv-
We gratefully acknowledge financial support from the Research
council of the Apadana Institute of Higher Education.
–
ative intermediate K. Finally, the mentioned compounds (7a-r) were
created by intra-molecular cyclization and cooperation with tautome-
rization of Michael’s additive K.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.jphotochem.2020.
113041.
4. Conclusion
The study indicated a catalyst-free preparation of spiroacenaph-
thylenes and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones -a biologically
significant scaffold- via visible light irradiation as a low-cost and green
promoter in aqueous ethyl lactate at room temperature according to the
principles of green chemistry. The important points in the current study
include the use of non-hazardous reaction circumstances, application of
cheap initiating substances, operational simplicity, catalyst-free, sepa-
ration of the pure product by easy filtration thus avoids the need for
column chromatography, efficient features of the reaction, excellent
yields, metal-free, one key characteristic of the existing work is to use
CFL irradiation as green endorsing media sufficiently remarking the
rising potential of CFL irradiation in organic synthesis.
References
[1] M. Zhang, Q.Y. Fu, G. Gao, H.Y. He, Y. Zhang, Y.S. Wu, Z.H. Zhang, ACS Sustain.
Chem. Eng. 5 (2017) 6175.
[2] F. Mohamadpour, J. Saudi. Chem. Soc. 24 (2020) 636.
[3] Y. Liu, H. Wang, J. Wan, Asian J. Org. Chem. 2 (2013) 374.
[4] A.H. Abdel-Rahman, E.M. Keshk, M.A. Hanna, S.M. El-Bady, Bioorg. Med. Chem.
12 (2004) 2483.
[5] G. Kumari, M. Modi, S.K. Gupta, R.K. Singh, Eur. J. Med. Chem. 46 (2011) 1181.
[6] B.K. Yeung, B. Zou, M. Rottmann, S.B. Lakshminarayana, S.H. Ang, S.Y. Leong,
J. Tan, J. Wong, S. Keller-Maerki, C. Fischli, A. Goh, J. Med. Chem. 53 (2010)
5155.
[7] V.V. Vintonyak, K. Warburg, H. Kruse, S. Grimme, K. Hübel, D. Rauh,
H. Waldmann, Angew. Chem. Int. Ed. Engl. 49 (2010) 5902.
[8] S. Yu, D. Qin, S. Shangary, J. Chen, G. Wang, K. Ding, D. McEachern, S. Qiu,
Z. Nikolovska-Coleska, R. Miller, S. Kang, J. Med. Chem. 52 (2009) 7970.
Declaration of Competing Interest
The authors report no declarations of interest.
9

F. Mohamadpour
Journal of Photochemistry & Photobiology, A: Chemistry 407 (2021) 113041
[9] A. Fensome, W.R. Adams, A.L. Adams, T.J. Berrodin, J. Cohen, C. Huselton,
A. Illenberger, J.C. Kern, V.A. Hudak, M.A. Marella, E.G. Melenski, J. Med. Chem.
51 (2008) 1861.
[24] S.H. Song, J. Zhong, Y.H. He, Z. Guan, Tetrahedron Lett. 53 (2012) 7075.
[25] D.S. Raghuvanshi, K.N. Singh, Tetrahedron Lett. 52 (2011) 5702.
[26] M.R. Nabid, S.J. Rezaei, R. Ghahremanzadeh, A. Bazgir, Ultrason. Sonochem. 17
(2010) 159.
[10] C.K. Ryu, R.E. Park, M.Y. Ma, J.H. Nho, Bioorg. Med. Chem. Lett. 17 (2007) 2577.
[11] J. Liu, J. Li, L. Zhang, L. Song, M. Zhang, W. Cao, S. Zhu, H. Deng, M. Shao,
Tetrahedron Lett. 53 (2012) 2469.
[27] M. Sayyafi, M. Seyyedhamzeh, H.R. Khavasi, A. Bazgir, Tetrahedron 64 (2008)
2375.
[12] N. Watanabe, Y. Kabasawa, Y. Takase, M. Matsukura, K. Miyazaki, H. Ishihara,
K. Kodama, H. Adachi, J. Med. Chem. 41 (1998) 3367.
[28] M.V. Reddy, P.C. Kumar, G.C. Reddy, C.S. Reddy, C. R. Chim. 17 (2014) 1250.
[29] J. Safaei-Ghomi, H. Shahbazi-Alavi, A. Ziarati, R. Teymuri, M.R. Saberi, Chin.
Chem. Lett. 25 (2014) 401.
[13] Y. Nomoto, H. Obase, H. Takai, M. Teranishi, J. Nakamura, K. Kubo, Chem. Pharm.
Bull. 38 (1990) 2179.
[30] R. Ghahremanzadeh, G.I. Shakibaei, A. Bazgir, Synlett 2008 (2008) 1129.
[31] R. Ghorbani-Vaghei, S. Noori, Z. Toghraei-Semiromi, Z. Salimi, RSC Adv. 4 (2014)
47925.
`
[14] S. Grasso, G. De Sarro, A. De Sarro, N. Micale, M. Zappala, G. Puja, M. Baraldi,
C. De Micheli, J. Med. Chem. 43 (2000) 2851.
[15] M. Saeedi, M.M. Heravi, Y.S. Beheshtiha, H.A. Oskooie, Tetrahedron 66 (2010)
5345.
[32] F. Mohamadpour, M.T. Maghsoodlou, R. Heydari, M. Lashkari, Res. Chem.
Intermed. 42 (2016) 7841.
[16] J. Zheng, Y. Li, Mendeleev. Commun. 3 (2012) 148.
[17] A. Hasaninejad, F. Mandegani, M. Beyrati, A. Maryamabadi, G. Mohebbi,
ChemistrySelect 2 (2017) 6784.
[33] M. Abdesheikhi, Z. Karimi-Jaberi, J. Chem. Res. 39 (2015) 482.
[34] Y.A. Tayade, D.S. Dalal, Catal. Lett. 147 (2017) 1411.
[35] M.A. Shaikh, M. Farooqui, S. Abed, Res. Chem. Intermed. 44 (2018) 5483.
[36] S. Patil, A. Mane, S. Dhongade-Desai, J. Iran. Chem. Soc. 16 (2019) 1665.
[37] B. Maleki, S. Barat Nam Chalaki, S. Sedigh Ashrafi, E. Rezaee Seresht,
F. Moeinpour, A. Khojastehnezhad, R. Tayebee, Appl. Organomet. Chem. 29 (2015)
290.
[18] P. Saluja, K. Aggarwal, J.M. Khurana, Synth. Commun. 43 (2013) 3239.
[19] M.T. Maghsoodlou, R. Heydari, F. Mohamadpour, M. Lashkari, Iran. J. Chem.
Chem. Eng. 36 (2017) 31.
[20] N.H. Nasab, J. Safari, J. Mol. Struct. 1193 (2019) 118.
[21] S. Javanshir, N.S. Pourshiri, Z. Dolatkhah, M. Farhadnia, Monatsh. Chem. 148
(2017) 703.
[38] F. Mohamadpour, Org. Prep. Proced. Int. 52 (2020) 64.
[39] F. Mohamadpour, Polycycl. Aromat. (2020), https://doi.org/10.1080/
10406638.2020.1768412.
[22] G.M. Ziarani, N.H. Mohtasham, A. Badiei, N. Lashgari, J. Chin. Chem. Soc. 61
(2014) 990.
[40] P. Arora, J.K. Rajput, Appl. Organomet. Chem. 32 (2018) e4001.
[41] F. Mohamadpour, Res. Chem. Intermed. 46 (2020) 1931.
[23] M.V. Reddy, Y.T. Jeong, Tetrahedron Lett. 54 (2013) 3546.
10