Atmospheric oxygen mediated synthesis of pyrazole under visible irradiation

Article abstract of DOI:10.1016/j.tetlet.2015.07.039

A novel protocol has been reported for synthesis of pyrazoles by visible light irradiation in the presence of eosin Y, an organophotocatalyst under atmospheric oxygen. We have successfully carried out a visible light induced Michael addition followed by i

Full text of DOI:10.1016/j.tetlet.2015.07.039

Accepted Manuscript
Atmospheric oxygen mediated synthesis of pyrazole under visible irradiation
Snehalata Yadav, Pratibha Rai, Madhulika Srivastava, Jaya Singh, Kamala
Prasad Tiwari, Jagdamba Singh
PII:
S0040-4039(15)01192-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.07.039
TETL 46528
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 January 2015
12 July 2015
13 July 2015
Please cite this article as: Yadav, S., Rai, P., Srivastava, M., Singh, J., Tiwari, K.P., Singh, J., Atmospheric oxygen
mediated synthesis of pyrazole under visible irradiation, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.07.039
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Atmospheric oxygen mediated synthesis of pyrazole
under visible irradiation
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Snehlata Yadav, a Pratibha Rai, a Madhulika Srivastava a, Jaya Singhb, Kamla Prasad Tiwaria,
Jagdamba Singha
NH2
NC
N
NH NH2
CN
CN
N
R
4
eosin Y (1 mol%)
Ethanol,
X
X
2

1
Atmospheric oxygen mediated synthesis of pyrazole under visible irradiation
Snehalata Yadav, a Pratibha Rai, a Madhulika Srivastava,a Jaya Singh,bKamala Prasad Tiwaria and Jagdamba Singha*
aUniversity of Allahabad, Allahabad, 211002, U.P., India
bLRPG College, Sahibabad, Ghaziabad, U. P. India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel protocol has been reported for synthesis of pyrazoles by visible light irradiation in
presence of eosin Y, an organophotocatalyst under atmospheric oxygen. We have successfully
carried out a visible light induced Michael addition followed by intramolecular cyclization
reactions for the formation of heterocyclic ring. The present the method in incoprate advantages
such as being eco-friendly, invoving metal free condition, reporting excellent yield, using
minimum reaction time, making use of an easily available catalyst and eliminating the use of
column chromatography.
Available online
Keywords:
Visible light
Eosin Y
Pyrazole
Celebrex
Viagra
———
* Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: dr.jdsau@gmail.com

2
Tetrahedron
Now the chemists are adopting new trends in organic
mediated, one pot synthesis of highly funtionalized pyrazole
derivatives from easily available and simple starting materials
involving aldehyde (1), malononitrile (2), and phenylhydrazine
(3) and employing eosin Y as an organophotoredox catalyst and
atmospheric air (O2) as an oxidant. This strategy is significant
due to the involvement of a highly eco-friendly approach.
(Scheme 1). The reported method outweighs previously used
methods since it eliminate the use of thermal energy, involves
short reaction time, does not require quenching and involves
simple work up.
synthesis. Amongst them the solar energy is the most readily
available and a good source of visible light. 1a-b Visible light
photoredox processes provide a wide platform for researchers
which satisfy all parameters of green chemistry-like mild reaction
conditions, easy availability of solar energy, easy handling and
non toxicity. Since reaction takes place at room temperature and
atmospheric pressure so the use of thermal energy is not required
to initiate the reaction1c-e. The fact that molecular oxygen is
easily available in the atmosphere allows this method to
outweigh traditional methods2. There are certain organic
molecules which are not able to absorb the broad range of visible
light3a.. To overcome this hurdle we make of use photo
sensitizers and photo catalysts. Generally photo catalysts are
smoothly reduced as well as oxidized in excited state, hence can
be used both as electron donor and electron acceptor 3b. A
number of methods have been reported which include the use of
CN
NH2
NC
NH
NH2
CN
eosin Y (1 mol%)/ visible light
N
air, r.t. 5-15min
Ethanol,
2
N
X
Br
Br
R
3
HO
Br
O
O
4
CHO
X
eosinY
Br
R
COOH
organanometallic photo catalysts4a-k
.
However we have
1
incorporated the use of eosin Y [2-(2, 4,5,7-tetrabromo-6-
hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid] as a photoredox
catalyst due to its high reactivity and sufficient stability under
irradiation with visible light. Eosin Y has been used frequently as
a photo catalyst in visible light photoredox reactions. In the
presence of visible light eosin Y undergoes excitation to a triplet
state, which is more oxidizing and reducing as compared to the
previous state. In addition, the photo excited state of eosin Y also
plays a role in energy transfer 4h. This outweighs the use of
transition metal photo catalysts due to the former being more cost
effective and being easily available. Furthermore analogous to
excited Ru2+ the excited eosin Y also undergoes both reductive
and oxidative quenching. It has been used in place of Ru2+, and
Ir2+ complexes in visible light catalyzed reaction involving single
electron transfer5. Pyrazole nucleus form an elite class of hetero
scaffold. In recent years they have been used as ligands6a, chiral
catalysts6b and moieties to increase regioselectivity and
stereoselectivity. In addition they have also been used for the
preparation of dyes6c, couplers for photographic substances6d
Scheme1. Synthesis of target compound (4)
In our initial attempt we carried out reaction of aldehyde (1a)
1mmol, malononitrile (2a) 1mmol, and phenyl hydrazine (3a)
1mmol in ethanol in presence of 1 mol% of eosin Y and air. The
reaction mixture was irradiated in presence of simple household
compact fluorescent light (CFL, 22W) at room temperature. The
desired product was obtained in high yield with excellent purity.
This encouraged us to perform a series of experiments to assure
the necessity of several reaction conditions such as catalyst,
solvent, light, time and air to increase the yield of the product.
Our next Endeavour was to employ the best reaction conditions
with respect to the amount of catalyst and solvent so that it not
only contributed to the increase in yield but also decreased the
overall reaction time. We discovered that the ideal amount of
eosin Y is 1 mol% (Table 1, entry 1) for the model reaction.
When we increase the amount of catalyst beyond 1mol% , it did
not affect the yield of the product (Table1, entry 7, 8). But
decrease in the amount of catalyst from 1mol% to 0.2 mol%
and materials used in
florescence, luminescence and
herbicides6e. They also find wide application in pharmaceutical
industries since they form the central nucleus of many
commercially available drugs e.g. Celebrex, Zometapina,
Viagara, and Acomplia. (Figure 1)
NH2
N
CHO
NC
eosin Y (1 mol%)/ visible light
O2N
NH NH2
N
1a
air, r.t. 5-15min
Ethanol,
O2N
DPPH
CN
CN
3a
4a
no (4a) was formed
2a
Cl
Scheme. 2
Cl
Cl
N
N
O
CH3
resulted in a decrease in the amount of product (Table 1, entry
9). We concluded that ethanol is the best solvent for the reaction
because
N
N
NH
N
O
H3
C
HN
Cl
AC OM PLIA
N
Cl
NH2
N
R1
ZOM ETAPINA
its use not
only
NC
NH NH2
eosin Y (1 mol%)/ visible light
Ethanol, air, r.t. 5-15min
CN
H2NO2
S
O
N
N
N
X
Br
Br
O
S
NH
O
enabled a
good yield
but also
provide
easy
2
R
N
HO
Br
O
O
N
3
CHO
4
X
N
eosinY
CF3
Br
COOH
R
O
N
H3
C
1
N
CEL EB REX
VIAGRA
R1= CN, COOEt
workup.
Water and ethanol mix due to hydrogen bonding such that the
product separates very easily. With the above optimized
condition in hand we continue our optimization for the best
solvent under the established condition and results were tabulated
in Table (1). A series of control experiment were further
Figure 1 biologically active drug with pyrazole nucleus
Knoevengel condensation occurs between an aldehyde and
malanonitrile and the adduct form is used as an intermediate for
the synthesis of substituted alkenes and coumarin derivatives
which has been found useful in perfume and in cosmetic
industries. In addition it also has wide application in bioactive
compounds and pharmacological industries7. Literature survey
has revealed that a number of methods have been reported for the
synthesis of pyrazole nucleus (i). B.A. Bhat et.al synthesized
pyrazole nucleus with use of chalcones8a (ii) Xinting Zhang and
co-workers also synthesized pyrazole8b (iii) Piyush N. Kalaria
used l-Proline for synthesis of pyrazole nucleus8c. In continuation
of our previous work9 we have developed a visible –light-
CHO
NH2
NC
Reaction conditions
O2N
NH NH2
N
1a
N
CN
CN
O2N
3a
4a
2a
performed which showed that absence of florescent light,
photocatalyst or air, reduced the yield of the product considerably
(Table2, entry6, 7, 8, 9). These results indicate that the reaction

3
chemistry and require no further purification of the desired
product.
condition (photo catalyst, visible light and air) all are essential In
order to observe the electronic effect of the substituent on the
reactant the reaction was performed with different types of
aldehydes. Result shows that aldehydes with electron
withdrawing group (EWG) provided better result as compared to
aldehydes with electron releasing group (ERG). The product
formation takes place via a knoevenagel condensation7a,10
followed by a 1, 2 type addition,11 intramolecular cyclization and
air oxidation.
Acknowledgement
We (authors) Pratibha Rai and Madhulika Srivastava are grateful
to UGC, New Delhi, for the award of senior Research Fellowship
and also to Snehlata yadav thankful to UGC, New Delhi, for the
Research Fellowship.
for present protocol. These result indicate that fluorescent light
and air both are essential for the present protocol
Table 1 Optimization of solvent and amount of catalyst
Reaction conditiona : aldehyde (1a) 1mmol, malanonitrile (2a) 1mmol, and
phenyl hydrazine (3a) 1mmol, ethanol(5ml), 22W CFL(compact fluorescent
lamp) in presence of given amount of catalyst eosin Y. In condition (b) The
yields are for pure, isolated products
Table-2 Optimization of reaction condition
Entry
EosinY(mol%)
Solvent
EtOH
Time(min)
5
Yieldb
95
.
1
2
1
1
Reaction condition : aldehyde (1a) 1mmol, malanonitrile (2a) 1mmol, and
phenyl hydrazine (3a) 1mmol, ethanol(5ml), 22W CFL(compact
fluorescent lamp) in presence of given amount of catalyst eosin Y. In
condition (b) the yields are for pure, isolated products (c) desired product
not formed.* only aldehyde with electron withdrawing substituent gives
sufficient yield
CH CN
air3
6
72
Yieldb
Entry
Visible light
EosinY
Time(min.)
(mol%)
1
-
1
1
1
1
1
-
(%)
71
3
1
1
1
1
2
3
.2
DMSO
Atm.O2
8
5
1
2
3
4
5
6
7
8
9
22WCFL
95
4
CH3NO
Atm.O22
7
65
22WCFL
Dark
8
68
Atm.O2
5
6
trace
62
5
DCM
Daylight
Atm.O2
6
70
6
MeOH
5
80
22WCFL
Dark
N2
10
60*
c
N2
15
-
7
EtOH
N2
5
95
Daylight
Daylight
12
27
c
N
15
-
8
EtOH
5
95
2
.
c
Dark
-
N2
20
-
9
EtOH
12
80
Table 3 Scope of aldehyde and active mehylene group
Scheme 3 Proposed mechanism for the synthesis of pyrazole derivatives
CN
CH
C
CN
N
C
N
Reaction conditiona aldehyde (1a) 1mmol, malononitrile (2a) 1mmol, and
phenyl hydrazine (3a) 1mmol, in ethanol in presence of given amount of
catalyst in condition. bThe yields are for pure, isolated products
C
HN
H2
N
1,3 H shift
B
NH NH2
1. On the basis of our investigation and literature survey a
plausible mechanism of the reaction is shown in scheme (3)
which seems to follow radical pathway because it is quenched by
the addition of DPPH (scheme 2). It was further proven by
experiment that the reaction was not quenched either in presence
of DABCO (2 mol%) or 2,3 dimethyl-2-butyl (2mol%). It s
obvious that singlet oxygen is not utilized in the reaction
mechanism. Presence of triplet oxygen is a characteristic feature
of radical reaction. EY, an organophotoredox catalyst is excited
CN
CH
C
C
NH
CN
CN
N
R
H2N
A
C
CN
CN
1
to its singlet state EY* on absorption of visible light which
CHO
NH
NH2
N
NC
further convert in to its more stable triplet state 3EY* via Inter
System Crossing and undergoes single electron transfer (SET).
3EY* may undergo both oxidative12 and reductive quenching13.
Aldehyde (1) reacts with malanonitrile (2) to give Knoevengel
product (A) which undergoes 1, 2-addition with phenyl hydrazine
(3) resulting in the formation of (B). In our next step (B)
undergoes 1, 3 H shift forming (C) which further undergoes
intramolecular cyclization resulting in the formation of (D). A
NC
R
N
H
N
N
H
H
D
EOSINY*
EOSINY
VISIBLE LIGHT
EOSIN Y
SET
O2(AIR)
3
O2
NH2
N
SET from D to EY* generates radical cation (E) which gives
NC
-.
desired product (F) by attack of O2 Generation of superoxide
-
N
radical anion O2 during the reaction was proven by conforming
H
the resulting hydrogen peroxide using KI/starch indicator.14
E
O2
H2O2
To conclude, here we have developed an eco-efficient, clean and
photoredox catalyzed synthesis of highly functionalized pyrazole
derivatives in good to excellent yield. The most important feature
of this protocol is that it satisfies all of the parameter of green
NH2
NC
N
N
F

Entry
(1)
(3)
time
(min)
5
10
6
12
7
9
6
6
15
5
Yieldb
(%)
95
1
2
3
4
5
6
7
8
4-NO2CHOC6H4
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
PhNHNH2
4
Tetrahedron
CHOC6H5
93
94
90
89
85
93
92
90
94
88
91
89
9.
(a) Srivastava, M.; Rai, P.; Singh J.; Singh. J.; New J. Chem.,
2014, 38, 302; (b) Srivastava, M.; Rai, P.; Singh. J.; Singh.
J.; RSC Adv., 2013, 3, 16994; (c) Rai, P.; Srivastava, M.; Singh.
J.; Singh. J.; RSC Adv., 2014, 4, 779; (d) Yadav, S.; Srivastava,
M.; Rai, P.; Singh, J.; Tiwari ; P. K.; Singh , J.; New J. Chem.,
DOI:10.1039/C5NJ00002E
3-NO2CHOC6H4
4-OCH3 C6H4
4-OHCC6H4
1-OH C6H4
2- Cl C6H4
4- Cl C6H4
4-CH3 C6H4
4-F C6H4
2-OCH3 C6H4
3-CN C6H4
4-N-dimethylC6H3CHO
10. Ghosh, S.; Das, J.; Chattopadhyay, S.; Tetrahedron Letter, 2011,
52, 2869
9
10
11
12
13
11. Ananthakrishnan, R.; Gazi, S.; Catal. Sci. Technol., 2012, 2,
1463; (b) Shen, L., Cao, S.; Wu, J.; Zhang, J.; Li, H.; Liu, N.;
Qian, X.; Green Chem., 2009, 11, 1414; (c) Shandala, M. Y.;
Hamdy, A. M.; National Journal of Chem., 2008, 30, 338
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http://dx.doi.org/ 10.1055/s-0033-1340623; (b) Neckers, D. C.;
Valdes-Aguilera, O. M. ;Adv. Photo chem., 1993, 18, 315; (c)
Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S.; RSC, Adv. ,
2014, 4, 4181; (d) Hari, D. P.; Schroll, P.; König, B.; J. Am.
Chem. Soc., 2012, 134, 2958; (e) Xiao, T.; Dong, X.; Tang, Y.;
Zhou, L.; Adv. Synth. Catal., 2012, 354, 3195.
11
8
13
14
15
16
3,4dimethoxyC6H3CHO
C6H5CHO
PhNHNH2
14
12
14
89
86
85
4-BrPhNHNH2
4-ClPhNHNH2
4-OCH3 C6H4
13. . (a) Zhang, J.; Wang, L.; Liu, Q.; Yang, Z.; Huang, Y. Chem.
Commun, 2013, 11662; (b) Yadav, A. K.; Srivastava, V. P.;
Yadav, L. D. S. ; New J. Chem., 2013, 37, 4111.
14. Fekarurhobo, G. K.; Angaye, S. S.; Obomann, F. G.; .Emerging,
J.; Trends Eng. Appl. Sci., 2013, 4, 394.
under photocatalytic condition
Aldehyde1(1.00mmol), malanonitrile 2 (1.00mmol ), phenylhydrazine
3(1.00mol) and eosinY(1mol%) in ethanol was stirred at room
temperature under irradiation with 22W visible light lamp in presence
of air atmosphere for 5-15 minutes. The progress of reaction was
monitored by TLC. After completion of reaction, the reaction mixture
was filtered and resulting precipitate was washed with hot ethanol.
Characterization of representative compound and all the remaining
compounds match with authentic sample.
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5
Graphical Abstract
NH2
N
NC
NH NH2
CN
CN
N
R
4
eosin Y (1 mol%)
Ethanol,
X
X
2
3
CHO
R
room temperature
5-15 min
1
metal free condition
no column chromatography