Straightforward synthesis of diverse dipyrazolylmethane derivatives and their application for fluorescence sensing of Cu2+ ions

Article abstract of DOI:10.1039/c6ra10530k

A variety of dipyrazolylmethane derivatives were synthesized from the reactions of readily available β-keto esters with arylhydrazine hydrochlorides and DMF in the presence of p-toluenesulfonic acid (p-TsOH). This methodology provides a concise and practical one-pot route for the construction of diverse dipyrazolylmethane derivatives in good yield. As an application, the synthesized nitro-substituted compound displayed an excellent turn-off fluorescence sensing property for the detection of Cu²⁺ ions.

Full text of DOI:10.1039/c6ra10530k

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PAPER
Straightforward synthesis of diverse
dipyrazolylmethane derivatives and their
application for fluorescence sensing of Cu ions†
Cite this: RSC Adv., 2016, 6, 56323
2+
Kaliappan Kaliraj, Likai Xia, Thomas Nesakumar Jebakumar Immanuel Edison
and Yong Rok Lee*
A variety of dipyrazolylmethane derivatives were synthesized from the reactions of readily available b-
keto esters with arylhydrazine hydrochlorides and DMF in the presence of p-toluenesulfonic acid (p-
TsOH). This methodology provides a concise and practical one-pot route for the construction of
diverse dipyrazolylmethane derivatives in good yield. As an application, the synthesized nitro-
substituted compound displayed an excellent turn-off fluorescence sensing property for the detection
Received 23rd April 2016
Accepted 6th June 2016
DOI: 10.1039/c6ra10530k
2
+
www.rsc.org/advances
of Cu ions.
dipyrazolylmethane derivatives include a thermal reaction of
-aryl-3-methylpyrazol-5-ones with quinazoline or quinoxa-
Introduction
1
1
3
Pyrazoles are important heteroaromatic compounds that line (path a, Scheme 1). More useful methods rely on the
possess a wide range of biological properties. Some of them reactions of 1-aryl-3-methylpyrazol-5-ones with formamide
1
4
3
have been currently commercialized as medicines or insecti- and phosphoryl chloride (POCl ) or DMSO in the presence of
1
5
cides, including Celebrex, Acomplia, Doramapimod, or NaOAc and LiBr (path b, Scheme 1). Although several
1
Fipronil. They have also been used as a building block for the synthetic approaches for the preparation of dipyrazolyl-
synthesis of bioactive natural products and functional methane derivatives starting from pyrazolones have been
materials, such as ligands, UV stabilizers, and dyes. Among developed, there is still a need for more facile and efficient
2
3
4
5
these, molecules bearing a dipyrazole moiety exhibit a range arsenals. To the best of the authors' knowledge, there are no
6
of important biological activities, such as antitumor, cyto- reports of the straightforward synthesis of dipyrazolyl-
7
8
9
7a
toxic, antibacterial, antifungal, anti-inammatory, anti- methanes from commercially available arylhydrazine hydro-
1
0
11
oxidant, and molluscicidal activities. Owing to their chlorides, b-keto esters, and DMF.
importance and usefulness, several methods for the prepa-
This paper describes a novel methodology for the
synthesis of a variety of dipyrazolylmethane derivatives 4
1
2
ration of dipyrazole derivatives have been developed.
Representative
approaches
for
the
synthesis
of using arylhydrazine hydrochlorides 1 with b-keto esters 2
and DMF as the carbon source and solvent in the presence of
Brønsted acid via pyrazolone 3 formation (Scheme 2). As an
application, the synthesized dipyrazolylmethanes were
2
+
evaluated as uorescence probe for the detection of Cu
ions.
Scheme
1
Reported
methods
for
the
synthesis
of
dipyrazolylmethanes.
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic
of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631; Tel: +82-53-810-2529
†
Electronic supplementary information (ESI) available: Experimental procedures,
characterization data for new compounds. CCDC 1474418. For ESI and
crystallographic data in CIF or other electronic format see DOI:
Scheme
2 Our strategy for the synthesis of a variety of
1
0.1039/c6ra10530k
dipyrazolylmethanes.
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Results and discussion
Reaction conditions optimization
Initially, the reaction of phenylhydrazine hydrochloride (1a)
ꢀ
and ethyl acetoacetate (2a) was conducted in DMF at 140 C for
2
4 h without any Brønsted acid. In this reaction, the desired
product 4a was produced in 47% yield together with the
intermediate pyrazolone 3a in 39% yield (entry 1, Table 1).
Treatment of 1a with ethyl acetoacetate (2a) in the presence of
one equivalent of pyridine p-toluene sulfonate (PPTS) in DMF
Fig. 1 X-ray structure of compound 4f (CCDC 1474418†).
ꢀ
at 140 C for 12 h provided product 3a (33%) together with 4a
(
5%) (entry 2). Using other Brønsted acids such as pyridinium
hydrochloride (Py$HCl), acetic acid (AcOH), or triuoroacetic
acid (TFA) at 140 C for 12 h, the desired product 4a was
ꢀ
Effect of substituents
formed in 52, 45, and 36% yield, respectively, together with the The scope of this reaction was further explored employing
formation of 3a in 27, 10, and 18% yield, respectively (entries different arylhydrazine hydrochlorides or benzylhydrazine
3
–5). Importantly, the best yield of 4a (75%) was obtained hydrochloride and several b-keto esters (Table 2). Reactions of
when the reaction was carried out with one equivalent of p- arylhydrazine hydrochlorides 1b–1h bearing electron-donating
ꢀ
toluenesulfonic acid monohydrate (p-TsOH$H
2
O) at 140 C for groups of 2-ethyl, 4-methyl, 4-isopropyl, 4-methoxy, 2,3-
6
h (entry 6). Decreasing the catalyst loading to 0.5 equivalent dimethyl, 2,4-dimethyl, and 2,5-dimethyl substituent on the
or increasing it to 2 equivalents failed to improve the yield benzene ring with ethyl acetoacetate (2a) in the presence of p-
ꢀ
(
entries 7 and 8). By using another one-carbon source, such as TsOH (1 equiv.) in DMF at 140 C for 6–8 h afforded the prod-
triethyl orthoformate, the desired product 4a was produced in ucts 4b–4h in 68–78% yield (entries 1–7, Table 2). In addition,
5% yield. The structure of 4a was assigned by spectroscopic reactions of arylhydrazine hydrochlorides 1i–1l bearing
data analysis and comparison with the reported spectral electron-withdrawing groups, such as 2-chloro, 4-nitro, 2,4-
6
1
4,15
1
data.
bonded OH peak at d 17.93 (s, 1H), ten aromatic peaks at provided products 4i–4l in 60–75% yield (entries 8–11). With the
.91 (d, J ¼ 7.8 Hz, 4H), 7.44 (dd, J ¼ 8.4, 7.8 Hz, 4H), 7.29–7.26 combinations of benzylhydrazine hydrochloride (1m) with ethyl
m, 2H), a vinyl proton peak at 7.25 (s, 1H), and a methyl peak acetoacetate (2a), the corresponding product 4m was obtained
The H NMR spectrum of 4a showed a hydrogen- dichloro, and 2,5-dichloro substituent on the aromatic ring
7
(
at 2.37 (s, 6H) ppm. The structure was further conrmed by the in 77% yield (entry 12). Other combinations of 2,5-dimethyl-
X-ray crystallographic analysis of related compound 4f phenylhydrazine hydrochloride (1h) with ethyl 3-oxohexanoate
1
6
(
Fig. 1).
(2b) or ethyl 4,4-diuoro-3-oxobutanoate (2c) afforded products
n and 4o in 72 and 73% yield, respectively (entries 13–14). With
4
ethyl 4,4,4-triuoro-3-oxobutanoate (2d), the desired product 4p
was isolated in 73% yield (entry 15).
Table 1 Optimization of the reaction conditions for the formation of
a
4a
Reaction mechanism
Scheme 3 presents the proposed reaction mechanism. Initially,
phenylhydrazine hydrochloride (1a) attacks the carbonyl group
of ethyl acetoacetate (2a) in the presence of p-TsOH to give 3-
0
methyl-1-phenyl-5-pyrazolone (3a), which converts to 3a by
0
keto–enol tautomerisation. Nucleophilic addition of 3a to 5,
b
Yield (%)
derived from the protonation of DMF by p-TsOH, affords
4a intermediate 6 which undergoes the elimination of water to
Entry
Brønsted acids
Time (h)
3a
0
form intermediate 7. The second nucleophilic addition of 3a to
leads to 8 followed by the elimination of dimethylamine to
furnish 9. The tautomerisation of 9 afforded nal product 4a.
To clarify this reaction mechanism via intermediate 3a,
1
2
3
4
5
6
7
8
—
24
12
12
12
12
6
8
6
6
39
33
27
10
47
5
52
45
7
PPTS
Py$HCI
AcOH
TFA
p-TsOH$H
p-TsOH$H
p-TsOH$H
p-TsOH$H
(1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
(0.5 equiv.)
(2 equiv.)
(1 equiv.)
18
36 control experiments were carried out, as shown in Scheme 4.
75 When phenylhydrazine hydrochloride (1a) was reacted with
2
2
2
2
O
O
O
O
Trace
Trace
Trace
Trace
55
60
65
ethyl acetoacetate (2a) in the presence of p-TsOH (1 equiv.) at
110 C for 1 h, two products 3a and 4a were isolated in 78 and
ꢀ
c
9
1
2% yield, respectively. In addition, the treatment of 3a in DMF
a
Reaction conditions: 1a (1.0 mmol). 2a (1.0 mmol) in DMF (5.0 mL) at
40 C. Isolated yields. Triethyl orthoformate (5.0 mL) was used
ꢀ
using p-TsOH at 140 C for 6 h provided the desired product 4a
in 75% yield. These results showed that the formation of 4a
proceeds via intermediate 3a.
ꢀ
b
c
1
instead of DMF.
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Table 2 Additional reactions for the synthesis of diverse dipyrazolylmethane derivatives in DMF
Entry Arylhydrazine hydrochlorides
b-Keto esters
Condition Product
Yield (%)
ꢀ
1
140 C, 6 h
68
ꢀ
2
140 C, 6 h
73
ꢀ
3
140 C, 6 h
69
ꢀ
4
5
6
140 C, 8 h
72
70
75
ꢀ
140 C, 8 h
ꢀ
140 C, 6 h
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Table 2 (Contd.)
Entry Arylhydrazine hydrochlorides
b-Keto esters
Condition Product
Yield (%)
ꢀ
7
8
140 C, 6 h
78
ꢀ
140 C, 6 h
75
ꢀ
9
140 C, 4 h
60
ꢀ
1
0
140 C, 6 h
73
ꢀ
1
1
1
2
140 C, 6 h
70
77
ꢀ
140 C, 6 h
ꢀ
1
3
1h
140 C, 6 h
72
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Table 2 (Contd.)
Entry Arylhydrazine hydrochlorides
b-Keto esters
Condition Product
Yield (%)
ꢀ
1
4
1h
140 C, 6 h
73
ꢀ
1
5
1f
140 C, 6 h
73
formation of different types of coordination compounds due to
18
keto–enol tautomeric effect of the pyrazolone derivatives. In
order to nd out the best uorescence probe, we have tested the

uorescence of ve synthesized dipyrazolylmethane derivatives
4a, 4e, 4j, 4k, and 4p), as shown in Fig. 2. Among these,
dipyrazolylmethane 4j is the best which showed maximum
(

uorescence intensity of 344 a.u. at 497 nm (lex ¼ 330 nm).
Other dipyrazolylmethane derivatives 4a, 4e, 4k, and 4p showed
very little uorescence intensity at excitation of 330 nm. In this
regard, the uorescence sensing ability of dipyrazolylmethane
4j was further examined. First, the selectivity of dipyrazolyl-
methane 4j was tested against ten different metal cations, such
3
+
2+
2+
2+
3+
2+
3+
2+
2+
2+
as Al , Ca , Cd , Co , Cr , Cu , Fe , Hg , Ni , and Pb
25 mM in MeCN), as shown in Fig. 3. The result suggested that
dipyrazolylmethane 4j could be used for the selective detection
(
Scheme 3 Proposed reaction mechanism for the formation of 4a.
2
+
of Cu ions by uorescence quenching. Aer the addition of
2
+
Cu to 4j, the uorescence of 4j was decreased approximately
Scheme 4 Control experiments.
2
+
Application for uorescence sensing of Cu ions
Most of the pyrazolone derivatives showed excellent uores-
17
cence sensing behavior on the metal cations and anions.
These on/off uorescence behaviors were attributed to the Fig. 2 Fluorescence spectra of dipyrazolylmethanes 4a, 4e, 4j, 4k and
4
p (1 ꢁ 10ꢂ4 M in MeCN, lex ¼ 330 nm).
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
uorescence quenching of 4j might be due to the formation of
2
+
20
a coordination complex between 4j and Cu ion (Scheme 5).
Conclusions
A simple and efficient methodology has been developed for the
synthesis of diverse and functionalized dipyrazolylmethane
derivatives starting from readily available b-keto esters and
phenylhydrazine hydrochlorides in DMF in the presence of p-
TsOH under relatively mild reaction conditions. The synthe-
sized nitro-substituted dipyrazolylmethane 4j exhibits excellent
2
+
turn-off uorescence sensing properties for Cu ions.
Fig. 3 Fluorescence responses of dipyrazolylmethane 4j in the pres- Acknowledgements
ence of 25 mM of various metal cations.
This study was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
NRF-2014R1A2A1A11052391) and the Nano Material Tech-
(
nology Development Program (2012M3A7B4049675).
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