Iodine-mediated construction of polyfunctionalized arylazopyrazoles from β-ketoesters or 2-arylpyrazol-3-ones and arylhydrazines

Article abstract of DOI:10.1039/c6ob01158f

This paper describes step-economic iodine-mediated construction of functionalized arylazopyrazoles in the presence of catalytic AgNO₃ starting from simple β-ketoesters and two equivalents of arylhydrazines. This cascade reaction includes in situ α-iodination of β-ketoesters, pyrazol-3-one formation, substitution with a nitrogen nucleophile, and oxidation/aromatization.

Full text of DOI:10.1039/c6ob01158f

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Iodine-mediated construction of polyfunctionalized
arylazopyrazoles from β-ketoesters or
2-arylpyrazol-3-ones and arylhydrazines†
Cite this: DOI: 10.1039/c6ob01158f
Rameshwar Prasad Pandit,a Sung Hong Kimb and Yong Rok Lee*a
Received 27th May 2016,
Accepted 24th June 2016
This paper describes step-economic iodine-mediated construction of functionalized arylazopyrazoles in
the presence of catalytic AgNO3 starting from simple β-ketoesters and two equivalents of arylhydrazines.
This cascade reaction includes in situ α-iodination of β-ketoesters, pyrazol-3-one formation, substitution
with a nitrogen nucleophile, and oxidation/aromatization.
DOI: 10.1039/c6ob01158f
www.rsc.org/obc
Azopyrazoles (or arylazopyrazoles) are also distributed
as the core structure in many food colorings, dyes and
Introduction
Pyrazoles (or arylpyrazoles) are heteroaromatic compounds bioactive compounds (Fig. 1).10 They exhibit biological activi-
possessing a wide range of biological and pharmacological ties, such as antifungal,11 antibacterial,12 and HIV-1 inhibitory
properties.1–9 These pyrazole-containing molecules have properties.13 Recently, arylazopyrazoles have been widely used
potent anti-inflammatory,1 antifungal,2 antibacterial,3 anti- as important photoswitches offering quantitative isomeriza-
viral,4 analgesic,5 antipyretic,6 and protein kinase inhibitory tion14 and light-responsive molecular switches in cyclodextrin-
activities.7 Some of them are currently used as commercialized based supramolecular systems.15 Because of their medicinal
medicines, such as rimonabant (1), celecoxib (2), and the and industrial significance, several synthetic methods for azo-
insecticide, fipronil (3) (Fig. 1).8 Pyrazoles are also used as pyrazoles and arylazopyrazoles have been developed over the
building blocks for the synthesis of bioactive natural products, past decade.16 Most of the synthetic strategies rely on the coup-
agrochemicals, and medicines.9
ling of diazotized salts with ketoesters12–13,16a and direct deri-
vatization from pyrazoles.16 Despite these achievements, they
suffer from certain drawbacks including the requirement of
multiple synthetic steps, raw material availability, harsh reac-
tion conditions, and low yield.
Recently, we have developed a novel method for the
synthesis of diverse arylazopyrazoles by a silver-catalyzed
cascade reaction of diazo compounds with aryl hydrazines
(Scheme 1).17 Nevertheless, more environmentally benign and
simple approaches for the construction of arylazopyrazoles
from commercially available starting materials with high diver-
sity are still in strong demand. As a part of an ongoing study
on the development of a safer and more reliable synthetic
methodology for arylazopyrazoles, we describe an iodine-
mediated cascade process for the construction of polyfunctio-
Fig. 1 Selected examples of bioactive molecules bearing the arylpy-
razole and arylazopyrazole skeleton.
aSchool 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
bAnalysis Research Division, Daegu Center, Korea; Basic Science Institute,
Daegu 702-701, Republic of Korea
†Electronic supplementary information (ESI) available: 1H NMR, 13C NMR,
IR and HRMS. See DOI: 10.1039/c6ob01158f
Scheme 1 Our previous strategy for the synthesis of arylazopyrazoles
from diazo compounds.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
next attempted using halogenating reagents to transform
β-ketoester 1a into arylazopyrazole. The treatment of 1a with
2a in the presence of one equivalent of iodine in acetonitrile at
70 °C for 12 h provided the product 3a in 90% yield (entry 3)
along with 5% of arylazopyrazole. With iodine (1 equiv.) and
acetic acid (1 equiv.), the product 4a was obtained in 45% yield
(entry 4). Importantly, the addition of several silver salts
(AgOTf, AgOAc, AgNO3, Ag2O, and Ag2CO3) as a catalyst in
different solvents provided the desired product 4a in higher
yield (entries 5–14). Among these, when the reaction was
carried out in the presence of iodine/acetic acid using
10 mol% AgNO3 in 1,2-dichloroethane, 4a was produced in the
highest yield (85%) (entry 12) without detection of 3a rather,
the complete conversion of 1a took place in just 6 h under the
above conditions. In other nonpolar or polar solvents, the
yield of 4a did not improve. The use of other halogenating
reagents, such as N-bromosuccinimide (NBS) and N-chloro-
succinimide (NCS) in combination with acetic acid and 10 mol%
AgNO3 was less effective than iodine/acetic acid (entries 15
and 16). In addition, the role of 2-iodoxybenzoic acid (IBX) as
an oxidizing reagent was unsatisfactory in increasing the yield
of 4a (entry 17). The structures of 3a and 4a were determined
by analysis of their spectral data and comparison with the
reported compound.17
Scheme 2 New synthetic strategy for the construction of multifunctio-
nalized arylazopyrazoles.
nalized arylazopyrazoles using commercially available β-keto-
esters or 2-arylpyrazol-3-ones instead of the corresponding
diazo compounds (Scheme 2). The current method avoids the
use of prefunctionalized and potential explosive α-diazo com-
pounds and features pseudo three-component reactions that
can install two different hydrazine moieties in the same molecule.
Results and discussion
This study was initiated by examining the reaction of ethyl
acetoacetate (1a) with two equivalents of phenylhydrazine (2a)
as model substrates to obtain an arylazopyrazole (Table 1).
A reaction of 1a with 2a in acetonitrile at 70 °C for 12 h pro-
vided 3a in 53% yield (entry 1) without the isolation of the
expected arylazopyrazole 4a. With 10 mol% of AgOTf as a cata-
lyst, the yield of 3a was increased to 65% (entry 2) along with
isolation of 5% of the desired product 4a. The reaction was
Under the optimized conditions, the substrate scope and
generality for the construction of various polyfunctionalized
arylazopyrazoles were examined using a variety of β-ketoesters
and arylhydrazines. Table 2 lists the results. Reactions of
Table 1 Optimization of the reaction conditionsa
Yieldb (%)
Entry
Reagent
Catalyst
Solvent
Time (h)
3a
4a
0c
5
5
45
76
79
1
2
3
4
5
6
7
8
—
—
I2
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Benzene
THF
ClCH2CH2Cl
MeOH
H2O
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
12
12
12
12
12
12
6
12
12
24
12
6
12
24
24
24
24
53
65
90
50
0
0
0
0
23
0
0
0
0
0
0
52
0
AgOTf (10 mol%)
—
—
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
I2/AcOH
NBS/AcOH
NCS/AcOH
IBX
AgOTf (10 mol%)
AgOAc (10 mol%)
AgNO3 (10 mol%)
Ag2O (10 mol%)
Ag2CO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
AgNO3 (10 mol%)
81
54c
75
9
10
11
12
13
14
15
16
17
53
78
85
79
40c
60c
Trace
17c
a Reaction conditions: 1a (0.5 mmol), 2a (1.2 mmol), reagent (1 equiv.), catalyst (10 mol%), solvent (3.0 mL) at 70 °C. b Yield of the isolated pro-
ducts 3a and 4a after column chromatography. c Incomplete reaction.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
products 4h and 4i in 48 and 93% yield, respectively.
The additional substituent effect of phenyl and aryl on
the β-carbon was next examined. A reaction of ethyl 3-oxo-
3-phenylpropanoate (1j) with phenylhydrazine (2a) for 12 h
afforded 4j in 95% yield. Both β-ketoesters 1k and 1l bearing
electron donating groups (4-Me or 4-OMe) and 1m bearing an
electron-withdrawing group (4-NO2) were well tolerated to
provide the corresponding products 4k–4m in 96, 96, and 85%
yield, respectively. Further reactions using various arylhydr-
azines were also successful. Diverse arylhydrazines 2b–2e
bearing electron-donating groups, such as 2-ethyl, 4-methyl,
4-isopropyl, and 4-methoxy, underwent reactions with ethyl
3-oxobutanoate (1a) and afforded the desired products 4n–4q
in 72–92% yield. Arylhydrazines 2f–2h with electron-withdraw-
ing groups, such as 2-chloro, 4-chloro, and 4-fluoro, were also
suitable for the construction of the corresponding arylazopyr-
azoles 4r–4t in 81, 93, and 90% yield, respectively. In addition,
arylhydrazines 2i and 2j bearing two electron-donating groups
on the benzene ring of phenylhydrazine reacted well with 1a to
afford products 4u and 4v in 77 and 80% yield, respectively.
Considering the generality for the synthesis of arylazopyr-
azoles using various β-ketoesters, this study has examined the
possibility of using 2-arylpyrazol-3-ones (Table 3). A reaction of
3a with arylhydrazines 2b, 2d, and 2e bearing electron-donat-
ing groups on the benzene ring provided the desired products
5a–5c in 96, 93, and 67% yield, respectively, whereas treatment
with arylhydrazines 2g and 2h bearing electron-withdrawing
groups afforded products 5d and 5e in 95 and 91% yield,
respectively. With an iodine-promoted reaction of 3a with
1-naphthalenylhydrazine (2k), product 5f was isolated in 83%
yield. A combination of 3b or 3c with phenylhydrazine (2a) pro-
vided the corresponding products 5g and 5h in 97 and 95%
yield, respectively. The arylazopyrazoles synthesized in this way
contained two different hydrazine units in the same molecule.
Thus the desired arylazopyrazoles can be synthesized by judi-
cious selection of arylpyrazol-3-ones and arylhydrazines.
Table 2 Scope of ketoesters 1a–1m and arylhydrazines 2a–2j for the
construction of arylazopyrazoles 4b–4v
Table 3 Scope of selected arylpyrazol-3-ones 3a–3c for the construc-
tion of polyfunctionalized arylazopyrazoles 5a–5h
β-ketoesters bearing alkyl groups on the β-carbon were first
examined. The treatment of ethyl 3-oxopentanoate (1b), ethyl
3-oxohexanoate (1c), methyl 4-methyl-3-oxopentanoate (1d), or
ethyl 4,4-dimethyl-3-oxopentanoate (1e) with phenylhydrazine
for 3–6 h provided the desired products 4b–4e in 90, 89, 83,
and 51% yield, respectively. The bulky group in the β-keto-
esters reduces the reactivity with phenylhydrazine to give a low
yield of arylazopyrazole (4e), possibly due to the steric hin-
drance. With an iodine-mediated reaction of β-ketoesters such
as methyl 3-oxooctanoate (1f) and methyl 3-oxododecanoate
(1g) bearing a long chain on the β-carbon with phenylhydr-
azine, the desired products 4f and 4g were isolated in 88 and
90% yields. Furthermore, β-ketoesters 1h and 1i containing a
CF3 or benzyl group on the β-carbon provided the desired
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
allowed the synthesis of a range of arylazopyrazoles bearing
two different arylhydrazine units from 2-arylpyrazol-3-ones.
The synthesized compounds can be expected to be widely used
for the evaluation of their biological activities and photoswitch
applications.
Experimental
General procedure for synthesis of arylazopyrazoles from
Scheme 3 Mechanistic investigation.
β-ketoesters
To a solution of β-ketoester (0.5 mmol) and arylhydrazine
(1.2 mmol) in 1,2-dichloroethane (3.0 mL) were added I2
(126 mg, 0.25 mmol), acetic acid (0.03 mL, 0.5 mmol) and
AgNO3 (8 mg, 10 mol%) and the reaction mixture was heated
at 70 °C under a nitrogen atmosphere until the completion of
reaction as indicated by TLC. The volatiles were removed
in vacuo and the residue was purified by silica gel column
chromatography (hexane : ethyl acetate = 30 : 1) to give the
desired arylazopyrazoles.
3-Methyl-1-phenyl-4-(phenyldiazenyl)-1H-pyrazol-5-ol (4a).17
Orange solid (118 mg, 85%); mp 130–132 °C; 1H NMR
(600 MHz, CDCl3): δ = 13.54 (s, 1H), 7.94 (d, J = 7.8 Hz, 2H),
7.42–7.37 (m, 6H), 7.19–7.16 (m, 2H), 2.34 (s, 3H); 13C NMR
(150 MHz, CDCl3): δ = 157.69, 148.48, 141.07, 137.99, 129.58,
128.84, 128.43, 125.71, 125.05, 118.46, 115.73, 11.72.
Scheme 4 Proposed mechanism for the formation of 4.
General procedure for synthesis of arylazopyrazoles from
arylpyrazol-3-ones
To gain insight into the mechanism, control experiments
were carried out (Scheme 3). The reaction of ethyl benzoyl-
acetate with iodine under acidic conditions in the absence of
phenylhydrazine for 4 h afforded the corresponding α-iodi-
nated intermediate 4j′ in 74% crude yield (eqn (1), Scheme 3)
(see details in the ESI†). Our attempt to isolate such an inter-
mediate as a pure compound encountered with frequent fail-
ures regarding instability with column chromatography. An
additional reaction of the crude mixture 4j′ with 2.2 equi-
valents of phenylhydrazine in the absence of iodine provided the
product 4j in 95% yield (eqn (2), Scheme 3). Based on control
experiments and the synthesized products, a mechanism for
the formation of 4 is depicted in Scheme 4. In acidic medium,
β-ketoester 1 first undergoes in situ iodination to give α-iodo-
β-ketoester (I),18 which then reacts with two equivalents of
phenylhydrazine to give another intermediate IV via two
different intermediates II and III. Oxidation of IV followed by
subsequent enolization in the presence of a silver catalyst
would lead to the final product 4.17
To a solution of 5-methyl-2-aryl-2,4-dihydro-3H-pyrazol-3-one
(0.5 mmol) and arylhydrazine (0.6 mmol) in 1,2-dichlroethane
(3.0 mL) were added I2 (126 mg, 0.25 mmol), acetic acid
(0.03 mL, 0.5 mmol) and AgNO3 (8 mg, 10 mol%) and the reac-
tion mixture was heated at 70 °C under a nitrogen atmosphere
until the completion of reaction as indicated by TLC. The vola-
tiles were removed in vacuo and the residue was purified by
silica gel column chromatography (hexane : ethyl acetate =
30 : 1) to give the desired products.
4-[(2-Ethylphenyl)diazenyl]-3-methyl-1-phenyl-1H-pyrazol-5-ol
1
(5a).17 Orange solid (146 mg, 96%); mp 107–109 °C; H NMR
(600 MHz, CDCl3): δ = 13.85 (s, 1H), 7.95–7.93 (m, 2H), 7.79 (d,
J = 7.8 Hz, 1H), 7.43–7.40 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.23
(d, J = 7.2 Hz, 1H), 7.20–7.18 (m, 1H), 7.15 (td, J = 7.2, 0.6 Hz,
1H), 2.77 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.34 (t, J = 7.2 Hz,
3H); 13C NMR (150 MHz, CDCl3): δ = 157.92, 148.50, 138.67,
138.00, 131.34, 129.15, 128.93, 127.40, 125.81, 125.18, 118.79,
114.79, 23.69, 13.82, 11.81.
Conclusions
Acknowledgements
In summary, highly functionalized arylazopyrazoles were syn-
thesized by an iodine-mediated reaction of β-ketoesters and This study was supported by the Nano Material Technology
arylhydrazines in the presence of AgNO3 as a one-pot pro- Development Program through the Korean National Research
cedure. This synthetic protocol includes in situ α-iodination, Foundation (NRF) funded by the Korean Ministry of Edu-
pyrazol-3-one formation, substitution with a nitrogen nucleo- cation, Science, and Technology (2012M3A7B4049675) and by
phile, oxidation and enolization. In addition, this protocol the Korea government (MSIP) (NRF-2014R1A2A1A11052391).
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
F. A. Amer, Dyes Pigm., 2012, 92, 902; (c) V. Kumar, K. Kaur,
G. K. Gupta and A. K. Sharma, Eur. J. Med. Chem., 2013, 69,
735; (d) S. Trofimenko, Chem. Rev., 1972, 72, 497.
11 V. Sareen, V. Khatri, D. Shinde and S. Sareen, Indian
J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2011, 50,
937.
Notes and references
1 A. A. Bekhit and T. Abdel-Aziem, Bioorg. Med. Chem., 2004,
12, 1935.
2 S. K. Sahu, M. Banerjee, A. Samantray, C. Behera and
M. A. Azam, Trop. J. Pharm. Res., 2008, 7, 961.
3 A. Mohammed, S. M. Hassan and A. Wadood, 12 P. D. Kale, J. Chem. Pharm. Res., 2013, 5, 130.
Orient. J. Chem., 2002, 18, 351.
13 P. C. Lyer, J. Zhao, L. A. Emert-Sedlak, K. K. Moore,
T. E. Smithgall and B. W. Day, Bioorg. Med. Chem. Lett.,
2014, 24, 1702.
14 C. E. Weston, R. D. Richardson, P. R. Haycock,
A. J. P. White and M. J. Fuchter, J. Am. Chem. Soc., 2014,
136, 11878.
4 A. E. Rashad, M. I. Hegab, R. E. Abdel-Megeid, J. A. Micky
and F. M. E. Abdel-Megeid, Bioorg. Med. Chem., 2008, 16,
7102.
5 Z. Tabarelli, M. A. Rubin, D. B. Berlese, P. D. Sauzem,
T. P. Missio, M. V. Teixeira, A. P. Sinhorin, M. A. P. Martins,
N. Zanatta, H. G. Bonacorso and C. F. Mello, Braz. J. Med. 15 L. Stricker, E.-C. Fritz, M. Peterlechner, N. L. Doltsinis and
Biol. Res., 2004, 37, 1531. B. J. Ravoo, J. Am. Chem. Soc., 2016, 138, 4547.
6 F. R. Souza, V. T. Souza, V. Ratzlaff, L. P. Borges, 16 (a) B. F. Abdel-Wahab, A.-A. S. El-Ahl and F. A. Badria,
M. R. Oliveira, H. G. Bonacorso, N. Zanatta,
M. A. P. Martins and C. F. Mello, Eur. J. Pharmacol., 2002,
451, 141.
Chem. Pharm. Bull., 2009, 57, 1348; (b) S. El-Metwally and
A. K. Khalil, Acta Chim. Slov., 2010, 57, 941; (c) N. Ergeç,
S. Rollas and Y. Topaloğlu, Arch. Pharm., 1986, 319,
545.
7 R. Tripathy, A. Ghose, J. Singh, E. R. Bacon, T. S. Angeles,
S. X. Yang, M. S. Albom, L. D. Aimone, J. L. Herman and 17 R. P. Pandit and Y. R. Lee, Adv. Synth. Catal., 2015, 357,
J. P. Mallamo, Bioorg. Med. Chem. Lett., 2007, 17, 1793. 2657.
8 (a) J. Elguero, in Comprehensive Heterocyclic Chemistry II, 18 (a) H. Cao, J. Yuan, C. Liu, X. Hu and A. Lei, RSC Adv.,
ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Perga-
mon, Oxford, 1996, vol. 3, p. 1; (b) C. Lamberth, Hetero-
cycles, 2007, 71, 1467; (c) T. Eicher, S. Hauptann and
A. Speicher, The Chemistry of Heterocycles, Wiley & Sons,
New York, 2004, p. 179; (d) N. Panda and A. K. Jena, J. Org.
Chem., 2012, 77, 9401.
2015, 5, 41493; (b) B. Sreedhar, P. S. Reddy and
M. Madhavi, Synth. Commun., 2007, 37, 4149;
(c) J. P. Whang, S. G. Yang and Y. H. Kim, Chem. Commun.,
1997, 1355; (d) I. Pravst, M. Zupan and S. Stavber, Tetra-
hedron, 2008, 64, 5191; (e) M. Jereb, M. Zupan and
S. Stavber, Chem. Commun., 2004, 2614; (f) H. M. Meshram,
P. N. Reddy, P. Vishnu, K. Sadashiv and J. S. Yadav, Tetra-
hedron Lett., 2006, 47, 991; (g) H. Erhardt, A. P. Häring,
A. Kotthaus, M. Roggel, M. L. Tong, P. Biallas,
M. Jübermann, F. Mohr and S. F. Kirsch, J. Org. Chem.,
2015, 80, 12460.
9 L. Le Corre, L. Tak-Tak, A. Guillard, G. Prestat, C. Gravier-
Pelletier and P. Busca, Org. Biomol. Chem., 2015, 43, 409.
10 (a) Y. Deng, B. Tang, H. Zhao, J. Xu, J. Xiao, X. Zhang,
H. Xu and S. Zhang, Color. Technol., 2012, 129, 144;
(b) M. A. Metwally, E. Abdel-Galil, A. Metwally and
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.