A novel methodology for synthesis of dihydropyrazole derivatives as potential anticancer agents

Article abstract of DOI:10.1039/c3ob42432d

A novel, simple, and efficient method for the synthesis of 4,5-dihydropyrazole derivatives has been developed. The reaction proceeded through the base-induced isomerization of easily accessible propargyl alcohols followed by cyclization of α,β-unsaturated hydrazones. Furthermore, selected compounds 3ab and 3ac exhibited good activities against Bel-7404 (human hepatoma cancer), HepG2 (human liver cancer), NCI-H460 (human lung cancer) and SKOV3 (human ovarian cancer) cell lines with IC₅₀ in the range of 22-46 μmol L^-1.

Full text of DOI:10.1039/c3ob42432d

Organic &
Biomolecular Chemistry
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A novel methodology for synthesis of dihydro-
pyrazole derivatives as potential anticancer
agents†
Cite this: Org. Biomol. Chem., 2014,
12, 2028
Received 5th December 2013,
Accepted 19th January 2014
Xu Wang, Ying-ming Pan,* Xiao-chao Huang, Zhong-yuan Mao and
Heng-shan Wang*
DOI: 10.1039/c3ob42432d
www.rsc.org/obc
A novel, simple, and efficient method for the synthesis of 4,5-di-
Due to the attractive medicinal properties of the dihydro-
hydropyrazole derivatives has been developed. The reaction pyrazole skeleton, various efficient approaches have been deve-
proceeded through the base-induced isomerization of easily loped for the preparation of these compounds.13 Nevertheless,
accessible propargyl alcohols followed by cyclization of α,β-un- the synthesis of substituted dihydropyrazoles directly from
saturated hydrazones. Furthermore, selected compounds 3ab and simple and readily available substrates is still in great demand.
3ac exhibited good activities against Bel-7404 (human hepatoma Recently, we reported a novel and efficient Cu(OTf)2-catalyzed
cancer), HepG2 (human liver cancer), NCI-H460 (human lung sp3–sp2 C–C bond formation reaction through the direct coup-
cancer) and SKOV3 (human ovarian cancer) cell lines with IC50 in ling of propargylic alcohols with terminal alkenes.14 Based on
the range of 22–46 μmol L−1
.
that work, we now report a novel methodology for the syn-
thesis of dihydropyrazoles from hydrazines and propargyl alco-
hols using t-BuOK (KTB) as a catalyst that accommodates
functionality including fluoro, chloro, bromo, methyl, methoxy
and hydroxy groups.
Pyrazolines play an important role in organic synthesis and
medicinal chemistry. Pyrazoline derivatives are reported to
possess antitumor,1 immunosuppressive,2 antibacterial,3
antitubercular,4 anti-inflammatory,5 antidiabetic,6 anti-
depressant,7 antimalarial,8 antiamoebic9 and anti-WN virus
activities.10 In particular, some trisubstituted dihydropyrazole
derivatives serve as valuable precursors in various biologically
and pharmaceutically active organic molecules,11 such as
2,5,5-trimethyl-1,5,6,10b-tetrahydro-pyrazolo[5,1-a]isoquinoline
and 3,5-diphenyl-4,5-dihydro-pyrazole-1-carbothioic acid amide
(Fig. 1).12
To identify suitable conditions for the reaction, a series of
catalysts and solvents were screened as shown in Table 1.
Initially, propargyl alcohol 1a (0.5 mmol) was treated with
hydrazine 2a (0.6 mmol) in the presence of 20 mol% of t-BuOK
in toluene at 100 °C for 4 h, and the desired 1,3,5-triphenyl-
4,5-dihydro-1H-pyrazole 3aa was isolated in 92% yield (Table 1,
entry 1).15 With other catalysts including CH3ONa, KOH,
NaOH, Cs2CO3, and CH3COONa, the desired product 3aa was
obtained in 60%, 55%, 40%, 30%, and 20% yields in 24 h at
100 °C, respectively (Table 1, entries 2–6). However, when
Na2CO3 or K2CO3 was used as the catalyst, the reaction did not
afford the desired product 3aa under the same reaction con-
ditions (Table 1, entries 7 and 8). Further optimization
suggested that solvents had a strong effect on this process.
Thus, a variety of solvents, such as DMSO, DMF, dioxane, DCE
and CH3CN, were screened (Table 1, entries 9–13). DMSO and
Fig. 1 Disclosed trisubstituted dihydropyrazoles as active organic DMF as solvents were also able to facilitate this reaction, while
molecules.
the use of toluene instead of DMSO and DMF reduced the
reaction time from 24 to 4 h (Table 1, entry 1 vs. entries 9 and
10). Other solvents, including dioxane, DCE and CH3CN, did
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources
not promote the reaction (Table 1, entries 11–13). Notably, the
yield of product 3aa decreased upon lowering the reaction
temperature to 90 °C (Table 1, entry 14). A very slow reaction
rate and low yield were also observed when the catalytic
amount of t-BuOK decreased from 20% to 10 mol% (Table 1,
entry 15), but no improvement in the yield could be obtained
(Ministry of Education of China), School of Chemistry & Chemical Engineering of
Guangxi Normal University, Guilin 541004, People’s Republic of China.
E-mail: panym2013@hotmail.com, wang_hengshan@yahoo.com.cn;
Fax: (+86)-773-2120958; Tel: (+86)-773-5846279
†Electronic supplementary information (ESI) available: Experimental section
and NMR data of the prepared compounds. CCDC 975487. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3ob42432d
2028 | Org. Biomol. Chem., 2014, 12, 2028–2032
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Table 1 Optimization of the formation of substituted 4,5-
dihydropyrazolea
Table 2 Synthesis of substituted 4,5-dihydropyrazoles from hydrazines
and propargyl alcoholsa
Propargyl
Entry alcohol
Yieldb
(%)
Entry Solvent
Catalyst
Time (h) Temp (°C) Yieldb (%)
Hydrazine
Product
1
1a: R1 = R2 =
Ph
2a: R3 = Ph
92
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
DMF
Dioxane t-BuOK
DCE
CH3CN
Toluene
Toluene
Toluene
t-BuOK
CH3ONa
KOH
NaOH
Cs2CO3
CH3COONa 24
Na2CO3
K2CO3
t-BuOK
t-BuOK
4
24
24
24
24
100
100
100
100
100
100
100
100
100
100
100
80
92
60
55
40
30
20
0
1b: R1 = 4-
2a: R3 = Ph
2a: R3 = Ph
2a: R3 = Ph
87
93
88
24
24
48
48
48
48
48
48
24
4
2
3
4
FC6H4; R2 = Ph
0
9
77
75
0
0
0
64
42
93
10
11
12
13
14
15c
16d
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
1c: R1 = 4-
MeC6H4; R2 =
Ph
80
90
100
100
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), and catalyst
(20 mol% to 1a) in solvent (2 mL). b Isolated yield of the pure product
based on 1a. c The reaction was carried in 10 mol% catalyst. d The
reaction was carried in 30 mol% catalyst.
1d: R1 = 2-
thienyl; R2 = Ph
as the amount of t-BuOK was increased to 30 mol% (Table 1,
entry 16). Hence, 1a (0.5 mmol), 2a (0.6 mmol), t-BuOK
(20 mole%) and toluene (2 mL) as solvent at 100 °C for 4 h
were chosen as the optimized conditions.
5
6
1e: R1 = Ph;
2a: R3 = Ph
85
72
R2 = H
With the optimized reaction conditions established, the
reaction was applied to a range of substrates. Typical results
are shown in Table 2. Using hydrazine as a model substrate,
secondary propargylic alcohols 1 bearing not only terminal
alkyne groups but also internal alkyne groups participated well
in the reaction. The propargyl alcohols 1c and 1h possessing
an electron-donating group at the aryl ring (R1 = 4-MeC6H4,
4-OHC6H4) afforded the desired products 3ca and 3ha in 93%
and 89% yields, respectively (Table 2, entries 3 and 8). The
crystallization of compound 3ca from anhydrous ethanol gave
single crystals suitable for X-ray analysis (Fig. 2). Substrates 1b
possessing an electron-withdrawing group (R1 = 4-FC6H4) at
the benzene ring also reacted smoothly and afforded the
desired product 3ba in 87% yield (Table 2, entry 2). We
have also observed some variation in yields as a function of
electronic effects: that is, aromatic propargyl alcohols with
an electron-donating group at the benzene ring gave the
corresponding products in higher yields than propargyl
alcohol which possessed an electron-withdrawing group on
the benzene ring (Table 2, entries 2, 3 and 8). The electron-
donating group presumably facilitated the rearrangement that
converted propargyl alcohols into α,β-unsaturated carbonyl
compounds. Additionally, the aromatic propargyl alcohol 1g
bearing both an electron-donating group and an electron-with-
drawing group was able to afford the corresponding product
1f: R1 = Ph;
2a: R3 = Ph
R2 = TMS
7
8
1g: R1 = 2-
BrC6H4;
R2 = 4-
2a: R3 = Ph
2a: R3 = Ph
94
89
MeOC6H4
1h: R1 = 4-
OHC6H4;
R2 = Ph
9
1a: R1 = R2 =
Ph
2b: R3 = 4-
MeOC6H4
95
87
10
1a: R1 = R2 =
Ph
2c: R3 = 3-
ClC6H4
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Table 2 (Contd.)
Table 2 (Contd.)
Propargyl
Entry alcohol
Yieldb
(%)
Propargyl
Entry alcohol
Yieldb
(%)
Hydrazine
Product
Hydrazine
Product
11
1b: R1 = 4-
FC6H4;
2b: R3 = 4-
MeOC6H4
89
20
21
22
1j: R1 = 3-
pyridine; R2 =
hexyl
2a: R3 = Ph
85
R2 = Ph
1b: R1 = 4-
FC6H4;
2c: R3 = 3-
ClC6H4
85
94
1k: R1 = 2-
thienyl; R2 =
propyl
2a: R3 = Ph
82
80
12
13
R2 = Ph
1c: R1 = 4-
MeC6H4;
R2 = Ph
2b: R3 = 4-
MeOC6H4
1l: R1 = 2-
thienyl; R2 =
butyl
2a: R3 = Ph
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), t-BuOK (20 mol%
to 1), toluene (2 mL), at 100 °C for 4 h. b Isolated yield of pure product
based on 1.
14
15
1c: R1 = 4-
MeC6H4;
R2 = Ph
2d: R3 = 4-
ClC6H4
82
92
1d: R1 = 2-
thienyl;
2b: R3 = 4-
MeOC6H4
3ga in excellent yield (Table 2, entry 7), and propargyl alcohol
bearing a heterocyclic substituent such as 1d (R1 = 2-thienyl)
gave the desired product 6da in 88% yield (Table 2, entry 4).
Moreover, compared to propargylic alcohols bearing internal
alkyne groups, propargylic alcohol 1e bearing a terminal
alkyne group gave slightly low yields (Table 2, entries 5 and
17). Interestingly, propargyl alcohol 1f (R1 = Ph; R2 = TMS) was
treated with hydrazines 2a and 2c under the optimal con-
ditions to afford 3ea and 3ec lacking the TMS group. Internal
R2 = Ph
16
17
1d: R1 = 2-
thienyl;
2c: R3 = 3-
ClC6H4
84
79
R2 = Ph
propargylic alcohols 1i (R2 = hexyl), 1j (R2 = hexyl), 1k (R2
=
1e: R1 = Ph;
2c: R3 = 3-
ClC6H4
propyl) and 1l (R2 = butyl) also gave good results (Table 2,
entries 19–22).
R2 = H
To expand the scope of hydrazine substrates, various hydra-
zines including 2b (R3 = 4-MeOC6H4), 2c (R3 = 3-ClC6H4) and
2d (R3 = 4-ClC6H4) were examined. Obviously, electron-rich
hydrazines provided the desired products in higher yields than
electron-poor hydrazines (Table 2, entries 9–18).
To our delight, the reaction of 1,3-diphenyl-prop-2-yn-1-ol
with isopropyl-hydrazine produced the product 1-isopropyl-3,5-
diphenyl-1H-pyrazole 3ae in 56% yield after 24 h (Scheme 1).
On the basis of a previous study by others,16 a possible reac-
tion mechanism is proposed as shown in Scheme 2. The first
step is the formation of the compound B via the abstraction of
the acidic propargyl C–H proton in the presence of t-BuOK.
Stabilization of compound B through delocalization followed
by protonation with the conjugate acid of t-BuOK delivers the
corresponding allenol. Allenol–enone tautomerism gives the
18
19
1f: R1 = Ph;
2c: R3 = 3-
ClC6H4
62
87
R2 = TMS
1i: R1 = Ph;
2a: R3 = Ph
R2 = hexyl
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Table 3 In vitro anticancer activities of 3ab and 3ac
IC50 a (μmol L−1
SKOV3 NCI-H460
)
Compound
HepG2
Bel-7404
HUVEC
3ab
3ac
5-FU
20
42
24
2
3
1
22
34
36
3
2
3
26
44
27
2
3
2
42
30
26
3
3
1
120
150
2
3
a IC50 (μmol L−1) is 50% inhibitory concentration and values are the
means of three experiments each done in duplicate.
Fig. 2 X-ray crystal structure of dihydropyrazole 3ca.
result indicated that the step from intermediate C to 3aa is
feasible via the cyclization process.
Subsequently, the in vitro antitumor activities with selected
compounds 3ab and 3ac were evaluated by the MTT assay
against NCI-H460, HepG2, Bel-7404, SKOV3 tumor cell lines
and HUVEC non-transformed human cells, using 5-fluoro-
uracil (5-FU) as the positive control. The tested results are
shown in Table 3. Compounds 3ab and 3ac exhibited moderate
to good cytotoxicities. Especially, compound 3ab exhibited the
best cytotoxicities against NCI-H460, HepG2 and SKOV3 cells
Scheme 1 Synthesis of 1-isopropyl-3,5-diphenyl-1H-pyrazole 3ae from
1,3-diphenyl-prop-2-yn-1-ol 1a and isopropyl-hydrazine 2e.
with IC50 22, 26 and 20 μmol L−1
.
In conclusion, we have successfully developed a flexible and
rapid route to synthesize a series of dihydropyrazole derivatives
from propargyl alcohols and hydrazines using t-BuOK as a
catalyst. The reaction was completed under an air atmosphere,
and displayed wide functional group compatibility. In
addition, the dihydropyrazole derivatives showed promising
anticancer potency through preliminary biological studies.
The current study provides a clue for the further development
of new types of anticancer agents.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21362002, 41206077 and 81260472), the
Scheme 2 Possible reaction mechanism.
Guangxi
Natural
Science
Foundation
of
China
(2012GXNSFAA053027 and 2011GXNSFD018010), the Guangxi
Scientific Research and Technology Development Program
(1355004-3) and the projects of Key Laboratory for the Chem-
istry and Molecular Engineering of Medicinal Resources
(Guangxi Normal University), Ministry of Education of China
(CMEMR2011-15, CMEMR2012-A and CMEMR2013-C01).
Scheme 3 Synthesis of 1,3,5-triphenyl-4,5-dihydro-1H-pyrazole 3aa
from (E)-chalcone and phenyl-hydrazine.
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