A one-pot approach to 4,5-dihydropyrazoles from ketones, arylacetylenes, and hydrazines

Article abstract of DOI:10.1016/j.tet.2014.01.021

An efficient and straightforward one-pot strategy for the synthesis of 4,5-dihydropyrazole derivatives from ketones, arylacetylenes, and hydrazines in the presence of KO^tBu/DMSO is described. This strategy provides a flexible and rapid route to polysubstituted 4,5-dihydropyrazoles.

Full text of DOI:10.1016/j.tet.2014.01.021

Tetrahedron 70 (2014) 1621e1628
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A one-pot approach to 4,5-dihydropyrazoles from ketones,
arylacetylenes, and hydrazines
Ying-Chun Wang b, Heng-Shan Wang a , Guo-Bao Huang , Fu-Ping Huang , Kun Hu ,
Ying-Ming Pan
a
a
,
,
a
a
a
*
a,
*
Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry & Chemical
Engineering of Guangxi Normal University, Guilin 541004, People’s Republic of China
b
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward one-pot strategy for the synthesis of 4,5-dihydropyrazole derivatives
from ketones, arylacetylenes, and hydrazines in the presence of KO Bu/DMSO is described. This strategy
provides a flexible and rapid route to polysubstituted 4,5-dihydropyrazoles.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 3 September 2013
Received in revised form 3 January 2014
Accepted 14 January 2014
Available online 18 January 2014
t
Keywords:
4,5-Dihydropyrazoles
Ketones
Arylacetylenes
Hydrazines
Tandem reactions
1
. Introduction
catalytic enantioselective 1,3-dipolar cycloadditions of diazo-
6
7
alkanes, diazoacetates, and catalytic asymmetric [3þ2] cycload-
8
9
Dihydropyrazole is a useful scaffold known for a wide variety of
ditions of azomethine imines, nitrile imine dipole precursors, and
10
pharmaceutical (antifungal, antibacterial, anti-inflammatory, anti-
tumor, and antiviral) and agrochemical activities. Recently, more
and more chemical compounds bearing dihydropyrazole moiety as
potential anticancer agents have been confirmed. For example, Liu
hydrazones. Recently, Bri eꢀ re et al. reported a powerful domino
aza-Michael addition/cyclocondensation reaction for the enantio-
selective synthesis of 3,5-diaryldihydropyrazoles by phase-transfer
1
2
11
catalysis. Furthermore, Bolm et al. described an unprecedented
et al. have disclosed a series of 4,5-dihydropyrazole derivatives as
strategy to access highly enantioenriched dihydropyrazoles by
V600E
potential V600E mutant BRAF kinase (BRAF
) inhibitors, which
formal [4þ1] cycloadditions of in situ-derived azoalkenes and sul-
12
are aimed to treat human cancer with good potency, pharmacoki-
fur ylides catalyzed by a chiral copper/ToleBINAP complex.
2
d
netics, and water solubility. More recently, Luo et al. reported
some aryl-2H-pyrazole derivatives as potential telomerase in-
hibitors, which exhibit high activities against human gastric cancer
Despite numerous diverse approaches toward the synthesis of
dihydropyrazole have been developed so far, the development of
more convenient methodologies, especially one-pot multicompo-
nent reactions, from readily available starting materials is still
highly desirable. Herein, we report a new one-pot strategy for the
synthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, ary-
2
e
cell SGC-7901 and human melanoma cell B16-F10. Moreover,
dihydropyrazoles are also of great importance in the preparation of
3
natural products and applications in asymmetric synthesis. It is no
t
wonder that the building up of a dihydropyrazole moiety invokes
ever growing synthetic efforts.
lacetylenes 2, and hydrazines 3 in the presence of KO Bu/DMSO
(Scheme 1).
Commonly, dihydropyrazole derivatives are constructed by the
4
reaction of chalcones with hydrazine hydrate, semicarbazide hy-
2. Results and discussion
5
drochloride or thiosemicarbazide. They are also formed via
To identify the suitable conditions for the three-component
tandem process, a series of bases and solvents were screened us-
ing acetophenone 1a, phenylacetylene 2a, and phenylhydrazine 3a
as a model reaction (Table 1). As shown in Table 1, the base/DMSO
*
Corresponding authors. E-mail addresses: wang_hengshan@yahoo.com.cn
(
H.-S. Wang), panym2013@hotmail.com (Y.-M. Pan).
0
040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.021

1622
Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
Scheme 1. One-pot synthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, arylacetylenes 2, and Hydrazines 3.
Table 1
Optimization of the formation of 5-benzyl-4, 5-dihydropyrazole
a
ꢀ
Yieldb (%)
Entry
Base
Solvent
Temp ( C)
Time (h)
1
2
3
4
5
6
7
8
9
NaOC
2
H
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
70e100
70e100
70e100
100
100
100
70
100
100
100
8
8
8
8
8
8
8
4
8
8
8
8
8
8
0
0
0
Cs
2
CO
3
LiOH
NaOH
KOH
Trace
15
25
56
78
0
0
0
0
0
t
KOH/Bu OH
t
KO Bu
t
KO Bu
t
KO Bu
t
10
11
12
13
14
KO Bu
THF
t
KO Bu
Dioxane
Toluene
DMSO
DMSO
100
100
100
100
t
KO Bu
t
c
KO Bu
t
d
KO Bu
48
a
ꢀ
C
Reaction conditions: 1.2 equiv of acetophenone 1a (1.2 mmol), and 1.0 equiv of phenylacetylene 2a (1.0 mmol), 1.5 equiv of base (1.5 mmol), solvent (4 mL), at 70e100
for 30 min, 1.2 equiv of phenylhydrazine 3a (1.2 mmol) then added for the period of time indicated at the same temperature.
b
Isolated yield of pure product based on phenylacetylene 2a.
c
t
KO Bu (10 mol %).
d
t
KO Bu (1.0 equiv).
t
system (except for NaOC
of the expected product 4aaa (trace to 25% yield) (Table 1, entries
2
H
5
, Cs
2
CO
3
, LiOH) promoted the formation
molar ratio of KO Bu also has a key effect on the reaction results:
t
with 10 mol % of KO Bu no product 4aaa was detected (Table 1,
entry 13), whereas with 1 equiv of KO Bu, only a 48% yield of 4aaa
t
t
1
e6), and the system of KO Bu/DMSO proved to be the most ef-
fective (yield of 4aaa being 78%) (Table 1, entries 7 and 8). Other
was obtained (Table 1, entry 14).
t
t
t
potentially promoting base systems, such as KO Bu/DMF, KO Bu/
With the optimal conditions in hand, we examined the KO Bu/
t
t
THF, KO Bu/dioxane, and KO Bu/toluene pairs appeared to be in-
efficient in the reaction studied (Table 1, entries 9e12). These re-
sults suggest that the solvent plays a crucial role for the success
formation of 5-benzyl-4,5-dihydropyrazole. Notably, the reactant
DMSO system for one-pot synthesis of 5-benzyl-4,5-
dihydropyrazoles from various ketones 1, arylacetylenes 2, and
hydrazines 3. Table 2 illustrates the wide generality and substrate
scope of this tandem reaction. As follows from Table 2, this strategy

Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
1623
Table 2
One-pot synthesis of 5-benzyl-4,5-dihydropyrazoles 4 from ketones 1, arylacetylenes 2, and hydrazines 3a
Entry
1
Ketone
Acetylene
Hydrazine
Product
Yieldb (%)
4aaa
78
2
3
4
5
4baa
4caa
4daa
4eaa
83
80
88
82
6
7
4faa
4gaa
52
28
8
9
4haa
81
4iaa
4jaa
78
58
1
0
1
1
1
2
4kaa
4lab
56
51
1
3
4mab
73
70
1
1
4
5
4nab
4oaa
54
65
1
1
6
7
4paa
4bba
83
(
continued on next page)

1624
Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
Table 2 (continued )
Entry
Ketone
Acetylene
Hydrazine
Product
Yieldb (%)
85
18
19
20
4bca
4bda
4aab
65
83
H
N
NH
2
21
4aac
78
Cl
a
t
ꢀ
Reaction conditions: 1.2 equiv of ketone 1 (1.2 mmol), and 1.0 equiv of arylacetylene 2 (1.0 mmol), 1.5 equiv of KO Bu (1.5 mmol), DMSO (4 mL), at 100 C for 30 min,
ꢀ
1
.2 equiv of hydrazine 3 (1.2 mmol) then added, kept at 100 C for an additional 3e6 h.
b
Isolated yield after column chromatography or recrystallization based on arylacetylene 2.
is effective for a great diversity of ketones such as aromatic (Table 2,
entries 1e11), heteroaromatic (Table 2, entries 12e15), and ali-
phatic (Table 2, entry 16), and as well as for a variety of arylacety-
lenes (Table 2, entries 17e19) and aromatic hydrazines (Table 2,
entries 20 and 21).
Among the ketones, which were examined, p-methox-
yacetophenone 1d gave the most desirable result, providing the 5-
benzyl-4,5-dihydropyrazole 4daa in 88% isolated yield (Table 2,
entry 4). The crystallization of compound 4daa from ethanol gave a
single crystal suitable for X-ray analysis. Fig. 1 illustrates the mo-
lecular structure of the substituted 5-benzyl-4,5-dihydropyrazole
yields (81% and 78%, respectively) (Table 2, entries 8 and 9).
Noteworthy, fluorine derivatives (both ketone 1f and arylacetylene
2d) could participate in the reaction in moderate yields (52% and
65%, respectively) (Table 2, entries 6 and 19), and p-chlor-
oacetophenone 1g was also suitable for the reaction to give 4gaa
albeit in a low yield (28%) (Table 2, entry 7). Obviously, electron-
rich aromatic ketones provided the desired products in higher
yields than electron-poor aromatic ketones. When heteroaromatic
ketone (1le1o) and aliphatic ketone (1p) were used as the sub-
strates, good yields (51%, 73%, 70%, 54% and 65%, respectively) of 5-
benzyl-4,5-dihydropyrazoles 4lab, 4mab, 4nab, 4oaa, and 4paa
were obtained (Table 2, entries 12e16). Arylacetylene 2c with an
4
daa.
Fig. 1. X-ray crystal structure of 5-benzyl-4,5-dihydropyrazole 4daa.
Gratifyingly, acylated condensed aromatics (2-acetonaphthone
h) and diphenyl derivatives (4-acetylbiphenyl 1i) fairly tolerated
the reaction conditions and afforded the desired products in good
3
electron-donating group (eOCH ) at the benzene ring gave the
corresponding products in higher yield than 2d, which possessed
an electron-withdrawing group (eF) on the benzene ring (Table 2,
1

Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
1625
entries 18 and 19). However, aliphatic alkynes did not give the
desired 5-benzyl-4,5-dihydropyrazoles under the present reaction
conditions. In case of hydrazines, the substituent effect on benzene
rings was not apparent, either with an electron-donating or an
electron-withdrawing group on the benzene ring, hydrazines 3
gave the corresponding 5-benzyl-4,5-dihydropyrazoles in high
yields (Table 2, entries 20 and 21).
To our delight, the thiosemicarbazide was also tolerated un-
der these reaction conditions. The corresponding compound
4
aad was synthesized successfully with moderate yield (52%)
Fig. 2. Structure of the isolated intermediates 5ia and 6jaa.
(
Scheme 2).
Scheme 2. Synthesis of 5-benzyl-4,5-dihydropyrazole 4aad.
The proposed mechanism for the formation of 5-benzyl-4,5-
3. Conclusion
dihydropyrazoles 4 was depicted in Scheme 3. The reaction
mechanism evidently represented the nucleophilic attack of the
enolate A at an acetylene to deliver the adduct 5 of E configu-
In summary, we have developed a mild, general, and efficient
strategy for the synthesis of polysubstituted 4,5-dihydropyrazoles
directly from ketones, arylacetylenes, and hydrazines in a single-
pot. This strategy is effective for a great diversity of ketones such
as aromatic, heteroaromatic, and aliphatic and as well as for a va-
riety of arylacetylenes and aromatic hydrazines, and it provides
a flexible and rapid route to the preparation of 5-benzyl-4,5-
dihydropyrazoles with both aliphatic and aromatic substituents at
C-3 of the dihydropyrazole ring.
ration, subsequently, the (E)-
readily react with aromatic hydrazines giving the hydrazones 6.
Then followed by prototropic rearrangement of -unsaturated
hydrazones 6 to -unsaturated hydrazones 7, which finally
b,g-unsaturated ketones 5 did
b,g
a,b
underwent cyclization to afford 4,5-dihydropyrazoles 4. This ra-
tionale has been proven by the intermediates 5ia and 6jaa iso-
lated from the reaction mixture under the same conditions
(
Fig. 2), and the E configuration of b,g-ethylenic ketone 5ia and
3
hydrazone 6jaa was confirmed by J value (16.3 Hz and 16.0 Hz,
4
4
. Experimental section
respectively) between protons at the double bond. Furthermore,
t
in the presence of KO Bu/DMSO, compound 6jaa can convert to
.1. General methods and materials
ꢀ
5
-benzyl-4,5-dihydropyrazole 4jaa in high yield (95%) at 100
C
after 4 h.
Melting points were uncorrected. NMR spectra were in CDCl
H at 500 MHz and C at 125 MHz). Column chromatography was
3
(1
13
Scheme 3. Proposed mechanism for the formation of 5-benzyl-4,5-dihydropyrazoles.

1626
Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
þ
performed on silica gel (300e400 mesh). Unless otherwise noted,
all reagents were obtained commercially and used without further
purification.
HRMS (m/z) (APCI): calcd for C23
343.1799.
23
H N
2
O 343.1810 [MþH ]; found
4
.3.5. 2-(5-Benzyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl
ꢀ
1
4
.2. General procedure for the synthesis of 5-benzyl-4,5-
methyl ether (4eaa). Pale yellow crystals; mp 96e97 C; H NMR
(500 MHz, CDCl ):
7.48 (d, J¼4.3 Hz, 1H), 7.39e7.32 (m, 6H),
.29e7.27 (m, 5H), 7.03e7.00 (m, 1H), 6.91e6.87 (m, 1H), 4.66e4.61
(m, 1H), 3.86 (s, 3H), 3.39 (dd, J¼17.6, 10.5 Hz, 1H), 3.30e3.23 (m,
dihydropyrazoles
3
d
7
To a 15-mL flask, ketones 1 (1.2 mmol), arylacetylenes 2
t
13
(
1.0 mmol), DMSO (4.0 mL), and KO Bu (1.5 mmol) were succes-
2H), 2.65 (dd, J¼13.7, 10.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
):
ꢀ
sively added. The reaction mixture was heated (100 C) and stirred
at 100 C for 30 min, followed by the addition of hydrazines 3
d 157.5, 147.9, 144.3, 137.8, 129.8, 129.4, 129.1, 128.7, 128.5, 126.4,
ꢀ
122.4, 120.7, 118.7, 113.4, 111.3, 61.0, 55.4, 40.4, 36.9 ppm; HRMS (m/
þ
(
(
1.2 mmol). The reaction mixture was kept at the same temperature
100 C) for an additional 3e6 h until completion (monitored by
z) (APCI): calcd for C23
23
H N
2
O 343.1810 [MþH ]; found 343.1600.
ꢀ
TLC). Upon cooling to room temperature, the reaction mixture was
diluted with H O (10 mL), neutralized with NH Cl. When pre-
4.3.6. 5-Benzyl-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyr-
1
2
4
azole (4faa). Pale yellow oil;
3
H NMR (500 MHz, CDCl ):
cipitated, the residue was filtered off, washed with water, and
recrystallized. If the residue did not precipitate, the reaction mix-
ture was extracted with ethyl acetate (3ꢁ10 mL). The organic ex-
d 7.72e7.67 (m, 2H), 7.40e7.35 (m, 4H), 7.32e7.27 (m, 5H),
7.12e7.07 (m, 2H), 6.94e6.90 (m, 1H), 4.74e4.67 (m, 1H), 3.34 (dd,
J¼13.8, 2.9 Hz, 1H), 3.24 (dd, J¼16.8, 10.9 Hz, 1H), 3.04 (dd, J¼16.8,
13
tract was washed with H
2
O (3ꢁ5 mL) and dried over magnesium
4.2 Hz, 1H), 2.63 (dd, J¼13.8, 10.1 Hz, 1H) ppm; C NMR (125 MHz,
1
sulfate. After filtration, the solvent was evaporated to dryness un-
der reduced pressure and the residue was purified by flash column
chromatography (petroleum ether/ethyl acetate 20:1) to afford 5-
benzyl-4,5-dihydropyrazoles 4.
CDCl
3
):
d
162.9 (d, JCF¼244.9 Hz), 146.6, 144.2, 137.4, 129.4, 129.3,
3
128.7, 128.6, 127.4 (d,
J
CF¼7.9 Hz), 126.7, 119.9, 115.5 (d,
2
J
CF¼21.8 Hz),113.5, 61.1, 37.5, 37.4 ppm; HRMS (m/z) (ESI): calcd for
þ
C
22
H
20FN
2
331.1611 [MþH ]; found 331.1600.
4
.3. Characterization of the compounds
4.3.7. 5-Benzyl-3-(4-chlorophenyl)-1-phenyl-4,5-dihydro-1H-pyr-
azole (4gaa). Red oil; H NMR (500 MHz, CDCl ): d 7.72e7.67 (m,
3
1
4
.3.1. 5-Benzyl-1,3-diphenyl-4,5-dihydro-1H-pyrazole (4aaa). Pale
2H), 7.40e7.35 (m, 4H), 7.32e7.27 (m, 5H), 7.12e7.07 (m, 2H),
6.94e6.89 (m, 1H), 4.74e4.67 (m, 1H), 3.34 (dd, J¼13.9, 3.4 Hz, 1H),
3.26 (dd, J¼16.9, 10.9 Hz, 1H), 3.07 (dd, J¼16.9, 4.1 Hz, 1H), 2.62 (dd,
ꢀ
1
yellow powder; mp 150e151 C; H NMR (500 MHz, CDCl
3
):
d, J¼7.6 Hz, 2H), 7.41e7.31 (m, 7H), 7.29e7.26 (m, 5H), 6.91e6.89
m, 1H), 4.72e4.68 (m, 1H), 3.34 (dd, J¼13.8, 3.3 Hz, 1H), 3.26 (dd,
d 7.72
(
(
13
J¼13.7, 10.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
): d 147.8, 144.3,
J¼16.8, 10.8 Hz, 1H), 3.07 (dd, J¼16.9, 4.1 Hz, 1H), 2.61 (dd, J¼13.8,
0.1 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl
): 147.5, 144.2, 137.5,
33.5, 129.4, 129.3, 128.7, 128.6, 128.5, 126.7, 125.7, 119.1, 113.5, 61.0,
138.5, 137.6, 130.2, 129.4, 129.2, 129.2, 128.7, 126.6, 125.6, 118.9,
1
1
3
d
113.5, 60.9, 37.5, 37.4 ppm; HRMS (m/z) (ESI): calcd for C22
347.1315 [MþH ]; found 347.1298.
H20ClN
2
þ
37.3 (2) ppm; HRMS (m/z) (ESI): calcd for C22
21
H N
2
313.1705
þ
[MþH ]; found 313.1688.
4.3.8. 5-Benzyl-3-(2-naphthyl)-1-phenyl-4,5-dihydro-1H-pyrazole
ꢀ
1
(
4haa). Yellow crystals; mp 122e124 C; H NMR (500 MHz, CDCl ):
3
4
.3.2. 5-Benzyl-3-(4-methylphenyl)-1-phenyl-4,5-dihydro-1H-pyr-
d
8.14 (dd, J¼8.7, 1.6 Hz, 1H), 7.84e7.79 (m, 4H), 7.51e7.46 (m, 2H),
ꢀ
1
azole (4baa). Pale yellow powder; mp 154e155 C; H NMR
500 MHz, CDCl ):
7.41e7.32 (m, 6H), 7.30e7.26 (m, 3H), 6.94e6.90 (m,1H), 4.74 (m,1H),
3.38e3.31 (m, 2H), 3.17 (dd, J¼16.7, 4.2 Hz, 1H), 2.65 (dd, J¼13.9,
(
3
d
7.62 (d, J¼8.1 Hz, 2H), 7.38e7.33 (m, 4H),
13
7
4
.32e7.27 (m, 5H), 7.22 (d, J¼8.1 Hz, 2H), 6.91e6.88 (m, 1H),
3
10.1 Hz, 1H) ppm; C NMR (125 MHz, CDCl ): d 147.6, 144.0, 137.5,
.70e4.65 (m, 1H), 3.34 (dd, J¼13.8, 3.3 Hz, 1H), 3.24 (dd, J¼16.8,
133.4, 133.3, 130.7, 129.4, 129.3, 128.7, 128.1, 128.0, 127.8, 126.7, 126.4,
126.2,124.9,123.4,119.2,113.6, 61.0, 37.5, 37.3 ppm; HRMS (m/z) (ESI):
calcd for C26
1
1
1
0.8 Hz, 1H), 3.05 (dd, J¼16.8, 4.1 Hz, 1H), 2.61 (dd, J¼13.8, 10.1 Hz,
H), 2.41 (s, 3H) ppm; 13C NMR (125 MHz, CDCl
): 147.1, 143.6,
37.8, 136.8, 129.5, 128.6, 128.5, 128.4, 127.9, 125.9, 124.9, 118.2,
þ
3
d
H N
23 2
363.1861 [MþH ]; found 363.1841.
1
C
12.8, 60.2, 36.7, 36.6, 20.6 ppm; HRMS (m/z) (APCI): calcd for
4.3.9. 5-Benzyl-3-(biphenyl-4-yl)-1-phenyl-4,5-dihydro-1H-pyrazole
þ
ꢀ
1
H
23 23
N
2
327.1861 [MþH ]; found 327.1853.
(4iaa). Yellow powder; mp 172e173 C; H NMR (500 MHz, CDCl
3
):
d
7.76e7.72 (m, 2H), 7.68e7.65 (m, 2H), 7.54e7.49 (m, 2H),
4
.3.3. 5-Benzyl-3-(2-methylphenyl)-1-phenyl-4,5-dihydro-1H-pyr-
7.38e7.35 (m, 4H), 7.32e7.25 (m, 6H), 7.23e7.20 (m, 3H), 4.68 (m,
1H), 3.34 (dd, J¼13.8, 3.3 Hz, 1H), 3.24 (dd, J¼16.8, 10.8 Hz, 1H), 3.05
ꢀ
1
azole (4caa). Pale yellow powder; mp 158e160 C; H NMR
500 MHz, CDCl ): 7.42e7.35 (m, 4H), 7.33e7.30 (m, 4H), 7.28 (m,
H), 7.27e7.24 (m, 2H), 6.92 (m, 1H), 4.71e4.64 (m, 1H), 3.37 (dd,
J¼16.7, 10.8 Hz, 1H), 3.31 (dd, J¼13.8, 3.2 Hz, 1H), 3.14 (dd, J¼16.7,
13
(
3
3
d
(dd, J¼16.8, 4.1 Hz, 1H), 2.61 (dd, J¼13.8, 10.1 Hz, 1H) ppm; C NMR
(125 MHz, CDCl
3
): d 147.3, 144.0, 141.1, 140.5, 137.5, 132.0, 129.4,
129.3, 128.8, 128.7, 127.3, 127.1, 126.9, 126.7, 126.1, 119.4, 113.8, 61.0,
13
3
(
1
2
.8 Hz, 1H), 2.73 (s, 3H), 2.66 (dd, J¼13.8, 9.9 Hz, 1H) ppm; C NMR
125 MHz, CDCl ): 148.4, 144.3, 137.5, 137.4, 131.6, 131.5, 129.5,
29.3, 128.7, 127.9, 127.8, 126.7, 125.7, 118.9, 113.5, 59.9, 39.5, 37.1,
39.7, 37.5 ppm; HRMS (m/z) (ESI): calcd for C28
[MþH ]; found 389.2036.
25
H N
2
389.2018
þ
3
d
3.7 ppm; HRMS (m/z) (APCI): calcd for C23
H
23
N
2
327.1861
4.3.10. 5-Benzyl-4-methyl-1,3-diphenyl-4,5-dihydro-1H-pyrazole
þ
1
[MþH ]; found 327.1851.
(4jaa). Yellow oil; H NMR (500 MHz, CDCl
.41e7.34 (m, 7H), 7.31e7.27 (m, 5H), 6.95e6.92 (m, 1H), 4.36e4.34
(m, 1H), 3.42e3.38 (m, 1H), 3.31e3.27 (m, 1H), 2.56 (dd, J¼13.7,
3
): d 7.73e7.71 (m, 2H),
7
4
.3.4. 4-(5-Benzyl-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenyl
ꢀ
1
13
methyl ether (4daa). Pale yellow crystals; mp 107e109 C; H NMR
500 MHz, CDCl ):
10.3 Hz, 1H), 1.17 (d, J¼7.2 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
):
(
3
d
7.67 (d, J¼8.5 Hz, 2H), 7.39e7.34 (m, 4H),
d
151.9, 143.9, 137.3, 132.1, 129.9, 129.2, 128.7, 127.9, 126.4, 125.9,
7.30e7.26 (m, 6H), 6.94 (d, J¼8.7 Hz, 2H), 4.68e4.62 (m,1H), 3.87 (s,
3
125.1, 118.2, 112.7, 69.3, 43.0, 34.5, 18.7 ppm; HRMS (m/z) (ESI):
þ
H), 3.34 (dd, J¼13.8, 3.2 Hz, 1H), 3.24 (dd, J¼16.7, 10.7 Hz, 1H), 3.04
calcd for C23
23
H N
2
327.1861 [MþH ]; found 327.1848.
13
(
(
1
dd, J¼16.9, 4.0 Hz, 1H), 2.61 (dd, J¼13.7, 10.2 Hz, 1H) ppm; C NMR
125 MHz, CDCl ): 147.2, 143.7, 137.9, 136.9, 129.6, 128.7, 128.6,
28.5, 128.0, 126.0, 125.0, 118.3, 112.9, 60.3, 36.8, 36.7, 20.7 ppm;
3
d
4.3.11. 5-Benzyl-4-ethyl-1,3-diphenyl-4,5-dihydro-1H-pyrazole
1
3
(4kaa). Yellow oil; H NMR (500 MHz, CDCl ): d 7.53e7.49 (m, 2H),

Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
1627
7.47e7.43 (m, 3H), 7.40e7.37 (m, 4H), 7.36e7.27 (m, 5H), 6.90e6.83
129.0, 128.9, 127.9, 125.4, 118.6, 113.2, 60.7, 37.3, 36.7, 28.2, 21.1,
(
4
2
1
1
m, 1H), 4.66e4.60 (m, 1H), 3.35e3.29 (m, 1H), 3.05 (dd, J¼16.8,
15.4 ppm; HRMS (m/z) (APCI): calcd for C25
[MþH ]; found 355.2163.
H
27
N
2
355.2174
þ
.3 Hz, 1H), 2.58 (dd, J¼13.9, 10.0 Hz, 1H), 2.01e1.96, 1.77e1.71 (m,
1
3
H), 1.07 (t, J¼7.3 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
) d 148.7,
45.3, 137.6, 134.4, 131.5, 131.0, 129.3, 129.1, 128.0, 127.1, 126.2, 119.5,
4.3.18. 5-(4-Methoxybenzyl)-3-(4-methylphenyl)-1-phenyl-4,5-
dihydro-1H-pyrazole (4bca). Yellow crystals; mp 95e96 C;
ꢀ
1
12.7, 66.0, 53.2, 36.2, 26.0, 12.1 ppm; HRMS (m/z) (ESI): calcd for
H
þ
C
H N
24 24 2
341.2018 [MþH ]; found 341.2002.
NMR (500 MHz, CDCl ):
3
d
7.62 (d, J¼8.1 Hz, 2H), 7.37 (m, 2H),
7
.31e7.28 (m, 2H), 7.22 (d, J¼8.1 Hz, 2H), 7.18 (d, J¼8.5 Hz, 2H),
4
.3.12. 5-Benzyl-3-(furan-2-yl)-1-(4-methoxyphenyl)-4,5-dihydro-
6.91e6.88 (m, 3H), 4.65e4.59 (m, 1H), 3.83 (s, 3H), 3.28e3.21 (m,
2H), 3.04 (dd, J¼16.8, 4.3 Hz, 1H), 2.57 (dd, J¼13.9, 10.0 Hz, 1H), 2.41
1
1
1
6
3
3
H-pyrazole (4lab). Red oil; H NMR (500 MHz, CDCl ): d 7.45 (s,
13
H), 7.31 (t, J¼7.4 Hz, 2H), 7.23 (t, J¼7.3 Hz, 1H), 7.19e7.17 (m, 4H),
.89 (d, J¼8.9 Hz, 2H), 6.51e6.39 (m, 2H), 4.54e4.45 (m,1H), 3.78 (s,
H), 3.20 (dd, J¼13.7, 3.1 Hz, 1H), 3.11 (dd, J¼16.7, 10.7 Hz, 1H), 2.92
3
(s, 3H) ppm; C NMR (125 MHz, CDCl ): d 158.1, 147.5, 147.4, 144.1,
138.3, 130.1, 129.2, 129.0, 128.9, 125.4, 118.6, 113.9, 113.2, 60.8, 55.0,
37.2, 36.2, 21.1 ppm; HRMS (m/z) (APCI): calcd for C24
25
H N
2
O
13
þ
(
(
dd, J¼16.7, 5.0 Hz, 1H), 2.55 (dd, J¼13.7, 10.2 Hz, 1H) ppm; C NMR
357.1967 [MþH ]; found 357.1953.
3
125 MHz, CDCl ): d 153.8, 148.7, 143.2, 139.6, 138.5, 137.6, 129.4,
1
28.7, 126.7, 116.1, 114.7, 111.6, 109.0, 62.1, 55.7, 37.4, 37.2 ppm;
4.3.19. 5-(4-Fluorobenzyl)-3-(4-methylphenyl)-1-phenyl-4,5-
þ
1
HRMS (m/z) (ESI): calcd for C21
H
21
N
2
O
2
333.1603 [MþH ]; found
dihydro-1H-pyrazole (4bda). Yellow oil; H NMR (500 MHz, CDCl
3
):
3
33.1593.
d
7.66 (d, J¼8.1 Hz, 2H), 7.46e7.40 (m, 2H), 7.34e7.33 (m, 2H),
7
.30e7.21 (m, 4H), 7.13e7.07 (m, 2H), 6.98e6.95 (m, 1H), 4.71e4.65
4
.3.13. 3-(Benzofuran-2-yl)-5-benzyl-1-(4-methoxyphenyl)-4,5-
(m, 1H), 3.32e3.25 (m, 2H), 3.05 (dd, J¼16.8, 4.2 Hz, 1H), 2.70 (dd,
ꢀ
1
13
dihydro-1H-pyrazole (4mab). Yellow crystals; mp 145e146 C;
NMR (500 MHz, CDCl ): 7.58e7.56 (m, 2H), 7.40e7.23 (m, 9H),
H
J¼14.0, 9.6 Hz, 1H), 2.46 (s, 3H) ppm; C NMR (125 MHz, CDCl
3
):
1
4
3
d
d
161.7 (d, JCF¼243.5 Hz), 147.6, 144.2, 138.5, 133.1 (d, JCF¼3.3 Hz),
3
7.00e6.95 (m, 2H), 6.82 (s, 1H), 4.71e4.65 (m, 1H), 3.86 (s, 3H),
130.8 (d,
J
CF¼7.8 Hz), 130.1, 129.2, 129.1, 125.5, 118.9, 115.4 (d,
2
3
.34e3.21 (m, 2H), 3.08 (dd, J¼16.6, 4.9 Hz, 1H), 2.67 (dd, J¼13.8,
J
CF¼21.1 Hz), 113.4, 60.7, 37.3, 36.5, 21.3 ppm; HRMS (m/z) (ESI):
13
þ
10.1 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
):
d
155.2, 154.0, 150.3,
calcd for C23
H22FN
2
345.1767 [MþH ]; found 345.1751.
138.7, 137.8, 137.3, 129.4, 128.8, 128.5, 126.8, 125.0, 123.2, 120.9,
1
16.2, 114.8, 111.5, 105.2, 62.2, 55.7, 37.2, 37.1 ppm; HRMS (m/z)
4.3.20. 4-(5-Benzyl-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)phenyl
þ
ꢀ
1
(
ESI): calcd for C25
H
23
N
2
O
2
383.1760 [MþH ]; found 383.1750.
methyl ether (4aab). Yellow powder; mp 123e124 C; H NMR
500 MHz, CDCl ): 7.74e7.70 (m, 2H), 7.42e7.35 (m, 5H),
(
3
d
4
3
.3.14. 2-(5-Benzyl-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-
-yl)pyridine (4nab). Yellow oil; H NMR (500 MHz, CDCl ): d 8.50
3
7.30e7.24 (m, 5H), 6.99e6.95 (m, 2H), 4.63e4.57 (m, 1H), 3.85 (s,
3H), 3.29 (dd, J¼13.8, 3.1 Hz, 1H), 3.23 (dd, J¼16.7, 10.7 Hz, 1H),
1
13
(
d, J¼4.8 Hz, 1H), 8.00 (d, J¼8.0 Hz, 1H), 7.60 (t, J¼7.7 Hz, 1H), 7.27 (t,
3.05 (dd, J¼16.7, 5.0 Hz, 1H), 2.66e2.59 (m, 1H) ppm; C NMR
J¼7.5 Hz, 2H), 7.23e7.18 (m, 5H), 7.12e7.09 (m, 1H), 6.92 (d,
3
(125 MHz, CDCl ) d 153.5, 147.2, 138.8, 137.6, 133.1, 129.3, 128.6,
J¼8.9 Hz, 2H), 4.65e4.55 (m, 1H), 3.78 (s, 3H), 3.35e3.19 (m, 3H),
128.4, 128.2, 126.5, 125.5, 115.6, 114.7, 62.3, 55.6, 46.8, 37.4 ppm;
1
3
þ
2
.62 (dd, J¼13.7, 10.0 Hz, 1H) ppm; C NMR (125 MHz, CDCl
3
):
HRMS (m/z) (ESI): calcd for C22
343.1800.
H
23
N
2
O 343.1810 [MþH ]; found
d
153.9, 152.5, 149.1, 148.2, 138.2, 137.5, 135.8, 129.4, 128.7, 126.6,
1
22.3, 120.3, 115.7, 114.8, 62.4, 55.7, 37.6, 37.2 ppm; HRMS (m/z)
þ
(
ESI): calcd for C22
H
22
N
3
O 344.1763 [MþH ]; found 344.1765.
4.3.21. 5-Benzyl-1-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyr-
1
3
azole (4aac). Yellow oil; H NMR (500 MHz, CDCl ): d 7.76e7.72 (m,
4
.3.15. 5-Benzyl-1-phenyl-3-(2-thienyl)-4,5-dihydro-1H-pyrazole
2H), 7.45e7.36 (m, 6H), 7.35e7.29 (m, 2H), 7.29e7.27 (m, 2H), 7.12
(d, J¼8.2 Hz, 1H), 6.88e6.86 (m, 1H), 4.69e4.64 (m, 1H), 3.29 (m,
2H), 3.09 (dd, J¼17.0, 3.9 Hz, 1H), 2.64 (dd, J¼13.8, 9.9 Hz, 1H) ppm;
ꢀ
1
(
4oaa). Yellow powder; mp 104e105 C; H NMR (500 MHz,
CDCl ): 7.38e7.35 (m, 3H), 7.34e7.31 (m, 2H), 7.30e7.26 (m, 5H),
.08e7.03 (m, 2H), 6.91e6.90 (m, 1H), 4.68e4.66 (m, 1H), 3.34 (dd,
J¼13.8, 3.3 Hz, 1H), 3.27 (dd, J¼16.7, 10.8 Hz, 1H), 3.05 (dd, J¼16.7,
3
d
13
7
3
C NMR (125 MHz, CDCl ): d 148.6, 145.2, 137.1, 135.2, 132.6, 130.2,
129.4, 128.8, 128.8, 128.5, 126.8, 125.8, 118.7, 113.5, 111.2, 60.7, 37.5,
13
4
.1 Hz, 1H), 2.62 (dd, J¼13.8, 10.1 Hz, 1H) ppm; C NMR (125 MHz,
37.4 ppm; HRMS (m/z) (ESI): calcd for C22
[MþH ]; found 347.1298.
H20ClN
2
347.1315
þ
CDCl ): 143.9, 143.6, 137.3, 137.0, 129.3, 129.2, 128.7, 127.2, 126.7,
3
d
126.3, 125.7, 119.2, 113.6, 61.2, 38.2, 37.3 ppm; HRMS (m/z) (APCI):
þ
calcd for C20
H
19
N
2
S 319.1269 [MþH ]; found 319.1261.
4.3.22. 5-Benzyl-N-(4-ethylphenyl)-3-phenyl-4,5-dihydro-1H-pyr-
1
azole-1-carbothioamide (4aad). Yellow oil; H NMR (500 MHz,
4
.3.16. 5-Benzyl-3-ethyl-4-methyl-1-phenyl-4,5-dihydro-1H-pyr-
CDCl
3
):
d
9.09 (s, 1H), 7.73 (d, J¼7.4 Hz, 2H), 7.58 (d, J¼7.8 Hz, 2H),
1
azole (4paa). Yellow oil; H NMR (500 MHz, CDCl
3
):
d
7.35e7.27 (m,
7.50e7.44 (m, 3H), 7.38e7.31 (m, 4H), 7.27 (d, J¼7.7 Hz, 3H), 5.44
(t, J¼10.0 Hz, 1H), 3.98e3.84 (m, 1H), 3.33 (dd, J¼17.6, 10.5 Hz, 1H),
3.10 (d, J¼17.7 Hz, 1H), 2.83 (dd, J¼12.8, 10.2 Hz, 1H), 2.71 (q,
6
3
9
3
H), 7.22 (d, J¼7.9 Hz, 2H), 7.14 (d, J¼8.6 Hz, 2H), 4.03e3.97 (m, 1H),
.19 (dd, J¼13.7, 3.5 Hz, 1H), 2.89e2.82 (m, 1H), 2.63 (dd, J¼13.8,
.3 Hz, 1H), 2.45e2.42 (m, 1H), 2.29e2.22 (m, 1H), 1.14 (t, J¼7.5 Hz,
13
J¼7.8 Hz, 2H), 1.30 (t, J¼7.6 Hz, 3H) ppm; C NMR (125 MHz,
13
H), 0.96 (d, J¼7.2 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
):
d
158.0,
3
CDCl ): d 173.8, 155.8, 141.8, 137.1, 136.3, 130.9, 129.6, 129.3, 128.9,
145.4, 137.4, 129.4, 129.1, 128.5, 126.5, 118.2, 113.0, 68.1, 46.6, 37.1,
128.7, 128.1, 126.8, 126.8, 125.0, 61.6, 38.6, 37.3, 28.5, 15.5 ppm;
HRMS (m/z) (ESI): calcd for C25
400.1830.
þ
21.5, 17.4, 11.2 ppm; HRMS (m/z) (ESI): calcd for C19
H
23
N
2
279.1861
H
26
N
3
S 400.1847 [MþH ]; found
þ
[MþH ]; found 279.1846.
4
1
.3.17. 5-(4-Ethylbenzyl)-3-(4-methylphenyl)-1-phenyl-4,5-dihydro-
4.3.23. (E)-1-Biphenyl-4-yl-4-phenyl-3-buten-1-one (5ia). White
ꢀ
1
ꢀ
13
ꢀ
1
H-pyrazole (4bba). Yellow crystals; mp 154e155 C; H NMR
):
7.71 (d, J¼8.0 Hz, 2H), 7.51e7.34 (m, 5H),
.30e7.25 (m, 5H), 7.01e6.95 (m, 1H), 4.76e4.66 (m, 1H),
powder; mp 100e102 C (lit. 101e102 C); H NMR (500 MHz,
CDCl ): 8.14e8.10 (m, 2H), 7.76e7.73 (m, 2H), 7.69e7.66 (m, 2H),
(
500 MHz, CDCl
3
d
3
d
7
3
2
7.53e7.49 (m, 2H), 7.44 (m, 3H), 7.37e7.31 (m, 2H), 7.28e7.23 (m,
.43e3.23 (m, 2H), 3.11 (dd, J¼16.8, 4.0 Hz, 1H), 2.78e2.78 (m, 2H),
1H), 6.56 (d, J¼16.3 Hz, 1H), 6.51 (dt, J¼16.3, 6.6 Hz, 1H), 3.98 (dd,
13
13
.66e2.59 (m, 1H), 2.48 (s, 3H), 1.37e1.34 (m, 3H) ppm; C NMR
): 147.5, 144.1, 142.3, 138.2, 134.5, 130.1, 129.1,
J¼6.5, 1.1 Hz, 2H) ppm; C NMR (125 MHz, CDCl
3
): d 197.5, 145.9,
(
125 MHz, CDCl
3
d
139.8, 136.9, 135.2, 133.5, 128.9, 128.5, 128.2, 127.4, 127.3, 127.2,

1628
Y.-C. Wang et al. / Tetrahedron 70 (2014) 1621e1628
1
C
26.2, 122.5, 77.2, 77.0, 76.7, 42.7 ppm; HRMS (m/z) (ESI): calcd for
2007, 17, 5897e5901; (c) Sahoo, A.; Yabanoglu, S.; Sinha, B. N.; Ucar, G.; Basu, A.;
Jayaprakash, V. Bioorg. Med. Chem. Lett. 2010, 20, 132e136; (d) Keche, A. P.;
Hatnapure, G. D.; Tale, R. H.; Rodge, A. H.; Kamble, V. M. Bioorg. Med. Chem. Lett.
þ
22
H19O 299.1436 [MþH ]; found 299.1422.
2012, 22, 6611e6615.
4
.3.24. (E)-1-((E)-2-Methyl-1,4-diphenylbut-3-enylidene)-2-phenyl-
2. For selected examples, see: (a) Liu, X.-H.; Liu, H.-F.; Chen, J.; Yang, Y.; Song, B.-
A.; Bai, L.-S.; Liu, J.-X.; Zhu, H.-L.; Qi, X.-B. Bioorg. Med. Chem. Lett. 2010, 20,
1
3
hydrazine (6jaa). Red oil; H NMR (500 MHz, CDCl ): d 8.10e7.95
5705e5708; (b) Congiu, C.; Onnis, V.; Vesci, L.; Castorina, M.; Pisano, C. Bioorg.
(
1
m, 2H), 7.89e7.71 (m, 2H), 7.55e7.19 (m, 12H), 6.52 (d, J¼16.0 Hz,
Med. Chem. 2010, 18, 6238e6248; (c) Liu, X.-H.; Ruan, B.-F.; Liu, J.-X.; Song, B.-
A.; Jing, L.-H.; Li, J.; Yang, Y.; Zhu, H.-L.; Qi, X.-B. Bioorg. Med. Chem. Lett. 2011, 21,
2916e2920; (d) Liu, J.-J.; Zhang, H.; Sun, J.; Wang, Z.-C.; Yang, Y.-S.; Li, D.-D.;
Zhang, F.; Gong, H.-B.; Zhu, H.-L. Bioorg. Med. Chem. 2012, 20, 6089e6096; (e)
Luo, Y.; Zhang, S.; Qiu, K.-M.; Liu, Z.-J.; Yang, Y.-S.; Fu, J.; Zhong, W.-Q.; Zhu, H.-L.
Bioorg. Med. Chem. Lett. 2013, 23, 1091e1095.
H), 6.36 (dd, J¼16.0, 8.2 Hz, 1H), 4.39e4.28 (m, 1H), 1.42 (d,
13
J¼6.8 Hz, 3H) ppm; C NMR (125 MHz, CDCl
3
): d 151.6, 140.2, 136.9,
136.4, 131.7, 129.8, 129.4, 128.7, 128.6, 128.6, 128.5, 127.6, 127.6,
126.3, 118.7, 44.9, 17.7 ppm; HRMS (m/z) (ESI): calcd for C23
H
23
N
2
þ
3. Kano, T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174e2175.
3
27.1861 [MþH ]; found 327.1848.
4
5
6
. For selected examples, see: (a) Wei, B.; Gao, Y.; Lin, C.-X.; Li, H.-D.; Xie, L.-L.;
Yuan, Y.-F. J. Organomet. Chem. 2011, 696, 1574e1578; (b) Liu, X.-H.; Li, J.; Shi, J.
B.; Song, B.-A.; Qi, X.-B. Eur. J. Med. Chem. 2012, 51, 294e299; (c) Xiao, C.; Luo,
X.-Y.; Li, D.-J.; Lu, H.; Liu, Z.-Q.; Song, Z.-G.; Jin, Y.-H. Eur. J. Med. Chem. 2012, 53,
Acknowledgements
159e167.
This research was supported by the Project 973
2011CB512005), Ministry of Education of China (IRT1225), Na-
. For selected examples, see: (a) Wang, S.; Shao, W.; Li, H.; Liu, C.; Wang, K.;
Zhang, J. Eur. J. Med. Chem. 2011, 46, 1914e1918; (b) Jain, S. K.; Jain, R.; Sahu, L.;
Yadav, A. K. J. Chem. Pharm. Res. 2012, 4, 3215e3223; (c) Khalil, N. A.; Ahmed, E.
M.; El-Nassan, H. B.; Ahmed, O. K.; Al-Abd, A. M. Arch. Pharm. Res. 2012, 35,
(
tional Natural Science Foundation of China (21362002, 41206077
and 81260472), Guangxi Natural Science Foundation of China
995e1002.
(
2012GXNSFAA053027 and 2011GXNSFD018010) and Key Project of
. Kanemasa, S.; Kanai, T. J. Am. Chem. Soc. 2000, 122, 10710e10711.
Guangxi Department of Education (2013ZD006).
7. For selected examples, see: (a) Sibi, M. P.; Stanley, L. M.; Soeta, T. Org. Lett. 2007,
9, 1553e1556; (b) Gao, L.; Hwang, G.-S.; Lee, M. Y.; Ryu, D. H. Chem. Commun.
2009, 5460e5462.
Supplementary data
8
. Suarez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
1244e11245.
. Sibi, M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127,
276e8277.
0. Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 11279e11282.
1. Mahe, O.; Dez, I.; Levacher, V.; Bri eꢀ re, J. F. Angew. Chem., Int. Ed. 2010, 49,
072e7075.
2. Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; J o€ rres, M.; Bolm, C. J. Am. Chem.
Soc. 2012, 134, 6924e6927.
1
9
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.01.021.
8
1
1
7
References and notes
1
1
. For selected examples, see: (a) Ali, M. A.; Shaharyar, M. Bioorg. Med. Chem. 2007,
5, 1896e1902; (b) Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H., Jr.;
Hills, P.; Mackay, H.; Brown, T.; Mooberry, S. L.; Lee, M. Bioorg. Med. Chem. Lett.
13. Trofimov, B. A.; Schmidt, E. Y.; Ushakov, I. A.; Zorina, N. V.; Skital’tseva, E. V.;
1
Protsuk, N. I.; Mikhaleva, A. I. Chem.dEur. J. 2010, 16, 8516e8521.