Cycloaddition of Nitrile Imines with Enamides: An Approach to Functionalized Pyrazolines and Pyrazoles

Article abstract of DOI:10.1021/acs.joc.0c02244

An efficient [3 + 2] cycloaddition of in situ generated nitrile imines with enamides has been established. A wide range of functionalized pyrazoline derivatives (53 examples) were obtained in moderate to good yields (up to 96%) under very mild conditions. This protocol features broad substrate scope, good functional group tolerance, and operational simplicity. Practical transformation of the products into useful pyrazoles via a one-pot process and the scalability of this protocol highlight the utility of this synthetic methodology.

Full text of DOI:10.1021/acs.joc.0c02244

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[3 + 2] Cycloaddition of Nitrile Imines with Enamides: An Approach
to Functionalized Pyrazolines and Pyrazoles
Liang Tu,† Limei Gao,† Xiaomeng Wang, Ruijie Shi, Rupei Ma, Junfei Li, Xiaoshuang Lan,
Yongsheng Zheng,* and Jikai Liu*
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ABSTRACT: An efficient [3 + 2] cycloaddition of in situ generated
nitrile imines with enamides has been established. A wide range of
functionalized pyrazoline derivatives (53 examples) were obtained in
moderate to good yields (up to 96%) under very mild conditions. This
protocol features broad substrate scope, good functional group tolerance,
and operational simplicity. Practical transformation of the products into
useful pyrazoles via a one-pot process and the scalability of this protocol
highlight the utility of this synthetic methodology.
bidihydropyrazoles.11 Su described [3 + 2] cycloaddition of
nitrile imines with para-quinone methides to synthesize spiro-
pyrazoline-cyclohexadienones.12 Despite these elegant strat-
egies, development of a novel method to generate pyrazolines
remains highly desirable.
On the other hand, although the cycloadditions of nitrile
imines have been well developed in the past decades, the most
reported strategies involving cycloaddition of nitrile imines are
mainly limited to the electron-deficient olefinic partners9−13
except for a few examples,14 which largely limits application of
this strategy. Therefore, development of a novel method to
construct pyrazolines using nitrile imine with electron-rich C
C derivatives is challenging and highly desirable, which would
expand the scope of nitrile imines and access pyrazolines that
cannot be obtained by other methods.
Enamides are versatile building blocks in organic synthesis
and have been widely employed as substrates in various
functionalization reactions15 and cycloadditions to construct
nitrogen-containing compounds.16 However, to our knowledge,
cycloaddition reaction of enamides with nitrile imines has not
been reported. We hypothesized that the nucleophilic and
electrophilic enamides would be matched with nitrile imines for
the preparation of pyrazolines via [3 + 2] cycloaddition.
Additionally, biologically important pyrazoles would also be
efficiently obtained by subsequent elimination of the acyl group.
We herein report the first [3 + 2] cycloaddition reaction
INTRODUCTION
■
Nitrogen-containing heterocyclic compounds represent versa-
tile structural motifs in natural products, pharmaceuticals, and
functional materials.1 In particular, pyrazoline and pyrazole
skeletons have received enormous attention as a ubiquitous
structural unit in pesticides and pharmaceutical compounds
displaying a wide range of biological activities (Figure 1).2 For
instance, compound I showed antitubercular activity.3 Com-
pound II was reported to be a CB-receptor ligand.4 Apixaban,
which contains a pyrazole core structure, has proved to be a
factor Xa inhibitor for the treatment of cardiovascular diseases.5
Thus, development of efficient and versatile synthetic strategies
for the preparation of these moieties has received enormous
research interest, and various elegant methods have been
reported (Scheme 1). Traditional access to pyrazole and
pyrazoline derivatives mainly involves condensation of
hydrazines with dicarbonyl compounds or unsaturated carbon-
yls (Scheme 1a).6 During the past decade, cycloadditions of two-
nitrogen synthons with various partners have been established as
the most prominent strategies for the synthesis of pyrazolines.
For example, [3 + 2] cycloaddition reactions of Bestmann−
Ohira reagent (BOR) and Seyferth−Gilbert reagent (SGR) with
olefinic derivatives to access spiro-phosphonylpyrazolines have
been developed by Peng and Mohanan (Scheme 1b).7 In
addition, [4 + 1] annulation reactions of in situ formed
azoalkenes with C1 synthons were also successfully demon-
strated for the construction of pyrazolines by several groups
(Scheme 1c).8 Recently, [3 + 2] cycloadditions of nitrile imines
with alkenes represent an attractive strategy to prepare
pyrazolines (Scheme 1d).9 For example, Feng and Stanley
developed asymmetric 1,3-dipolar cycloaddition reactions of
nitrile imines with 3-alkenyl-oxindoles to afford chiral spiro-
pyrazoline-oxindoles, respectively.10 Guo reported 1,3-dipolar
cycloaddition of nitrilimines with allenoates to afford spiro-
Received: September 17, 2020
https://dx.doi.org/10.1021/acs.joc.0c02244
© XXXX American Chemical Society
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A

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Figure 1. Representive drugs and biologically active compounds bearing pyrazoline and pyrazole units.
Scheme 1. Different Strategies for Pyrazolines Synthesis
between in situ generated nitrile imines and enamides for the
efficient synthesis of pyrazolines.
of the designed [3 + 2] cycloaddition reaction (Table 1). With
the use of Na2CO3 as the base, the reaction was performed in
1,2-dichloroethane at room temperature for 40 h to give the
desired product fused pyrazoline 3aa as a single diastereoisomer
in 66% yield (Table 1, entry 1). Investigation on solvents
indicated that CH2Cl2 and CHCl3 are also suitable for the
reaction (entries 2 and 3). It was found that the oxygenated
RESULTS AND DISCUSSION
■
We began our study using the readily accessible N-phenyl-
benzohydrazonoyl chloride 1a and N-(3,4-dihydronaphthalen-
1-yl)acetamide 2a as the model substrates to test the feasibility
B
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a
3da, 3ea vs 3aa, 3ba). Although the substrate bearing electron-
donating ortho-substituent gave decent yield (3fa), those with
electron-withdrawing ortho-substituted halogen led to low to
moderate yields (3ga, 3ha, 3ia, 3ja). These results showed that
electron-donating substituents on the phenyl ring may increase
the electron cloud density of the nitrogen, which is beneficial to
the reaction. The significant steric effect of the substituent on the
aromatic ring of hydrazonoyl chlorides on the reaction efficiency
has also been observed (3da, 3ea, 3ga). Then, the effect of
substituents linked to CN was investigated. Generally,
substrates with electron-donating or electron-withdrawing
group on the phenyl ring afforded the products in 80−90%
yield. Ester group was also tolerated in these reaction conditions
and delivered the desired product 3ta in 87% yield. Moreover,
substrates with heteroaryl, such as furanyl and thienyl, generated
the corresponding products in uncompromising yields (3ua and
3va). Notably, the aliphatic-substituted hydrazonyl chloride
could also be subjected to the reaction. However, the product
was very unstable and decomposed to the corresponding
pyrazole in chloroform even without any promotor (3wa).
To further examine the generality of the reaction, we next
investigated the scope of different cyclic enamindes under the
established conditions to prepare the fused pyrazolines. First, we
tested a range of benzo five-membered cyclic enamides bearing
various substituents on the benzene ring. Electron-rich
enamides showed good reactivity to yield the product in
excellent yields (Scheme 3, 3ab, 3ac). Enamides with electron-
withdrawing substituents led to relatively lower yields (Scheme
3, 3ad, 3ae, 3af). A ring expansion as in enamides (n = 2, 3) was
possible without any difficulty and gave the product in 82 and
73% yields, respectively (Scheme 3, 3ag, 3ah). Then, different
N-benzoyl enamides were investigated. In general, the trans-
formation displayed high functional group tolerance and proved
to be a reliable methodology for the preparation of multi-
substituted pyrazolines in 74−89% yields (Scheme 3, 3ai−as).
However, N-naphthoyl enamide led to fair yield, probably due to
the steric hindrance (3at). Finally, we tried to expand the
substrate scope to aliphatic-substituted enamides, and excellent
yields were obtained (3au−aw). It is worth noting that this
reaction proceeded in a highly diastereoselective manner and
also only one diastereoisomer was observed by crude NMR
(3aw).
Based on the above examples, we envisioned that if acyclic
enamides were used to couple with nitrile imines, the
biologically important and highly functionalized nonfused
pyrazolines would be obtained. As shown in Scheme 4, a series
of acyclic enamides with electron-withdrawing or electron-
donating substituents on the benzene ring could smoothly
perform the reaction under mild conditions, affording the
desired pyrazolines in good to excellent yields (82−90%)
(Scheme 4, 4a−i).
To further demonstrate the practical utility of this method, a
one-pot synthesis of pyrazoles and tetralone-fused pyrazoles was
conducted via [3 + 2] cycloaddition reaction, followed by
subsequent elimination induced by a catalytic amount of AlCl3.
A wide range of acyclic and cyclic N-acetyl enamides were
reacted with nitrile imines to synthesize the useful pyrazole
derivatives (Scheme 5, 5a−q). The acid-sensitive methoxyl and
tert-butyl on the benzene ring of enamides are also compatible
with the reaction conditions, giving the product in 91 and 87%
yields (Scheme 5, 5g and 5h), respectively. The ester-
substituted hydrazonyl chloride performed the reaction to
yield the product 5n in 87% yield.
Table 1. Optimization of Reaction Conditions
b
entry
Base
solvent
t (h)
yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
NaOH
DIPEA
TEA
DABCO
K2CO3
K2CO3
K2CO3
DCE
40
24
40
72
72
72
60
40
5
72
72
72
72
72
24
48
24
36
66
72
62
40
37
46
79
53
65
27
42
59
53
45
92
85
92
75
DCM
CHCl3
dioxane
THF
MeOH
MeCN
toluene
DMF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
c
16
17
18
d
e
K2CO3
a
The reactions were performed with 1a (0.3 mmol), 2a (0.2 mmol),
and base (0.6 mmol) in the solvent (2.0 mL) at room temperature.
Isolated yields, only one diastereoisomer was observed by crude
NMR analysis. 0.4 mmol K2CO3 was used. 1a (0.4 mmol), 2a (0.2
b
c
d
e
mmol). 1a (0.22 mmol), 2a (0.2 mmol).
solvent has a detrimental effect on the reaction for an unknown
reason, giving low to moderate yields even with prolonged time
(entries 4−6). Further screening of the solvents resulted in no
improvement of the reaction efficiency (entries 7−9). It is worth
noting that when the reaction was exposed in dimethylforma-
mide (DMF), the reaction time was decreased to 5 h from the
previous 24 h, although the yield of 3aa decreased slightly (entry
9). Then, different bases were screened to improve the yield
(entries 10−15). Unfortunately, NaHCO3, NaOH, or organic
bases only gave moderate yields (entries 10−14). To our
delight, the yield was increased to 92% with the use of K2CO3 as
the base. Lowering the amount of the base resulted in a slight
decrease of the yield (entries 15 and 16). Attempts on further
improving the efficiency of the reaction by screening the ratios of
the substrates were unsuccessful (entries 17 and 18). As a result,
a combination of K2CO3 (3.0 equiv) and CH2Cl2 at room
temperature was established as the most suitable reaction
condition.
With the optimized reaction conditions in hand, we
emphasize on exploring the substrate scope of this protocol by
employing a variety of hydrazonyl chlorides 1. Initially,
hydrazonyl chlorides derived from various substituted phenyl-
hydrazines and benzoyl chloride were examined, and the results
are summarized in Scheme 2. Hydrazonyl chlorides 1 with
electron-donating groups, including ortho-substituted hydra-
zonyl chlorides, were good substrates and gave the desired
pyrazolines in good to excellent yields (87−96%) (Scheme 2,
3aa−ca, 3fa, 3ma). However, electron-withdrawing substituents
have an adverse effect on reaction efficiency. Hydrazonyl
chlorides with electron-withdrawing groups resulted in slightly
lower yields compared to the electron-donating ones (Scheme 2,
C
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a b
,
Scheme 2. Substrate Scope of Hydrazonoyl Chloride
a
b
Reaction condition: 1 (0.3 mmol), 2 (0.2 mmol), and K2CO3 (0.6 mmol) in dichloromethane (DCM; 2.0 mL) at rt for 24 h. Isolated yield, only
one diastereoisomer was observed by crude NMR analysis.
The developed cycloaddition reaction could be performed on
a gram scale. Under the optimal reaction conditions, the
preparative scale reaction of 1a and 2r proceeded smoothly and
gave the product 3ar in 80% yield, which could be further
derived by Suzuki coupling (Scheme 6). In addition, treating
pyrazole 5n with KOH, oxalyl chloride, and piperdin-1-amine,
could produce hydrazide 7 in 79% yield over three steps.
A plausible mechanism was proposed, as shown in Scheme 7.
Intermediate A was first generated from the corresponding
hydrazonyl chloride 1a by dechlorination. Then, the nitrile
imine B formed in the presence of a base by deprotonation
reacted with enamide 2a through either a concerted or stepwise
process to generate the desired product. The pyrazole 5o could
be obtained by AlCl3-facilitated β-elimination. This mechanistic
scheme was supported by the detection of key intermediates A
by high-resolution mass spectrometry (HRMS).
CONCLUSIONS
■
In summary, we have developed the first [3 + 2] cycloadditions
of in situ generated nitrile imines with enamides. A very wide
range of nitrile imines and enamides were compatible with the
mild reaction conditions and provided the highly functionalized
pyrazolines. In addition, the products could be efficiently
converted to useful pyrazoles via a one-pot process. This
protocol expands the chemistry of both enamides and nitrile
imines. The potential application of these compounds is under
investigation in our laboratory.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise specified, all reactions
were carried out under a nitrogen atmosphere in anhydrous conditions.
All chemicals and solvents which are commercially available were used
without further purification. Analytical thin-layer chromatography
(TLC) was performed on silica gel plates (GF-254) using UV light (254
and 365 nm). Flash chromatography was conducted on silica gel (200−
D
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a b
,
Scheme 3. Substrate Scope of Cyclic Enamides
a
b
Reaction condition: 1 (0.3 mmol), 2 (0.2 mmol), and K2CO3 (0.6 mmol) in DCM (2.0 mL) at rt for 24 h. Isolated yield, only one
diastereoisomer was observed by crude NMR analysis.
300 mesh). NMR spectra were recorded at ambient temperature in
CDCl3 on a Bruker Ascend III TM600 NMR spectrometer (1H NMR at
600 MHz and 13C{1H} NMR at 150 MHz) and a Bruker Avance NEO
NMR spectrometer (1H NMR at 500 MHz and 13C{1H} NMR at 125
MHz). Chemical shifts were reported in parts per million (ppm)
downfield from an internal standard, tetramethylsilane (0 ppm). All
high-resolution mass spectra were obtained on an Agilent 6200 Q-TOF
MS. Melting points were determined on a WRX-4 melting point
apparatus. Enamides16a and hydrazonoyl chloride13d,17 were prepared
according to the literature procedures.
General Procedure for the Synthesis of Pyrazolines. To a
dried test tube with a magnetic stirring bar under N2 at room
temperature were added hydrazonoyl chloride 1 (0.3 mmol) and
enamide 2 (0.20 mmol), followed by the addition of K2CO3 (0.6
mmol). Then, dichloromethane (2.00 mL) was introduced by a syringe
and the mixture was stirred at room temperature for 24 h. The solvent
was removed by rotary evaporation, and the residue was purified by
column chromatography on silica gel to afford the desired product.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)acetamide (3aa). The product was obtained by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
10:1 to 5:1) as a white solid (73.2 mg, yield: 96%); mp 180−181 °C. 1H
NMR (600 MHz, CDCl3): δ 7.82 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.5 Hz,
2H), 7.38 (d, J = 7.3 Hz, 1H), 7.36−7.32 (m, 1H), 7.23−7.20 (m, 2H),
7.12 (t, J = 7.8 Hz, 3H), 7.00−6.89 (m, 3H), 6.32 (s, 1H), 4.45 (d, J =
7.8 Hz, 1H), 2.62−2.50 (m, 2H), 2.13 (d, J = 13.3 Hz, 1H), 1.95 (s,
3H), 1.93−1.87 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ 170.1,
153.8, 141.9, 140.9, 133.2, 131.8, 129.1, 128.9, 128.7, 128.18, 128.0,
127.3, 126.6, 125.9, 123.4, 120.7, 82.8, 52.9, 27.8, 26.0, 23.9; HRMS
(ESI) m/z: [M + H]+ calcd. for C25H24N3O, 382.1914; found,
382.1911.
N-((3a,9b)-3-Phenyl-1-(p-tolyl)-1,3a,4,5-tetrahydro-9bH-benzo-
[g]indazol-9b-yl)acetamide (3ba). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (72.7 mg, yield: 92%); mp 177−
178 °C. 1H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H), 7.35−
E
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a b
,
Scheme 4. Substrate Scope of Acyclic Enamides
a
b
Reaction condition: 1 (0.3 mmol), 2 (0.2 mmol), and K2CO3 (0.6 mmol) in DCM (2.0 mL) at rt for 24 h. Isolated yield.
a b
,
Scheme 5. One-Pot Preparation of Pyrazoles
a
Reaction condition: (1) 1 (0.3 mmol), 2 (0.2 mmol), and K2CO3 (0.6 mmol) in DCM (2.0 mL) at rt for 24 h; (2) AlCl3 (0.02 mmol), 0.5 h.
b
Isolated yield.
7.27 (m, 3H), 7.20−7.17 (m, 1H), 7.15−7.11 (m, 2H), 7.07−7.05 (m,
51.5, 26.8, 24.8, 22.8, 19.7; HRMS (ESI) m/z: [M + H]+ calcd. for
C26H26N3O, 396.2070; found, 396.2070.
N-((3a,9b)-3-Phenyl-1-(m-tolyl)-1,3a,4,5-tetrahydro-9bH-benzo-
[g]indazol-9b-yl)acetamide (3ca). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (71.9 mg, yield: 91%); mp 178−
1H), 6.85 (d, J = 8.2 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.15 (s, 1H),
4.36 (dd, J = 8.3, 1.5 Hz, 1H), 2.55 (dd, J = 8.2, 3.5 Hz, 2H), 2.15 (s,
3H), 2.07−2.03 (m, 1H), 1.86 (s, 3H), 1.87−1.81 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3): δ 168.9, 152.7, 139.8, 138.3, 132.5, 132.4,
130.8, 128.2, 127.9, 127.7, 127.0, 126.8, 126.0, 125.4, 124.8, 120.4, 81.7,
F
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Scheme 6. Gram-Scale Synthesis and Derivation
Scheme 7. Plausible Reaction Mechanism
1
179 °C. H NMR (500 MHz, CDCl3): δ 7.78−7.72 (m, 2H), 7.37−
CDCl3): δ 169.2, 153.0, 142.0, 139.8, 133.2, 131.3, 130.4, 128.4, 127.8,
127.3, 127.0, 126.5, 126.2, 125.6, 124.8, 121.4, 118.4, 116.0, 81.6, 52.2,
26.5, 25.0, 22.8; HRMS (ESI) m/z: [M + H]+ calcd. for C25H23ClN3O,
416.1524; found: 416.1523.
7.34 (m, 2H), 7.32−7.28 (m, 1H), 7.26−7.22 (m, 1H), 7.16−7.13 (m,
2H), 7.08−7.05 (m, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 7.5 Hz,
1H), 6.66 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 4.38 (d, J = 8.5
Hz, 1H), 2.56−2.52 (m, 2H), 2.12 (s, 3H), 2.09−2.01 (m, 1H), 1.89 (s,
3H), 1.87−1.80 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.9,
152.7, 140.7, 139.9, 137.5, 132.4, 130.8, 128.0, 127.7, 127.4, 127.1,
126.9, 126.2, 125.5, 124.7, 123.3, 120.6, 116.8, 81.7, 51.5, 26.7, 24.9,
22.9, 20.4; HRMS (ESI) m/z: [M + H]+ calcd. for C26H26N3O,
396.2070; found, 396.2069.
N-((3a,9b)-1-(4-Chlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3da). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (68.1 mg, yield: 82%);
mp 189−190 °C. 1H NMR (500 MHz, CDCl3): δ 7.81−7.79 (m, 2H),
7.46−7.34 (m, 5H), 7.24−7.19 (m, 2H), 7.07−7.03 (m, 2H), 6.89−
6.83 (m, 2H), 6.38 (s, 1H), 4.41 (d, J = 8.2 Hz, 1H), 2.60−2.46 (m,
2H), 2.19−2.08 (m, 1H), 1.96 (s, 3H), 1.91−1.85 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3): δ 170.2, 154.1, 140.9, 140.5, 132.7, 131.5,
129.4, 128.9, 128.6, 128.4, 128.1, 127.3, 126.6, 125.9, 121.2, 114.9, 82.7,
53.1, 27.6, 25.9, 23.8; HRMS (ESI) m/z: [M + H]+ calcd. for
C25H23ClN3O, 416.1524; found, 416.1526.
N-((3a,9b)-1-(3-Chlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ea). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (68.1 mg, yield: 82%);
mp 185−186 °C. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 7.0 Hz,
2H), 7.39−7.32 (m, 3H), 7.20−7.13 (m, 3H), 7.03 (d, J = 7.2 Hz, 1H),
6.98 (t, J = 2.0 Hz, 1H), 6.90 (t, J = 8.1 Hz, 1H), 6.77 (d, J = 7.8 Hz,
1H), 6.70 (d, J = 6.8 Hz, 1H), 6.30 (s, 1H), 4.35 (d, J = 8.3 Hz, 1H),
2.49 (d, J = 16.3 Hz, 1H), 2.39 (t, J = 13.5 Hz, 1H), 2.03 (d, J = 12.4 Hz,
1H), 1.90 (s, 3H), 1.85−1.74 (m, 1H); 13C{1H} NMR (125 MHz,
N-((3a,9b)-3-Phenyl-1-(o-tolyl)-1,3a,4,5-tetrahydro-9bH-benzo-
[g]indazol-9b-yl)acetamide (3fa). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (68.8 mg, yield: 87%); mp 166−
167 °C. 1H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 7.4 Hz, 2H), 7.33
(t, J = 7.4 Hz, 2H), 7.29 (d, J = 7.1 Hz, 1H), 7.16−7.08 (m, 5H), 7.03
(d, J = 7.1 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H),
6.32 (s, 1H), 4.41 (t, J = 6.5 Hz, 1H), 2.84−2.76 (m, 2H), 2.11−2.06
(m, 2H), 1.84 (s, 3H), 1.40 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 169.7, 154.8, 140.0, 139.8, 137.7, 133.9, 131.9, 129.0, 128.8,
128.2 128.1, 128.0, 127.4, 126.6, 126.3, 126.2, 126.0, 82.8, 51.5, 28.4,
25.0, 24.1, 17.7; HRMS (ESI) m/z: [M + H]+ calcd. for C26H26N3O,
396.2070; found, 396.2070.
N-((3a,9b)-1-(2-Chlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ga). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (35.7 mg, yield: 43%);
mp 170−171 °C. 1H NMR (500 MHz, CDCl3): δ 7.79−7.78 (m, 2H),
7.44−7.37 (m, 4H), 7.28 (dd, J = 1.4 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H),
7.04−7.00 (m, 3H), 6.97−6.94 (m, 2H), 6.62 (dd, J = 7.9, 1.5 Hz, 1H),
4.41 (dd, J = 6.9, 3.3 Hz, 1H), 2.71−2.64 (m, 1H), 2.60−2.53 (m, 1H),
2.25−2.17 (m, 2H), 2.05 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3):
δ 169.2, 154.2, 140.3, 139.2, 133.0, 131.8, 131.7, 130.0, 129.8, 129.1,
128.8, 128.0, 127.9, 127.8, 127.0, 126.7, 126.1, 126.0, 83.7, 53.9, 27.7,
24.5, 23.9; HRMS (ESI) m/z: [M + H]+ calcd. for C25H23ClN3O,
416.1524; found, 416.1523.
N-((3a,9b)-1-(2-Chloro-4-fluorophenyl)-3-phenyl-1,3a,4,5-tetra-
hydro-9bH-benzo[g]indazol-9b-yl)acetamide (3ha). The product
was obtained by column chromatography on silica gel (eluent:
G
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petroleum ether/ethyl acetate = 10:1 to 5:1) as a white solid (30.3 mg,
yield: 35%); mp 190−191 °C. 1H NMR (600 MHz, CDCl3): δ 7.69 (d,
J = 7.2 Hz, 2H), 7.36−7.30 (m, 3H), 7.10 (s, 1H), 7.04 (d, J = 7.8 Hz,
1H), 7.02−6.95 (m, 3H), 6.90 (t, J = 7.4 Hz, 1H), 6.63−6.57 (m, 1H),
6.49 (dd, J = 8.8, 5.7 Hz, 1H), 4.32 (dd, J = 6.9, 3.6 Hz, 1H), 2.61 (d, J =
14.1 Hz, 1H), 2.49−2.44 (m, 1H), 2.18−2.09 (m, 2H), 1.98 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ 168.2, 159.5 (d, J = 250.5 Hz),
ether/ethyl acetate = 10:1 to 5:1) as a white solid (75.3 mg, yield: 92%);
mp 189−190 °C. 1H NMR (600 MHz, CDCl3): δ 7.75 (d, J = 7.3 Hz,
2H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.5
Hz, 1H), 7.18−7.12 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.55 (s, 1H),
6.41 (s, 2H), 6.12 (s, 1H), 4.38 (d, J = 8.3 Hz, 1H), 2.56−2.54 (m, 2H),
2.08 (s, 6H), 2.06−2.01 (m, 1H), 1.89 (s, 3H), 1.88−1.83 (m, 1H);
13C{1H} NMR (150 MHz, CDCl3): δ 168.9, 152.6, 140.6, 139.9, 137.2,
153.3, 138.0, 135.7 (d, J = 3.7 Hz), 131.9, 131.7 (d, J = 10.8 Hz), 130.5,
129.9 (d, J = 9.2 Hz), 128.1, 127.8, 127.1, 127.0, 125.6, 125.2, 124.8,
116.0 (d, J = 25.8 Hz), 113.2 (d, J = 21.9 Hz), 82.5, 52.9, 26.6, 23.5,
22.8; HRMS (ESI) m/z: [M + Na]+ calcd. for C25H21ClFN3NaO,
456.1249; found, 456.1249.
132.5, 130.8, 127.9, 127.7, 127.1, 126.9, 126.3, 125.5, 124.5, 124.4,
117.8, 81.7, 51.3, 28.9, 26.7, 24.9, 22.9, 20.3; HRMS (ESI) m/z: [M +
Na]+ calcd. for C27H27N3NaO, 432.2046; found, 432.2046.
N-((3a,9b)-1-(3-Chloro-4-methylphenyl)-3-phenyl-1,3a,4,5-tetra-
hydro-9bH-benzo[g]indazol-9b-yl)acetamide (3na). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1 to 5:1) as a yellow solid (50.6
mg, yield: 59%); mp 201−202 °C. 1H NMR (600 MHz, CDCl3): δ 7.74
(d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 (dd, J = 14.8, 7.5 Hz,
2H), 7.18−7.14 (m, 2H), 7.05 (d, J = 6.2 Hz, 1H), 6.93 (s, 1H), 6.83 (d,
J = 8.3 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 6.19 (s, 1H), 4.35 (d, J = 8.2
Hz, 1H), 2.53−2.42 (m, 2H), 2.15 (s, 3H), 2.03 (d, J = 13.1 Hz, 1H),
1.90 (s, 3H), 1.86−1.81 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3):
δ 169.0, 153.0, 139.8, 139.8, 133.2, 131.8, 130.5, 129.5, 129.4, 128.2,
127.8, 127.3, 127.0, 126.2, 125.6, 124.8, 119.7, 117.3, 81.6, 52.0, 26.6,
24.9, 22.8, 18.3; HRMS (ESI) m/z: [M + H]+ calcd. for C26H25ClN3O,
430.1681; found, 430.1681.
N-((3a,9b)-3-(2-Bromophenyl)-1-(3-chlorophenyl)-1,3a,4,5-tetra-
hydro-9bH-benzo[g]indazol-9b-yl)acetamide (3oa). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1 to 5:1) as a white solid (63.1
mg, yield: 64%); mp 190−191 °C. 1H NMR (500 MHz, CDCl3): δ 7.60
(d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H),
7.32 (t, J = 7.4 Hz, 1H), 7.22−7.10 (m, 3H), 7.04 (d, J = 7.0 Hz, 1H),
6.99 (s, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.77 (dd, J = 18.1, 7.8 Hz, 2H),
6.29 (s, 1H), 4.63 (d, J = 7.8 Hz, 1H), 2.54−2.41 (m, 2H), 1.97 (s, 3H),
1.83−1.60 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 168.9,
153.9, 142.0, 139.6, 133.2, 132.9, 131.6, 131.3, 130.3, 129.5, 128.4,
127.3, 127.2, 126.5, 126.5, 124.9, 121.7, 121.4, 118.5, 116.2, 81.3, 54.6,
26.5, 24.3, 22.8; HRMS (ESI) m/z: [M + H]+ calcd. for
C25H22BrClN3O, 494.0629; found, 494.0630.
N-((3a,9b)-1-Phenyl-3-(p-tolyl)-1,3a,4,5-tetrahydro-9bH-benzo-
[g]indazol-9b-yl)acetamide (3pa). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (68.0 mg, yield: 86%); mp 175−
176 °C. 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.1 Hz, 3H), 7.35−
7.33 (m, 1H), 7.24−7.21 (m, 3H), 7.16−7.09 (m, 3H), 6.96 (t, J = 7.2
Hz, 1H), 6.91 (d, J = 3.4 Hz, 2H), 6.21 (s, 1H), 4.45 (d, J = 9.0 Hz, 1H),
2.64−2.59 (m, 2H), 2.40 (s, 3H), 2.13 (d, J = 13.3 Hz, 1H), 1.98 (s,
3H), 1.95−1.87 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.0,
154.0, 142.0, 140.9, 133.3, 129.5, 129.4, 129.2, 128.9, 128.7, 128.1,
128.0, 127.2, 126.5, 125.8, 123.3, 120.6, 113.6, 82.7, 52.8, 27.7, 26.0,
23.9, 21.4; HRMS (ESI) m/z: [M + H]+ calcd. for C26H26N3O,
396.2070; found, 396.2070.
N-((3a,9b)-3-(4-Fluorophenyl)-1-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3qa). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (65.5 mg, yield: 82%);
mp 217−218 °C. 1H NMR (500 MHz, CDCl3): δ 7.79 (dd, J = 8.8, 5.4
Hz, 2H), 7.356−7.31 (m, 1H), 7.22−7.20 (m, 2H), 7.14−7.09 (m,
5H), 6.95 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.7 Hz, 2H), 6.34 (s, 1H), 4.41
(d, J = 7.7 Hz, 1H), 2.66−2.49 (m, 2H), 2.08 (d, J = 13.5 Hz, 1H), 1.94
(s, 3H), 1.93−1.85 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
170.1, 163.3 (d, J = 249.7 Hz), 152.9, 141.9, 140.8, 133.1, 128.7, 128.4
(d, J = 8.2 Hz), 128.2, 128.1 (d, J = 3.3 Hz), 128.0, 127.3, 125.9, 123.5,
120.7, 115.9 (d, J = 21.8 Hz), 82.8, 52.9, 27.7, 25.9, 23.8; HRMS (ESI)
m/z: [M + H]+ calcd. for C25H23FN3O, 400.1820; found, 400.1819.
N-((3a,9b)-3-(4-Chlorophenyl)-1-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ra). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (66.4 mg, yield: 80%);
mp 167−168 °C. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.6 Hz,
2H), 7.39 (d, J = 8.6 Hz, 2H), 7.35−7.31 (m, 1H), 7.23−7.21 (m, 2H),
N-((3a,9b)-1-(2,4-Difluorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ia). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (50.1 mg, yield: 60%);
mp 188−189 °C. 1H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 7.0 Hz,
2H), 7.46−7.35 (m, 3H), 7.26−7.24 (m, 1H), 7.07−6.99 (m, 2H), 6.96
(d, J = 8.1 Hz, 1H), 6.86−6.79 (m, 2H), 6.69−6.54 (m, 2H), 4.44 (d, J
= 5.5 Hz, 1H), 2.58 (d, J = 15.1 Hz, 1H), 2.35 (t, J = 14.0 Hz, 1H),
2.23−2.16 (m, 1H), 2.09 (s, 3H), 2.08−2.02 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 169.4, 161.3, 161.2, 159.3, 159.2, 157.6, 157.5,
155.6, 155.5, 154.6, 139.4, 132.2, 131.5, 129.3, 128.9, 128.1, 127.9,
127.5, 127.4, 126.8, 126.1, 125.9, 125.8, 111.1, 111.1, 110.9, 110.9,
104.0, 103.8, 103.6, 82.7, 54.0, 27.5, 24.5, 23.9; HRMS (ESI) m/z: [M
+ Na]+ calcd. for C25H21F2N3NaO, 440.1545; found, 440.1544.
N-((3a,9b)-1-(2,4-Dichlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ja). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a yellow solid (37.7 mg, yield:
42%); mp 189−190 °C. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 6.8
Hz, 2H), 7.39−7.30 (m, 3H), 7.23 (d, J = 2.4 Hz, 1H), 7.09 (d, J = 7.7
Hz, 1H), 7.07−7.00 (m, 2H), 6.99−6.91 (m, 2H), 6.87 (dd, J = 8.7, 2.5
Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 4.40−4.24 (m, 1H), 2.63−2.58 (m,
1H), 2.51−2.41 (m, 1H), 2.21−2.07 (m, 2H), 1.99 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 168.2, 153.7, 138.1, 131.7, 130.5, 129.6,
129.3, 128.7, 127.8, 127.6, 127.1, 126.7, 126.4, 126.2, 125.7, 125.3,
124.9, 120.3, 82.6, 53.0, 26.7, 23.57, 22.9; HRMS (ESI) m/z: [M +
Na]+ calcd. for C25H21Cl2N3NaO, 472.0954; found, 472.0955.
N-((3a,9b)-1-(3,4-Dichlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3ka). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (60.2 mg, yield: 67%);
mp 199−200 °C. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 6.9 Hz,
2H), 7.40−7.34 (m, 3H), 7.33 (d, J = 6.3 Hz, 1H), 7.21−7.15 (m, 3H),
7.08 (d, J = 2.6 Hz, 1H), 7.03 (dd, J = 14.3, 7.9 Hz, 2H), 6.70−6.65 (m,
1H), 6.27 (s, 1H), 4.35 (d, J = 8.4 Hz, 1H), 2.50 (d, J = 14.6 Hz, 1H),
2.40−2.26 (m, 1H), 2.03 (d, J = 13.4 Hz, 1H), 1.93 (s, 3H), 1.86−1.76
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.2, 153.4, 140.3,
139.8, 131.3, 131.0, 130.2, 128.9, 128.5, 127.9, 127.5, 127.2, 126.4,
125.7, 124.9, 124.5, 119.6, 117.0, 81.6, 52.4, 26.5, 25.0, 22.8; HRMS
(ESI) m/z: [M + H]+ calcd. for C25H22Cl2N3O, 450.1134; found,
450.1133.
N-((3a,9b)-1-(3,5-Dichlorophenyl)-3-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3la). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (71.0 mg, yield: 79%);
mp 210−211 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz,
2H), 7.52 (d, J = 7.6 Hz, 1H), 7.49−7.41 (m, 3H), 7.33 (t, J = 7.3 Hz,
1H), 7.28 (d, J = 1.3 Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 6.93 (d, J = 1.8
Hz, 2H), 6.85 (t, J = 1.8 Hz, 1H), 6.07 (s, 1H), 4.48 (d, J = 8.5 Hz, 1H),
2.59 (d, J = 14.8 Hz, 1H), 2.50−2.38 (m, 1H), 2.16−2.11 (m, 1H), 2.10
(s, 3H), 1.96−1.85 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
170.0, 154.6, 143.62, 140.9, 134.8, 131.7, 131.1, 129.7, 128.9, 128.7,
128.2, 127.5, 126.8, 126.1, 121.7, 116.4, 82.7, 53.4, 27.5, 26.2, 24.0;
HRMS (ESI) m/z: [M + Na]+ calcd. for C25H21Cl2N3NaO, 472.0954;
found, 472.0956.
N-((3a,9b)-1-(3,5-Dimethylphenyl)-3-phenyl-1,3a,4,5-tetrahy-
dro-9bH-benzo[g]indazol-9b-yl)acetamide (3ma). The product was
obtained by column chromatography on silica gel (eluent: petroleum
H
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7.17−7.10 (m, 3H), 6.97 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.7 Hz, 2H),
6.26 (s, 1H), 4.41 (d, J = 7.8 Hz, 1H), 2.67−2.52 (m, 2H), 2.07 (d, J =
13.4 Hz, 1H), 1.96 (s, 3H), 1.95−1.86 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 170.1, 152.7, 141.7, 140.8, 134.9, 133.1, 130.4, 129.0,
128.8, 128.3, 128.0, 127.7, 127.3, 125.9, 123.6, 120.7, 82.9, 52.7, 27.7,
25.9, 23.9; HRMS (ESI) m/z: [M + H]+ calcd. for C25H23ClN3O,
416.1524; found, 416.1524.
N-((3a,9b)-3-(4-Bromophenyl)-1-phenyl-1,3a,4,5-tetrahydro-
9bH-benzo[g]indazol-9b-yl)acetamide (3sa). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (79.9 mg, yield: 87%);
mp 170−171 °C. 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 8.5 Hz,
2H), 7.56 (d, J = 8.5 Hz, 2H), 7.35−7.31 (m, 1H), 7.25−7.22 (m, 2H),
7.16−7.13 (m, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H),
6.19 (s, 1H), 4.42 (d, J = 7.9 Hz, 2H), 2.70−2.51 (m, 2H), 2.08 (d, J =
12.1 Hz, 1H), 1.99 (s, 3H), 1.95−1.86 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 170.0, 152.8, 141.7, 140.8, 133.1, 132.0, 130.8, 129.5,
128.8, 128.3, 128.0, 127.9, 127.2, 126.0, 123.7, 123.2, 120.8, 82.9, 52.6,
27.7, 25.9, 23.9; HRMS (ESI) m/z: [M + H]+ calcd. for C25H23BrN3O,
460.1019; found, 460.1019.
N-((3a,8b)-1,3-Diphenyl-3a,4-dihydroindeno[1,2-c]pyrazol-8b-
(1H)-yl)acetamide (3ab). The product was obtained by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate =
10:1 to 5:1) as a yellow solid (63.9 mg, yield: 87%); mp 236−237 °C.
1H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 7.2 Hz, 2H), 7.42−7.28 (m,
3H), 7.29 (d, J = 7.4 Hz, 2H), 7.24−7.19 (m, 2H), 7.10 (t, J = 7.1 Hz,
1H), 7.03 (t, J = 7.3 Hz, 1H), 6.49 (s, 1H), 4.77 (dd, J = 9.8, 4.5 Hz,
1H), 3.64 (dd, J = 16.5, 9.8 Hz, 1H), 3.20 (dd, J = 16.6, 4.4 Hz, 1H),
1.96 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.2, 152.0, 143.3,
142.6, 140.1, 132.1, 129.3, 128.8, 128.6, 126.9, 126.1, 125.2, 123.8,
123.0, 120.0, 92.4, 56.6, 36.6, 23.8; HRMS (ESI) m/z: [M + H]+ calcd.
for C24H22N3O, 368.1757; found, 368.1756.
N-((3a,8b)-6-Methyl-1,3-diphenyl-3a,4-dihydroindeno[1,2-c]-
pyrazol-8b(1H)-yl)acetamide (3ac). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (64.8 mg, yield: 85%); mp 160−
161 °C. 1H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 7.4 Hz, 2H), 7.41−
7.33 (m, 5H), 7.29−7.27 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.04−6.98
(m, 2H), 6.89 (d, J = 7.9 Hz, 1H), 6.55 (s, 1H), 4.73 (dd, J = 9.6, 4.1 Hz,
1H), 3.64−3.52 (m, 1H), 3.14 (dd, J = 16.5, 4.1 Hz, 1H), 2.26 (s, 3H),
1.95 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.2, 151.9, 143.3,
142.8, 139.3, 137.3, 132.1, 128.8, 128.6, 128.5, 127.8, 126.1, 125.7,
123.5, 122.7, 119.7, 92.1, 56.7, 36.4, 23.8, 21.3; HRMS (ESI) m/z: [M
+ Na]+ calcd. for C25H23N3NaO, 404.1733; found, 404.1732.
N-((3a,8b)-6-Chloro-1,3-diphenyl-3a,4-dihydroindeno[1,2-c]-
pyrazol-8b(1H)-yl)acetamide (3ad). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (49.7 mg, yield: 62%); mp 174−
175 °C. 1H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 7.3 Hz, 2H), 7.41
(t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.29 (d, J = 7.7 Hz, 2H),
7.25 (t, J = 7.8 Hz, 2H), 7.13 (s, 1H), 7.07−6.96 (m, 3H), 6.76 (s, 1H),
4.63 (dd, J = 9.8, 4.2 Hz, 1H), 3.61 (dd, J = 16.7, 9.9 Hz, 1H), 3.10 (dd, J
= 16.7, 4.0 Hz, 1H), 1.95 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
169.5, 152.4, 144.6, 142.9, 138.3, 135.0, 131.7, 128.9, 128.7, 126.9,
126.1, 125.2, 124.9, 123.4, 120.2, 91.8, 57.3, 36.3, 23.7; HRMS (ESI)
m/z: [M + Na]+ calcd. for C24H20ClN3NaO, 424.1187; found,
424.1187.
N-((3a,8b)-7-Chloro-1,3-diphenyl-3a,4-dihydroindeno[1,2-c]-
pyrazol-8b(1H)-yl)acetamide (3ae). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (56.2 mg, yield: 70%); mp 180−
181 °C. 1H NMR (600 MHz, CDCl3): δ 7.71 (d, J = 8.4 Hz, 2H), 7.41
(t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.32−7.27 (m, 4H), 7.16
(dd, J = 8.1, 1.7 Hz, 1H), 7.12−7.03 (m, 3H), 6.71 (s, 1H), 4.68 (dd, J =
9.8, 4.3 Hz, 1H), 3.60 (dd, J = 16.6, 9.9 Hz, 1H), 3.10 (dd, J = 16.6, 4.2
Hz, 1H), 1.96 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.5,
152.5, 142.8, 141.6, 141.0, 132.3, 131.7, 129.3, 129.0, 128.9, 128.7,
126.1, 126.1, 124.1, 123.6, 120.2, 92.1, 57.4, 36.2, 23.7; HRMS (ESI)
m/z: [M + H]+ calcd. for C24H21ClN3O, 402.1368; found, 402.1368.
N-((3a,8b)-6-Bromo-1,3-diphenyl-3a,4-dihydroindeno[1,2-c]-
pyrazol-8b(1H)-yl)acetamide (3af). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (62.3 mg, yield: 70%); mp 187−
188 °C. 1H NMR (500 MHz, DMSO-d6): δ 9.03 (s, 1H), 7.65 (d, J =
7.4 Hz, 2H), 7.37 (dd, J = 14.8, 7.6 Hz, 6H), 7.33−7.28 (m, 2H), 7.20
(t, J = 7.9 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 4.66 (dd, J = 9.8, 3.4 Hz,
1H), 3.56 (dd, J = 17.4, 9.9 Hz, 1H), 2.95 (d, J = 17.5 Hz, 1H), 1.84 (s,
3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 169.7, 145.3, 143.0,
139.8, 132.3, 130.0, 129.2, 128.8, 128.7, 128.5, 127.1, 126.2, 123.0,
121.1, 117.0, 90.6, 55.6, 36.0, 23.5; HRMS (ESI) m/z: [M + Na]+ calcd.
for C24H20BrN3NaO, 468.0682; found, 468.0684.
Ethyl (3a,9b)-9b-Acetamido-1-phenyl-3a,4,5,9b-tetrahydro-1H-
benzo[g]indazole-3-carboxylate (3ta). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 5:1 to 2:1) as a white solid (65.6 mg, yield: 87%); mp 185−
1
186 °C. H NMR (500 MHz, CDCl3): δ 7.35−7.31 (m, 1H), 7.20−
7.17 (m, 2H), 7.14−7.08 (m, 3H), 7.00 (t, J = 7.4 Hz, 1H), 6.91−6.87
(m, 2H), 6.58 (s, 1H), 4.47−4.26 (m, 2H), 4.14 (d, J = 7.6 Hz, 1H),
2.63 (d, J = 14.8 Hz, 1H), 2.44−2.38 (m, 1H), 2.21 (d, J = 15.1 Hz, 1H),
2.04 (s, 3H), 1.89−1.81 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 169.7, 162.3, 144.4, 140.7, 134.0, 131.6,
128.7, 128.5, 128.1, 127.4, 125.9, 124.9, 121.6, 83.5, 61.3, 52.7, 27.5,
25.6, 23.8, 14.4; HRMS (ESI) m/z: [M + Na]+ calcd. for
C22H23N3NaO3, 400.1632; found, 400.1632.
N-((3a,9b)-3-(Furan-2-yl)-1-phenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)acetamide (3ua). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 5:1 to 2:1) as a white solid (65.3 mg, yield: 88%); mp 191−
1
192 °C. H NMR (500 MHz, CDCl3): δ 7.35−7.31 (m, 2H), 7.16−
7.12 (m, 3H), 7.07−7.05 (m, 1H), 7.03−7.01 (m, 1H), 6.98 (t, J = 7.8
Hz, 1H), 6.86−6.81 (m, 4H), 4.23 (d, J = 8.0 Hz, 1H), 2.57−2.52 (m,
1H), 2.49−2.43 (m, 1H), 2.22−2.18 (m, 1H), 1.93 (s, 3H), 1.91−1.87
(m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.3, 150.0, 141.6,
140.5, 136.0, 132.7, 128.4, 128.1, 127.9, 127.8, 127.5, 127.0, 126.9,
125.8, 123.3, 120.8, 82.6, 54.7, 27.7, 26.1, 23.8. HRMS (ESI) m/z: [M +
H]+ calcd. for C23H22N3O2, 372.1707; found, 372.1705.
N-((3a,9b)-1-Phenyl-3-(thiophen-2-yl)-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)acetamide (3va). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (68.5 mg, yield: 89%); mp 200−
201 °C. 1H NMR (500 MHz, CDCl3) δ: 7.55 (d, J = 1.9 Hz, 1H), 7.36−
7.29 (m, 1H), 7.24−7.18 (m, 2H), 7.17−7.05 (m, 3H), 6.96 (t, J = 7.3
Hz, 1H), 6.91−6.84 (m, 2H), 6.69 (d, J = 3.5 Hz, 1H), 6.53 (dd, J = 3.5,
1.8 Hz, 1H), 6.21 (s, 1H), 4.47−4.23 (m, 1H), 2.76−2.55 (m, 2H),
2.23−2.19 (m, 1H), 2.01 (s, 3H), 1.99−1.86 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 169.9, 147.8, 146.4, 143.7, 141.6, 140.7, 132.9,
128.6, 128.2, 127.9, 127.2, 125.9, 123.7, 121.0, 111.7, 110.4, 82.2, 53.4,
27.7, 26.4, 23.9. HRMS (ESI) m/z: [M + H]+ calcd. for C23H22N3OS,
388.1478; found, 388.1478.
3-Methyl-1-phenyl-4,5-dihydro-1H-benzo[g]indazole (3wa). The
product was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1) as a light yellow solid (40.1 mg,
yield: 77%); mp 113−114 °C. 1H NMR (500 MHz, CDCl3): δ 7.53−
7.42 (m, 4H), 7.42−7.36 (m, 1H), 7.27 (dd, J = 7.6, 1.3 Hz, 1H), 7.12
(td, J = 7.5, 1.3 Hz, 1H), 6.98 (td, J = 7.7, 1.3 Hz, 1H), 6.83 (dd, J = 7.9,
1.3 Hz, 1H), 2.98 (dd, J = 8.4, 6.4 Hz, 2H), 2.77−2.57 (m, 2H), 2.31 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 146.0, 140.9, 138.0, 137.2,
129.2, 128.6, 127.8, 127.3, 127.2, 126.3, 125.6, 123.1, 118.6, 30.7, 19.3,
11.8. HRMS (ESI) m/z: [M + H]+ calcd. for C18H17N2, 261.1386;
found, 261.1385.
N-((3a,9b)-8-Bromo-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)acetamide (3ag). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a yellow solid (75.3 mg, yield: 82%); mp 185−
1
186 °C. H NMR (500 MHz, DMSO-d6): δ 9.01 (s, 1H), 7.74−7.72
(m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.35−7.31
(m, 1H), 7.20 (dd, J = 7.9, 2.0 Hz, 1H), 7.05−7.01 (m, 2H), 6.95 (d, J =
7.5 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 4.17 (d, J
= 7.8 Hz, 1H), 2.47 (s, 1H), 2.03−1.95 (m, 1H), 1.94 (s, 3H), 1.93−
I
https://dx.doi.org/10.1021/acs.joc.0c02244
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1.87 (m, 1H), 1.68−1.52 (m, 1H); 13C{1H} NMR (125 MHz, DMSO-
d6): δ 170.4, 150.9, 142.0, 139.8, 135.5, 132.0, 131.4, 130.5, 129.9,
129.4, 129.2, 128.4, 126.7, 122.2, 119.4, 118.7, 81.3, 54.3, 26.5, 25.8,
23.5; HRMS (ESI) m/z: [M + Na]+ calcd. for C25H22BrN3NaO,
482.0838; found, 482.0839.
HRMS (ESI) m/z: [M + Na]+ calcd. for C31H27N3NaO2, 496.1995;
found, 496.2004.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-2-methoxybenzamide (3am). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (80.4 mg, yield: 85%);
mp 152−153 °C. 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 8.12
(dd, J = 7.9, 1.8 Hz, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.44−7.37 (m, 4H),
7.35 (d, J = 7.3 Hz, 1H), 7.28−7.16 (m, 5H), 7.04−7.00 (m, 4H), 6.85
(d, J = 8.3 Hz, 1H), 4.71 (d, J = 7.9 Hz, 1H), 3.52 (s, 3H), 2.83−2.64
(m, 2H), 2.22 (d, J = 13.3 Hz, 1H), 2.15−1.98 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 164.8, 157.7, 154.0, 143.1, 141.3, 134.6, 133.3,
132.2, 132.0, 129.0, 128.8, 128.1, 128.0, 127.4,127.4 126.6, 126.1,
123.5, 121.3, 121.3, 121.0, 111.3, 83.6, 55.6, 52.9, 28.0, 26.2; HRMS
(ESI) m/z: [M + H]+ calcd. for C31H28N3O2, 474.2176; found,
474.2175.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-4-(trifluoromethyl)benzamide (3an). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1 to 5:1) as a white solid (75.7
mg, yield: 74%); mp 166−167 °C. 1H NMR (500 MHz, CDCl3): δ 7.84
(d, J = 7.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H),
7.45−7.37 (m, 3H), 7.30−7.17 (m, 6H), 7.06 (t, J = 7.4 Hz, 1H), 6.98
(d, J = 7.6 Hz, 2H), 6.92 (s, 1H), 4.62 (d, J = 8.2 Hz, 1H), 2.73 (dd, J =
8.2, 3.7 Hz, 2H), 2.24 (d, J = 13.3 Hz, 1H), 2.12−2.02 (m, 1H);
13C{1H} NMR (125 MHz, CDCl3): δ 165.3, 154.5, 141.8, 140.9, 137.0,
133.0, 131.6, 129.3, 129.0, 128.8, 128.4, 128.14, 127.4, 127.0, 126.6,
126.0, 125.8, 125.8, 124.4, 121.7, 83.3, 52.7, 27.8, 25.9; HRMS (ESI)
m/z: [M + H]+ calcd. for C31H25F3N3O, 512.1944; found, 512.1947.
4-Cyano-N-((3a,9b)-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)benzamide (3ao). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (70.2 mg, yield: 75%); mp 190−
191 °C. 1H NMR (600 MHz, CDCl3): δ 7.83 (d, J = 7.1 Hz, 2H), 7.74
(d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.45−7.40 (m, 2H), 7.41−
7.35 (m, 1H), 7.27−7.24 (m, 2H), 7.22−7.18 (m, 4H), 7.04 (t, J = 7.4
Hz, 1H), 6.97 (d, J = 7.5 Hz, 3H), 4.57 (d, J = 10.0 Hz, 1H), 2.75−2.61
(m, 2H), 2.23 (d, J = 13.4 Hz, 1H), 2.11−1.99 (m, 1H); 13C{1H} NMR
(150 MHz, CDCl3): δ 164.8, 154.3, 141.7, 140.9, 137.5, 132.7, 132.6,
131.5, 129.29, 128.9, 128.8, 128.4, 128.1, 127.6, 126.9, 126.6, 126.0,
124.3, 121.5, 117.9, 115.5, 83.3, 52.8, 27.8, 25.9; HRMS (ESI) m/z: [M
+ Na]+ calcd. for C31H24N4NaO, 491.1842; found, 491.1847.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-4-fluorobenzamide (3ap). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (79.3 mg, yield: 86%); mp 184−
185 °C. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.2 Hz, 2H), 7.66
(dd, J = 8.7, 5.3 Hz, 2H), 7.43−7.34 (m, 3H), 7.30 (d, J = 7.7 Hz, 1H),
7.27−7.14 (m, 5H), 7.08−6.95 (m, 5H), 6.87 (s, 1H), 4.60 (d, J = 8.2
Hz, 1H), 2.69 (dd, J = 8.4, 3.8 Hz, 2H), 2.21 (d, J = 11.7 Hz, 1H), 2.09−
2.00 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.5, 165.0 (d, J =
251.3 Hz), 154.4, 141.9, 140.9, 133.3, 131.6, 130.0 (d, J = 3.2 Hz), 129.2
(d, J = 8.7 Hz), 129.2, 128.9, 128.8, 128.3, 128.0, 127.1, 126.6, 126.0,
124.2, 121.5, 115.8 (d, J = 22.0 Hz), 83.2, 52.8, 27.8, 26.0; HRMS (ESI)
m/z: [M + Na]+ calcd. for C30H24FN3NaO, 484.1796; found, 484.1797.
4-Chloro-N-((3a,9b)-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)benzamide (3aq). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (79.2 mg, yield: 83%); mp 155−
156 °C. 1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 7.3 Hz, 2H), 7.58
(d, J = 8.4 Hz, 2H), 7.45−7.32 (m, 5H), 7.31−7.13 (m, 6H), 7.07−6.95
(m, 3H), 6.88 (s, 1H), 4.59 (d, J = 7.0 Hz, 1H), 2.71−2.68 (m, 2H),
2.21 (d, J = 14.8 Hz, 1H), 2.11−1.96 (m, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 165.6, 154.4, 141.9, 141.0, 138.4, 133.2, 132.3, 131.7,
129.3, 129.1, 129.0, 128.9, 128.4, 128.4, 128.1, 127.2, 126.7, 126.0,
124.3, 121.6, 83.3, 52.9, 27.9, 26.0; HRMS (ESI) m/z: [M + Na]+ calcd.
for C30H24ClN3NaO, 500.1500; found, 500.1499.
N-((3a,10b)-1,3-Diphenyl-3a,4,5,6-tetrahydrobenzo[6,7]-
cyclohepta[1,2-c]pyrazol-10b(1H)-yl)acetamide (3ah). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 10:1 to 5:1) as a yellow solid (57.7
mg, yield: 73%); mp 201−202 °C. 1H NMR (500 MHz, DMSO-d6): δ
8.86 (s, 1H), 7.74−7.42 (m, 2H), 7.53 (dd, J = 7.6, 1.3 Hz, 1H), 7.39 (t,
J = 7.5 Hz, 2H), 7.34−7.29 (m, 1H), 7.16−7.11 (m, 2H), 7.03 (d, J =
7.5 Hz, 1H), 6.96 (d, J = 4.3 Hz, 4H), 6.70−6.64 (m, 1H), 4.18 (d, J =
8.2 Hz, 1H), 2.27−2.14 (m, 1H), 1.92 (s, 3H), 1.81−1.74 (m, 1H),
1.45−1.38 (m, 1H), 1.08 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (125
MHz, DMSO-d6): δ 170.3, 151.2,144.1, 142.0, 132.4, 132.1, 129.4,
129.2, 129.1, 128.3, 127.9, 126.5, 125.3, 123.9, 121.3, 118.3, 81.7, 53.3,
35.0, 29.2, 23.6, 18.5; HRMS (ESI) m/z: [M + Na]+ calcd. for
C26H25N3NaO, 418.1890; found, 418.1890.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-4-methylbenzamide (3ai). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (77.7 mg, yield: 85%); mp 155−
156 °C. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.2 Hz, 2H), 7.56
(d, J = 8.2 Hz, 2H), 7.43−7.30 (m, 4H), 7.25−7.13 (m, 7H), 7.02−6.99
(m, 3H), 6.88 (s, 1H), 4.64 (d, J = 6.9 Hz, 1H), 2.71−2.66 (m, 2H),
2.33 (s, 3H), 2.21 (d, J = 13.3 Hz, 1H), 2.14−1.97 (m, 1H); 13C{1H}
NMR (125 MHz, CDCl3): δ 166.7, 154.4, 142.7, 142.2, 141.0, 133.6,
131.8, 131.1, 129.5, 129.2, 128.9, 128.9, 128.3, 128.0, 127.3, 127.0,
126.7, 126.0, 124.2, 121.6, 83.2, 53.0, 27.9, 26.1, 21.6; HRMS (ESI) m/
z: [M + Na]+ calcd. for C31H27N3NaO, 480.2046; found, 480.2047.
4-(tert-Butyl)-N-((3a,9b)-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)benzamide (3aj). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (81.9 mg, yield: 82%); mp 151−
152 °C. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 8.5 Hz, 2H), 7.61
(d, J = 8.5 Hz, 2H), 7.41−7.38 (m, 4H), 7.36−7.30 (m, 2H), 7.25−7.16
(m, 5H), 7.06−6.97 (m, 3H), 6.90 (s, 1H), 4.65 (d, J = 6.6 Hz, 1H),
2.75−2.66 (m, 2H), 2.21 (d, J = 15.0 Hz, 1H), 2.12−1.99 (m, 1H), 1.28
(s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 166.4, 155.6, 154.3,
141.9, 140.8, 133.5, 131.7, 130.9, 129.0, 128.8, 128.7, 128.1, 127.9,
127.3, 127.2, 126.7, 126.5, 125.9, 125.6, 124.1, 121.5, 83.1, 52.7, 34.9,
31.1, 27.8, 26.0; HRMS (ESI) m/z: [M + Na]+ calcd. for
C34H33N3NaO, 522.2516; found, 522.2517.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-3-methoxybenzamide (3ak). The product was ob-
tained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (77.6 mg, yield: 82%);
mp 170−171 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 7.2 Hz,
2H), 7.42 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.33−7.25 (m,
3H), 7.24−7.19 (m, 5H), 7.14 (d, J = 7.9 Hz, 1H), 7.06−6.97 (m, 4H),
6.91 (s, 1H), 4.63 (d, J = 9.8 Hz, 1H), 3.78 (s, 3H), 2.74−2.67 (m, 2H),
2.26−2.19 (m, 1H), 2.10−1.98 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 166.4, 159.9, 154.4, 141.9, 140.9, 135.2, 133.4, 131.7, 129.7,
129.1, 128.9, 128.8, 128.2, 128.0, 127.4, 127.1, 126.6, 126.0, 124.2,
121.6, 118.5, 111.9, 83.1, 55.4, 52.8, 27.8, 26.0; HRMS (ESI) m/z: [M
+ Na]+ calcd. for C31H27N3NaO2, 496.1995; found, 496.1997.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-4-methoxybenzamide (3al). The product was ob-
tained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (84.2 mg, yield: 89%);
mp 161−162 °C. 1H NMR (600 MHz, CDCl3): δ 7.84 (d, J = 7.4 Hz,
2H), 7.62 (d, J = 8.8 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 7.3
Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.24−7.17 (m, 5H), 7.05−6.99 (m,
3H), 6.88 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 4.63 (d, J = 7.2 Hz, 1H),
3.81 (s, 3H), 2.75−2.66 (m, 2H), 2.22 (d, J = 13.3 Hz, 1H), 2.14−1.93
(m, 1H); 13C{1H} NMR (150 MHz, CDCl3): δ 166.2, 162.6, 154.3,
142.0, 140.9, 133.6, 131.7, 129.1, 128.9, 128.7,128.7, 128.1, 127.9,
127.2, 126.6, 126.1, 125.9, 124.1, 121.4, 113.9, 83.1, 52.9, 27.8, 26.0;
4-Bromo-N-((3a,9b)-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)benzamide (3ar). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
J
https://dx.doi.org/10.1021/acs.joc.0c02244
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
acetate = 10:1 to 5:1) as a white solid (89.6 mg, yield: 86%); mp 170−
171 °C. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 7.1 Hz, 2H), 7.56−
7.47 (m, 4H), 7.43−7.36 (m, 3H), 7.30−7.16 (m, 6H), 7.04 (t, J = 6.9
Hz, 1H), 6.97 (d, J = 7.6 Hz, 2H), 6.85 (s, 1H), 4.60 (dd, J = 8.3, 1.7 Hz,
1H), 2.70 (dd, J = 8.3, 3.6 Hz, 2H), 2.38−2.19 (m, 1H), 2.09−1.97 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 165.6, 154.3, 141.8, 140.9,
133.1, 132.6, 132.0, 131.6, 129.2, 128.9, 128.8, 128.4, 128.2, 128.0,
127.0, 126.8, 126.6, 125.9, 124.2, 121.5, 83.2, 52.8, 27.8, 25.9; HRMS
(ESI) m/z: [M + Na]+ calcd. for C30H24BrN3NaO, 544.0995; found,
544.0996.
2-Bromo-N-((3a,9b)-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)benzamide (3as). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a yellow solid (90.7 mg, yield: 87%); mp 180−
181 °C. 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 7.0 Hz, 2H), 7.60
(dd, J = 7.7, 1.7 Hz, 1H), 7.59−7.55 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.43 (d, J = 7.7 Hz, 2H), 7.36−7.27 (m, 5H), 7.22−7.19 (m, 1H), 7.15
(t, J = 7.9 Hz, 2H), 7.01−6.94 (m, 3H), 6.87 (s, 1H), 4.65 (d, J = 9.8 Hz,
1H), 2.77−2.67 (m, 2H), 2.22 (d, J = 13.3 Hz, 1H), 2.15−1.97 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 166.6, 154.2, 142.0, 140.,
133.6, 131.8, 130.5, 129.3, 129.1, 128.8, 128.8, 128.6, 128.3, 128.0,
127.7, 127.6, 127.4, 126.6, 126.0, 125.9, 123.9, 121.4, 83.7, 52.8, 27.8,
26.1; HRMS (ESI) m/z: [M + Na]+ calcd. for C30H24BrN3NaO,
544.0995; found, 544.0997.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)-1-naphthamide (3at). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (70.0 mg, yield: 71%); mp 188−
189 °C. 1H NMR (500 MHz, CDCl3): δ 8.17 (s, 1H), 7.88−7.78 (m,
5H), 7.70 (dd, J = 8.6, 1.7 Hz, 1H), 7.53−7.46 (m, 2H), 7.42−7.38 (m,
3H), 7.37−7.31 (m, 1H), 7.24−7.17 (m, 5H), 7.09 (s, 1H), 7.07−7.01
(m, 3H), 4.70 (dd, J = 8.4, 1.8 Hz, 1H), 2.78−2.65 (m, 2H), 2.27−2.20
(m, 1H), 2.12−2.05 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
166.7, 154.4, 142.0, 141.0, 134.9, 133.4, 132.5, 131.7, 131.0, 129.2,
129.1, 128.9, 128.8, 128.7, 128.3, 128.0, 128.0, 127.8, 127.7, 127.3,
127.0, 126.7, 126.0, 124.2, 123.2, 121.5, 83.3, 52.9, 27.9, 26.1; HRMS
(ESI) m/z: [M + Na]+ calcd. for C34H27N3NaO, 516.2046; found,
516.2048.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9byl)cyclopropanecarboxamide (3au). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10:1 to 5:1) as a white solid (69.2 mg, yield: 85%);
mp 150−151 °C. 1H NMR (600 MHz, CDCl3): δ 7.84 (d, J = 7.5 Hz,
2H), 7.44 (t, J = 7.4 Hz, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.36−7.31 (m,
1H), 7.24−7.20 (m, 2H), 7.19−7.10 (m, 3H), 7.00−6.91 (m, 3H), 6.36
(s, 1H), 4.45 (d, J = 8.0 Hz, 1H), 2.67−2.55 (m, 2H), 2.15 (d, J = 13.1
Hz, 1H), 1.98−1.84 (m, 1H), 1.39−1.35 (m, 1H), 0.93 (s, 2H), 0.76−
0.73 (m, 1H), 0.71−0.68 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3):
δ 173.2, 153.8, 142.0, 140.9, 133.5, 131.8, 129.0, 128.8, 128.7, 128.0,
127.8, 127.1, 126.5, 125.9, 123.5, 120.9, 82.6, 52.9, 27.7, 26.0, 15.0, 7.7,
7.1; HRMS (ESI) m/z: [M + H]+ calcd. for C27H26N3O, 408.2070;
found, 408.2069.
168 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 7.4 Hz, 2H), 7.44
(t, J = 7.4 Hz, 2H), 7.40 (d, J = 7.1 Hz, 1H), 7.36−7.31 (m, 2H), 7.29−
7.22 (m, 3H), 7.14 (t, J = 7.8 Hz, 2H), 6.96 (t, J = 7.3 Hz, 1H), 6.92 (d, J
= 7.9 Hz, 2H), 6.16 (s, 1H), 4.49 (d, J = 7.7 Hz, 1H), 2.75 (s, 1H), 2.01
(d, J = 12.2 Hz, 1H), 1.97 (s, 3H), 1.77−1.68 (m, 1H), 1.29 (d, J = 6.7
Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.0, 154.2, 144.5,
141.9, 132.9, 131.8, 129.1, 128.8, 128.8, 128.3, 127.2, 126.6, 125.6,
124.4, 123.4, 120.5, 82.9, 51.80, 34.46, 29.8, 24.0, 18.4; HRMS (ESI)
m/z: [M + H]+ calcd. for C26H26N3O, 396.2070; found, 396.2070.
N-(1,3,5-Triphenyl-4,5-dihydro-1H-pyrazol-5-yl)acetamide (4a).
The product was obtained by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 5:1 to 2:1) as a yellow solid
(60.4 mg, yield: 85%); mp 178−179 °C. 1H NMR (600 MHz, CDCl3):
δ 7.72 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7.40−7.34 (m, 4H),
7.32 (q, J = 7.2 Hz, 2H), 7.13 (t, J = 7.9 Hz, 2H), 7.05 (d, J = 7.8 Hz,
2H), 6.82 (t, J = 7.2 Hz, 1H), 6.53 (s, 1H), 4.43 (d, J = 17.8 Hz, 1H),
3.42 (d, J = 17.8 Hz, 1H), 1.87 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3): δ 170.1, 147.4, 142.8, 142.0, 132.3, 129.2, 128.8, 128.8, 128.5,
128.3, 125.8, 125.4, 120.3, 115.5, 82.7, 50.3, 23.7; HRMS (ESI) m/z:
[M + H]+ calcd. for C23H22N3O, 356.1757; found, 356.1756.
N-(5-(4-Fluorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)acetamide (4b). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (65.7 mg, yield: 88%); mp 176−177 °C. 1H NMR (500
MHz, CDCl3): δ 7.73−7.71 (m, 2H), 7.49−7.44 (m, 2H), 7.41−7.32
(m, 4H), 7.17−7.13 (m, 2H), 7.04 (d, J = 8.6 Hz, 3H), 6.85 (t, J = 7.3
Hz, 1H), 6.46 (s, 1H), 4.46 (d, J = 17.9 Hz, 1H), 3.44 (d, J = 17.9 Hz,
1H), 1.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.2, 162.4
(d, J = 248.0 Hz), 147.8, 141.9, 138.6 (d, J = 3.2 Hz), 132.2, 129.0,
128.9, 128.6, 127.9 (d, J = 8.2 Hz), 125.9, 120.7, 116.1 (d, J = 21.7 Hz),
115.7, 82.5, 50.4, 23.9; HRMS (ESI) m/z: [M + H]+ calcd. for
C23H21FN3O, 374.1663; found, 374.1663.
N-(5-(4-Chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)acetamide (4c). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (70.0 mg, yield: 90%); mp 174−176 °C. 1H NMR (500
MHz, CDCl3): δ 7.73−7.71 (m, 2H), 7.44−7.41 (m, 2H), 7.40−7.33
(m, 5H), 7.17−7.14 (m, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.86 (t, J = 7.3
Hz, 1H), 6.41 (s, 1H), 4.46 (d, J = 18.0 Hz, 1H), 3.44 (d, J = 18.0 Hz,
1H), 1.92 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.2, 147.8,
141.8, 141.3, 134.2, 129.3, 129.1, 129.0, 128.6, 127.4, 127.2, 125.9,
120.8, 115.7, 82.5, 50.4, 23.9; HRMS (ESI) m/z: [M + H]+ calcd. for
C23H21ClN3O, 390.1368; found, 390.1367.
N-(5-(4-Bromophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)acetamide (4d). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (75.4 mg, yield: 87%); mp 185−186 °C. 1H NMR (500
MHz, CDCl3): δ 7.72 (d, J = 7.1 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H),
7.41−7.31 (m, 5H), 7.17−7.12 (m, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.86
(d, J = 7.3 Hz, 1H), 6.44 (s, 1H), 4.46 (d, J = 18.0 Hz, 1H), 3.43 (d, J =
18.0 Hz, 1H), 1.91 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
170.3, 147.8, 141.8, 141.8, 132.3, 132.2, 129.1, 129.0, 128.6, 127.6,
125.9, 122.4, 120.8, 115.7, 82.6, 50.4, 23.9; HRMS (ESI) m/z: [M +
H]+ calcd. for C23H21BrN3O, 434.0863; found, 434.0866.
N-((3a,9b)-1,3-Diphenyl-1,3a,4,5-tetrahydro-9bH-benzo[g]-
indazol-9b-yl)isobutyramide (3av). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (74.5 mg, yield: 91%); mp 144−
145 °C. 1H NMR (500 MHz, CDCl3): δ 7.83 (d, J = 7.3 Hz, 2H), 7.43
(t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.28−7.24 (m, 1H), 7.23−
7.19 (m, 2H), 7.16−7.12 (m, 3H), 6.98 (t, J = 7.3 Hz, 1H), 6.93 (d, J =
7.9 Hz, 2H), 6.23 (s, 1H), 4.45 (d, J = 7.3 Hz, 1H), 2.63−2.60 (m, 2H),
2.40−2.35 (m, 1H), 2.14 (d, J = 12.0 Hz, 1H), 1.99−1.91 (m, 1H), 1.14
(d, J = 6.9 Hz, 3H), 1.08 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 176.6, 153.9, 142.0, 140.9, 133.5, 131.9, 129.1, 128.8, 128.7,
128.1, 127.9, 127.0, 126.6, 125.9, 123.7, 121.1, 82.4, 52.9, 35.8, 27.8,
26.0, 19.7, 19.3; HRMS (ESI) m/z: [M + H]+ calcd. for C27H28N3O,
410.2227; found, 410.2227.
N-(5-(3-Chlorophenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)acetamide (4e). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (68.5 mg, yield: 88%); mp 166−167 °C. 1H NMR (500
MHz, CDCl3): δ 7.72−7.69 (m, 2H), 7.49 (s, 1H), 7.40−7.32 (m, 4H),
7.31−7.28 (m, 2H), 7.16−7.13 (m, 2H), 7.04−7.02 (m, 2H), 6.85 (t, J
= 7.3 Hz, 1H), 6.59 (s, 1H), 4.41 (d, J = 17.9 Hz, 1H), 3.41 (d, J = 17.9
Hz, 1H), 1.86 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.4,
147.6, 145.0, 141.8, 135.2, 132.1, 130.6, 129.1, 128.9, 128.6, 128.6,
125.9, 125.9, 124.0, 120.7, 115.7, 82.4, 50.4, 23.8; HRMS (ESI) m/z:
[M + H]+ calcd. for C23H21ClN3O, 390.1368; found, 390.1366.
N-(5-(4-Methoxyphenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-
yl)acetamide (4f). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (69.3 mg, yield: 90%); mp 183−185 °C. 1H NMR (500
MHz, CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 7.42−7.29 (m, 5H), 7.14 (t, J
N-((3a,9b)-5-Methyl-1,3-diphenyl-1,3a,4,5-tetrahydro-9bH-
benzo[g]indazol-9b-yl)acetamide (3aw). The product was obtained
by column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 10:1 to 5:1) as a white solid (72.7 mg, yield: 92%); mp 167−
K
https://dx.doi.org/10.1021/acs.joc.0c02244
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
= 7.9 Hz, 2H), 7.07 (d, J = 7.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.83 (t,
J = 7.2 Hz, 1H), 6.47 (s, 1H), 4.41 (d, J = 17.8 Hz, 1H), 3.79 (s, 3H),
3.40 (d, J = 17.8 Hz, 1H), 1.87 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 170.1, 159.4, 147.5, 142.1, 135.0, 132.5, 128.8, 128.6, 127.4,
126.8, 125.9, 120.4, 115.6, 114.5, 82.6, 55.4, 50.3, 23.8; HRMS (ESI)
m/z: [M + H]+ calcd. for C24H24N3O2, 386.1863; found, 386.1863.
N-(5-(4-(tert-Butyl)phenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-
5-yl)acetamide (4g). The product was obtained by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate
= 5:1 to 2:1) as a white solid (67.4 mg, yield: 82%); mp 170−171 °C.
1H NMR (500 MHz, CDCl3): δ 7.73−7.70 (m, 2H), 7.43−7.29 (m,
7H), 7.18−7.12 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.83 (t, J = 7.2 Hz,
1H), 6.44 (s, 1H), 4.42 (d, J = 17.7 Hz, 1H), 3.43 (s, 1H), 1.87 (s, 3H),
1.32 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.0, 151.4, 147.4,
142.2, 140.0, 132.5, 128.8, 128.76, 128.5, 126.2, 125.7, 125.1, 120.2,
115.6, 82.6, 50.2, 34.6, 31.3, 23.8; HRMS (ESI) m/z: [M + H]+ calcd.
for C27H30N3O, 412.2383; found, 412.2383.
N-(5-(4-Ethylphenyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazol-5-yl)-
acetamide (4h). The product was obtained by column chromatog-
raphy on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1)
as a white solid (63.6 mg, yield: 83%); mp 188−189 °C. 1H NMR (500
MHz, CDCl3): δ 7.72−7.70 (m, 2H), 7.42−7.29 (m, 5H), 7.21 (d, J =
8.3 Hz, 2H), 7.16−7.12 (m, 2H), 7.08−7.06 (m, 2H), 6.82 (t, J = 7.2
Hz, 1H), 6.49 (s, 1H), 4.41 (d, J = 17.7 Hz, 1H), 3.40 (d, J = 17.7 Hz,
1H), 2.65 (q, J = 7.5 Hz, 2H), 1.86 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 170.1, 147.4, 144.5, 142.2, 140.3,
125.9, 125.4, 105.3; HRMS (ESI) m/z: [M + H]+ calcd. for
C21H16ClN2, 331.0997; found, 331.0996.
5-(4-Bromophenyl)-1,3-diphenyl-1H-pyrazole (5c). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a yellow solid (65.8 mg,
yield: 88%); mp 120−121 °C. 1H NMR (500 MHz, CDCl3): δ 7.93−
7.88 (m, 2H), 7.43−7.40 (m, 4H), 7.36−7.27 (m, 6H), 7.14−7.08 (m,
2H), 6.79 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 152.2, 143.2,
139.9, 132.9, 131.8, 130.3, 129.5, 129.15, 128.8, 128.2, 127.8, 125.9,
125.4, 122.7, 105.4; HRMS (ESI) m/z: [M + H]+ calcd. for
C21H16BrN2, 375.0491; found, 375.0493.
5-(3-Chlorophenyl)-1,3-diphenyl-1H-pyrazole (5d). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (55.5 mg,
yield: 84%); mp 144−145 °C. 1H NMR (500 MHz, CDCl3): δ 7.92−
7.90 (m, 2H), 7.44−7.39 (m, 2H), 7.38−7.26 (m, 8H), 7.19 (t, J = 7.9
Hz, 1H), 7.07−7.05 (m, 1H), 6.82 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 152.1, 142.9, 139.9, 134.47, 132.9, 132.3, 129.8, 129.1,
128.8, 128.7, 128.4, 128.2, 127.8, 127.0, 125.9, 125.4, 105.6; HRMS
(ESI) m/z: [M + H]+ calcd. for C21H16ClN2, 331.0997; found,
331.0996.
1,3,5-Triphenyl-1H-pyrazole (5e). The product was obtained by
column chromatography on silica gel (eluent: petroleum ether/ethyl
acetate = 20:1) as a yellow solid (51.5 mg, yield: 87%); mp 142−143
°C. 1H NMR (500 MHz, CDCl3): δ 7.99−7.87 (m, 2H), 7.43 (t, J = 7.6
Hz, 2H), 7.39−7.27 (m, 11H), 6.83 (s, 1H); 13C NMR (125 MHz,
CDCl3): δ 152.0, 144.4, 140.1, 133.0, 130.6, 128.9, 128.8, 128.7, 128.5,
128.3, 128.0, 127.4, 125.8, 125.3, 105.2; HRMS (ESI) m/z: [M + H]+
calcd. for C21H17N2, 297.1386; found, 297.1385.
132.5, 128.8, 128.7, 128.5, 126.1, 125.9, 125.4, 120.3, 115.6, 82.6, 50.3,
28.5, 23.8, 15.5; HRMS (ESI) m/z: [M + H]+ calcd. for C25H26N3O,
384.2070; found, 384.2071.
1,3-Diphenyl-5-(p-tolyl)-1H-pyrazole (5f). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 20:1) as a white solid (52.7 mg, yield: 85%); mp
N-(1,3-Diphenyl-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-5-yl)-
acetamide (4i). The product was obtained by column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate = 5:1 to 2:1) as a
white solid (65.7 mg, yield: 89%); mp 177−178 °C. H NMR (500
1
1
133−134 °C. H NMR (500 MHz, CDCl3): δ 8.00−7.88 (m, 2H),
MHz, CDCl3): δ 7.72 (d, J = 7.3 Hz, 2H), 7.38−7.29 (m, 5H), 7.19 (d, J
= 8.0 Hz, 2H), 7.14 (t, J = 7.8 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.82 (t,
J = 7.2 Hz, 1H), 6.44 (s, 1H), 4.42 (d, J = 17.8 Hz, 1H), 3.40 (d, J = 17.8
Hz, 1H), 2.35 (s, 3H), 1.88 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 170.1, 147.4, 142.1, 140.1, 138.2, 132.5, 129.9, 128.8, 128.5,
125.9, 125.4, 120.3, 115.6, 82.6, 50.4, 23.8, 21.1; HRMS (ESI) m/z: [M
+ H]+ calcd. for C24H24N3O, 370.1914; found, 370.1914.
General Procedure for the One-Pot Synthesis of Pyrazoles 5.
To a dried test tube with a magnetic stirring bar under N2 at room
temperature were added hydrazonoyl chloride 1 (0.3 mmol) and
enamide 2 (0.20 mmol), followed by addition of K2CO3 (0.6 mmol).
Then, dichloromethane (2.00 mL) was introduced by a syringe and the
mixture was stirred at room temperature for 24 h. The reaction mixture
was treated with AlCl3 (0.02 mmol) and stirred at room temperature for
0.5 h. The reaction was then quenched with water and extracted with
ethyl acetate three times. The combined organic layer was washed with
brine, dried over Na2SO4, and the solvent was removed by rotary
evaporation. The residue was purified by column chromatography on
silica gel (petroleum/ethyl acetate = 20:1) to afford the desired
pyrazoles 5.
5-(4-Fluorophenyl)-1,3-diphenyl-1H-pyrazole (5a). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (52.1 mg,
yield: 83%); mp 139−140 °C. 1H NMR (500 MHz, CDCl3): δ 7.85−
7.78 (m, 2H), 7.35−7.30 (m, 2H), 7.25−7.17 (m, 6H), 7.15−7.11 (m,
2H), 6.93−6.86 (m, 2H), 6.68 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 161.5 (d, J = 248.7 Hz), 150.9, 142.3, 138.9, 131.9, 129.5 (d,
J = 8.3 Hz), 127.9, 127.6, 127.0, 126.5, 125.6 (d, J = 3.3 Hz), 124.7,
124.2, 114.6 (d, J = 21.8 Hz), 104.1; HRMS (ESI) m/z: [M + H]+ calcd.
for C21H16FN2, 315.1292; found, 315.1290.
5-(4-Chlorophenyl)-1,3-diphenyl-1H-pyrazole (5b). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (56.1 mg,
yield: 85%); mp 135−136 °C. 1H NMR (500 MHz, CDCl3): δ 7.95−
7.86 (m, 2H), 7.45−7.39 (m, 2H), 7.37−7.26 (m, 8H), 7.21−7.16 (m,
2H), 6.80 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3); δ 152.1, 143.2,
139.9, 134.4, 132.9, 130.0, 129.1, 129.05, 128.8, 128.7, 128.2, 127.7,
7.44−7.27 (m, 8H), 7.18−7.09 (m, 4H), 6.78 (s, 1H), 2.34 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 152.0, 144.5, 140.3, 138.3, 133.2,
129.3, 128.9, 128.7, 128.7, 128.0, 127.7, 127.4, 125.9, 125.4, 105.0,
21.3; HRMS (ESI) m/z: [M + H]+ calcd. for C22H19N2, 311.1543;
found, 311.1541.
5-(4-Methoxyphenyl)-1,3-diphenyl-1H-pyrazole (5g). The prod-
uct was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (59.4 mg, yield:
91%); mp 129−130 °C. 1H NMR (500 MHz, CDCl3): δ 7.97−7.88 (m,
2H), 7.44−7.27 (m, 8H), 7.21−7.16 (m, 2H), 6.85−6.81 (m, 2H), 6.76
(s, 1H), 3.78 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.6,
151.9, 144.3, 140.3, 133.2, 130.1, 129.0, 128.7, 128.0, 127.4, 125.9,
125.4, 123.0, 114.0, 104.8, 55.3; HRMS (ESI) m/z: [M + H]+ calcd. for
C22H19N2O, 327.1492; found, 327.1490.
5-(4-(tert-Butyl)phenyl)-1,3-diphenyl-1H-pyrazole (5h). The prod-
uct was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (61.3 mg, yield:
87%); mp 122−123 °C. 1H NMR (500 MHz, CDCl3): δ 7.94−7.90 (m,
2H), 7.42−7.24 (m, 10H), 7.21−7.17 (m, 2H), 6.79 (s, 1H), 1.29 (s,
9H); 13C{1H} NMR (125 MHz, CDCl3): δ 152.0, 151.5, 144.5, 140.4,
133.2, 129.0, 128.7, 128.4, 128.1, 127.7, 127.5, 125.9, 125.5, 125.5,
105.1, 34.7, 31.3; HRMS (ESI) m/z: [M + H]+ calcd. for C25H25N2,
353.2012; found, 353.2011.
5-(4-Ethylphenyl)-1,3-diphenyl-1H-pyrazole (5i). The product was
obtained by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 20:1) as a white solid (54.5 mg, yield: 84%); mp
1
140−141 °C. H NMR (500 MHz, CDCl3): δ 7.96−7.89 (m, 2H),
7.44−7.24 (m, 8H), 7.20−7.10 (m, 4H), 6.78 (s, 1H), 2.63 (q, J = 7.6
Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
152.0, 144.6, 140.3, 133.2, 129.0, 128.7, 128.7, 128.2, 128.1, 128.0,
127.9, 127.4, 125.9, 125.4, 105.1, 28.7, 15.4; HRMS (ESI) m/z: [M +
H]+ calcd. for C23H21N2, 325.1699; found, 325.1698.
3-(4-Fluorophenyl)-1-phenyl-4,5-dihydro-1H-benzo[g]indazole
(5j). The product was obtained by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 20:1) as a yellow solid (60.5
1
mg, yield: 89%); mp 200−201 °C. H NMR (500 MHz, CDCl3): δ
7.78−7.71 (m, 2H), 7.56 (d, J = 7.3 Hz, 2H), 7.53−7.41 (m, 3H), 7.31
L
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(d, J = 7.4 Hz, 1H), 7.19−7.09 (m, 3H), 7.01 (t, J = 7.5 Hz, 1H), 6.82
(d, J = 7.8 Hz, 1H), 3.03−3.00 (m, 2H), 2.96−2.92 (m, 2H); 13C{1H}
NMR (125 MHz, CDCl3): δ 162.5 (d, J = 246.6 Hz), 147.8, 140.8,
139.1, 137.2, 129.6 (d, J = 3.2 Hz), 129.4, 129.0 (d, J = 8.2 Hz), 128.6,
128.4, 127.6, 126.9, 126.3, 125.9, 123.2, 117.3, 115.5 (d, J = 21.3 Hz),
30.8, 20.7; HRMS (ESI) m/z: [M + H]+ calcd. for C23H18FN2,
341.1449; found, 341.1447.
127.4, 126.6, 126.3, 126.3, 126.0, 125.2, 124.7, 122.0, 116.2, 29.7, 20.2,
19.7; HRMS (ESI) m/z: [M + H]+ calcd. for C24H21N2, 337.1699;
found, 337.1697.
1-(4-Chlorophenyl)-3-phenyl-4,5-dihydro-1H-benzo[g]indazole
(5q). The product was obtained by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate = 20:1) as a white solid (62.0
1
mg, yield: 87%); mp 177−178 °C. H NMR (500 MHz, CDCl3): δ
7.76−7.74 (m, 2H), 7.54−7.50 (m, 2H), 7.47−7.42 (m, 4H), 7.39−
7.34 (m, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.20−7.17 (m, 1H), 7.05 (t, J =
8.1 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.03−2.99 (m, 2H), 2.98−2.92
(m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 149.1, 139.4, 139.1,
137.3, 133.9, 133.2, 129.5, 128.7, 127.9, 127.7, 127.4, 127.0, 126.8,
126.4, 123.1, 118.0, 30.8, 20.8; HRMS (ESI) m/z: [M + H]+ calcd. for
C23H18ClN2, 357.1153; found, 357.1153.
3-(4-Chlorophenyl)-1-phenyl-4,5-dihydro-1H-benzo[g]indazole
(5k). The product was obtained by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate = 20:1) as a white solid (64.8
1
mg, yield: 91%); mp 188−189 °C. H NMR (500 MHz, CDCl3): δ
7.74−7.69 (m, 2H), 7.57−7.53 (m, 2H), 7.51−7.38 (m, 5H), 7.30 (d, J
= 7.3 Hz, 1H), 7.17−7.14 (m, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.81 (d, J =
7.7 Hz, 1H), 3.03−2.99 (m, 2H), 2.96−2.91 (m, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ 147.5, 140.8, 139.2, 137.1, 133.6, 132.0, 129.4,
128.8, 128.6, 128.6, 128.4, 127.6, 126.9, 126.4, 125.9, 123.2, 117.5, 30.7,
20.8; HRMS (ESI) m/z: [M + H]+ calcd. for C23H18ClN2, 357.1153;
found, 357.1153.
Gram-Scale Synthesis. To a dried test tube with a magnetic
stirring bar under N2 at room temperature were added hydrazonoyl
chloride 1a (4.65 mmol, 1.5 equiv) and enamide 2r (3.1 mmol, 1
equiv), followed by the addition of K2CO3 (1.28 g, 9.3 mmol). Then,
dichloromethane (31 mL) was introduced and the mixture was stirred
at room temperature for 24 h. The solvent was removed by rotary
evaporation, and the residue was purified by column chromatography
on silica gel (petroleum/ethyl acetate = 10:1 to 5:1) to afford the
desired product 3ar (1.29 g, 80% yield).
Procedure for the Derivation. To a solution of 3ar (200 mg,
0.385 mmol) in toluene (10 mL) under a nitrogen atmosphere was
added Pd(P(Ph)3)4 (45 mg, 0.039 mmol). After stirring for 30 min, a
solution of phenylboronic acid in ethanol (5 mL) and saturated
NaHCO3 (3 mL) was added. Then, the mixture was heated to reflux in
an oil bath for 24 h. After cooling to room temperature, the mixture was
added to saturated aqueous NaCl solution and extracted with ethyl
acetate. The organic layer was combined, washed with saturated brine,
dried with anhydrous Na2SO4, and concentrated. The residue was
chromatographed on silica gel to give the desired product 6. The
product was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 5:1) as a yellow solid (102 mg, yield:
51%); mp 110−111 °C. 1H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 7.2
Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.56 (d, J =
7.3 Hz, 2H), 7.45−7.39 (m, 4H), 7.38−7.33 (m, 3H), 7.24−7.17 (m,
5H), 7.03 (dd, J = 14.4, 7.4 Hz, 3H), 6.95 (s, 1H), 4.66 (d, J = 9.5 Hz,
1H), 2.82−2.67 (m, 2H), 2.23 (d, J = 13.3 Hz, 1H), 2.14−1.98 (m,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 166.4, 154.4, 144.9, 142.0,
141.0, 139.9, 133.5, 132.5, 131.8, 129.2, 129.0, 128.9, 128.9, 128.3,
128.2, 128.1, 127.5, 127.5, 127.3, 126.7, 126.1, 125.9, 124.2, 121.6, 83.3,
52.9, 27.9, 26.1; HRMS (ESI) m/z: [M + Na]+ calcd. for
C36H29N3NaO, 542.2203; found, 542.2204.
3-(4-Bromophenyl)-1-phenyl-4,5-dihydro-1H-benzo[g]indazole
(5l). The product was obtained by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 20:1) as a white solid (73.6
1
mg, yield: 92%); mp 178−179 °C. H NMR (500 MHz, CDCl3): δ
7.68−7.63 (m, 2H), 7.57−7.54 (m, 4H), 7.52−7.43 (m, 3H), 7.30 (d, J
= 7.2 Hz, 1H), 7.18−7.145 (m, 1H), 7.00 (t, J = 8.2 Hz, 1H), 6.81 (d, J =
7.8 Hz, 1H), 3.03−2.99 (m, 2H), 2.97−2.92 (m, 2H); 13C{1H} NMR
(125 MHz, CDCl3): δ 147.5, 140.8, 139.3, 137.1, 132.5, 131.7, 129.4,
128.9, 128.6, 128.5, 127.6, 126.8, 126.4, 125.9, 123.2, 121.8, 117.5, 30.7,
20.8; HRMS (ESI) m/z: [M + H]+ calcd. for C23H18BrN2, 401.0648;
found, 401.0649.
1-Phenyl-3-(p-tolyl)-4,5-dihydro-1H-benzo[g]indazole (5m). The
product was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (57.1 mg, yield:
85%); mp 154−155 °C. 1H NMR (500 MHz, CDCl3): δ 7.68−7.66 (m,
2H), 7.59−7.55 (m, 2H), 7.52−7.42 (m, 3H), 7.31 (d, J = 7.0 Hz, 1H),
7.27−7.25 (m, 2H), 7.18-7.14 (m, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.83
(d, J = 7.7 Hz, 1H), 3.05−3.00 (m, 2H), 2.99−2.93 (m, 2H), 2.40 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 148.7, 140.9, 138.9, 137.5,
137.3, 130.6, 129.3, 129.3, 128.5, 128.2, 127.4, 127.3, 127.1, 126.3,
125.9, 123.2, 117.5, 30.8, 21.3, 20.8; HRMS (ESI) m/z: [M + H]+ calcd.
for C24H21N2, 337.1699; found, 337.1697.
Ethyl 1-Phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate
(5n). The product was obtained by column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate = 20:1) as a yellow solid
(55.4 mg, yield: 87%); mp 152−153 °C. 1H NMR (500 MHz, CDCl3):
δ 7.56−7.47 (m, 5H), 7.30 (d, J = 7.4 Hz, 1H), 7.18−7.15 (m, 1H), 6.98
(t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H),
3.13−3.07 (m, 2H), 3.05−2.97 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 163.0, 140.4, 140.2, 139.6, 137.4,
To a mixture of the ester 5n (0.31 mmol, 0.1 g, 1.0 equiv) in
methanol (5.0 mL) was added potassium hydroxide (0.62 mmol, 2.0
equiv). The resulting mixture was heated under reflux in an oil bath for
1 h. The mixture was allowed to cool to room temperature and then
poured into water, acidified with 1 N hydrochloric acid, and extracted
with ethyl acetate. The organic layer was combined, washed with
saturated brine, dried with anhydrous Na2SO4, and concentrated to
yield the acid. The crude product was used for next step without
purification. A 25 mL round-bottom flask was charged with acid (0.31
mmol, 1.0 equiv), dry DCM (10 mL), and a catalytic amount of DMF.
The reaction mixture was cooled to 0 °C and stirred for 5 min. Then,
oxalyl chloride (0.47 mmol, 40 μL, 1.5 equiv) was added dropwise to
the reaction mixture and stirred at room temperature for 2 h. The
resulting mixture was concentrated under reduced pressure to afford
the crude product and used directly for the next step. The white solid
was dissolved in CH2Cl2 (2 mL). To the resulting solution were added
1-aminopiperidine (0.46 mmol, 1.5 equiv) and Et3N (0.46 mmol, 1.5
equiv) at 0 °C. The mixture was warmed to room temperature and
stirred for 1 h. Then, the mixture was quenched with brine and
extracted with CH2Cl2. The combined organic layer was washed with
brine, dried over Na2SO4, and the solvent was removed by rotary
evaporation. The residue was purified by column chromatography on
silica gel (petroleum/ethyl acetate = 10:1) to afford the product 7 as a
129.4, 129.1, 128.7, 128.0, 126.4, 126.2, 126.2, 123.0, 122.9, 60.9, 30.2,
20.2, 14.5; HRMS (ESI) m/z: [M + H]+ calcd. for C20H19N2O2,
319.1441; found, 319.1441.
1,3-Diphenyl-4,5-dihydro-1H-benzo[g]indazole (5o). The product
was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a yellow solid (54.8 mg,
yield: 85%); mp 176−177 °C. 1H NMR (500 MHz, CDCl3): δ 7.81−
7.75 (m, 2H), 7.59−7.56 (m, 2H), 7.51−7.47 (m, 2H), 7.45 (t, J = 7.6
Hz, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.18−7.15
(m, 1H), 7.01 (t, J = 8.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.05−3.00
(m, 2H), 3.00−2.95 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ
148.6, 140.9, 139.0, 137.2, 133.4, 129.3, 128.6, 128.5, 128.3, 127.7,
127.5, 127.4, 127.0, 126.3, 125.9, 123.1, 117.6, 30.8, 20.8; HRMS (ESI)
m/z: [M + H]+ calcd. for C23H19N2, 323.1543; found, 323.1543.
3-Phenyl-1-(p-tolyl)-4,5-dihydro-1H-benzo[g]indazole (5p). The
product was obtained by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate = 20:1) as a white solid (63.9 mg, yield:
95%); mp 150−151 °C. 1H NMR (500 MHz, CDCl3): δ 7.75−7.65 (m,
2H), 7.38−7.31 (m, 4H), 7.27−7.23 (m, 1H), 7.19 (t, J = 6.7 Hz, 3H),
7.06−7.03 (m, 1H), 6.91 (t, J = 8.1 Hz, 1H), 6.76 (d, J = 7.3 Hz, 1H),
2.93−2.89 (m, 2H), 2.88−2.84 (m, 2H), 2.34 (s, 3′H); 13C{1H} NMR
(125 MHz, CDCl3): δ 147.3, 137.9, 137.4, 137.2, 136.1, 132.5, 127.5,
1
white solid (92.1 mg, 79% yield over 3 steps); mp 195−196 °C. H
NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.57−7.47 (m, 5H), 7.29 (d,
M
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J = 7.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.7 Hz, 1H), 6.72
(d, J = 7.6 Hz, 1H), 3.17−3.12 (m, 2H), 3.04−2.96 (m, 2H), 2.88−2.84
(m, 3H), 1.90−1.70 (m, 5H), 1.53−1.38 (m, 2H); 13C{1H} NMR (125
MHz, CDCl3): δ 160.0, 141.8, 140.4, 139.7, 137.7, 129.5, 129.0, 128.8,
127.9, 126.2, 126.1, 125.9, 122.8, 122.1, 57.2, 30.2, 25.4, 23.4, 19.7.
HRMS (ESI) m/z: [M + H]+ calcd. for C23H25N4O, 373.2023; found,
373.2020.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02244.
1
Copies of H and 13C NMR spectra for all compounds
(PDF)
AUTHOR INFORMATION
Corresponding Authors
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́
Chem. 2011, 11, 771−821. (f) Fustero, S.; Sanchez, R. M.; Barrio, P.;
́
Simon, F. A. From 2000 to Mid-2010: A Fruitful Decade for the
Yongsheng Zheng − School of Pharmaceutical Sciences, South-
Central University for Nationalities, Wuhan 430074, China;
orcid.org/0000-0002-1019-5521; Email: zhysh@
mail.scuec.edu.cn
Synthesis of Pyrazoles. Chem. Rev. 2011, 111, 6984−7034.
(3) (a) Suzuki, Y.; Oishi, S.; Takei, Y.; Yasue, M.; Misu, R.; Naoe, S.;
Hou, Z. Y.; Kure, T.; Nakanishi, I.; Ohno, H.; Hirasawa, A.; Tsujimoto,
G.; Fujii, N. Design and Synthesis of a Novel Class of CK2 inhibitors:
Application of Copper- and Gold-Catalysed Cascade Reactions for
Fused Nitrogen Heterocycles. Org. Biomol. Chem. 2012, 10, 4907−
4915. (b) Maurya, H. K.; Verma, R.; Alam, S.; Pandey, S.; Pathak, V.;
Sharma, S.; Srivastava, K. K.; Negi, A. S.; Gupta, A. Studies on
Substituted Benzo[h]quinazolines, Benzo[g]indazoles, Pyrazoles, 2,6-
Diarylpyridines as Anti-tubercular Agents. Bioorg. Med. Chem. Lett.
2013, 23, 5844−5849.
Jikai Liu − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China;
orcid.org/0000-0001-6279-7893; Email: liujikai@
mail.scuec.edu.cn
Authors
Liang Tu − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Limei Gao − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Xiaomeng Wang − School of Pharmaceutical Sciences, South-
Central University for Nationalities, Wuhan 430074, China
Ruijie Shi − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Rupei Ma − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Junfei Li − School of Pharmaceutical Sciences, South-Central
University for Nationalities, Wuhan 430074, China
Xiaoshuang Lan − School of Pharmaceutical Sciences, South-
Central University for Nationalities, Wuhan 430074, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02244
Author Contributions
†L.T. and L.G. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the National Natural
Science Foundation of China (nos. 81973208 and
2191101099), Hubei Provincial Natural Science Foundation
of China (2019CFB624), and “the Fundamental Research
Funds for the Central Universities”, the South-Central
University for Nationalities (CZP1800).
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