Synthesis of trifluoromethylated pyrazolidines by [3 + 2] cycloaddition

Article abstract of DOI:10.1039/c7ob01299c

A highly efficient [3 + 2] cycloaddition between trifluoromethylated N-acylhydrazones and nitroolefins in the presence of potassium hydroxide under phase transfer catalysis is developed to afford potentially bioactive trifluoromethylated pyrazolidines, which can be further transformed into trifluoromethylated pyrazoles in good yields.

Full text of DOI:10.1039/c7ob01299c

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Synthesis of trifluoromethylated pyrazolidines by
3 + 2] cycloaddition†
[
Cite this: DOI: 10.1039/c7ob01299c
a
a
a
a
a
Xiansha Peng, Danfeng Huang,* Ke-Hu Wang, Yalin Wang, Juanjuan Wang,
a
a,b
Yingpeng Su
and Yulai Hu
*
Received 27th May 2017,
Accepted 4th July 2017
A highly efficient [3 + 2] cycloaddition between trifluoromethylated N-acylhydrazones and nitroolefins in
the presence of potassium hydroxide under phase transfer catalysis is developed to afford potentially bio-
active trifluoromethylated pyrazolidines, which can be further transformed into trifluoromethylated pyra-
zoles in good yields.
DOI: 10.1039/c7ob01299c
rsc.li/obc
prevalent fluorine-containing group appearing in organofluor-
ine compounds. Incorporation of the trifluoromethyl group
Introduction
5
Pyrazolidines and their derivatives are valuable compounds into drugs usually dramatically alters their metabolic stability,
1
5a,b
because of their widespread natural occurrence, important lipophilicity and bioactivities.
However, there were only two
reports about the synthesis of trifluoromethylated pyrazoli-
Fig. 1). After N–N bond cleavage, pyrazolidines can be easily dines from the [3 + 2] cycloaddition of azomethine imines
2
3
biological properties, and applications in materials science
(
6
converted to 1,3-diamines, which are important building with trifluoromethylated olefins. Therefore, introduction of
blocks for the synthesis of nitrogen-containing bioactive com- the CF group into pyrazolidines should be very desirable and
3
4
pounds. In addition, the trifluoromethyl group is the most will result in further advances in pharmacological application.
In general, there are two principal ways of introducing the tri-
fluoromethyl group into organic molecules: the direct
7
a
trifluoromethylation by using trifluoromethylating reagents,
or the trifluoromethylated synthetic building-block strate-
7
b
8
gies. In our research studies on fluorine chemistry, we
found that trifluoromethylated N-acylhydrazones could be
easily prepared from commercially available aqueous trifluoro-
acetaldehyde methyl hemiacetal and N-acylhydrazines, and
were also found to be bench stable. Thus, we tried to develop
the trifluoromethylated N-acylhydrazones into trifluoromethyl
building blocks to access trifluoromethylated nitrogen-contain-
8
c
ing organic compounds.
Pyrazolidine derivatives are usually constructed by [3 + 2]
cycloaddition between azomethine imines and alkenes or
9
alkynes. The [3 + 2] cycloaddition between N-acylhydrazones
and alkenes represents another convenient access to pyrazoli-
dine derivatives, which are generally achieved under acidic
1
0
11
Fig. 1 Some bioactive molecules containing pyrazolidine units.
conditions or at high temperature. Recently, it was reported
that the base-promoted reaction between 2-aroyl-1-chlorocyclo-
propanecarboxylates and N-acylhydrazones could also afford
a
College of Chemistry and Chemical Engineering, Northwest Normal University,
1
2
pyrazolidine derivatives. In our research studies, we found
that trifluoromethylated N-acylhydrazones could react with
β-nitrostyrene derivatives in the presence of potassium hydro-
xide under phase transfer catalysis to give trifluoromethylated
pyrazolidine derivatives in good to excellent yields. Herein, we
would like to report the results of [3 + 2] cycloaddition
between trifluoromethylated N-acylhydrazones and nitroolefins
Lanzhou, Gansu, 730070, P. R. China. E-mail: huangdf@nwnu.edu.cn,
huyl@nwnu.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
†
Electronic supplementary information (ESI) available: General experimental
1
13
details, X-ray representations and copies of H and C NMR spectra. CCDC
537670 and 1537674. For ESI and crystallographic data in CIF or other elec-
1
tronic format see DOI: 10.1039/c7ob01299c
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Table 1 Optimization of reaction conditions
a
Mole ratio of
Yield 3aa
Entry
1a/2a/base
Base
Solvent
(%)
1
2
3
4
5
6
7
8
9
1/2.5/2.5
1/2.5/2.5
1/2.5/2.5
1/2.5/2.5
1/2.5/2.5
1/2.5/2.5
1/2.5/1.5
1/2.5/1.0
1/2.5/0.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
1/3.5/1.5
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
CH
CH
Toluene
MeOH
THF
3
CN
Cl
47
38
22
18
16
32
48
32
22
58
Trace
14
48
55
48
33
64
79
67
75
86
2
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN/H
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
2
O = 9/1
Scheme 1 Synthesis of trifluoromethylated pyrazolidines.
1
1
1
0
1
2
Na
CaCO
2
CO
3
3
under basic conditions (Scheme 1). Furthermore, the produced 13
K
K
2
CO
3
1
1
1
1
1
1
4
5
6
7
8
9
3
PO
4
pyrazolidines could be easily transformed into trifluoromethyl-
ated pyrazoles.
Na
NaOH
KOH
KOH
KOH
KOH
KOH
3
PO
4
b
c
b
d
e
b
Results and discussion
20
3
CH CN
CH
b
21
3
CN
To commence the investigation, N′-(2,2,2-trifluoroethylidene)-
benzohydrazide 1a (1 equiv.), (E)-β-nitrostyrene 2a (2 equiv.)
and DBU (2.5 equiv.) were dissolved in THF and stirred at of Bu NI (0.1 equiv.).
a
b
c
Isolated yields. Ground to fine powder. In the presence of Bu
4
NF
d
e
(
4
0.1 equiv.). In the presence of Bu NCl (0.1 equiv.). In the presence
4
room temperature, but there was no product formed after
2
4 hours. The reaction was then carried out again at 50 °C,
and it occurred to afford the product 3aa in 5% yield. After
With the optimized reaction conditions in hand, the sub-
careful examination of reaction conditions, the yield of 3aa strate scope was investigated. Firstly, a series of substituted
increased to 47% when 1a reacted with 2a in the presence of trifluoromethylated N-acylhydrazones were reacted with 2a to
Cs
2
CO
3
in acetonitrile at room temperature by using Bu
4
NBr check the generality of N-acylhydrazones. As shown in Table 2,
all of the trifluoromethylated aromatic N-acylhydrazones
as the phase transfer catalyst (Table 1, entry 1).
Encouraged by this result, the reaction conditions were with both electron-donating and electron-withdrawing groups
optimized in detail. The solvent screening showed that aceto- reacted with 2a to give the corresponding products in
nitrile was the suitable solvent (Table 1, entries 1–6). good to excellent yields. However, the trifluoromethylated
Examination of the mole ratio of the reactants indicated that N-acylhydrazones with electron-withdrawing groups on their
2 3
the suitable ratio of 1a/2a/Cs CO
was 1/3.5/1.5 (Table 1, entry phenyl rings usually produced the products in higher yields
1
0), which gave the product 3aa in 58% yield. The investigation (Table 2, entries 4–11). For instance, N′-(2,2,2-trifluoroethyl-
of different bases revealed that potassium hydroxide was the idene)-4-methylbenzohydrazide gave the product 3da in 76%
suitable one, which let the yield of product 3aa to increase to yield, but the yield of product 3la increased to 96% when N′-
6
4% (Table 1, entries 11–17). It was found that the yield of (2,2,2-trifluoroethylidene)-4-nitrobenzohydrazide was used as
product 3aa could be further increased to 79% when the pot- the substrate. Further observation of the results indicated that
assium hydroxide pellet was ground to fine powder (Table 1, the stronger the ability of electron-withdrawing groups on the
entry 18). Finally, examination of the effects of different qua- phenyl rings of N-acylhydrazones were, the higher the yields of
ternary ammonium salts demonstrated that tetrabutyl the corresponding products were (Table 2, entries 7 and 11).
ammonium iodide was the best phase transfer catalyst, which The reason was that the acidity of the proton in the N–H bond
afforded the product in 86% yield (Table 1, entries 18–21).
of N-acylhydrazones was influenced by the electronic pro-
In the above reaction, only one isomer of 3aa was obtained. perties of substituents on the phenyl rings. The stronger the
1
9
The F NMR spectra showed that another isomer maybe exist- electron-withdrawing ability of the substituents on the phenyl
ing (see the ESI†), but we never obtained it in our experiments. rings was, the more acidic the proton in the N–H bond of
The relative configuration of 3aa was determined by single- N-acylhydrazones became. Thus, the N-acylhydrazones with
crystal X-ray diffraction. Its formation could be explained in stronger electron-withdrawing groups on their phenyl rings
Scheme 3.
would be easier to be deprotonated, and made the reaction
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a
a
Table 2 Scope of trifluoromethylated N-acylhydrazones
Table 3 Scope of nitroolefins
1
b
Entry
R
Products
Yield (%)
2
b
Entry
R
Products
Yield (%)
1
2
3
4
5
6
7
8
9
o-MeC
m-MeC
p-MeC
6
H
H
6 4
4
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
3sa
72
78
76
85
78
80
83
76
81
85
96
88
57
88
86
83
78
54
1
2
3
4
5
6
7
8
9
p-MeOC
6
H
4
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3aa
68
68
70
76
73
79
85
86
88
85
95
82
77
75
89
o-MeC
m-MeC
p-MeC
o-ClC
m-ClC
p-ClC
o-FC
6 4
H
6
H
4
6 4
H
p-FC
o-ClC
6
H
4
6 4
H
6 4
H
6
H
4
m-ClC
p-ClC
p-CF
o-O NC
m-O NC
p-O NC
6
H
4
6
H
4
6
H
4
6
H
4
H
4
3
C
6
H
4
6
2
6
H
4
p-FC
p-CF
6
H
4
H
10
11
12
13
14
15
16
17
18
2
6
H
4
10
11
12
13
14
15
3
C
6
4
2
6 4
H
6 4
p-BrC H
2-Naphthyl
2-Furyl
Phenethyl
Cyclohexyl
Isopropyl
2-Naphthyl
2-Thienyl
2-Furyl
c
6 5
C H
a
n-C11
n-C17
H
H
23
Reactions were carried out by using 0.2 mmol of 1a, 3.5 equiv. of
NI, 1.5 equiv. of KOH, 4 mL of CH CN,
35
nitroolefins 2, 0.1 equiv. of Bu
at room temperature, 12–24 h. Isolated yields. (Z)-β-Nitrostyrene was
used.
4
3
b
c
a
Reactions were carried out by using 0.2 mmol of 1, 3.5 equiv. of 2a,
.1 equiv. of Bu NI, 1.5 equiv. of KOH, 4 mL of CH CN, at room temp-
0
4
3
b
erature, 12–24 h. Isolated yields.
entries 13 and 14). When cis-nitrostyrene reacted with
give the products in higher yields. Aliphatic N-acylhydrazones trifluoromethylated N-acylhydrazones 1a, the product 3aa was
also afforded the corresponding products, but the yields obtained (yield 89%, Table 3, entry 15).
decreased with the aliphatic chains becoming longer (Table 2,
The trifluoromethylated pyrazolidines obtained in the
entries 16–18).
above reactions could be further transformed into trifluoro-
In order to investigate the reactivity of ketone-derived methylated pyrazole derivatives 4. As summarized in Table 4,
N-acylhydrazones, the reaction of 2,2,2-trifluoroacetophenone trifluoromethylated pyrazoles were produced in good yields
derived acylhydrazone and nitrostyrene 2a was conducted when pyrazolidines 3 were refluxed in ethanol in the presence
under the standard reaction conditions. The reaction did not of copper chloride. In this transformation, the acyl groups and
occur, and only substrates were recovered (Scheme 2).
Next, the generality of β-nitrostyrene derivatives 2 was
checked by using 1a as the substrate under the optimized reac-
tion conditions (Table 3). The results revealed that all of the Table 4 Further transformation of the products
a
nitroolefins with both electron-donating and electron-with-
drawing groups on their phenyl rings smoothly reacted with 1a
to afford the corresponding products in good yields. It was
noteworthy that the nitroolefins with para-substituents on
their phenyl rings usually gave products in higher yields than
those with meta- or ortho-substituents (Table 3, entries 2–4 and
5
–7). Heteroaromatic nitroolefins could also be used in the
reactions to produce the products in good yields (Table 3,
1
6
2
b
Entry
R
R
Time (h) Products Yield (%)
1
2
3
4
5
6
C
H
5
C
6
C
6
C
6
H
H
H
5
5
5
6
8
6
8
6
8
4a
4a
4a
4b
4c
4d
88
78
80
68
87
87
Isobutyl
m-MeC H
4
6
6
C H
6
C H
6
C H
5
5
5
p-MeOC
p-ClC
2-Naphthyl
6 4
H
H
4
6
a
Scheme 2 Reaction of 2,2,2-trifluoroacetophenone derived acylhydra-
zone and nitrostyrene 2a.
Reactions were carried out by using 0.1 mmol of 3, 3.0 equiv. of
b
2
CuCl , 4 mL of EtOH, reflux, 6–8 h. Isolated yields.
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EtOAc (3 × 10 mL). The combined organic extracts were dried
(
MgSO ) and concentrated. Purification of the residue by silica
4
gel column chromatography using petroleum ether : acetone
(
4 : 1) as the eluent furnished the products 3.
(3R,4S,5R)-4-Nitro-5-phenyl-3(trifluoromethyl)pyrazolidin-
-yl)(phenyl)methanone (3aa). White solid (63 mg, 86% yield);
(
1
1
m.p. 198–199 °C; H NMR (600 MHz, CDCl
3
) δ 7.75 (d, J =
7
7
5
1
1
6
.2 Hz, 2H), 7.52–7.50 (m, 1H), 7.44 (t, J = 7.2 Hz, 2H),
.38–7.34 (m, 3H), 7.32–7.31 (m, 2H), 6.22 (d, J = 7.8 Hz, 1H),
.90 (d, J = 5.4 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 4.41–4.38 (m,
1
3
H); C NMR (100 MHz, CDCl ) δ 172.4, 134.0, 132.8, 131.2,
3
Scheme 3 Plausible mechanism.
29.2, 128.9, 128.8, 127.9, 126.3, 122.9 (q, J = 280.0 Hz), 90.1,
1
9
5.4, 64.9 (q, J = 32.0 Hz); F NMR (376 MHz, CDCl ) δ −73.85
3
(
d, J = 7.52 Hz); HRMS (ESI): calculated for C H F N O
17 15 3 3 3
nitro group were lost from pyrazolidines, which were aroma-
tized to produce trifluoromethylated pyrazoles.
+
[
M + H] 366.1060, found 366.1055.
(3R,4S,5R)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
-yl)(o-tolyl)methanone (3ba). White solid (55 mg, 72% yield);
(
Finally, the mechanism is proposed in Scheme 3 based
1
1
3
on our experiments and literature.
In the inorganic
1
m.p. 193–194 °C; H NMR (600 MHz, (CD
3
)
2
CO) δ 7.57 (d, J =
phase, anions exchange between Bu NI and KOH producing
4
7
7
6
.2 Hz, 2H), 7.52 (d, J = 6.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H),
4
Bu NOH, which was then transferred into the organic
.33–7.31 (m, 2H), 7.27–7.22 (m, 2H), 6.85 (d, J = 6.0 Hz, 1H),
phase. Deprotonation of N-acylhydrazone 1a by Bu NOH gave
13
4
.27–6.26 (m, 2H), 4.98–4.96 (m, 1H), 2.39 (s, 3H); C NMR
N-acylhydrazonyl anion 5a, which attached to 2a to give carbon
anion B. The nitro group rotated around the C–C σ bond in
carbon anion B to form carbon anion C because of the steric
hindrance between CF3 and NO2 groups in carbon anion B.
The carbon anion C cyclized to produce intermediate 6a. After
proton extraction of intermediate 6a from water, product 3aa
was then produced.
(
1
6
150 MHz, (CD
3
)
2
CO) δ 173.6, 137.2, 136.5, 135.9, 131.2, 130.1,
29.4, 129.3, 128.9, 128.0, 125.9, 125.0 (q, J = 279.0 Hz), 91.6,
6.2, 65.4 (q, J = 31.5 Hz), 19.7; F NMR (376 MHz, (CD ) CO)
3 2
19
δ −69.32 (d, J = 7.52 Hz); HRMS (ESI): calculated for
C H F N O [M + H] 380.1217, found 380.1215.
+
1
8
17 3 3 3
(
(3R,4S,5S)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
1
-yl)(m-tolyl)methanone (3ca). White solid (59 mg, 78%
1
yield); m.p. 175–176 °C; H NMR (400 MHz, CDCl ) δ 7.52
3
(
5
br, 2H), 7.34–7.25 (m, 7H), 6.19 (d, J = 8.0 Hz, 1H), 5.83 (d, J =
.6 Hz, 1H), 5.72 (d, J = 8.4 Hz, 1H), 4.35–4.28 (m, 1H), 2.39
Conclusions
1
3
(
s, 3H); C NMR (150 MHz, CDCl ) δ 172.7, 137.6, 134.0,
3
In conclusion, a novel [3 + 2] cycloaddition reaction between
trifluoromethylated N-acylhydrazones and nitroolefins is devel-
oped in the presence of potassium hydroxide under phase
transfer catalysis. This method provides an efficient way to
access potentially bioactive trifluoromethylated pyrazolidines
in good to excellent yields under mild reaction conditions. The
trifluoromethylated pyrazolidines can be easily transformed
into trifluoromethylated pyrazoles. Further studies to develop
the trifluoromethylated N-acylhydrazones into trifluoromethyl
building blocks to access trifluoromethylated nitrogen-contain-
ing compounds are in progress in our laboratory.
1
32.8, 131.9, 129.2, 129.1, 128.9, 127.7, 126.3, 125.8, 122.9 (q,
1
9
J = 279.0 Hz), 90.1, 65.3, 64.8 (q, J = 31.5 Hz), 21.3; F NMR
376 MHz, CDCl ) δ −73.83 (d, J = 7.52 Hz); HRMS (ESI): calcu-
(
3
+
lated for C18
(3R,4S,5R)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
-yl)(p-tolyl)methanone (3da). White solid (65 mg, 86% yield);
17 3 3 3
H F N O [M + H] 380.1217, found 380.1214.
(
1
1
m.p. 217–220 °C; H NMR (600 MHz, (CD
3
)
2
CO) δ 7.84 (d, J =
8
7
1
.4 Hz, 2H), 7.55 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H),
.31–7.28 (m, 1H), 7.25 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 6.0 Hz,
H), 6.34 (d, J = 8.4 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 5.06–5.01
1
3
(
m, 1H), 2.38 (s, 3H); C NMR (150 MHz, (CD
3 2
) CO) δ 173.1,
1
42.0, 136.1, 133.2, 130.4, 129.3, 129.2, 129.1, 128.0, 125.0 (q,
1
9
J = 279.0 Hz), 91.4, 66.5, 65.6 (q, J = 31.5 Hz), 21.6; F NMR
Experimental section
General experimental procedures for the synthesis of
(
(
3
376 MHz, (CD
ESI): calculated for C H F N O [M + H] 380.1217, found
80.1213.
3 2
) CO) δ −74.74 (d, J = 11.28 Hz); HRMS
+
1
8
17 3 3 3
compounds 3aa–3sa and 3ab–3ao
A solution of trifluoromethylated N-acylhydrazones 1 (0.2 mmol),
(4-Fluorophenyl)((3R,4S,5S)-4-nitro-5-phenyl-3-(trifluoromethyl)
nitroolefins 2 (0.7 mmol), KOH (0.3 mmol) and Bu NI pyrazolidin-1-yl)methanone (3ea). White solid (65 mg, 85%
4
1
(
3 3
0.02 mmol) in CH CN (5 mL) was stirred at room temperature yield); m.p. 181–182 °C; H NMR (600 MHz, CDCl ) δ 7.84–7.81
for 6–24 h and monitored by thin layer chromatography (TLC) (m, 2H), 7.35–7.34 (m, 3H), 7.30–7.29 (m, 2H), 7.11 (t, J =
until the starting materials were not detected. CH CN was 9.0 Hz, 2H), 6.21 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 4.8 Hz, 1H),
3
1
3
removed from the reaction mixture under vacuum. The satu- 5.73 (d, J = 8.4 Hz, 1H), 4.39–4.36 (m, 1H); C NMR (150 MHz,
rated NH Cl solution (10 mL) was poured into the mixture and CDCl ) δ 171.2, 164.4 (d, J = 250.5 Hz), 132.7, 131.4 (d, J = 7.5 Hz),
stirred for 10 min, and then the mixture was extracted with 129.8 (d, J = 3.0 Hz), 129.2, 128.9, 126.3, 122.9 (q, J = 279.0 Hz),
4
3
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1
9
1
(
(
15.0 (d, J = 21.0 Hz), 90.0, 65.6, 64.9 (q, J = 31.5 Hz); F NMR 1H), 6.30 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 5.02–4.97
1
3
376 MHz, CDCl ) δ −73.85 (d, J = 7.52 Hz), −108.24; HRMS (m, 1H); C NMR (150 MHz, (CD ) CO) δ 168.9, 147.2, 135.2,
ESI): calculated for C17H F N O [M + H] 384.0966, found 134.9, 133.6, 131.4, 130.2, 129.5, 129.3, 128.0, 125.0, 124.9 (q,
14 4 3 3
3
3 2
+
1
9
3
84.0960.
J = 279.0 Hz), 91.3, 66.7, 64.8 (q, J = 31.5 Hz); F NMR
(
2-Chlorophenyl)((3R,4S,5R)-4-nitro-5-phenyl-3-(trifluoro- (376 MHz, (CD ) CO) δ −69.07 (d, J = 7.52 Hz); HRMS (ESI):
3
2
+
methyl)pyrazolidin-1-yl)methanone (3fa). White solid (62 mg, calculated for C17
H F N O
14 3 4 5
[M + H] 411.0911, found 411.0915.
((3R,4S,5S)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
δ 7.57 (d, J = 7.8 Hz, 2H), 7.52–7.50 (m, 1H), 7.47–7.45 (m, 2H), 1-yl)(3-nitrophenyl)methanone (3ka). White solid (70 mg,
1
7
3 2
8% yield); m.p. 216–218 °C; H NMR (600 MHz, (CD ) CO)
1
7
1
7
.43–7.40 (m, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 85% yield); m.p. 179–180 °C; H NMR (600 MHz, (CD
H), 6.77 (d, J = 6.0 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H), 6.24 (d, J = δ 8.80 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H),
.8 Hz, 1H), 5.03–4.98 (m, 1H); C NMR (150 MHz, (CD ) CO) 7.79 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.40 (d, J =
3 2
) CO)
1
3
3
2
δ 170.3, 137.3, 135.4, 131.8, 131.7, 130.3, 129.9, 129.4, 129.3, 5.4 Hz, 1H), 7.37–7.32 (m, 3H), 6.36 (d, J = 8.4 Hz, 1H), 6.29 (d,
1
3
1
28.0, 127.8, 124.9 (q, J = 279.0 Hz), 91.5, 66.4, 65.0 (q, J = 31.5 Hz); J = 8.4 Hz, 1H), 5.15–5.10 (m, 1H); C NMR (150 MHz,
1
9
F NMR (376 MHz, (CD ) CO) δ −74.44 (d, J = 11.28 Hz); (CD ) CO) δ 171.1, 148.8, 137.6, 136.1, 135.5, 130.3, 129.5,
3
2
3 2
+
HRMS (ESI): calculated for C17
found 400.0667.
3 3 3
H14ClF N O [M + H] 400.0670, 129.3, 128.0, 126.4, 125.0, 124.9 (q, J = 279 Hz), 91.3, 67.0, 64.5
1
9
3 2
(q, J = 31.5 Hz); F NMR (376 MHz, (CD ) CO) δ −69.47 (d, J =
+
(
3-Chlorophenyl)((3R,4S,5R)-4-nitro-5-phenyl-3-(trifluoro- 7.52 Hz); HRMS (ESI): calculated for C H F N O [M + H]
17 14 3 4 5
methyl)pyrazolidin-1-yl)methanone (3ga). White solid (64 mg, 411.0911, found 411.0916.
1
8
0% yield); m.p. 189–190 °C; H NMR (600 MHz, (CD
3
)
2
CO)
((3R,4S,5S)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
δ 8.0 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.58–7.54 (m, 3H), 7.48 (t, 1-yl)(4-nitrophenyl)methanone (3la). White solid (79 mg, 96%
1
J = 7.8 Hz, 1H), 7.35–7.29 (m, 3H), 7.20 (d, J = 5.4 Hz, 1H), 6.32 yield); m.p. 209–210 °C; H NMR (600 MHz, (CD
3 2
) CO) δ 8.33
(
d, J = 7.8 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 5.10–5.05 (m, 1H); (d, J = 9.0 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 7.2 Hz,
1
3
C NMR (150 MHz, (CD ) CO) δ 171.8, 138.0, 135.6, 134.0, 2H), 7.37–7.31 (m, 3H), 7.24 (d, J = 5.4 Hz, 1H), 6.33 (d, J =
3
2
1
3
1
31.7, 130.5, 130.0, 129.4, 129.3, 128.5, 128.0, 124.9 (q, J = 279 8.4 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.13–5.08 (m, 1H);
C
1
9
3 2
Hz), 91.3, 66.7, 65.54 (q, J = 30.0 Hz); F NMR (376 MHz, NMR (150 MHz, (CD ) CO) δ 171.7, 150.1, 142.2, 135.4, 131.1,
(
C
CD ) CO) δ −74.68 (d, J = 7.52 Hz); HRMS (ESI): calculated for 129.5, 129.4, 128.0, 124.9 (q, J = 279.0 Hz), 123.8, 91.3, 66.8,
3
2
+
19
17
H
14ClF
3
N
3
O
3
[M + H] 400.0670, found 400.0665.
3 2
65.3 (q, J = 30.0 Hz); F NMR (376 MHz, (CD ) CO) δ −74.67
(
14 3 4 5
4-Chlorophenyl)((3R,4S,5S)-4-nitro-5-phenyl-3-(trifluoro- (d, J = 7.52 Hz); HRMS (ESI): calculated for C17H F N O
+
methyl)pyrazolidin-1-yl)methanone (3ha). White solid (66 mg, [M + H] 411.0911, found 411.0906.
3% yield); m.p. 212–213 °C; H NMR (600 MHz, (CD
1
8
3
)
2
CO)
Naphthalen-2-yl((3R,4S,5S)-4-nitro-5-phenyl-3-(trifluoromethyl)
δ 7.95 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.49 (d, J = pyrazolidin-1-yl)methanone (3ma). White solid (73 mg, 88%
1
8
.4 Hz, 2H), 7.35–7.30 (m, 3H), 7.15 (d, J = 6.0 Hz, 1H), 6.33 yield); m.p. 217–219 °C; H NMR (600 MHz, (CD ) CO) δ 8.58
3 2
(
d, J = 8.4 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), 5.09–5.04 (m, 1H); (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 8.00–7.95 (m, 3H), 7.62–7.57
1
3
3 2
C NMR (150 MHz, (CD ) CO) δ 172.2, 137.3, 135.8, 134.7, (m, 4H), 7.35 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.21 (s,
1
6
32.0, 129.4, 129.3, 128.8, 128.0, 124.9 (q, J = 279.0 Hz), 91.3, 1H), 6.43–6.42 (m, 1H), 6.29–6.28 (m, 1H), 5.09–5.04 (m, 1H);
1
9
13
6.7, 65.5 (q, J = 30.0 Hz); F NMR (376 MHz, (CD
3
)
2
CO)
3 2
C NMR (150 MHz, (CD ) CO) δ 173.3, 136.0, 135.5, 133.5,
δ −69.53 (d, J = 7.52 Hz); HRMS (ESI): calculated for 133.4, 130.7, 129.9, 129.4, 129.3, 128.7, 128.5, 128.1, 128.0,
+
C H ClF N O [M + H] 400.0670, found 400.0667.
(
127.5, 126.9, 125.0 (q, J = 279.0 Hz), 91.5, 66.6, 65.5 (q, J = 30.5
1
7
14
3 3 3
1
9
(3R,4S,5S)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin- Hz); F NMR (376 MHz, (CD
-yl)(4-(trifluoromethyl)phenyl)methanone (3ia). White solid HRMS (ESI): calculated for C21H F N O [M + H] 416.1217,
66 mg, 76% yield); m.p. 205–206 °C; H NMR (600 MHz, found 416.1210.
CD CO) δ 8.10 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), Furan-2-yl((3R,4S,5S)-4-nitro-5-phenyl-3-(trifluoromethyl)pyr-
.58 (d, J = 7.8 Hz, 2H), 7.37–7.31 (m, 3H), 7.20 (d, J = 6.0 Hz, azolidin-1-yl)methanone (3na). White solid (41 mg, 57% yield);
3 2
) CO) δ −74.71 (d, J = 7.52 Hz);
+
1
(
17 3 3 3
1
(
3 2
)
7
1
(
1
H), 6.34 (d, J = 8.4 Hz, 1H), 6.28 (d, J = 8.4 Hz, 1H), 5.11–5.06 m.p. 167–169 °C; H NMR (600 MHz, (CD ) CO) δ 7.76–7.75
m, 1H); C NMR (150 MHz, (CD
3
2
1
3
3
)
2
CO) δ 172.1, 140.7, 135.6, (m, 1H), 7.69 (d, J = 3.6 Hz, 1H), 7.48–7.46 (m, 2H), 7.33–7.27
1
3
31.4 (q, J = 31.5 Hz), 130.6, 129.5, 129.4, 128.0, 125.6 (q, J = (m, 3H), 7.07 (d, J = 5.4 Hz, 1H), 6.65–6.64 (m, 1H), 6.26–6.23
1
3
.0 Hz), 124.9 (q, J = 279.0 Hz), 91.4, 66.7, 65.4 (q, J = 31.5 Hz); (m, 2H), 5.23–5.18 (m, 1H); C NMR (150 MHz, (CD ) CO)
3
2
1
9
F NMR (376 MHz, (CD
3 2
) CO) δ −63.77, −74.71 (d, J = 7.52 δ 161.2, 147.3, 146.7, 135.8, 129.3, 129.2, 127.9, 125.1 (q, J =
+
Hz); HRMS (ESI): calculated for C18
4
H
14
F
6
N
3
O
3
[M + H]
279.0 Hz), 119.8, 112.4, 90.9, 66.9, 65.5 (q, J = 31.5 Hz);
F NMR (376 MHz, (CD ) CO) δ −74.88 (d, J = 7.52 Hz); HRMS
1
9
34.0934, found 434.0928.
(3R,4S,5R)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin- (ESI): calculated for C15
-yl)(2-nitrophenyl)methanone (3ja). White solid (66 mg, 81% 356.0650.
3
2
+
(
13 3 3 4
H F N O [M + H] 356.0653, found
1
1
yield); m.p. 169–170 °C; H NMR (600 MHz, (CD ) CO) δ 8.22
1-((3R,4S,5S)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin-
d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1-yl)-2-phenylethan-1-one (3oa). White solid (67 mg, 88%
3
2
(
1
1
H), 7.62 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.37 yield); m.p. 166–167 °C; H NMR (600 MHz, (CD
3 2
) CO)
(t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 6.88 (d, J = 6.0 Hz, δ 7.36–7.22 (m, 10H), 6.87 (d, J = 5.4 Hz, 1H), 6.23 (d, J =
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8
1
.4 Hz, 1H), 6.06–6.05 (m, 1H), 5.15–5.12 (m, 1H), 4.16 (d, J = 68% yield); m.p. 169–170 °C; H NMR (600 MHz, (CD
5.0 Hz, 1H), 3.94–3.93 (m, 1H);
3
)
2
CO)
1
3
C NMR (150 MHz, δ 7.89 (d, J = 7.8 Hz, 2H), 7.51–7.42 (m, 5H), 7.08 (d, J = 6.0 Hz,
(
CD
3
)
2
CO) δ 174.3, 136.7, 135.9, 130.6, 129.9, 129.2, 129.1, 1H), 6.89–6.87 (m, 2H), 6.29 (d, J = 8.4 Hz, 1H), 6.17 (d, J =
1
3
1
3
7
3
27.8, 127.4, 125.2 (q, J = 279.0 Hz), 91.6, 66.1, 65.4, (q, J = 8.4 Hz, 1H), 5.04–4.99 (m, 1H), 3.77 (s, 3H); C NMR
1.5 Hz), 41.0; F NMR (376 MHz, (CD ) CO) δ −69.61 (d, J = (150 MHz, (CD ) CO) δ 173.1, 160.9, 136.2, 131.6, 130.1, 129.3,
.52 Hz); HRMS (ESI): calculated for C18
80.1217, found 380.1214.
1
9
3
2
3 2
+
H
17
F
3
N
3
O
3
[M + H]
128.5, 127.6, 125.0 (q, J = 279.0 Hz), 114.6, 91.4, 66.1, 65.4 (q,
J = 31.5 Hz), 55.7; F NMR (376 MHz, (CD ) CO) δ −74.76 (d,
3 2
1
9
+
Cyclohexyl((3R,4S,5R)-4-nitro-5-phenyl-3-(trifluoromethyl) J = 7.52 Hz); HRMS (ESI): calculated for C H F N O [M + H]
1
8
17 3 3 4
pyrazolidin-1-yl)methanone (3pa). White solid (64 mg, 86% 396.1166, found 396.1161.
1
yield); m.p. 206–207 °C; H NMR (600 MHz, (CD
3
)
2
CO) δ 7.37
((3R,4S,5R)-4-Nitro-5-(o-tolyl)-3-(trifluoromethyl)pyrazolidin-
(
d, J = 7.2 Hz, 2H), 7.30–7.25 (m, 3H), 6.90 (d, J = 6.0 Hz, 1H), 1-yl)(phenyl)methanone (3ac). White solid (52 mg, 68% yield);
1
6
1
1
1
6
.19 (d, J = 8.4 Hz, 1H), 6.00 (d, J = 8.4 Hz, 1H), 5.09–5.04 (m, m.p. 206–207 °C; H NMR (600 MHz, (CD
3 2
) CO) δ 7.92 (d, J =
H), 3.24–3.20 (m, 1H), 1.79–1.76 (m, 2H), 1.71–1.66 (m, 2H), 7.8 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H),
1
3
.46–1.19 (m, 6H); C NMR (150 MHz, (CD ) CO) δ 179.0, 7.43 (t, J = 7.8 Hz, 2H), 7.20 (d, J = 4.2 Hz, 2H), 7.14–7.11 (m,
3
2
36.2, 129.2, 129.1, 127.8, 125.2 (q, J = 279.0 Hz), 91.5, 65.8, 1H), 7.09 (d, J = 5.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 6.29 (d, J =
1
9
13
5.3 (q, J = 30.0 Hz), 42.0, 31.3, 28.6, 26.9, 26.8, 26.2; F NMR 8.4 Hz, 1H), 5.06–5.02 (m, 1H), 2.56 (s, 3H); C NMR
(
376 MHz, (CD ) CO) δ −74.77 (d, J = 7.52 Hz); HRMS (ESI): cal- (150 MHz, (CD ) CO) δ 172.9, 137.3, 136.0, 134.3, 131.7, 131.2,
3
2
3 2
+
culated for C17
H
21
F
3
N
3
O
3
[M + H] 372.1530, found 372.1527.
130.1, 129.4, 128.5 127.0, 126.9, 124.7 (q, J = 279.0 Hz), 90.0,
1
9
2
-Methyl-1-((3R,4S,5R)-4-nitro-5-phenyl-3-(trifluoromethyl) 65.5 (q, J = 30.0 Hz), 64.0, 19.9; F NMR (376 MHz, (CD
3 2
) CO)
pyrazolidin-1-yl)propan-1-one (3qa). White solid (55 mg, 83% δ −69.31 (d, J = 7.52 Hz); HRMS (ESI): calculated for
1
+
yield); m.p. 197–198 °C; H NMR (600 MHz, CDCl
(
3
) δ 7.33–7.30
C
18
H
17
F
3
N
3
O
3
[M + H] 380.1217, found 380.1219.
((3R,4S,5S)-4-Nitro-5-(m-tolyl)-3-(trifluoromethyl)pyrazolidin-
.4 Hz, 1H), 5.62 (d, J = 6.0 Hz, 1H), 4.44–4.40 (m, 1H), 1-yl)(phenyl)methanone (3ad). White solid (53 mg, 70% yield);
m, 3H), 7.17–7.16 (m, 2H), 5.91 (d, J = 8.4 Hz, 1H), 5.69 (d, J =
8
3
3
1
3
7
3
1
.40–3.35 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H), 1.11 (d, J = 7.2 Hz, m.p. 206–207 °C; H NMR (600 MHz, (CD
3
)
2
CO) δ 7.91 (d, J =
) δ 180.0, 133.0, 129.0, 128.8, 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.39
26.0, 123.1 (q, J = 279.0 Hz), 90.2, 64.9, 64.8 (q, J = 31.5 Hz), (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.11
1
3
H); C NMR (150 MHz, CDCl
3
1
9
1.5, 20.4, 17.7; F NMR (376 MHz, CDCl ) δ −73.95 (d, J = (d, J = 7.8 Hz, 1H), 7.07 (d, J = 6.0 Hz, 1H), 6.30 (d, J = 7.8 Hz,
.52 Hz); HRMS (ESI): calculated for C14
32.1217, found 332.1214.
3
+
H
17
F
3
N
3
O
3
[M + H]
1H), 6.22 (d, J = 9.0 Hz, 1H), 5.04–4.99 (m, 1H), 2.30 (s,
3H); C NMR (150 MHz, (CD ) CO) δ 173.2, 138.8, 136.2,
1
3
3
2
1
-((3R,4S,5R)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin- 135.9, 131.7, 130.1, 130.0, 129.2, 128.6, 128.5, 125.1, 125.0 (q,
1
9
1
-yl)dodecan-1-one (3ra). White solid (69 mg, 78% yield); J = 279.0 Hz), 91.4, 66.5, 65.4 (q, J = 31.5 Hz), 21.5; F NMR
m.p. 115–116 °C; H NMR (600 MHz, CDCl ) δ 7.32–7.30 (376 MHz, (CD ) CO) δ −69.53 (d, J = 11.2 Hz); HRMS (ESI):
m, 3H), 7.19–7.17 (m, 2H), 5.91 (d, J = 7.8 Hz, 1H), 5.68 (d, J = calculated for C18H F N O [M + H] 380.1217, found
17 3 3 3
1
3
3 2
+
(
8
2
.4 Hz, 1H), 5.60 (d, J = 5.4 Hz, 1H), 4.43–4.38 (m, 1H), 380.1221.
.71–2.59 (m, 2H), 1.65–1.61 (m, 2H), 1.34–1.26 (m, 16H), 0.88
((3R,4S,5R)-4-Nitro-5-(p-tolyl)-3-(trifluoromethyl)pyrazolidin-
1
3
(t, J = 6.6 Hz, 3H); C NMR (150 MHz, CDCl
3
) δ 176.5, 133.0, 1-yl)(phenyl)methanone (3ae). White solid (58 mg, 76% yield);
1
1
29.0, 128.8, 126.1, 123.1 (q, J = 279.0 Hz), 90.3, 65.1, 64.8 m.p. 207–208 °C; H NMR (600 MHz, (CD
3
)
2
CO) δ 7.90 (d, J =
(
q, J = 31.5 Hz), 33.6, 31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 7.2 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 4H), 7.14
1
9
2
7
4
3
4.6, 22.7, 14.1; F NMR (376 MHz, CDCl ) δ −74.06 (d, J = (d, J = 7.8 Hz, 2H), 7.06 (d, J = 6.0 Hz, 1H), 6.30 (d, J = 8.4 Hz,
+
.52 Hz); HRMS (ESI): calculated for C22
44.2469, found 444.2465.
H
33
F
3
N
3
O
3
[M + H]
1H), 6.20 (d, J = 8.4 Hz, 1H), 5.04–5.00 (m, 1H), 2.29 (s, 3H);
1
3
C NMR (150 MHz, (CD ) CO) δ 173.1, 139.0, 136.2, 132.9,
3
2
1
-((3R,4S,5R)-4-Nitro-5-phenyl-3-(trifluoromethyl)pyrazolidin- 131.6, 130.1, 129.9, 128.5, 128.0, 125.2 (q, J = 279.0 Hz), 91.4,
1
9
1
3 2
-yl)octadecan-1-one (3sa). White solid (60 mg, 54% yield); 66.3, 65.4 (q, J = 31.5 Hz), 21.3; F NMR (376 MHz, (CD ) CO)
m.p. 106–108 °C; H NMR (600 MHz, CDCl ) δ 7.33–7.28 δ −74.75 (d, J = 7.52 Hz); HRMS (ESI): calculated for
1
3
+
(
m, 3H), 7.19–7.17 (m, 2H), 5.92 (d, J = 8.4 Hz, 1H), 5.69 (d, J =
C
18
H
17
F
3
N
3
O
3
[M + H] 380.1217, found 380.1215.
((3R,4S,5S)-5-(2-Chlorophenyl)-4-nitro-3-(trifluoromethyl)
.71–2.65 (m, 1H), 2.65–2.59 (m, 1H), 1.65–1.61 (m, 2H), pyrazolidin-1-yl)(phenyl)methanone (3af). White solid
8
2
1
.4 Hz, 1H), 5.60 (d, J = 5.4 Hz, 1H), 4.42–4.40 (m, 1H),
1
3
1
.34–1.25 (m, 28H), 0.88 (t, J = 6.6 Hz, 3H); C NMR (58 mg, 73% yield); m.p. 200–201 °C; H NMR (600 MHz,
) δ 176.5, 133.0, 129.0, 128.8, 126.1, 123.1 (q, (CD CO) δ 7.96 (s, 2H), 7.75 (d, J = 6.0 Hz, 1H), 7.54–7.45 (m,
J = 279.0 Hz), 90.3, 65.1, 64.7 (q, J = 31.5 Hz), 33.6, 31.9, 29.7, 4H), 7.37–7.30 (m, 2H), 7.20 (s, 1H), 6.45–6.44 (m, 1H),
(
150 MHz, CDCl
3
3 2
)
1
3
2
1
9.69, 29.67, 29.65, 29.62, 29.5, 29.4, 29.3, 29.2, 24.6, 22.7, 6.22–6.19 (m, 1H), 5.12–5.09 (m, 1H); C NMR (150 MHz,
4.1; F NMR (376 MHz, CDCl
HRMS (ESI): calculated for C H F N O [M + H] 528.3408, 130.2, 129.1, 128.6, 128.3, 124.8 (q, J = 279.0 Hz), 89.8, 65.5 (q,
1
9
3
3 2
) δ −74.06 (d, J = 7.52 Hz); (CD ) CO) δ 173.3, 135.7, 134.1, 133.8, 131.9, 131.3, 130.3,
+
2
8
45 3 3 3
1
9
found 528.3401.
(3R,4S,5R)-5-(4-Methoxyphenyl)-4-nitro-3-(trifluoromethyl)
pyrazolidin-1-yl)(phenyl)methanone (3ab). White solid (54 mg, [M + H] 400.0670, found 400.0664.
J = 31.5 Hz), 64.6; F NMR (376 MHz, (CD
3
)
2
CO) δ −74.66 (d,
3 3 3
14ClF N O
(
J = 7.52 Hz); HRMS (ESI): calculated for C17
H
+
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Paper
(
(3R,4S,5R)-5-(3-Chlorophenyl)-4-nitro-3-(trifluoromethyl) (d, J = 4.8 Hz, 1H), 6.43–6.40 (m, 1H), 6.34 (dd, J = 8.4, 2.4 Hz,
1
3
pyrazolidin-1-yl)(phenyl)methanone (3ag). White solid (63 mg, 1H), 5.11–5.09 (m, 1H); C NMR (150 MHz, (CD ) CO) δ 173.4,
9% yield); m.p. 189–190 °C; H NMR (600 MHz, (CD
3
2
1
7
3 2
) CO) 140.7, 135.8, 131.9, 131.0 (q, J = 31.5 Hz), 130.2, 128.9, 128.6,
δ 7.95–7.94 (m, 2H), 7.65–7.61 (m, 1H), 7.55–7.50 (m, 2H), 126.3 (q, J = 4.5 Hz), 125.3 (q, J = 270.0 Hz), 124.9 (q, J = 279.0
1
9
7
6
1
1
.46–7.44 (m, 2H), 7.39–7.34 (m, 2H), 7.20 (d, J = 6.0 Hz, 1H), Hz), 91.4, 66.3, 65.5 (q, J = 31.5 Hz); F NMR (376 MHz,
.34 (d, J = 7.8 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 5.11–5.06 (m, (CD CO) δ −63.52, −74.74 (d, J = 7.52 Hz); HRMS (ESI):
3 2
)
1
3
+
H); C NMR (150 MHz, (CD
3 2 14 6 3 3
) CO) δ 173.4, 138.4, 135.8, calculated for C18H F N O [M + H] 434.0934, found
34.8, 131.8, 131.0, 130.2, 129.5, 128.6, 127.9, 126.8, 124.9 (q, 434.0929.
19
J = 279.0 Hz), 91.3, 66.2, 65.5 (q, J = 31.5 Hz); F NMR
((3R,4S,5R)-5-(4-Bromophenyl)-4-nitro-3-(trifluoromethyl)
(
376 MHz, (CD CO) δ −69.54 (d, J = 11.2 Hz); HRMS (ESI): pyrazolidin-1-yl)(phenyl)methanone (3al). White solid (84 mg,
3 2
)
+
1
calculated for C H ClF N O [M + H] 400.0670, found 95% yield); m.p. 175–176 °C; H NMR (600 MHz, (CD ) CO)
1
7
14
3
3
3
3 2
4
00.0672.
δ 7.92 (d, J = 7.8 Hz, 2H), 7.54–7.50 (m, 5H), 7.45 (t, J = 7.2 Hz,
(
(3R,4S,5S)-5-(4-Chlorophenyl)-4-nitro-3-(trifluoromethyl) 2H), 7.13 (d, J = 5.4 Hz, 1H), 6.31 (d, J = 7.8 Hz, 1H), 6.25 (d, J =
1
3
pyrazolidin-1-yl)(phenyl)methanone (3ah). White solid (68 mg, 8.4 Hz, 1H), 5.08–5.04 (m, 1H); C NMR (150 MHz, (CD ) CO)
5% yield); m.p. 182–184 °C; H NMR (600 MHz, (CD
3
2
1
8
3 2
) CO) δ 173.3, 135.9, 135.5, 132.4, 131.8, 130.1, 128.6, 127.7, 124.9
δ 7.92 (d, J = 7.8 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.55–7.50 (m, (q, J = 279.0 Hz), 122.9, 91.3, 66.1, 65.5 (q, J = 31.5 Hz);
1
9
1
6
5
1
H), 7.45 (t, J = 7.8 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.13 (d, J =
F NMR (376 MHz, (CD ) CO) δ −74.75 (d, J = 7.52 Hz); HRMS
3
2
+
.0 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 6.25 (d, J = 8.4 Hz, 1H), (ESI): calculated for C17
H
3 3 3
14BrF N O [M + H] 444.0165, found
1
3
.09–5.04 (m, 1H); C NMR (150 MHz, (CD
3
)
2
CO) δ 173.3, 444.0158.
((3R,4S,5R)-5-(Naphthalen-2-yl)-4-nitro-3-(trifluoromethyl)
J = 279.0 Hz), 91.4, 66.1, 65.4 (q, J = 31.5 Hz); F NMR pyrazolidin-1-yl)(phenyl)methanone (3am). White solid
35.9, 135.0, 134.8, 131.8, 130.1, 129.8, 129.4, 128.6, 124.9 (q,
19
1
(376 MHz, (CD
3 2
) CO) δ −74.74 (d, J = 7.52 Hz); HRMS (ESI): cal- (68 mg, 82% yield); m.p. 210–211 °C; H NMR (600 MHz,
+
culated for C H ClF N O [M
+
H] 400.0670, found (CD ) CO) δ 8.59 (d, J = 8.4 Hz, 1H), 7.98–7.97 (m, 2H), 7.94 (d,
1
7
14
3
3
3
3 2
4
00.0665.
J = 7.8 Hz, 1H), 7.90–7.87 (m, 2H), 7.64–7.61 (m, 1H), 7.56–7.54
(
(3R,4S,5S)-5-(2-Fluorophenyl)-4-nitro-3-(trifluoromethyl) (m, 1H), 7.52–7.50 (m, 1H), 7.46–7.43 (m, 3H), 7.19 (d, J = 4.2
pyrazolidin-1-yl)(phenyl)methanone (3ai). White solid (66 mg, Hz, 1H), 7.08–7.06 (m, 1H), 6.60 (dd, J = 8.4, 4.2 Hz, 1H),
1
13
8
6% yield); m.p. 199–201 °C; H NMR (600 MHz, (CD
δ 7.93 (d, J = 7.8 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 136.1, 134.7, 132.2, 131.8, 131.7, 130.2, 130.1, 129.7, 128.6,
.2 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.41–7.38 (m, 1H), 7.17 (t, 127.6, 127.0, 126.2, 125.3, 125.0 (q, J = 279.0 Hz), 124.5, 90.8,
3 2 3 2
) CO) 5.11–5.06 (m, 1H); C NMR (150 MHz, (CD ) CO) δ 173.1,
7
1
9
J = 6.0 Hz, 2H), 7.10 (d, J = 5.4 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 65.4 (q, J = 31.5 Hz), 64.0; F NMR (376 MHz, (CD
.22 (d, J = 7.8 Hz, 1H), 5.13–5.08 (m, 1H); C NMR (150 MHz, δ −74.38 (d, J = 7.52 Hz); HRMS (ESI): calculated for
CD ) CO) δ 173.2, 164.3 (d, J = 244.5 Hz), 135.7, 131.9, 131.7 C H F N O [M + H] 416.1217, found 416.1214.
3 2 21 17 3 3 3
d, J = 7.5 Hz), 130.1, 129.1 (d, J = 3.0 Hz), 128.6, 125.5 (d, J =
3
)
2
CO)
1
3
6
(
(
+
((3R,4S,5R)-4-Nitro-5-(thiophen-2-yl)-3-(trifluoromethyl)pyr-
4
.5 Hz), 124.9 (q, J = 279.0 Hz), 123.1 (d, J = 13.5 Hz), 116.1 (d, azolidin-1-yl)(phenyl)methanone (3an). White solid (57 mg,
1
9
1
J = 21.0 Hz), 90.4, 65.5 (q, J = 31.5 Hz), 61.1; F NMR 77% yield); m.p. 182–183 °C; H NMR (600 MHz, (CD ) CO)
3
2
(
(
3
376 MHz, (CD
ESI): calculated for C17
84.0962.
3 2
) CO) δ −74.62 (d, J = 7.52 Hz), −117.81; HRMS δ 7.87–7.86 (m, 2H), 7.53–7.50 (m, 1H), 7.46–7.43 (m, 2H), 7.41
+
H
14
F
4
N
3
O
3
[M + H] 384.0966, found (dd, J = 4.8, 1.8 Hz, 1H), 7.25–7.24 (m, 1H), 7.08 (d, J = 6.6 Hz,
1H), 7.00 (dd, J = 4.8, 1.2 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.23
1
3
(
(3R,4S,5S)-5-(4-Fluorophenyl)-4-nitro-3-(trifluoromethyl)pyr- (dd, J = 7.8, 1.2 Hz, 1H), 5.13–5.07 (m, 1H); C NMR
azolidin-1-yl)(phenyl)methanone (3aj). White solid (68 mg, (150 MHz, (CD CO) δ 173.2, 138.2, 135.7, 131.9, 130.1, 128.6,
8% yield); m.p. 214–215 °C; H NMR (600 MHz, (CD ) CO) 128.0, 127.5, 126.6, 125.0 (q, J = 279.0 Hz), 90.9, 65.4 (q, J =
3 2
)
1
8
3
2
1
9
δ 7.92 (t, J = 6.0 Hz, 2H), 7.64–7.62 (m, 2H), 7.52–7.50 31.5 Hz), 62.2; F NMR (376 MHz, (CD
3
)
2
CO) δ −74.44 (d, J =
(
m, 1H), 7.46–7.43 (m, 2H), 7.13–7.10 (m, 3H), 6.34 (t, J = 7.52 Hz); HRMS (ESI): calculated for SNa
15 12 3 3 3
C H F N O
+
7
1
2
7
1
.8 Hz, 1H), 6.24 (dd, J = 8.4, 3.0 Hz, 1H), 5.06–5.04 (m, [M + Na] 394.0444, found 394.0440.
1
3
H); C NMR (150 MHz, (CD
3
)
2
CO) δ 173.4, 163.7 (d, J =
((3R,4S,5R)-5-(Furan-2-yl)-4-nitro-3-(trifluoromethyl)pyrazolidin-
43.0 Hz), 136.0, 132.1, 131.8 (d, J = 3.0 Hz), 130.2 (d, J = 1-yl)(phenyl)methanone (3ao). White solid (53 mg, 75% yield);
1
.5 Hz), 130.1, 128.6 (d, J = 1.5 Hz), 124.9 (q, J = 279.0 Hz), m.p. 165–167 °C; H NMR (600 MHz, (CD ) CO) δ 7.83 (d, J =
3
2
1
9
16.1 (d, J = 22.5 Hz), 91.4, 66.0, 65.5 (q, J = 30.0 Hz); F NMR 7.2 Hz, 2H), 7.53–7.49 (m, 2H), 7.43 (t, J = 7.8 Hz, 2H), 6.96 (d,
CO) δ −74.74 (d, J = 7.52 Hz), −115.78; HRMS J = 6.6 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H),
ESI): calculated for C H F N O [M + H] 384.0966, found 6.42 (dd, J = 3.0, 1.8 Hz, 1H), 6.18 (dd, J = 8.4, 3.0 Hz, 1H),
(376 MHz, (CD
3 2
)
+
(
3
1
7
14 4 3 3
1
3
84.0964.
3 2
5.18–5.12 (m, 1H); C NMR (150 MHz, (CD ) CO) δ 172.5,
(
(3R,4S,5S)-4-Nitro-3-(trifluoromethyl)-5-(4-(trifluoromethyl) 149.1, 144.5, 135.3, 131.9, 130.2, 128.6, 125.4 (q, J = 279.0 Hz),
1
9
phenyl)pyrazolidin-1-yl)(phenyl)methanone (3ak). White solid 111.7, 110.5, 88.8, 65.7 (q, J = 31.5 Hz), 59.6; F NMR
74 mg, 85% yield); m.p. 203–204 °C; H NMR (600 MHz, (376 MHz, (CD
CD CO) δ 7.95–7.93 (m, 2H), 7.83 (d, J = 7.8 Hz, 2H), 7.72 (d, calculated for C15
1
(
(
3 2
) CO) δ −75.21 (d, J = 7.52 Hz); HRMS (ESI):
+
3
)
2
H
13
F
3
N
3
O
3
[M + H] 356.0853, found
J = 8.4 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.47–7.45 (m, 2H), 7.20 356.0849.
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Organic & Biomolecular Chemistry
General experimental procedures for the synthesis of compounds 4
Rings, in The Chemistry of Heterocyclic Compounds, ed.
R. H. Wiley, Interscience Publishers, New York, 1967, vol.
A solution of trifluoromethylated pyrazolidine 3 (0.1 mmol)
22; (b) C. Kadouri-Puchot and C. Agami, in Asymmetric
and 3.0 equiv. of CuCl
2
in EtOH (4 mL) was stirred at reflux for
Synthesis of Nitrogen Heterocycles, ed. J. Royer, Wiley-VCH,
Weinheim, Germany, 2009, ch. 6.
(a) H. Berenson, United States Patent 3931406, 1976;
6
–8 h and monitored by thin layer chromatography (TLC) until
the starting material was not detected, and the reaction
mixture was cooled to room temperature. The solid was filtered
from the reaction mixture. The filtrate was concentrated under
vacuum. Purification of the residue by silica gel column
chromatography using petroleum ether : acetone (4 : 1) as the
eluent furnished the products 4.
2
(
b) B. Cross, C. P. Grasso and B. L. Walworth, United States
Patent 3948936, 1976; (c) C. Nishino, T. Otake, K. Adachi
and R. Inada, United States Patent 5849930, 1998;
(
3
d) M. J. Kornet and R. J. Garrett, J. Pharm. Sci., 1979, 68,
77; (e) P. D. Boatman, C. O. Ogbu, M. Eguchi, H.-O. Kim,
5
-Phenyl-3-(trifluoromethyl)-1H-pyrazole (4a). White solid;
1
1
H. Nakanishi, B. Cao, J. P. Shea and M. Kahn, J. Med.
Chem., 1999, 42, 1367; (f) J. H. Ahn, J. A. Kim, H.-M. Kim,
H.-M. Kwon, S.-C. Huh, S. D. Rhee, K. R. Kim, S.-D. Yang,
S.-D. Park, J. M. Lee, S. S. Kim and H. G. Cheon, Bioorg.
Med. Chem. Lett., 2005, 15, 1337; (g) J. H. Ahn, S. H. Jung,
J. A. Kim, S. B. Song, S. J. Kwon, K. R. Kim, S. D. Rhee,
S.-D. Park, J. M. Lee, S. S. Kim and H. G. Cheon, Chem.
Pharm. Bull., 2005, 53, 1048; (h) M. J. Kornet and P. A. Thio,
J. Pharm. Sci., 1969, 58, 724.
(
R
= phenyl, 37 mg, 88% yield; R = isobutyl, 32 mg, 78%
1
yield; R = m-tolyl, 34 mg, 80% yield); m.p. 118–119 °C;
1
H NMR (600 MHz, CDCl
.45–7.39 (m, 3H), 6.70 (s, 1H); C NMR (150 MHz, CDC)
δ 145.1, 129.4, 129.2, 127.9, 125.6, 120.5 (q, J = 267.0 Hz),
01.0; F NMR (376 MHz, CDCl
lated for C H F N [M + H] 213.0634, found 213.0632.
3
) δ 12.6 (s, 1H), 7.56–7.55 (m, 2H),
1
3
7
1
9
1
3
) δ −62.55; HRMS (ESI): calcu-
+
1
0
8 3 2
5
-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole
(4b).
1
White solid (33 mg, 68% yield); m.p. 145–146 °C; H NMR
3
4
(a) X.-C. Gao, H. Cao, L.-Q. Zhang, B.-W. Zhang, Y. Cao and
C.-H. Huang, J. Mater. Chem., 1999, 9, 1077; (b) H.-B. Fu
and J.-N. Yao, J. Am. Chem. Soc., 2001, 123, 1434;
(c) S. W. Oh, D. R. Zhang and Y. S. Kang, Mater. Sci. Eng., C,
2004, 24, 131.
(a) W. L. F. Armarego and T. Kobayashi, J. Chem. Soc., 1970,
1597; (b) J. E. Shurig, W. T. Brandner, J. B. Huflutalen,
G. J. Doyle and J. A. Gylys, Toxic side effects of platinum
analogs. Cisplatin: current status and new developments,
Academic Press, New York, 1980, vol. 227.
(
6
600 MHz, CDCl ) δ 11.7 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H),
.97–6.96 (m, 2H), 6.6 (s, 1H), 3.8 (s, 3H); C NMR (150 MHz,
3
13
CDCl
00.3, 55.4; F NMR (376 MHz, CDCl ) δ −62.60; HRMS (ESI):
3
) δ 160.5, 144.9, 127.0, 121.2 (q, J = 267.0 Hz), 120.6, 114.6,
19
1
3
+
calculated for C H F N O [M + H] 243.0740, found 243.0742.
11
10 3 2
5
-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole
(4c).
1
White solid (43 mg, 87% yield); m.p. 149–150 °C; H NMR
(
(
600 MHz, CDCl ) δ 12.74 (s, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.40
3
1
3
3
d, J = 8.4 Hz, 2H), 6.69 (s, 1H); C NMR (150 MHz, CDCl )
δ 144.2, 135.5, 129.5, 126.8, 126.3, 121.9 (q, J = 267.0 Hz),
1
lated for C10
1
9
5 (a) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317,
1881; (b) S. Purser, P. R. Moore, S. Swallow and
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320;
(c) W. K. Hagmann, J. Med. Chem., 2008, 51, 4359.
01.3; F NMR (376 MHz, CDCl ) δ −62.55; HRMS (ESI): calcu-
3
+
7 3 2
H ClF N [M + H] 247.0244, found 247.0247.
5
-(Naphthalen-2-yl)-3-(trifluoromethyl)-1H-pyrazole
(4d).
1
White solid (45 mg, 87% yield); m.p. 101–102 °C; H NMR
(
6
(a) S. Ogawa, T. Nishimine, E. Tokunaga and N. Shibata,
Synthesis, 2010, 3274; (b) D. Wang, H.-P. Deng, Y. Wei,
Q. Xu and M. Shi, Eur. J. Org. Chem., 2013, 401.
600 MHz, CDCl
3
) δ 10.75 (s, 1H), 7.99–7.93 (m, 3H), 7.57–7.54
1
3
(m, 4H), 6.83 (s, 1H); C NMR (150 MHz, CDCl ) δ 143.2,
3
1
1
33.7, 131.1, 130.2, 128.7, 127.5, 127.4, 126.6, 126.1, 125.2,
1
9
7 (a) J. Hu, W. Zhang and F. Wang, Chem. Commun., 2009,
465; (b) J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem.
24.5, 121.2 (q, J = 267.0 Hz), 104.7; F NMR (376 MHz,
7
CDCl ) δ −62.50; HRMS (ESI): calculated for C H F N [M +
H] 263.00791, found 263.0794.
3
14 10 3 2
+
Rev., 2011, 111, 455.
8
(a) S. Ji, A. E. Alkhalil, Y. Su, X. Xia, S. Chong, K.-H. Wang,
D. Huang, Y. Fu and Y. Hu, Synlett, 2015, 1725;
(b) W. Zhang, Y. Su, S. Chong, L. Wu, G. Cao, D. Huang,
K.-H. Wang and Y. Hu, Org. Biomol. Chem., 2016, 14, 11162;
Acknowledgements
We thank the financial support from the National Natural
Science Foundation of China (Grant No. 21662030; 21462037);
Key Laboratory Polymer Materials of Gansu Province
(
c) W. Zhang, Y. Su, K.-H. Wang, L. Wu, B. Chang, Y. Shi,
D. Huang and Y. Hu, Org. Lett., 2017, 19, 376; (d) G. Du,
D. Huang, K.-H. Wang, X. Chen, Y. Xu, J. Ma, Y. Su, Y. Fu
and Y. Hu, Org. Biomol. Chem., 2016, 14, 1492.
(
Northwest Normal University); Key Laboratory of Eco-
Environment-Related Polymer Materials, Ministry of Education,
China; and State Key Laboratory of Applied Organic Chemistry,
Lanzhou University.
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(a) L. M. Stanley and M. P. Sibi, Chem. Rev., 2008, 108,
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2
011, 133, 13337; (c) T. Hashimoto, M. Omote and
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1
(a) L. C. Behr, R. Fusco and C. H. Jarboe, Pyrazoles,
Pyrazolines, Pyrazolidines, Indazoles and Condensed
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48.
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0 (a) S. Kobayashi, H. Shimizu, Y. Yamashita, H. Ishitani and
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(
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J. L. Leighton, J. Am. Chem. Soc., 2005, 127, 9974; 12 (a) Z. Huang, J. Hu and Y. Gong, Org. Biomol. Chem., 2015,
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2
2
008, 10, 3165; (f) A. Zamfir and S. B. Tsogoeva, Synthesis,
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(
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Org. Biomol. Chem.