Synthesis of Trifluoroethyl Pyrazolines via Trichloroisocyanuric Acid Promoted Cascade Cyclization/Trifluoromethylation of β,γ-Unsaturated Hydrazones

Article abstract of DOI:10.1021/acs.joc.8b00009

A novel and efficient protocol for the construction of trifluoroethyl pyrazolines has been developed by cascade cyclization/trifluoromethylation reaction of β,γ-unsaturated hydrazones. This strategy uses cheap and commercially available trichloroisocyanuric acid as promoter and TMSCF₃ as the trifluoromethylating reagent, which make the trifluoromethylating process much cheaper. A wide range of substrates can be applied in this process to afford the trifluoroethyl pyrazolines in good yield.

Full text of DOI:10.1021/acs.joc.8b00009

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Synthesis of Trifluoroethyl Pyrazolines via
Trichloroisocyanuric Acid Promoted Cascade Cyclization/
Trifluoromethylation of #,#-Unsaturated Hydrazones
Bingbing Chang, Yingpeng Su, Danfeng Huang, Ke-Hu
Wang, Weigang Zhang, Ya Shi, Xinghu Zhang, and Yulai Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00009 • Publication Date (Web): 30 Mar 2018
Downloaded from http://pubs.acs.org on March 30, 2018
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Page 1 of 30
The Journal of Organic Chemistry
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Synthesis of Trifluoroethyl Pyrazolines via
Trichloroisocyanuric Acid Promoted Cascade
Cyclization/Trifluoromethylation of β,γ-Unsaturated
Hydrazones
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Bingbing Chang,† Yingpeng Su,† Danfeng Huang,† KeꢀHu Wang,† Weigang Zhang,† Ya Shi,† Xinghu
Zhang,
†
Yulai Hu*†‡
†College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning East Road, Lanzhou
7
30070, China
‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
Eꢀmail: huyl@nwnu.edu.cn.
Abstract
A novel and efficient protocol for the construction of trifluoroethyl pyrazolines has been
developed by cascade cyclization/trifluoromethylation reaction of β,γꢀunsaturated hydrazones. This
strategy uses cheap and commercially available trichloroisocyanuric acid as promoter and TMSCF
3
as the trifluoromethylating reagent, which make trifluoromethylating process much cheaper. A wide
range of substrates can be applied in this process to afford the trifluoroethyl pyrazolines in good
yield.
INTRODUCTION
Trifluoromethyl group is the most prevalent fluorineꢀcontaining group appeared in
1
2
3
pharmaceuticals, agrochemicals and material science owing to its unique properties such as
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significantly enhanced lipophilicity, metabolic stability, and bioactivities comparing to their parent
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compounds. Thus, strategies to introduce CF group into organic compounds have been greatly
1
d,4
investigated in recent years.
Among existed methods, trifluoromethylation reagents such as
4
a,5
6
4b,4g,7
Togni, Umemoto, RuppertꢀPrakash reagent (Me SiCF ),
Langlois/Baran reagent (CF SO M;
3 2
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M = Na, Zn) and others provide direct and effective ways to introduce CF
compounds. Due to its advantages such as easy handling and storage, low cost and commercially
availability in large quantity, Me SiCF has been widely applied in trifluoromethylation process.
3
group into organic
3
3
Except its traditional nucleophilic trifluoromethylation process, the radical trifluoromethylation
9
protocol with Me SiCF is another interesting way. For instance, combinations of Me SiCF with
3
3
3
3
2
PhI(OAc) , silver or copper salts have been demonstrated as an effective way for the formation of
9
a,9b,9d
CꢀCF bond.
3
Despite such achievements, a more cheap and practical method for the synthesis
of trifluoromethyl organic compound is still highly desirable.
Trichloroisocyanuric acid (TCCA) has been produced on large scale in 100000 t/year and used for
many purposes, such as disinfecting swimming pools, nonshrinking treatment of wool, cleaning and
10
sterilizing bathrooms, laundry bleach and other purpose. In organic synthesis, TCCA has been
11
mainly applied as chlorination and oxidation reagents. In our research works on fluorine chemistry,
we find that TCCA can successfully induce the trifluoromethylation reaction of allylic oximes by
12
using Me
3
SiCF
3
as trifluoromethyl source. Obviously, low cost and easy availability of TCCA and
Me SiCF make it a very interesting trifluoromethylation process.
3
3
3
Figure 1. Examples of biologically active CF ꢀcontaining pyrazolines.
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On the other hand, pyrazolines play an important role in drug discovery and organic synthesis.
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As for their fluorine derivatives, CF
3
ꢀcontaining pyrazolines have been proven to possess remarkable
bioactivities (Figure 1). However, efficient methods for the synthesis of CF ꢀcontaining pyrazoline
[3+2] Cycloadditions of CF CH N with
14
3
1
5
derivatives have been scarce in literature.
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5aꢀc
electronꢀdeficient olefins are reported to give CF
3
ꢀsubstituted pyrazolines.
Cyclocondensations
of hydrazines with trifluoromethylated α,βꢀunsaturated ketones or 1,3ꢀdicarbonyl compounds are
15dꢀe
other ways to obtain CF
3
ꢀsubstituted pyrazolines.
Recently, a cascade photocatalytic radical
trifluoromethylation/cyclization of β,γꢀunsaturated hydrazones was reported to afford trifluoroethyl
pyrazolines by using Umemoto’s reagent as trifluoromethyl source in the presence of Ru(bpy) (PF6)2
3
15f
as photocatalyst (Scheme 1, a). Herein, we would like to report that TCCA promoted cascade
3 3
cyclization/trifluoromethylation of β,γꢀunsaturated hydrazones by using Me SiCF as trifluoromethyl
source to give trifluoroethyl pyrazolines in good yields (Scheme 1, b).
Scheme 1. Synthesis of Trifluoroethyl Pyrazolines.
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RESULTS AND DISCUSSION
The initial investigation commenced with the reaction of Nꢀpꢀtoluenesulfonylꢀβ,γꢀunsaturated
hydrazones 1a between TMSCF and TCCA in the presence of CsF and CuCl in acetonitrile
CH CN) under argon atmosphere at room temperature. After the reaction finished, the desired
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(
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trifluoroethyl pyrazoline 5a was formed in 55% yield along with chlorinated byꢀproduct 6a in 23%
yield (Table 1, entry 1). As reported in literature, metal salts usually have great influence on the
trifluoromethylation by using TMSCF
3
as trifluoromethyl reagent due to the formation of
16
trifluoromethyl organometallic reagents (MCF
3
). Thus, different metal salts were firstly examined
in order to improve the selectivity for desired trifluoromethylated product 5a. When CuCN was used,
the reaction did not occur, and only starting material hydrazones 1a was recovered in 86% yield
2 2 2
(Table 1, entry 2). If Cu(OAc) , CuCl or ZnCl was applied in the reaction, there were no
trifluoromethylated product 5a formed, but only the chlorinated product 6a was produced in
moderate yield (Table 1, entries 3−5). Silver acetate could only give the product 5a without the
formation of byꢀproduct 6a, but the yield of 5a was low (Table 1, entry 6). However, the yield of 5a
was not elevated when the amount of TCCA was further increased (Table 1, entry 7). Finally, when
copper(I) acetate was used in the reaction, the yield of 5a could be improved to 75% meanwhile the
starting material 1a was recovered in 13% and trace amount of byꢀproduct 6a could be seen on TLC
(Table 1, entry 8). Afterwards, the amount of TCCA was examined to improve the yield of
trifluoromethylated product 5a. It was found that the amount of TCCA also have some influence on
the reaction. When its amount was increased from 0.5 equiv to 0.67 equiv, the yield of 5a went up to
83%, meanwhile the starting material 1a disappeared and trace amount of byꢀproduct 6a could be
seen on TLC (Table 1, entries 8 and 9). However, further increasing of the TCCA amount to 0.84
equiv led to the decreasing of yield of 5a down to 15%, and the yield of byꢀproduct 6a went up to
56% at the same time (Table 1, entry 10). Next, other additives such as NꢀClꢀphthalimide,
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NꢀChlorosuccinimide (NCS), NꢀBromosuccinimide (NBS) and NꢀIodosuccinimide (NIS) were tested
for the reaction, but the yield and selectivity for 5a were not improved (Table 1, entries 11ꢀ14).
Finally, it was found both of copper(I) acetate and TCCA were crucial in the reaction to obtain the
desired product 5a. For instance, only chlorinated product 6a was obtained if there was no copper(I)
acetate in the reaction (Table 1, entry 15), and the reaction could not occur neither without TCCA
(Table 1, entry 16). Therefore, the optimized reaction conditions were found to be the use of 1a,
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0
3
CuOAc, CsF, TMSCF and TCCA in a molar ratio of 1:3.5:4.2:4.2:0.67 in MeCN at room
temperature under argon atmosphere.
a
Table 1 Optimization of Reaction Conditions
yield (%)
a 6a
metal salt
entry
additive (equiv)
time
2
5
1
2
3
4
5
6
7
8
9
CuCl
CuCN
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.5)
TCCA (0.67)
TCCA (0.5)
TCCA (0.67)
TCCA (0.84)
NꢀClꢀphthalimide (2.0)
NCS (2.0)
0.5 h
4 h
55
−
23
−
Cu(OAc)2
CuCl2
5 h
−
58
78
63
−
1.5 h
1.5 h
0.5 h
20 min
4 h
−
ZnCl2
−
AgOAc
AgOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
35
33
75
83
15
14
54
37
32
−
trace
trace
56
24
23
1.5 h
15 min
4 h
1
0
1
1
12
0.5 h
0.5 h
0.5 h
b
13
NIS (2.0)
(44)
c
14
NBS (2.0)
(53)
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1
1
5
6
−
TCCA (0.67)
−
15 min
4 h
−
−
46
−
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9
1
1
1
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6
CuOAc
a
Unless otherwise noted, the reactions were performed with 1a (0.3 mmol), additive (0.15ꢀ0.6
mmol, 0.5ꢀ2.0 equiv), 2 (1.1 mmol, 3.5 equiv), 3 (1.3 mmol, 4.2 equiv), and 4 (1.3 mmol, 4.2 equiv)
in 6 mL CH
dihydroꢀ1Hꢀpyrazole (6b). Yield of 5ꢀ(bromomethyl)ꢀ3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole
6c).
b
3
CN at room temperature.
Yield of 5ꢀ(iodomethyl)ꢀ3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀ
c
(
0
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With the optimized reaction conditions in hand, the substrate scope was then investigated. The
β,γꢀunsaturated hydrazones derived from homoallylic ketones 1 were examined firstly. As shown in
Table 2, both of aromatic and aliphatic β,γꢀunsaturated hydrazones 1 could produce the
corresponding products 5 in good yields. As for the aromatic ketoneꢀderived β,γꢀunsaturated
hydrazones, electronic properties of substituents on the phenyl rings had little effect on the yields of
the products. The β,γꢀunsaturated hydrazones with both of electronꢀdonating and
electronꢀwithdrawing groups on phenyl rings could afford the products in reasonable to good yields
(
Table 2, 5a−5j). However, if the substituents on the phenyl rings were the same, the
orthoꢀsubstituted ones gave the product in lowest yields (Table 2, 5e−5g). Heterocyclic
β,γꢀunsaturated hydrazones such as 2ꢀthiophenehydrazone and Bocꢀprotected 3ꢀindolehydrazone
were also suitable for this reaction to give the desired product 5k and 5l in 47% and 75% yields,
respectively. In addition, this protocol could be further applied successfully to a range of linear and
branched aliphatic β,γꢀunsaturated hydrazones 1m−1p; and the desired products 5m−5p were
obtained in moderate to high yields (Table 2, 5m−5p).
a
Table 2. Scope of β,γ-Unsaturated Hydrazones
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a
All reactions were carried out using 0.3 mmol of 1a, 0.2 mmol of TCCA (0.67 equiv), 1.1 mmol of
CuOAc (3.5 equiv), 1.3 mmol of TMSCF (4.2 equiv), 1.3 mmol of CsF (4.2 equiv), and 4 mL of
3
3
CH CN.
In order to examine the generality of the reaction further, the hydrazones with other Nꢀprotecting
2
groups (R ) such as benzyloxycarbonyl (Cbz), methyl carbonate, tertꢀbutoxycarbonyl (Boc) and acyl
groups had been investigated (Table 3). It was indicated that the Cbz, carbonate and Boc groups
were compatible in the reactions to allow the corresponding products formed in good yields.
However, when aliphatic acyl groups such as acetyl and isobutyryl groups were used, the yields of
the products were low. For instance, the products 5ar and 5as were obtained in only 27% and 34%
yields (Table 3, 5ar and 5as).
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a
Table 3. Scope of N-Protected Hydrazones
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
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2
2
2
2
2
3
3
3
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3
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3
3
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5
5
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5
5
5
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Cbz
Cbz
N
Cbz
N
Cbz
N
N
N
CF3
N
CF3
N
CF3
N
CF3
MeO
Cl
Cl
5ag: 58% yield, 17 h
MeO
ad: 57% yield, 16 h
5
5ae: 63% yield, 16h
5af: 50% yield, 16 h
a
All reactions were carried out using 0.3 mmol of 1a, 0.2 mmol of TCCA (0.67 equiv), 1.1 mmol of
CuOAc (3.5 equiv), 1.3 mmol of TMSCF (4.2 equiv), 1.3 mmol of CsF (4.2 equiv), and 4 mL of
CH CN.
3
3
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The products obtained in above reaction could be further transformed into pyrazoles. For instance,
when compound 5a was refluxed in methanol in the presence of sodium hydroxide, pyrazole 7 could
be produced in 94% yield. Bocꢀprotected compound 5an could also be transformed into pyrazole 7
1
2
3
4
5
6
7
8
9
in the presence of CuCl under reflux in ethanol (Scheme 2).
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
Scheme 2. Transformation of the Products
To consider the reaction mechanism, some control experiments were carried out (Scheme 3).
Firstly, chlorinated product 6a obtained at the beginning of this work was used as substrate to carry
out the reaction under the standard reaction conditions, but there was no trifluoromethylated product
5
a formed, and 6a was recovered in 94% yield (Scheme 3, a). This result indicated that desired
product 5a was not produced from the 6a. Next, TEMPO was added into the reaction of hydrazones
a under the standard conditions. The product 5a was not produced, but products 8 and 9 were
1
formed in 25% and 71% yields, respectively (Scheme 3, b). This meant that the reaction proceeded
in radical manner, and the radical 10 was the major intermediate (Scheme 4).
1
7
Based on the experimental results and literature, a mechanism was proposed finally. As showed
3
in Scheme 4, a trifluoromethyl copper complex 11 was formed firstly when TMSCF was stirred
18
with CuOAc and CsF. The decomposition of TCCA afforded chlorine radical 12 and radical 13,
which abstracted a hydrogen from hydrazone 1a to produce radical 14. TCCA was finally converted
into isocyanuric acid, which was detected from reaction mixture. Cyclization of radical 14 afforded
carbon radical 10, which combined the trifluoromethyl group from complex 11 to give the final
product 5a.
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Scheme 3. Control Experiments for Mechanism
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Proposed Mechanism
CuOAc, CsF
TMSCF3
CuCF3
Ts
N
2Cl
4
11
12
N
Cu
CuCl2
Ts
Cl
N
NH
O
O
N
10
N
N
Ts
Cl
Cl
Ts
N
1a
N
N
CF3
O
N
O
O
N
O
5a
N
N
14
Cl
Cl
H
N
O
13
H
Cl
O
O
N
O
12
N
N
HN
NH
Cl
Cl
O
O
CONCLUSIONS
In summary, an efficient cascade cyclization/trifluoromethylation reaction of β,γꢀunsaturated
hydrazones has been developed by using TMSCF as CF source and TCCA acid as promoter. Both
3
3
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of the low cost and commercial availability of TMSCF
3
and TCCA make this process practical for
1
2
3
4
5
6
7
8
9
preparation of trifluoroethyl pyrazolines. It is further demonstrated that TCCA can be an effective
3
promoter for trifluoromethylation by using TMSCF as trifluoromethylating reagent.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General Methods. All reactions were performed in flameꢀdried glassware with magnetic stirring
bar and sealed with a rubber septum. The solvents were distilled by standard methods. Reagents
were obtained from commercial suppliers and used without further purification unless otherwise
noted. Silica gel column chromatography was carried out using silica Gel 60 (230–400 mesh).
Analytical thin layer chromatography (TLC) was done using silica Gel (silica gel 60 F254). TLC
plates were analyzed by an exposure to ultraviolet (UV) light and/or submersion in
phosphomolybdic acid solution or submersion in KMnO
experiments were carried out in deuterochloroform (CDCl
4
solution or in Iodine vapor. NMR
1
3
) or deuterated acetone ((CD
3
)
2
CO). H
13
1
NMR, C{ H} NMR spectra were recorded at 400 MHz or 600 MHz and 100 MHz or 150 MHz
19
spectrometers, respectively. F NMR spectra were recorded at 376 MHz or 564 MHz spectrometers.
1
Chemical shifts are reported as δ values relative to internal TMS (δ 0.00 for H NMR), chloroform (δ
1
1
13
1
7
.26 for H NMR), acetone (δ 2.05 for H NMR), chloroform (δ 77.00 for C{ H} NMR), and
13
1
acetone (δ 206.26 for C{ H} NMR) in parts per million (ppm). The following abbreviations are
used for the multiplicities: s: singlet, d: doublet, dd: doublet of doublet, t: triplet, q: quartet, m:
multiplet, br: broad signal for proton spectra; Coupling constants (J) are reported in Hertz (Hz).
Melting points were uncorrected. High resolution mass spectra (HRMS) were recorded on
MicroTOFꢀQII mass instrument (ESI).
3
General Procedure for the Synthesis of CF -Containing Pyrazolines 5. Under argon
atmosphere, TMSCF
3
(179.0 mg, 1.3 mmol, 4.2 equiv) was added into a suspension of CuOAc
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(
129.0 mg, 1.1 mmol, 3.5 equiv) and CsF (191.0 mg, 1.3 mmol, 4.2 equiv) in dried MeCN (4 mL) at
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
room temperature. After the reaction mixture was stirred at room temperature for 30 min, TCCA (0.2
mmol, 0.67 equiv) was added into the reaction mixture followed by addition of hydrazones 1 (0.3
mmol) immediately. The mixture was stirred at room temperature, and the reaction was monitored
by thin layer chromatography (TLC) until the starting material was not detected. The reaction
mixture was then quenched with water and extracted with ethyl acetate (3 × 5 mL). The combined
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2 4
organic layer was dried over Na SO , and the solvent was evaporated off under vacuum. The residue
was purified by silica gel column chromatography (petroleumether : EtOAc = 3 : 1) to afford the
desired products 5 and byꢀproducts 6.
3ꢀPhenylꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5a): 92 mg, 80% yield, white
o
1
solid, mp 167−169 C; H NMR (600 MHz, CDCl
3
) δ 7.80 (d, J = 8.4, 2H), 7.66 (d, J = 7.2, 2H),
7
1
.44−7.38 (m, 3H), 7.31 (d, J = 7.8, 2H), 3.93−3.87 (m, 1H), 3.51−3.42 (m, 1H), 3.30 (dd, J = 17.4,
13
1
0.8 Hz, 1H), 3.01 (dd, J = 17.4, 10.2 Hz, 1H), 2.61−2.52 (m, 1H), 2.40 (s, 3H); C{ H} NMR (150
MHz, CDCl ) δ 157.6, 144.8, 130.9, 130.8, 130.2, 129.7, 128.9, 128.7, 126.9, 125.6 (q, J = 275.4
3
19
3
Hz), 56.8 (q, J = 3.0 Hz), 40.1 (q, J = 27.0 Hz), 40.0, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.55 (t,
+
J = 10.9 Hz); HRMS (ESI): calcd for C18
H
17
F
3
N
2
O
2
SNa [M + Na] 405.0855, found 405.0854.
3ꢀ(mꢀTolyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5b): 77 mg, 65% yield,
o
1
white solid, mp 151−153 C; H NMR (600 MHz, CDCl
) δ 7.81 (d, J = 8.4, 2H), 7.50 (s, 1H), 7.43
3
(d, J = 7.8, 1H), 7.31 (d, J = 7.8, 2H), 7.27 (t, J = 7.8, 1H), 7.24 (d, J = 7.2, 1H), 3.90−3.84 (m, 1H),
3
1
1
.50−3.41 (m, 1H), 3.29 (dd, J = 17.4, 10.8 Hz, 1H), 2.99 (dd, J = 17.4, 10.8 Hz, 1H), 2.60−2.50 (m,
13
1
H), 2.40 (s, 3H), 2.37 (s, 3H); C{ H} NMR (150 MHz, CDCl
3
) δ 157.7, 144.7, 138.5, 131.7,
30.8, 130.1, 129.7, 128.9, 128.6, 127.4, 125.6 (q, J = 275.3 Hz), 124.1, 56.7 (q, J = 3.0 Hz), 40.1 (q,
19
J = 27.6 Hz), 40.0, 21.6, 21.3; F NMR (376 MHz, CDCl
3
) δ ꢀ64.55 (t, J = 10.9 Hz); HRMS (ESI):
calcd for C H F N O SNa [M + Na]+ 419.1012, found 419.1017.
19
19
3
2
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3
ꢀ(pꢀTolyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5c): 77 mg, 65% yield, white
1
2
3
4
5
6
7
8
9
o
1
solid, mp 170−171 C; H NMR (400 MHz, CDCl
) δ 7.79 (d, J = 8.4, 2H), 7.55 (d, J = 8.4, 2H),
3
7
1
.30 (d, J = 8.0, 2H), 7.19 (d, J = 8.0, 2H), 3.90−3.81 (m, 1H), 3.52−3.39 (m, 1H), 3.28 (dd, J = 17.2,
13
1
0.8 Hz, 1H), 2.98 (dd, J = 17.2, 10.4 Hz, 1H), 2.63−2.51 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H); C{ H}
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NMR (150 MHz, CDCl
3
) δ 157.6, 144.7, 141.4, 130.8, 129.7, 129.4, 128.4, 127.5, 126.9, 125.6 (q, J
19
= 275.7 Hz), 56.7 (q, J = 2.9 Hz), 40.1 (q, J = 27.2 Hz), 40.0, 21.6, 21.5; F NMR (376 MHz,
+
CDCl
found 419.1021.
ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5d): 90 mg, 73%
3
) δ ꢀ64.56 (t, J = 10.9 Hz); HRMS (ESI): calcd for C19
H
19
F
3
N
2
O
2
SNa [M + Na] 419.1012,
3
o
1
yield, white solid, mp 191−193 C; H NMR (600 MHz, CDCl
) δ 7.79 (d, J = 8.4, 2H), 7.60 (d, J =
.4, 2H), 7.30 (d, J = 8.4, 2H), 6.89 (d, J = 8.4, 2H), 3.88−3.84 (m, 1H), 3.83 (s, 3H), 3.49−3.40 (m,
H), 3.26 (dd, J = 17.4, 10.8 Hz, 1H), 2.98 (dd, J = 17.4, 10.8 Hz, 1H), 2.59−2.50 (m, 1H), 2.40 (s,
3
8
1
3
13
1
3
H); C{ H} NMR (150 MHz, CDCl ) δ 161.7, 157.3, 144.7, 130.8, 129.6, 128.9, 128.6, 125.6 (q, J
19
=
275.6 Hz), 122.8, 114.1, 56.7 (q, J = 3.0 Hz), 55.4, 40.1 (q, J = 27.2 Hz), 40.0, 21.6; F NMR
+
3 19 3 2 3
(376 MHz, CDCl ) δ ꢀ64.56 (t, J = 10.9 Hz); HRMS (ESI): calcd for C19H F N O SNa [M + Na]
435.0961, found 435.0968.
3ꢀ(2ꢀChlorophenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5e): 70 mg, 56%
o
1
yield, white solid, mp 125−127 C; H NMR (600 MHz, CDCl
) δ 7.82 (d, J = 8.4, 2H), 7.56−7.54
3
(m, 1H), 7.38−7.32 (m, 4H), 7.29−7.26 (m, 1H), 3.94−3.88 (m, 1H), 3.51−3.45 (m, 1H), 3.42 (dd, J
1
3
1
=
18.0, 10.2 Hz, 1H), 3.01 (dd, J = 17.4, 10.8 Hz, 1H), 2.64−2.57 (m, 1H), 2.44 (s, 3H); C{ H}
NMR (150 MHz, CDCl
3
) δ 157.8, 145.0, 132.8, 131.3, 130.8, 130.6, 130.4, 129.7, 129.6, 129.0,
19
126.9, 125.5 (q, J = 275.4 Hz), 57.4 (q, J = 3.0 Hz), 43.0, 39.9 (q, J = 27.5 Hz), 21.6; F NMR (376
+
3 3 2 2
MHz, CDCl ) δ ꢀ64.60 (t, J = 10.9 Hz); HRMS (ESI): calcd for C18H16ClF N O SNa [M + Na]
439.0465, found 439.0470.
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3
ꢀ(3ꢀChlorophenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5f): 92 mg, 74%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o
1
yield, white solid, mp 165−166 C; H NMR (600 MHz, CDCl
) δ 7.79 (d, J = 8.4, 2H), 7.64 (t, J =
.8 Hz, 1H), 7.52−7.50 (m, 1H), 7.40−7.38 (m, 1H), 7.33−7.31 (m, 3H), 3.95−3.89 (m, 1H),
.50−3.41 (m, 1H), 3.28 (dd, J = 17.4, 10.8 Hz, 1H), 3.01 (dd, J = 17.4, 10.8 Hz, 1H), 2.60−2.54 (m,
3
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
3
H), 2.41 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ 156.3, 145.0, 134.9, 132.0, 130.8, 130.7,
130.0, 129.8, 128.8, 126.8, 125.5 (q, J = 275.6 Hz), 125.0, 56.9 (q, J = 3.0 Hz), 40.0 (q, J = 27.5 Hz),
19
3
9.8, 21.6; F NMR (376 MHz, CDCl
3
) δ ꢀ64.53 (t, J = 10.9 Hz); HRMS (ESI): calcd for
+
C
18
H
16ClF
3
N
2
O
2
SNa [M + Na] 439.0465, found 439.0469.
3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5g): 94 mg, 75%
o
1
yield, white solid, mp 136−138 C; H NMR (600 MHz, CDCl
) δ 7.79 (d, J = 8.4, 2H), 7.59 (d, J =
3
8
.4, 2H), 7.36 (d, J = 8.4, 2H), 7.32 (d, J = 7.8, 2H), 3.93−3.87 (m, 1H), 3.50−3.42 (m, 1H), 3.28 (dd,
13
1
J = 16.8, 10.8 Hz, 1H), 2.98 (dd, J = 16.8, 10.8 Hz, 1H), 2.61−2.52 (m, 1H), 2.40 (s, 3H); C{ H}
NMR (150 MHz, CDCl ) δ 156.5, 144.9, 137.0, 130.8, 129.7, 129.0, 128.9, 128.7, 128.1, 125.5 (q, J
3
1
9
=
272.6 Hz), 57.0 (q, J = 3.0 Hz), 40.0 (q, J = 27.5 Hz), 39.8, 21.6; F NMR (376 MHz, CDCl ) δ
3
+
3 2 2
ꢀ64.56 (t, J = 10.5 Hz); HRMS (ESI): calcd for C18H16ClF N O SNa [M + Na] 439.0465, found
4
39.0468.
3ꢀ(4ꢀFluorophenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5h): 76 mg, 63%
o
1
yield, white solid, mp 206−207 C; H NMR (600 MHz, CDCl
) δ 7.79 (d, J = 8.4, 2H), 7.67−7.63
3
(
m, 2H), 7.32 (d, J = 8.4, 2H), 7.09−7.05 (m, 2H), 3.93−3.87 (m, 1H), 3.50−3.41 (m, 1H), 3.28 (dd,
13
1
J = 17.4, 10.8 Hz, 1H), 2.99 (dd, J = 17.4, 10.8 Hz, 1H), 2.61−2.51 (m, 1H), 2.40 (s, 3H); C{ H}
NMR (150 MHz, CDCl ) δ 165.8 (d, J = 250.7), 156.5, 144.9, 130.8, 129.7, 128.9 (d, J = 8.7), 128.8,
26.5 (d, J = 3.0 Hz), 125.6 (q, J = 275.4 Hz), 115.9 (d, J = 21.9), 56.9 (q, J = 3.3 Hz), 40.0 (q, J =
3
1
2
1
9
3
7.3 Hz), 39.9, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.55 (t, J = 10.5 Hz), ꢀ108.77; HRMS (ESI):
+
calcd for C H F N O SNa [M + Na] 423.0761, found 423.0763.
18
16
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3
ꢀ(4ꢀBromophenyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5i): 105 mg, 76%
1
2
3
4
5
6
7
8
9
o
1
yield, white solid, mp 197−198 C; H NMR (600 MHz, CDCl
) δ 7.79 (d, J = 7.8, 2H), 7.52 (s, 4H),
3
7
.32 (d, J = 7.8, 2H), 3.93−3.88 (m, 1H), 3.50−3.42 (m, 1H), 3.28 (dd, J = 17.4, 10.8 Hz, 1H), 2.98
1
3
1
(
dd, J = 17.4, 10.8 Hz, 1H), 2.61−2.51 (m, 1H), 2.40 (s, 3H); C{ H} NMR (150 MHz, CDCl ) δ
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
56.6, 144.9, 132.0, 130.8, 129.7, 129.1, 128.9, 128.3, 125.5 (q, J = 275.7 Hz), 125.4, 57.0 (q, J =
1
9
3
2.0 Hz), 40.0 (q, J = 27.5 Hz), 39.8, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.55 (t, J = 10.5 Hz);
+
HRMS (ESI): calcd for C18
H16BrF
3
N
2
O
2
SNa [M + Na] 482.9960, found 482.9967.
1ꢀTosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5j): 97
o
1
mg, 72% yield, white solid, mp 152−154 C; H NMR (600 MHz, CDCl ) δ 7.80 (d, J = 7.8 Hz, 2H),
3
7
3
1
1
5
.77 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 3.98−3.93 (m, 1H),
.52−3.44 (m, 1H), 3.33 (dd, J = 16.8, 10.8 Hz, 1H), 3.02 (dd, J = 16.8, 10.2 Hz, 1H), 2.63−2.54 (m,
13
1
H), 2.41 (s, 3H); C{ H} NMR (150 MHz, CDCl
3
) δ 156.1, 145.1, 133.5, 132.5 (q, J = 32.7 Hz),
30.8, 129.8, 128.8, 127.1, 125.7 (q, J = 3.6 Hz), 125.5 (q, J = 275.1 Hz), 123.7 (q, J = 271.0 Hz),
19
7.1 (q, J = 3.2 Hz), 40.0 (q, J = 27.5 Hz), 39.8, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ63.39, ꢀ64.54
3
+
(t, J = 10.5 Hz); HRMS (ESI): calcd for C19
H
16
F N
6 2
O
2
SNa [M + Na] 473.0729, found 473.0735.
3ꢀ(Thiophenꢀ2ꢀyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5k): 54 mg, 46%
o
1
yield, white solid, mp 124−125 C; H NMR (600 MHz, CDCl
) δ 7.78 (d, J = 7.8 Hz, 2H),
.44−7.43 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.18−7.17 (m, 1H), 7.03−7.02 (m, 1H), 3.90−3.84 (m,
H), 3.47−3.39 (m, 1H), 3.26 (dd, J = 17.4, 10.8 Hz, 1H), 3.01 (dd, J = 16.8, 10.8 Hz, 1H),
3
7
1
2
1
2
1
3
1
.60−2.51 (m, 1H), 2.40 (s, 3H); C{ H} NMR (150 MHz, CDCl
) δ 153.1, 144.8, 133.6, 130.6,
3
29.7, 129.6, 129.4, 129.0, 127.5, 125.5 (q, J = 275.6 Hz), 56.9 (q, J = 3.2 Hz), 40.6, 39.9 (q, J =
1
9
3
7.5 Hz), 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.57 (t, J = 10.5 Hz); HRMS (ESI): calcd for
+
C
16
H
15
F
3
N
2
O
2
S
2
Na [M + Na] 411.0419, found 411.0434.
tertꢀButyl
3ꢀ(1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ1Hꢀindoleꢀ1ꢀ
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o
1
carboxylate (5l): 117 mg, 75% yield, white solid, mp 165−167 C; H NMR (600 MHz, CDCl
.34 (d, J = 7.2 Hz, 1H), 8.12 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.66 (s, 1H), 7.43−7.38
m, 2H), 7.26 (d, J = 6.6 Hz, 2H), 3.89−3.83 (m, 1H), 3.53−3.45 (m, 1H), 3.30 (dd, J = 16.8, 10.8 Hz,
3
) δ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
(
1
3
1
1
H), 3.04 (dd, J = 16.8, 10.8 Hz, 1H), 2.62−2.52 (m, 1H), 2.36 (s, 3H), 1.67 (s, 9H); C{ H} NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(150 MHz, CDCl
3
) δ 153.1, 149.0, 144.7, 135.7, 130.7, 129.7, 128.9, 127.8, 126.9, 125.7, 125.6 (q, J
= 275.7 Hz), 124.1, 122.9, 115.1, 112.8, 85.0, 55.9 (q, J = 3.3 Hz), 40.7, 40.0 (q, J = 27.2 Hz), 28.1,
19
2
1.6; F NMR (376 MHz, CDCl
3
) δ ꢀ64.54 (t, J = 10.5 Hz); HRMS (ESI): calcd for
+
C
25
H
26
F
3
N
3
O
4
SNa [M + Na] 544.1488, found 544.1490.
3
ꢀ(tertꢀButyl)ꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5m): 96 mg, 88% yield,
o
1
white solid, mp 119−120 C; H NMR (600 MHz, CDCl
) δ 7.73 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4
3
Hz, 2H), 3.66−3.61 (m, 1H), 3.37−3.28 (m, 1H), 2.82 (dd, J = 17.4, 10.2 Hz, 1H), 2.56 (dd, J = 17.4,
1
3
1
1
1
3
0.8 Hz, 1H), 2.49−2.44 (m, 1H), 2.43 (s, 3H), 1.06 (s, 9H); C{ H} NMR (150 MHz, CDCl
3
) δ
69.8, 144.6, 130.3, 129.3, 129.1, 125.6 (q, J = 275.4 Hz), 56.8 (q, J = 3.0 Hz), 40.0 (q, J = 27.3 Hz),
19
9.0, 34.2, 27.7, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.69 (t, J = 10.9 Hz); HRMS (ESI): calcd for
3
+
C
16
H
21
F
3
N
2
O
2
SNa [M + Na] 385.1171, found 385.1168.
3
ꢀCyclohexylꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5n): 69 mg, 59% yield,
o
1
white solid, mp 144−145 C; H NMR (600 MHz, CDCl
) δ 7.73 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4
3
Hz, 2H), 3.67−3.61 (m, 1H), 3.37−3.29 (m, 1H), 2.78 (dd, J = 17.4, 10.2 Hz, 1H), 2.57 (dd, J = 17.4,
1
0.2 Hz, 1H), 2.48−2.39 (m, 4H), 2.28−2.24 (m, 1H), 1.75−1.65 (m, 5H), 1.30−1.13 (m, 5H);
1
3
1
C{ H} NMR (150 MHz, CDCl
3
) δ 166.6, 144.6, 130.5, 129.4, 129.0, 125.6 (q, J = 275.6 Hz), 56.0
19
(
q, J = 3.0 Hz), 40.5, 40.0 (q, J = 27.3 Hz), 39.1, 30.2, 29.8, 25.7, 25.6, 25.5, 21.6; F NMR (376
+
MHz, CDCl
3 23 3 2 2
) δ ꢀ64.69 (t, J = 10.5 Hz); HRMS (ESI): calcd for C18H F N O SNa [M + Na]
411.1325, found 411.1332.
3ꢀIsopropylꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5o): 72 mg, 69% yield,
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o
1
white solid, mp 118−119 C; H NMR (600 MHz, CDCl
3
) δ 7.73 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4
1
2
3
4
5
6
7
8
9
Hz, 2H), 3.69−3.63 (m, 1H), 3.38−3.29 (m, 1H), 2.79 (dd, J = 17.4, 10.2 Hz, 1H), 2.60−2.54 (m, 2H),
13
1
2
.50−2.40 (m, 4H), 1.05 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H); C{ H} NMR (150 MHz,
CDCl ) δ 167.4, 144.6, 130.5, 129.4, 129.0, 125.6 (q, J = 275.4 Hz), 56.3 (q, J = 3.0 Hz), 40.1, 40.0
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
9
(
3
q, J = 27.3 Hz), 29.7, 21.6, 19.9, 19.5; F NMR (376 MHz, CDCl ) δ ꢀ64.71 (t, J = 10.9 Hz);
+
HRMS (ESI): calcd for C15
H
19
F
3
N
2
O
2
SNa [M + Na] 371.1012, found 371.1009.
3
ꢀPhenethylꢀ1ꢀtosylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (5p): 75 mg, 61% yield,
o
1
white solid, mp 64−66 C; H NMR (400 MHz, CDCl
) δ 7.72 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4
3
Hz, 2H), 7.26−7.20 (m, 3H), 7.05 (d, J = 7.2 Hz, 2H), 3.72−3.63 (m, 1H), 3.39−3.26 (m, 1H),
2
3
1
.90−2.81 (m, 1H), 2.76 (dd, J = 14.0, 7.6 Hz, 1H), 2.69 (dd, J = 17.6, 10.4, Hz, 1H), 2.62−2.49 (m,
1
3
1
H), 2.45 (s, 3H), 2.43−2.34 (m, 1H); C{ H} NMR (150 MHz, CDCl
3
) δ 162.2, 144.7, 140.1,
30.7, 129.6, 128.9, 128.5, 128.1, 126.4, 125.5 (q, J = 275.3 Hz), 56.1 (q, J = 3.2 Hz), 42.7, 39.9 (q,
19
3
J = 27.2 Hz), 32.4, 31.5, 21.6; F NMR (376 MHz, CDCl ) δ ꢀ64.70 (t, J = 10.5 Hz); HRMS (ESI):
+
calcd for C H F N O SNa [M + Na] 433.1168, found 433.1175.
20
21
3
2
2
Benzyl 3ꢀphenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5aa): 74 mg,
o
1
6
8% yield, white solid, mp 119−120 C; H NMR (400 MHz, CDCl
3
) δ 7.76−7.73 (m, 2H),
7.47−7.32 (m, 8H), 5.37−5.29 (m, 2H), 4.75−4.67 (m, 1H), 3.52 (dd, J = 18.0, 11.2 Hz, 1H), 3.18
13
1
(
dd, J = 17.6, 5.6 Hz, 1H), 3.04 (br, 1H), 2.41−2.24 (m, 1H); C{ H} NMR (150 MHz, CDCl
3
) δ
1
5
54.3, 152.7, 135.9, 130.8, 130.5, 128.6, 128.5, 128.3, 128.2, 126.7, 125.6 (q, J = 275.9 Hz), 67.8,
19
3 17 3 2 2
3.0, 38.4, 37.5; F NMR (376 MHz, CDCl ) δ ꢀ63.71; HRMS (ESI): calcd for C19H F N O Na [M
+
+
Na] 385.1134, found 385.1141.
Benzyl 3ꢀ(mꢀtolyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ab): 62 mg,
o
1
5
5% yield, white solid, mp 140−141 C; H NMR (600 MHz, CDCl
3
) δ 7.60 (s, 1H), 7.50 (d, J = 7.8
Hz, 1H), 7.46 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.35−7.32 (m, 1H), 7.29 (t, J = 7.8 Hz,
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1
1
H), 7.23 (d, J = 7.8 Hz, 1H), 5.36−5.30 (m, 2H), 4.72−4.67 (m, 1H), 3.50 (dd, J = 17.4, 11.4 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
H), 3.17 (dd, J = 18.0, 5.4 Hz, 1H), 3.03 (br, 1H), 2.38 (s, 3H), 2.35−2.28 (m, 1H); C{ H} NMR
(150 MHz, CDCl
3
) δ 154.5, 152.7, 138.4, 136.0, 131.3, 130.7, 128.6, 128.5, 128.3, 128.2, 127.2,
19
125.6 (q, J = 275.4 Hz), 124.0, 67.9. 53.0, 38.5, 37.5, 21.2; F NMR (376 MHz, CDCl ) δ ꢀ68.45;
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESI): calcd for C20
H
19
F
3
N
2
O
2
Na [M + Na] 399.1291, found 399.1293.
Benzyl 3ꢀ(pꢀtolyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ac): 70 mg,
o
1
6
2% yield, white solid, mp 158−159 C; H NMR (600 MHz, CDCl
3
) δ 7.63 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.35−7.32 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H),
5
1
1
3
.36ꢀ5.30 (m, 2H), 4.71ꢀ4.66 (m, 1H), 3.48 (dd, J = 17.4, 10.8 Hz, 1H), 3.15 (dd, J = 17.4, 5.4 Hz,
13
1
H), 3.04 (br, 1H), 2.38 (s, 3H), 2.35−2.25 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 154.4,
3
52.7, 140.8, 136.0, 129.3, 128.5, 128.3, 128.2, 128.1, 126.7, 125.6 (q, J = 275.9 Hz), 67.8, 53.0,
19
3 19 3 2 2
8.4, 37.5, 21.4; F NMR (376 MHz, CDCl ) δ −68.47; HRMS (ESI): calcd for C20H F N O Na
+
[
M + Na] 399.1291, found 399.1294.
Benzyl 3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ad):
o
1
67 mg, 57% yield, white solid, mp 151−152 C; H NMR (400 MHz, CDCl
H), 7.45 (d, J = 7.6 Hz, 2H), 7.40−7.33 (m, 3H), 6.91 (d, J = 8.4 Hz, 2H), 5.36ꢀ5.29 (m, 2H),
4.71ꢀ4.65 (m, 1H), 3.84 (s, 3H), 3.49 (dd, J = 17.6, 11.2 Hz, 1H), 3.14 (dd, J = 18.0, 5.6 Hz, 1H),
) δ 7.69 (d, J = 8.4 Hz,
3
2
13
1
3
1
.04 (br, 1H), 2.37−2.23 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 161.5, 154.1, 152.4, 136.0,
3
19
28.5, 128.4, 128.3, 128.2, 128.1, 125.6 (q, J = 275.9 Hz), 123.4, 67.8, 55.4, 52.9, 38.5, 37.4; F
+
NMR (376 MHz, CDCl
3
) δ ꢀ63.72; HRMS (ESI): calcd for C20
H
20
F
3
2
N O
3
[M + H] 393.1421, found
3
93.1417.
Benzyl 3ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ae):
o
1
4 mg, 63% yield, white solid, mp 135−136 C; H NMR (600 MHz, CDCl
7 ) δ 7.45 (d, J = 7.2 Hz,
3
2H), 7.39−7.36 (m, 2H), 7.34−7.30 (m, 3H), 7.26−7.25 (m, 1H), 6.98−6.96 (m, 1H), 5.35−5.30 (m,
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2
1
1
5
+
H), 4.72−4.67 (m, 1H), 3.84 (s, 3H), 3.50 (dd, J = 17.4, 11.4 Hz, 1H), 3.16 (dd, J = 17.4, 5.4 Hz,
1
2
3
4
5
6
7
8
9
13
1
H), 3.02 (br, 1H), 2.35−2.26 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 159.7, 154.3, 152.5,
3
35.9, 132.1, 129.7, 128.6, 128.3, 128.2, 125.6 (q, J = 275.7 Hz), 119.4, 116.8, 111.5, 67.9, 55.4,
19
3.0, 38.5, 37.4; F NMR (376 MHz, CDCl ) δ ꢀ63.72; HRMS (ESI): calcd for C H F N O Na [M
3
20 19
3
2
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
Na] 415.1240, found 415.1236.
Benzyl 3ꢀ(3ꢀchlorophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5af):
o
1
6
0 mg, 50% yield, white solid, mp 120−121 C; H NMR (600 MHz, CDCl
3
) δ 7.74 (s, 1H), 7.60 (d,
J = 7.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.40−7.38 (m, 3H), 7.35−7.33 (m, 2H), 5.36−5.30 (m, 2H),
4
2
1
.74−4.69 (m, 1H), 3.49 (dd, J = 18.0, 11.4 Hz, 1H), 3.14 (dd, J = 18.0, 5.4 Hz, 1H), 3.03 (br, 1H),
1
3
1
.37−2.28 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 152.9, 152.6, 135.8, 134.8, 132.6, 130.4,
3
1
9
29.9, 128.6, 128.4, 128.3, 126.7, 125.5 (q, J = 275.9 Hz), 124.8, 68.0, 53.3, 38.3, 37.4; F NMR
+
(376 MHz, CDCl
3
) δ ꢀ68.45; HRMS (ESI): calcd for C19
H16ClF
3
N
2
O
2
Na [M + Na] 419.0745, found
419.0749.
Benzyl 3ꢀ(4ꢀchlorophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ag):
o
1
69 mg, 58% yield, white solid, mp 136−137 C; H NMR (400 MHz, CDCl
) δ 7.67 (d, J = 8.8 Hz,
3
2H), 7.45 (d, J = 6.8 Hz, 2H), 7.41−7.32 (m, 5H), 5.36−5.29 (m, 2H), 4.75−4.67 (m, 1H), 3.49 (dd, J
13
1
= 18.0, 11.2 Hz, 1H), 3.15 (dd, J = 18.0, 5.6 Hz, 1H), 3.03 (br, 1H), 2.39−2.25 (m, 1H); C{ H}
NMR (150 MHz, CDCl ) δ 153.2, 152.5, 136.5, 135.9, 129.4, 129.0, 128.6, 128.4, 128.3, 128.0,
3
19
125.6 (q, J = 276.0 Hz), 68.0, 53.2, 38.4, 37.5; F NMR (376 MHz, CDCl ) δ ꢀ68.47; HRMS (ESI):
3
+
3 2 2
calcd for C19H16ClF N O Na [M + Na] 419.0745, found 419.0748.
Benzyl 3ꢀ(3ꢀfluorophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ah):
o
1
4
0 mg, 35% yield, white solid, mp 114−115 C; H NMR (600 MHz, CDCl
) δ 7.49−7.45 (m, 4H),
3
7
.40−7.33 (m, 4H), 7.13−7.10 (m, 1H), 5.35ꢀ5.30 (m, 2H), 4.75−4.70 (m, 1H), 3.50 (dd, J = 17.4,
13
1
10.8 Hz, 1H), 3.15 (dd, J = 18.0, 5.4 Hz, 1H), 3.04 (br, 1H), 2.37−2.28 (m, 1H); C{ H} NMR (150
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MHz, CDCl
3
) δ 162.8 (d, J = 245.4 Hz), 153.1, 152.6, 135.8, 133.0 (d, J = 8.1 Hz), 130.3 (d, J = 8.1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz), 128.6, 128.4, 128.3, 125.5 (q, J = 275.9 Hz), 122.5 (d, J = 3.0 Hz), 117.4 (d, J = 21.3 Hz), 113.5
19
3
(d, J = 23.1 Hz), 68.0, 53.2, 38.3, 37.4; F NMR (376 MHz, CDCl ) δ ꢀ63.72, ꢀ112.59; HRMS (ESI):
+
calcd for C H F N O Na [M + Na] 403.1040, found 403.1048.
19
16
4
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Benzyl 3ꢀ(thiophenꢀ2ꢀyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ai): 64
o
1
mg, 58% yield, white solid, mp 124−125 C; H NMR (400 MHz, CDCl
.40−7.31 (m, 3H), 7.26 (d, J = 3.2 Hz, 1H), 7.07−7.05 (m, 1H), 5.35−5.27 (m, 2H), 4.73−4.65 (m,
1H), 3.52 (dd, J = 17.6, 11.2 Hz, 1H), 3.17 (dd, J = 17.6, 5.6 Hz, 1H), 3.02 (br, 1H), 2.38−2.24 (m,
3
) δ 7.45−7.42 (m, 3H),
7
13
1
1
1
H); C{ H} NMR (150 MHz, CDCl ) δ 152.5, 149.9, 135.9, 134.3, 129.0, 128.8, 128.5, 128.3,
3
1
9
3
28.2, 127.5, 125.5 (q, J = 275.9 Hz), 67.9, 53.1, 39.2, 37.3; F NMR (376 MHz, CDCl ) δ ꢀ63.73;
+
HRMS (ESI): calcd for C17
H
15
F
3
N
2
O
2
SNa [M + Na] 391.0699, found 391.0708.
Methyl 3ꢀphenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5aj): 52 mg,
o
1
6
1% yield, white solid, mp 122−123 C; H NMR (600 MHz, CDCl
3
) δ 7.74 (d, J = 7.8 Hz, 2H),
7.44−7.39 (m, 3H), 4.72−4.67 (m, 1H), 3.90 (s, 3H), 3.53 (dd, J = 18.0, 11.4 Hz, 1H), 3.01 (dd, J =
13
1
18.0, 5.4 Hz, 1H), 3.08 (br, 1H), 2.37−2.28 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 154.4,
3
19
153.3, 130.7, 130.5, 128.7, 126.7, 125.6 (q, J = 275.7 Hz), 53.4, 53.0 (q, J = 2.9 Hz), 38.3, 37.3; F
3 13 3 2 2
NMR (376 MHz, CDCl ) δ ꢀ63.68 (t, J = 10.9 Hz); HRMS (ESI): calcd for C13H F N O Na [M +
+
Na] 309.0821, found 309.0811.
Methyl 3ꢀ(pꢀtolyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ak): 50 mg,
o
1
5
5% yield, white solid, mp 147−149 C; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 8.4 Hz, 2H),
7.21 (d, J = 8.0 Hz, 2H), 4.72−4.64 (m, 1H), 3.90 (s, 3H), 3.51 (dd, J = 17.6, 11.2 Hz, 1H), 3.16 (dd,
13
1
J = 18.0, 5.6 Hz, 1H), 3.08 (br, 1H), 2.38 (s, 3H), 2.36−2.67 (m, 1H); C{ H} NMR (150 MHz,
CDCl ) δ 154.5, 153.3, 140.9, 129.4, 127.9, 125.7, 125.6 (q, J = 275.9 Hz), 53.4, 52.9 (q, J = 3.3 Hz),
3
19
38.4, 37.4, 21.4; F NMR (376 MHz, CDCl ) δ ꢀ68.88 (t, J = 10.5 Hz); HRMS (ESI): calcd for
3
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The Journal of Organic Chemistry
+
C
14
H
15
F
3
N
2
O
2
Na [M + Na] 323.0978, found 323.0978.
1
2
3
4
5
6
7
8
9
Methyl 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5al):
o
1
6
1 mg, 56% yield, white solid, mp 112−113 C; H NMR (400 MHz, CDCl
3
) δ 7.61 (d, J = 8.8 Hz,
2
H), 7.54 (d, J = 8.4 Hz, 2H), 4.74−4.67 (m, 1H), 3.90 (s, 3H), 3.51 (dd, J = 18.0, 11.2 Hz, 1H), 3.16
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(
dd, J = 18.0, 5.6 Hz, 1H), 3.08 (br, 1H), 2.40−2.26 (m, 1H); C{ H} NMR (150 MHz, CDCl
3
) δ
153.3, 153.2, 131.9, 129.7, 128.1, 125.6 (q, J = 275.9 Hz), 124.9, 53.5, 53.0 (q, J = 3.2 Hz), 38.2,
19
3
7.4; F NMR (376 MHz, CDCl
3
) δ ꢀ63.67 (t, J = 10.5 Hz); HRMS (ESI): calcd for
+
C
13
H12BrF
3
N
2
O
2
Na [M + Na] 386.9926, found 386.9917.
Methyl 3ꢀ(tertꢀbutyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5am): 36
1
mg, 45% yield, colorless oil; H NMR (400 MHz, CDCl
3
) δ 4.55−4.48 (m, 1H), 3.83 (s, 3H), 3.11
(
dd, J = 18.0, 11.2 Hz, 1H), 2.95 (br, 1H), 2.78 (dd, J = 18.0, 5.2 Hz, 1H), 2.28−2.14 (m, 1H), 1.21 (s,
13
1
9
3
H); C{ H} NMR (150 MHz, CDCl ) δ 166.0, 153.4, 125.6 (q, J = 275.9 Hz), 53.3, 52.6 (q, J =
19
2
3
.9 Hz), 37.3, 37.0 (q, J = 23.1 Hz), 34.0, 27.9; F NMR (376 MHz, CDCl ) δ ꢀ63.66 (t, J = 10.5
+
Hz); HRMS (ESI): calcd for C H F N O Na [M + Na] 289.1134, found 289.1128.
11
17
3
2
2
tertꢀButyl 3ꢀphenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5an): 66 mg,
o
1
6
7% yield, white solid, mp 113−114 C; H NMR (400 MHz, CDCl
3
) δ 7.74 (d, J = 3.6 Hz, 2H),
7.41−7.39 (m, 3H), 4.68−4.62 (m, 1H), 3.51 (dd, J = 18.0, 11.6 Hz, 1H), 3.14 (dd, J = 18.0, 5.2 Hz,
13
1
1
1
H), 2.97 (br, 1H), 2.37−2.24 (m, 1H), 1.58 (s, 9H); C{ H} NMR (150 MHz, CDCl
) δ 153.3,
3
51.7, 131.1, 130.2, 128.6, 126.6, 125.7 (q, J = 272.4 Hz), 82.1, 52.8 (q, J = 3.0 Hz), 38.6, 38.0, 28.3;
1
9
+
F NMR (376 MHz, CDCl
3 19 3 2 2
) δ ꢀ68.75; HRMS (ESI): calcd for C16H F N O Na [M + Na]
351.1291, found 351.1297.
tertꢀButyl 3ꢀ(pꢀtolyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate (5ao): 60 mg,
o
1
5
8% yield, white solid, mp 117−118 C; H NMR (400 MHz, CDCl
3
) δ 7.63 (d, J = 7.6 Hz, 2H), 7.63
(d, J = 7.6 Hz, 2H), 4.65−4.60 (m, 1H), 3.48 (dd, J = 17.6, 11.2 Hz, 1H), 3.12 (dd, J = 17.6, 5.6 Hz,
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1
3
1
1
H), 2.95 (br, 1H), 2.37 (s, 3H), 2.33−2.22 (m, 1H), 1.57 (s, 9H); C{ H} NMR (100 MHz, CDCl
3
)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
δ 153.3, 151.6, 140.5, 129.8, 128.3, 126.6, 125.7 (q, J = 275.8 Hz), 82.0, 52.7 (q, J = 2.5 Hz), 38.7,
19
3
3 21 3 2 2
7.8, 28.3, 21.4; F NMR (376 MHz, CDCl ) δ ꢀ64.01; HRMS (ESI): calcd for C17H F N O Na [M
+
+
Na] 365.1447, found 365.1449.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tertꢀButyl
(5ap): 67 mg, 55% yield, white solid, mp 125−127 C; H NMR (400 MHz, CDCl
.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 4.68−4.61 (m, 1H), 3.48 (dd, J = 17.6, 11.2 Hz, 1H), 3.11 (dd,
3ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate
o
1
3
) δ 7.60 (d, J =
8
13
1
J = 17.6, 5.6 Hz, 1H), 2.96 (br, 1H), 2.38−2.24 (m, 1H), 1.57 (s, 9H); C{ H} NMR (150 MHz,
CDCl ) δ 152.2, 151.4, 131.8, 130.1, 128.1, 125.6 (q, J = 275.9 Hz), 124.6, 82.3, 53.0 (q, J = 3.3 Hz),
3
19
3
3 3 2 2
8.5, 38.0, 28.3; F NMR (376 MHz, CDCl ) δ ꢀ63.99; HRMS (ESI): calcd for C16H18BrF N O Na
+
[
M + Na] 429.0396, found 429.0408.
tertꢀButyl
5aq): 65 mg, 53% yield, white solid, mp 110−111 C; H NMR (400 MHz, CDCl
) δ 7.67 (d, J = 8.8
3
3ꢀ(4ꢀchlorophenyl)ꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ1ꢀcarboxylate
o
1
(
Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 4.69−4.61 (m, 1H), 3.48 (dd, J = 17.6, 11.2 Hz, 1H), 3.11 (dd, J =
1
3
1
17.6, 5.2 Hz, 1H), 2.97 (br, 1H), 2.38−2.24 (m, 1H), 1.57 (s, 9H); C{ H} NMR (150 MHz, CDCl
)
3
δ 152.1, 136.2, 129.6, 128.9, 127.9, 125.6 (q, J = 275.9 Hz), 82.3, 53.0 (q, J = 3.2 Hz), 38.5, 38.0,
19
+
28.3; F NMR (376 MHz, CDCl
85.0901, found 385.0902.
ꢀ(3ꢀPhenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazolꢀ1ꢀyl)ethanꢀ1ꢀone (5ar): 22 mg, 27%
3 3 2 2
) δ ꢀ63.97; HRMS (ESI): calcd for C16H18ClF N O Na [M + Na]
3
1
o
1
yield, white solid, mp 120−121 C; H NMR (600 MHz, CDCl
) δ 7.73 (d, J = 8.4 Hz, 2H),
3
7
1
1
.46−7.42 (m, 3H), 4.86−4.81 (m, 1H), 3.49 (dd, J = 18.0, 11.4 Hz, 1H), 3.20 (dd, J = 18.0, 5.4 Hz,
1
3
1
H), 3.17−3.11 (m, 1H), 2.39 (s, 3H), 2.33−2.24 (m, 1H); C{ H} NMR (150 MHz, CDCl
) δ 169.5,
3
54.3, 131.0, 130.6, 128.8, 126.5, 125.7 (q, J = 275.7 Hz), 51.6 (q, J = 3.2 Hz), 38.0, 36.4 (q, J =
1
9
26.9 Hz), 22.1; F NMR (376 MHz, CDCl ) δ ꢀ68.20 (t, J = 10.9 Hz); HRMS (ESI): calcd for
3
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The Journal of Organic Chemistry
+
C
13
H
13
F
3
N
2
ONa [M + Na] 293.0872, found 293.0881.
1
2
3
4
5
6
7
8
9
2
ꢀMethylꢀ1ꢀ(3ꢀphenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ4,5ꢀdihydroꢀ1Hꢀpyrazolꢀ1ꢀyl)propanꢀ1ꢀone
(5as):
o
1
3
7
3
0 mg, 34% yield, white solid, mp 86−87 C; H NMR (600 MHz, CDCl
3
) δ 7.74−7.72 (m, 2H),
.46−7.41 (m, 3H), 4.85−4.80 (m, 1H), 3.50−3.42 (m, 2H), 3.18 (dd, J = 18.0, 5.4 Hz, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
.15−3.06 (m, 1H), 2.33−2.24 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H); C{ H}
NMR (150 MHz, CDCl
3
) δ 176.0, 154.0, 131.1, 130.4, 128.7, 126.5, 125.8 (q, J = 275.9 Hz), 51.7 (q,
19
J = 3.0 Hz), 37.7, 36.4 (q, J = 26.9 Hz), 32.0, 18.9, 18.6; F NMR (376 MHz, CDCl
3
) δ ꢀ63.54 (t, J
+
= 10.9 Hz); HRMS (ESI): calcd for C15
H
18
F
3
N
2
O [M + H] 299.1366, found 299.1366.
5ꢀ(Chloromethyl)ꢀ3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (6a): 24 mg, 23% yield (Table 1,
o
1
Entry 1), white solid, mp 126−127 C; H NMR (600 MHz, CDCl
) δ 7.80 (d, J = 8.4 Hz, 2H), 7.67
3
(d, J = 7.2 Hz, 2H), 7.43−7.37 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H), 4.19−4.12 (m, 2H), 3.80−3.77 (m,
13
1
1H), 3.24 (dd, J = 17.4, 10.8 Hz, 1H), 3.17 (dd, J = 17.4, 8.4 Hz, 1H), 2.39 (s, 3H); C{ H} NMR
(
150 MHz, CDCl
3
) δ 157.5, 144.6, 131.9, 130.8, 130.4, 129.6, 128.6, 128.5, 126.9, 61.9, 46.6, 38.6,
+
21.6; HRMS (ESI): calcd for C H ClN O SNa [M + Na] 371.0591, found 371.0599.
17
17
2
2
5ꢀ(Iodomethyl)ꢀ3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (6b): 58 mg, 44% yield, white solid,
o
1
mp 141−142 C; H NMR (400 MHz, CDCl
3
) δ 7.80 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 6.8 Hz, 2H),
7.44−7.36 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 4.08−4.00 (m, 1H), 3.83 (dd, J = 10.0, 3.2 Hz, 1H),
3
3
1
4
.45 (t, J = 10.0 Hz, 1H), 3.32 (dd, J = 17.2, 10.8 Hz, 1H), 3.00 (dd, J = 17.6, 9.2 Hz, 1H), 2.39 (s,
1
3
1
H); C{ H} NMR (100 MHz, CDCl ) δ 156.6, 144.6, 131.9, 130.8, 130.4, 129.7, 128.6, 128.5,
3
+
26.9, 62.2, 41.6, 21.6, 9.8; HRMS (ESI): calcd for C17
62.9947.
H17IN
2
O
2
SNa [M + Na] 462.9948, found
5ꢀ(Bromomethyl)ꢀ3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazole (6c): 62 mg, 53% yield, white solid,
o
1
mp 135−136 C; H NMR (400 MHz, CDCl
) δ 7.80 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 7.2 Hz, 2H),
3
7.44−7.37 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 4.20−4.12 (m, 1H), 4.00 (dd, J = 10.0, 3.2 Hz, 1H),
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3
3
1
4
.62 (t, J = 9.6 Hz, 1H), 3.28 (dd, J = 17.6, 11.2 Hz, 1H), 3.12 (dd, J = 17.6, 8.8 Hz, 1H), 2.39 (s,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
H); C{ H} NMR (100 MHz, CDCl
3
) δ 157.3, 144.6, 131.7, 130.8, 130.3, 129.7, 128.6, 128.5,
+
26.9, 61.8, 39.7, 35.2, 21.6; HRMS (ESI): calcd for C17
15.0094.
H17BrN
2
O
2
SNa [M + Na] 415.0086, found
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure I for the Synthesis of Compound 7. Substrate 5a (76.48 mg, 0.20 mmol),
NaOH (16.00 mg, 0.40 mmol, 2.0 equiv) and MeOH (3.0 mL) were added to a flask equipped with a
o
magnetic stir bar under argon atmosphere. The mixture was stirred at 90 C until the reaction was
completed as monitored by TLC analysis. The crude product was purified by flash chromatography
on silica gel (petroleumether : EtOAc = 3 : 1) directly to give the corresponding product 7 in 94%
yield as a white solid.
General Procedure II for the Synthesis of Compound 7. A solution of trifluoroethyl pyrazoline
2
5an (65.67 mg, 0.20 mmol) and CuCl (80.67 mg, 0.60 mmol, 3.0 equiv) in EtOH (4.0 mL) was
stirred under reflux for 8 h. The reaction process was monitored by TLC until the starting material
disappeared. The reaction mixture was then cooled to room temperature, and the solid was filtered
off from the reaction mixture. The filtrate was concentrated under vacuum. The crude product was
purified by flash chromatography on silica gel (petroleumether : EtOAc = 3 : 1) directly to give the
corresponding product 7 in 65% yield as a white solid.
3ꢀPhenylꢀ5ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ1Hꢀpyrazole (7): 42 mg, 94% yield (Synthesized by Procedure I),
o
1
white solid, mp 118−120 C; H NMR (600 MHz, CDCl ) δ 11.35 (br, 1H), 7.60 (d, J = 7.2 Hz, 2H),
3
13
1
7
.43−7.40 (m, 2H), 7.37−7.34 (m, 1H), 6.54 (s, 1H), 3.45−3.41 (m, 2H); C{ H} NMR (150 MHz,
CDCl ) δ 146.1, 141.6, 129.7, 129.1, 128.7, 125.5, 125.3 (q, J = 274.8 Hz), 103.4, 32.9 (q, J = 31.2
3
19
3 9 3 2
Hz); F NMR (376 MHz, CDCl ) δ ꢀ70.78 (t, J = 10.9 Hz); HRMS (ESI): calcd for C11H F N Na
+
[
M + Na] 249.0610, found 249.0613.
Control Experiments.
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Reaction of 6a with TCCA, Me
3
SiCF
3
, CsF, CuOAc.
1
2
3
4
5
6
7
8
9
Under argon atmosphere, Me SiCF
3
3
(179.0 mg, 1.3 mmol, 4.2 equiv) was added to a suspension
of CuOAc (129.0 mg, 1.1 mmol, 3.5 equiv) and CsF (191.0 mg, 1.3 mmol, 4.2 equiv) in dried
MeCN (4 mL) at room temperature. After the reaction mixture was stirred at room temperature for
1
1
1
1
1
1
1
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0 min, TCCA (47 mg, 0.2 mmol, 0.67 equiv) was added to the reaction mixture. Subsequently, 6a
(0.3 mmol) was added to the system. The mixture was stirred at room temperature and monitored by
thin layer chromatography (TLC). No desired product 5a was observed and 6a was recovered in
94% yield.
Reaction of TEMPO with TCCA, Me
Under argon atmosphere, TMSCF (179.0 mg, 1.3 mmol, 4.2 equiv) was added to a suspension of
CuOAc (129.0 mg, 1.1 mmol, 3.5 equiv) and CsF (191.0 mg, 1.3 mmol, 4.2 equiv) and
,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO, 94.0 mg, 0.6 mmol, 2.0 equiv) in dried MeCN (4 mL)
3 3
SiCF , CsF, CuOAc, and 1a.
3
2
at room temperature. After the reaction mixture was stirred at room temperature for 30 min,
α,α,αꢀtrifluorotoluene (internal standard, 44.0 mg, 0.3 mmol) and TCCA were added to the reaction
19
mixture. Subsequently, hydrazones 1a (0.3 mmol) was added to the system. F NMR analysis of this
reaction mixture showed that TEMPOꢀCF were formed in 25% and no desired product 5a was
observed. Then the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 5
mL). The organic layer was dried over Na SO , and evaporated in vacuum. The residue was purified
by silica gel column chromatography (petroleumether : EtOAc = 5 : 1) to afford the compound 9 in
3
2
4
71% yield.
2,2,6,6ꢀTetramethylꢀ1ꢀ((3ꢀphenylꢀ1ꢀtosylꢀ4,5ꢀdihydroꢀ1Hꢀpyrazolꢀ5ꢀyl)methoxy)piperidine
(9):
o
1
1
02 mg, 71% yield, white solid, mp 169−170 C; H NMR (400 MHz, CDCl
) δ 7.78 (d, J = 8.4 Hz,
3
2
H), 7.71−7.68 (m, 2H), 7.44−7.36 (m, 3H), 7.27 (d, J = 8.4 Hz, 2H), 4.31 (dd, J = 9.2, 3.6 Hz, 1H),
4.12 (dd, J = 9.6, 7.2 Hz, 1H), 4.00−3.92 (m, 1H), 3.21−3.06 (m, 2H), 2.38 (s, 3H), 1.51−1.45 (m,
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1
3
1
5
1
3
H), 1.32−1.31 (m, 1H), 1.23 (s, 6H), 1.08 (s, 6H); C{ H} NMR (150 MHz, CDCl ) δ 158.3, 144.1,
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32.2, 130.9, 130.5, 129.5, 128.6, 128.5, 126.9, 59.9, 39.6, 37.4, 33.2, 33.0, 21.6, 20.1, 17.0; HRMS
+
(ESI): calcd for C26
H
35
N
3
O
3
SNa [M + Na] 492.2300, found 492.2291.
0
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
1
19
13
1
Copies of the H NMR, F NMR, C{ H} NMR and HRMS spectra of 5, 6, 7, 9 and crystallography
of 5ac (PDF).
Crystallographic data for 5ac
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: huyl@nwnu.edu.cn.
ORCID
Yingpeng Su: 0000ꢀ0002ꢀ4396ꢀ4198
Yulai Hu: 0000ꢀ0002ꢀ9630ꢀ4150
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are thankful for financial support from the National Natural Science Foundation of China
(
Grant Nos. 21662030 and 21462037); Key Laboratory Polymer Materials of Gansu Province
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(
Northwest Normal University); Bioactive Product Engineering Research Center for Gansu
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Distinctive Plants; and State Key Laboratory of Applied Organic Chemistry, Lanzhou University.
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