Regioselective Synthesis of 5-Trifluoromethylpyrazoles by [3 + 2] Cycloaddition of Nitrile Imines and 2-Bromo-3,3,3-trifluoropropene

Article abstract of DOI:10.1021/acs.joc.0c02765

A general and practical method for the synthesis of 5-trifluoromethylpyrazoles is reported that occurs by the coupling of hydrazonyl chlorides with environmentally friendly and large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropropene (BTP). This exclusively regioselective [3 + 2] cycloaddition of nitrile imines and with BTP is catalyst-free and operationally simple and features mild conditions, high yields, gram-scalable, a broad substrate scope, and valuable functional group tolerance. Significantly, our method has been applied for the synthesis of the key intermediate of an active agonist of sphingosine 1-phosphate receptor.

Full text of DOI:10.1021/acs.joc.0c02765

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Regioselective Synthesis of 5‑Trifluoromethylpyrazoles by [3 + 2]
Cycloaddition of Nitrile Imines and 2‑Bromo-3,3,3-trifluoropropene
Hao Zeng, Xiaojie Fang, Zhiyi Yang, Chuanle Zhu,* and Huanfeng Jiang
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ABSTRACT: A general and practical method for the synthesis of 5-
trifluoromethylpyrazoles is reported that occurs by the coupling of hydrazonyl
chlorides with environmentally friendly and large-tonnage industrial feedstock
2-bromo-3,3,3-trifluoropropene (BTP). This exclusively regioselective [3 + 2]
cycloaddition of nitrile imines and with BTP is catalyst-free and operationally
simple and features mild conditions, high yields, gram-scalable, a broad
substrate scope, and valuable functional group tolerance. Significantly, our
method has been applied for the synthesis of the key intermediate of an active
agonist of sphingosine 1-phosphate receptor.
during the transformation. In this context, the development of
efficient methods for the regioselective construction of 5-
trifluoromethylpyrazoles from simple raw materials is always
highly demanded.
INTRODUCTION
■
Compounds with a trifluoromethylpyrazole skeleton have been
found with broad applications in many pharmaceutials,
agrochemicals, and bioactive compounds.1 For example,
celecoxib and mavacoxib (COX-2 inhibitors),2a,b SC-560
(human lung cancer inhibitor),2c AS-136A (measles virus
inhibitor),2d DPC-602 (arterial thrombosis),2e Razaxaban
(anticoagulant),2f and DP-23 (insecticidal activity)2g have a
3-trifluoromethylpyrazole core. Fluazolate (herbicide),3a com-
pound I (soluble epoxide hydrolase inhibitor),3b compound II
(store operated calcium entry modulator),3c and compound III
(active agonist of sphingosine 1-phosphate (S1P) receptor)3d
feature a 5-trifluoromethylpyrazole skeleton (Figure 1).
Traditionally, the dehydrative condensation between hydra-
zines and 1,3-dicarbonyl compounds could lead to the
formation of trifluoromethylpyrazole frameworks. However,
this strategy suffers from the formation of regioisomeric
mixtures of both 3- and 5-trifluoromethylpyrazole isomers.4
Although considerable progress has been achieved on the
regioselective synthesis of 3-trifluoromethylpyrazoles,5 in sharp
contrast, the methods for the regioselective construction of 5-
trifluoromethylpyrazoles are still underdeveloped. The early
study for the regioselective synthesis of 5-trifluoromethylpyr-
azoles was documented by Harrity via a [3 + 2] cycloaddition
of 4-trifluoromethylsydnones and alkynes, which needed a six-
step synthesis for the preparation of the starting material 4-
trifluoromethylsydnones and suffered from high reaction
temperature (140 or 180 °C), long reaction time, and also
with the generation of two regioisomers (Scheme 1, a).6a Later,
the groups of Hsieh6b and Nenajdenko6c independently
reported the elegant one pot, two-step protocols for the
regioselective synthesis of 5-trifluoromethylpyrazoles by the [3
+ 2] dehydrative condensation of trifluoromethylated ynones
and hydrazines (Scheme 1, b). However, the corresponding 3-
trifluoromethylpyrazole isomer was still unavoidably generated
2-Bromo-3,3,3-trifluoropropene (BTP) is an environmen-
tally benign and large-tonnage industry feedstock, which is a
stable liquid at room temperature. Especially, it is not
recognized as an ozone depletion molecule and is supposed
to be an attractive alternative to halon fire suppressants7 as well
as a useful and attractive raw material in synthetic
chemistry.5h,8 Recently, we utilized it as a C2 synthon in the
regioselective synthesis of 3-trifluoromethylpyrazoles (Scheme
1, c).5h Inspired by it, we envision that the regioselective [3 +
2] cycloaddition of a C1N2 synthon with BTP might become a
straightforward and efficient method for the synthesis of 5-
trifluoromethylpyrazoles. Nitrile imines, generally in situ
generated by a base-induced dehydrodechlorination of
hydrazonyl chlorides,9 could serve as the attractive C1N2
synthons in [3 + 2] cycloaddition reactions;10 however, their
[3 + 2] cycloaddition reactions with alkenes usually give
pyrazoline derivatives as the products.10f−h As our recent
interest in exploiting the synthetic application of BTP,5h as well
as our continuous effort in the synthesis of trifluoromethylated
compounds,11 herein we report the exclusively regioselective
[3 + 2] cycloaddition reaction of nitrile imines with BTP under
mild conditions, delivering various 5-trifluoromethylpyrazoles
in high yields (Scheme 1, d).
Received: November 18, 2020
Published: January 11, 2021
https://dx.doi.org/10.1021/acs.joc.0c02765
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 2810−2819
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Figure 1. Selected examples of bioactive 5-trifluoromethylpyrazole derivatives.
Scheme 1. Background and Reaction Design for Regioselective Synthesis of 5-Trifluoromethylpyrazoles
not further improve the yield of 2a (Table 1, entry 20).
Remarkably, no other regioselective isomers were detected
under all these conditions.
RESULTS AND DISCUSSION
■
By using hydrazonyl chloride 1a as the precursor of the nitrile
imine, the initial experiment was carried out with 1a and BTP
in the presence of Cs2CO3 in toluene at room temperature
(Table 1, entry 1). We are delighted that this regioselective [3
+ 2] cycloaddition reaction could give the desired product 2a
in 72% isolated yield. Next, different types of inorganic bases
such as K2CO3, Na2CO3, Li2CO3, t-BuOLi, t-BuOK, and
MeONa and organic bases such as Et3N, DABCO
(triethylenediamine), and DBU (1,8-diazabicyclo[5.4.0]-
undec-7-ene) were screened (Table 1, entries 2−10). A base
of DABCO gave product 2a in 93% yield. Owing to the failure
to generate the reactive nitrile imine from its precursor 1a, no
reaction happened in the absence of a base (Table 1, entry 11).
Furthermore, different types of solvents were investigated
(Table 1, entries 12−19). A solvent of xylene further enhanced
the isolated yield of 2a to 98%, which might be related to the
efficient generation and the stability of the nitrile imine
intermediate in low-polar aprotic solvent. In addition,
performing the reaction in anhydrous xylene under N2 did
With the optimized reaction conditions in hand, we then
examined the scope of hydrazonyl chlorides 1 (Scheme 2).
Generally, this reaction could tolerate a broad scope of
hydrazonyl chlorides bearing different R1 substituents,
delivering products 2a−2v in high to excellent yields with
exclusive regioselectivity. Regardless of the electronic proper-
ties (electron-neutral, electron-donating, and electron-with-
drawing) of the substituents on the phenyl ring, the
corresponding products 2a−2p were isolated in high to
excellent yields (71−98%). Valuable functional groups such as
alkyl, alkoxyl, fluoro, chloro, bromo, iodo, trifluoromethyl, and
cyano at para-, meta-, and ortho-positions of the phenyl ring
could be well tolerated, providing ample potential for further
synthetic applications of the products. Significantly, product 2a
proved to be crystalline; thus its structure was further
confirmed by X-ray crystallographic analysis.12 Symmetric 5-
trifluoromethyl pyrazole 2q derived from the corresponding
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On the basis of the previous literatures,9,10 the possible
reaction mechanism is illustrated in Scheme 5. Dehydrodech-
lorination of hydrazonyl chloride 1a in the presence of the base
afforded the reactive nitrile imine intermediates with two
resonance forms as A and A′, of which A′ underwent the
regioselective [3 + 2] cycloaddition with BTP to give the
pyrazoline intermediate B. The subsequent aromatization of
intermediate B via HBr elimination under basic conditions
delivered the desired 5-trifluoromethylpyrazole product 2a.3
a
Table 1. Optimization of the Reaction Conditions
b
entry
base
solvent
toluene
yield (%)
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
Na2CO3
Li2CO3
t-BuOLi
t-BuOK
MeONa
Et3N
72
69
<10
0
<10
<10
16
90
93
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
CONCLUSION
■
In summary, we have reported a general and practical method
for the synthesis of 5-trifluoromethylpyrazoles by the coupling
of hydrazonyl chlorides with environmentally friendly and
large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropro-
pene (BTP). This exclusively regioselective [3 + 2] cyclo-
addition of nitrile imines and with BTP is catalyst-free and
operationally simple and features mild conditions, high yields,
gram-scalable, a broad substrate scope, and valuable functional
group tolerance. Significantly, our method has been applied for
the synthesis of the key intermediate of an active agonist of
sphingosine 1-phosphate (S1P) receptor.
DABCO
DBU
10
11
12
13
14
15
16
17
18
19
0
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
98
14
35
19
70
30
<10
20
98
DCE
MeCN
1,4-dioxane
THF
DMF
DMSO
EtOH
EXPERIMENTAL SECTION
■
General Information. Toluene and THF were distilled from
sodium/benzophenone, 1,2-dichloroethane (DCE) was distilled from
calcium hydride, and acetonitrile (MeCN) was distilled from
phosphorus pentoxide. Other commercially available reagents were
purchased and used without further purification. Analytical thin-layer
c
20
xylene
a
Unless otherwise noted, all reactions were carried out with 1a (1
mmol), BTP (2 mmol), base (3 mmol), and solvent (10 mL) in a 25
mL test tube at room temperature for 24 h. Isolated yields. Under
N2 with anhydrous xylene.
b
c
chromatography was performed on 0.20 mm silica gel plates (GF254
)
using UV light as a visualizing agent. Flash column chromatography
was carried out using silica gel (200−300 mesh) with the indicated
solvent system. All reactions were conducted in oven-dried test tubes.
All the reaction temperatures reported are oil bath temperatures.
Melting points were measured using a melting point instrument and
are uncorrected. Chemical shifts were reported in ppm from the
solvent resonance as the internal standard (CDCl3 δH = 7.26 ppm, δC
= 77.16 ppm). Multiplicity was indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet). Coupling constants
were reported in hertz (Hz). IR spectra were obtained with an
infrared spectrometer on either potassium bromide pellets or liquid
films between two potassium bromide pellets. HRMS was carried out
on a high-resolution mass spectrometer (LCMS-IT-TOF). X-ray
structural analyses were conducted on a Bruker APEX-II CCD
diffractometer. TLC was performed using commercially available
100−400 mesh silica gel plates (GF254). These known compounds
1a,10c 1b,10c 1c,10c 1d,10e 1e,10c 1f,10c 1g,10c 1h,10e 1i,13a 1j,10c 1k,10h
1l,10c 1m,13b 1n,10h 1o,13c 1p,13d 1q,13e 1s,13f 1t,13g 1u,10c 1v,10g
1w,10e 1x,10e 3a,13h 3b,13i 3c,13h and 3d13i were synthesized according
to the reported literatures.
Procedure for the Synthesis of Hydrazonyl Chloride 1r. An
oven-dried clean round-bottom flask equipped with a magnetic
stirring bar, (S)-(−)-perillaldehyde (750.0 mg, 5.0 mmol), phenyl-
hydrazine (540.0 mg, 5.0 mmol), and MeOH (15 mL) was vigorously
stirred at 60 °C for 4 h. Then the mixture was stopped stirring, water
was added (15 mL), and the mixture was extracted with EtOAc (20
mL × 3). The combined organic phases were dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo to obtain crude product.
The crude was added into the suspension of TCCA (trichloroiso-
cyanuric acid, 0.8 equiv), CH2Cl2 (20 mL), and dimethyl sulfide (2.4
equiv) at 0 °C, and then the mixture was vigorously stirred at room
temperature for 1 h. Then the mixture was stopped stirring, water was
added (20 mL), and the mixture was extracted with EtOAc (20 mL ×
3). The combined organic phases were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. Further purification by flash
column chromatography on silica gel (eluting with petroleum ether/
symmetric hydrazonyl chloride was obtained in 85% yield.
Hydrazonyl chloride derived from α,β-unsaturated (S)-peril-
laldehyde afforded product 2r in 87% yield. Heteroaromatic
hydrazonyl chlorides such as thienyl-, and furanyl hydrazonyl
chlorides were also found to be good substrates and delivered
products 2s and 2t in high yields. Ethyl 2-oxoacetate derived
hydrazonyl chloride also gave the desired product 2u in 90%
yield. Additionally, different R2-substituted hydrazonyl chlor-
ides also worked well to give the 5-trifluoromethyl pyrazole
products 2v−2x.
Hydrazonyl chlorides 1 with an alkyl R1 substitutent are
quite unstable and have usually been found to be more difficult
to synthesize, isolate, and store in the laboratory. Then, a one
pot, two-step procedure was developed for the synthesis of the
corresponding 5-trifluoromethyl pyrazole products by directly
using hydrazones 3 as the reactant (Scheme 3). Gratifyingly,
hydrazones 3 derived from tertiary, secondary, and primary
aliphatic aldehydes were all found to be suitable substrates in
this one pot, two-step procedure to afford products 2y−2aa in
moderate to high yields. Additionally, hydrazone 3d derived
from benzaldehyde also delivered 2a in 83% yield under these
one pot, two-step procedure conditions.
Intrigued by this unique [3 + 2] cyclization reaction, a 10
mmol scale experiment was performed with 1u and BTP as the
reaction partners, delivering the corresponding product 2u in
87% yield (2.471 g) (Scheme 4). Further reduction of 2u gave
alcohol product 4 in 85% yield. Bromination of the alcohol 4 in
the presence of PBr3 afforded the brominated compound 5 in
75% yield, which was a key intermediate for the synthesis of an
active agonist of sphingosine 1-phosphate receptor.3d
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a
Scheme 2. Scope of Hydrazonyl Chlorides
a
Unless otherwise noticed, the reaction conditions were: hydrazonyl chlorides 1 (1 mmol), BTP (2 mmol), DABCO (3 mmol), and xylene (10
b
c
mL) in a 25 mL test tube at room temperature for 24 h. Isolated yield. ORTEP representation with 50% probability thermal ellipsoids of a crystal
structure of 2a; H atoms were omitted for clarity. At 90 °C.
d
ethyl acetate = 30:1) provided the product 1r in 52% isolated yield
(719.7 mg).
(S,Z)-N-Phenyl-4-(prop-1-en-2-yl)cyclohex-1-ene-1-carbohydra-
zonoyl Chloride (1r).
745 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for
C16H20ClN2, 275.1309; found, 275.1306.
General Procedure for the Synthesis of 5-Trifluoromethyl-
pyrazoles 2. An oven-dried clean round-bottom flask was charged
with a magnetic stirring bar, hydrazonyl chlorides 1 (1.0 mmol)
diluted in xylene (10 mL), 2-bromo-3,3,3-trifluoropropene (BTP)
(349.9 mg, 2.0 mmol), and DABCO (336.5 mg, 3.0 mmol), and the
mixture was vigorously stirred at room temperature for 24 h. Then the
mixture was stopped stirring, water was added (15 mL), and the
mixture was extracted with EtOAc (15 mL × 3). The combined
organic phases were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Further purification by flash column
chromatography on silica gel (eluting with petroleum ether/ethyl
acetate) provided the product 2.
719.7 mg, 52%, brown solid, mp: 110−111 °C; eluting with
1
petroleum ether/ethyl acetate = 30:1; H NMR (500 MHz, CDCl3)
δ 7.86 (s, 1H), 7.26−7.29 (m, 2H), 7.06−7.08 (m, 2H), 6.87−6.91
(m, 1H), 6.47 (s, 1H), 4.77 (d, J = 9.5 Hz, 2H), 2.76 (d, J = 17.0 Hz,
1H), 2.36−2.44 (m, 2H), 2.12−2.24 (m, 2H), 1.93 (d, J = 13.0 Hz,
1H), 1.77 (s, 3H), 1.50−1.58 (m, 1H); 13C{1H} NMR (126 MHz,
CDCl3) δ 149.2, 143.7, 132.7, 130.3, 129.3, 127.0, 120.8, 113.2, 109.1,
40.9, 31.3, 27.5, 26.4, 20.8. IR (KBr): 3062, 2928, 1596, 1504, 1138,
One Pot, Two-Step Transformation Directly from Hydra-
zones 3. An oven-dried clean 25 mL round-bottom flask was charged
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a
Scheme 3. One Pot, Two-Step Transformation Directly from Hydrazones 3
a
Unless otherwise noted, the reaction conditions were: Step (1): hydrazone 3 (1 mmol), trichloroisocyanuric acid (185.6 mg, 0.8 mmol), Me2S
(148.8 mg, 2.4 mmol), and DCM (8 mL) in a 25 mL test tube at room temperature for 12 h. Removal of the volatiles under reduced pressure. Step
b
(2): BTP (349.9 mg, 2 mmol), DABCO (336.5 mg, 3 mmol), and xylene (10 mL) in a 25 mL test tube at room temperature for 24 h. Isolated
yield.
Scheme 4. Gram-Scale Experiment and Transformation of 2u
1,3-Diphenyl-5-(trifluoromethyl)-1H-pyrazole (2a). 282.5 mg,
Scheme 5. Proposed Mechanism
98% yield, light yellow solid, mp: 70−71 °C; eluting with petroleum
ether/ethyl acetate = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.85−7.86
(m, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.45−7.50 (m, 3H), 7.42 (t, J = 7.0
Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.09 (s, 1H); 13C{1H} NMR (126
MHz, CDCl3) δ 151.8, 139.3, 134.0 (q, 2JF‑C = 39.3 Hz), 131.9, 129.4,
1
129.2, 128.9, 128.8, 126.0, 125.8, 119.9 (q, JF‑C = 269.5 Hz), 106.2
(q, 3JF‑C = 1.9 Hz); 19F NMR (471 MHz, CDCl3) δ −57.6 (s, 3F); IR
(KBr): 3061, 1687, 1444, 1148, 691 cm−1; HRMS (APCI-TOF, m/
z): [M + H]+ Calcd for C16H12F3N2, 289,0947; found, 289,0940.
3-(Naphthalen-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2b). 284.2 mg, 84% yield, yellow oil; eluting with petroleum ether/
1
ethyl acetate = 20:1; H NMR (500 MHz, CDCl3) δ 8.27−8.30 (m,
1H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.78−
7.80 (m, 1H), 7.55 (d, J = 7.0 Hz, 2H), 7.40−7.47 (m, 5H), 7.17 (s,
1H); 13C{1H} NMR (126 MHz, CDCl3) δ 151.7, 139.3, 134.0 (q,
with a magnetic stirring bar, hydrazone 3 (1 mmol), trichloroisocya-
2JF‑C = 39.3 Hz), 133.6, 133.6, 129.4, 129.2, 128.6, 128.4, 127.9, 126.5,
nuric acid (185.6 mg, 0.8 mmol), Me2S (148.8 mg, 2.4 mmol), and
DCM (8 mL), and the mixture was stirred at room temperature for 12
h. The volatiles were removed under reduced pressure. Then BTP
(349.9 mg, 2 mmol), DABCO (336.5 mg, 3 mmol), and xylene (10
126.4, 125.8, 124.9, 123.8, 119.9 (q, 1JF‑C = 269.5 Hz), 106.4 (q, 3JF‑C
= 2.3 Hz); 19F NMR (471 MHz, CDCl3) δ −57.4 (s, 3F); IR (KBr):
3056, 1599, 1492, 1144, 762 cm−1; HRMS (APCI-TOF, m/z): [M +
H]+ Calcd for C20H13F3N2 + H, 339.1104; found, 339.1099.
mL) were added, and the resulting mixture was vigorously stirred at
1-Phenyl-3-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole (2c). 260.0
mg, 86% yield, yellow solid, mp: 71−72 °C; eluting with petroleum
ether/ethyl acetate = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J
= 8.0 Hz, 2H), 7.61−7.64 (m, 2H), 7.52−7.58 (m, 3H), 7.30 (d, J =
8.0 Hz, 2H), 7.14 (s, 1H), 2.45 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3) δ 151.8, 139.4, 138.7, 134.0 (q, 2JF‑C = 39.1 Hz), 129.6, 129.3,
room temperature for 24 h. Then the mixture was stopped stirring,
water was added (15 mL), and the mixture was extracted with EtOAc
(15 mL × 3). The combined organic phases were dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. Further
purification by flash column chromatography on silica gel (eluting
with petroleum ether/ethyl acetate) provided the product 2.
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129.2, 129.1, 125.9, 125.8, 119.9 (q, 1JF‑C = 269.5 Hz), 106.0 (q, 3JF‑C
= 2.0 Hz), 21.4; 19F NMR (471 MHz, CDCl3) δ −57.5 (s, 3F); IR
(KBr): 3059, 1596, 1444, 1138, 779 cm−1; HRMS (APCI-TOF, m/
z): [M + H]+ Calcd for C17H14F3N2, 303.1104; found, 303.1099.
3-(4-(tert-Butyl)phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyra-
zole (2d). 278.9 mg, 81% yield, brown oil; eluting with petroleum
ether/ethyl acetate = 20:1; 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J
= 8.4 Hz, 2H), 7.44−7.56 (m, 7H), 7.08 (s, 1H), 1.35 (s, 9H);
1F), −111.9 to −111.8 (m, 1F); IR (KBr): 3059, 1596, 1444, 1138,
779 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for
C16H20F5N2, 325.0759; found, 325.0754.
3-(4-Chlorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2j). 251.2 mg, 78% yield, yellow solid, mp: 70−72 °C; eluting with
petroleum ether/ethyl acetate = 15:1; 1H NMR (400 MHz, CDCl3) δ
7.80 (d, J = 8.4 Hz, 2H), 7.48−7.54 (m, 5H), 7.43 (d, J = 8.4 Hz,
2H), 7.11 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.0, 137.7,
135.5, 134.8, 134.2 (q, J = 39.5 Hz), 130.2, 129.5, 129.2, 127.2, 127.0,
119.7 (q, J = 269.3 Hz), 106.5; 19F NMR (376 MHz, CDCl3) δ −57.6
(s, 3F); IR (KBr): 3061, 1589, 1446, 1117, 755 cm−1; HRMS (APCI-
TOF, m/z): [M + H]+ Calcd for C16H11ClF3N2, 323.0557; found,
323.0551.
13C{1H} NMR (126 MHz, CDCl3) δ 151.9, 151.8, 139.4, 133.8 (q,
1
2JF‑C = 38.8 Hz), 129.3, 129.2, 129.1, 125.9, 125.7, 119.9 (q, JF‑C
=
267.4 Hz), 106.1, 34.8, 31.4; 19F NMR (471 MHz, CDCl3) δ −57.5
(s, 3F); IR (KBr): 3060, 2958, 1595, 1492, 1143, 757 cm−1; HRMS
(APCI-TOF, m/z): [M + H]+ Calcd for C20H20F3N2, 345.1573;
found, 345.1568.
3-(2-Chlorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2k). 264.6 mg, 82% yield, yellow solid, mp: 80−81 °C; eluting with
petroleum ether/ethyl acetate = 15:1; 1H NMR (400 MHz, CDCl3) δ
7.87−7.90 (m, 1H), 7.46−7.58 (m, 6H), 7.36 (s, 1H), 7.29−7.33 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.4, 139.2, 133.2 (q,
2JF‑C = 38.9 Hz), 132.5, 130.8, 130.8, 130.6, 129.8, 129.5, 129.3, 127.2,
3-(4-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2e). 273.7 mg, 86% yield, yellow solid; eluting with petroleum ether/
1
ethyl acetate = 10:1; H NMR (400 MHz, CDCl3) δ 7.85−7.88 (m,
2H), 7.60−7.63 (m, 2H), 7.50−7.56 (m, 3H), 7.09 (s, 1H), 7.00−
7.04 (m, 2H), 3.86 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
1
125.8, 119.9 (q, JF‑C = 267.5 Hz), 110.1; 19F NMR (376 MHz,
2
160.2, 151.5, 139.3, 133.8 (q, JF‑C = 38.9 Hz), 129.2, 129.1, 127.2,
125.7, 124.5, 119.9 (q, 1JF‑C = 267.5 Hz), 114.3, 105.7, 55.3; 19F NMR
(376 MHz, CDCl3) δ −57.5 (s, 3F); IR (KBr): 3059, 2923, 1596,
1444, 1138, 779 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd
for C17H14F3N2O, 319.1053; found, 319.1052.
CDCl3) δ −57.5 (s, 3F); IR (KBr): 3060, 1590, 1434, 1116, 761
cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C16H11ClF3N2,
323.0557; found, 323.0553.
3-(4-Bromophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2l). 260.7 mg, 71% yield, red solid, mp: 70−71 °C; eluting with
petroleum ether/ethyl acetate = 15:1; 1H NMR (400 MHz, CDCl3) δ
7.75 (d, J = 8.4 Hz, 2H), 7.57−7.60 (m, 4H), 7.50−7.54 (m, 3H),
7.09 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.6, 139.1,
3-(3-Methoxyphenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2f). 257.8 mg, 81% yield, brown solid, mp: 80−81 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz, CDCl3) δ
7.62−7.65 (m, 2H), 7.50−7.57 (m, 5H), 7.40 (t, J = 8.0 Hz, 1H),
7.17 (s, 1H), 6.98−7.01 (m, 1H), 3.89 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 160.1, 151.6, 139.2, 133.8 (q, 2JF‑C = 39.0 Hz), 133.1,
2
134.0 (q, JF‑C = 39.1 Hz), 132.0, 130.8, 129.4, 129.2, 127.4, 125.7,
122.8, 119.7 (q, 1JF‑C = 267.6 Hz), 106.1 (q, 3JF‑C = 2.5 Hz); 19F NMR
(376 MHz, CDCl3) δ −57.5 (s, 3F); IR (KBr): 3065, 1589, 1440,
1147, 820 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for
C16H11BrF3N2, 367.0052; found, 367.0049.
1
129.9, 129.3, 129.1, 125.8, 119.9 (q, JF‑C = 267.6 Hz), 118.4, 114.7,
111.0, 106.3, 55.2 (d, JF‑C = 6.1 Hz); 19F NMR (376 MHz, CDCl3) δ
−57.5 (s, 3F); IR (KBr): 3074, 2937, 1609, 1442, 1135, 830 cm−1;
HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C17H14F3N2O,
319.1053; found, 319.1045.
3-(4-Iodophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2m). 310.6 mg, 75% yield, brown solid, mp: 80−81 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz, CDCl3) δ
7.75 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.48−7.55 (m,5H),
7.07 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.7, 139.2,
134.2 (q, 2JF‑C = 39.2 Hz), 131.4, 129.5, 129.3, 127.6, 125.8, 119.7 (q,
1JF‑C = 267.8 Hz), 106.1, 94.5; 19F NMR (376 MHz, CDCl3) δ −57.6
3-(4-Fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2g). 269.5 mg, 88% yield, yellow solid, mp: 80−81 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (500 MHz, CDCl3) δ
7.78−7.83 (m, 2H), 7.51−7.56 (m, 2H), 7.43−7.49 (m, 3H), 7.06−
7.12 (m, 2H), 7.02 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ
1
2
163.2 (d, JF‑C = 248.5 Hz), 150.8, 139.3, 134.0 (q, JF‑C = 39.2 Hz),
(s, 3F); IR (KBr): 3061, 1588, 1442, 1145, 813 cm−1; HRMS (APCI-
TOF, m/z): [M + H]+ Calcd for C16H11F3IN2, 414.9914; found,
414.9906.
4
3
129.5, 129.2, 128.1 (d, JF‑C = 3.0 Hz), 127.7 (d, JF‑C = 8.3 Hz),
1
2
125.8, 119.9 (q, JF‑C = 269.8 Hz), 115.9 (d, JF‑C = 21.5 Hz), 106.0
(q, JF‑C = 2.4 Hz); 19F NMR (471 MHz, CDCl3) δ −57.6 (s, 3F),
1-Phenyl-5-(trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)-1H-
3
pyrazole (2n). 277.9 mg, 78% yield, yellow solid, mp: 70−71 °C;
−112.9 to −112.8 (m, 1F); IR (KBr): 3068, 1603, 1447, 1148, 826
cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C16H11F4N2,
307.0853; found, 307.0847.
1
eluting with petroleum ether/ethyl acetate = 10:1; H NMR (400
MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H),
7.53−7.61 (m, 5H), 7.19 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ 150.3, 139.2, 135.3, 134.4 (q, 2JF‑C = 39.3 Hz), 130.3 (q, 2JF‑C = 32.4
3-(2-Fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2h). 229.7 mg, 75% yield, yellow solid, mp: 81−82 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (500 MHz, CDCl3) δ
8.05−8.09 (m, 1H), 7.54−7.55 (m, 2H), 7.44−7.50 (m, 3H), 7.26−
7.33 (m, 2H), 7.12−7.21 (m, 2H); 13C{1H} NMR (126 MHz,
3
Hz), 129.7, 129.3, 126.2, 125.9 (q, JF‑C = 3.8 Hz), 125.8, 124.3 (q,
1JF‑C = 270.3 Hz), 119.8 (q, 1JF‑C = 267.6 Hz), 106.5; 19F NMR (376
MHz, CDCl3) δ −57.8 (s, 3F), −62.7 (s, 3F); IR (KBr): 3061, 1588,
1445, 1145, 813 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd
for C17H11F6N2, 357.0821; found, 357.0815.
1
2
CDCl3) δ 160.4 (d, JF‑C = 250.4 Hz), 146.5, 139.3, 133.7 (q, JF‑C
=
37.8 Hz), 130.1 (d, 3JF‑4C = 8.3 Hz), 129.5, 129.2, 128.6 (d, 4JF‑C = 3.4
1
Hz), 125.8, 124.5 (d, JF‑C = 3.3 Hz), 119.9 (q, JF‑C = 269.6 Hz),
4-(1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzonitrile
(2o). 209.9 mg, 67% yield, brown solid, mp: 105−106 °C; eluting
with petroleum ether/ethyl acetate = 8:1; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.50−
7.56 (m, 5H), 7.16 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
119.8 (d, 3JF‑C = 11.7 Hz) 116.3 (d, 2JF‑C = 22.2 Hz), 109.5 (d, 3JF‑C
=
9.7 Hz); 19F NMR (376 MHz, CDCl3) δ −57.5 (s, 3F), −115.9 to
−115.8 (m, 1F); IR (KBr): 3062, 1589, 1446, 1117, 755 cm−1;
HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C16H11F4N2,
307.0853; found, 307.0847.
2
149.7, 138.9, 136.1, 134.5 (q, JF‑C = 39.3 Hz), 132.7, 129.8, 129.3,
3-(2,4-Difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2i). 223.7 mg, 69% yield, yellow solid, mp: 82−83 °C; eluting with
petroleum ether/ethyl acetate = 15:1; 1H NMR (400 MHz, CDCl3) δ
8.11 (q, J = 8.0 Hz, 1H), 7.53−7.59 (m, 5H), 7.26 (d, J = 2.8 Hz,
1H), 6.93−7.00 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.1
(dd, JF‑C = 249.2, 11.9 Hz), 160.4 (dd, JF‑C = 251.0, 11.7 Hz), 145.7,
126.3, 125.7, 119.6 (q, 1JF‑C = 267.7 Hz), 118.8, 112.1, 106.6 (q, 3JF‑C
= 2.6 Hz); 19F NMR (376 MHz, CDCl3) δ −57.7 (s, 3F); IR (KBr):
3065, 2223, 1598, 1442, 1113, 825 cm−1; HRMS (APCI-TOF, m/z):
[M + H]+ Calcd for C17H11F3N3, 314.0900; found, 314.0893.
3-(1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzonitrile
(2p). 260.0 mg, 83% yield, light yellow solid, mp: 158−159 °C;
eluting with petroleum ether/ethyl acetate = 8:1; 1H NMR (400
MHz, CDCl3) δ 8.17 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.63 (d, J =
8.0 Hz, 1H), 7.51−7.55 (m, 5H), 7.13 (s, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 149.4, 138.9, 134.5 (q, 2JF‑C = 39.5 Hz), 133.1, 132.0,
139.1, 133.8 (q, 2JF‑C = 38.9 Hz), 129.6, 129.3, 125.8, 119.8 (q, 1JF‑C
=
267.6 Hz), 116.2 (dd, JF‑C = 11.9, 4.0 Hz), 112.0 (dd, JF‑C = 21.4, 3.6
Hz), 109.1 (dq, JF‑C = 11.0, 2.3 Hz), 104.5 (t, JF‑C = 25.6 Hz); 19F
NMR (376 MHz, CDCl3) δ −57.6 (s, 3F), −109.3 to −109.2 (m,
2815
https://dx.doi.org/10.1021/acs.joc.0c02765
J. Org. Chem. 2021, 86, 2810−2819

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
1
130.0, 129.8, 129.7, 129.4, 129.3, 125.7, 119.6 (q, JF‑C = 267.5 Hz),
118.6, 113.2, 106.6 (q, 3JF‑C = 1.8 Hz); 19F NMR (376 MHz, CDCl3)
δ −57.7 (s, 3F); IR (KBr): 3058, 1534, 1424, 1082, 690 cm−1; HRMS
(APCI-TOF, m/z): [M + H]+ Calcd for C17H11F3N3, 314.0900;
found, 314.0892.
ethyl acetate = 15:1; H NMR (400 MHz, CDCl3) δ 7.82−7.85 (m,
2H), 7.34−7.51 (m, 7H), 7.10 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 152.7, 137.8, 135.4, 134.0 (q, 2JF‑C = 39.0 Hz), 131.6, 129.5,
129.0, 127.0, 126.0, 119.8 (q, 1JF‑C = 267.5 Hz), 106.6; 19F NMR (376
MHz, CDCl3) δ −57.6 (s, 3F); IR (KBr): 3063, 1502, 1443, 1289,
1145, 830 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd for
C16H11ClF3N2, 323.0557; found, 323.0552.
1,4-Bis(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzene
(2q). 423.7 mg, 85% yield, yellow solid, mp: 170−171 °C; eluting
with petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz,
CDCl3) δ 7.97 (s, 4H), 7.51−7.61 (m, 10H), 7.18 (s, 2H); 13C{1H}
4-(3-Phenyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile
(2x). 175.4 mg, 56% yield, white solid, mp: 78−79 °C; eluting with
petroleum ether/ethyl acetate = 10:1; 1H NMR (400 MHz, CDCl3) δ
7.85−7.87 (m, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz,
2H), 7.39−7.48 (m, 3H), 7.18 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 152.8, 142.6, 133.9 (q, 2JF‑C = 39.4 Hz), 133.3, 131.2, 129.3,
129.0, 126.0, 125.7 (q, JF‑C = 1.7 Hz), 119.8 (q, JF‑C = 267.6 Hz),
117.9, 112.9, 107.8; 19F NMR (376 MHz, CDCl3) δ −57.2 (s, 3F); IR
(KBr): 3163, 1589, 1450, 1229, 1113, 759 cm−1; HRMS (APCI-TOF,
m/z): [M + H]+ Calcd for C17H11F3N3, 314.0899; found, 314.0894.
3-(tert-Butyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole (2y).
214.6 mg, 80% yield, yellow oil; eluting with petroleum ether/ethyl
2
NMR (101 MHz, CDCl3) δ 151.3, 139.3, 134.2 (q, JF‑C = 39.0 Hz),
1
132.1, 129.5, 129.3, 126.4, 125.9, 119.9 (q, JF‑C = 267.5 Hz), 106.3;
19F NMR (376 MHz, CDCl3) δ −57.6 (s, 6F); IR (KBr): 3063, 1594,
1434, 1143, 758 cm−1; HRMS (APCI-TOF, m/z): [M + H]+ Calcd
for C26H17F6N4, 499.1352; found, 499.1346.
3
1
(S)-1-Phenyl-3-(4-(prop-1-en-2-yl)cyclohex-1-en-1-yl)-5-(trifluor-
omethyl)-1H-pyrazole (2r). 289.2 mg, 87% yield, brown oil; eluting
with petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz,
CDCl3) δ 7.44−7.57 (m, 5H), 6.92 (s, 1H), 6.48 (t, J = 2.8 Hz, 1H),
4.84 (s, 2H), 2.76−2.82 (m, 1H), 2.49−2.59 (m, 1H), 2.29−2.45 (m,
2H), 2.17−2.24 (m, 1H), 2.01−2.05 (m, 1H), 1.84 (s, 3H), 1.62−
1.72 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 149.4,
1
acetate = 30:1; H NMR (400 MHz, CDCl3) δ 7.42−7.45 (m, 5H),
6.67 (s, 1H), 1.35 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ
162.6, 138.0, 134.9, 132.8 (q, 2JF‑C = 38.6 Hz), 129.4, 127.0, 119.8 (q,
1JF‑C = 267.4 Hz), 106.2, 32.4, 30.4; 19F NMR (376 MHz, CDCl3) δ
−57.3 (s, 3F); IR (KBr): 3057, 2961, 1497, 1241, 1131, 829 cm−1;
HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C14H16F3N2,
269.1260; found, 269.1252.
2
139.4, 133.2 (q, JF‑C = 38.7 Hz), 129.3, 129.0, 129.0, 125.8, 125.7,
1
3
119.9 (q, JF‑C = 267.5 Hz), 109.0, 105.1 (q, JF‑C = 1.4 Hz), 40.8,
31.0, 27.4, 26.2, 20.8; 19F NMR (376 MHz, CDCl3) δ −57.5 (s, 3F);
IR (KBr): 3073, 2941, 1715, 1462, 1152, 700 cm−1; HRMS (APCI-
TOF, m/z): [M + H]+ Calcd for C19H20F3N2, 333.1573; found,
333.1567.
1-Phenyl-3-(thiophen-2-yl)-5-(trifluoromethyl)-1H-pyrazole (2s).
247.2 mg, 84% yield, brown solid, mp: 70−71 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz, CDCl3) δ
7.50−7.58 (m, 5H), 7.45 (d, J = 3.6 Hz, 1H), 7.32 (d, J = 5.2 Hz,
1H), 7.11 (t, J = 4.4 Hz, 1H), 7.03 (s, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 147.1, 139.0, 134.7, 133.9 (q, 2JF‑C = 39.3 Hz), 129.5,
3-Cyclohexyl-1-phenyl-5-(trifluoromethyl)-1H-pyrazole (2z).
176.6 mg, 60% yield, yellow oil; eluting with petroleum ether/ethyl
1
acetate = 30:1; H NMR (400 MHz, CDCl3) δ 7.39−7.49 (m, 5H),
6.61 (s, 1H), 2.70−2.77 (m, 1H), 2.02−2.07 (m, 2H), 1.70−1.85 (m,
3H), 1.28−1.52 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 158.5,
139.5, 132.7 (q, 2JF‑C = 38.6 Hz), 129.1, 129.0, 125.7, 120.1 (q, 1JF‑C
=
267.3 Hz), 106.2, 37.5, 33.1, 26.3, 26.1; 19F NMR (376 MHz, CDCl3)
δ −57.4 (s, 3F); IR (KBr): 3064, 2928, 1462, 1289, 1145, 771 cm−1;
HRMS (APCI-TOF, m/z): [M + H]+ Calcd for C16H18F3N2,
295.1417; found, 295.1413.
1
129.2, 127.7, 125.8, 125.8, 125.0, 119.8 (q, JF‑C = 267.8 Hz), 106.1
(q, 3JF‑C = 1.9 Hz); 19F NMR (376 MHz, CDCl3) δ −57.6 (s, 3F); IR
(KBr): 3079, 1590, 1487, 1144, 699 cm−1; HRMS (APCI-TOF, m/
z): [M + H]+ Calcd for C14H10F3N2S, 295.0511; found, 295.0507.
3-(Furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole (2t).
217.0 mg, 78% yield, yellow oil; eluting with petroleum ether/ethyl
Phenyl-3-propyl-5-(trifluoromethyl)-1H-pyrazole (2aa). 122.1
mg, 48% yield, yellow oil; eluting with petroleum ether/ethyl acetate
1
= 30:1; H NMR (400 MHz, CDCl3) δ 7.44−7.48 (m, 5H), 6.61 (s,
1
acetate = 20:1; H NMR (400 MHz, CDCl3) δ 7.49−7.54 (m, 6H),
1H), 2.68 (t, J = 7.6 Hz, 2H), 2.68 (m, 2H), 2.68 (t, J = 7.6 Hz, 3H);
7.04 (s, 1H), 6.80 (t, J = 2.0 Hz, 1H), 6.50 (d, J = 1.2 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 153.7, 139.4, 133.0 (q, JF‑C
=
2
13C{1H} NMR (101 MHz, CDCl3) δ 147.1, 144.2, 142.6, 138.9, 133.7
38.8 Hz), 129.2, 129.1, 125.8, 120.0 (q, 1JF‑C = 267.2 Hz), 107.8, 30.1,
22.8, 14.0; 19F NMR (376 MHz, CDCl3) δ −57.5 (s, 3F); IR (KBr):
3061, 2953, 1476, 1288, 1132, 759 cm−1; HRMS (APCI, m/z): [M +
H]+ Calcd for C13H14F3N2, 255.1104; found, 255.1099.
1
(q, 2JF‑C = 39.4 Hz), 129.5, 129.1, 125.8, 119.6 (q, JF‑C = 267.6 Hz),
111.5, 107.2, 105.8; 19F NMR (376 MHz, CDCl3) δ −57.8 (s, 3F); IR
(KBr): 3061, 1703, 1474, 1148, 758 cm−1; HRMS (APCI-TOF, m/
z): [M + H]+ Calcd for C14H10F3N2O, 279.0740; found, 279.0736.
Ethyl 1-Phenyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate
(2u). 255.8 mg, 90% yield, yellow oil; eluting with petroleum ether/
Gram-Scale Synthesis of 2u. An oven-dried clean round-bottom
flask was charged with a magnetic stirring bar, hydrazonyl chloride 1u
(2.266 g, 10 mmol) diluted in xylene (50 mL), 2-bromo-3,3,3-
trifluoropropene (BTP) (3.499 g, 20 mmol), and DABCO (3.365 g,
30 mmol), and the mixture was vigorously stirred at 90 °C for 24 h.
Then the mixture was stopped stirring, water was added (60 mL), and
the mixture was extracted with EtOAc (60 mL × 3). The combined
organic phases were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Further purification by flash column
chromatography on silica gel (eluting with petroleum ether/ethyl
acetate = 10:1) provided the product 2u in 87% isolated yield (2.471
g).
Ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (2u)
(284.2 mg, 1 mmol) was diluted in anhydrous CH2Cl2 (10 mL), and
DIBAL (2 mL, 1.5 M in toluene, 3 mmol) was added dropwise to the
solution at 0 °C under N2. The reaction mixture was stirred at room
temperature for 6 h, and then the solution was cooled to 0 °C, after
which MeOH (10 mL) was added dropwise. The solvent was
evaporated under reduced pressure, and the solid was subsequently
extracted with EtOAc (20 mL × 3). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. Further purification by flash column chromatography on silica
gel (eluting with petroleum ether/ethyl acetate = 6:1) provided the
product 4 in 85% isolated yield.
1
ethyl acetate = 10:1; H NMR (400 MHz, CDCl3) δ 7.44−7.54 (m,
5H), 7.33 (s, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 161.2, 144.0, 138.5, 134.2 (q,
1
2JF‑C = 39.7 Hz), 130.1, 129.2, 126.0, 119.0 (q, JF‑C = 267.7 Hz),
111.2, 61.6, 14.3; 19F NMR (376 MHz, CDCl3) δ −58.0 (s, 3F); IR
(KBr): 3071, 2975, 1733, 1484, 1234, 769 cm−1; HRMS (APCI-TOF,
m/z): [M + H]+ Calcd for C13H12F3N2O2, 285.0845; found,
285.0841.
1-(4-Fluorophenyl)-3-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2v). 257.3 mg, 84% yield, brown solid, mp: 78−79 °C; eluting with
petroleum ether/ethyl acetate = 20:1; 1H NMR (400 MHz, CDCl3) δ
7.83−7.85 (m, 2H), 7.50−7.54 (m, 2H), 7.41−7.45 (m, 2H), 7.35−
7.39 (m, 1H), 7.16−7.20 (m, 2H), 7.09 (s, 1H); 13C{1H} NMR (101
1
4
MHz, CDCl3) δ 162.8 (d, JF‑C = 248.2 Hz), 151.9, 135.3 (d, JF‑C
=
3.4 Hz), 134.1 (q, 2JF‑C = 39.0 Hz), 131.7, 129.0, 128.9, 127.9 (d, 3JF‑C
1
2
= 8.7 Hz), 126.0, 119.8 (q, JF‑C = 267.5 Hz), 116.2 (d, JF‑C = 23.0
Hz), 106.2; 19F NMR (376 MHz, CDCl3) δ −57.7 (s, 3F), −111.3 (s,
1F); IR (KBr): 3063, 1512, 1438, 1123, 837 cm−1; HRMS (APCI-
TOF, m/z): [M + H]+ Calcd for C16H11F4N2, 307.0853; found,
307.0848.
1-(4-Chlorophenyl)-3-phenyl-5-(trifluoromethyl)-1H-pyrazole
(2w). 258.2 mg, 80% yield, brown oil; eluting with petroleum ether/
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(1-Phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanol (4).
205.7 mg, 85% yield, colorless oil; H NMR (400 MHz, CDCl3) δ
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China; orcid.org/0000-0002-4355-
0294
1
7.44−7.49 (m, 5H), 6.81 (s, 1H), 4.75 (s, 2H), 2.48 (brs, 1H);
2
13C{1H} NMR (101 MHz, CDCl3) δ 152.6, 139.0, 133.7 (q, JF‑C
=
39.2 Hz), 129.5, 129.3, 125.8, 119.7 (q, 1JF‑C = 267.4 Hz), 107.5, 58.7;
19F NMR (376 MHz, CDCl3) δ −57.7 (s, 3F); IR (KBr): 3391, 3065,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02765
2934, 1498, 1136, 765 cm−1; HRMS (APCI, m/z): [M + H]+ Calcd
for C11H10F3N2O, 243.0740; found, 243.073.
Notes
PBr3 (405 mg, 1.5 mmol) was added to a solution of alcohol 4
(242.2 mg, 1 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was
stirred at room temperature for 12 h, cooled to 0 °C, quenched with
ice water, and then diluted with CH2Cl2 (50 mL). The organic layer
was dried and evaporated. Further purification by flash column
chromatography on silica gel (eluting with petroleum ether/ethyl
acetate = 30:1) provided the product 5 in 75% isolated yield.
3-(Bromomethyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole
(5).3d 228.8 mg, 75% yield, colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.51 (s, 5H), 6.91 (s, 1H), 4.54 (s, 2H); 13C{1H} NMR (101 MHz,
CDCl3) δ 149.5, 138.9, 134.0 (q, J = 39.5 Hz), 129.7, 129.3, 125.7,
119.6 (q, J = 269.3 Hz), 109.0, 23.8; 19F NMR (376 MHz, CDCl3) δ
−57.7 (s, 3F); IR (KBr): 3063, 2953, 1485, 1133, 686 cm−1.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21702064), the Guangdong Basic and Applied Basic
Research Foundation (2020B1515020012), the Pearl River
S&T Nova Program of Guangzhou (201806010138), the
Fundamental Research Funds for the Central Universities
(2019ZD19), and the open-fund of the National & Local Joint
Engineering Research Center for Mineral Salt Deep Utilization
(SF201903) for financial support.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02765.
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AUTHOR INFORMATION
Corresponding Author
■
Chuanle Zhu − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China; National & Local Joint
Engineering Research Center for Mineral Salt Deep
Utilization, Huaiyin Institute of Technology, Huaian
223003, People’s Republic of China; orcid.org/0000-
0002-0096-258X; Email: cechlzhu@scut.edu.cn;
Fax: (+86) 20-87112906
Authors
Hao Zeng − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China
Xiaojie Fang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China
Zhiyi Yang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology,
Guangzhou 510640, China
Huanfeng Jiang − Key Laboratory of Functional Molecular
Engineering of Guangdong Province, School of Chemistry and
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