Design and synthesis of 3-trifluoromethyl-3h-pyrazoles and further investigations of their transformation to 1h-pyrazoles

Article abstract of DOI:10.1002/ejoc.201403141

An efficient intramolecular cycloaddition strategy for the synthesis of trifluoromethyl-substituted 3H-pyrazoles was developed. Subsequently, their wide applications were demonstrated: they (1) react with dioxane by a radical process and (2) undergo [1,5] sigmatropic rearrangements. These applications are useful as the products were obtained in high yields and with excellent regioselectivity.

Full text of DOI:10.1002/ejoc.201403141

Job/Unit: O43141
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Date: 27-10-14 13:06:44
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201403141
Design and Synthesis of 3-Trifluoromethyl-3H-pyrazoles and Further
Investigations of Their Transformation to 1H-Pyrazoles
Qiang Sha,[a][‡] Haixuan Liu,[a][‡] and Yunyang Wei*[a]
Keywords: Cycloaddition / Sigmatropic rearrangement / Nitrogen heterocycles
An efficient intramolecular cycloaddition strategy for the
synthesis of trifluoromethyl-substituted 3H-pyrazoles was
and (2) undergo [1,5] sigmatropic rearrangements. These ap-
plications are useful as the products were obtained in high
developed. Subsequently, their wide applications were dem- yields and with excellent regioselectivity.
onstrated: they (1) react with dioxane by a radical process
still highly desirable. Trifluoromethylated compounds have
Introduction
gained growing interest because of their unique physical
and chemical properties such as their strong electron-with-
drawing ability and good lipophilicity.[7] Therefore, we de-
cided to investigate both the synthetic methods and applica-
tions of new trifluoromethyl-substituted 3H-pyrazoles.
Herein, we disclose our successful development of an ef-
ficient protocol for the synthesis of 3-trifluoromethyl-3H-
pyrazoles and subsequently demonstrate their applications
in the synthesis of 1H-pyrazoles.
Pyrazoles and their derivatives are five-membered nitro-
gen-containing heterocycles with wide applications in the
pharmaceutical and agrochemical industries.[1] Among
them, 3H-pyrazoles have attracted continuous interest for a
long time because they are important synthetic intermedi-
ates. They have mainly been used in two aspects: firstly, for
the synthesis of cyclopropenes by the extrusion of nitrogen
from the 3H-pyrazole ring[2] and, secondly, for the synthesis
of 1H-pyrazoles by intramolecular rearrangement reactions
of 3H-pyrazoles.[3]
Owing to the importance of 3H-pyrazoles in organic
chemistry, methods for their synthesis have been extensively
studied. Generally, there are two pathways for the synthesis
of 3H-pyrazoles, namely, the intermolecular and intra-
molecular 1,3-dipolar cycloaddition reactions of diazo com-
pounds with alkynes. The intermolecular cycloaddition re-
action[4] has been extensively studied, but studies of the in-
tramolecular cycloaddition reaction are rare. Furthermore,
the diazo compounds used were limited to those stabilized
by electron-withdrawing groups. Studies of unstabilized di-
azo compounds are rare because they are highly explosive
and toxic. N-Tosylhydrazones are safe diazo precursors[5]
and provide an alternative way to study unstabilized diazo
compounds. In recent years, N-tosylhydrazones have been
widely used in organic synthesis.[6]
Results and Discussion
At the outset, we investigated the intermolecular cyclo-
addition reactions of 1-phenyl-2,2,2-trifluorodiazoethane
with alkynes to form 3H-pyrazoles (see Supporting Infor-
mation). However, after many investigations, we found this
transformation to be less useful, because it has a narrow
substrate scope and cannot be used to synthesize 3H-pyr-
azoles on a large scale.[8]
As an alternative, we decided to study the intramolecular
cycloaddition reaction of 4a with K2CO3 as a base and 1,4-
dioxane as the solvent. We were delighted to find that the
desired product 3a formed in 95% yield. Encouraged by
this result, we next investigated the scope of the process
with respect to the N-tosylhydrazone substrate (see
Scheme 1). N-Tosylhydrazones with halogen atoms on the
aromatic ring (fluorine, chorine, bromine) afforded the 3H-
pyrazoles in high yields (Scheme 1, 3b–3d). N-Tosylhydraz-
ones with electron-donating groups (methyl, methoxy) and
those with electron-withdrawing groups (phenyl, trifluoro-
methyl, nitro) also gave the desired products in good yields
(Scheme 1, 3e–3j, 3m, and 3n). However, if the ortho posi-
tion of the aromatic ring is blocked, the product yields de-
cline dramatically (Scheme 1, 3k and 3l). Notably, these
transformations also proceed on a large scale; reactions
with 5 mmol of the N-tosylhydrazone also afforded the
products in 87–92% yields (Scheme 1, 3a, 3d, and 3g).
Although new synthetic methods for 3H-pyrazoles and
their applications have been studied extensively, the design
and synthesis of 3H-pyrazoles with N-tosylhydrazone start-
ing materials and the development of new applications are
[a] School of Chemical Engineering, Nanjing University of Science
and Technology,
XiaoLingWei 200, Nanjing 210094, P. R. China
E-mail: ywei@mail.njust.edu.cn
http://sce.njust.edu.cn/s/54/t/503/45/69/info17769.htm
[‡] These two authors contribute equally.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403141.
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Q. Sha, H. Liu, Y. Wei
FULL PAPER
Scheme 1. Scope of the intramolecular cyclization reaction[a] for the synthesis of 3,5-diaryl-3-(trifluoromethyl)-3H-pyrazoles. [a] Reaction
conditions: 4 (0.5 mmol), K2CO3 (0.6 mmol), 1,4-dioxane (3 mL), 75 °C, 5 h, under air. All yields refer to isolated yield. [b] 5 mmol scale.
With these trifluoromethyl-substituted 3H-pyrazoles in oxide (DMSO) were investigated, and we were delighted to
hand, we next studied their properties to find new applica- find that 6a was obtained in high yield. When toluene and
tions for them. Owing to their relatively unstable nature, we acetonitrile were used, 6a was obtained in a lower yield.
investigated the effect of the solvent on their decomposition
After these investigations, we can conclude that the syn-
(see Table 1). With 1,4-dioxane as solvent, we were sur- thesis of 3a is very useful because it can be applied to the
prised to observe the cleavage of the trifluoromethyl group. synthesis of new 1H-pyrazoles such as 5a and 6a. The prod-
Compounds 5a and 7a were obtained in 53 and 42% yield, ucts can be obtained with excellent regioselectivity, and no
respectively (Table 1, Entry 1). When di-tert-butyl peroxide metal catalyst was used in the whole process.
(DTBP, 3.0 equiv) was added, we were satisfied that 5a was
We next investigated the scope of the formation of 5 with
obtained in 82% yield (Table 1, Entry 10). A decrease in respect to substrates 3 (Scheme 2). Compounds 3 substi-
the amount of DTBP added or the reaction temperature tuted with halogen atoms, electron-donating groups, or
decreased the yield of 5a (Table 1, Entries 11 and 12). When electron-withdrawing groups also afford products 5 in high
(2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) or phenol yields (Scheme 2, 5b–5g). When THF was used as the reac-
(1.1 equiv.) was added to the reaction system, no 5a or 7a tant, the desired product 5h was formed in very low yield
was obtained; instead, 6a was obtained in 83 and 76% (Scheme 2, 5h).
yield, respectively (Table 1, Entries 13 and 14). These results
Products 5 may have isomers 5Ј because there are two
reveal that 5a and 7a may form by radical process. The for- nitrogen atoms, and we must determine which atom was
mation of 6a was believed to occur by a [1,5] sigmatropic substituted in the reaction [this may also be the reason why
rearrangement. Other solvents were studied subsequently; there have been no reported cross-dehydrogenative coupling
when tetrahydrofuran (THF) was used as the solvent, 7a (CDC) reactions between 1H-pyrazoles and dioxane, i.e.,
was obtained in 43% yield as the major product. Com- it is too hard to control the regioselectivity]. To solve this
pound 3a was relatively stable in cyclohexane below 110 °C. problem, the 2D NMR spectrum of 5b was recorded,[8] and
Then, N,N-dimethylformamide (DMF) and dimethyl sulf- from analysis of the 2D spectrum, we unambiguously con-
2
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Design and Synthesis of 3-Trifluoromethyl-3H-pyrazoles
Table 1. The decomposition reaction of 3a in different solvents.[a]
Entry
Solvent
Atmosphere
Additive
5a [%][b]
6a [%][b]
7a [%][b]
1
2
3
4
5
6
7
8
1,4-dioxane
THF
cyclohexane
DMF
DMSO
toluene
acetonitrile
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
air
air
air
air
air
air
air
N2
O2
N2
N2
N2
O2
O2
–
–
–
–
–
–
–
–
–
53
–
–
–
–
–
–
50
59
82
73
41
0
0
Ͻ5
Ͻ5
80
84
65
61
0
0
0
0
0
42
43
Ͻ5
Ͻ5
0
0
0
43
32
Ͻ5
18
Ͻ5
0
9
10
11
12
13
14
DTBP[c]
DTBP[d]
DTBP[e]
TEMPO[f]
phenol[f]
83
76
0
0
[a] Reaction conditions: 3a (0.3 mmol), solvent (3 mL), 110 °C, 16 h. [b] Isolated yield. [c] DTBP (3.0 equiv.) was added, 6 h. [d] DTBP
(0.2 equiv.) was added, 12 h. [e] DTBP (3.0 equiv.) was added, 80 °C, 6 h. [f] 1.1 equiv. of additive was added.
Scheme 2. Scope of the reaction of 3 with 1,4-dioxane.[a,b] [a] Reaction conditions: 3 (0.3 mmol), DTBP (0.9 mmol), 1,4-dioxane (3 mL),
110 °C, N2 atmosphere, 6 h. [b] All yields refer to isolated yields. [c] Determined by GC–MS.
firmed that the product is 5b. The method for the synthesis
Subsequently, we investigated the scope of the formation
of 5 is useful, because 5 can be obtained in high regioselec- of 6 with respect to substrates 3 (Scheme 3). The results
tivity; thus, we can design the synthesis of both 5 and 5Ј revealed that the substituent of the aromatic ring has no
(for comparison, see Scheme 3, 5d and 5g).
significant influence on the yield, that is, similar yields were
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Q. Sha, H. Liu, Y. Wei
FULL PAPER
Scheme 3. Scope of the [1,5] sigmatropic rearrangement of 3 in DMSO. Reaction conditions: 3 (0.3 mmol), DMSO (3 mL), 110 °C, under
air, 10 h. All yields refer to isolated yields.
Scheme 4. One-pot procedure for the synthesis of 5a and 6a.
obtained with halogen groups (Scheme 4, 6b and 6c), elec- terial, the formation of 5a and 6a proceeded smoothly, and
tron-donating groups (Scheme 3, 6d–6f and 6h), or electron- they formed in 84 and 82% yield, respectively (Scheme 4).
withdrawing groups (Scheme 3, 6g and 6i). The trifluoro-
A possible mechanism for the reactions is depicted in
methyl-substituted 1H-pyrazoles were obtained in good Scheme 5. Initially, the diazo compound forms in situ from
yields (69–89%). This reaction was believed to be proceed 4a under basic conditions and subsequently undergoes an
by a [1,5] sigmatropic rearrangement reaction. Both the tri- intramolecular cycloaddition reaction to form the 3H-pyr-
fluoromethyl group and the aromatic ring could migrate, so azole 3a. When 3a is heated in 1,4-dioxane at 110 °C, the
there could be two kinds of products. Eventually, we proved cleavage of trifluoromethyl group occurs, and radical A
that the products were 6, and the structure of 6a was con- forms. Then, radical A captures a hydrogen atom from 1,4-
firmed by X-ray analysis (Scheme 3).[8,9]
dioxane to form product 7a. When 3a is heated in 1,4-di-
To simplify the procedure of the abovementioned reac- oxane at 110 °C, another pathway also occurs. The CF3 or
tions, we investigated a one-pot procedure. We were de- OtBu radical reacts with 1,4-dioxane to form a 1,4-dioxane
lighted to find that with the N-tosylhydrazone starting ma- radical, which reacts with 3a smoothly to form intermediate
4
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Design and Synthesis of 3-Trifluoromethyl-3H-pyrazoles
Scheme 5. Proposed mechanism of the transformations.
to ambient temperature. After concentration in vacuo, the crude
product was purified by column chromatography.
B in excellent regioselectivity owing to the low steric hin-
drance of the nitrogen atom adjacent to the aromatic ring
A. Then, the CF3 group is cleaved from B to afford product
5a. When 3a was heated in DMSO at 110 °C, the CF3 group
is not cleaved; instead, a [1,5] sigmatropic rearrangement
occurs, maybe via intermediate C, and 6a forms in high
yield.
Synthesis of 3,5-Diaryl-3-(trifluoromethyl)-3H-pyrazoles on
a
5 mmol Scale: A Schlenk tube with a magnetic stir bar was charged
with N-tosylhydrazone 4a (5.0 mmol), K2CO3 (6.0 mmol), and 1,4-
dioxane (30 mL). The system was heated to 75 °C with stirring for
5 h. The reaction mixture was then cooled to ambient temperature.
After concentration in vacuo, the crude product was purified by
column chromatography.
Conclusions
Decomposition Reactions of 3,5-Diaryl-3-(trifluoromethyl)-3H-pyr-
azoles in 1,4-Dioxane: A Schlenk tube with a magnetic stir bar was
We have designed and synthesized a series of trifluoro-
methyl-substituted 3H-pyrazoles. They were obtained in
moderate-to-excellent yields (33–96%). Furthermore, we
applied them in the synthesis of N-substituted 1H-pyrazoles
and trifluoromethyl-substituted 1H-pyrazoles. The 1H-pyr-
azoles were all obtained with excellent regioselectivity. The
whole processes can also be performed in one-pot, which
makes the synthesis of 1H-pyrazoles very simple. Further
investigations into the new applications of trifluoromethyl-
substituted 3H-pyrazoles, especially applications involving
radicals (metal-free or metal-catalyzed), are in progress in
our laboratory.
charged
with
3,5-diaryl-3-(trifluoromethyl)-3H-pyrazole
3
(0.3 mmol), DTBP (0.9 mmol), and 1,4-dioxane (3 mL). The sys-
tem was heated to 110 °C under a N2 atmosphere with stirring for
6 h. The reaction mixture was then cooled to ambient temperature.
After concentration in vacuo, the crude product was purified by
column chromatography.
Rearrangement Reactions of 3,5-Diaryl-3-(trifluoromethyl)-3H-pyr-
azoles in DMSO: A Schlenk tube with a magnetic stir bar was
charged
(0.3 mmol) and DMSO (3 mL). The system was heated to 110 °C
with stirring for 10 h. The reaction mixture was then cooled to
ambient temperature, diluted with ethyl acetate (50 mL), and
washed with brine (30 mL) and water (30 mL); the organic layer
was then dried with Na2SO4. After concentration in vacuo, the
crude product was purified by column chromatography.
with
3,5-diaryl-3-(trifluoromethyl)-3H-pyrazole
3
Experimental Section
One-pot Procedure for the Synthesis of 5a: A Schlenk tube with a
magnetic stir bar was charged with N-tosylhydrazone 4a
(0.3 mmol), K2CO3 (0.6 mmol), DTBP (0.9 mmol), and 1,4-di-
oxane (3 mL). The system was heated to 110 °C under a N2 atmo-
sphere with stirring for 6 h. The reaction mixture was then cooled
to ambient temperature. After concentration in vacuo, the crude
product was purified by column chromatography.
General: All chemicals (AR grade) were obtained from commercial
sources and were used without further purification. Petroleum
ether (PE) refers to the fraction boiling in the 60–90 °C range. The
progress of the reactions was monitored by TLC (silica gel, Poly-
gram SILG/UV 254 plates). Column chromatography was per-
formed with silica gel (Silicycle, 200–300 mesh). 1H, 13C, and 19F
NMR spectra were obtained with a Bruker DRX 500 (500 MHz)
spectrometer with samples in CDCl3 or [D6]DMSO with tetrameth-
ylsilane (TMS) as the internal standard. Melting points were ob-
tained with a Yamato melting point apparatus Model MP-21.
One-pot Procedure for the Synthesis of 6a: A Schlenk tube with a
magnetic stir bar was charged with N-tosylhydrazone 4a
(0.3 mmol), K2CO3 (0.6 mmol), and DMSO (3 mL). The system
was heated to 110 °C with stirring for 12 h. The reaction mixture
was then cooled to ambient temperature, diluted with ethyl acetate,
and washed with brine (30 mL) and water (30 mL). The organic
layer was then dried with Na2SO4. After concentration in vacuo,
the crude product was purified by column chromatography.
Synthesis of 3,5-Diaryl-3-(trifluoromethyl)-3H-pyrazoles by Intra-
molecular Cycloaddition Reactions: A Schlenk tube with a magnetic
stir bar was charged with N-tosylhydrazone 4 (0.5 mmol), K2CO3
(0.6 mmol), and 1,4-dioxane (3 mL). The system was heated to
75 °C with stirring for 5 h. The reaction mixture was then cooled
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3,5-Diphenyl-3-(trifluoromethyl)-3H-pyrazole (3a): White solid;
yield 136.8 mg (95%); Rf = 0.75 (PE/EtOAc 10:1); m.p. 133–135 °C.
124.98, 122.28 (q, J = 282 Hz), 103.64 (q, J = 27 Hz) ppm. 19F
NMR (470 MHz, CDCl3): δ = –69.80 ppm. MS (EI, 70 eV): m/z =
364. HRMS (EI, 70 eV): calcd. for C22H15F3N2 364.1186; found
364.1187.
IR (film): ν = 3108, 1625, 1489, 1171, 1156, 1120, 766, 698 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 8.11 (d, J = 7.0 Hz, 2 H), 7.77–
7.76 (m, 2 H), 7.53–7.47 (m, 3 H), 7.46–7.43 (m, 3 H), 7.38 (s, 1
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.69, 130.44, 129.78,
129.32, 129.13, 128.86, 127.78, 125.25, 122.27 (q, J = 282 Hz),
103.55 (q, J = 27 Hz) ppm. 19F NMR (470 MHz, CDCl3): δ =
–69.83 ppm. MS (EI, 70 eV): m/z = 288. HRMS (EI, 70 eV): calcd.
for C16H11F3N2 288.0870; found 288.0874.
5-(4-Methoxyphenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3g):
White solid; yield 146.3 mg (92%); Rf = 0.36 (PE/EtOAc 10:1); m.p.
113–115 °C. IR (film): ν = 3104, 1625, 1511, 1276, 1199, 1169,
˜
1
1157, 731, 722, 698 cm–1. H NMR (500 MHz, CDCl3): δ = 8.06
(d, J = 9 Hz, 2 H), 7.77–7.76 (m, 2 H), 7.43–7.42 (m, 3 H), 7.21 (s,
1 H), 7.02 (d, J = 8.5 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 161.37, 159.40, 130.06, 129.68, 129.34,
129.31, 128.79, 122.52, 122.37 (q, J = 282 Hz), 121.88, 114.58,
103.45 (q, J = 27 Hz), 55.44 ppm. 19F NMR (470 MHz, CDCl3): δ
= –69.93 ppm. MS (EI, 70 eV): m/z = 318. HRMS (EI, 70 eV):
calcd. for C17H13F3N2O 318.0977; found 318.0980.
5-(4-Fluorophenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3b):
White solid; yield 137.7 mg (90%); Rf = 0.70 (PE/EtOAc 10:1); m.p.
111–112 °C. IR (film): ν = 3102, 1627, 1601, 1174, 1160, 1120,
˜
1
1072, 718, 698 cm–1. H NMR (500 MHz, CDCl3): δ = 8.11 (dd, J
= 8.5, 5.5 Hz, 2 H), 7.76 (s, 2 H), 7.44–7.43 (m, 3 H), 7.32 (s, 1 H),
7.22–7.18 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 163.94
(d, J = 250 Hz), 158.61, 129.84, 129.79, 129.70, 129.29, 128.88,
125.50, 124.83, 122.23 (q, J = 282 Hz), 116.33 (d, J = 22 Hz),
103.81 (q, J = 27 Hz) ppm. 19F NMR (470 MHz, CDCl3): δ =
–69.85, –109.11 ppm. MS (EI, 70 eV): m/z = 306. HRMS (EI,
70 eV): calcd. for C16H10F4N2 306.0782; found 306.0783.
5-(3-Methoxyphenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3h):
White solid; yield 147.9 mg (93%); Rf = 0.51 (PE/EtOAc 10:1); m.p.
92–93 °C. IR (film): ν = 3103, 1629, 1589, 1172, 1159, 1120, 759,
˜
695 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.77–7.76 (m, 2 H),
7.68–7.66 (m, 2 H), 7.47–7.40 (m, 4 H), 7.36 (s, 1 H), 7.02 (dd, J
= 8.5, 2.5 Hz, 1 H), 3.89 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 160.13, 159.57, 130.43, 130.23, 129.79, 129.31, 128.86,
125.59, 122.26 (q, J = 282 Hz), 120.22, 116.58, 112.81, 103.54 (q,
J = 27 Hz), 55.47 ppm. 19F NMR (470 MHz, CDCl3): δ = –69.80
ppm. MS (EI, 70 eV): m/z = 318. HRMS (EI, 70 eV): calcd. for
C17H13F3N2O 318.0984; found 318.0983.
5-(4-Chlorophenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3c):
White solid; yield 138.5 mg (86%); Rf = 0.72 (PE/EtOAc 10:1); m.p.
136–138 °C. IR (film): ν = 3105, 1627, 1494, 1175, 1159, 1106, 726,
˜
699, 591 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J =
8.5 Hz, 2 H), 7.76–7.14 (m, 2 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.44–
7.43 (m, 3 H), 7.37 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ
= 158.54, 136.52, 129.87, 129.58, 129.45, 129.28, 129.04, 128.91,
127.67, 125.67, 122.17 (q, J = 282 Hz), 103.88 (q, J = 27 Hz) ppm.
19F NMR (470 MHz, CDCl3): δ = –69.79 ppm. MS (EI, 70 eV):
m/z = 322. HRMS (EI, 70 eV): calcd. for C16H10ClF3N2 322.0487;
found 322.0485.
5-(4-Nitrophenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3i):
Yellow solid; yield 146.5 mg (88%); Rf = 0.41 (PE/EtOAc 10:1);
m.p. 133–135 °C. IR (film): ν = 3106, 1606, 1515, 1341, 1204, 1168,
˜
717, 693 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.37 (d, J = 9 Hz,
2 H), 8.29 (d, J = 9 Hz, 2 H), 7.76–7.75 (m, 2 H), 7.61 (s, 1 H),
7.46–7.44 (m, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 157.37,
148.78, 134.98, 130.14, 129.47, 129.28, 129.07, 128.67, 124.40,
121.99 (q, J = 282 Hz), 104.36 (q, J = 27 Hz) ppm. 19F NMR
(470 MHz, CDCl3): δ = –69.58 ppm. MS (EI, 70 eV): m/z = 333.
HRMS (EI, 70 eV): calcd. for C16H10F3N3O2 333.0720; found
333.0716.
5-(4-Bromophenyl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3d):
White solid; yield 173.8 mg (95%); Rf = 0.70 (PE/EtOAc 10:1); m.p.
151–153 °C. IR (film): ν = 3105, 1626, 1489, 1174, 1159, 843, 820,
˜
1
586 cm–1. H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.5 Hz, 2
H), 7.76–7.75 (m, 2 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.44–7.43 (m, 3
H), 7.40 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 158.63,
132.41, 129.90, 129.53, 129.29, 129.24, 128.93, 128.10, 125.83,
124.85, 122.15 (q, J = 282 Hz), 103.92 (q, J = 26 Hz) ppm. 19F
NMR (470 MHz, CDCl3): δ = –69.76 ppm. MS (EI, 70 eV): m/z =
366. HRMS (EI, 70 eV): calcd. for C16H10BrF3N2 365.9981; found
365.9980.
3-Phenyl-3-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3H-pyr-
azole (3j): White solid; yield 170.9 mg (96%); Rf = 0.66 (PE/EtOAc
10:1); m.p. 115–117 °C. IR (film): ν = 3110, 1612, 1469, 1168, 1131,
˜
1
1109, 746, 699 cm–1. H NMR (500 MHz, CDCl3): δ = 8.24 (d, J
= 8 Hz, 2 H), 7.78–7.76 (m, 4 H), 7.54 (s, 1 H), 7.47–7.44 (m, 3 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 158.24, 132.49, 132.17 (q,
J = 33 Hz), 130.01, 129.31, 129.00, 128.10, 127.80, 126.12, 123.80
(q, J = 271 Hz), 122.13 (q, J = 282 Hz), 104.11 (q, J = 27 Hz) ppm.
19F NMR (470 MHz, CDCl3): δ = –62.94, –69.72 ppm. MS (EI,
70 eV): m/z = 356. HRMS (EI, 70 eV): calcd. for C17H10F6N2
356.0746; found 356.0748.
3-Phenyl-5-(p-tolyl)-3-(trifluoromethyl)-3H-pyrazole (3e): White so-
lid; yield 137.5 mg (91%); Rf = 0.77 (PE/EtOAc 10:1); m.p. 148–
150 °C. IR (film): ν = 3104, 1624, 1160, 1120, 1073, 812, 727, 713
˜
1
cm–1. H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 8.0 Hz, 2 H),
7.77–7.76 (m, 2 H), 7.43–7.42 (m, 3 H), 7.32–7.30 (m, 3 H), 2.43
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.76, 140.74,
129.93, 129.83, 129.72, 129.31, 128.82, 127.71, 126.45, 124.07,
122.33 (q, J = 282 Hz), 103.45 (q, J = 27 Hz), 21.53 ppm. 19F NMR
(470 MHz, CDCl3): δ = –69.86 ppm. MS (EI, 70 eV): m/z = 302.
HRMS (EI, 70 eV): calcd. for C17H13F3N2 302.1032; found
302.1031.
5-(Naphthalen-1-yl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole (3k):
White solid; yield 55.8 mg (33%); Rf = 0.71 (PE/EtOAc 10:1); m.p.
111–113 °C. IR (film): ν = 3107, 1626, 1584, 1177, 1165, 729, 693
˜
1
cm–1. H NMR (500 MHz, CDCl3): δ = 8.07–8.05 (m, 1 H), 8.01–
7.98 (m, 2 H), 7.96–7.94 (m, 1 H), 7.85–7.84 (m, 2 H), 7.60–7.55
(m, 3 H), 7.48–7.47 (m, 4 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 159.70, 131.24, 130.81, 130.47, 129.90, 129.62, 129.43, 128.97,
128.88, 128.59, 127.35, 127.00, 126.46, 125.22, 124.86, 122.34 (q, J
= 282 Hz), 103.87 (q, J = 27 Hz) ppm. 19F NMR (470 MHz,
CDCl3): δ = –69.79 ppm. MS (EI, 70 eV): m/z = 338. HRMS (EI,
70 eV): calcd. for C20H13F3N2 338.1028; found 338.1031.
5-([1,1Ј-Biphenyl]-4-yl)-3-phenyl-3-(trifluoromethyl)-3H-pyrazole
(3f): White solid; yield 125.6 mg (69%); Rf = 0.59 (PE/EtOAc 10:1);
m.p. 199–202 °C. IR (film): ν = 3095, 1625, 1488, 1172, 1120, 1073,
˜
720, 700 cm–1 1H NMR (500 MHz, CDCl3): δ = 8.19 (d, J =
.
8.5 Hz, 2 H), 7.78–7.77 (m, 2 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.65
(d, J = 7.5 Hz, 2 H), 7.49–7.43 (m, 5 H), 7.41–7.38 (m, 2 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 159.40, 143.20, 140.12, 129.79,
3-Phenyl-5-(o-tolyl)-3-(trifluoromethyl)-3H-pyrazole (3l): White so-
129.31, 128.97, 128.87, 128.24, 128.07, 127.98, 127.77, 127.14, lid; yield 69.5 mg (46 %); Rf = 0.77 (PE/EtOAc 10:1); m.p. 80–
6
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Job/Unit: O43141
/KAP1
Date: 27-10-14 13:06:44
Pages: 10
Design and Synthesis of 3-Trifluoromethyl-3H-pyrazoles
82 °C. IR (film): ν = 3111, 1619, 1489, 1198, 1170, 730, 693 cm–1. 3.83 (td, J = 11, 2 Hz, 1 H), 3.77–3.75 (m, 1 H) ppm. 13C NMR
˜
1H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 7.5 Hz, 1 H), 7.79–
(125 MHz, CDCl3): δ = 152.12, 145.19, 132.79, 132.12, 130.49,
7.78 (m, 2 H), 7.45–7.44 (m, 3 H), 7.40–7.33 (m, 3 H), 7.24 (s, 1
128.75, 128.60, 128.18, 125.97, 123.47, 104.23, 81.00, 68.45, 66.66,
H), 2.49 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.69, 65.70 ppm. MS (EI, 70 eV): m/z = 384. HRMS (EI, 70 eV): calcd.
137.44, 131.25, 130.01, 129.81, 129.70, 129.32, 129.13, 128.89, for C19H17BrN2O2 384.0476; found 384.0473.
126.29, 122.32 (q, J = 282 Hz), 103.38 (q, J = 26 Hz), 21.67 ppm.
1-(1,4-Dioxan-2-yl)-3-phenyl-5-(p-tolyl)-1H-pyrazole (5d): White so-
19F NMR (470 MHz, CDCl3): δ = –69.92 ppm. MS (EI, 70 eV):
lid; yield 74.8 mg (78 %); Rf = 0.38 (PE/EtOAc 10:1); m.p. 99–
m/z = 302. HRMS (EI, 70 eV): calcd. for C17H13F3N2 302.1033;
found 302.1033.
101 °C. IR (film): ν = 2915, 2850, 1461, 1309, 1122, 1082, 1075,
˜
1
921, 760, 688, 636 cm–1. H NMR (500 MHz, CDCl3): δ = 7.87–
3-(4-Bromophenyl)-5-phenyl-3-(trifluoromethyl)-3H-pyrazole (3m): 7.86 (m, 2 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.41–7.38 (m, 2 H), 7.33–
White solid; yield 162.9 mg (89%); Rf = 0.73 (PE/EtOAc 10:1); m.p. 7.29 (m, 3 H), 6.64 (s, 1 H), 5.41 (dd, J = 9, 2.5 Hz, 1 H), 4.54 (dd,
125–126 °C. IR (film): ν = 3099, 1626, 1489, 1181, 1167, 1128, 713, J = 11.5, 9 Hz, 1 H), 4.05–4.02 (m, 1 H), 3.94–3.89 (m, 2 H), 3.84
˜
1
689 cm–1. H NMR (500 MHz, CDCl3): δ = 8.10 (d, J = 6.5 Hz, 2 (td, J = 11.5, 2.5 Hz, 1 H), 3.75 (dd, J = 11.5, 2.5 Hz, 1 H), 2.44
H), 7.64 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 8.5 Hz, 2 H), 7.53–7.47 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.00, 146.42,
(m, 3 H), 7.31 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
139.07, 133.10, 129.56, 128.85, 128.53, 127.99, 126.96, 125.98,
160.07, 132.09, 130.82, 130.63, 129.19, 128.96, 128.61, 127.83, 103.82, 80.94, 68.94, 66.68, 65.71, 21.36 ppm. MS (EI, 70 eV): m/z
124.46, 121.97 (q, J = 282 Hz), 103.13 (q, J = 27 Hz) ppm. 19F = 320. HRMS (EI, 70 eV): calcd. for C20H20N2O2 320.1529; found
NMR (470 MHz, CDCl3): δ = –69.87 ppm. MS (EI, 70 eV): m/z =
366. HRMS (EI, 70 eV): calcd. for C16H10BrF3N2 366.9978; found
366.9979.
320.1525.
1-(1,4-Dioxan-2-yl)-5-(3-methoxyphenyl)-3-phenyl-1H-pyrazole (5e):
White solid; yield 75.7 mg (75%); Rf = 0.22 (PE/EtOAc 10:1); m.p.
5-Phenyl-3-(p-tolyl)-3-(trifluoromethyl)-3H-pyrazole (3n): White so-
lid; yield 142.0 mg (94%); Rf = 0.80 (PE/EtOAc 10:1); m.p. 164–
123–125 °C. IR (film): ν = 2967, 2850, 1578, 1436, 1409, 1233,
˜
1
1075, 783, 693 cm–1. H NMR (500 MHz, CDCl3): δ = 7.87 (d, J
166 °C. IR (film): ν = 3102, 1625, 1512, 1193, 1165, 763, 710, 690 = 7.5 Hz, 2 H), 7.42–7.39 (m, 3 H), 7.34–7.31 (m, 1 H), 7.16–7.13
˜
1
cm–1. H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 7 Hz, 2 H), (m, 2 H), 7.01 (d, J = 7.5 Hz, 1 H), 6.68 (s, 1 H), 5.45 (d, J =
7.67 (d, J = 8 Hz, 2 H), 7.53–7.46 (m, 3 H), 7.40 (s, 1 H), 7.25 (d,
9.5 Hz, 1 H), 4.58–4.54 (m, 1 H), 4.05 (d, J = 11.5 Hz, 1 H), 3.96–
J = 8 Hz, 2 H), 7.37 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): 3.92 (m, 2 H), 3.87 (s, 3 H), 3.85–3.83 (m, 1 H), 3.76 (d, J =
δ = 159.59, 139.97, 130.40, 129.58, 129.29, 129.20, 129.13, 127.77, 11.5 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 159.85,
126.79, 125.53, 122.39 (q, J = 282 Hz), 103.46 (q, J = 27 Hz), 21.20
152.02, 146.23, 133.00, 131.06, 129.93, 128.55, 128.05, 125.98,
ppm. 19F NMR (470 MHz, CDCl3): δ = –69.95 ppm. MS (EI, 121.29, 114.84, 114.33, 104.03, 80.99, 68.55, 66.70, 65.71, 55.37
70 eV): m/z = 302. HRMS (EI, 70 eV): calcd. for C17H13F3N2 ppm. MS (EI, 70 eV): m/z = 336. HRMS (EI, 70 eV): calcd. for
302.1032; found 302.1031.
C20H20N2O3 336.1478; found 336.1747.
1-(1,4-Dioxan-2-yl)-3,5-diphenyl-1H-pyrazole (5a): White solid;
yield 75.3 mg (82%); Rf = 0.36 (PE/EtOAc 10:1); m.p. 132–134 °C.
1-(1,4-Dioxan-2-yl)-3-phenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyr-
azole (5f): White solid; yield 100.9 mg (90%); Rf = 0.38 (PE/EtOAc
IR (film): ν = 2915, 2857, 1486, 1439, 1258, 1116, 1088, 1076, 928,
10:1); m.p. 72–74 °C. IR (film): ν = 2956, 2926, 1462, 1324, 1123,
˜
˜
1
1
765, 702, 691 cm–1. H NMR (500 MHz, CDCl3): δ = 7.85 (d, J =
1085, 766, 678 cm–1. H NMR (500 MHz, CDCl3): δ = 7.88 (m, 2
7.5 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 2 H), 7.48–7.43 (m, 3 H), 7.39–
H), 7.77 (d, J = 8 Hz, 2 H), 7.71 (d, J = 8.5 Hz, 2 H), 7.43–7.40
7.36 (m, 2 H), 7.31–7.28 (m, 1 H), 6.64 (s, 1 H), 5.39 (dd, J = 6, (m, 2 H), 7.35–7.33 (m, 1 H), 6.73 (s, 1 H), 5.36 (dd, J = 9.5,
2.5 Hz, 1 H), 4.03–4.00 (m, 1 H), 3.93–3.81 (m, 3 H), 3.74–3.71 (m, 2.5 Hz, 1 H), 4.56 (dd, J = 11.5, 9 Hz, 1 H), 4.06 (d, J = 11.5 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.05, 146.37, 1 H), 3.97–3.90 (m, 2 H), 3.85 (td, J = 11.5, 2.5 Hz, 1 H), 3.79–
133.01, 129.87, 129.05, 128.98, 128.88, 128.57, 128.06, 125.99, 3.76 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.20,
104.05, 80.97, 68.57, 66.71, 65.72 ppm. MS (EI, 70 eV): m/z = 306.
144.85, 133.39, 132.66, 129.26, 128.62, 128.26, 125.97, 125.85,
HRMS (EI, 70 eV): calcd. for C19H18N2O2 306.1365; found 104.68, 81.09, 68.41, 66.65, 65.69 ppm. 19F NMR (470 MHz,
306.1368.
CDCl3): δ = –62.74 ppm. MS (EI, 70 eV): m/z = 374. HRMS (EI,
70 eV): calcd. for C20H17F3N2O2 374.1246; found 374.1242.
5-(4-Chlorophenyl)-1-(1,4-dioxan-2-yl)-3-phenyl-1H-pyrazole (5b):
White solid; yield 86.7 mg (85%); Rf = 0.41 (PE/EtOAc 10:1); m.p.
1-(1,4-Dioxan-2-yl)-5-phenyl-3-(p-tolyl)-1H-pyrazole (5g): White so-
lid; yield 77.8 mg (81%); Rf = 0.33 (PE/EtOAc 10:1); m.p. 100–
120–122 °C. IR (film): ν = 2920, 2851, 1463, 1318, 1083, 1074,
˜
1030, 919, 763, 682 cm–1. H NMR (500 MHz, CDCl3): δ = 7.87– 102 °C. IR (film): ν = 2917, 2857, 1456, 1298, 1082, 1061, 1035,
1
˜
1
7.85 (m, 2 H), 7.52–7.46 (m, 4 H), 7.42–7.39 (m, 2 H), 7.34–7.31
921, 852, 834, 701 cm–1. H NMR (500 MHz, CDCl3): δ = 7.77 (d,
(m, 1 H), 6.66 (s, 1 H), 5.34 (dd, J = 9, 2.5 Hz, 1 H), 4.55 (dd, J =
J = 8 Hz, 2 H), 7.58–7.56 (m, 2 H), 7.52–7.45 (m, 3 H), 7.22 (d, J
11.5, 9 Hz, 1 H), 4.05–4.02 (m, 1 H), 3.96–3.88 (m, 2 H), 3.84 (td, = 8 Hz, 2 H), 6.64 (s, 1 H), 5.41 (dd, J = 9.5, 2.5 Hz, 1 H), 4.55
J = 11.5, 2.5 Hz, 1 H), 3.77–3.75 (m, 1 H) ppm. 13C NMR (dd, J = 11.5, 9.5 Hz, 1 H), 4.04 (d, J = 11.5 Hz, 1 H), 3.95–3.90
(125 MHz, CDCl3): δ = 152.08, 145.18, 135.28, 132.77, 130.24,
(m, 2 H), 3.85 (td, J = 11.5, 2.5 Hz, 1 H), 3.77–3.74 (m, 1 H), 2.38
129.16, 128.59, 128.28, 128.18, 125.98, 104.25, 81.01, 68.44, 66.67, (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 152.11, 146.25,
65.70 ppm. MS (EI, 70 eV): m/z = 340. HRMS (EI, 70 eV): calcd.
for C19H17ClN2O2 340.0974; found 340.0974.
137.80, 130.23, 129.96, 129.56, 129.25, 128.97, 128.85, 125.89,
103.89, 80.97, 68.59, 66.70, 65.71, 21.34 ppm. MS (EI, 70 eV): m/z
= 320. HRMS (EI, 70 eV): calcd. for C20H20N2O2 320.1520; found
320.1525.
5-(4-Bromophenyl)-1-(1,4-dioxan-2-yl)-3-phenyl-1H-pyrazole (5c):
White solid; yield 92.1 mg (80%); Rf = 0.39 (PE/EtOAc 10:1); m.p.
111–113 °C. IR (film): ν = 2962, 2850, 1463, 1317, 1083, 956, 875, 4,5-Diphenyl-3-(trifluoromethyl)-1H-pyrazole (6a): White solid;
˜
713, 681 cm–1 1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = yield 72.6 mg (84%); Rf = 0.56 (PE/EtOAc 3:1); m.p. 187–188 °C.
.
7.5 Hz, 2 H), 7.63 (d, J = 8 Hz, 2 H), 7.45–7.39 (m, 4 H), 7.34–
7.31 (m, 1 H), 6.66 (s, 1 H), 5.34 (dd, J = 9, 2.5 Hz, 1 H), 4.54 (dd,
IR (film): ν = 2922, 1479, 1159, 1127, 986, 743, 694 cm–1. 1H NMR
˜
(500 MHz, [D6]DMSO): δ = 14.05 (s, 1 H), 7.38–7.28 (m, 8 H),
J = 11.5, 9 Hz, 1 H), 4.03 (d, J = 12 Hz, 1 H), 3.96–3.88 (m, 2 H), 7.23–7.22 (m, 2 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43141
/KAP1
Date: 27-10-14 13:06:44
Pages: 10
Q. Sha, H. Liu, Y. Wei
142.07, 140.03 (q, J = 35 Hz), 131.28, 130.58, 129.28, 129.21, 3:1); m.p. 173–176 °C. IR (film): ν = 2924, 1479, 1325, 1125, 1066,
FULL PAPER
˜
128.96, 128.57, 128.28, 128.11, 122.38 (q, J = 268 Hz), 117.93 ppm.
846, 706 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 14.29 (s, 1
19F NMR (470 MHz, [D6]DMSO): δ = –58.13 ppm. MS (EI, H), 7.71 (d, J = 8 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.40–7.35 (m,
70 eV): m/z = 288. HRMS (EI, 70 eV): calcd. for C16H11F3N2 3 H), 7.25–7.23 (m, 2 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ
288.0873; found 288.0874.
= 140.62, 140.28 (q, J = 37 Hz), 132.56, 130.77, 130.49, 129.45 (q,
J = 32 Hz), 129.09, 128.77, 128.51, 126.12, 124.39 (q, J = 270 Hz),
122.22 (q, J = 270 Hz), 118.87 ppm. 19F NMR (470 MHz, [D6]-
DMSO): δ = –58.28, –61.42 ppm. MS (EI, 70 eV): m/z = 356.
HRMS (EI, 70 eV): calcd. for C17H10F6N2 356.0746; found
356.0748.
5-(4-Fluorophenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (6b):
White solid; yield 72.5 mg (79%); Rf = 0.60 (PE/EtOAc 3:1); m.p.
213–214 °C. IR (film): ν = 3066, 1156, 1119, 987, 842, 696, 651
˜
1
cm–1. H NMR (500 MHz, [D6]DMSO): δ = 14.07 (s, 1 H), 7.37–
7.31 (m, 5 H), 7.23–7.18 (m, 4 H) ppm. 13C NMR (125 MHz, [D6]-
DMSO): δ = 162.68 (d, J = 245 Hz), 141.19, 140.03 (q, J = 35 Hz), 5-Phenyl-4-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazole (6h): White so-
131.11, 130.55, 130.43, 130.37, 129.00, 128.32, 125.09, 122.34 (q, J
lid; yield 80.7 mg (89 %); Rf = 0.55 (PE/EtOAc 3:1); m.p. 193–
194 °C. IR (film): ν˜ = 3205, 2928, 1534, 1474, 1126, 1092, 986, 822,
= 268 Hz), 117.93, 116.28 (d, J = 22 Hz) ppm. 19F NMR
(470 MHz, [D6]DMSO): δ = –58.21, –112.24 ppm. MS (EI, 70 eV): 697 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 14.01 (s, 1 H),
m/z = 306. HRMS (EI, 70 eV): calcd. for C16H10F4N2 306.0775;
found 306.0780.
7.33–7.31 (m, 5 H), 7.17 (d, J = 8 Hz, 2 H), 7.11 (d, J = 8 Hz, 2
H), 2.30 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ =
141.96, 140.09 (q, J = 34 Hz), 137.49, 130.41, 129.58, 129.20,
128.69, 128.22, 128.08, 122.41 (q, J = 268 Hz), 117.85, 21.24 ppm.
19F NMR (470 MHz, [D6]DMSO): δ = –58.14 ppm. MS (EI,
70 eV): m/z = 302. HRMS (EI, 70 eV): calcd. for C17H13F3N2
302.1034; found 302.1031.
5-(4-Bromophenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (6c):
White solid; yield 79.1 mg (72%); Rf = 0.65 (PE/EtOAc 3:1); m.p.
207–208 °C. IR (film): ν = 2990, 1476, 1260, 1171, 1156, 987, 828,
˜
697 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 14.13 (s, 1 H),
7.56 (d, J = 8.5 Hz, 2 H), 7.39–7.36 (m, 3 H), 7.22–7.21 (m, 4 H)
ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 141.01, 140.11 (q, J
= 35 Hz), 132.25, 130.94, 130.50, 130.10, 129.07, 128.42, 127.77,
122.80, 122.29 (q, J = 268 Hz), 118.22 ppm. 19F NMR (470 MHz,
[D6]DMSO): δ = –58.17 ppm. MS (EI, 70 eV): m/z = 366. HRMS
(EI, 70 eV): calcd. for C16H10BrF3N2 366.9978; found 366.9979.
5-(4-Nitrophenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (6i):
Yellow solid; yield 84.9 mg (85%); Rf = 0.53 (PE/EtOAc 3:1); m.p.
243–245 °C. IR (film): ν = 2933, 1523, 1345, 1176, 1125, 1002, 861,
˜
778, 696 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 14.40 (s, 1
H), 8.20 (d, J = 8.5 Hz, 2 H), 7.53 (d, J = 9 Hz, 2 H), 7.41–7.40 (m,
3 H), 7.26–7.25 (m, 2 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ
= 147.72, 140.39 (q, J = 35 Hz), 140.10, 134.81, 130.49, 129.21,
128.71, 124.42, 122.13 (q, J = 268 Hz), 119.44 ppm. 19F NMR
(470 MHz, [D6]DMSO): δ = –58.21 ppm. MS (EI, 70 eV): m/z =
333. HRMS (EI, 70 eV): calcd. for C16H10F3N3O2 333.0724; found
333.0725.
4-Phenyl-5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazole (6d): White so-
lid; yield 63.4 mg (70 %); Rf = 0.65 (PE/EtOAc 3:1); m.p. 202–
203 °C. IR (film): ν = 2970, 1477, 1265, 1155, 1121, 986, 820, 697
˜
1
cm–1. H NMR (500 MHz, [D6]DMSO): δ = 13.98 (s, 1 H), 7.37–
7.32 (m, 3 H), 7.21 (d, J = 6.5 Hz, 2 H), 7.17 (d, J = 8 Hz, 2 H),
7.13 (d, J = 8 Hz, 2 H), 2.25 (s, 3 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 142.13, 139.98 (q, J = 34 Hz), 131.42, 130.56,
129.75, 128.92, 128.18, 127.98, 125.72, 122.41 (q, J = 282 Hz),
117.61, 21.19 ppm. 19F NMR (470 MHz, [D6]DMSO): δ = –58.14
ppm. MS (EI, 70 eV): m/z = 302. HRMS (EI, 70 eV): calcd. for
C17H13F3N2 302.1033; found 302.1031.
Supporting Information (see footnote on the first page of this arti-
cle): All experimental procedures, characterization data, and the
1H, 13C, and 19F NMR spectra.
Acknowledgments
5-(3-Methoxyphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (6e):
White solid; yield 77.3 mg (81%); Rf = 0.50 (PE/EtOAc 3:1); m.p.
The authors thank the Jiangsu Higher Education Institutions, Pri-
ority Academic Program Development (PAPD) for project funding.
We also thank the Shanghai Institute of Organic Chemistry, Chi-
nese Academy of Sciences for recording the MS and HRMS spec-
tra. Nanjing University is thanked for the X-ray analysis.
161–162 °C. IR (film): ν = 2940, 1605, 1471, 1300, 1144, 1120, 980,
˜
759, 698 cm–1. 1H NMR (500 MHz, [D6]DMSO): δ = 14.06 (s, 1
H), 7.40–7.36 (m, 3 H), 7.25–7.23 (m, 3 H), 6.90–6.85 (m, 3 H),
3.59 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 159.67,
141.78, 140.09 (q, J = 35 Hz), 131.38, 130.64, 130.37, 129.71,
128.97, 128.32, 122.36 (q, J = 267 Hz), 120.08, 118.02, 114.97,
113.42, 55.38 ppm. 19F NMR (470 MHz, [D6]DMSO): δ = –58.18
ppm. MS (EI, 70 eV): m/z = 318. HRMS (EI, 70 eV): calcd. for
C17H13F3N2O 318.0978; found 318.0980.
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5-(4-Methoxyphenyl)-4-phenyl-3-(trifluoromethyl)-1H-pyrazole (6f):
White solid; yield (Z+E): 65.8 mg (69%); Rf = 0.38 (PE/EtOAc
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3:1); m.p. 179–180 °C. IR (film): ν = 3171, 2969, 1615, 1477, 1184,
˜
1
1128, 1095, 986, 834, 698 cm–1. H NMR (500 MHz, [D6]DMSO):
δ = 13.91 (s, 1 H), 7.39–7.34 (m, 3 H), 7.22–7.20 (m, 4 H), 6.90 (d,
J = 8.5 Hz, 2 H), 3.72 (s, 3 H) ppm. 13C NMR (125 MHz, [D6]-
DMSO): δ = 160.05, 141.97, 139.92 (d, J = 35 Hz), 131.51, 130.60,
129.45, 128.95, 128.19, 122.42 (q, J = 268 Hz), 120.86, 117.21,
114.69, 55.67 ppm. 19F NMR (470 MHz, [D6]DMSO): δ = –58.14
ppm. MS (EI, 70 eV): m/z = 318. HRMS (EI, 70 eV): calcd. for
C17H13F3N2O 318.0981; found 318.0981.
4-Phenyl-3-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyr-
azole (6g): White solid; yield 90.8 mg (85%); Rf = 0.60 (PE/EtOAc
8
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Job/Unit: O43141
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Design and Synthesis of 3-Trifluoromethyl-3H-pyrazoles
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[8] For details, see Supporting Information.
[9] CCDC-1012432 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: August 28, 2014
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O43141
/KAP1
Date: 27-10-14 13:06:44
Pages: 10
Q. Sha, H. Liu, Y. Wei
FULL PAPER
Nitrogen Heterocycles
Q. Sha, H. Liu, Y. Wei* ................. 1–10
Design and Synthesis of 3-Trifluoromethyl-
3H-pyrazoles and Further Investigations of
Their Transformation to 1H-Pyrazoles
Keywords: Cycloaddition / Sigmatropic re-
arrangement / Nitrogen heterocycles
The synthesis of trifluoromethyl-substi-
tuted 3H-pyrazoles by an intramolecular
cycloaddition strategy is developed. Sub-
sequently, their wide applications are dem-
onstrated: they (1) react with dioxane by a
radical process and (2) undergo [1,5] sigma-
tropic rearrangements. The products are
obtained in high yields and with excellent
regioselectivity.
10
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