Aluminum Chloride Mediated Reactions of N-Alkylated Tosylhydrazones and Terminal Alkynes: A Regioselective Approach to 1,3,5-Trisubstituted Pyrazoles

Article abstract of DOI:10.1055/s-0035-1561646

Aluminum chloride mediated reactions of N-alkylated tosylhydrazones and terminal alkynes are reported. The protocol is applied to a wide range of substrates, and demonstrates excellent functional group tolerance. A series of 1,3,5-trisubstituted pyrazoles is prepared in good to high yields with complete regioselectivity.

Full text of DOI:10.1055/s-0035-1561646

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
M. Tang et al.
Paper
Synthesis
Aluminum Chloride Mediated Reactions of N-Alkylated Tosyl-
hydrazones and Terminal Alkynes: A Regioselective Approach to
1,3,5-Trisubstituted Pyrazoles
Meng Tang*
R1
R1
complete regioselectivity
Yun Wang
NNTs
N
N
AlCl3, DCE
rt
Hu Wang
R3
high functional group tolerence
65 examples, including 39 new examples
up to 96% isolated yield
+
R2
H
R3
R2
Yuanfang Kong
R1 = alkyl, allyl, benzyl, propargyl
R2 = Ar, furyl; R3 = Ar
School of Pharmacy, Lanzhou University, Lanzhou 730000,
P. R. of China
tangmeng@lzu.edu.cn
Received: 24.03.2016
Accepted after revision: 25.04.2016
Published online: 24.05.2016
tions, lower yields were observed when R2 contained elec-
tron-withdrawing substituents, and only alkyl moieties
were suitable for R1.
DOI: 10.1055/s-0035-1561646; Art ID: ss-2016-h0209-op
Abstract Aluminum chloride mediated reactions of N-alkylated tosyl-
hydrazones and terminal alkynes are reported. The protocol is applied
to a wide range of substrates, and demonstrates excellent functional
group tolerance. A series of 1,3,5-trisubstituted pyrazoles is prepared in
good to high yields with complete regioselectivity.
our previous work, ref. 12
R1
R1
a)
NNTs
N
N
t-BuOK, 18-crown-6
R3
+
R2
H
R3
pyridine, 0 °C
R2
R1 = alkyl;
R2 = Ar; R3 = Ar
Key words aluminum chloride, tosylhydrazones, alkynes, pyrazoles,
regioselectivity
this work
R1
R1
b)
NNTs
N
N
AlCl3, DCE
Pyrazole rings have been found in numerous com-
pounds displaying diverse applications, from pharmaceuti-
cals and agrochemicals1 to supramolecular chemistry2 and
materials science.3 Compounds containing the pyrazole
moiety have been shown to possess a wide range of biologi-
cal activities, and pyrazoles are frequently employed as
building blocks in drug discovery programs.4 Since Knorr’s
seminal report over 130 years ago,5 a wide range of synthet-
ic variants have been reported in the literature.6,7 However,
regioselectivity is still the major issue associated with their
synthesis.8 Meanwhile, 1,3-dipolar cycloaddition reactions
of diazo compounds with alkenes or alkynes have long been
utilized for constructing pyrazole rings.9
R3
+
R2
H
R3
R2
rt
R1 = alkyl, allyl, benzyl, propargyl;
R2 = Ar, furyl; R3 = Ar
Scheme 1 Two complementary methods to access 1,3,5-trisubstituted
pyrazoles
Referring back to previous literature, we found that the
tosylhydrazones react with an alkene or alkyne under acid-
ic conditions resulting in pyrazolines and pyrazoles, respec-
tively.13 Deng and Mani developed a regioselective synthe-
sis of pyrazoles using N-monosubstituted hydrazones in re-
actions with nitroalkenes under acidic conditions.14
A
As an in situ source of diazo compounds,10 tosylhydra-
zones have been reported to react with alkenes or alkynes
to produce pyrazoles under basic conditions.11 More recent-
ly, we reported a regioselective synthesis of 1,3,5-trisubsti-
tuted pyrazoles from N-alkylated tosylhydrazones and ter-
minal alkynes in the presence of t-BuOK and 18-crown-6,12
in which the corresponding diazo intermediates were not
formed, and complete control of the regioselectivity was
achieved (Scheme 1, a). However, possibly due to the insta-
bility of N-alkylated tosylhydrazones under basic condi-
TfOH-mediated cycloaddition reaction of tosylhydrazones
and terminal alkynes to produce pyrazoles has also been re-
ported.15 In addition, metal-catalyzed reactions of hydra-
zones and alkynes are well known.16 Inspired by these find-
ings, we hypothesized that N-alkylated tosylhydrazones
might react with terminal alkynes under acidic conditions
to afford pyrazoles. In continuation of our ongoing interest
in the regioselective synthesis of pyrazoles,12,17 herein, we
present the results of our investigations on this chemistry
(Scheme 1, b).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

B
M. Tang et al.
Paper
Synthesis
Initially, we reacted N-methyl tosylhydrazone 1a with
phenylacetylene (2a) in the presence of various Brønsted
acids in 1,2-dichloroethane (DCE) at room temperature (Ta-
ble 1), and observed that some Brønsted acids promoted
the reaction, even though in most cases the starting materi-
al was not consumed (Table 1, entries 1–7). Next, we tested
several Lewis acids (Table 1, entries 8–12). Gratifyingly, the
use of aluminum chloride (AlCl3) resulted in a good yield of
3a and the reaction was complete within 0.5 hours (Table 1,
entry 8). Decreasing the amount of AlCl3 resulted in a lower
yield (Table 1, entry 9). Of the solvents screened, CH2Cl2,
benzene and toluene gave moderate yields and the reac-
tions required longer times (Table 1, entries 13–15).
dehydes featuring ortho-, meta- and para-substituents as
well as electron-donating and -withdrawing substituents
worked well to furnish the corresponding pyrazole deriva-
tives, and the yields were not affected when the R2 moiety
contained electron-withdrawing substituents. Further-
more, N-alkylated tosylhydrazones derived from furfural
were also suitable substrates for this reaction, with prod-
ucts 3bl and 3bm being obtained in moderate yields. The
reaction was also general for all types of phenylacetylene
derivatives, and the electronic effect on the aromatic ring
had little influence on the reaction. It is noteworthy that,
possibly due to the coordination between the O atom and
AlCl3, when p-methoxyphenylacetylene was used, the
amount of AlCl3 had to be increased to four equivalents to
ensure that the N-alkylated tosylhydrazones were con-
sumed (products 3c, 3g, 3z, 3ad and 3ba), and the yields
were also affected slightly when using N-alkylated tosylhy-
drazones derived from p-methoxybenzaldehyde (products
3ao–at). It was necessary to employ five equivalents of
AlCl3 in the case of the N-methyl tosylhydrazone derived
from 3,4-dimethoxybenzaldehyde (product 3au).
Table 1 Screening the Reaction Conditionsa
Me
Me
NNTs
acid (2.5 equiv), solvent
rt
N
N
+
Ph
Ph
H
Ph
Ph
1a
2a
3a
Entry
Acid
Solvent
Time (h)
Yield (%)b
Compared to our previously reported reactions of N-al-
kylated tosylhydrazones and terminal alkynes in the pres-
ence of t-BuOK, this reaction carried forward the main fa-
vorable characteristics, including both good compatibility
with different substituents and complete control of the re-
gioselectivity. More importantly, the reaction conditions
showed higher functional group tolerance, with the R1 sub-
stituent no longer being limited to alkyl. Allyl, propargyl
and benzyl groups were all applicable and gave the corre-
sponding pyrazoles in good to high yields. Furthermore, in
most cases, the amount of alkyne was reduced (from 4.0
equiv to 2.5 equiv) and the yields were improved. For exam-
ple, the yield of product 3av increased from 48%12 to 90%,
and even pyrazoles containing a nitro group (products 3bi,
3bj and 3bk) were isolated in moderate yields. However, N-
alkylated aliphatic aldehyde tosylhydrazones, aliphatic ter-
minal alkynes and internal alkynes were still unsuitable for
the reaction.
1
2
TfOH
H2SO4
DCE
24
24
24
24
12
12
12
0.5
2
trace
9
DCE
3
HCl (concd)
Cl3CCO2H
AcOH
DCE
trace
6
4
DCE
5
DCE
–
6
PhCO2H
TsOH
DCE
–
7
DCE
–
8
AlCl3
DCE
85
72c
–
9
AlCl3
DCE
10
11
12
13
14
15
Al(Oi-Pr)3
BF3·OEt2
ZnBr2
DCE
12
24
24
2
DCE
trace
trace
70
61
40
DCE
AlCl3
CH2Cl2
benzene
toluene
AlCl3
2
AlCl3
2
Two plausible mechanisms for the transformation are
proposed as shown in Scheme 2. An intuitive pathway is
that the reaction is initiated by the ene-type reaction of the
N-alkylated tosylhydrazone iminium salt 4 with the termi-
nal alkyne, and then H-elimination results in intermediate
5, which subsequently undergoes a 1,3-H shift and intra-
molecular cyclization to form pyrazole 3 (path A). Mean-
while, according to Deng’s hypothesis,13a we proposed a
similar mechanism for the AlCl3-mediated [3+2] cycloaddi-
tion of N-alkylated tosylhydrazone iminium salt 4 with the
terminal alkyne (path B). However, in view of the experi-
mental phenomena, including the fact that internal alkynes
were unsuitable for the reaction and that more than two
equivalents of AlCl3 were needed, we speculate that path A
is more likely.
a Reactions were performed with N-methyl tosylhydrazone 1a (0.2 mmol),
phenylacetylene (2a) (0.5 mmol) and acid (0.5 mmol) in solvent (2 mL).
b Yield of isolated product.
c AlCl3 (0.4 mmol, 2.0 equiv) was used.
Employing the above-optimized conditions, we then at-
tempted to synthesize a variety of pyrazoles to test the gen-
erality and scope of the method. N-Alkylated tosylhydra-
zones 1 were prepared according to our recently reported
procedure via an improved one-pot version.12,18 First, the
scope of the reaction was evaluated with regard to the na-
ture of the R1 substituent. Delightfully, as shown in Table 2,
functional groups such as Me, Et, allyl, propargyl and ben-
zyl were all suitable and allowed the corresponding pyra-
zole derivatives to be prepared in good to high yields. Addi-
tionally, N-alkylated tosylhydrazones derived from benzal-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
M. Tang et al.
Paper
Synthesis
Table 2 Regioselective Synthesis of 1,3,5-Trisubstituted Pyrazolesa
R1
R1
NNTs
+
H
N
N
AlCl3, DCE
rt
R3
R2
R3
R2
1
2
3
Product
Yieldb
Product
Yieldb
81%c
Me
Me
Et
Me
N
N
N
N
N
N
N
N
95%
87%
79%
86%
Ph
Ph
Me
OMe
3b
3c
Et
N
N
N
N
N
56%
81%c
67%
Ph
Ph
Ph
3e
F
3d
Et
N
Ph
Ph
Me
OMe
3f
3g
Et
Ph
N
N
N
N
N
Ph
Ph
Ph
3i
F
3h
Ph
Ph
N
80%
72%
95%
64%
Ph
Ph
F
Me
3j
3k
N
N
N
N
N
Ph
Ph
Ph
3l
Me
3m
N
N
N
N
N
81%
88%
83%
59%
Ph
Ph
Ph
3o
F
3n
N
N
Ph
Ph
Me
F
3p
3q
Me
Me
Me
Me
N
N
N
N
92%
86%
80%
95%
Ph
Me
3r
3s
Me
Me
Me
N
N
N
N
Me
3u
Ph
F
3t
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
M. Tang et al.
Paper
Synthesis
Table 2 (continued)
Product
Yieldb
82%
Product
Me
Yieldb
88%
Me
Me
N
N
N
N
Me
Me
F
3v
3w
Me
Me
N
N
N
N
Ph
83%
90%c
80%
80%
96%
71%
Me
Me
3x
Me
3y
Me
Me
N
N
N
N
F
OMe
Me
3aa
Me
3z
Et
Et
Et
N
N
N
N
Ph
Me
Me
3ab
Me
3ac
Et
N
N
N
N
N
N
N
N
87%c
69%
87%
60%
78%
62%
73%
47%
62%
70%
60%
89%c
OMe
F
Me
3ad
Me
3ae
Ph
Me
Me
3af
Me
3ag
Ph
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
F
Me
3ah
Me
3ai
Ph
Ph
Me
F
Me
3aj
Me
3ak
Ph
Me
Me
3al
Me
3am
Me
N
N
Ph
F
Me
MeO
3an
3ao
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
M. Tang et al.
Paper
Synthesis
Table 2 (continued)
Product
Yieldb
91%c
Product
Yieldb
65%c
Me
Et
N
N
N
N
N
N
N
N
Ph
Ph
Me
Me
Me
MeO
3ap
MeO
3aq
Et
N
61%c
45%c
90%
86%
69%
94%
65%
88%
92%
51%c
63%d
70%
87%
63%c
58%
73%
87%
47% e
MeO
3as
MeO
3ar
Me
N
N
N
MeO
Ph
MeO
3at
MeO
3au
Me
Me
Br
Br
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ph
Me
3av
3ax
3az
3aw
Me
Me
Me
Me
Br
Cl
Cl
Cl
Ph
F
3ay
Me
Cl
Me
OMe
3ba
Cl
Me
N
N
N
Ph
F
3bb
Cl
3bc
Cl
Me
Me
N
N
F
Me
3bd
3be
Me
Me
N
N
N
N
Ph
Me
Cl
3bg
Cl
3bf
Me
Me
N
N
N
N
Ph
F
Cl
O2N
3bh
3bi
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

F
M. Tang et al.
Paper
Synthesis
Table 2 (continued)
Product
Yieldb
36%e
Product
Yieldb
31%e
N
N
N
N
Ph
Ph
O2N
O2N
3bj
3bk
Me
Me
N
N
N
N
54%e
44%e
O
O
Ph
Me
3bl
3bm
a Reactions were performed with N-alkylated tosylhydrazones 1 (0.2 mmol), terminal alkynes 2 (0.5 mmol) and AlCl3 (0.5 mmol) in DCE (2 mL) at r.t. for 30–60
min.
b Yield of isolated product.
c AlCl3 (0.8 mmol, 4.0 equiv) was used.
d AlCl3 (1.0 mmol, 5.0 equiv) was used.
e The corresponding alkyne 2 (0.8 mmol, 4.0 equiv) was used.
R1
N
R1
N
R1
N
1H and 13C NMR spectra were recorded on a Varian Mercury 400 MHz
or a Bruker AVANCE III 400 MHz spectrometer. HRMS data were ob-
tained using a Bruker Daltonics APEXII 47e FT-ICR spectrometer.
Cl3Al
ene
– Ts–
N
N
N
Ts
– H+
R3
R2
A
R2
R3
R2
H
R3
R1
4
5
H
Pyrazoles 3; General Procedure
R1
NH
R1
R1
Under an Ar atm, a mixture of N-alkylated tosylhydrazone 1 (0.2
mmol), alkyne 2 (0.5 mmol) and AlCl3 (0.5 mmol) in DCE (2 mL) was
stirred at r.t. for 30–60 min. After quenching with H2O, the product
was extracted with CH2Cl2 and the organic layer washed with sat.
Na2CO3 solution and brine, dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification by chromatography on silica gel
(PE–EtOAc) afforded the product 3. The NMR data of pyrazoles 3a–h,
3r–t, 3v, 3x, 3y, 3ad, 3ao–ar, 3av, 3ay, 3bb, 3bc, 3be, 3bf and 3bh
have been reported in our previous paper.12
1,3-H
shift
N
N
N
N
NNTs
H+
N
AlCl3
R3
R3
R2
R2
R2
H
AlCl3
R2
Cl3Al
R3
AlCl3
3
– H+
R1
R1
R1
N
Ts
Cl3Al
R2
N
N
Cl3Al
[3+2]
N
Ts
N
– Ts–
H
N
R3
R3
R3
R2
B
R2
H
4
Scheme 2 Proposed mechanism for the AlCl3-mediated reaction of N-
alkylated tosylhydrazones with terminal alkynes
1-Benzyl-3,5-diphenyl-1H-pyrazole (3i)
Compound 3i was obtained as a white solid (41.6 mg, 67%) according
to the general procedure.
Mp 114–117 °C.
In summary, we have developed a Lewis acid mediated
reaction of N-alkylated tosylhydrazones with terminal
alkynes to synthesize 1,3,5-trisubstituted pyrazoles with
complete regioselectivity. The protocol was applied to a
wide range of substrates, and demonstrated excellent toler-
ance to a variety of substituents, including both electron-
donating and -withdrawing examples. Additionally, com-
pared with the reactions of N-alkylated tosylhydrazones
and terminal alkynes in the presence of t-BuOK, the present
reaction conditions showed superior functional group tol-
erance.
1H NMR (400 MHz, CDCl3): δ = 5.38 (s, 2 H), 6.66 (s, 1 H), 7.09 (d, J =
7.2 Hz, 2 H), 7.21–7.30 (m, 4 H), 7.32–7.42 (m, 7 H), 7.87 (d, J = 7.2 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 53.2, 103.7, 125.6, 126.7, 127.4, 127.6,
128.55, 128.56, 128.6, 128.8, 130.6, 133.4, 137.7, 145.4, 150.9.
HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1543; found:
311.1536.
1-Benzyl-3-phenyl-5-(p-tolyl)-1H-pyrazole (3j)
Compound 3j was obtained as a yellow solid (51.9 mg, 80%) according
to the general procedure.
Mp 83–85 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 5.38 (s, 2 H), 6.64 (s, 1 H),
7.11 (d, J = 7.2 Hz, 2 H), 7.18–7.32 (m, 8 H), 7.38–7.42 (m, 2 H), 7.86–
7.88 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 53.1, 103.5, 125.6, 126.6, 127.3,
127.6, 128.6, 128.7, 129.3, 133.5, 137.8, 138.6, 145.5, 150.9.
Products were purified by flash column chromatography using Qing-
dao Haiyang silica gel (200–300 mesh). Light petroleum ether (PE) re-
fers to the fraction boiling in the 30–60 °C range. All organic extracts
were dried over anhydrous MgSO4. Melting points are uncorrected.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
M. Tang et al.
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2: 325.1699; found:
3,5-Diphenyl-1-(prop-2-yn-1-yl)-1H-pyrazole (3o)
325.1704.
Compound 3o was obtained as a white solid (42.9 mg, 83%) according
to the general procedure.
1-Benzyl-5-(4-fluorophenyl)-3-phenyl-1H-pyrazole (3k)
Mp 93–95 °C.
Compound 3k was obtained as a yellow solid (62.4 mg, 95%) accord-
ing to the general procedure.
1H NMR (400 MHz, CDCl3): δ = 2.42 (t, J = 2.4 Hz, 1 H), 4.90 (d, J = 2.4
Hz, 2 H), 6.62 (s, 1 H), 7.28–7.32 (m, 1 H), 7.38–7.50 (m, 5 H), 7.55–
7.58 (m, 2 H), 7.84–7.86 (m, 2 H).
Mp 112–114 °C.
1H NMR (400 MHz, CDCl3): δ = 5.36 (s, 2 H), 6.64 (s, 1 H), 7.05–7.09
13C NMR (100 MHz, CDCl3): δ = 39.7, 73.6, 78.4, 103.7, 125.7, 127.8,
(m, 4 H), 7.22–7.34 (m, 6 H), 7.40–7.46 (m, 2 H), 7.87 (d, J = 7.2 Hz, 2
128.5, 128.7, 128.8, 130.1, 133.1, 145.0, 151.4.
H).
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2: 259.1230; found:
259.1223.
13C NMR (100 MHz, CDCl3): δ = 53.5, 103.8, 115.7 (d, J = 22 Hz), 125.6,
126.6, 127.5, 127.7, 128.62, 128.63, 130.6, 130.7, 133.3, 137.5, 144.3,
150.9, 162.8 (d, J = 247 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C22H18FN2: 329.1449; found:
329.1452.
3-Phenyl-1-(prop-2-yn-1-yl)-5-(p-tolyl)-1H-pyrazole (3p)
Compound 3p was obtained as a yellow solid (47.9 mg, 88%) accord-
ing to the general procedure.
Mp 81–83 °C.
1-Allyl-3,5-diphenyl-1H-pyrazole (3l)
1H NMR (400 MHz, CDCl3): δ = 2.42–2.44 (m, 4 H), 4.91 (d, J = 2.4 Hz, 2
H), 6.61 (s, 1 H), 7.29–7.33 (m, 3 H), 7.38–7.42 (m, 2 H), 7.46 (d, J = 8.0
Hz, 2 H), 7.84–7.86 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 39.7, 73.5, 78.5, 103.5, 125.7,
127.1, 127.8, 128.5, 128.6, 129.5, 133.1, 138.9, 145.1, 151.4.
Compound 3l was obtained as a colorless oil (37.5 mg, 72%) according
to the general procedure.
1H NMR (400 MHz, CDCl3): δ = 4.77 (dd, J = 3.2, 1.6 Hz, 2 H), 5.03 (dd,
J = 16.8, 1.2 Hz, 1 H), 5.20 (dd, J = 10.4, 1.2 Hz, 1 H), 6.00–6.09 (m, 1 H),
6.61 (s, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.37–7.46 (m, 7 H), 7.84–7.86 (m,
2 H).
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2: 273.1386; found:
273.1390.
13C NMR (100 MHz, CDCl3): δ = 52.0, 103.3, 117.2, 125.6, 127.6,
128.52, 128.56, 128.59, 128.7, 130.6, 133.4, 133.8, 145.1, 150.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H17N2: 261.1386; found:
261.1385.
5-(4-Fluorophenyl)-3-phenyl-1-(prop-2-yn-1-yl)-1H-pyrazole (3q)
Compound 3q was obtained as a yellow solid (32.6 mg, 59%) accord-
ing to the general procedure.
Mp 80–85 °C.
1-Allyl-3-phenyl-5-(p-tolyl)-1H-pyrazole (3m)
1H NMR (400 MHz, CDCl3): δ = 2.43 (t, J = 2.4 Hz, 1 H), 4.89 (d, J = 2.4
Hz, 2 H), 6.61 (s, 1 H), 7.16–7.21 (m, 2 H), 7.30–7.33 (m, 1 H), 7.39–
7.42 (m, 2 H), 7.54–7.57 (m, 2 H), 7.83–7.85 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 39.8, 73.7, 78.2, 103.8, 116.0 (d, J = 22
Hz), 125.7, 126.2 (d, J = 4 Hz), 127.9, 128.6, 130.7 (d, J = 8 Hz), 133.0,
144.0, 151.5, 163.0 (d, J = 248 Hz).
Compound 3m was obtained as a yellow oil (35.1 mg, 64%) according
to the general procedure.
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 4.76–4.79 (m, 2 H), 5.04
(dd, J = 17.2, 0.8 Hz, 1 H), 5.22 (dd, J = 10.0, 1.2 Hz, 1 H), 6.01–6.11 (m,
1 H), 6.60 (s, 1 H), 7.24–7.28 (m, 3 H), 7.30–7.42 (m, 4 H), 7.85 (d, J =
7.2 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H14FN2: 277.1136; found:
277.1141.
13C NMR (100 MHz, CDCl3): δ = 21.3, 52.0, 103.2, 117.1, 125.6, 127.56,
127.64, 128.5, 128.6, 129.3, 133.5, 133.9, 138.6, 145.2, 150.8.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2: 275.1543; found:
275.1550.
1-Methyl-5-phenyl-3-(m-tolyl)-1H-pyrazole (3u)
Compound 3u was obtained as a yellow oil (47.2 mg, 95%) according
to the general procedure.
1-Allyl-5-(4-fluorophenyl)-3-phenyl-1H-pyrazole (3n)
1H NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.93 (s, 3 H), 6.60 (s, 1 H),
7.13 (d, J = 7.2 Hz, 1 H), 7.24–7.32 (m, 1 H), 7.40–7.47 (m, 5 H), 7.61
(d, J = 7.6 Hz, 1 H), 7.68 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.4, 37.5, 103.2, 122.6, 126.1, 128.4,
128.5, 128.66, 128.69, 130.6, 133.2, 138.2, 145.0, 150.6.
Compound 3n was obtained as a yellow solid (45.1 mg, 81%) accord-
ing to the general procedure.
Mp 47–49 °C.
1H NMR (400 MHz, CDCl3): δ = 4.76 (dd, J = 3.2, 1.6 Hz, 2 H), 5.02 (dd,
J = 17.2, 0.8 Hz, 1 H), 5.22 (dd, J = 10.4, 1.2 Hz, 1 H), 6.00–6.10 (m, 1 H),
6.60 (s, 1 H), 7.13–7.17 (m, 2 H), 7.29–7.33 (m, 1 H), 7.39–7.46 (m, 4
H), 7.84 (d, J = 7.6 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2: 249.1386; found:
249.1391.
13C NMR (100 MHz, CDCl3): δ = 52.0, 103.5, 115.7 (d, J = 22 Hz), 117.3,
125.6, 126.7, 127.7, 128.6, 130.6 (d, J = 9 Hz), 133.3, 133.8, 144.1,
150.9, 162.9 (d, J = 247 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C18H16FN2: 279.1292; found:
279.1296.
5-(4-Fluorophenyl)-1-methyl-3-(m-tolyl)-1H-pyrazole (3w)
Compound 3w was obtained as a yellow solid (46.9 mg, 88%) accord-
ing to the general procedure.
Mp 69–71 °C.
1H NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.90 (s, 3 H), 6.57 (s, 1 H),
7.12–7.19 (m, 3 H), 7.25–7.32 (m, 1 H), 7.41–7.45 (m, 2 H), 7.59 (d, J =
7.6 Hz, 1 H), 7.67 (s, 1 H).
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13C NMR (100 MHz, CDCl3): δ = 21.4, 37.4, 103.3, 115.8 (d, J = 22 Hz),
122.6, 126.1, 126.7 (d, J = 3 Hz), 128.5 (d, J = 6 Hz), 130.5 (d, J = 9 Hz),
130.6, 133.1, 138.2, 143.9, 150.6, 162.8 (d, J = 247 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C17H16FN2: 267.1292; found:
267.1297.
1-Ethyl-5-(4-fluorophenyl)-3-(p-tolyl)-1H-pyrazole (3ae)
Compound 3ae was obtained as a yellow solid (40.9 mg, 73%) accord-
ing to the general procedure.
Mp 71–74 °C.
1H NMR (400 MHz, CDCl3): δ = 1.43 (t, J = 7.2 Hz, 3 H), 2.37 (s, 3 H),
4.16 (q, J = 7.2 Hz, 2 H), 6.51 (s, 1 H), 7.14–7.25 (m, 4 H), 7.39–7.42 (m,
2 H), 7.72 (d, J = 7.6 Hz, 2 H).
5-(4-Methoxyphenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (3z)
Compound 3z was obtained as a yellow solid (50.1 mg, 90%) according
to the general procedure using AlCl3 (0.8 mmol, 4 equiv).
13C NMR (100 MHz, CDCl3): δ = 16.0, 21.2, 44.5, 103.2, 115.7 (d, J = 21
Hz), 125.4, 127.0, 129.3, 130.6 (d, J = 8 Hz), 137.3, 143.3, 150.6, 162.7
(d, J = 246 Hz).
Mp 68–71 °C.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 3 H), 3.86 (s, 3 H), 3.90 (s, 3 H),
6.53 (s, 1 H), 6.98–7.00 (m, 2 H), 7.21 (d, J = 7.6 Hz, 2 H), 7.37–7.39 (m,
2 H), 7.72 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H18FN2: 281.1449; found:
281.1450.
13C NMR (100 MHz, CDCl3): δ = 21.2, 37.3, 55.3, 102.7, 114.1, 123.0,
1-Allyl-5-phenyl-3-(p-tolyl)-1H-pyrazole (3af)
125.4, 129.3, 130.0, 130.5, 137.3, 144.8, 150.4, 159.8.
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O: 279.1492; found:
Compound 3af was obtained as a yellow solid (37.9 mg, 69%) accord-
ing to the general procedure.
279.1496.
Mp 54–57 °C.
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 4.79 (d, J = 2.4 Hz, 2 H),
5.04 (d, J = 17.2 Hz, 1 H), 5.22 (d, J = 10.4 Hz, 1 H), 6.06 (ddd, J = 22.4,
10.4, 5.2 Hz, 1 H), 6.60 (s, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.40–7.47 (m, 5
H), 7.74 (d, J = 7.6 Hz, 2 H).
5-(4-Fluorophenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (3aa)
Compound 3aa was obtained as a yellow solid (51.1 mg, 96%) accord-
ing to the general procedure.
13C NMR (100 MHz, CDCl3): δ = 21.2, 52.0, 103.2, 117.1, 125.5, 128.6,
Mp 111–114 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 3.89 (s, 3 H), 6.54 (s, 1 H),
7.13–7.25 (m, 4 H), 7.40–7.44 (m, 2 H), 7.71 (d, J = 8.0 Hz, 2 H).
128.7, 129.2, 130.6, 133.9, 137.4, 145.1, 151.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2: 275.1543; found:
13C NMR (100 MHz, CDCl3): δ = 21.2, 37.4, 103.1, 115.8 (d, J = 22 Hz),
125.4, 126.8, 129.3, 130.5 (d, J = 8 Hz), 137.4, 143.9, 150.6, 162.8 (d,
J = 247 Hz).
275.1549.
1-Allyl-3,5-di-p-tolyl-1H-pyrazole (3ag)
HRMS (ESI): m/z [M + H]+ calcd for C17H16FN2: 267.1292; found:
Compound 3ag was obtained as a yellow solid (27.1 mg, 47%) accord-
ing to the general procedure.
267.1290.
Mp 77–79 °C.
1-Ethyl-5-phenyl-3-(p-tolyl)-1H-pyrazole (3ab)
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 2.41 (s, 3 H), 4.78 (dt, J =
4.8, 1.6 Hz, 2 H), 5.01–5.07 (m, 1 H), 5.19–5.22 (m, 1 H), 6.01–6.10 (m,
1 H), 6.56 (s, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.24–7.26 (m, 2 H), 7.34–
7.36 (m, 2 H), 7.74 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.26, 21.29, 52.0, 103.0, 117.1, 125.6,
127.7, 128.6, 129.25, 129.32, 130.6, 134.0, 137.3, 138.6, 145.1, 150.9.
Compound 3ab was obtained as a pale yellow solid (42.0 mg, 80%) ac-
cording to the general procedure.
Mp 61–63 °C.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 2.37 (s, 3 H),
4.20 (q, J = 7.2 Hz, 2 H), 6.54 (s, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.41–7.48
(m, 5 H), 7.73 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H21N2: 289.1699; found:
13C NMR (100 MHz, CDCl3): δ = 16.0, 21.2, 44.6, 103.1, 125.5, 128.4,
289.1705.
128.7, 128.8, 129.3, 130.8, 131.0, 137.2, 144.4, 150.6.
1-Allyl-5-(4-Fluorophenyl)-3-(p-tolyl)-1H-pyrazole (3ah)
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2: 263.1543; found:
Compound 3ah was obtained as a yellow solid (50.8 mg, 87%) accord-
263.1543.
ing to the general procedure.
1-Ethyl-3,5-di-p-tolyl-1H-pyrazole (3ac)
Mp 53–56 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 4.75 (d, J = 4.8 Hz, 2 H),
5.01 (d, J = 17.2 Hz, 1 H), 5.21 (d, J = 10.4 Hz, 1 H), 6.04 (ddd, J = 22.4,
10.4, 4.8 Hz, 1 H), 6.57 (s, 1 H), 7.14 (t, J = 8.4 Hz, 2 H), 7.21 (d, J = 8.0
Hz, 2 H), 7.43 (dd, J = 8.4, 5.2 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 52.0, 103.3, 115.7 (d, J = 22 Hz),
117.2, 125.5, 129.3, 130.4, 130.6 (d, J = 8 Hz), 133.8, 137.4, 144.0,
151.0, 162.8 (d, J = 247 Hz).
Compound 3ac was obtained as a yellow solid (39.2 mg, 71%) accord-
ing to the general procedure.
Mp 89–91 °C.
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.2 Hz, 3 H), 2.37 (s, 3 H),
2.41 (s, 3 H), 4.19 (q, J = 7.2 Hz, 2 H), 6.51 (s, 1 H), 7.20–7.34 (m, 6 H),
7.72 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.0, 21.25, 21.27, 44.5, 103.0, 125.4,
128.0, 128.7, 129.2, 129.3, 130.8, 137.1, 138.4, 144.4, 150.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H18FN2: 293.1449; found:
293.1452.
HRMS (ESI): m/z [M + H]+ calcd for C19H21N2: 277.1699; found:
277.1704.
1-Benzyl-5-phenyl-3-(p-tolyl)-1H-pyrazole (3ai)
Compound 3ai was obtained as a yellow solid (40.2 mg, 62%) accord-
ing to the general procedure.
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Mp 86–88 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H19N2: 287.1543; found:
287.1548.
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 5.39 (s, 2 H), 6.63 (s, 1 H),
7.09 (d, J = 6.8 Hz, 2 H), 7.21–7.29 (m, 5 H), 7.33–7.39 (m, 5 H), 7.76
(d, J = 8.0 Hz, 2 H).
5-(4-Fluorophenyl)-1-(prop-2-yn-1-yl)-3-(p-tolyl)-1H-pyrazole
(3an)
13C NMR (100 MHz, CDCl3): δ = 21.3, 53.2, 103.5, 125.6, 126.7, 127.3,
Compound 3an was obtained as a yellow solid (36.0 mg, 62%) accord-
ing to the general procedure.
128.6, 128.8, 129.3, 130.6, 137.4, 137.7, 145.3, 151.0.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2: 325.1699; found:
325.1705.
Mp 95–97 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 2.43 (t, J = 2.4 Hz, 1 H),
4.88 (d, J = 2.4 Hz, 2 H), 6.58 (s, 1 H), 7.16–7.22 (m, 4 H), 7.53–7.57 (m,
2 H), 7.73 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 39.7, 73.7, 78.3, 103.7, 115.9 (d,
J = 22 Hz), 125.6, 126.3 (d, J = 3 Hz), 129.3, 130.2, 130.6 (d, J = 8 Hz),
130.7, 137.7, 143.9, 151.6, 163.0 (d, J = 248 Hz).
1-Benzyl-3,5-di-p-tolyl-1H-pyrazole (3aj)
Compound 3aj was obtained as a white solid (40.6 mg, 60%) according
to the general procedure.
Mp 113–115 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 6 H), 5.37 (s, 2 H), 6.60 (s, 1 H),
7.10 (d, J = 7.2 Hz, 2 H), 7.17–7.29 (m, 9 H), 7.76 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 53.1, 103.3, 125.5, 126.6, 127.3,
127.7, 128.5, 128.7, 129.2, 129.3, 130.7, 137.3, 137.9, 138.5, 145.4,
151.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H16FN2: 291.1292; found:
291.1298.
1-Allyl-3-(4-methoxyphenyl)-5-phenyl-1H-pyrazole (3as)
Compound 3as was obtained as a yellow oil (29.6 mg, 51%) according
to the general procedure using AlCl3 (0.8 mmol, 4 equiv).
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 4.77 (dd, J = 3.6, 1.6 Hz, 2
H), 5.04 (dd, J = 16.8, 1.2 Hz, 1 H), 5.21 (dd, J = 10.4, 1.2 Hz, 1 H), 6.01–
6.10 (m, 1 H), 6.55 (s, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 7.42–7.46 (m, 5 H),
7.76–7.79 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 52.0, 55.3, 102.9, 114.0, 117.2, 126.3,
126.9, 128.56, 128.62, 128.7, 130.8, 134.0, 145.1, 150.8, 159.3.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O: 291.1492; found:
291.1495.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2: 339.1856; found:
339.1862.
1-Benzyl-5-(4-fluorophenyl)-3-(p-tolyl)-1H-pyrazole (3ak)
Compound 3ak was obtained as a yellow solid (47.9 mg, 70%) accord-
ing to the general procedure.
Mp 84–89 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 5.35 (s, 2 H), 6.60 (s, 1 H),
7.04–7.09 (m, 4 H), 7.21–7.31 (m, 7 H), 7.76 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 53.2, 103.7, 115.7 (d, J = 21 Hz),
125.5, 126.6, 126.7, 127.4, 128.6, 129.3, 130.5, 130.7 (d, J = 8 Hz),
137.5 (d, J = 12 Hz), 144.3, 151.0, 162.8 (d, J = 248 Hz).
1-Allyl-3-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazole (3at)
Compound 3at was obtained as a yellow solid (27.4 mg, 45%) accord-
ing to the general procedure using AlCl3 (0.8 mmol, 4 equiv).
HRMS (ESI): m/z [M + H]+ calcd for C23H20FN2: 343.1605; found:
343.1611.
Mp 70–73 °C.
1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 3.84 (s, 3 H), 4.76 (d, J =
4.8 Hz, 2 H), 5.04 (d, J = 17.2 Hz, 1 H), 5.21 (d, J = 10.4 Hz, 1 H), 6.06
(ddd, J = 22.0, 10.4, 4.8 Hz, 1 H), 6.52 (s, 1 H), 6.94 (d, J = 8.8 Hz, 2 H),
7.25–7.27 (m, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 51.9, 55.3, 102.7, 113.9, 117.1,
126.3, 126.9, 127.8, 128.6, 129.3, 134.0, 138.5, 145.1, 150.7, 159.2.
5-Phenyl-1-(prop-2-yn-1-yl)-3-(p-tolyl)-1H-pyrazole (3al)
Compound 3al was obtained as a yellow solid (42.5 mg, 78%) accord-
ing to the general procedure.
Mp 93–95 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 2.42 (t, J = 2.4 Hz, 1 H),
4.91 (d, J = 2.4 Hz, 2 H), 6.60 (s, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.42–7.50
(m, 3 H), 7.56–7.58 (m, 2 H), 7.74 (d, J = 8.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H21N2O: 305.1648; found:
305.1653.
13C NMR (100 MHz, CDCl3): δ = 21.3, 39.8, 73.5, 78.5, 103.5, 125.7,
128.75, 128.8, 128.83, 129.3, 130.2, 130.3, 137.6, 145.0, 151.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2: 273.1386; found:
273.1392.
3-(3,4-Dimethoxyphenyl)-1-methyl-5-phenyl-1H-pyrazole (3au)
Compound 3au was obtained as a yellow solid (37.1 mg, 63%) accord-
ing to the general procedure using AlCl3 (1.0 mmol, 5 equiv).
Mp 87–89 °C.
1-(Prop-2-yn-1-yl)-3,5-di-p-tolyl-1H-pyrazole (3am)
1H NMR (400 MHz, CDCl3): δ = 3.91 (s, 3 H), 3.92 (s, 3 H), 3.98 (s, 3 H),
6.55 (s, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.32–7.35 (m, 1 H), 7.42–7.47 (m,
6 H).
13C NMR (100 MHz, CDCl3): δ = 37.5, 55.88, 55.91, 102.9, 108.6, 111.2,
118.1, 126.6, 128.5, 128.67, 128.69, 130.7, 145.1, 148.7, 149.1, 150.4.
Compound 3am was obtained as a yellow solid (34.4 mg, 60%) accord-
ing to the general procedure.
Mp 117–118 °C.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 2.42–2.43 (m, 4 H), 4.89
(d, J = 2.4 Hz, 2 H), 6.57 (s, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 7.6
Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O2: 295.1441; found:
295.1448.
13C NMR (100 MHz, CDCl3): δ = 21.25, 21.29, 39.6, 73.4, 78.5, 103.3,
125.6, 127.2, 128.6, 129.2, 129.5, 130.4, 137.5, 138.8, 145.0, 151.5.
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3-(2-Bromophenyl)-1-methyl-5-(p-tolyl)-1H-pyrazole (3aw)
13C NMR (100 MHz, CDCl3): δ = 21.3, 37.6, 103.1, 123.5, 125.5, 127.4,
127.5, 128.6, 129.4, 129.8, 134.5, 135.3, 138.7, 145.3, 149.0.
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2: 283.0997; found:
Compound 3aw was obtained as a yellow oil (45.6 mg, 70%) according
to the general procedure.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.95 (s, 3 H), 6.80 (s, 1 H),
7.16–7.20 (m, 1 H), 7.25–7.30 (m, 2 H), 7.34–7.40 (m, 3 H), 7.65 (d, J =
8.0 Hz, 1 H), 7.75 (dd, J = 8.0, 1.6 Hz, 1 H).
283.1004.
3-(4-Chlorophenyl)-1-methyl-5-(p-tolyl)-1H-pyrazole (3bg)
13C NMR (100 MHz, CDCl3): δ = 21.3, 37.6, 106.9, 121.9, 127.4, 127.6,
Compound 3bg was obtained as a yellow solid (49.1 mg, 87%) accord-
ing to the general procedure.
128.7, 128.9, 129.4, 131.0, 133.5, 134.5, 138.5, 144.0, 149.3.
HRMS (ESI): m/z [M + H]+ calcd for C17H16BrN2: 327.0491; found:
Mp 93–96 °C.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.91 (s, 3 H), 6.55 (s, 1 H),
327.0498.
7.25–7.29 (m, 2 H), 7.33–7.38 (m, 4 H), 7.74–7.76 (m, 2 H).
3-(2-Bromophenyl)-5-(4-fluorophenyl)-1-methyl-1H-pyrazole
(3ax)
13C NMR (100 MHz, CDCl3): δ = 21.3, 37.6, 103.0, 126.7, 127.5, 128.6,
128.7, 129.4, 132.0, 133.2, 138.6, 145.3, 149.2.
Compound 3ax was obtained as a yellow oil (56.8 mg, 86%) according
to the general procedure.
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2: 283.0997; found:
283.1000.
1H NMR (400 MHz, CDCl3): δ = 3.93 (s, 3 H), 6.80 (s, 1 H), 7.16–7.21
(m, 3 H), 7.35–7.38 (m, 1 H), 7.45–7.48 (m, 2 H), 7.66 (d, J = 8.0 Hz, 1
H), 7.74–7.76 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 37.5, 107.2, 115.8 (d, J = 21 Hz), 121.9,
126.6, 127.4, 129.0, 130.6 (d, J = 8 Hz), 130.9, 133.5, 134.3, 142.9,
149.4, 161.5.
1-Methyl-3-(4-nitrophenyl)-5-phenyl-1H-pyrazole (3bi)
Compound 3bi was prepared obtained as a yellow solid (26.3 mg,
47%) according to the general procedure using phenylacetylene (0.8
mmol, 4 equiv).
Mp 114–116 °C.
HRMS (ESI): m/z [M + H]+ calcd for C16H13BrFN2: 331.0241; found:
331.0248.
1H NMR (400 MHz, CDCl3): δ = 3.96 (s, 3 H), 6.70 (s, 1 H), 7.44–7.52
(m, 5 H), 7.98 (d, J = 8.4 Hz, 2 H), 8.26 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 37.8, 104.2, 124.1, 125.8, 128.7, 128.8,
128.9, 130.0, 139.7, 145.7, 147.0, 148.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H14N3O2: 280.1081; found:
280.1086.
3-(2-Chlorophenyl)-1-methyl-5-(p-tolyl)-1H-pyrazole (3az)
Compound 3az was obtained as a yellow solid (38.9 mg, 69%) accord-
ing to the general procedure.
Mp 58–60 °C.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.95 (s, 3 H), 6.82 (s, 1 H),
7.23–7.33 (m, 4 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 1 H),
7.85 (dd, J = 7.6, 1.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 37.6, 107.0, 126.8, 127.6, 128.6,
128.7, 129.4, 130.2, 130.4, 132.1, 132.4, 138.5, 144.2, 147.9.
1-Allyl-3-(4-nitrophenyl)-5-phenyl-1H-pyrazole (3bj)
Compound 3bj was obtained as a yellow solid (22.0 mg, 36%) accord-
ing to the general procedure using phenylacetylene (0.8 mmol, 4
equiv).
Mp 106–109 °C.
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2: 283.0997; found:
283.1004.
1H NMR (400 MHz, CDCl3): δ = 4.81 (dd, J = 3.6, 1.6 Hz, 2 H), 5.07 (dd,
J = 17.2, 0.8 Hz, 1 H), 5.26 (dd, J = 10.4, 0.8 Hz, 1 H), 6.06 (ddd, J = 22.4,
10.4, 5.2 Hz, 1 H), 6.72 (s, 1 H), 7.44–7.52 (m, 5 H), 8.00 (d, J = 8.8 Hz, 2
H), 8.26 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 52.4, 104.3, 117.7, 124.1, 126.0,
128.76, 128.79, 129.0, 130.0, 133.4, 139.8, 145.8, 147.0, 148.6.
3-(2-Chlorophenyl)-5-(4-methoxyphenyl)-1-methyl-1H-pyrazole
(3ba)
Compound 3ba was obtained as a yellow oil (37.6 mg, 63%) according
to the general procedure using AlCl3 (0.8 mmol, 4 equiv).
1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 3.93 (s, 3 H), 6.79 (s, 1 H),
7.00 (d, J = 8.8 Hz, 2 H), 7.22–7.29 (m, 1 H), 7.31–7.33 (m, 1 H), 7.40–
7.45 (m, 3 H), 7.84–7.86 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 37.5, 55.4, 106.9, 114.1, 122.9, 126.8,
128.6, 130.1, 130.3, 130.4, 132.1, 132.4, 144.0, 147.9, 159.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H16ClN2O: 299.0946; found:
299.0950.
HRMS (ESI): m/z [M + H]+ calcd for C18H16N3O2: 306.1237; found:
306.1243.
3-(4-Nitrophenyl)-5-phenyl-1-(prop-2-yn-1-yl)-1H-pyrazole (3bk)
Compound 3bk was obtained as a yellow solid (18.8 mg, 31%) accord-
ing to the general procedure using phenylacetylene (0.8 mmol, 4
equiv).
Mp 119–121 °C.
1H NMR (400 MHz, CDCl3): δ = 2.48 (t, J = 2.4 Hz, 1 H), 4.95 (d, J = 2.4
Hz, 2 H), 6.73 (s, 1 H), 7.47–7.59 (m, 5 H), 8.01–8.03 (m, 2 H), 8.26–
8.28 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 40.1, 74.0, 77.9, 104.5, 124.1, 126.1,
128.8, 129.0, 129.3, 129.5, 139.4, 145.7, 149.1.
3-(3-Chlorophenyl)-1-methyl-5-(p-tolyl)-1H-pyrazole (3bd)
Compound 3bd was obtained as a yellow solid (36.7 mg, 65%) accord-
ing to the general procedure.
Mp 72–74 °C.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.92 (s, 3 H), 6.57 (s, 1 H),
7.25–7.36 (m, 6 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.83 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H14N3O2: 304.1081; found:
304.1096.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
M. Tang et al.
Paper
Synthesis
3-(Furan-2-yl)-1-methyl-5-phenyl-1H-pyrazole (3bl)
(6) For selected reviews about pyrazole synthesis, see: (a) Pizzuti,
L.; Barschak, A. G.; Stefanello, F. M.; Farias, M. D.; Lencina, C.;
Roesch-Ely, M.; Cunico, W.; Moura, S.; Pereira, C. M. P. Curr. Org.
Chem. 2014, 18, 115. (b) Janin, Y. L. Chem. Rev. 2012, 112, 3924.
(c) Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A.
Chem. Rev. 2011, 111, 6984. (d) Dadiboyena, S.; Nefzi, A. Eur. J.
Med. Chem. 2011, 46, 5258. (e) Fustero, S.; Simón-Fuentes, A.;
Sanz-Cervera, J. F. Org. Prep. Proced. Int. 2009, 41, 253.
(f) Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1999,
36, 321. (g) Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl.
Chem. 1998, 35, 489.
Compound 3bl was obtained as a yellow solid (24.2 mg, 54%) accord-
ing to the general procedure using phenylacetylene (0.8 mmol, 4
equiv).
Mp 82–85 °C.
1H NMR (400 MHz, CDCl3): δ = 3.91 (s, 3 H), 6.47 (dd, J = 3.2, 1.6 Hz, 1
H), 6.53 (s, 1 H), 6.67 (d, J = 3.2 Hz, 1 H), 7.40–7.49 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 37.6, 103.0, 105.5, 111.2, 128.68,
128.72, 130.3, 141.7, 142.9, 144.8, 148.8.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O: 225.1022; found:
(7) For selected recent examples about pyrazole synthesis, see:
(a) Li, D. Y.; Mao, X. F.; Chen, H. J.; Chen, G. R.; Liu, P. N. Org. Lett.
2014, 16, 3476. (b) Guo, H.; Zhang, D.; Zhu, C.; Li, J.; Xu, G.; Sun,
J. Org. Lett. 2014, 16, 3110. (c) Schneider, Y.; Prévost, J.; Gobin,
M.; Legault, C. Y. Org. Lett. 2014, 16, 596. (d) Sun, A.; Ye, J.-H.;
Yu, H.; Zhang, W.; Wang, X. Tetrahedron Lett. 2014, 55, 889.
(e) Shao, N.; Chen, T.; Zhang, T.; Zhu, H.; Zheng, Q.; Zou, H. Tet-
rahedron 2014, 70, 795. (f) Kumar, R.; Nair, D.; Namboothiri, I.
N. N. Tetrahedron 2014, 70, 1794. (g) Harigae, R.; Moriyama, K.;
Togo, H. J. Org. Chem. 2014, 79, 2049. (h) Tran, G.; Pardo, D. G.;
Tsuchiya, T.; Hillebrand, S.; Vors, J.-P.; Cossy, J. Org. Lett. 2013,
15, 5550. (i) Zhang, G.; Ni, H.; Chen, W.; Shao, J.; Liu, H.; Chen,
B.; Yu, Y. Org. Lett. 2013, 15, 5967. (j) Wang, L.; Yu, X.; Feng, X.;
Bao, M. J. Org. Chem. 2013, 78, 1693. (k) Li, X.; He, L.; Chen, H.;
Wu, W.; Jiang, H. J. Org. Chem. 2013, 78, 3636. (l) Xu, S.-X.; Hao,
L.; Wang, T.; Ding, Z.-C.; Zhan, Z.-P. Org. Biomol. Chem. 2013, 11,
294. (m) Hao, L.; Hong, J.-J.; Zhu, J.; Zhan, Z.-P. Chem. Eur. J.
2013, 19, 5715. (n) Foster, R. S.; Jakobi, H.; Harrity, J. P. A. Org.
Lett. 2012, 14, 4858. (o) Hu, J.; Chen, S.; Sun, Y.; Yang, J.; Rao, Y.
Org. Lett. 2012, 14, 5030. (p) Kirkham, J. D.; Edeson, S. J.; Stokes,
S.; Harrity, J. P. A. Org. Lett. 2012, 14, 5354. (q) Liu, P.; Pan, Y.-M.;
Xu, Y.-L.; Wang, H.-S. Org. Biomol. Chem. 2012, 10, 4696.
(r) Borkin, D. A.; Puscau, M.; Carlson, A.; Solan, A.; Wheeler, K.
A.; Török, B.; Dembinski, R. Org. Biomol. Chem. 2012, 10, 4505.
(s) Kumara, C. K.; Trivedia, R.; Kumara, K. R.; Giribabua, L.;
Sridhar, B. J. Organomet. Chem. 2012, 718, 64. (t) Yoshimatsu,
M.; Ohta, K.; Takahashi, N. Chem. Eur. J. 2012, 18, 15602.
(u) Panda, N.; Jena, A. K. J. Org. Chem. 2012, 77, 9401.
225.1029.
3-(Furan-2-yl)-1-methyl-5-(p-tolyl)-1H-pyrazole (3bm)
Compound 3bm was obtained as a yellow solid (21.0 mg, 44%) ac-
cording to the general procedure using p-methylphenylacetylene (0.8
mmol, 4 equiv).
Mp 102–104 °C.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 3.90 (s, 3 H), 6.46 (dd, J =
3.2, 1.6 Hz, 1 H), 6.50 (s, 1 H), 6.66 (d, J = 2.8 Hz, 1 H), 7.26–7.30 (m, 2
H), 7.34 (d, J = 8.0 Hz, 2 H), 7.45 (d, J = 1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 37.5, 102.8, 105.4, 111.2, 127.4,
128.6, 129.4, 138.7, 141.7, 142.9, 144.8, 148.9.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2O: 239.1179; found:
239.1187.
Acknowledgment
This research was supported by the Fundamental Research Funds for
the Central Universities (lzujbky-2015-311) and partly supported by
NSFC (No. 21002044).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561646.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) (a) Gerstenberger, B. S.; Rauckhorst, M. R.; Starr, J. T. Org. Lett.
2009, 11, 2097. (b) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8,
2675. (c) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J.
Org. Chem. 2005, 70, 10030. (d) Patel, M. V.; Bell, R.; Majest, S.;
Henry, R.; Kolasa, T. J. Org. Chem. 2004, 69, 7058. (e) Norris, T.;
Colon-Cruz, R.; Ripin, D. H. B. Org. Biomol. Chem. 2005, 3, 1844.
(f) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro, J. A.
S.; Elguero, J. Eur. J. Org. Chem. 2004, 4348. (g) Bishop, B. C.;
Brands, K. M. J.; Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43.
(h) Miller, R. D.; Reiser, O. J. Heterocycl. Chem. 1993, 30, 755.
(9) (a) Padwa, A. In 1,3-Dipolar Cycloaddition Chemistry; Vol. 1;
John Wiley & Sons: New York, 1984. (b) Padwa, A. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Het-
erocycles and Natural Products; Pearson, W. H., Ed.; John Wiley
& Sons: New York, 2002.
(10) For selected reviews, see: (a) Xiao, Q.; Zhang, Y.; Wang, J. Acc.
Chem. Res. 2013, 46, 236. (b) Zhang, Y.; Wang, J. Top. Curr. Chem.
2012, 327, 239. (c) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41,
560. (d) Barluenga, J.; Valdés, C. Angew. Chem. Int. Ed. 2011, 50,
7486. (e) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011, 1015.
(11) (a) Pérez-Aguilar, M. C.; Valdés, C. Angew. Chem. Int. Ed. 2013,
52, 7219. (b) Wu, L.-L.; Ge, Y.-C.; He, T.; Zhang, L.; Fu, X.-L.; Fu,
H.-Y.; Chen, H.; Li, R.-X. Synthesis 2012, 44, 1577. (c) Kumar, R.;
Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016.
References
(1) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry; Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon:
Oxford, 1996. (b) Hirai, K.; Uchida, A.; Ohno, R. In Herbicide
Classes in Development; Boger, P.; Hirai, K.; Wakabyashi, K., Eds.;
Springer-Verlag: Heidelberg, 2002, 179.
(2) (a) Nieto, S.; Pérez, J.; Riera, L.; Riera, V.; Miguel, D. Chem. Eur. J.
2006, 12, 2244. (b) Moyano, S.; Serrano, J. L.; Elduque, A.;
Gimenez, R. Soft Matter 2012, 8, 6799.
(3) Cavero, E.; Uriel, S.; Romero, P.; Serrano, J. L.; Giménez, R. J. Am.
Chem. Soc. 2007, 129, 11608.
(4) For selected recent examples, see: (a) Pathak, R. B.; Chovatia, P.
T.; Parekh, H. H. Bioorg. Med. Chem. Lett. 2012, 22, 5129. (b) Abu,
T. B.; Arnsmann, M.; Totzke, F.; Ehlert, J. E.; Kubbutat, M. H. G.;
Schachtele, C.; Zimmermann, M. O.; Koch, P.; Boeckler, F. M.;
Laufer, S. A. J. Med. Chem. 2012, 55, 961. (c) Donohue, S. R.;
Dannals, R. F.; Halldin, C.; Pike, V. W. J. Med. Chem. 2011, 54,
2961. (d) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.;
Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222.
(5) Knorr, L. Ber. 1883, 16, 2587.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

L
M. Tang et al.
Paper
Synthesis
(d) Muruganantham, R.; Namboothiri, I. J. Org. Chem. 2010, 75,
2197. (e) Xie, J.-W.; Wang, Z.; Yang, W.-J.; Kong, L.-C.; Xu, D.-C.
Org. Biomol. Chem. 2009, 7, 4352. (f) Muruganantham, R.;
Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2007, 9, 1125.
(g) Ivanova, O. A.; Budynina, E. M.; Averina, E. B.; Kuznetsova, T.
S.; Grishin, Y. K.; Zefirova, N. S. Synthesis 2007, 2009. (h) Jiang,
N.; Li, C.-J. Chem. Commun. 2004, 394. (i) Aggarwal, V. K.; de
Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68, 5381.
(j) Jończyk, A.; Włostowskab, J.; Mąkosza, M. Tetrahedron 2001,
57, 2827. (k) Kano, K.; Scarpetti, D.; Warner, J. C.; Anselime, J.-P.
Can. J. Chem. 1986, 64, 2211.
(13) (a) Wang, W.-L.; Feng, Y.-L.; Gao, W.-Q.; Luo, X.; Deng, W.-P. RSC
Adv. 2013, 3, 1687. (b) Padwa, A.; Kao, H. J. Org. Chem. 1980, 45,
3756. (c) Wilson, R. M.; Rekers, J. W.; Packard, A. B.; Elder, R. C.
J. Am. Chem. Soc. 1980, 102, 1633. (d) Ito, S.; Tanaka, Y.; Kakehi,
A.; Fukuyama, T.; Osawa, N.; Sayo, N. Bull. Chem. Soc. Jpn. 1983,
56, 545.
(14) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412.
(15) Liu, P.; Xu, Q.-Q.; Dong, C.; Lei, X.; Lin, G. Synlett 2012, 23, 2087.
(16) Leyva, A.; Corma, A. Adv. Synth. Catal. 2009, 351, 2876.
(17) (a) Tang, M.; Zhang, F.-M. Tetrahedron 2013, 69, 1427. (b) Tang,
M.; Zhang, W.; Kong, Y. Org. Biomol. Chem. 2013, 11, 6250.
(18) Kong, Y.; Zhang, W.; Tang, M.; Wang, H. Tetrahedron 2013, 69,
7487.
(12) Kong, Y.; Tang, M.; Wang, Y. Org. Lett. 2014, 16, 576.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L