Facile one-pot synthesis of 3,5-disubstituted 1 h -pyrazoles from propargylic alcohols via propargyl hydrazides

Article abstract of DOI:10.1055/s-0032-1316856

A new and efficient metal-free, two-component, one-pot approach to a variety of 3,5-disubstituted 1H-pyrazoles has been developed from propargylic alcohols. This transformation proceeds via an acid-catalyzed propargylation of N,N-diprotected hydrazines followed by base-mediated 5-endo-dig cyclization leading to 3,5-disubstituted 1H-pyrazoles in good overall yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1316856

830▌
PAPER
paper
Facile One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles from Propargylic
Alcohols via Propargyl Hydrazides
3,5-Disubstituted 1H-Pyrazoles
Chada Raji Reddy,*a Jonnalagadda Vijaykumar,a René Gréeb
a
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b
Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex,
France
Fax +91(40)27160512; E-mail: rajireddy@iict.res.in
Received: 17.12.2012; Accepted after revision: 25.01.2013
Cl
Abstract: A new and efficient metal-free, two-component, one-pot
approach to a variety of 3,5-disubstituted 1H-pyrazoles has been de-
OH
veloped from propargylic alcohols. This transformation proceeds
via an acid-catalyzed propargylation of N,N-diprotected hydrazines
followed by base-mediated 5-endo-dig cyclization leading to 3,5-
disubstituted 1H-pyrazoles in good overall yields.
CF3
O
N
N
N
N
Key words: pyrazole, propargylic alcohol, one-pot reaction, acid
catalysis, hydrazines
SO2NH2
OMe
Celecoxib
Lonazolac
Pyrazoles are a key core heterocyclic structural moieties
present in many pharmaceutically active compounds for
various therapeutic activities including metabolic diseas-
es, CNS disorders, and anti-obesity etc.1 For instance,
Celecoxib (Celebrex), Linazolac, Rimonabant, and
Mepiprazole are representative clinical drugs having pyr-
azole as a key framework (Figure 1). Accordingly, pyr-
azoles have attracted the attention of synthetic chemists
and to date several methods have been reported for the
synthesis of substituted pyrazoles2 including the tradition-
al Knorr reaction involving the condensation of hydra-
zines with 1,3-dicarbonyls,3 1,3-dipolar cycloaddition of
diazoalkanes or nitrile imines to alkenes or alkynes,4 and
others.5 All of these methods, while offering advantages,
also suffer from disadvantages, such as the formation of
undesired isomers, structural limitations, the use of ex-
pensive catalysts, and toxic and explosive starting materi-
als. Thus, the development of new approaches to
pyrazoles from readily available starting materials under
mild and efficient reaction conditions is welcome.
O
N
NH
Cl
N
N
N
N
Cl
Cl
N
N
H
Cl
Rimonabant
Mepiprazole
Figure 1 Structures of representative pyrazole drugs
gen, nitrogen, and sulfur nucleophiles and further conver-
sion into the heterocycles.8,9 We also have successfully
explored the propargylation of a variety of nucleophiles
under acid catalysis in the synthesis of benzofurans, isox-
azoles, dihydroisoxazoles, and furans.10 These results en-
couraged us to investigate the direct propargylation of
hydrazines to propargyl hydrazides, which are expected to
provide 3,5-disubstituted 1H-pyrazoles. While this manu-
script was in preparation, Yoshimatsu et al. and Zhan et al.
independently reported the synthesis of pyrazoles from
propargylic alcohols.11 Although these are attractive one-
pot methods employing tosylhydrazine as the nucleophile,
the use of a metal catalyst [AgOTf or Sc(OTf)3 or
La(OTf)3] is essential for C–N bond formation (nucleo-
philic substitution). In contrast, the present paper de-
scribes a novel method for the synthesis of 3,5-
disubstituted 1H-pyrazoles 4 from propargylic alcohols 1
using N-acetyl-N-tosylhydrazine (2) as a nucleophile un-
der metal-free reaction conditions, via propargyl hydra-
zides 3 (Scheme 1).
In the past decade, π-activated alcohols (benzylic/allylic/
propargylic) have gained prominence as alkylating agents
in green and atom-economic approaches, as they generate
only water as the byproduct in the reaction.6 In particular,
propargylic alcohols have received substantial attention in
alkylation reactions involving nucleophilic substitution,
since the obtained propargylated compounds can be easily
transformed to various heterocycles with the help of the
alkyne functionality.6,7 The efficacy of propargylic alco-
hols as carbon electrophiles has been explored in direct
nucleophilic SN1-type reactions with various carbon, oxy-
SYNTHESIS 2013, 45, 0830–0836
Advanced online publication: 08.02.2013
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DOI: 10.1055/s-0032-1316856; Art ID: SS-2012-Z0977-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
3,5-Disubstituted 1H-Pyrazoles
831
OH
NHNHTs
Ts
N
TsNHNH2
OH
R1
TsN(Ac)-NH2 (2)
Ph
Ph
HN
R1
Ac
PTSA or TfOH
(10 mol%)
CH2Cl2, reflux, 12 h
propargyl
hydrazide (3)
Ph
Ph
BF3⋅OEt2 (10 mol%)
1a
3a', 15%
R2
MeCN, r.t.
R2
KOtBu
propargyl alcohol (1)
R1 = aryl, heteroaryl
R2 = aryl, alkyl
Scheme 2
H
of 2 with 1a was examined using 10 mol% 4-toluenesul-
fonic acid in dichloromethane at room temperature. To
our delight, the formation of the desired N-propargyl hy-
drazide 3a was observed in 73% yield (Table 1, entry 1).
In order to improve the yield, other catalysts were
screened and the results are summarized in Table 1.
Among the catalysts tested, boron trifluoride–diethyl
ether complex was found to give 3a in an improved 87%
yield (entry 2). After the successful formation of 3a, our
aim was to convert it into the pyrazole. We envisioned
that a base-mediated detosylation/deacetylation would in-
duce cyclization to give the pyrazole 4a. Consequently,
the isolated 3a was treated with potassium carbonate in
acetonitrile at 50 °C to provide 3,5-diphenyl-1H-pyrazole
(4a) in 10% yield together with 1-acetyl-3,5-diphenyl-
1H-pyrazole (4a′) (8%) (Scheme 3).
N
‘one-pot’
N
R2
R1
3,5-disubstituted
1H-pyrazole (4)
Scheme 1 Approach to 3,5-disubstituted 1H-pyrazoles
We initiated our investigation by examining the reaction
of propargylic alcohol (1a) with tosylhydrazine in the
presence of various acid catalysts (PTSA, BF3·OEt2, and
TfOH) in dichloromethane. However, the expected
propargyl hydrazide was formed in very low yields even
under reflux conditions. In the case of boron trifluoride–
diethyl ether complex, the formation of a complex mix-
ture was observed. The reaction of 1a with tosylhydrazine
in the presence of 4-toluenesulfonic acid or triflic acid
provided the propargyl hydrazide 3a′11a in only 15% yield
(Scheme 2). This may be due to nucleophilic as well as
more basic nature of tosylhydrazine, which could neutral-
ize the acidic catalysts.
Ts
K2CO3
MeCN
H
Ac
N
N
N
HN
Ac
N
N
+
Ph
Ph
50 °C, 2 h
Therefore, we next considered N-acetyl-N-tosylhydrazine
(2)12 as the nucleophile, which is anticipated to have a
milder basic character. Accordingly, the N-propargylation
Ph
Ph
Ph
Ph
3a
4a (10%)
4a' (8%)
Scheme 3
Table 1 Optimization of the Reaction Conditions
Ts
OH
H
N
TsN(Ac)-NH2 (2)
N
N
base
HN
Ac
Ph
Ph
acid catalyst
step 1
step 2
Ph
Ph
Ph
Ph
1a
3a
4a
Entry
Nucleophilic substitutiona (step 1)
Deprotection/cyclizationb (step 2)
Product
Yieldc (%)
1
2
3
4
5
6
7
8f
PTSA, CH2Cl2, r.t., 15 min
–
3a
3a
3a
4a
4a
4a
4a
4a
73
87
0d
BF3·OEt2, CH2Cl2, r.t., 10 min
–
B(C6F5)3, CH2Cl2, r.t., 5 h
–
–
K2CO3, 50 °C 8 h
Cs2CO3, 50 °C, 8 h
TBAF, 50 °C, 8 h
KOt-Bu, r.t., 0.5 h
KOt-Bu, r.t., 0.5 h
10e
12e
15e
85
82
–
–
–
BF3·OEt2, MeCN, r.t. 10 min
a Catalyst (10 mol%).
b Catalyst (3 equiv) in MeCN.
c Isolated yields.
d After 12 h at refluxing temperature 10% 3a was formed.
e The formation of 4a′ was also observed (see Scheme 3).
f One-pot reaction.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 830–836

832
C. Raji Reddy et al.
PAPER
Table 2 One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazolesa
Entry
Propargylic alcohol
Time (min)
Step 1
Pyrazoleb
Yieldc (%)
Step 2
15
OH
N
NH
Ph
1
10
15
15
82
85
78
Ph
Ph
Ph
4a
1a
OH
N
NH
Ph
Br
2
3
30
30
Ph
Br
4b
1b
OH
N
NH
R2
MeO
R2
MeO
R2 = Ph, 4c
R2 = Ph, 1c
R2 = CH2OBn, 1d
4
5
15
10
20d
20d
R2 = CH2OBn, 4d
R2 = Pr, 4e
MeO
76
75
R2 = Pr, 1e
OH
MeO
N
NH
R2
MeO
R2
6
10
30
81
MeO
OMe
MeO
R2 = Ph, 4f
R2 = Ph, 1f
7
8
R2 = CH2OBn, 1g
15
5
30d
20d
R2 = CH2OBn, 4g
R2 = Pr, 4h
77
74
R2 = Pr, 1h
OH
NH
N
R2
9
10
30
76
R2
TsN
TsN
R2 = Ph, 1i
R2 = CH2OBn, 1j
R2 = Ph, 4i
10
11
10
10
25d
20d
R2 = CH2OBn, 4j
83
73
R2 = Pr, 1k
R2 = Pr, 4k
OH
12e
13e
120
0
–
–
–
Ph
O2N
1l
OH
120
0
–
Ph
1m
a Reaction conditions: (step 1) propargyl alcohol 1 (1 mmol), 2 (0.95 mmol), BF3·OEt2 (10 mol%), r.t.; (step 2) KOt-Bu (3 equiv), r.t. or 50 °C.
b Characterized by 1H and 13C NMR, and MS.
c Isolated yields.
d Step 2 was successful at 50 °C.
e Nucleophilic substitution reaction did not proceed.
Synthesis 2013, 45, 830–836
© Georg Thieme Verlag Stuttgart · New York

PAPER
3,5-Disubstituted 1H-Pyrazoles
833
Ts
Ac
Ts
N
H2N
N
2
OH
+
H+
HN
Ac
Ph
Ph
– H+
– H2O
Ph
A
Ph
Ph
1a
3a
Ph
KOtBu
nucleophilic substitution
detosylation
– TsH
Ac
N
H
H
N
H
Ac
N
Ac
+
base
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
–
Ph
4a
4a'
deacetylation
C
B
Ph
5-endo-dig cyclization
Scheme 4 Proposed mechanism
To improve the yield of the reaction, various bases aldehydes and not with alcohols generated from aliphatic
(Cs2CO3, TBAF, KOt-Bu) were examined and it was aldehydes. This may be due to the benzylic group, which
found that potassium tert-butoxide provided the best yield can facilitate the formation of the carbenium ion.
(85%, Table 1, entry 7). Having optimized the reaction
A possible reaction mechanism is shown in Scheme 4. In
conditions for the synthesis of propargyl hydrazide 3a and
the first step, propargylic alcohol 1a reacts with nucleo-
its conversion into 3,5-disubstituted 1H-pyrazole 4a, per-
phile 2 in the presence of an acid catalyst to give the
N-propargyl hydrazide 3a via carbocation A. Next, a base
can induce either detosylation or deacetylation to provide
the hydrazone. Based on our observation (formation of
4a′, Scheme 3), we suggest that the detosylation takes
place first to give the N-acetylhydrazone B and subse-
quent 5-endo-dig cyclization produces the intermediate C
which afford N-acetylpyrazole 4a′. A final base-mediated
forming both the reactions in a one-pot procedure would
be attractive. Hence, propargylic alcohol 1a was treated
first with N-acetyl-N-tosylhydrazine (2) in presence of 10
mol% boron trifluoride–diethyl ether in acetonitrile and
after 10 minutes, potassium tert-butoxide (3 equiv) was
added and stirring continued for a further 30 minutes at
room temperature, which gave clean formation of 3,5-di-
phenyl-1H-pyrazole (4a) in 82% yield (entry 8).
deacetylation furnishes the product 4a.
Encouraged by the above results, the generality of this
In conclusion, we have developed a new one-pot, acid-
one-pot method was studied for the synthesis of various
3,5-disubstituted 1H-pyrazoles from different propargylic
catalyzed N-propargylation of N-acetyl-N-tosylhydrazine
using propargylic alcohols to propargyl hydrazides fol-
alcohols. As can be seen from Table 2, propargylic alco-
lowed by their base-mediated conversion into 3,5-disub-
hol 1b (bearing 4-bromophenyl in the benzylic position)
stituted 1H-pyrazoles. The reaction conditions are metal-
provided the corresponding 3,5-disubstituted 1H-pyrazole
free, mild, and efficient, and provide the products in good
yields.
4b in 85% yield using the one-pot reaction conditions (en-
try 2). Next, alcohols 1c–e, derived from the reaction of 4-
methoxybenzaldehyde with aryl- or alkylacetylenes, were
reacted with nucleophile 2 followed by treatment with
base to afford the corresponding pyrazoles 4c–e in good
yields (entries 3–5). Similarly, propargylic alcohols
1H and 13C NMR spectra were recorded in CDCl3 solvent on 300
MHz, 500 MHz or 75 MHz spectrometer at r.t. with TMS as an in-
ternal standard. FTIR spectra were recorded as KBr thin films or
neat. All the reagents and solvents were reagent grade and used
obtained from 3,4,5-trimethoxybenzaldehyde 1f–h and
1-tosyl-1H-indole-3-carbaldehyde 1i–k also efficiently
participated in the one-pot reaction to give 3,5-disubstitut-
ed 1H-pyrazoles, 4f–k (entries 6–11). In the case of
propargylic alcohols with an alkyl group on the alkyne,
the cyclization (Step 2) was successful at 50 °C and in
good yields.
without further purification unless specified otherwise. Technical
grade EtOAc and petroleum ether used for column chromatography
were distilled prior to use. Column chromatography was carried out
using silica gel (60–120 mesh) packed in glass columns. All the re-
actions were performed under an atmosphere of N2 in oven-dried
glassware with magnetic stirring.
N-Acetyl-N-tosylhydrazine (2) was prepared using the literature
procedure.12b
However, propargylic alcohols 1l and 1m failed to give
the expected products, because the initial nucleophilic
substitution did not proceed in the presence of boron
trifluoride–diethyl ether complex even under refluxing
conditions. These results obviously reveal that the direct
propargylation of hydrazine 2 was successful only in the
case of propargylic alcohols generated from aromatic
(without electron-withdrawing groups)/heteroaromatic
1-Substituted Alk-2-yn-1-ols 1a–m; General Procedure
To the alkyne (1.1 mmol) in anhyd THF (5 mL) was added BuLi (1
mmol) slowly at –78 °C. After 40 min, the aromatic aldehyde (1
mmol) in THF (5 mL) was added at –78 °C to the mixture. The mix-
ture was stirred at –78 °C until complete consumption of the alde-
hyde, then the reaction was quenched by the addition of aq sat.
NH4Cl soln and extracted with EtOAc (2 × 15 mL). The combined
organic layers were dried (anhyd Na2SO4), concentrated in vacuo,
and purified by column chromatography (silica gel) to afford pure
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 830–836

834
C. Raji Reddy et al.
PAPER
propargylic alcohols 1a–m. The products obtained were character-
1H NMR (500 MHz, CDCl3): δ = 7.99–7.66 (m, 5 H, Ar), 7.36–7.18
(m, 4 H, Ar), 5.65 (s, 1 H, CH), 2.28–2.23 (m, 5 H, CH3Ts, CH2),
1.68–1.53 (m, 2 H, CH2–CH3), 1.01 (t, J = 7.3 Hz, 3 H, CH3).
ized by IR, 1H and 13C NMR, and mass spectroscopy.
The spectral data of 1a,8g 1c,9a 1d,13a 1e,13b 1i,13c 1l,13d and 1m13e
were in full agreement with the literature data.
13C NMR (75 MHz, CDCl3): δ = 144.9, 129.8, 126.9, 125.6, 124.9,
124.7, 123.0, 120.5, 113.3, 88.1, 62.7, 61.7, 22.0, 21.5, 20.8, 13.6.
HRMS (ESI): m/z [M + Na]+ calcd for C21H21NNaO3S: 390.1134;
found: 390.1132.
1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol (1b)
Viscous liquid; yield: 1.1 g (74%).
IR (KBr): 3365, 2196, 1485, 1068, 1011, 704 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.56–7.44 (m, 6 H, Ar), 7.36–7.30
(m, 3 H, Ar), 5.65 (s, 1 H, CH), 2.36 (s, 1 H, OH).
13C NMR (125 MHz, CDCl3): δ = 139.4, 131.6, 131.5, 128.6, 128.3,
128.2, 122.2, 122.0, 88.1, 86.8, 64.2.
N-Acetyl-N′-(1,3-diphenylprop-2-ynyl)-4-methylbenzenesul-
fonohydrazide (3a) (Table 1, Entry 2)
To a mixture of propargylic alcohol 1a (1.0 mmol) and N-acetyl-N-
tosylhydrazine (2, 0.9 mmol) in CH2Cl2 (5 mL) was added
BF3·OEt2 (5 mol%) at r.t. and the mixture was stirred for 10 min
(Table 1, entry 2). The mixture was diluted with sat. aq NaHCO3
soln (5 mL) and extracted with CH2Cl2 (2 × 15 mL). The combined
organic layers were washed with H2O (2 × 15 mL) and dried (anhyd
Na2SO4), concentrated in vacuo and purified by column chromatog-
raphy to afford 3a as a white solid; yield: 174.8 mg (87%); mp 120–
122 °C.
3-Phenyl-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (1f)
Viscous liquid; yield: 1.1 g (76%).
IR (KBr): 3431, 2939, 2216, 1595, 1461, 1127 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.49–7.46 (m, 2 H, Ar), 7.35–7.30
(m, 3 H, Ar), 6.87 (s, 2 H, Ar), 5.63 (s, 1 H, CH), 3.90 (s, 6 H,
OCH3), 3.86 (s, 3 H, OCH3).
IR (KBr): 3312, 2237, 1707, 1491, 1358, 1164, 758 cm–1.
13C NMR (75 MHz, CDCl3): δ = 153.0, 137.4, 136.3, 131.4, 128.4,
128.1, 122.1, 103.5, 88.7, 86.1, 64.7, 60.6, 55.8.
HRMS (ESI): m/z [M + Na]+ calcd for C18H18NaO4: 321.1097;
found: 321.1097.
1H NMR (500 MHz, CDCl3): δ = 8.02 (d, J = 6.9 Hz, 2 H, Ar), 7.65
(s, 2 H, Ar), 7.50–7.14 (m, 10 H, Ar), 5.68 (s, 1 H, CH), 5.31 (s, 1
H, NH), 2.51 (s, 3 H, CH3), 2.41 (s, 3 H, COCH3).
13C NMR (75 MHz, CDCl3): δ = 172.8, 144.9, 136.2, 131.3, 129.2,
128.9, 128.8, 128.5, 128.4, 128.1, 87.6, 85.2, 57.5, 23.9, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O3S: 419.1423;
found: 419.1426.
4-(Benzyloxy)-1-(3,4,5-trimethoxyphenyl)but-2-yn-1-ol (1g)
Viscous liquid; yield: 1.4 g (81%).
IR (KBr): 3433, 2939, 2841, 1594, 1234, 1125 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.30 (m, 5 H, Ar), 6.78 (s, 2
H, Ar), 5.46 (s, 1 H, CH), 4.61 (s, 2 H, PhCH2), 4.27 (d, J = 1.7 Hz,
2 H, OCH2), 3.86 (s, 6 H, OCH3), 3.84 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 152.8, 137.3, 136.8, 136.1, 128.1,
127.7, 103.3, 86.4, 81.8, 71.3, 64.0, 60.5, 57.1, 55.7.
HRMS (ESI): m/z [M + Na]+ calcd for C20H22NaO5: 3651359;
found: 365.1361.
3,5-Diphenyl-1H-pyrazole (4a); Procedure from 3a (Table 1,
Entry 7)
To a soln of 3a (1.0 mmol) in MeCN (5 mL) was added KOt-Bu (3
mmol) at r.t. and the mixture was stirred for 30 min (Table 1, entry
7). The solvent was removed on a rotary evaporator and the crude
product was extracted with EtOAc (2 × 15 mL). The combined or-
ganic layers were washed with H2O (2 × 15 mL), dried (anhyd
Na2SO4), and concentrated in vacuo. The resulting crude product
was purified by column chromatography to afford 4a as a viscous
liquid; yield: 44.7 mg (85%).
1-(3,4,5-Trimethoxyphenyl)hex-2-yn-1-ol (1h)
Viscous liquid; yield: 1.0 g (79%).
IR (KBr): 3446, 2963, 2226, 1594, 1460, 1420, 1331, 1233 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.77 (s, 2 H, Ar), 5.37 (s, 1 H,
ArCH), 3.85 (s, 6 H, OCH3), 3.81 (s, 3 H, OCH3), 2.24 (td, J = 2.0,
6.9 Hz, 2 H, CH2), 1.59–1.51 (m, 2 H, CH2CH3), 0.99 (t, J = 6.9 Hz,
3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 152.6, 137.1, 136.9, 103.3, 86.5,
80.0, 64.1, 60.2, 55.5, 21.6, 20.3, 13.0.
IR (KBr): 3097, 2923, 1461, 1181, 972, 753 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.75–7.70 (m, 4 H, Ar), 7.44–7.31
(m, 6 H, Ar), 6.85 (s, 1 H, =CH).
13C NMR (75 MHz, CDCl3): δ = 147.7, 131.2, 128.3, 127.4, 125.1,
99.0.
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found:
221.1072.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20NaO4: 287.1253;
found: 287.1252.
1-(3,5-Diphenyl-1H-pyrazol-1-yl)ethanone (4a′)
Viscous liquid; yield: 5 mg (8%).
IR (KBr): 3055, 1742, 1324, 941, 763 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.92–7.88 (m, 2 H, Ar), 7.49–7.39
(m, 8 H, Ar), 6.72 (s, 1 H, CH), 2.80 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 170.4, 153.3, 147.1, 131.7, 131.0,
129.1, 128.9, 128.8, 128.7, 127.8, 126.1, 109.8, 23.7.
MS (ESI): m/z = 263 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O: 263.1179; found:
263.1196.
4-(Benzyloxy)-1-(1-tosyl-1H-indol-3-yl)but-2-yn-1-ol (1j)
Viscous liquid; yield: 1.2 g (85%).
IR (KBr): 3521, 2856, 1447, 1369, 1173, 748 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 7.5 Hz, 1 H, Ar), 7.76
(t, J = 8.3 Hz, 3 H, Ar), 7.70 (s, 1 H, N-CH), 7.37–7.16 (m, 9 H, Ar),
5.72 (s, 1 H, CH), 4.60 (s, 2 H, PhCH2), 4.28 (d, J = 2.2 Hz, 2 H,
CH2O), 2.32 (s, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C26H23NO4NaS: 468.1240;
found: 468.1233.
One-Pot Synthesis of 3,5-Disubstituted 1H-Pyrazoles 4; Gener-
al Procedure
1-(1-Tosyl-1H-indol-3-yl)hex-2-yn-1-ol (1k)
Viscous liquid; yield: 1.0 g (83%).
IR (KBr): 2964, 2232, 1917, 1447, 1374, 1174, 972, 749 cm–1.
To a stirred soln of propargyl alcohol 1 (1 mmol) in MeCN (5 mL)
was added N-acetyl-N-tosylhydrazine (2, 0.95 mmol) and BF3·OEt2
(10 mol%) and the mixture was stirred at r.t. (see Table 2). Then,
KOt-Bu (3 mmol) was added and the stirring was continued at r.t.
or 50 °C (see Table 2). After completion of the reaction (for reaction
time, see Table 2), the mixture was evaporated in vacuo and the
Synthesis 2013, 45, 830–836
© Georg Thieme Verlag Stuttgart · New York

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3,5-Disubstituted 1H-Pyrazoles
835
crude mixture was diluted with EtOAc (10 mL) and washed with
H2O (5 mL) and brine (5 mL). The EtOAc layer was evaporated and
the residue was purified by column chromatography (silica gel,
EtOAc–hexanes) to give the corresponding pyrazole 4.
5-[(Benzyloxy)methyl]-3-(3,4,5-trimethoxyphenyl)-1H-pyr-
azole (4g)
Viscous liquid; yield: 79.7 mg (77%).
IR (KBr): 2932, 1589, 1468, 1126, 772 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.29 (m, 5 H, Ar), 6.95 (s, 2
H, Ar), 6.50 (s, 1 H, =CH), 4.63 (s, 2 H, PhCH2), 4.59 (s, 2 H,
CH2O), 3.90 (s, 6 H, OCH3), 3.87 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 153.4, 149.3, 144.5, 137.9, 137.3,
128.4, 127.8, 127.5, 104.1, 102.8, 101.8, 72.3, 63.8, 60.8, 56.0.
HRMS (ESI): m/z [M + H]+ calcd for C20H23N2O4: 355.1652; found:
355.1652.
3-(4-Bromophenyl)-5-phenyl-1H-pyrazole (4b)
White solid; yield: 88.5 mg (85%); mp 210–213 °C.
IR (KBr): 3448, 2922, 1488, 1453, 1067, 759 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 7.82–7.71 (m, 4 H, Ar), 7.54
(d, J = 8.3 Hz, 2 H, Ar), 7.42 (t, J = 7.5 Hz, 2 H, Ar), 7.32 (t, J = 7.5
Hz, 1 H, Ar), 6.88 (s, 1 H, CH=).
13C NMR (125 MHz, CDCl3): δ = 130.2, 127.3, 126.4, 125.6, 123.9,
119.6, 98.0.
MS (ESI): m/z = 299 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN2: 299.0178; found:
5-Propyl-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole (4h)
Viscous liquid; yield: 77.3 mg (74%).
IR (KBr): 2959, 2933, 1590, 1467, 1236, 1126, 1004 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.97 (s, 2 H, Ar), 6.33 (s, 1 H,
=CH), 3.90 (s, 6 H, OCH3), 3.87 (s, 3 H, OCH3), 2.64 (t, J = 7.5 Hz,
2 H, CH2), 1.78–1.64 (m, 2 H, CH2CH3), 0.99 (t, J = 7.3 Hz, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): δ = 153.3, 150.0, 147.4, 137.8, 128.4,
102.9, 100.7, 60.7, 55.9, 28.1, 22.4, 13.6.
299.0188.
3-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole (4c)
White solid; yield: 81.9 mg (78%); mp 150–154 °C.
IR (KBr): 2925, 2854, 1461, 1252, 1176, 764 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.71 (d, J = 7.1 Hz, 2 H, Ar), 7.63
(d, J = 8.6 Hz, 2 H, Ar), 7.43–7.30 (m, 3 H, Ar), 6.91 (d, J = 8.5 Hz,
2 H, Ar), 6.75 (s, 1 H, =CH), 3.83 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 158.7, 147.8, 131.4, 128.1, 127.1,
126.2, 124.9, 113.5, 98.2, 54.7.
HRMS (ESI): m/z [M + H]+ calcd for C15H21N2O3: 277.1546; found:
277.1546.
3-(5-Phenyl-1H-pyrazol-3-yl)-1-tosyl-1H-indole (4i)
Viscous liquid; yield: 78.2 mg (76%).
IR (KBr): 2926, 2207, 1683, 1445, 1372, 1174, 1134, 754 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C16H15NO2: 251.1178; found:
251.1178.
1H NMR (500 MHz, CDCl3): δ = 8.06 (t, J = 7.9 Hz, 2 H, Ar), 7.91
(s, 1 H, NCH=), 7.81 (d, J = 7.9 Hz, 2 H, Ar), 7.70 (t, J = 7.9 Hz, 2
H, Ar), 7.45 (t, J = 6.9 Hz, 2 H, Ar), 7.38 (t, J = 6.9 Hz, 2 H, Ar),
7.34–7.29 (m, 1 H, Ar), 7.22 (d, J = 7.9 Hz, 2 H, Ar), 6.86 (s, 1 H,
=CH), 2.33 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 147.0, 145.0, 143.2, 135.2, 134.9,
131.9, 130.3, 129.8, 128.8, 128.5, 128.4, 126.8, 125.5, 125.0, 123.7,
123.3, 121.2, 115.0, 113.6, 101.1, 21.4.
5-[(Benzyloxy)methyl]-3-(4-methoxyphenyl)-1H-pyrazole (4d)
White solid; yield: 79.2 mg (76%); mp 97–100 °C.
IR (KBr): 2925, 2855, 1511, 1251, 1029, 835 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8.7 Hz, 2 H, Ar), 7.39–
7.29 (m, 5 H, Ar), 6.95 (d, J = 7.8 Hz, 2 H, Ar), 6.49 (s, 1 H, =CH),
4.64 (s, 2 H, CH2O), 4.60 (s, 2 H, CH2Ph), 3.85 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 159.5, 148.1, 145.8, 137.6, 128.4,
127.9, 127.7, 126.8, 124.1, 114.1, 101.4, 72.2, 64.3, 55.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H20N3O2S: 414.1270;
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O2: 295.1441; found:
found: 414.1274.
295.1440.
3-{5-[(Benzyloxy)methyl]-1H-pyrazol-3-yl}-1-tosyl-1H-indole
(4j)
3-(4-Methoxyphenyl)-5-propyl-1H-pyrazole (4e)
Viscous liquid; yield: 79.4 mg (75%).
IR (KBr): 2960, 2871, 1457, 1249, 1177, 834 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 8.3 Hz, 2 H, Ar), 6.93
(d, J = 8.3 Hz, 2 H, Ar), 6.30 (s, 1 H, =CH), 3.84 (s, 3 H, OCH3),
2.64 (t, J = 7.5 Hz, 2 H, N=CH2), 1.77–1.64 (m, 2 H, CH2CH3), 0.99
(t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 159.3, 149.2, 147.8, 126.9, 125.1,
114.0, 100.4, 55.2, 28.3, 22.4, 13.7.
Viscous liquid; yield: 85.2 mg (83%).
IR (KBr): 3064, 2924, 1597, 1446, 1371, 1174 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.03 (t, J = 6.7 Hz, 2 H, Ar), 7.86
(s, 1 H, NCH), 7.78 (d, J = 8.3 Hz, 2 H, Ar), 7.39–7.28 (m, 7 H, Ar),
7.19 (d, J = 8.3 Hz, 2 H, Ar), 6.54 (s, 1 H, =CH), 4.66 (s, 2 H,
PhCH2), 4.60 (s, 2 H, CH2O), 2.31 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 145.0, 143.8, 137.3, 135.1, 134.8,
129.8, 128.4, 126.7, 125.0, 123.6, 123.2, 121.3, 115.1, 113.5, 102.9,
72.3, 63.6, 21.4.
HRMS (ESI): m/z [M + H]+ calcd for C13H17NO2: 217.1335; found:
217.1335.
HRMS (ESI): m/z [M + H]+ calcd for C26H24N3O3S: 458.1532;
found: 458.1532.
5-Phenyl-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole (4f)
3-(5-Propyl-1H-pyrazol-3-yl)-1-tosyl-1H-indole (4k)
Viscous liquid; yield: 84.2 mg (81%).
Viscous liquid; yield: 75.3 mg (73%).
IR (KBr): 2929, 1590, 1468, 1239, 1127, 765 cm–1.
IR (KBr): 2926, 2868, 1371, 1174, 772 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 7.3 Hz, 2 H, Ar), 7.37–
7.29 (m, 3 H, Ar), 6.94 (s, 2 H, Ar), 6.74 (s, 1 H, =CH), 3.86 (s, 3
H, OCH3), 3.81 (s, 6 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 153.3, 149.4, 147.6, 137.8, 130.4,
128.6, 128.0, 127.0, 125.3, 102.5, 99.4, 60.7, 55.7.
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 7.4 Hz, 1 H, Ar), 8.01
(d, J = 8.1 Hz, 1 H, Ar), 7.84 (s, 1 H, NCH), 7.78 (d, J = 8.7 Hz, 2
H, Ar), 7.35 (t, J = 7.4 Hz, 1 H, Ar), 7.29 (t, J = 7. 4 Hz, 1 H, Ar),
7.20 (d, J = 8.1 Hz, 2 H, Ar), 6.37 (s, 1 H, =CH), 2.68 (t, J = 7.4 Hz,
2 H, CH2), 2.32 (s, 3 H, CH3Ts), 1.76–1.70 (m, 2 H, CH2CH3), 1.01
(t, J = 7. 4 Hz, 3 H, CH3CH2).
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O3: 311.1390; found:
311.1388.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 830–836

836
C. Raji Reddy et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 146.4, 144.9, 143.9, 135.2, 135.0,
129.8, 128.6, 126.8, 124.9, 123.6, 123.2, 121.5, 115.9, 113.5, 102.0,
27.9, 22.3, 21.4, 13.6.
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HRMS (ESI): m/z [M + H]+ calcd for C21H22N3O2S: 380.1427;
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Y. Org. Lett. 2011, 13, 1024. (f) Yin, G.; Zhu, Y.; Zhang, L.;
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Chem. 2011, 9, 3940. (i) Zhang, M.; Yang, H.; Cheng, Y.;
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(k) Sanz, R.; Martinez, A.; Alvarez-Gutierez, J. M.;
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2011, 7308. (b) Debleds, O.; Gayon, E.; Vrancken, E.;
Campagne, J.-M. Beilstein J. Org. Chem. 2011, 7, 866.
(c) Sanz, R.; Miguel, D.; Gohain, M.; Garcia-Garcia, P.;
Fernandez-Rodriguez, M. A.; Gonzalez-Perez, A.; Nieto-
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found: 380.1425.
Acknowledgement
J.V. thanks Department of Science and Technology (DST), New
Delhi for research fellowship. This work has been carried out as part
of the Indo-French ‘Joint Laboratory for Sustainable Chemistry at
Interfaces’. We thank CSIR-New Delhi, CNRS, and University of
Rennes 1, France for support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York