Propargyl Hydrazides as Useful Intermediates Leading to Pyrazoles via Reaction with Certain Electrophiles

Article abstract of DOI:10.1002/ejoc.201600708

The reactions of propargyl hydrazides with certain electrophiles successfully led to the regioselective formation of various alkylated hydrazides. Reactions with electrophiles directly afforded the alkylated, chlorinated, brominated, and iodinated pyrazol

Full text of DOI:10.1002/ejoc.201600708

A Journal of
Accepted Article
Title: Propargyl Hydrazides as a Useful Intermediate Leading to Pyrazoles via Cer-
tain Electrophiles
Authors: Mitsuhiro Yoshimatsu; Kosuke Kiyokawa; Yukiteru Ito; Ryoma Kakehi; Ta-
kahiro Ogawa; Yusuke Goto
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600708
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600708
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European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
Propargyl Hydrazides as a Useful Intermediate Leading to Pyrazoles via
Certain Electrophiles
Kosuke Kiyokawa, Yukiteru Ito, Ryoma Kakehi, Takahiro Ogawa, Yusuke Goto, and Mitsuhiro
Yoshimatsu*
Abstract: The reactions of propargyl hydrazides with certain
electrophiles successfully led to the regioselective formation of
various alkylated hydrazides. Reactions with electrophiles directly
afforded the alkylated, chlorinated, brominated, and iodinated
pyrazoles.
Introduction
Pyrazoles are one of the most important classes of nitrogen-
containing heterocycles owing to their broad spectrum of
biological activities and useful applications.[1] Typical pyrazole
synthesis methods[2] are based on the condensation of
hydrazines with more stable and easy–to–handle starting
materials such as 1,3-diketones,[3] enones,[4] ynoes,[5] and
enynes.[6] One recent trend is the one-pot synthesis[7] of the
classical condensation reactions featuring three- and four-
component coupling, intermolecular 1,3-dipolar cycloaddition,
and [3+2] cycloaddition reactions. However, most of these
approaches suffer from the formation of
regioisomers.[9]
a mixture of
Recently, we reported the regioselective synthesis of
pyrazoles from propargyl alcohols with tosylhydrazine via the
corresponding hydrazides, which were isolated by our original
procedure.[10] Hydrazones have been reported to be a good tool
for the synthesis of pyrazoles via intra and intermolecular
cyclization reactions[11] with alkynes,[9] cyclobutanones,[12] and
other substituted pyrazoles;[13-16] however, the corresponding
hydrazides are much rarer than the corresponding
hydrazones.[10,15] Continuing our study, we next focused on the
modification of key intermediate propargyl hydrazides leading to
some useful pyrazoles. The identification of suitable chemical
processes for the hydrazides could easily lead to the discovery
of convenient and regioselective synthetic methods for
substituted pyrazoles. Herein, we report the direct synthesis of
pyrazoles from propargyl hydrazides to control the reactions with
electrophiles (Scheme 1).
Scheme 1. Propargyl Hydrazines Leading to Some Substituted Pyrazoles.
Results and Discussion
First, we conducted the base-promoted alkylation of propargyl
tosyl hydrazines, which were easily prepared from the
corresponding alcohols and p-tosyl hydrazide. We selected
hydrazine 1a and propargyl bromide as relatively reactive
alkylating reagents for the screening of the alkylation of
hydrazines. The results are shown in the Table of Supplement
data.
[a]
Professor, Dr. Mitsuhiro, Yoshimatsu, Corresponding Author
Department of Chemistry, Faculty of Education
Gifu University
Yanagido 1-1, Gifu 501-1193, Japan
E-mail: yoshimae@gifu-u.ac.jp
Supporting information for this article is given via a link at the end of
the document
Having identified the appropriate reaction conditions, we
investigated the scope of the alkylation of hydrazines. The
results are summarized in Table 1. The reaction was typically
completed within 10 min to 3 h at room temperature or 50 °C.

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
The reactions of 1 with some alkyl halides were first examined.
Propargyl bromide (entry 1), allylic bromide (entry 3),
bromoacetonitrile (entry 4), and methyl bromoacetates (entry 5)
were tolerated under the base-promoted alkylation conditions to
afford N1-alkyl hydrazines 13a-d in high yields. Interestingly, the
use of amine bases yielded N-propargylpyrazole 14, which was
obtained through a one-pot alkylation–cyclization, accompanied
by the expected alkylated product 13a in low yield (entry 2). We
next investigated the reactions of various hydrazides (R1–R2)
with certain alkyl halides. The cyanomethylation of hydrazine 2
(R2 = n-Bu) proceeded in good yield (entry 6). Interestingly, the
addition of a small amount of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) or heating at 50 oC resulted in the formation of N-
19
12
propargyl
rt, 1
27 (92)
[a] DBU was used as a base. [b] The reaction was examined for 1h at rt,
and then for 2 h at 80 oC.
These results motivated a detailed study of the base-promoted
alkylation of propargyl hydrazides. We performed some
variations of the model reaction, as shown in Scheme 2. The
reaction of N-alkylated hydrazide 13c (R1 = R2 = Ph) under
similar conditions more easily afforded N-cyanomethylpyrazole
14 in 90% yield. In particular, the thermal reaction of 13c in
toluene also afforded 28 in 48% yield. Conversely, reactions
with amines such as DBU or triethylamine gave hydrazone 28a
through the detosylation and isomerization of 13c. From this
evidence and the previous insights in the base-promoted [3+2]
cycloadditions,[9a,b,d,15a] we speculated that the base-promoted
cyclization would proceed via a stepwise process. The first step
is the base-promoted dehydrosulfonylation and isomerization to
the corresponding hydrazones, which is supported by the
isolation of some hydrazones 29b-29c. Second, the
cycloisomerization of propargyl hydrazones occurs under the
thermal or base-catalyzed conditions. Otherwise, the treatment
of 13c with NaH in DMF afforded the decyanomethylated
pyrazole 30.
cyanomethylpyrazoles 16-17, and 19 (entries 7-8, 10)
.
Reactions of hydrazide bearing either electron-withdrawing or
electron-donating groups at R1 also provided 18 and 20-21 in
excellent yields (entries 9 and 11-12). Hydrazine bearing a 2-
thienyl group also reacted with similar alkyl halides (entries 13-
14). Sulfur-substituted hydrazines (R3 = SPh) successfully afford
the alkylated products as almost pure products 23-27 (entries
15–19).
Table 1. Scope of base-promoted alkylation of hydrazides.
entry
Hydrazide
R3
Temp (oC),
time (h)
Products (%yields)
1
2
1
1
propargyl
propargyl
Allyl
rt, 0.17
rt, 0.17
50, 0.5
rt, 2
13a (84)
14 (23)[a]
13b (85)
13c (90)
13d (81)
15 (69)
16 (67)[a]
17 (80)
18 (85)
19 (80)
20 (87)
21 (87)
22a (96)
22b (94)
23 (86)
24 (96)
25 (82)
26 (95)
Scheme 2. Reactions of Propargyl Hydrazides with Other Bases.
3
1
We noted that the propargyl hydrazides easily form
substituted pyrazoles under the base-promoted alkylation
conditions. On this basis, we explored the reactions with
halogenating agents as readily available electrophiles, and the
results are listed in Table 2. The reaction of 13a with N-
chlorosuccinimide in dichloromethane (DCM) directly provided 4-
chloropyrazole 31a in 45% yield (entry 1 of Table 3). Reaction
with N-bromosuccinimide quantitatively afforded the 4-bromo
derivative 31b. Iodocyclization also succeeded in the iodination–
cycloaromatizations (entries 2 and 3). Recently, Wada and co-
workers reported that the iodocyclization of propargyl hydrazides,
prepared by the Mitsunobu reaction of the alcohol with
diisopropyl azodicarboxylate (DIPA),[16b] afforded either 4-
iodopyrazoles or 4-iodo-dihydropyrazoles by a useful switchable
process. Comparing our halo-cyclization of N-tosyl propargyl
hydrazides with the DIPA system, our method has strong
potential to provide access to the pyrazole core because
detosylation of hydrazides or hydrazones proceed much more
easily than the decarboxylation of the DIPA system. We
examined the substrate scope of the halo-cyclizations of tosyl
hydrazides. The results are shown in entries 4–10 of Table 2.
4
1
CH2CN
CH2CO2Me
CH2CN
CH2CN
propargyl
allyl,
5
1
50, 0.5
rt, 1
6
2
7
2
rt, 2
8
3
50, 0.5
rt, 0.8
0.17
9
4
10
11
12
13
14
15
16
17
18
4
CH2CN
CH2CN
5
0.17
t
6
CH2CO2 Bu
0.25
7
allyl
rt, 0.67
50, 0.17
50, 3
7
CH2CN
propargyl
8
t
9
CH2CO2 Bu
rt, 0.25
50, 0.5
rt, 0.17
10
11
propargyl
CH2CN

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
Scheme 4. Transformation of 1-alkyl-1-tosyl-2-propargylhydrazides.
Table 2. Detosylative cyclization of 1-alkyl-1-tosyl-2-propargylhydrazines.
entry
R1
R2
R3
time (h)
X
Products
(%yields)
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bu
propargyl
propargyl
propargyl
allyl
18.5
0.25
1
Cl
Br
I
31a (45)
31b (93)
31c (82)
31d (81)
31e (58)
31f (74)
31g (67)
31h (97)
31i (61)
31j (52)
We performed the further transformation of propargyl
hydrazides (Scheme 4). Halogenated pyrazoles underwent
arylation to afford 32. We also attempted the reactions with
metal catalysts or Lewis acids. The reaction with Lewis acid
underwent dehydrazination exclusively to afford allene 33.
Silver-catalyzed cyclizations in acetic acids successfully
provided the N-alkylated pyrazoles 34a and 34b in high yields.
Ph
3
Ph
4
Ph
0.75
0.5
Br
I
5
Ph
allyl
6
Ph
CH2CN
CH2CN
propargyl
CN
1.25
4
Br
I
7
Ph
8
Naph-
pFC6H4
2Thien-
40 min
2.5
Br
Br
I
Conclusions
9
In summary, we have shown a regioselective synthesis of new
propargyl hydrazides, N-alkylated propargyl hydrazones, and
pyrazoles, respectively. Reactions of N-alkylated hydrazides
with electrophiles such as NCS, NBS, and NIC easily underwent
10
allyl
0.25
From these studies, the proposed mechanism for the pyrazole
formation of N-alkylated propargyl hydrazides are shown in
Scheme 3. Alkylation reactions of S1 easily gives S2 under the
basic conditions. Reactions under the high temperature and/or
more basic conditions result in the formations of propargyl
hydrazone S4 through the dehydrosulfonylation-isomerization of
hydrazine S2 via either S3 or S3’ as mentioned above (Scheme
cyclization directly to give the 4-halopyrazoles.
We are
presently investigating the silver-catalyzed synthesis of
pyrazoles, and further transformation of N-alkylated propargyl
hydrazones. These results will be reported elsewhere.
2).
intermediate S5. The subsequent inter- or intramolecular proton
shift of the intermediate S5 would give S6.[17]
While,
Intramolecular cyclization of S4 would give the key
Experimental Section
General Experimental Details
halogenation of S2 with NXC would also provide the hydrazone
S4 by the similar pathway in the base-promoted alkylations.
Electrophilic cyclization of (Z)-S4 would proceed via the
intermediate S7 to give the cation S8.[5h] Deprotonation of S8
provide the 4-halopyrazole S9.
Dry solvents were purchased from commercial suppliers and used
without further purification. Analytical thin-layer chromatography (TLC)
was performed on glass plates coated with 0.25 mm Silicagel 60F254.
Silicagel column chromatography was performed on Merck silica gel 60
(0.063-0.200 mm) and thin-layer chromatography (TLC) was performed
on glass plates coated with Silicagel 60 PF254. IR spectra were
recorded on JASCO FT/IR. NMR-spectra were recorded on a JEOL ECA
600 spectrometer at Gifu University. Chemical shifts are expressed in
parts per million (ppm) with respect to tetramethylsilane as an internal
standard. Splitting patterns are designated as follows: s, singlet; d,
doublet; q, quartet. EI mass spectra (MS) were obtained using JEOL
MS-700 spectrometer with direct-insertion probe at 70 eV. All high
resolution mass determinations were obtained on the JMSD300 JMS
2000 on line system. Melting points apparatus were determined on a J-
Science Lab. Micro melting point apparatus and uncorrected. Elemental
analyses were performed at the Center of Instrumentation of Gifu
University. All propargyl hydrazines 1-12 are prepared by the following
known procedure.[10]
Scheme 3. Proposed reaction mechanism.
1.
Alkylation of Propargyl Hydrazides.
2-(1,3-diphenylprop-2-yn-1-yl)-1-propargyl-p-toluenesulfonylhydrazine
(13a).
Typical experimental procedure: To an acetonitrile (20.0 mL) solution of
2-(1,3-diphenylprop-2-yn-1-yl)-p-toluenesulfonylhydrazine (1) (1.00 g,
2.66 mmol) were added propargyl bromide (734 mg, 5.31 mmol) and
cesium carbonate (63.2 mg, 3.19 mmol) at room temperature. The
reaction mixture was stirred for 0.5 h at 50 oC and then poured into water
(50 mL). The organic layer was separated and the aqueous layer was

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
extracted with AcOEt (20 mL × 2). The solvent was removed under
reduced pressure. The residue was purified by column chromatography
on silica gel eluting with AcOEt-n-hexane (1:20, then 1:10). 2-(1,3-
Diphenylprop-2-yn-1-yl)-1-propargyl-1-(p-toluenesulfonyl)hydrazine (13a)
(0.94 g, 85%) was obtained as a yellow oil.
5.5 Hz, CH), 7.33-7.40 (7H, m, ArH), 7.45-7.47 (2H, m, ArH), 7.56 (2H,
brd, J = 6.9 Hz, ArH), 7.83 (2H, d, J = 8.3 Hz, ArH); 13C NMR (150 MHz,
CDCl3)  21.7 (q), 40.2 (t), 57.1 (d), 86.9 (s), 87.0 (s), 113.5 (s), 122.1 (s),
128.3 (d × 2), 128.4 (d × 2), 128.7 (d × 4), 128.8 (d × 2), 130.0 (d × 2),
131.7 (d × 2), 132.0 (s), 136.7 (s), 145.4 (s); MS m/z 414 (M+ - 1). Anal.
Calcd for C24H21N3O2S: C, 69.38; H, 5.09; N, 10.11. Found: C, 69.08; H,
5.10; N, 9.96.
IR (KBr, cm-1) 3294, 3265, 3063, 3031, 2923, 2850, 2118, 1712, 1598,
1491, 1453, 1443, 1352, 1305, 1222, 1166, 1092, 1029, 917, 849, 815,
758, 694, 662, 580, 547, 527; 1H NMR (600 MHz, CDCl3)  2.05 (1H, t,
J=2.3 Hz, acetylenic H), 2.40 (3H, s, Me), 3.91 (1H, d, J = 8.2 Hz, NH),
4.46 (1H, brd, J = 18.3 Hz, CH), 4.47 (1H, dd, J = 2.3 and 18.3 Hz, CH),
5.16 (1H, brd, J = 7.3 Hz, CH), 7.25 (2H, brd, J = 5.0 Hz, ArH), 7.26-7.38
(6H, m, ArH), 7.45-7.46 (2H, m, ArH), 7.60 (2H, d, J = 6.4 Hz, ArH), 7.83
(2H, d, J = 8.3 Hz, ArH); 13C NMR (150 MHz, CDCl3)  21.6 (q), 40.3 (t),
56.9 (d), 75.3 (s), 76.8 (d), 86.7 (s), 87.8 (s), 122.5 (s), 128.2 (d × 2),
128.3 (d × 2), 128.4 (d × 2), 128.5 (d), 129.1 (d × 2), 129.2 (d × 2), 131.6
(d × 2), 133.6 (s), 137.2 (s), 144.0 (s); MS m/z 414 (M+). Anal. Calcd for
C25H22N2O2S: C, 72.44; H, 5.35; N, 6.76. Found: C, 72.55; H, 5.37; N,
6.73.
methyl
4-(1,3-diphenylprop-2-yn-1-yl)-3-p-
toluenesulfonylhydrazinylacetate (13d).
To an acetonitrile (2.0 mL) solution of 2-(1,3-diphenylprop-2-yn-1-yl)-p-
toluenesulfonylhydrazine 1 (100 mg, 0.27 mmol) were added methyl
bromoacetate (121.9 mg, 0.80 mmol) and cesium carbonate (173.1 mg,
0.53 mmol) at room temperature. The reaction mixture was stirred for 10
o
min at 50 C and then poured into water (50ml). The organic layer was
separated and extracted with AcOEt (20mL × 2). The combined organic
layer was dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by preparative TLC on silica gel
eluting with AcOEt-n-hexane (3:13). Methyl 4-(1,3-diphenylprop-2-yn-1-
yl)-3-(p-toluenesulfonyl)hydrazinylacetate (13d) (97 mg, 81%) as white
prisms (mp 73-75 oC, from CHCl3-n-hexane).
3,5-diphenyl-1-(2-propyn-1-yl)-1H-pyrazole (14), entry 2 in Table 1.[18]
The reaction of 1 (25 mg, 0.07 mmol), propargyl bromide (16 mg, 0.13
mmol), and DBU (20 mg, 0.13 mmol) in acetonitrile (0.50 mmol) was
examined at 50 oC for 1.2 h. The workup procedure gave 14 (4.0 mg,
23%) as a yellow oil.
IR (KBr, cm-1) 3394, 3294, 3062, 3032, 2952, 1743, 1712, 1598, 1573,
1491, 1442, 1404, 1347, 1305, 1289, 1219, 1164, 1093, 853, 816, 759,
694, 660, 547; 1H NMR (600 MHz, CDCl3)  2.40 (3H, s, Me), 3.53 (3H, s,
Me), 4.42 (1H, brd, J = 7.9 Hz, NH), 4.64-4.67 (2H, m, CH2), 5.16 (1H, d,
J = 7.6 Hz, CH), 7.27 (2H, d, J = 8.3 Hz, ArH), 7.31-7.36 (6H, m, ArH),
7.41-7.43 (2H, m, ArH), 7.53 (2H, d, J = 6.9 Hz, ArH), 7.79 (2H, d, J = 8.3
Hz, ArH); 13C NMR (150 MHz, CDCl3)  21.6 (q), 50.7 (t), 52.0 (q), 56.5
(d), 86.7 (s), 88.0 (s), 122.4 (s), 128.2 (d × 2), 128.3 (d × 3), 128.4 (d × 4),
128.5 (d), 129.3 (d × 2), 131.5 (d × 2), 135.0 (s), 137.3 (s), 143.8 (s),
169.3 (s); MS m/z 448 (M+), 292 (M+-TsH). Anal. Calcd for C25H24N2O4S:
C, 66.95; H, 5.39; N, 6.25. Found: C, 66.82; H, 5.46; N, 6.19.
White powders (from n-hexane), mp 108-109 oC, IR (KBr, cm-1) 3288,
3054, 2931, 1712, 1486, 1462, 1439, 1362, 1299, 785, 758, 696; 1H
NMR (600 MHz, CDCl3) δ 2.44 (1H, t, J = 2..7 Hz, CH), 4.92 (2H, d, J =
2.7 Hz, CH2), 6.64 (1H, s, ArH), 7.32 (1H, t, J = 7.6 Hz, ArH), 7.41 (2H, t,
J = 7.6 Hz, ArH), 7.45 (1H, t, J = 7.6 Hz, ArH), 7.50 (2H, t, J = 6.9 Hz,
ArH), 7.58 (2H, d, J = 6.9 Hz, ArH), 7.86 (2H, d, J = 7.5 Hz, ArH); 13C
NMR (150 MHz, CDCl3) δ 39.8 (q), 73.6 (d), 78.4 (s), 103.7 (d), 125.8 (d
× 2), 127.8 (d), 128.6 (d × 2), 128.8 (d × 2), 128.9 (d × 2), 130.1 (s),
133.1 (s), 145.1 (s), 151.5 (s); MS m/z 258 (M+). Anal. Calcd for
C18H14N2: C, 83.69; H, 5.46; N, 10.84. Found: C, 83.46; H, 5.64; N,
10.77.
1-cyanomethyl-2-(1-phenylhept-2-yn-1-yl)-p-toluensulfonylhydrazine (15).
To an acetonitrile (10.0 mL) solution of 2-(1-phenylhept-2-yn-1-yl)-p-
toluenesulfonylhydrazine
2
(500 mg, 1.40 mmol) were added
1-allyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-toluensulfonylhydrazine (13b).
To an acetonitrile (10.0 mL) solution of 2-(1,3-diphenylprop-2-yn-1-yl)-p-
toluenesulfonylhydrazine 1 (500 mg, 1.33 mmol) were added allyl
bromide (0.32 g, 2.66 mmol) and cesium carbonate (0.94 g, 2.66 mmol).
The reaction mixture was stirred for 40 min and then poured into water
(50.0 mL). The organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic layer was dried over
MgSO4. The solvent was removed under reduced pressure. The residue
was precipitated from hexane and filtered off to give 1-allyl-2-(1,3-
diphenylprop-2-yn-1-yl)-p-toluensulfonylhydrazine (13b) (0.51 g, 92%)
(pale yellow plates, mp 90-91 oC).
bromoacetonitrile (0.25 g, 2.10 mmol) and cesium carbonate (0.55 g,
1.70 mmol). The reaction mixture was stirred for 1 h at room
temperature and then poured into water (50 mL). The organic layer was
separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was
removed under reduced pressure. The residue was purified by the
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10) to give
1-cyanomethyl-2-(1-phenylhept-2-yn-1-yl)-p-toluensulfonylhydrazine (15)
(0.38 g, 69%) as white powders (mp 80-81 oC, from CH2Cl2-hexane).
IR (KBr, cm-1) 3277, 2960, 2933, 2873, 2861, 1599, 1494, 1451, 1401,
1343, 1304, 1184, 1162, 1092, 919, 865, 836, 808, 743, 697, 661; 1H
NMR (600 MHz, CDCl3)  0.92 (3H, t, J = 7.6 Hz, Me), 1.38-1.44 (2H, m,
CH2), 1.50-1.54 (2H, m, CH2), 2.25 (2H, td, J = 2.0 and 6.9 Hz, CH2),
2.44 (3H, s, CH3), 3.74 (1H, d, J = 5.5 Hz, NH), 4.23 (1H, d, J = 17.9 Hz,
CH2), 4.57 (1H, d, J = 17.8 Hz, CH2), 5.01 (1H, dt, J = 2.1 and 5.5 Hz,
CH), 7.30-7.36 (5H, m, ArH), 7.47 (2H, d, J = 6.9 Hz, ArH), 7.81 (2H, d, J
= 8.3 Hz, ArH); 13C NMR (150 MHz, CDCl3)  13.5 (q), 18.5 (t), 21.6 (q),
22.0 (t), 30.6 (t), 40.1 (t), 56.6 (d), 77.9 (s), 87.9 (s), 113.5 (s), 128.2
(d×2), 128.5 (d), 128.6 (d × 2), 128.7 (d × 2), 129.9 (d × 2), 132.2 (s),
137.5 (s), 145.3 (s); MS m/z 394 (M+ - 1), 396 (M+-CN). Anal. Calcd for
C22H25N3O2S: C, 66.81; H, 6.37; N, 10.62. Found: C, 66.58; H, 6.36; N,
10.58.
IR (KBr, cm-1) 3281, 3064, 3032, 2925, 1712, 1598, 1490, 1453, 1443,
1353, 1304, 1289, 1166, 1091, 1028, 993, 921, 849, 815, 759, 693, 663,
549; 1H NMR (600 MHz, CDCl3)  2.41 (3H, s, Me), 3.75 (1H, s, NH),
4.13 (1H, dd, J = 6.3 and 14.9 Hz, CH), 4.25 (1H, dd, J = 8.0 and 14.9 Hz,
CH), 5.01 (1H, s, CH), 5.21-5.24 (2H, m, CH2), 5.56-5.63 (1H, m, CH),
7.27 (2H, d, J = 9.2 Hz, ArH), 7.31-7.35 (6H, m, ArH), 7.43-7.45 (2H, m,
ArH), 7.48-7.49 (2H, m, ArH), 7.82 (2H, d, J = 8.0 Hz, ArH); 13C NMR
(150 MHz, CDCl3)  21.5 (q), 53.3 (t), 56.9 (d), 86.4 (s), 88.2 (s), 122.2 (t),
122.7 (s), 128.3 (d), 128.3 (d × 4), 128.4 (d × 2), 128.5 (d), 128.7 (d × 2),
129.4 (d × 2), 131.0 (d), 131.6 (d × 2), 134.5 (s), 137.6 (s), 143.8 (s); MS
m/z 261 (M+ - Tos). Anal. Calcd for C25H24N2O2S: C, 72.09; H, 5.81; N,
6.73. Found: C, 71.89; H, 5.83; N, 6.56.
5-butyl-1-cyanomethyl-3-phenylpyrazole (16).
To an acetonitrile (1.0 mL) solution of 2-(1-phenylhept-2-yn-1-yl)-p-
cyanomethyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-toluensulfonylhydrazine
(13c).
toluenesulfonylhydrazine
2
(30 mg, 0.80 mmol) were added
To an acetonitrile (20.0 mL) solution of 2-(1,3-diphenylprop-2-yn-1-yl)-p-
bromoacetonitrile (29 mg, 0.24 mmol) and cesium carbonate (78 mg,
0.24 mmol) and DBU (2.4 mg, 0.02 mmol). The reaction mixture was
stirred for 2 h. The workup procedure gave 5-butyl-1-cyanomethyl-3-
phenylpyrazole (16)(13 mg, 67%) as a yellow oil.
toluenesulfonylhydrazine
1
(1.00 g, 2.66 mmol) were added
bromoacetonitrile (478 mg, 3.98 mmol) and cesium carbonate (1.04 g,
3.19 mmol) at room temperature. The reaction mixture was stirred for 2
h and then poured into water (50.0 mL). The organic layer was
separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. Cyanomethyl-2-(1,3-
diphenylprop-2-yn-1-yl)-p-toluensulfonylhydrazine (13c) (995 mg, 90%)
was obtained as white powders (mp 96-101 oC).
IR (KBr, cm-1) 3062, 2958, 2932, 2872, 2359, 1711, 1552, 1469, 1446,
1
1368, 1305, 1222, 1079, 958, 915, 768, 695; H NMR (600 MHz, CDCl3)
 0.99 (3H, t, J = 6.8 Hz, Me), 1.46-1.49 (2H, m, CH2), 1.71-1.76 (2H, m,
CH2), 2.69 (2H, t, J = 7.5 Hz, CH2), 5.04 (2H, s, CH2), 6.41 (1H, s, ArH),
7.31-7.33 (1H, m, ArH), 7.38-7.41 (2H, m, ArH), 7.75-7.77 (2H, m, ArH);
13C NMR (150 MHz, CDCl3)  13.7 (q), 22.3 (t), 25.2 (t), 30.4 (t), 37.2 (t),
103.2 (d), 114.0 (s), 125.6 (dx2), 128.1 (d), 128.6 (dx2), 132.7 (s), 145.2
IR (KBr, cm-1) 3286, 3062, 3033, 2923, 2852, 2219, 1598, 1491, 1454,
1444, 1358, 1166, 1092, 848, 815, 758, 697, 662, 588, 548; 1H NMR
(600 MHz, CDCl3)  2.43 (3H, s, Me), 3.88 (1H, d, J = 5.5 Hz, NH), 4.32
(1H, d, J = 7.9 Hz, CH), 4.61 (1H, d, J = 17.9 Hz, CH), 5.29 (1H, d, J =

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
(s), 152.1 (s); MS m/z 239 (M+); high resolution mass calcd for C15H17N3:
239.1422, found m/z 239.1427.
0.26 mmol) at room temperature. The reaction mixture was stirred at 50
oC for 10min and then poured into water (50 mL). The workup procedure
gave
1-allyl-2-[1-(p-chlorophenyl)-hept-2-yn-1-yl]-p-
3-(1-naphthyl)-5-phenyl-1-propargyl-1H-pyrazole (17).
toluenesulfonylhydrazine (20) (48 mg, 87 %) as white powders.
o
To an acetonitrile (1.0 mL) solution of 2-(1-naphthyl-3-phenylprop-2-yn-1-
yl)-p-toluenesulfonylhydrazine (3) (50 mg, 0.11 mmol) was added
proprgyl bromide (27.8 mg, 0.23 mmol) and cesium carbonate (114 mg,
0.35 mmol) at room temperature. The reaction mixture was stirred for
1.5 h and then DBU (1.8 mg, 0.01 mmol) was added to the mixture. The
whole was heated at 80 oC and then poured into water (50 mL). The
organic layer was separated and the aqueous layer was extracted with
AcOEt. The combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The residue was purified by
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:20). 3-
(naphthalene-1-yl)-5-phenyl-1-(2-propyn-1-yl)-1H-pyrazole (17) (27 mg,
80 %) was obtained as white powders.
mp 80-84 C, IR (KBr, cm-1) 3285, 2959, 2931, 2872, 2355, 2333, 1712,
1597, 1489, 1462, 1408, 1360, 1222, 1166, 1092, 1016, 939, 814, 745;
1H NMR (600 MHz, CDCl3)  0.92 (3H, t, J = 7.6 Hz, Me), 1.37-1.44 (2H,
m, CH2), 1.49-1.53 (2H, m, CH2), 2.25 (2H, dt, J = 2.1 and 6.9 Hz, CH2),
2.44 (3H, s, CH3), 3.76 (1H, d, J = 5.5 Hz, CH), 4.29 (1H, d, J = 17.9 Hz,
CH), 4.56 (1H, d, J = 17.9 Hz, CH), 4.99 (1H, dd, J = 2.1 and 5.5 Hz, CH),
7.30 (2H, d, J = 8.2 Hz, ArH), 7.35 (2H, d, J = 8.3Hz, ArH), 7.40 (2H, d, J
= 8.3 Hz, ArH), 7.80 (2H, d, J = 8.9 Hz, CH2); 13C NMR (150 MHz, CDCl3)
 13.5 (q), 18.4 (t), 21.6 (q), 22.0 (t), 30.5 (t), 40.1 (t), 55.9 (d), 77.5 (s),
88.4 (s), 113.4 (s), 128.6 (d × 2), 128.7 (d × 2), 129.6 (d × 2), 129.9 (d ×
2), 131.9 (s), 134.3 (s), 136.0 (s), 145.4 (s); MS m/z 429 (M+ - 1), 274 (M+
- Ts). Anal. Calcd for C22H24ClN3O2S: C, 61.46; H, 5.63; N, 9.77. Found:
C, 61.56; H, 5.59; N, 9.73.
mp 131-134 oC, IR (KBr, cm-1) 3420, 3290, 3051, 2925, 1549, 1514, 1493,
1457, 1424, 1382, 1363, 1349, 1300, 1263, 1215, 1159, 1007, 937, 917,
800, 775, 760, 700; 1H NMR (600 MHz, CDCl3)  2.46 (1H, t, J = 2.8 Hz,
CH), 5.01 (2H, d, J = 2.7 Hz, CH2), 6.66 (1H, s, ArH),7.45-7.54 (6H, m,
ArH), 7.65 (2H,d, J = 6.9 Hz, ArH), 7.76 (1H, d, J = 6.9 Hz, ArH), 7.86
(1H, d, J = 8.3 Hz, ArH), 7.89 (1H, d, J = 8.3 Hz, ArH), 8.61 (1H, d, J =
8.2 Hz, ArH); 13C NMR (150 MHz, CDCl3)  39.9 (t), 73.6 (d), 78.4 (s),
107.4 (d), 125.3 (d), 125.7 (d), 126.2 (d), 126.3 (d), 127.1 (d), 128.3 (d),
128.4 (d), 128.8 (d × 2), 128.9 (d), 128.9 (d × 2), 130.1(s), 131.2 (s),
131.4 (s), 134.0 (s), 144.4 (s), 151.2 (s); MS m/z 308 (M+); high
resolution mass calcd for C22H16N2: 308.1313, found m/z 308.1344.
t-butyl
2-[[2-(1-p-methoxyphenyl)-3-phenylprop-2-yn-1-yl]-p-
toluenesulfonylhydrazin-1-yl]acetate (21).
To an acetonitrile (1.0 mL) solution of 2-[1-(p-methoxypheny)-3-
phenyllprop-2-yn-1-yl]-p-toluenesulfonylhydrazine (6) (50 mg, 0.12 mmol)
was added t-butyl bromoacetete (48.0 mg, 0.25 mmol) and cesium
carbonate (80.2 mg, 0.25 mmol) at room temperature. The reaction
mixture was stirred at 50 oC for 0.25 h and then poured into water (50
mL). The workup procedure gave t-butyl 2-[2-[1-(p-methoxyphenyl)-3-
phenylprop-2-yn-1-yl]-p-toluenesulfonylhydrazin-1-ylacetate (21)(56 mg,
87 %) as a brown oil.
1-allyl-2-(1-p-fluorophenyl-3-phenylprop-2-ynyl)-p-
toluenesulfonylhydrazine (18).
IR (KBr, cm-1) 3301, 2979, 2934, 2838, 1734, 1610, 1599, 1586, 1511,
1491, 1457, 1443, 1395, 1368, 1346, 1304, 1251, 1164, 1093, 1034, 910,
814, 760, 693; 1H NMR (600 MHz, CDCl3)  1.31 (9H, s, t-Bu), 2.39 (3H,
s, CH3), 3.81 (3H, s, OCH3), 4.36 (1H, brs, NH), 4.59 (1H, d, J = 18.6 Hz,
CH), 4.76 (1H. d. J = 7.5 Hz, CH), 5.07 (1H, d, J = 7.5Hz, CH), 6.86 (2H,
d, J = 8.9 Hz, CH2), 7.25 (2H, d, J = 8.3 Hz, CH2), 7.31-7.32 (3H, m, ArH),
7.41-7.43 (4H, m, ArH), 7.45 (2H, d, J = 8.2 Hz, ArH), 7.78 (2H, d, J = 8.2
Hz, ArH); 13C NMR (150 MHz, CDCl3)  21.5 (q), 27.8 (q × 3), 50.7 (t),
55.3 (q), 55.9 (d), 82.4 (s), 86.4 (s), 88.6 (s), 113.7 (d × 2), 122.6 (s),
128.3 (d × 2), 128.4 (d × 2), 128.5 (d), 129.2 (d × 2), 129.3 (d × 2), 129.7
(s), 131.6 (d × 2), 135.4 (s), 143.5 (s), 159.5 (s), 168.1 (s); MS m/z 364
(M+ - TsH); high resolution mass calcd for C29H32N2O5S: 520.2031; found
519.2022.
To an acetonitrile (1.0 mL) solution of 2-[1-(p-fluorophenyl)-3-phenylprop-
2-yn-1-yl]-p-toluenesulfonylhydrazine (4) (50 mg, 0.13 mmol) was added
to allyl bromide (46.0 mg, 0.38 mmol) and cesium carbonate (82.6 mg,
0.25 mmol) at room temperature. The reaction mixture was stirred for 50
min and poured into water (50 mL). The organic layer was separated
and the aqueous layer was extracted with AcOEt. The combined organic
layer was dried over MgSO4. The solvent was removed under reduced
pressure. The residue was purified by preparative TLC on silica gel
eluting with AcOEt-n-hexane (1:10). 1-allyl-2-[1-(p-fuluorophenyl)-2-(3-
phenylprop-2-yn-1-yl)]-p-toluenesulfonylhydrazine (18)(47 mg, 85 %) as
pale yellow powders.
o
mp 61-64 C, IR (KBr, cm-1) 3284, 3067, 2923, 1712, 1601, 1508, 1491,
1443, 1352, 1305, 1294, 1223, 1166, 1092, 840, 815, 758, 692, 662, 585,
549; H NMR (600 MHz, CDCl3)  2.41 (3H, s, Me), 3.76 (1H, d, J = 6.9
1-allyl -2-[1-(2-thienyl)hept-2-yn-1-yl]-p-toluenesulfonylhydrazine (22a).
To an acetonitrile (5.0 mL) solution of 2-[1-(2-thienyl)hept-2-yn-1-yl]-p-
toluenesulfonylhydrazine (7) (200 mg, 0.55 mmol) was added allyl
bromide (133.5 mg, 1.01 mmol) and cesium carbonate (215.7 mg, 0.66
mmol) at room temperature. The reaction mixture was stirred for 40 min
and then poured into water (50 mL). The workup procedure gave 1-allyl -
2-[1-(2-thienyl)-hept-2-yn-1-yl]-p-toluenesulfonylhydrazine (22a) (213 mg,
96 %) as a yellow oil.
1
Hz, CH), 4.14-4.23 (2H, m, CH2), 5.07 (1H, d, J = 6.9 Hz, CH), 5.22-5.25
(2H, m, CH2), 5.57-5.63 (1H, m, CH), 6.98-7.01 (2H, m, ArH), 7.26 (2H, d,
J = 8.3 Hz, ArH), 7.31-7.34 (2H, m, ArH), 7.42-7.46 (5H, m, ArH), 7.78
(2H, d, J = 8.9 Hz, CH2); 13C NMR (150 MHz, CDCl3)  21.5 (q), 53.3 (t),
56.1 (d), 86.6 (s), 87.9 (s), 115.1 (d), 115.3 (d), 122.2 (t), 122.4 (s), 128.4
(d × 2), 128.6 (d), 128.7 (d × 2), 129.4 (d × 2), 130.1 (d), 130.1 (d), 131.0
(d), 131.6 (d × 2), 133.4 (s), 134.4 (s), 144.0 (s), 162.6 (d, J = 247.1 Hz);
MS m/z 279 (M+ - TsH). Anal. Calcd for C25H23FN2O2S: C, 69.10; H, 5.34;
N, 6.45. Found: C, 69.02; H, 5.28; N, 6.33.
IR (KBr, cm-1) 2959, 2934, 2862, 1712, 1598, 1465, 1436, 1353, 1230,
1167, 1092, 930, 815, 705, 666, 567, 517, 484, 462; 1H NMR (600 MHz,
CDCl3)  0.92 (3H, t, J = 6.2 Hz, Me), 1.40-1.46 (2H, m, CH2), 1.50-1.56
(2H, m, CH2), 2.23-2.28 (2H, m, Me), 2.43 (3H, s, Me), 3.70 (1H, d, J =
6.9 Hz, CH), 4.12 (1H, dd, J = 6.2 and 15.1 Hz, CH), 4.19 (1H, dd, J =
8.2 and 15.1 Hz, CH), 4.98 (1H, brs, CH), 5.19-5.22 (2H, m, olefinic H),
5.54-5.61 (1H, m, olefinic H), 6.91 (1H, dd, J = 3.4 and 4.8 Hz, ArH), 7.05
(1H, dt, J = 3.5 and 1.3 Hz, ArH), 7.23-7.26 (1H, m, ArH), 7.29 (2H, d, J =
7.6 Hz, ArH), 7.85(2H, d, J = 8.3 Hz, ArH); 13C NMR (150 MHz, CDCl3) 
13.5 (q), 18.4 (t), 21.6 (q), 22.0 (t), 30.5 (t), 52.2 (d), 53.4(t) 78.8 (s), 86.5
(s), 122.2 (t), 125.9 (d), 126.4 (d × 2), 128.8 (d × 2), 129.4 (d × 2), 130.9
(d), 134.5 (s), 142.1 (s), 143.8 (s); MS m/z 247 (M+ - TsH). Anal. Calcd
for C21H26N2O2S2: C, 62.66; H, 6.51; N, 6.96. Found: C, 62.77; H, 6.35; N,
6.97.
1-cyanomethyl-3-(p-fluorophenyl)-5-phenyl-1H-pyrazole (19).
To an acetonitrile (5.0 mL) solution of 2-[1-(p-fluorophenyl)-3-phenylprop-
2-yn-1-yl]-p-toluenesulfonylhydrazine (4) (0.20 g, 0.51 mmol) was added
cesium carbonate (0.50 g, 1.52 mmol). The reaction mixture was
refluxed for 0.5 h and then poured into water (50 mL). The workup
procedure gave the titled compound 19 (0.11 g, 80%) as white powders.
mp 101-103 oC, IR (KBr, cm-1) 3407, 3064, 2992, 2953, 2925, 2853,
2261, 1606, 1525, 1490, 1456, 1437, 1410, 1348, 1306, 1224, 1160,
1099, 908, 846, 817, 803, 781, 757, 697; 1H NMR (600 MHz, CDCl3) 
5.02 (2H, s, CH2), 6.62 (1H, s, ArH), 7.10-7.14 (2H, m, ArH), 7.46-7.54
(5H, m, ArH), 7.80-7.83 (2H, m, ArH); 13C NMR (150 MHz, CDCl3)  37.9
(t), 104.4 (d), 114.4 (s), 115.6 (d), 115.7 (d), 127.5 (d), 127.7 (d), 128.7
(s), 128.8 (d × 2), 128.9 (s), 129.3 (d × 2), 129.6 (d), 146.1 (s), 151.8 (s),
162.9 (d, J = 247.1 Hz); MS m/z 277 (M+). Anal. Calcd for C17H12N3F: C,
73.63; H, 4.36; N, 15.15. Found: C, 73.47; H, 4.33; N, 15.31.
1-cyanomethyl-2-[1-(2-thienyl)hept-2-yn-1-yl]-p-toluenesulfonylhydrazine
(22b).
To an acetonitrile (1.0 mL) solution of 2-[1-(2-thienyl)hept-2-yn-1-yl]-p-
toluenesulfonylhydrazide (7) (50 mg, 0.14 mmol) was added
bromoacetonitrile (33 mg, 0.28 mmol) and cesium carbonate (90.0 mg,
0.28 mmol) at room temperature. The reaction mixture was stirred at 50
oC for 10 min and then poured into water (50 mL). The workup
1-cyanomethyl-2-[1-(p-chlorophenyl)hept-2-ynyl]-p-
toluenesulfonylhydrazine (20)
To an acetonitrile (1.0 mL) solution of 2-[1-(p-chlorophenyl)hept-2-yn-1-
yl]-p-toluenesulfonylhydrazine (5) (50 mg, 0.13 mmol) was added
bromoacetonitrile (31 mg, 0.26 mmol) and cesium carbonate (83 mg,
procedure
gave
1-cyanomethyl-2-[1-(2-thienyl)hept-2-yn-1-yl]-p-
toluenesulfonylhydrazine (22b) (52 mg, 94%) as white powders.

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
o
mp 70-72 C, IR (KBr, cm-1) 2958, 2935, 2871, 1711, 1597, 1493, 1456,
was separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was
1433, 1407, 1359, 1306, 1230, 1230, 1166, 1092, 815, 732, 707; 1H
NMR (600 MHz, CDCl3) δ 0.92 (3H, t, J = 7.9 Hz, Me), 1.39-1.46 (2H, m,
CH2), 1.50-1.64 (2H, m, CH2), 2.26 (2H, dt, J = 2.3 and 7.4 Hz, CH2),
2.44 (3H, s, CH3), 3.78 (1H, d, J = 6.3 Hz, NH), 4.35 (1H, d, J = 17.8 Hz,
CH2), 4.61 (1H, d, J = 18.3 Hz, CH), 5.21 (1H, d, J = 6.3Hz, CH), 6.94-
6.96 (1H, m, ArH), 7.11 (1H, d, J = 3.4 Hz, ArH), 7.29 (1H, d, J = 5.1 Hz,
ArH), 7.37 (2H, d, J = 8.0 Hz, ArH), 7.85 (2H, d, J = 8.0 Hz, ArH); 13C
NMR (150 MHz, CDCl3) δ 13.5 (q), 18.3 (t), 21.6 (q), 21.9 (t), 30.4 (t),
40.0 (t), 52.2 (d), 77.3 (s), 87.5 (s), 113.4 (s), 126.4 (d), 126.6 (d), 126.8
(d), 128.9 (d × 2), 128.9 (d × 2), 131.9 (s), 141.0 (s), 145.3 (s); MS m/z
400 (M+ - 1), 375 (M+ - CN), 246 (M+ - Ts). Anal. Calcd for
C20H23N3O2S2: C, 59.82; H, 5.77; N, 10.46. Found: C, 59.50; H, 5.60; N,
10.46.
removed under reduced pressure.
The residue was purified by
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10). 2-[1-
phenylsulfanylethynylcyclohex-1-yl]-1-propargyl-p-
toluenesulfonylhydrazine (25) (45 mg, 82%) as a pale yellow oil.
IR (KBr, cm-1) 3295, 3257, 3062, 2935, 2895, 2856, 1712, 1620, 1598,
1583, 1479, 1442, 1355, 1167, 1146, 1091, 1058, 1023, 814, 804, 740,
688, 661, 587, 580, 549; 1H NMR (600 MHz, CDCl3)  1.58-1.73 (10H, m,
CH2), 2.00 (1H, t, J = 2.0 Hz, acetylenic H), 2.41 (3H, s, Me), 3.72 (1H, s,
CH), 4.68 (2H, d, J = 2.0 Hz, CH2), 7.20-7.35 (6H, m, ArH), 7.38 (2H, d, J
= 7.6 Hz, ArH), 7.90 (2H, d, J = 8.3 Hz, ArH); 13C NMR (150 MHz, CDCl3)
 21.6 (q), 22.4 (t × 2), 25.5 (t × 2), 39.8 (t), 41.2 (t), 57.2 (s), 70.9 (s),
74.9 (s), 76.3 (d), 102.5 (s), 126.1 (d × 2), 126.5 (d), 128.9 (d × 2), 129.1
(d × 2), 129.5 (d × 2), 132.6 (s), 133.6 (s), 143.8 (s); MS m/z 438 (M+),
283 (M+ – Ts). Anal. Calcd for C24H26N2O2S2: C, 64.02; H, 5.93; N, 6.39.
Found: C, 64.10; H, 5.92; N, 6.23.
2-(1-naphthyl-3-phenylsulfanylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine (23).
To
an acetonitrile (2.0 mL) solution of 2-(1-naphthyl-3-
phenylsulfanylprop-2-yn-1-yl)-p-toluenesulfonylhydrazine (8) (100 mg,
0.22 mmol) were added propargyl bromide (90.4 mg, 0.65 mmol) and
potassium carbonate (51.9 mg, 0.44 mmol) at room temperature. The
reaction mixture was stirred for 3 h at 50 oC and poured into water (50
mL). The organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic layer was dried over
MgSO4. The solvent was removed under reduced pressure. The residue
was purified by preparative TLC on silica gel eluting with AcOEt-n-
1-cyanomethyl-2-[1-(phenylsulfanylethynyl)-1-cyclopentyl]-p-
toluenesulfonylhydrazine (26).
To an acetonitrile (1.0 mL) solution of 2-(1-phenylsulfanylethynyl-1-
cyclopentyl)-p-toluenesulfonylhydrazine (11) (50 mg, 0.13 mmol) were
added bromoacetonitrile (96.5 mg, 0.34 mmol) and cesium carbonate
(84.3 mg, 0.26 mmol) at room temperature. The reaction mixture was
stirred for 10 min and then poured into water (50 mL). The organic layer
was separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was
hexane (1:5).
2-(1-Naphthyl-3-phenylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine (23) (93 mg, 86%) was obtained as pale yellow
removed under reduced pressure.
The residue was purified by
plates (mp 105-107 oC, from CHCl3-n-hexane).
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10). 1-
cyanomethyl-2-(1-phenylsulfanylethynyl-1-cyclopentyl)-p-
IR (KBr, cm-1) 3294, 3264, 3064, 2920, 2850, 2181, 2118, 1710, 1597,
1582, 1511, 1478, 1442, 1397, 1352, 1320, 1164, 1092, 1037, 1022, 940,
toluenesulfonylhydrazine (26) (52 mg, 95%) as a pale yellow oil.
IR (KBr, cm-1) 3284, 2963, 2871, 1709, 1597, 1582, 1478, 1442, 1404,
1358, 1214, 1185, 1168, 1092, 1023, 815, 802, 741, 688, 661, 579, 552;
1H NMR (600 MHz, CDCl3)  1.79-2.11 (8H, m, CH2), 2.42 (3H, s, Me),
3.18 (1H, s, NH), 4.85 (2H, s, CH2), 7.23-7.35 (6H, m, ArH), 7.77 (2H, d,
J = 8.2 Hz, ArH); 13C NMR (150 MHz, CDCl3)  21.6 (q), 23.7 (t × 2), 39.6
(t × 2), 63.0 (s), 70.8 (s), 102.3 (s), 112.9 (s), 126.3 (d × 2), 126.8 (d),
129.2 (d × 2), 129.4 (d × 2), 129.6 (d × 2), 131.8 (s), 132.0 (s), 145.1 (s);
MS m/z 425 (M+), 269 (M+ – TsH); high resolution mass calcd for
C22H23N3O2S2: 425.1231, found: 425.1207.
1
916, 871, 804, 780, 741, 687, 662, 586, 553; H NMR (600 MHz, CDCl3)
 1.95 (1H, t, J = 2.8 Hz, acetylenic H), 2.27 (3H, s, Me), 3.85 (1H, d, J =
8.2 Hz, NH), 4.58 (1H, brd, J = 18.6 Hz, CH), 4.67 (1H, dd, J = 2.7 and
18.5 Hz, CH), 5.99 (1H, d, J = 8.2 Hz, CH), 7.07 (2H, d, J = 7.6 Hz, ArH),
7.21-7.23 (1H, m, ArH), 7.30-7.33 (2H, m, ArH), 7.41-7.44 (3H, m, ArH),
7.53-7.55 (1H, m, ArH), 7.63-7.66 (1H, m, ArH), 7.71 (2H, d, J = 8.2 Hz,
ArH), 7.83-7.87 (3H, m, ArH), 8.62 (1H, d, J = 8.9 Hz, ArH); 13C NMR
(150 MHz, CDCl3)  21.4 (q), 40.7 (t), 55.6 (d), 73.7 (s), 75.0 (s), 75.9 (d),
97.5 (s), 124.7 (d), 125.0 (d), 126.0 (d), 126.4 (d × 2), 126.5 (d), 126.7 (d
× 2), 128.4 (d), 128.9 (d × 2), 129.1 (d × 2), 129.3 (d × 2), 129.7 (d),
131.2 (s), 131.9 (s), 132.0 (s), 133.1 (s), 133.8 (s), 143.9 (s); MS m/z 340
(M+ – TsH). Anal. Calcd for C29H24N2O2S2: C, 70.13; H, 4.87; N, 5.64.
Found: C, 69.93; H, 4.84; N, 5.62.
2-(1-phenylsulfanylethynyl-1-cycloheptyl)-1-propargyl-p-
toluenesulfonylhydrazine (27).
To an acetonitrile (1.0 mL) solution of 2-(1-phenylsulfanylethynyl-1-
cycloheptyl)-p-toluenesulfonylhydrazine (12) (50 mg, 0.12 mmol) were
added propargyl bromide (43.0 mg, 0.36 mmol) and cesium carbonate
(78.6 mg, 0.24 mmol) at room temperature. The reaction mixture was
stirred for 1 h and then poured into water (50 mL). The organic layer was
separated and the aqueous layer was extracted with AcOEt-n-hexane.
The combined organic layer was dried over MgSO4. The solvent was
t-butyl
2-[1-(1,3-benzodioxol-5-yl)-3-phenylsulfanylprop-2-ynyl]-p-
toluenesulfonylhydrazin-1-ylacetate (24).
To an acetonitrile (3.0 mL) solution of 2-[1-(1,3-benzodioxol-5-yl)-3-
phenylsulfanylprop-2-ynyl]-p-tosylhydrazine (9) (150 mg, 0.33 mmol) was
added t-butyl bromoacetate (129 mg, 0.66 mmol) and cesium carbonate
(216 mg, 0.66 mmol). The reaction mixture was stirred for 15 min. The
removed under reduced pressure.
2-(1-Phenylsulfanylethynyl-1-
workup
procedure
gave
t-butyl
2-[1-(1,3-benzodioxol-5-yl)-3-
cycloheptyl)-1-propargyl-p-toluenesulfonylhydrazine (27) (50 mg, 92%)
was obtained without further purification.
phenylsulfanylprop-2-ynyl]-p-toluenesulfonylhydrazin-1-ylacetate
(24)
IR (KBr, cm-1) 3296, 3261, 3061, 2930, 2856, 1712, 1597, 1583, 1493,
1479, 1460, 1442, 1353, 1185, 1167, 1092, 1024, 814, 802, 739, 687,
661, 586, 557, 548; 1H NMR (600 MHz, CDCl3)  1.64 (12H, m, CH2),
2.01 (1H, t, J = 2.8 Hz, acetylenic H), 2.42 (3H, s, Me), 3.60 (1H, s, NH),
4.69 (2H, d, J = 2.8 Hz, CH2), 7.19-7.22 (1H, m, ArH), 7.27 (2H, d, J = 8.2
Hz, ArH), 7.30-7.33 (2H, m, ArH), 7.37 (2H, d, J = 8.2 Hz, ArH), 7.80 (2H,
d, J = 8.3 Hz, ArH); 13C NMR (150 MHz, CDCl3)  21.6 (q), 22.4 (t × 4),
29.1 (t × 2), 40.9 (t), 60.0 (s), 69.6 (s), 75.0 (s), 76.3 (d), 104.0 (s), 126.0
(d × 2), 126.5 (d), 128.9 (d × 2), 129.2 (d × 2), 129.5 (d × 2), 132.7 (s),
133.6 (s), 143.9 (s); MS m/z 452 (M+), 296 (M+ – TsH); high resolution
mass calcd for C25H28N2O2S2: 452.1592, found: 452.1577.
(181 mg, 96 %) as a yellow oil.
IR (KBr, cm-1) 3443, 3303, 2981, 2930, 1734, 1505, 1489, 1443, 1369,
1347, 1236, 1164, 1095, 1039, 926, 812, 743, 709, 690, 551; 1H NMR
(600 MHz, CDCl3)  1.34 (9H, s, Me × 3), 2.40 (3H, s, CH3), 4.42 (1H, d,
J = 18.6 Hz, CH), 4.83 (1H, d, J = 6.9 Hz, CH), 5.07 (1H, d, J = 6.9 Hz,
CH), 5.97 (2H, d, J = 1.4 Hz, CH2), 6.75 (1H, d, J = 8.3 Hz, CH), 6.94 (1H,
d, J = 7.5 Hz, ArH), 6.96 (1H, brs, ArH), 7.22-7.26 (3H, m, ArH), 7.33 (2H,
t, J = 7.6 Hz, CH2), 7.38-7.39 (2H, m, ArH), 7.76 (2H, d, J = 8.3 Hz, ArH);
13C NMR (150 MHz, CDCl3)  21.6 (q), 27.9 (q × 3), 50.8 (t), 56.8 (d),
73.0 (s), 82.5 (s), 97.5 (s), 101.2 (t), 108.0 (d), 108.6 (d), 121.6 (d), 126.3
(d × 2), 126.7 (d), 128.4 (d × 2), 129.2 (d × 2), 129.3 (d × 2), 131.0 (s),
132.1 (s), 135.1 (s), 143.7 (s), 147.6 (s), 147.7 (s), 168.1 (s); MS m/z 410
(M+ - TsH). Anal. Calcd for C29H30N2O6S2: C, 61.47; H, 5.34; N, 4.94.
Found: C, 61.19; H, 5.35; N, 4.96.
2.
Experimental for Scheme 2.
2-(3,5-diphenyl-1H-pyrazol-1-yl)acetonitrile (28).[17]
Cyanomethyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-toluensulfonylhydrazine
(13c) (42 mg, 0.10 mmol) in toluene (1.0 ml) was stirred at 100 oC for 1h.
The solvent was removed under reduced pressure. The residue was
purified by preparative TLC on silica gel eluting with AcOEt-n-hexane
(1:10). 2-(3,5-Diphenyl-1H-pyrazol-1-yl)acetonitrile (28) (12 mg, 48%) as
white powders.
1-propargyl-2-[1-(phenylsulfanylethynyl)-1-cyclohexyl]-p-
toluenesulfonylhydrazine (25).
To an acetonitrile (2.0 mL) solution of 2-[1-(phenylsulfanylethynyl)-1-
cyclohexyl]-p-toluenesulfonylhydrazine (10) (50 mg, 0.12 mmol) were
added propargyl bromide (59.4 mg, 0.50 mmol) and cesium carbonate
(122.0 mg, 0.37 mmol) at room temperature. The reaction mixture was
stirred for 1 h at 50 oC and poured into water (50 mL). The organic layer
Cesium carbonate (71 mg, 0.22 mmol) was added to an acetonitrile (1.0
mL) solution of 13c (30 mg, 0.072 mmol). The reaction mixture was

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
stirred at 80 oC for 1 h and then poured into water. The workup
procedure gave 28 (33 mg, 90%).
N-Chlorosuccinimide (24.2 mg, 0.18 mmol) was added to a DCE (1.0
mL)
solution
of
2-(1,3-diphenylprop-2-yn-1-yl)-1-propargyl-p-
mg, 0.12 mmol) at room
mp 108-109 oC, IR (KBr, cm-1) 3061, 2923, 2851, 1709, 1553, 1487, 1462,
toluenesulfonylhydrazine (13a) (50
1
1441, 1415, 1364, 1301, 957, 917, 760, 690; H NMR (600 MHz, CDCl3)
temperature. The reaction mixture was stirred for 18.5 h and poured into
water (50 mL). The organic layer was separated and the aqueous layer
was extracted with AcOEt. The combined organic layer was purified by
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10). 4-
Chloro-3,5-diphenyl-1-propargyl-1-1-pyrazole (31a) (16 mg, 45 %)
was obtained as white powders.
 5.03 (2H, s, CH2), 6.07 (1H, s, ArH), 7.36 (1H, t, J = 7.6 Hz, ArH), 7.43
(2H, t, J = 7.6 Hz, ArH), 7.48-7.55 (5H, m, ArH), 7.84 (2H, dd, J = 1.4 and
7.6 Hz, ArH); 13C NMR (150 MHz, CDCl3)  37.9 (t), 104.7 (d), 114.4 (s),
125.8 (d × 2), 128.4 (d), 128.7 (d × 2), 128.8 (d × 2), 129.0 (s), 129.3 (d ×
2), 129.6 (d), 134.4 (s); MS m/z 259 (M+), 233 (M+ - CN), 219 (M+
-
mp 141 oC, IR (KBr, cm-1) 3277, 3058, 2921, 2851, 1484, 1461, 1450,
1413, 1352, 1317, 1306, 1241, 1162, 1017, 990, 942, 916, 814, 771, 696,
678, 654, 611; 1H NMR (600 MHz, CDCl3)  2.42 (1H, t, J = 2.8 Hz,
acetylenic H), 4.85 (2H, d, J = 2.8 Hz, CH2), 7.37-7.39 (1H, m, ArH),
7.44-7.46 (2H, m, ArH), 7.50-7.58 (5H, m, ArH), 7.96-7.97 (2H, dd, J =
1.3 and 7.6 Hz, ArH); 13C NMR (150 MHz, CDCl3)  40.6 (t), 73.9 (d),
77.7 (s), 107.3 (s), 127.6 (d × 2), 127.7 (s), 128.3 (d), 128.4 (d × 2),
128.9 (d × 2), 129.5 (d), 129.8 (d × 2), 131.6 (s), 141.1 (s), 147.6 (s); MS
m/z 291 (M+-1), 257 (M+ – Cl). Anal. Calcd for C18H13ClN2: C, 73.85; H,
4.48; N, 9.57. Found: C, 73.57; H, 4.24; N, 9.38.
CH2CN). Anal. Calcd for C17H13N3: C, 78.74; H, 5.05; N, 16.20. Found: C,
78.54; H, 5.07; N, 15.98.
1,3-diphenylprop-2-ynone cyanomethylhydrazone (29a).
To a THF (1.0 mL) solution of 1-cyanomethyl-2-(1,3-diphenylprop-2-yn-1-
yl)-p-toluensulfonylhydrazine (13c) (50 g, 0.12 mmol) was added DBU
(18 mg, 0.12 mmol) at room temperature. The reaction mixture was
stirred for 1 h and then poured into water (50 mL). The workup
procedure gave 1,3-diphenylprop-2-yn-1-one cyanomehylhydrazone
(29a) (17 mg, 55%) as an orange powders.
o
mp 83-85 C, IR (KBr, cm-1) 3261, 3061, 1525, 1489, 1410, 1348, 1229,
1144, 1072, 1027, 1016, 916, 878, 850, 758, 687, 669, 628; 1H NMR
(600 MHz, CDCl3)  4.35 (2H, d, J = 5.5 Hz, CH2), 6.48 (1H, brt, J = 5.5
Hz, NH), 7.34-7.46 (6H, m, ArH), 7.60 (2H, dd, J = 1.4 and 8.2 Hz, ArH),
7.90 (2H, dd, J = 1.4 and 8.2 Hz, ArH); 13C NMR (150 MHz, CDCl3) 
39.0 (t), 78.3 (s), 103.6 (s), 117.1 (s), 121.0 (s), 125.9 (d × 2), 128.4 (d ×
2), 128.7 (s), 129.0 (d), 129.9 (d), 131.7 (s), 132.0 (d×2), 135.0 (s); MS
m/z 259 (M+); high resolution mass calcd for C17H13N3: 259.1109, found:
259.1087.
4-bromo-3,5-diphenyl-1-propargyl-1H-pyrazole (31b).
N-Bromosuccinimide (32.2 mg, 0.18 mmol) was added to a DCE (0.50
mL)
solution
of
2-(1,3-diphenylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine (13a) (25 mg, 0.06 mmol) at room temperature.
The reaction mixture was stirred for 15 min and then poured into water
(50 mL). The workup procedure gave 4-bromo-3,5-diphenyl-1-propargyl-
1H-pyrazole (31b)(19 mg, 93 %) as white powders.
White powders, mp 125-130 oC (dec), IR (KBr, cm-1) 3294, 3065, 2920,
2851, 2358, 1709, 1606, 1537, 1515, 1480, 1456, 1354, 1302, 1232,
1213, 1176, 1156, 1073, 1059, 1043, 1032, 1013, 981, 817, 803, 769,
761, 698, 612, 601, 591, 571, 560, 519, 507; 1H NMR (600 MHz, CDCl3)
 2.40 (1H, t, J = 2.8 Hz, acetylenic H), 4.84 (2H, d, J = 2.8 Hz, CH2),
7.36-7.39 (1H, m, ArH), 7.44 (2H, t, J = 7.6 Hz, ArH), 7.50-7.56 (5H, m,
ArH), 7.92-7.94 (2H, dd, J = 1.3 and 8.3 Hz, ArH); 13C NMR (150 MHz,
CDCl3)  40.6 (t), 73.8 (d), 93.0 (s), 128.0 (d × 2), 128.3 (d × 2), 128.8 (d
× 2), 129.6 (d), 130.0 (d × 2), 132.0 (s), 142.8 (s), 149.2 (s); MS m/z 336
(M+), 257 (M+ – Br); high resolution mass calcd for C18H13BrN2: 336.0262;
found 336.0230.
1-phenylhept-2-ynone cyanomethylhydrazone (29b).
To a dioxane (1.0 mL) solution of 1-cyanomethyl-2-(1-phenylhept-2-yn-1-
yl)-1p-toluensulfonylhydrazine (15) (30 mg, 0.076 mmol) was added 1M
Bu4NF (0.23 mL in THF, 0.23 mmol) at room temperature. The reaction
mixture was stirred for 2 h and then poured into water (50 mL). The
workup procedure gave the titled compound 29b (16 mg, 84%) as white
powders and 16 (3 mg, 14%) as a yellow oil.
28b: IR (KBr, cm-1) 3262, 3061, 2959, 2927, 2855, 2213, 1734, 1711,
1530, 1458, 1331, 1110, 1073, 918, 883, 768, 694; 1H NMR (600 MHz,
CDCl3)  0.98 (3H, t, J = 7.4 Hz, Me), 1.48-1.55 (2H, m, CH2), 1.65-1.70
(2H, m, CH2), 2.58 (2H, t, J = 7.5 Hz, CH2), 4.30 (2H, d, J = 5.7 Hz, CH2),
6.32 (1H, t, J = 5.7 Hz, NH), 7.30-7.38 (3H, m, ArH), 7.83-7.84 (2H, m,
ArH); 13C NMR (150 MHz, CDCl3)  13.5 (q), 19.3 (t), 22.1 (t), 30.4 (t),
38.8 (t), 70.8 (s), 106.1 (s), 117.2 (s), 125.9 (d × 2), 128.2 (d × 2), 128.8
(d), 132.5 (s), 135.3 (s); MS m/z 239 (M+); high resolution mass calcd for
C15H17N3: 239.1422, found m/z 239.1408.
4-iodo-3,5-diphenyl-1-propargyl-1H-pyrazole (31c).
N-Iodosuccinimide (40.7 mg, 0.18 mmol) was added to a DCE (0.50 mL)
solution
of
2-(1,3-diphenylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine (13a) (25 mg, 0.06 mmol) at room temperature.
The reaction mixture was stirred for 1 h and then poured into a 2%
sodium thiosulfate solution (10 mL) and water (50 mL). The organic layer
was separated and the aqueous layer was extracted with CHCl3. The
combined organic layer was dried over MgSO4. The workup procedure
gave 4-iodo-3,5-diphenyl-1-propargyl-1H-pyrazole (31c)(19 mg, 82 %) as
a pale yellow oil.
1-(2-thienyl)hept-2-ynone cyanomethylhydrzone (29c).
DBU (38 mg, 0.25 mmol) was added to a dioxane (1.0 mL) solution of 1-
cyanomethyl-2-[1-(2-thienyl)hept-2-yn-1-yl]-p-toluenesulfonylhydrazine
(22b) (50 mg, 0.12 mmol). The reaction mixture was stirred for 0.5 h and
then poured into water (50 mL). The workup procedure gave 1-(2-
thienyl)hept-2-ynone cyanomethylhydrazone (29c)(32 mg, quant) as a
yellow oil.
A Yellow oil, IR (KBr, cm-1) 3434, 3293, 3062, 2924, 2853, 1711, 1478,
1453, 1353, 1302, 1224, 1177, 1150, 974, 801, 765, 698, 672, 598; 1H
NMR (600 MHz, CDCl3)  2.39 (1H, t, J = 2.8 Hz, acetylenic H), 4.86 (2H,
d, J = 2.7 Hz, CH2), 7.38-7.40 (1H, m, ArH), 7.50-7.56 (4H, m, ArH), 7.89
(2H, d, J = 6.9 Hz, ArH); 13C NMR (150 MHz, CDCl3)  40.7 (t), 61.2 (s),
73.8 (d), 77.7 (s), 128.2 (d × 2), 128.3 (d), 128.5 (d × 2), 128.8 (d × 2),
129.4 (s), 129.6 (d), 130.3 (d × 2), 132.8 (s), 146.3 (s), 152.5 (s); MS m/z
384 (M+), 257 (M+ - I); high resolution mass calcd for C18H13N2I:
384.0125; found 384.0098.
IR (KBr, cm-1) 3262, 2958, 2933, 2871, 2360, 2219, 1709, 1519, 1457,
1
1435, 1455, 1329, 1231, 1155, 1092, 1038, 887, 833, 705; H NMR (600
MHz, CDCl3)  0.97 (3H, t, J = 7.4 Hz, Me), 1.43-1.55 (2H, m, CH2), 1.65-
1.88 (2H, m, CH2), 2.55 (2H, t, J = 6.8 Hz, CH2), 4.25 (2H, d, J = 5.5 Hz,
CH2), 6.19 (1H, t, J = 5.5 Hz, NH), 6.99 (1H, dd, J = 3.7 Hz, 5.0 Hz, ArH),
7.24 (1H, dd, J = 1.4 and 5.0 Hz, ArH), 7.31 (1H, dd, J = 1.0 and 3.7 Hz,
ArH); 13C NMR (150 MHz, CDCl3)  13.5 (q), 19.2 (t), 22.0 (t), 30.2 (t),
38.7 (t), 70.0 (s), 104.8 (s), 117.1 (s), 126.3 (dx2), 126.4 (dx2), 126.9
(dx2), 128.5 (s), 140.0 (s); MS m/z 245 (M+); high resolution mass calcd
for C13H15N3S: 245.0987, found m/z 245.0988.
1-allyl-4-bromo-3,5-diphenyl-1H-pyrazole (31d).
N-Bromosuccinimide (573 mg, 3.22 mmol) was added to a DCE (9.0 mL)
solution
of
1-allyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-
toluensulfonylhydrazine (13b) (445 mg, 1.07 mmol) at room temperature.
The reaction mixture was stirred for 50 min. The workup procedure gave
1-allyl-4-bromo-3,5-diphenyl-1H-pyrazole (31d)(295 mg, 81 %) as a pale
yellow powders.
3,5-diphenyl-1H-pyrazole (30).[10]
Sodium hydride (42 mg, 0.10 mmol) was added to a DMF (1.0 mL)
mp 53-55 oC (from CH2Cl2-n-hexane), IR (KBr, cm-1) 3060, 3036, 2927,
2359, 2342, 1713, 1480, 1456, 1359, 1308, 1221, 1161, 981, 926, 771,
689, 606, 528; 1H NMR (600 MHz, CDCl3)  4.70 (2H, dt, J = 1.4 and 5.5
Hz, CH2), 5.01-5.04 (1H, m, olefinic H), 5.19 (1H, dd, J = 1.4 and 10.3 Hz,
olefinic H), 5.94-6.00 (1H, m, olefinic H), 7.36-7.39 (1H, m, ArH), 7.43-
7.52 (7H, m, ArH), 7.93-7.94 (2H, m, ArH); 13C NMR (150 MHz, CDCl3) 
50.1 (t), 92.5 (s), 117.8 (t), 127.9 (d × 2), 128.1 (d), 128.3 (d × 2), 128.7
(d × 2), 128.8 (s), 129.4 (d), 130.0 (d × 2), 132.3 (s), 133.1 (d), 143.0 (s),
solution
of
cyanomethyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-
toluensulfonylhydrazine (13c) (42 g, 0.10 mmol) at 0 oC. The reaction
mixture was stirred for 5 min and then poured into water (50 mL). The
workup procedure gave 3,5-diphenyl-1H-pyrazole (29) (24 mg, 63%) as
colorless prisms.
4.Halogenation and Cyclization of Propargyl Hydrazides.
4-chloro-3,5-diphenyl-1-propargyl-1H-pyrazole (31a).

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
148.5 (s); MS 339 (M+), 259 (M+ – Br). Anal. Calcd for C18H15BrN2: C,
63.73; H, 4.46; N, 8.26. Found: C, 63.69; H, 4.50; N, 8.27.
(1H, d, J = 6.9 Hz, ArH), 8.68 (1H, d, J = 8.3 Hz, ArH); 13C NMR (150
MHz, CDCl3) δ 21.5 (q), 40.8 (t), 54.9 (d), 75.2 (s), 75.9 (s), 87.1 (s), 88.3
(s), 122.5 (s), 124.8 (d), 125.0 (d), 126.0 (d), 126.6 (d), 126.7 (d), 128.4
(d), 128.5 (d × 2), 128.6 (d), 128.9 (d × 2), 129.2 (d × 2), 129.6 (d), 131.4
(s), 131.6 (d × 2), 132.2 (s), 133.3 (s), 133.8 (s), 143.8 (s); MS m/z 464
(small M+), 424 (M+ – propargyl H). Anal. Calcd for C29H24N2O2S: 74.97;
H, 5.21; N, 6.03. Found: C, 74.69; H, 5.31; N, 6.04.
N-Bromosuccinimide (29 mg, 0.16 mmol) was added to acetonitrile (1.0
mL) solution of 2-(1-naphthyl-3-phenylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine (50 mg, 0.05 mmol). The reaction mixture was
stirred at room temperature for 40 min. The workup procedure gave 4-
bromo-3-naphtyl-5-phenyl-1-propargyl-1H-pyrazole (31h)(16 mg, 97 %)
as a yellow oil.
1-allyl-4-iodo-3,5-diphenyl-1H-pyrazole (31e).
N-Iodosuccinimide (81 mg, 0.36 mmol) was added to a DCE (1.0 mL)
solution
of
1-allyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-
toluensulfonylhydrazine (13b) (50 mg, 0.12 mmol) at room temperature.
The reaction mixture was stirred at room temperature for 0.5 h. The
workup procedure gave 1-allyl-4-iodo-3,5-diphenyl-1H-pyrazole (31e)(27
mg, 58 %) as pale yellow plates.
mp 135-140 oC, IR (KBr, cm-1) 3062, 1712, 1475, 1453, 1352, 1308,
1222, 1154, 973, 915, 903, 698, 621, 610, 560, 518, 503; 1H NMR (600
MHz, CDCl3)  4.71 (2H, dd, J = 1.3 and 5.4 Hz, CH2), 5.01 (1H, d, J =
17.2 Hz, olefinic H), 5.17 (1H, dd, J = 1.4 and 10.3 Hz, olefinic H), 5.92-
5.97 (1H, m, olefinic H), 7.37-7.52 (8H, m, ArH), 7.89 (2H, d, J = 7.6 Hz,
ArH); 13C NMR (150 MHz, CDCl3)  53.2 (t), 60.7 (s), 117.8 (t), 128.1 (d),
128.2 (d × 2), 128.4 (d × 2), 128.6 (d × 2), 129.4 (d), 130.0 (s), 130.2 (d ×
2), 133.0 (s), 133.2 (d), 146.4 (s), 151.8 (s); MS m/z 386 (M+), 258 (M+ -
I), 345 (M+ - CH2CN). Anal. Calcd for C18H15N2I: C, 55.98; H, 3.91; N,
7.25. Found: C, 55.82; H, 3.89; N, 7.14.
IR (KBr, cm-1) 3293, 3059, 1710, 1515, 1490, 1454, 1382, 1356, 1302,
1220, 1155, 1081, 1052, 1012, 954, 805, 780, 763, 701, 655; 1H NMR
(600 MHz, CDCl3)  2.45 (1H, d, J = 2.7 Hz, CH), 4.94 (2H, d, J = 2.7
Hz,CH2), 7.51-7.59 (6H, m, ArH), 7.65 (2H, d, J = 6.9 Hz, ArH), 7.70 (1H,
d, J = 6.2 Hz, ArH), 7.90-7.94 (2H, m, ArH), 8.10-8.12 (1H, m, ArH); 13C
NMR (150 MHz, CDCl3)  40.7 (t), 73.9 (d), 77.7 (s), 95.7 (s), 125.0 (d),
125.9 (d), 126.3 (d × 2), 128.2 (d), 128.6 (d), 128.9 (d × 2), 129.1 (d),
129.3 (s), 129.6 (d), 130.0 (d × 2), 131.8 (s), 133.7 (s), 142.2 (s), 149.7
(s); MS m/z 387 (M+), 307(M+ - Br); high resolution mass calcd for
C22H15BrN2: 386.0419, found m/z 386.0419.
1-cyano-4-bromo-3,5-diphenyl-1H-pyrazole (31f).
To a DCM (1.0 mL) solution of cyanomethyl-2-(1,3-diphenylprop-2-yn-1-
yl)-p-toluensulfonylhydrazine (13c) (50 mg, 0.12 mmol) was added N-
bromosuccinimide (64 mg, 0.36 mmol). The reaction mixture was stirred
at room temperature for 1 h. The workup procedure gave 4-bromo-1-
cyanomethyl-3,5-diphenyl-1H-pyrazole (31f)(34 mg, 74 %) as pale yellow
plates.
4-bromo-1-cyanomethyl-3-p-fuluorophenyl-5-diphenyl-1H-pyrazole (31i).
Preparation of 1-cyanomethyl-1-(p-fluorophenyl)-2-(3-phenylprop-2-yn-1-
yl)-p-toluenesulfonylhydrazine.
To an acetonitrile (1.0 mL) solution of 2-(1-fluorophenyl-3-phenylprop-2-
yn-1-yl)-p-toluenesulfonylhydrazine (50 mg, 0.13 mmol) were added
bromoacetonitrile (30.4 mg, 0.26 mmol) and cesium carbonate (82.6 mg,
0.26 mmol) at room temperature. The reaction mixture was stirred for 10
min at 50 oC and poured into water (50 mL). The organic layer was
separated and the aqueous layer was extracted with AcOEt. The
combined organic layer was dried over MgSO4. The solvent was
A Yellow oil, IR (KBr, cm-1) 3063, 2977, 2938, 1482, 1456, 1449, 1405,
1349, 1314, 1239, 1158, 1012, 982, 914, 814, 772, 761, 716, 700, 607;
1H NMR (600 MHz, CDCl3)  4.97 (2H, s, CH2), 7.41-7.43 (1H, m, ArH),
7.46-7.51 (4H, m, ArH), 7.56-7.60 (3H, m, ArH), 7.92-7.94 (2H, m, ArH);
13C NMR (150 MHz, CDCl3)  38.6 (t), 94.3 (s), 113.9 (s), 127.2 (s),
127.9 (d × 2), 128.8 (d), 129.3 (d × 2), 129.8 (d × 2), 130.3 (d), 131.3 (s),
143.7 (s), 150.5 (s); MS m/z 338 (M+), 258 (M+ – Br). Anal. Calcd for
C17H12BrN3: C, 60.37; H, 3.58; N, 12.40. Found: C, 59.54; H, 3.63; N,
11.99.
removed under reduced pressure.
The residue was purified by
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10). 1-
Cyanomethyl-2-[1-(p-fluorophenyl)-3-phenylprop-2-yn-1-yl]-p-
o
toluenesulfonylhydrazine (53 mg, 96%) as white powders (mp 79-81 C,
from n-hexane).
1-cyanomethyl-4-iodo-3,5-diphenyl-1H-pyrazole (31g).
IR (KBr, cm-1) 3286, 3058, 2987, 2923, 2853, 1711, 1604, 1509, 1492,
1443, 1413, 1359, 1306, 1296, 1224, 1186, 1166, 1092, 1017, 976, 840,
816, 759, 741, 731, 692, 660; H NMR (600 MHz, CDCl3) δ 2.45 (3H, s,
N-iodosuccinimide (81 mg, 0.36 mmol) was added to a DCE (1.0 mL)
solution
of
cyanomethyl-2-(1,3-diphenylprop-2-yn-1-yl)-p-
1
toluensulfonylhydrazine (13c) (50 mg, 0.12 mmol). The reaction mixture
was stirred at 83 oC for 15 min. The workup procedure gave 1-
cyanomethyl-4-iodo-3,5-diphenyl-1H-pyrazole (31g)(31 mg, 67 %) as
pala yellow plates.
Me), 3.87 (1H, d, J = 5.5 Hz, NH), 4.35 (1H, d, J = 17.9 Hz, CH), 4.61
(1H, d, J = 17.9 Hz, CH), 5.28 (1H, d, J = 5.5 Hz, CH), 7.07 (2H, d, J =
17.2 Hz, ArH), 7.34-7.38 (5H, m, ArH), 7.45-7.46 (2H, m, ArH), 7.53-7.55
(2H, m, ArH), 7.82 (2H, d, J = 8.2 Hz, ArH); 13C NMR (150 MHz, CDCl3) δ
21.6 (q), 40.2 (t), 56.3 (d), 86.6 (s), 87.2 (s), 113.4 (s), 115.5 (d), 115.6
(d), 121.9 (s), 128.4 (d × 2), 128.7 (d × 2), 128.9 (d), 130.0 (d × 2), 130.1
(d), 130.2 (d), 131.7 (d × 2), 131.9 (s), 132.6 (s), 145.5 (s), 162.8 (d, J =
274.4 Hz, ArH); MS m/z 433 (M+), 277 (M+ – TsH). Anal. Calcd for
C24H20FN3O2S: C, 66.50; H, 4.65; N, 9.69. Found: C, 66.42; H, 4.78; N,
9.57.
N-Bromosuccinimide (61.6 mg, 0.35 mmol) was added to an acetonitrile
(1.0 mL) solution of 1-cyanomethyl-1-(p-fluorophenyl)-2-(3-phenylprop-2-
yn-1-yl)-p-toluenesulfonylhydrazine (50 mg, 0.12 mmol). The reaction
mixture was stirred at room temperature for 2.5 h. The workup
procedure gave 4-bromo-1-cyanomethyl-3-(p-fuluorophenyl)-5-phenyl-
1H-pyrazole (31i) (25 mg, 61 %) as white powders.
mp 135-140 oC, IR (KBr, cm-1)3437, 3063, 2927, 1709, 1479, 1454, 1351,
1
1306, 1228, 1178, 1151, 1075, 1031, 1011, 975, 919, 808, 764, 699; H
NMR (600 MHz, CDCl3)  4.97 (2H, s, CH2), 7.41-7.49 (5H, m, ArH),
7.56-7.60 (3H, m, ArH), 7.87-7.88 (2H, m, ArH) ; 13C NMR (150 MHz,
CDCl3)  38.7 (t), 62.6 (s), 113.9 (s), 128.3 (d × 2), 128.4 (d × 2), 128.8
(d), 129.3 (d × 2), 130.0 (d × 2), 130.3 (d), 132.1 (s), 147.1 (s), 153.7 (s);
MS m/z 385 (M+), 258 (M+ - I), 345 (M+ - CH2CN); high resolution mass
calcd for C17H12N3I: 385.0078; found 385.0085.
4-Bromo-3-naphtyl-5-phenyl-1-propargyl-1H-pyrazole (31h).
Preparation
of
2-(1-naphthyl-3-phenylprop-2-yn-1-yl)-1-propargyl-p-
toluenesulfonylhydrazine.
To an acetonitrile (2.0 mL) solution of 2-(1-naphthyl-3-phenylprop-2-yn-1-
yl)-1-(p-toluenesulfonyl)hydrazine (3) (97.0 mg, 0.70 mmol) and
potassium carbonate (55.6 mg, 0.47 mmol). The reaction mixture was
stirred for 3.5 h at 50 oC and then poured into water (50 mL). The
organic layer was separated and the aqueous layer was extracted with
AcOEt. The combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The residue was purified by
preparative TLC on silica gel eluting with AcOEt-n-hexane (1:10). 2-(1-
Naphthyl-3-phenylprop-2-yn-1-yl)-1-propargyl-1-(p-
mp 107-114 oC, IR (KBr, cm-1) 3431, 2927, 1709, 1607, 1527, 1508,
1484, 1449, 1361, 1298, 1233, 1160, 1096, 1014, 984, 919, 842, 799,
764, 732, 701, 595, 550; 1H NMR (600 MHz, CDCl3)  4.97 (2H, s, CH2),
7.17 (2H, t, J = 8.2 Hz,CH2), 7.49-7.51 (2H, m, ArH), 7.57-7.60 (3H, m,
ArH), 7.91-7.94 (2H, m, ArH); 13C NMR (150 MHz, CDCl3)  38.6 (t), 91.2
(s), 113.8 (s), 115.4 (d), 115.5 (d), 127.1 (s), 129.4 (d × 2), 129.7 (d × 3),
129.8 (d), 130.3 (d), 143.7 (s), 149.6 (s), 162.2 (s), 163.9(s); MS m/z 356
(M+), 276 (M+ - Br). Anal. Calcd for C17H11BrFN3: C, 57.32; H, 3.11; N,
11.80. Found: C, 57.14; H, 3.12; N, 11.74.
toluenesulfonyl)hydrazine (97 mg, 89%) was obtained as a yellow oil.
IR (KBr, cm-1) 3285, 3260, 3064, 2922, 2851, 2118, 1711, 1598, 1511,
1491, 1442, 1398, 1350, 1320, 1264, 1165, 1092, 1036, 964, 915, 868,
1-allyl-5-butyl-4-iodo-3-phenyl-1H-pyrazole (31j).
N-Iodosuccinimide (111 mg, 0.44 mmol) was added to DCM (1.0 mL)
1
804, 781, 759, 732, 692, 663, 585, 567, 547; H NMR (600 MHz, CDCl3)
solution
of
1-allyl-2-[1-(2-thienyl)hept-2-yn-1-yl]-p-
δ 1.96 (1H, t, J = 2.8 Hz, acetylenic H), 2.29 (3H, s, CH3), 3.84 (1H, d, J =
9.6 Hz, NH), 4.76 (1H, d, J = 18.6 Hz, CH2), 4.86 (1H, dd, J = 2.0 and
18.6 Hz, CH2), 5.98 (1H, d, J = 9.0 Hz, CH), 7.06 (2H, d, J = 8.3 Hz, ArH),
7.34-7.36 (3H, m, ArH), 7.45-7.54 (4H, m, ArH), 7.66 (1H, t, J = 6.8 Hz,
ArH), 7.72 (2H, d, J = 8.3 Hz, ArH), 7.86 (2H, t, J = 8.2 Hz, ArH), 7.95
toluenesulfonylhydrazine (22a) (66 mg, 0.16 mmol). The reaction
mixture was stirred at room temperature for 0.25 h. The workup
procedure gave 1-allyl-5-butyl-4-iodo-3-(2-thienyl)-1H-pyrazole (31j)(32
mg, 52 %) as white powders.

European Journal of Organic Chemistry
10.1002/ejoc.201600708
FULL PAPER
mp 30-31 oC, IR (KBr, cm-1) 2956, 2930, 2365,2356, 2335, 1712, 1510,
1465, 1222, 1073, 919, 704, 609, 600, 593, 584, 505; 1H NMR (600 MHz,
CDCl3)  0.96 (3H, t, J = 7.5 Hz, Me), 1.39-1.45 (2H, m, CH2), 1.53-1.58
(2H, m, CH2), 2.69 (2H, t, J = 8.3 Hz, CH2), 4.77-4.78 (2H, m, CH2), 5.08
(1H, brd, J = 17.2 Hz, olefinic H), 5.22 (1H, dd, J = 1.4 and 10.3 Hz,
olefinic H), 5.96-6.01 (1H, m, olefinic H), 7.08 (1H, dd, J = 3.4 and 4.8 Hz,
ArH), 7.29 (1H, dd, J = 1.4 and 4.1 Hz, ArH), 7.45 (1H, dd, J = 1.4 and
3.5 Hz, ArH); 13C NMR (150 MHz, CDCl3)  13.8 (q), 22.5 (t), 25.8 (t),
30.7 (t), 53.0 (t), 117.6 (t), 125.1 (d), 125.4 (d), 127.1 (d), 133.0 (d), 135.4
(s), 146.0 (s), 146.1 (s); MS m/z 372 (M+), 245 (M+ - I). Anal. Calcd for
C14H17N2SI2: C, 45.17; H, 4.60; N, 7.52. Found: C, 45.07; H, 4.58; N,
7.38.
ethyl 2-[5-butyl- 3-(thiophen-2-yl)-1H-pyrazol-1-yl]acetate (33b).
To an acetonitrile (1.0 mL) solution of 2-[1-(2-thienyl)hept-2-yn-1-yl]-p-
toluenesulfonylhydrazide (7) (100 mg, 0.28 mmol) was added ethyl
bromoacetate (46 mg, 0.28 mmol) and cesium carbonate (90.0 mg, 0.28
mmol) at room temperature. The reaction mixture was stirred at 50 oC for
10 min and then poured into water (50 mL). The workup procedure gave
ethyl 2-[1-(2-thienyl)hept-2-yn-1-yl]-p-toluenesulfonylhydrazine (61 mg,
99%) as white needles.
o
mp 49-50 C, IR (KBr, cm-1) 3302, 2959, 2930, 2862, 1739, 1599, 1458,
1402, 1344, 1305, 1292, 1213, 1164, 1094, 1021, 953, 815, 754, 708; 1H
NMR (600 MHz, CDCl3) δ 0.91 (3H, t, J = 7.4 Hz, Me), 1.17 (3H, t, J = 7.5
Hz, Me), 1.37-1.44 (2H, m, CH2), 1.47-1.53 (2H, m, CH2), 2.23 (1H, dt, J
= 1.7 and 5.1 Hz, CH2), 2.41 (3H,s, CH3), 3.99-4.11 (2H, m, CH2), 4.40
(1H, d, J = 8.4 Hz, CH2), 4.60-4.64 (2H, m, NH and CH), 5.06 (1H, d, J =
7.4 Hz, CH), 6.92 (1H, dd, J = 3.4 and 5.1 Hz, ArH), 7.06 (1H, d, J = 3.4
Hz, ArH), 7.25 (1H, dd, J = 1.1 and 5.1 Hz, ArH), 7.29 (2H, d, J = 8.0 Hz,
ArH), 7.82 (2H, d, J = 8.6 Hz, ArH); 13C NMR (150 MHz, CDCl3) δ 13.5
(q), 13.9 (q), 18.3 (t), 21.5 (q), 21.9 (t), 30.4 (t), 50.5 (t), 51.9 (d), 61.2 (t),
78.8 (s), 86.8 (s), 125.9 (d), 126.2 (d), 126.4 (d), 128.5 (d × 2), 129.2 (d ×
2), 134.9 (s), 142.0 (s), 143.7 (s), 168.9 (s); MS m/z 449 (small M+), 292
(M+ - TsOH). Anal. Calcd for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24.
Found: C, 58.83; H, 6.31; N, 6.25.
Transformation of 1-Alkyl-1-tosyl-2-propargylhydrazines to Functionalized
Experimental for Scheme 4.
Suzuki coupling reaction of 31e.
To an ethanol (1.0 mL) solution of 31e (50 mg, 0.15 mmol) was added p-
methoxyphenylboronic acid (67 g, 0.44 mmol), potassium carbonate (102
mg, 0.74 mmol) in H2O (0.50 mL) solution, and palladium
bis(triphenylphosphine) dichloride (21 mg, 0.03 mmol). The reaction
mixture was stirred at 80 oC for 2.5 h and then poured into water (50 mL).
The
workup
procedure
gave
1-allyl-4-(p-methoxyphenyl)-3,5-
To an acetonitrile (0.60 mL)-acetic acid (0.30 mL) mixture of ethyl-2-[1-
(2-thienyl)-hept-2-yn-1-yl]-p-toluenesulfonylhydrazine (50 mg, 0.11 mmol)
was added to a 0.1 M silver nitrate (0.1 ml, 0.022 mmol) solution at room
diphenylpyrazole (32)(38 mg, 70%) as a yellow oil.
IR (KBr, cm-1) 3065, 2956, 2927, 2852, 2836, 1712, 1606, 1576, 1552,
1519, 1458, 1440, 1363, 1319, 1287, 1247, 1176, 1106, 1073, 1035, 974,
o
1
temperature. The reaction mixture was stirred at 50 C for 5 h and then
921, 839, 779, 699; H NMR (600 MHz, CDCl3)  3.76 (3H, s, Me), 4.71
poured into water (50 mL). The workup procedure gave ethyl 2-[5-butyl-
3-(thiophen-2-yl)-1H-pyrazol-1-yl]acetate (33b)(23 mg, 71 %) as a yellow
oil.
(2H, dt, J=1.4 and 16.9 Hz, olefinic H), 5.07 (1H, dd, J=1.4 and 10.1 Hz,
olefinic H), 6.00-6.09 (1H, m, olefinic H), 6.71 (2H, d, J=8.7 Hz, ArH),
6.95 (2H, d, J=8.7 Hz, ArH), 7.24-7.27 (6H, m, ArH), 7.34-7.36 (2H, m,
ArH), 7.48-7.50 (2H, m, ArH); 13C NMR (150 MHz, CDCl3)  52.3 (t), 55.0
(q), 113.5 (d × 2), 114.2 (d), 117.4 (t), 118.8 (s), 125.6 (s), 127.2 (d),
128.1 (d × 2), 128.2 (d × 2), 128.4 (d × 2), 128.5 (s), 130.3 (d × 2), 131.5
(d × 2), 133.6 (s), 133.8 (d), 142.1 (s), 148.8 (s), 158.1 (s); MS m/z 366
(M+).
IR (KBr, cm-1) 2958, 2932, 2871, 2360, 2337, 1754, 1712, 1568, 1531,
1467, 1377, 1311, 1264, 1209, 1024, 849, 701; 1H NMR (600 MHz,
CDCl3)  0.95 (3H, t, J = 7.6 Hz, Me), 1.27 (3H, t, J = 7.6 Hz, Me), 1.40-
1.46 (2H, m, CH2), 1.64-1.76 (2H, m, CH2), 2.53 (2H, t, J = 7.6 Hz, CH2),
4.21-4.24 (2H, m, CH2), 4.85 (2H, s, CH2), 6.30 (1H, s, ArH), 7.02 (1H, dd,
J = 3.5 and 4.8 Hz, ArH), 7.21 (1H, d, J = 6.2 Hz, ArH), 7.28 (1H, d, J =
3.4 Hz, ArH); 13C NMR (150 MHz, CDCl3)  13.8 (q), 14.1 (t), 22.3 (t),
25.1 (t), 30.2 (t), 50.6 (t), 61.7 (t), 102.1 (d), 123.5 (d), 124.2 (d), 127.3
(d), 136.8 (s), 145.5 (s), 146.3 (s), 167.8 (s); MS m/z 292 (M+), 263 (M+ -
Et), 219 (M+ - CO2Et). Anal. Calcd for C15H20N2O2S: C, 61.62; H, 6.89; N,
9.58. Found: C, 61.55; H, 6.88; N, 9.24.
1-phenylhepta-1,2-diene (33).[19]
To a nitromethane (1.0 mL)-H2O (0.20 mL) solution of 2-(1-phenylhept-2-
yn-1-yl)-p-toluenesulfonylhydrazine (2) (50 mg, 0.14 mmol) were added
tetrabutylammonium hydrogensulfate (4.8 mg, 0.014 mmol) and
lanthanum triflate (8.2 mg, 0.014 mmol). The reaction mixture was
refluxed for 0.5 h and poured into a sat. NaHCO3 (30 mL) solution. The
workup procedure gave the titled compound 32 (26 mg, 99%) as a yellow
oil.
Keywords: Hydrazines • Propargyl • Pyrazoles • Alkylation •
The titled compound 33 (25 mg, 54%) was also obtained by the direct
reaction of 1-phenylhept-2-yn-1-ol (50 mg, 0.27 mmol), p-toluenesulfonyl
hydrazine (0.15 g, 0.80 mmol), tetrabutylammonium hydrogensulfate (9.0
mg, 0.027 mmol), lanthanum triflate (16 mg, 0.027 mmol), and
magnesium triflate (9.0 mg, 0.027 mmol).
Halogenation
[1]
a) T. A. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W.
Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M.
Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G.
Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K.
Seibert, A. W. Veenhurizen, Y. Y. Zhan, P. C. Isakson, J. Med. Chem.
1997, 40, 1347-1365; b) M. J. Genin, C. Biles, B. J. Keiser, S. M.
Poppe, S. M. Swaney, W. G. Tarpley, Y. Yagi, D. L. Romero, J. Med.
Chem. 2000, 43, 1034-1040; M. Atobe, K. Naganuma, M. Kawanishi, A.
Morimoto, K. Kasahara, S. Ohashi, T. Hayashi, S. Miyoshi, Bioorg. Med.
Chem. Lett. 2013, 23, 6569-6576; c) K. Puaruch, T. Guzi, M. P. Dwyer,
WO 2009127612, 2009; d) M. Rouse, M. A. Seefeld, WO 2010093885,
2010; e) A. Le-Brun, F. Thompson, G. Tiraboschi, J. M. Salvino, P.
Mailliet, US 200550130989, 2005; f) J. Close, R. W. Heidelbrecht, S.
Katter, T. A. Miller, D. Sloman, M. G. Stanton, P. Tempest, WO
2007055941, 2007; H. Li, J. Yuan, R. Bakthavatchalam, K. J. Hodgetts,
S. M. Capitosti, J. Mao, D. J. Wustrow, Q. Guo, WO 2009012482,
2009; C, Bolea, WO 10079239, 2010.
silver nitrate catalyzed cyclization of propargyl hydrazides.
2-[5-butyl- 3-(thiophen-2-yl)-1H-pyrazol-1-yl]acetate (33a).
To a mixture of acetonitrile (0.60 mL) and acetic acid (0.30 mL) of
cyanomethyl-2-[1-(2-thienyl)hept-2-yn-1-yl]-p-toluenesulfonylhydrazine
(22b)(50 mg, 0.13 mmol) was added to a 0.1 M silver nitrate solution (0.1
ml, 0.025 mmol) and gold (I) chloride (1.4 mg, 0.0062 mmol) at room
temperature. The reaction mixture was stirred for 0.5 h and then poured
into water (50 mL). The organic layer was separated and the aqueous
layer was extracted with AcOEt. The combined organic layer was
washed with sat. NaHCO3 (20 mL) and water (30 mL) and then dried
over MgSO4. The solvent was removed under reduced pressure. The
residue was purified by preparative TLC on silica gel eluting with AcOEt-
n-hexane (1:10) to give 2-[5-butyl-3-(thiophen-2-yl)-1H-pyrazol-1-
yl]acetonitrile (33a)(19 mg, 86 %) as white powders (mp 108-109 oC).
White powders, mp 108-109 oC, IR (KBr, cm-1) 3107, 3074, 2958, 2932,
2871, 1711, 1597, 1570, 1531, 1466, 1430, 1414, 1400, 1381, 1305,
1
1227, 1180, 1090, 1057, 916, 849, 799, 706; H NMR (600 MHz, CDCl3)
[2]
Review on Synthesis pyrazoles: a) J. Elguero, Comprehensive
Heterocyclic Chemistry; A. R. Katritzky, C. W. Rees, E. F. V. Scriven,
Eds.; Pergamon: Oxford, 1996, Vol. 5; b) A. N. Kost, I. I. Gradberg, Adv.
Heterocycl. Chem. 1966, 6, 347-429; c) Y. L. Janin Chem. Rev. 2012,
112, 3924-3958; d) S. Fustero, M. Sánchez-Roselló, P. Barrio, A.
Simón-Fuentes, Chem. Rev. 2011, 111, 6984-7034; e) S. Fustero, A.
Simon-Fuentes, J. F. Sanz-Cervera, Org. Prep. Proced. Int. 2009, 41,
253-290; f) K. Makino, H. S. Kim, Y. Kurosawa, J. Heterocycl. Chem.
 0.98 (3H, t, J = 7.6 Hz, Me), 1.44-1.49 (2H, m, CH2), 1.69-1.74 (2H, m,
CH2), 2.66 (2H, t, J = 8.3 Hz, CH2), 5.00 (2H, s, CH2), 6.32 (1H, s, ArH),
7.05 (1H, dd, J = 3.5 and 4.5 Hz, ArH), 7.26 (1H, d, J = 4.6 Hz, ArH),
7.30 (1H, J = 2.7 Hz, ArH); 13C NMR (150 MHz, CDCl3)  13.7 (q), 22.3
(t), 25.1 (t), 30.2 (t), 37.1 (t), 103.2 (d), 113.8 (s), 124.2 (d), 124.9 (d),
127.4 (d), 135.8 (s), 145.4 (s), 147.4 (s); MS m/z 245 (M+). Anal. Calcd
for C13H15N3S: C, 63.64; H, 6.16; N, 17.13. Found: C, 63.60; H, 6.15; N,
16.89.

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European Journal of Organic Chemistry
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Text for Table of Contents
Key Topic*
Platform of Pyrazoles: Alkylation
and halogenation of isolable
propargyl hydrazides successfully
gives some useful substituted
pyrazoles in high yields.
Kosuke Kiyokawa, Yukiteru Ito, Ryoma
Kakehi, Takahiro Ogawa, Yusuke Goto
and Prof. Dr. Mitsuhiro Yoshimatsu*
Page No. – Page No.
Propargyl Hydrazides as a Useful
Intermediate Leading to Pyrrazoles
via Certain Electrophiles.
*