[1,3]-Dipolar cycloaddition of N-aryl sydnones to benzothiophene 1,1-dioxide, 1-cyclopropylprop-2-yn-1-ol and 1-(prop-2-ynyl)-1H-indole

Article abstract of DOI:10.1016/j.tet.2014.04.083

[1,3]-Dipolar cycloadditions of N-aryl sydnones to benzothiophene 1,1-dioxide, 1-cyclopropylprop-2-yn-1-ol and 1-(prop-2-ynyl)indole gave fused pyrazole derivatives when carried out in refluxing toluene. While the first two dipolarophiles gave single regi

Full text of DOI:10.1016/j.tet.2014.04.083

Accepted Manuscript
[1,3]-Dipolar cycloaddition of N-aryl sydnones to benzothiophene 1,1-dioxide, 1-
cyclopropylprop-2-yn-1-ol and 1-(prop-2-ynyl)-1H-indole
Yaşar Dürüst , Akın Sağırlı , Benson M. Kariuki , David W. Knight
PII:
S0040-4020(14)00617-6
10.1016/j.tet.2014.04.083
TET 25533
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 January 2014
Revised Date: 11 April 2014
Accepted Date: 25 April 2014
Please cite this article as: Dürüst Y, Sağırlı A, Kariuki BM, Knight DW, [1,3]-Dipolar cycloaddition of N-
aryl sydnones to benzothiophene 1,1-dioxide, 1-cyclopropylprop-2-yn-1-ol and 1-(prop-2-ynyl)-1H-indole,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.083.
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Graphical Abstract
[1,3]-Dipolar cycloaddition of N-aryl sydnones to
benzothiophene 1,1-dioxide, 1-cyclopropylprop-2-yn
-1-ol and 1-(prop-2-ynyl)-1H-indole
Leave this area blank for abstract info.
Yaşar Dürüst,a,* Akın Sağırlıa, Benson M. Kariukib and David W. Knightb,*
a Department of Chemistry, Abant İzzet Baysal University, TR-14280, Bolu,Turkey
b School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK.
O
O
HO
S
OH
O
O
O
O
N
S
N
N
N
N
R
N
R
R
R
a
b
c
d
e
f
H
4-Me
4-I
N
4-Cl
N
4-OMe
4-F
N
N
N
N
N
+
R
R
g
3,4-OCH2O
R

ACCEPTED MANUSCRIPT
[1,3]-Dipolar cycloaddition of N-aryl sydnones to benzothiophene 1,1-dioxide, 1-
cyclopropylprop-2-yn-1-ol and 1-(prop-2-ynyl)-1H-indole
Yaşar Dürüst,a,* Akın Sağırlıa, Benson M. Kariukib and David W. Knightb,*
a Department of Chemistry, Abant İzzet Baysal University, TR-14280, Bolu,Turkey
b School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK.
ABSTRACT
_____________________________________________________________________________________________
[1,3]-Dipolar cycloadditions of N-aryl sydnones to benzothiophene1,1-dioxide, 1-cyclopropylprop-2-yn-1-ol and 1-(prop-2-
ynyl)indole gave fused pyrazole derivatives when carried out in refluxing toluene. While the first two dipolarophiles gave
single regioisoimers, this indolic derivative gave mixtures, the ratios of which appeared to be controlled by the phenyl
substituents. Their structures were identified in the usual manner, supported by single crystal X-ray diffraction
measurements.
Keywords: cycloaddition, pyrazole, sydnone, alkyne, benzothiophene, propynyl alcohol
1.Introduction
Sydnones constitute a well-defined class of mesoionic compounds obtained by cyclodehydration,
induced by either acetic anhydride or 1,3-dibromo-5,5-dimethylhydantoin, of N-nitroso derivatives of N-
substituted α-amino acids.1-3 These compounds are of interest because of the varied types of biological
activity displayed by some of them, particularly sydnone-4-heterocycles, and especially because they
can provide ready access to a variety of heterocyclic systems.4–6 For example, pyrazole derivatives,
which are both important building blocks in organic synthesis and which have numerous applications as
pharmaceuticals and agrochemicals, can be sourced from sydnones following [1,3]-dipolar
cycloadditions with a variety of dipolarophiles.7 Amongst the latter group of compounds,
poly(hetero)aromatic-substituted pyrazoles are particularly important showing a broad spectrum of
useful biological effects, including kinase inhibition,8 estrogen receptor binding,9 anti-inflammatory10
and herbicidal activities11 as illustrated in Scheme 1.
[Type text]
Corresponding author: Tel.: +44 2920 874 210; fax: +44 2920 874 030. E-mail address: knightdw@cf.ac.uk

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3
SO2Me
OH
Cl
Br
CO2Me
N
N
N
N
N
N
F
N
N
N
N
F
HO
F
F
OH
Estrogen receptor ligand
F
MAP Kinase inhibitor
Anti-inflammatory activity
Herbicidal activity
Scheme 1. Some biologically active pyrazole derivatives.
In general, it is a considerable advantage in drug discovery to work with structures, which contain one or
more benzene rings as this facilitates alterations to the initial molecule in a rational and fairly
quantifiable manner, in terms of both electronic and steric properties. This implies that a particular
synthetic approach to such targets should be successful with many types of different substituent, for
example ones placed around a phenyl substituent. A potential problem in the synthesis of pyrazoles from
N-aryl sydnones, by cycloadditions to unsymmetrical alkenes and alkynes, is one of regioselectivity, as
formation of two regioisomers is always possible. Taking account of these considerations, together with
our continuing interest in the [1,3]-dipolar cycloaddition chemistry of various ylides leading to
pyrazoles, triazoles and spiropyrroles,12-15 we focus herein on the synthesis of various pyrazole
derivatives starting from N-aryl sydnone dipoles 1, which differ by the nature of the 4-substituent on an
N-phenyl group, in order to probe what influence these might have on both reactivity and
regioselectivity. This series of sydnones was reacted with three representative dipolarophiles: an alkene,
benzothiophene 1,1-dioxide (2) and two 1-alkynes, 1-cyclopropylprop-2-yn-1-ol (4) and 1-(prop-2-
ynyl)-1H-indole (8).
Heterocyclic compounds with a benzothiophene dioxide structural feature have been used for the
synthesis of pharmaceutically important molecules showing bioactivities including hepatitis C virus
NS5B polymerase inhibition and various cytotoxic properties.16-19

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2.Results and Discussion
The key starting compounds, the N-arylsydnones 1a-g, were prepared according to the procedures
previously reported.1-3 As the only examples of similar [1,3]-dipolar cycloadditions of benzothiophene
dioxide which have been reported are with nitrilimines,20 we first carried out a brief optimization study
which showed that relatively prolonged thermolysis in toluene gave the best yields. Thus, the
dipolarophile 2 underwent cycloadditions with sydnones 1a-g and gave only the regioisomers 3a-g in
moderate yields as the only isolable products (Scheme 2).
O
O
O
O
N
S
O
O
N
S
N
toluene
N
+
reflux, 12h
R
R
1
2
3
R
R
Yield (%)
Yield (%)
H
4-OMe
4-F
3a
3b
3c
3d
35
33
38
40
3e
3f
35
45
30
4-Me
4-I
3,4-OCH2O
3g
4-Cl
Scheme 2. Cycloadditions of sydnones 1 to benzothiophene 1,1-dioxide 2 affording 3.
Typical characteristics of these cycloadducts in their IR spectra are the symmetric and asymmetric
stretching vibrations of SO2 moiety at around 1150 and 1300 cm–1, respectively. Aliphatic ring protons of
these compounds resonate in the range of 4-5 ppm as two double doublets and one triplet which
correspond to the three hydrogens of the pyrazoline portion in the cycloadduct; the chemical shifts
observed strongly support the structural assignment as being the regioisomers 3. The proton at the bridge
position was split into a doublet of doublets (which usually appeared as an apparent triplet) and usually

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5
appeared between the AB double doublet resonances due to the methylene group adjacent to nitrogen.
13C NMR data showed the methylene carbons of the pyrazole ring resonating at around 51 ppm while
the bridge methine adjacent to the sulfone resonates at around 63 ppm, again supporting the structural
assignment. This outcome also corresponds to a previous observation that nitrile oxides add to
benzothiophene-S-oxide with the same regioselectivity, consistent with the addition of the electron-rich
end of the dipole to the more electron deficient end of the dipolarophiles, the 3-position of the
benzothiophene.21
The second dipolarophile used in this work was the acetylenic alcohol 1-cyclopropylprop-2-yn-1-ol 4
which is obtained from ethynylmagnesium bromide and cyclopropanecarboxaldehyde.22 [1,3]-Dipolar
cycloadditions of sydnones 1a-g to alkynol 4 in toluene, under reflux, proceeded slowly but smoothly
and were also highly regioselective, yielding the regioisomers 5a-g as the only isolable products
(Scheme 3). That single regioisomers had been formed was clear from the 1H NMR data, which showed
a pair of doublets resonating at 6.42 and 7.81 ppm (J = 2.4 Hz) in adduct 5a, assigned to the vicinal
methines of the pyrazole ring; similar resonances were evident in the remaining adducts 5b-g. This
structural assignment is in agreement with with earlier reports4,23 on the structural elucidation of
isomeric 3-methyl-1-phenyl-1H-pyrazole and 5-methyl-1-phenyl-1H-pyrazoles, both in terms of
chemical shifts and coupling constant values, the latter being in the range J = 2.3-2.5 Hz. The structural
assignments in general were also supported by the 13C NMR spectroscopic data. As for carbon chemical
shifts of the cycloadducts, the carbon attached to the hydroxyl group resonated at around 72.0 ppm, the
pyrazole iminic carbon (C3-pyrazole ring numbering) at around 158-160 ppm and the most shielded
aliphatic carbons were the cyclopropyl ring carbons24-27 In the mass spectra, while significant molecular
ions were observed, the base peaks were due to loss of a molecule of water.

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6
R
HO
toluene
N
O
1
+
reflux, 12h
N
O
4
OH
A
R
H
Yield (%)
Yield (%)
R
4-OMe
4-F
5a
5b
5c
5d
33
35
40
43
33
38
30
5e
5f
OH
4-Me
N
N
4-I
3,4-OCH2O
5g
4-Cl
R
5
Scheme 3. The formation of single regioisomers 5 from sydnones 1 and 1-alkynol 4.
This regiochemical outcome is also consistent with previous reports, wherein single isomers are formed
from many types of 1-alkyne and strongly suggests the specific formation of intermediate A (Scheme
3).4,23 The present work also shows that there is a lack of an obvious sensitivity to the nature of the 4-
substituent on the N-phenyl ring in these cycloadditions as, in all cases, single isomers were obtained in
similar yields (see also below).
A final example of a dipolarophile, 1-(prop-2-ynyl)-1H-indole 8 which was easily obtained from indole
6 and propargyl bromide 7 as shown, underwent [1,3]-dipolar cycloadditions to sydnones 1a-g, but
afforded regioisomeric products 9a-g and 10a-g in the ratios shown below (Scheme 4). Fortunately,
these proved to be reasonably easy to separate by routine column chromatography, although structural
proof of which isomer was which was not immediately forthcoming.

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7
HN
6
Br
7
NaH
DMF, 0-20 oC
N
N
N
R
9
toluene
reflux, 12h
N
+
1
+
N
8
N
N
R
10
~Ratio
R
H
Yield 9 (%) Yield 10 (%)
Yield (%)
a
b
c
d
e
f
18
28
20
35
10
20
20
36
42
5
1:2
2:3
4:1
5:1
1:4
2:1
2:1
54
70
25
42
50
30
30
4-Me
4-I
7
4-Cl
4-OMe
4-F
40
10
10
g
3,4-OCH2O
Scheme 4. Synthesis of propynylindole 8 and cycloaddition to N-aryl sydnones 1 affording
regioisomeric products 9 and 10.
While proton and carbon resonances were in accord with those previously reported for some related
indoly pyrazoles,28-30 this did not seem to provide a sufficiently reliable basis for structural assignment,
particularly as analysis of the proton data was incomplete owing to many overlapping resonances (see
Experimental section). Fortunately, many of the products were crystalline and we were able to resort to
X-ray crystallographic analysis, specifically of products 9d and 10d. Exact structures of the
regioisomers were established by the X-ray ORTEP views of the single crystals (Figures 1 and 2).

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Crystallographic data have been deposited at the CCDC, reference numbers 934162 (9d) and 934163
(10d), respectively.
Figure 1. ORTEP diagram of pyrazole isomer 9d, showing the indole attached to the 3-position.
Figure 2. ORTEP diagram of pyrazole isomer 10d, with the indole attached to the 4-position.
Neither ORTEP diagram revealed any unusual features in these structures. Comparative NMR data then
allowed structural assignments to be made to all the remaining products with certainty (See Figs. 3-6 in
the Experimental section under compounds 9c and 10c).

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By examining the ratios of the regioisomers based on the reaction yields, it is seen that, in the case of
electron donating groups on the sydnone N-aryl substituent, the regioisomers 10 are the major products
while regioisomers 9 are minor products. The reverse is true when there is an electron withdrawing
halogen atom at the 4-position of the phenyl group and the regioisomers 9 are the major products and the
regioisomers 10 the minor. However, the reasons behind the relative differences between the 4-methoxy
and 3,4-dimethoxy are not obvious. These regioselectivities are somewhat unusual, given the typical
propensity for the formation of very largely or exclusively 3-substituted pyrazoles shown by such
cycloadditions.3,4 Some recent exceptions have come to light when using 2-pyridyl- and 2-pyrimidinyl-
1-alkynes as the dipolarophiles,4 although it is not obvious why the present indolic analogues react with
a similar lack of selectivity. At least, these results provide something of a predictive pattern for future
use in pyrazole synthesis. In contrast, the complete regioselectivity shown by the alkynol 4, which gave
only products 5 (Scheme 3),
3. Conclusions
In summary, we report a practical catalyst-free protocol that allows access to a variety of substituted
indolyl pyrazoles, cyclopropyl-(1-substituted-phenyl)-1H-pyrazol-3-yl)methanols and 2-(4-substituted
phenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxides using [1,3]-dipolar cycloaddition
reactions of mesoionic N-aryl sydnones. The reactions proceed in moderate yields and the
regioselectivities vary substantially depending on the nature of the 4-substituents on the phenyl ring in
sydnones 1, in the case of the sydnone-propynylindole cycloadditions, where the major-minor ratio are
largely reversed by replacing electron releasing substituents with electron withdrawing ones. However,
the remaining two types of cycloaddition studied, with an alkynyl cyclopropylmethanol and
benzothiophene dioxide, lead to only one regioisomeric cycloadduct, the nature of which is unaffected
by the aryl 4-substituent.

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4. Experimental
4.1. General
Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. Infrared
spectra were obtained from KBr pellets or neat on NaCl plates for liquids and were recorded on Perkin
Elmer 1600 FTIR and Shimadzu spectrophotometers. Mass spectra were recorded on a Fisons VG
Platform II spectrometer and on a Waters Synapt spectrometer using the ionization modes specified.
NMR spectra were recorded on Varian and Bruker spectrometers operating at 500, 400, 300 and 250
1
13
MHz for H and at 125, 100 MHz and 75 for C , respectively, all at 25 ºC, as specified for each data
set. All chemical shifts are reported in ppm downfield from TMS. Coupling constants (J) are reported in
Hz. Routine TLC analyses were carried out on pre-coated silica gel plates with fluorescent indicator.
Flash column chromatography was performed on silica gel (230-400 Mesh ASTM). A rotary TLC
apparatus (Chromatotron) was utilized for further separation and purifications. Stain solutions of
potassium permanganate and iodine were used for visualization of the TLC spots.
4.2. 2-(4-Substituted phenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxides 3a-g:
General procedure
A mixture of benzo[b]thiophene 1,1-dioxide 2 (83 mg, 0.5 mmol) and a substituted sydnone 1 (0.5
mmol) was refluxed in toluene (10 mL) for 12 h. After completion of the reaction, as monitored by TLC
(n-hexane-EtOAc, 1:1), the solvent was removed under reduced pressure. The crude product was then
purified by column chromatography to give compounds 3.
4.2.1. 2-Phenyl-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3a
Yield: 50 mg (35%); yellow powder. Mp 135–137 °C; Rf = 0.49 (n-hexane-EtOAc, 1:1). IR (KBr):
3061, 2924, 1653, 1597, 1500, 1465, 1375, 1296 (SO2 asym), 1145 (SO2 sym), 1062, 1001, 752 cm−1. 1H
NMR (400 MHz, CDCl3): δ = 7.83-7.79 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.35

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11
(t, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.2 Hz, 1H), 5.04 (dd, J = 13.6, 10.4 Hz, 1H),
4.50 (t, J = 10.4 Hz, 1H), 4.14 (dd, J = 13.6, 10.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ = 145.9,
145.1, 143.5, 134.3, 131.2, 130.1, 129.6, 123.2, 122.9, 121.7, 114.0, 66.8, 50.3. HRMS: m/z (ESI-TOF,
[M+H]+) calcd for C15H13N2O2S: 285.0698. Found: 285.0701.
4.2.2. 2-(4-Methylphenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3b
Yield: 49 mg (33%); yellow oil. Rf = 0.50 (n-hexane-EtOAc, 1:1). IR (KBr): 2928, 1653, 1516, 1460,
1
1379, 1307 (SO2 asym), 1168 (SO2 sym), 1112, 954, 817 cm−1. H NMR (400 MHz, CDCl3): δ = 7.84-
7.78 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6
Hz, 2H), 5.03 (dd, J = 13.6, 10.4 Hz, 1H), 4.48 (t, J = 10.4 Hz, 1H), 4.10 (dd, J = 13.6, 10.4 Hz, 1H),
2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 145.6, 142.8, 142.7, 134.0, 131.0, 130.8, 129.9, 129.8,
122.9, 122.6, 113.9, 66.6, 50.4, 20.6. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C16H15N2O2S:
299.0854. Found: 299.0852.
4.2.3. 2-(4-Iodophenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3c
Yield: 78 mg (38%); yellow oil. Rf = 0.47 (n-hexane-EtOAc, 1:1). IR (KBr): 2924, 1683, 1586,
1490,1381, 1305 (SO2 asym), 1265, 1166 (SO2 sym), 1146, 1070, 825, 833 cm−1. 1H NMR (300 MHz,
CDCl3): δ = 7.81 (t, J = 6.7 Hz, 2H), 7.65 (td, J = 7.6, 3.2 Hz, 1H), 7.62-7.55 (m, 2H), 6.89 (dt, J = 9.7,
4.7 Hz, 2H), 5.04 (dd, J = 13.6, 10.7 Hz, 1H), 4.47 (app. t, J = 10.7 Hz, 1H), 4.10 (dd, J = 13.6, 10.7 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ = 146.0, 144.7, 144.2, 138.2, 134.3, 131.5, 129.8, 123.3, 122.9,
116.0, 83.8 (C-I), 66.9 (C-SO2), 50.1. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C15H12IN2O2S:
410.9664. Found: 410.9664.
4.2.4. 2-(4-Chlorophenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3d

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12
Yield: 64 mg (40%); orange solid. Mp 163-165 °C. Rf = 0.45 (n-hexane-EtOAc, 1:1). IR (KBr): 2926,
1683, 1653, 1593, 1492, 1465, 1379, 1303 (SO2 asym), 1165 (SO2 sym), 1145, 1124, 825, 767 cm−1. 1H
NMR (300 MHz, CDCl3): δ = 7.82 (t, J = 7.0 Hz, 2H), 7.71 (t, J = 6.7 Hz, 1H), 7.60 (t, J = 6.7 Hz, 1H),
7.25 (d, J = 8.7 Hz, 2H), 7.11-7.04 (m, 2H), 5.06 (dd, J = 13.7, 10.5 Hz, 1H), 4.49 (t, J = 10.5 Hz, 1H),
13
4.12 (dd, J = 13.7, 10.5 Hz, 1H). C NMR (75 MHz, CDCl3): δ = 146.0, 144.1, 143.7, 134.3, 131.4,
129.8, 129.5, 126.7, 123.3, 122.9, 115.2, 66.9 (C-SO2), 50.4. HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C15H12ClN2O2S: 319.0308. Found: 319.0308.
4.2.5. 2-(4-Methoxyphenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3e
Yield: 55 mg (35%); yellow oil. Rf = 0.46 (n-hexane-EtOAc, 1:1). IR (KBr): 3450, 1653, 1510, 1460,
1
1303 (SO2 asym), 1244, 1145 (SO2 sym), 1124, 1070, 1035, 827, 763 cm−1. H NMR (300 MHz,
CDCl3): δ = 7.81 (t, J = 7.6 Hz, 2H), 7.73-7.20 (m, 2H), 7.11 (d, J = 8.7 Hz, 2H), 6.89-6.82 (m, 2H),
5.04 (dd, J = 14.0, 10.8 Hz, 1H), 4.48 (t, J = 10.5 Hz, 1H), 4.08 (dd, J = 14.0, 10.5 Hz, 1H), 3.80 (s, 3H).
13C NMR (75 MHz, CDCl3): δ = 155.1, 145.8, 139.4, 134.2, 133.8, 132.5, 131.0, 123.1, 122.8, 115.7,
114.9, 66.9 (C-SO2), 55.8 (OCH3), 51.4. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C16H15N2O3S:
315.0803. Found: 315.0808.
4.2.6. 2-(4-Fluorophenyl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3f
Yield: 68 mg (45%); yellow powder. Mp 170–172 °C; Rf = 0.45 (n-hexane-EtOAc, 1:1). IR (KBr): 2928,
1
1653, 1508, 1375, 1303 (SO2 asym), 1224, 1145 (SO2 sym), 1070, 825, 748 cm−1. H NMR (300 MHz,
CDCl3): δ = 7.82 (t, J = 7.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.12-7.01 (m,
13
5H), 5.05 (dd, J = 13.7, 10.5 Hz, 1H), 4.49 (t, J = 10.5 Hz, 1H), 4.10 (dd, J = 13.7, 10.5 Hz, 1H). C
NMR (75 MHz, CDCl3): δ = 159.3 (J = 245.2 Hz, C-F), 145.9, 143.9, 141.7, 134.3, 131.3, 129.9, 123.4,
123.2, 116.0, 115.3, 67.0 (C-SO2), 51.0. HRMS: (ESI-TOF, [M+H]+) calcd for C15H12FN2O2S:
303.0604. Found: 303.0602.

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13
4.2.7. 2-(1,3-Benzodioxol-5-yl)-3,3a-dihydro-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide 3g
Yield: 49 mg (30%); orange solid. Mp 155–157 °C; Rf = 0.46 (n-hexane-EtOAc, 1:1). IR (KBr): 2924,
1
1683, 1587, 1506, 1489, 1303 (SO2 asym), 1234, 1213, 1145 (SO2 sym), 1037, 935, 812, 736 cm−1. H
NMR (300 MHz, CDCl3): δ = 7.83-7.78 (m, 2H), 7.69 (t, J = 6.7 Hz, 1H), 7.58 (t, J = 6.7 Hz, 1H), 6.89
(dd, J = 4.6, 2.6 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.42 (dd, J = 8.4, 2.3 Hz, 1H), 5.95 (s, 2H), 5.06 (dd,
J = 13.7, 10.5 Hz, 1H), 4.42 (t, J = 10.5 Hz, 1H), 4.06 (dd, J = 13.7, 10.5 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ = 148.7, 145.9, 143.2, 142.9, 140.8, 134.2, 131.1, 130.0, 123.1, 122.8, 108.5, 106.0, 101.4,
97.6, 66.9 (C-SO2), 51.3. HRMS: (ESI-TOF, [M+H]+) calcd for C16H13N2O4S: 329.0596. Found:
329.0591.
4.3. 1-Cyclopropylprop-2-yn-1-ol 422
Cyclopropylcarboxaldehyde (700 mg, 10 mmol) was added dropwise into a solution of
o
ethynylmagnesium bromide (22 ml of a 0.5M solution in THF, 11 mmol) in dry THF at 0 C. The
reaction mixture was left to warm up to room temperature. After completion of the reaction, as indicated
by TLC (n-hexane-EtOAc, 1:1), saturated aqueous ammonium chloride was added to the reaction
mixture which was then extracted with ethyl acetate (3 x 20 mL). The combined organic solutions were
dried over Na2SO4 and the solvents evaporated. The crude oily product was then purified by column
chromatography on silica gel using n-hexane-EtOAc (4:1) to give 4 as brown oil; yield: 768 mg (80%).
Rf = 0.67 (n-hexane-EtOAc, 1:1). IR (KBr): 3373, 2966, 2110, 1712, 1452, 1438, 1381, 1317, 1207,
1078, 997, 945 cm−1. 1H NMR (400 MHz, CDCl3): δ = 4.13 (d, J = 5.8 Hz, 1H), 2.51-2.27 (m, 2H), 1.20
(tdt, J = 8.1, 6.6, 5.0 Hz, 1H), 0.62-0.31 (m, 4H).
4.3.1 Cyclopropyl(1-substituted-1H-pyrazol-3-yl)methanols 5a-g: General procedure.
A mixture of 1-cyclopropylprop-2-yn-1-ol 4 (48 mg, 0.5 mmol) and a substituted sydnone 1 (0.5 mmol)
was refluxed in toluene for 12h. After completion of the reaction, as monitored by TLC (hexane-EtOAc,

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1:1), the solvent was removed under reduced pressure. The crude product was purified by column
chromatography to give regioisomers 5 as the only isolable products.
4.3.1.1. Cyclopropyl(1-phenyl-1H-pyrazol-3-yl)methanol 5a
Yield: 36 mg (33%); yellow oil. Rf = 0.32 (n-hexane-EtOAc, 1:1). IR (KBr): 3385, 1600, 1525, 1502,
1390, 1251, 1228, 1035, 754, 680 cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 2.4 Hz, 1H), 7.61-
7.59 (m, 2H), 7.40-7.34 (m, 2H), 7.24-7.18 (m, 1H), 6.42 (d, J = 2.4 Hz, 1H), 4.16 (d, J = 8.3 Hz, 1H),
2.55 (br s, 1H, OH), 1.30-1.13 (m, 1H), 0.62–0.32 (m, 4H). 13C NMR (125 MHz, CDCl3): δ = 154.4 (C-
3, C=N), 137.8, 127.1 (C-5), 125.4, 124.1, 116.9, 102.6 (C-4), 70.7 (C-OH), 15.3, 0.9. LC-MS (ES+):
m/z (%) 215 (M+H, 25), 197 (M-H2O, 100). HRMS: (ESI-TOF, M+Na) calcd for C13H14N2ONa:
237.1005. Found: 237.1004.
4.3.1.2. Cyclopropyl(1-p-tolyl-1H-pyrazol-3-yl)methanol 5b
Yield: 36 mg (35%); yellow oil. Rf = 0.34 (n-hexane-EtOAc, 1:1). IR (KBr): 3408, 2922, 1739,
1
1612,1533, 1514, 1388, 1259,1035, 817 cm−1. H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 2.3 Hz,
1H), 7.48 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.40 (d, J = 2.3 Hz, 1H), 4.15 (d, J = 8.3 Hz,
1H), 2.51 (br s, 1H, OH), 2.31 (s, 3H), 1.30-1.17 (m, 1H), 0.63–0.34 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ = 156.3 (C-3, C=N), 136.6, 130.3, 128.1 (C-5), 119.5, 104.9 (C-4), 73.5 (C-OH), 21.3, 18.0,
3.6, 2.6. LC-MS (ES+): m/z (%) 229 (M+H, 78), 211 (M-H2O, 100). HRMS: (ESI-TOF, M+Na) calcd
for C14H16N2ONa: 229.1341. Found: 229.1346.
4.3.1.3. Cyclopropyl(1-(4-iodophenyl)-1H-pyrazol-3-yl)methanol 5c
Yield: 64 mg (40%); light yellow oil. Rf = 0.32 (n-hexane-EtOAc, 1:1). IR (KBr): 3408, 2924, 1589,
1
1529, 1491,1383, 1251, 1033, 1004, 943, 823 cm−1. H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 2.5
Hz, 1H), 7.65 (d, J = 6.8 Hz, 2H), 7.38 (d, J = 6.8 Hz, 2H), 6.43 (d, J = 2.5 Hz, 1H), 4.13 (d, J = 8.4 Hz,
1H), 2.51 (br s, 1H, OH), 1.31-1.08 (m, 1H), 0.66-0.32 (m, 4H). 13C NMR (125 MHz, CDCl3): δ = 154.7
(C-3, C=N), 136.1, 125.2 (C-5), 118.4, 103.1 (C-4), 88.0 (C-I), 70.6 (C-OH), 15.3, 0.9, 0.0. LC-MS

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(ES+): m/z (%): 341 (M+H, 53), 323 (M-H2O, 100). HRMS: (ESI-TOF, M+Na) calcd for
C13H13IN2ONa: 341.0151. Found: 341.0138.
4.3.1.4. 1-(4-Chlorophenyl)-1H-pyrazol-3-yl)(cyclopropyl)methanol 5d
Yield: 53 mg (43%); brown oil. Rf = 0.32 (n-hexane-EtOAc, 1:1). IR (KBr): 3381, 1597, 1533, 1498,
1386, 1096, 1033, 1010, 947, 829, 738 cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 2.4 Hz, 1H),
7.54 (dt, J = 9.6, 2.8 Hz, 2H), 7.33 (dt, J = 9.6, 2.8 Hz, 2H), 6.43 (d, J = 2.4 Hz, 1H), 4.13 (d, J = 8.3 Hz,
1H), 2.58 (br s, 1H, OH), 1.33-1.10 (m, 1H), 0.68-0.30 (m, 4H). 13C NMR (125 MHz, CDCl3): δ = 154.7
(C-3, C=N), 136.3, 129.5, 127.2, 125.3 (C-5), 117.9, 103.0 (C-4), 70.6 (C-OH), 15.3, 0.9. LC-MS (ES+):
m/z (%) 249 (M+H, 18), 231 (M-H2O, 100). HRMS: (ESI-TOF, M+Na) calcd for C13H13ClN2ONa:
271.0614. Found 271.0627.
4.3.1.5. Cyclopropyl(1-(4-methoxyphenyl)-1H-pyrazol-3-yl)methanol 5e
Yield: 40 mg (33%); yellow oil. Rf = 0.23 (n-hexane-EtOAc, 1:1). IR (KBr): 3385, 1658, 1525, 1514,
1
1249, 1031, 829, 798 cm−1. H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 6.8
Hz, 2H), 6.87 (d, J = 6.8 Hz, 2H), 6.39 (d, J = 2.4 Hz, 1H), 4.14 (d, J = 8.3 Hz, 1H), 3.77 (s, 3H), 2.54
(br s, 1H, OH), 1.35-1.13 (m, 1H), 0.67-0.31 (m, 4H). 13C NMR (125 MHz, CDCl3): δ = 156.0 (C-3,
C=N), 153.9 (C-OCH3), 131.7, 125.5 (C-5), 122.4, 118.6, 112.2, 102.1 (C-4), 70.7 (C-OH), 53.3
(OCH3), 15.3, 0.9. LC-MS (ES+): m/z (%) 245 (M+H, 27), 227 (M-H2O, 100). HRMS: (ESI-TOF,
M+Na) calcd for C14H16ClN2O2: 267.1109. Found: 267.1112.
4.3.1.6. Cyclopropyl(1-(4-fluorophenyl)-1H-pyrazol-3-yl)methanol 5f
Yield: 44 mg (38%); yellow oil. Rf = 0.30 (n-hexane-EtOAc, 1:1). IR (KBr): 3381, 1533, 1512, 1388,
1
1232, 1035, 835, 752 cm−1. H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 2.4 Hz, 1H), 7.56 (dd, J =
12.0, 4.5 Hz, 2H), 7.07 (t, J = 8.0 Hz, 2H), 6.42 (d, J = 2.4 Hz, 1H), 4.14 (d, J = 8.4 Hz, 1H), 2.49 (br s,
1H, OH), 1.31-1.10 (m, 1H), 0.66-0.33 (m, 4H). 13C NMR (100 MHz, CDCl3): δ = 161.4 (C-F) (d, J =
247.0 Hz), 157.0 (C-3, C=N), 128.2, 121.3 (C-5), 116.7, 116.4, 105.4 (C-4), 73.4 (C-OH), 18.0, 3.6, 2.7.

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LC-MS (ES+): m/z (%) 233 (M+H, 48), 215 (M-H2O, 100). HRMS: m/z (ESI-TOF, M+Na) calcd for
C13H13FN2O: 255.0910. Found: 255.0915.
4.3.1.7. (1-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-3-yl)(cyclopropyl)methanol 5g
Yield: 39 mg (30%); brown oil. Rf = 0.27 (n-hexane-EtOAc, 1:1). IR (KBr): 3431, 1527, 1512, 1467,
1247, 1228, 1037, 933, 810 cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J =2.4 Hz, 1H), 7.13 (d, J =
2.2 Hz, 1H), 7.01 (dd, J = 8.3, 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 5.95 (s,
2H), 4.13 (d, J = 8.3 Hz, 1H), 2.48 (br s, 1H, OH), 1.30-1.10 (m, 1H), 0.66-0.32 (m, 4H). 13C NMR (125
MHz, CDCl3): δ = 154.3 (C-3, C=N), 146.2, 144.0, 125.6 (C-5), 110.3, 106.0 (C-4), 102.3 (OCH2O),
99.6, 99.4, 70.7 (C-OH), 27.4, 15.3, 0.9, 0.0. LC-MS (ES+): m/z (%) 259 (M+H, 50), 241 (M-H2O, 100).
HRMS: m/z (ESI-TOF, M+Na) calcd for C14H14N2O3Na: 281.0902. Found: 281.0906.
4.4. The preparation of 1-(prop-2-ynyl)-1H-indole 8
A procedure has been followed, which was used in the literature for a similar compound.31 Thus, indole
6 (1.170 g, 10 mmol) in dry DMF (2 mL) was added dropwise to a suspension of NaH (0.40 g, 10
o
mmol) in dry DMF (5 mL) maintained at 0 C and then the reaction mixture was stirred at room
temperature for 8h, followed by the addition of propargyl bromide 7 (1.190 g, 10 mmol) in dry DMF (1
mL). After completion of reaction (monitored by TLC), the mixture was poured into cold water (30 mL)
and the organic products extracted with dichloromethane (3 x 20 mL). The combined organic extracts
were dried over anhydrous Na2SO4, filtered and the dichloromethane evaporated. The crude oily product
was purified by column chromatography on silica gel using n-hexane-EtOAc (8:1) to give 8 as a yellow
solid; yield: 1.160 g (75%). Mp 65-69 °C; (lit.32 mp. 36-37 ᵒC). Rf = 0.67 (n-hexane-EtOAc, 1:1). IR
(KBr): 3292, 3055, 2123, 1612, 1514, 1483, 1464, 1396, 1336, 1315, 1259, 1186, 1012, 931, 883, 742
1
cm−1. H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J = 7.8, 0.9 Hz, 1H), 7.29 (dd, J = 8.2, 0.7 Hz, 1H),
7.15 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.11-7.01 (m, 2H), 6.44 (dd, J = 3.2, 0.8 Hz, 1H), 4.73 (d, J = 2.6
Hz, 2H), 2.27 (t, J = 2.6 Hz, 1H).

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4.4.1. Preparation of pyrazolyl-1H-indoles 9 and 10 General procedure.
A solution of 1-(prop-2-ynyl)-1H-indole 8 (76 mg, 0.5 mmol) and a 4-aryl sydnone 1 (0.5 mmol) was
refluxed in toluene (10 mL) for 12 h. After completion of the reaction, as indicated by TLC monitoring
(n-hexane-EtOAc, 1:1), the solvent was removed under reduced pressure. The crude product was
purified by column chromatography (silica gel, 230-400 Mesh ASTM) to give, separately, regioisomers
9 which were eluted first as less polar fractions and 10 as second, more polar fractions.
4.4.1.1. ((1-Phenyl-1H-pyrazol-3-yl)methyl)-1H-indole 9a
Yield: 25 mg (18%); white powder. Mp 110-112 °C; Rf = 0.58 (n-hexane-EtOAc, 1:1). IR (KBr): 3442,
1641, 1530, 1485, 1463, 1390, 1330, 1315, 1259, 1188, 1153, 1074, 1045, 754, 742 cm−1. 1H NMR (400
MHz, CDCl3): δ = 7.67 (d, J = 2.4 Hz, 1H), 7.62-7.50 (m, 3H), 7.44-7.30 (m, 3H), 7.26-7.17 (m, 1H),
7.17-7.09 (m, 2H), 7.09-6.99 (m, 1H), 6.45 (dd, J = 3.1, 0.7 Hz, 1H, Hc), 6.02 (d, J = 2.4 Hz, 1H, Hb),
5.32 (s, 2H, Ha). 13C NMR (100 MHz, CDCl3): δ = 151.2, 140.4, 136.6, 129.9, 129.1, 128.4 (2C;
coincident), 126.9, 122.0, 121.3, 119.9, 119.5, 110.1, 106.8, 102.1, 44.7. HRMS: (ESI-TOF, [M+H]+)
calcd for C18H16N3: 274.1344. Found: 274.1349.
4.4.1.2. 1-((1-Phenyl-1H-pyrazol-4-yl)methyl)-1H-indole 10a
Yield: 49 mg (36%); light yellow solid. Mp 105-107 °C; Rf = 0.44 (n-hexane-EtOAc, 1:1). IR (KBr):
3442, 1642, 1600, 1567, 1504, 1460, 1396, 1333, 1313, 1265, 1217, 1186, 1109, 1042, 1012, 958, 902,
854, 798 cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.61-7.55 (m, 3H), 7.54 (m, 1H), 7.50 (dd, J = 9.2, 1.6
Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.20-7.09 (m, 3H), 7.07-7.02 (m, 2H), 6.45 (dd, J = 2.8, 0.4 Hz, 1H,
Hb), 5.18 (s, 2H, Ha). 13C NMR (101 MHz, CDCl3): δ = 140.4, 140.2, 136.3, 129.8, 129.2, 127.9, 127.0,
125.8, 122.1, 121.5, 120.4, 120.0, 119.5, 109.8, 102.1, 41.2. HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C18H16N: 274.1344. Found: 274.1354.
4.4.1.3. 1-((1-p-Tolyl-1H-pyrazol-3-yl)methyl)-1H-indole 9b

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Yield: 40 mg (28%); yellow solid. Mp 95-97 °C; Rf = 0.57 (n-hexane-EtOAc, 1:1). IR (KBr): 3435,
1638, 1527, 1511, 1441, 1383, 1354, 1297, 1238, 1198, 1058, 1004, 950, 810, 736 cm−1. 1H NMR (400
MHz, CDCl3): δ = 7.65 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.39 (d, J
= 8.0 Hz, 1H), 7.18-7.10 (m, 4H), 7.03 (t, J = 8.0 Hz, 1H), 6.46 (d, J = 3.2 Hz, 1H, Hc), 6.02 (d, J = 2.4
Hz, 1H, Hb), 5.33 (s, 2H, Ha), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3): δ = 150.9, 139.4, 136.8,
135.9, 133.1, 132.5, 130.3, 128.4, 122.0, 121.4, 119.9, 119.5, 110.1, 106.5, 102.0, 44.7, 21.3. HRMS:
(ESI-TOF, [M+H]+) calcd for C19H18N3: 288.1501. Found: 288.1501.
4.4.1.4. 1-((1-p-Tolyl-1H-pyrazol-4-yl)methyl)-1H-indole 10b
Yield: 61 mg (42%); dark yellow solid. Mp 75–77 °C; Rf = 0.40 (n-hexane-EtOAc, 1:1). IR (KBr): 3449,
1612, 1569, 1518, 1485, 1464, 1402, 1315, 1257, 1122, 1083, 1037, 1012, 957, 883, 813, 738 cm−1. 1H
NMR (400 MHz, CDCl3): δ = 7.62-7.51 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.8 Hz, 1H),
13
7.16-7.01 (m, 5H), 6.45 (dd, J = 3.2, 0.8 Hz, 1H, Hb), 5.17 (s, 2H, Ha), 2.27 (s, 3H). C NMR (100
MHz, CDCl3): δ = 140.2, 138.1, 136.9, 136.3, 130.3, 129.1, 127.9, 125.8, 122.1, 121.5, 120.1, 120.0,
119.4, 109.8, 102.1, 41.2, 21.3. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C19H18N3: 288.1501. Found:
288.1491.
4.4.1.5. 1-((1-(4-Iodophenyl)-1H-pyrazol-3-yl)methyl)-1H-indole 9c
Yield: 40 mg (20%); light yellow solid. Mp 136–138 °C; Rf = 0.61 (n-hexane-EtOAc, 1:1). IR (KBr):
3435, 1637, 1587, 1383, 1298, 1240, 1197, 1059, 1004, 946, 815, 765, 750, 665 cm−1. 1H NMR (400
MHz, CDCl3) (Fig. 3): δ = 7.66 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.36 (dd, J = 8.0, 0.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.13 (td, J = 10.0, 7.2, 1.2 Hz, 2H), 7.04 (td, J =
8.8, 8.0, 1.2 Hz, 1H), 6.46 (dd, J = 3.2, 0.8 Hz, 1H, Hc), 6.03 (d, J = 2.4 Hz, 1H, Hb), 5.31 (s, 2H, Ha).
13C NMR (100 MHz, CDCl3): δ = 151.6, 140.0, 138.8, 136.6, 129.1, 128.4, 128.2, 122.2, 121.2, 121.1,

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119.9, 110.1, 107.2, 102.2, 91.0, 44.6. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C18H15IN3: 400.0311.
Found: 400.0317.
4.4.1.6. 1-((1-(4-Iodophenyl)-1H-pyrazol-4-yl)methyl)-1H-indole 10c
Yield: 10 mg (5%): yellow solid. Mp 125–127 °C; Rf = 0.55 (n-hexane-EtOAc, 1:1). IR (KBr): 3428,
1647, 1492, 1460, 1394, 1332, 1311, 1257, 1195, 1168, 1082, 1041, 1011, 952, 860, 812, 738 cm−1. 1H
NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.8 Hz, 2H), 7.59-7.55 (m, 2H), 7.28 (t, J = 10.8 Hz, 3H),
13
7.20-7.01 (m, 4H), 6.46 (d, J = 2.8 Hz, 1H, Hb), 5.18 (s, 2H, Ha). C NMR (100 MHz, CDCl3): δ =
140.7, 139.9, 138.8, 136.3, 129.1, 127.9, 125.5, 122.2, 121.5, 121.1, 121.0, 120.1, 109.7, 102.3, 91.1 (C-
I), 41.2. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C18H15IN3: 400.0311. Found: 400.0311.
4.4.1.7. 1-((1-(4-Chlorophenyl)-1H-pyrazol-3-yl)methyl)-1H-indole 9d
Yield: 54 mg (35%); yellow solid. Mp 105-107 °C; Rf = 0.64 (n-hexane-EtOAc, 1:1). IR (KBr): 3422,
1615, 1597, 1530, 1498, 1464, 1383, 1309, 1256, 1174, 1093, 1051, 1010, 948, 830, 742 cm−1. 1H NMR
(400 MHz, CDCl3): δ = 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.36
(d, J = 8.8 Hz, 1H), 7.32 (d, J = 9.2 Hz, 2H), 7.17-7.10 (m, 2H), 7.03 (td, J = 7.9, 0.9 Hz, 1H), 6.46 (d, J
13
= 4.0 Hz, 1H, Hc), 6.03 (d, J = 2.4 Hz, 1H, Hb), 5.31 (s, 2H, Ha). C NMR (101 MHz, CDCl3): δ =
151.5, 138.9, 136.6, 132.3, 129.9, 129.1, 128.4, 128.3, 122.1, 121.4, 120.6, 119.9, 110.1, 107.2, 102.2,
44.6. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C18H15ClN3: 308.0955. Found: 308.0948.
4.4.1.8. 1-((1-(4-Chlorophenyl)-1H-pyrazol-4-yl)methyl)-1H-indole 10d
Yield: 11 mg (7%); yellow solid. Mp 108–110 °C; Rf = 0.55 (n-hexane-EtOAc, 1:1). IR (KBr): 3435,
1639, 1500, 1471, 1408, 1309, 1215, 1122, 1092, 1037, 1012, 952 cm−1. 1H NMR (400 MHz, CDCl3): δ
= 7.59 (s, 1H), 7.57 (d, J = 4.0 Hz, 2H), 7.45 (dt, J = 10.0, 5.2, 3.2 Hz, 2H), 7.31-7.26 (m, 2H), 7.14 (td,
J = 8.4, 7.2, 1.2 Hz, 2H), 7.09-7.02 (m, 2H), 6.46 (dd, J = 3.2, 0.8 Hz, 1H, Hb), 5.18 (s, 2H, Ha). 13C
NMR (100 MHz, CDCl3): δ = 140.6, 138.7, 136.3, 132.5, 129.9, 129.1, 127.9, 125.7, 122.2, 121.5,

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120.9, 120.6, 120.0, 109.7, 102.3, 41.2. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C18H15ClN3:
308.0955. Found: 308.0945.
4.4.1.9. 1-((1-(4-Methoxyphenyl)-1H-pyrazol-3-yl)methyl)-1H-indole 9e
Yield: 15 mg (10%); light yellow solid. Mp 93-96 °C; Rf = 0.44 (n-hexane-EtOAc, 1:1). IR (KBr): 3442,
1637, 1597, 1533, 1514, 1464, 1446, 1390, 1359, 1301, 1247, 1190, 1112, 1051, 1033, 962, 837, 768
cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.47 (d, J =
9.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.17-7.09 (m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 9.2 Hz,
2H), 6.46 (d, J = 3.2 Hz, 1H, Hc), 6.02 (d, J = 2.4 Hz, 1H, Hb), 5.32 (s, 2H, Ha), 3.76 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ = 158.7, 150.7, 136.6, 134.2, 129.1, 128.5, 128.4, 122.0, 121.3, 119.8, 114.9,
110.1, 106.3, 102.0, 56.0 (OCH3), 44.7 (one quaternary coincident). HRMS: m/z (ESI-TOF, [M+H]+)
calcd for C19H18N3O: 304.1450. Found: 304.1442.
4.4.1.10. 1-((1-(4-Methoxyphenyl)-1H-pyrazol-4-yl)methyl)-1H-indole 10e
Yield: 61 mg (40%); light yellow solid. Mp 106-108 °C; Rf = 0.28 (n-hexane-EtOAc, 1:1). IR (KBr):
3435, 1646, 1566, 1518, 1464, 1452, 1402, 1292, 1247, 1203, 1174, 1109, 1087, 1047, 1024, 958, 868,
836, 788, 741 cm−1. 1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.0 Hz, 1H), 7.53 (s, 2H), 7.40 (dt, J =
12.4, 10.0, 3.2 Hz, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.17-7.01 (m, 3H), 6.84 (dt, J = 12.4, 8.0, 3.2 Hz, 2H),
6.46 (dd, J = 3.2, 0.4 Hz, 1H, Hb), 5.18 (s, 2H, Ha), 3.74 (s, 3H). 13C NMR (100 MHz, CDCl3): δ =
158.7 (C-OCH3), 140.0, 136.3, 134.0, 129.1, 127.9, 125.9, 122.1, 121.4, 121.1, 119.9, 114.8, 109.8,
102.1, 55.9 (OCH3), 41.2 (one quaternary coincident). HRMS: m/z (ESI-TOF, [M+H]+) calcd for
C19H18N3O: 304.1450; found: 304.1451.
4.4.1.11. 1-((1-(4-Fluorophenyl)-1H-pyrazol-3-yl)methyl)-1H-indole 9f
Yield: 26 mg (20%); light yellow solid. Mp 94-96 °C; Rf = 0.63 (n-hexane-EtOAc, 1:1). IR (KBr): 3442,
1647, 1533, 1510, 1464, 1429, 1392, 1330, 1315, 1238, 1188, 1097, 1051, 1043, 1009, 952, 838, 755
cm−1. 1H NMR (250 MHz, CDCl3): δ = 7.60 (d, J = 2.5 Hz, 1H), 7.57-7.48 (m, 3H), 7.37 (d, J = 8.7 Hz,

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1H), 7.15-7.00 (m, 5H), 6.46 (dd, J = 3.2, 0.7 Hz, 1H, Hc), 6.03 (d, J = 2.2 Hz, 1H, Hb), 5.31 (s, 2H,
Ha). 13C NMR (125.7 MHz, CDCl3): δ = 161.1 (d, J = 246.3 Hz, C-F), 150.9, 136.4, 136.3, 136.2, 128.7,
128.1, 128.0, 121.6, 121.0, 120.9, 119.5, 116.3, 116.2, 109.7, 106.5, 101.7, 44.2 (one quaternary
coincident). HRMS: m/z (ESI-TOF, [M+H]+) calcd for C18H15FN3: 292.1250. Found: 292.1249.
4.4.1.12. 1-((1-(4-Fluorophenyl)-1H-pyrazol-4-yl)methyl)-1H-indole 10f
Yield: 14 mg (10%); yellow oil. Rf = 0.44 (n-hexane-EtOAc, 1:1). IR (KBr): 3442, 1642, 1516, 1485,
1
1462, 1400, 1313, 1264, 1228, 1153, 1097, 1035, 1010, 954, 835, 815, 738 cm−1. H NMR (250 MHz,
CDCl3): δ = 7.59 (t, J = 1.0 Hz, 1H), 7.53 (d, J = 3.0 Hz, 2H), 7.50-7.40 (m, 2H), 7.30 (d, J = 8.2 Hz,
1H), 7.17–7.11 (td, J = 8.2, 7.0, 2.2 Hz, 2H), 7.09–6.96 (m, 3H), 6.46 (dd, J = 3.0, 0.7 Hz, 1H, Hb),
5.18 (s, 2H, Ha). 13C NMR (125 MHz, CDCl3): δ = 161.1 (d, J = 244.6 Hz, C-F), 140.0, 136.2, 135.9,
127.5, 125.5, 121.8, 121.1, 120.9, 120.8, 119.6, 116.2, 116.1, 109.4, 101.8, 40.8. HRMS: m/z (ESI-TOF,
[M+H]+) calcd for C18H15FN3: 292.1250. Found: 292.1248.
4.4.1.13. 1-((1-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-3-yl)methyl)-1H-indole 9g
Yield: 32 mg (20%); white solid. Mp 121-123 °C; Rf = 0.58 (n-hexane-EtOAc, 1:1). IR (KBr): 3431,
1631, 1529, 1504, 1462, 1384, 1334, 1313, 1265, 1249, 1109, 1037, 934, 875, 739 cm−1. 1H NMR (400
MHz, CDCl3): δ = 7.56 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.15-7.09
(m, 3H), 7.02 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.4, 2.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.45 (d, J =
13
3.2 Hz, 1H, Hc), 5.99 (d, J = 2.4 Hz, 1H, Hb), 5.92 (s, 2H, OCH2O), 5.29 (s, 2H, Ha). C NMR (100
MHz, CDCl3): δ = 150.8, 148.8, 146.7, 136.6, 135.3, 129.1, 128.6, 128.4, 122.0, 121.3, 119.9, 112.9,
110.1, 108.7, 106.5, 102.3, 102.2, 102.1, 44.6. HRMS: m/z (ESI-TOF, [M+H]+) calcd for C19H16N3O2:
318.1243. Found: 318.1242.
4.4.1.14. 1-((1-(Benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-4-yl)methyl)-1H-indole 10g
Yield: 16 mg (10%); brown oil. Rf = 0.45 (n-hexane-EtOAc, 1:1). IR (KBr): 3442, 1642, 1508, 1464,
1396, 1334, 1311, 1265, 1247, 1201, 1105, 1037, 966, 935, 881, 802, 738 cm−1. 1H NMR (400 MHz,

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CDCl3): δ = 7.57 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.17-7.02 (m,
4H), 6.90 (dd, J = 8.4, 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.46 (dd, J = 3.2, 0.7 Hz, 1H, Hb), 5.92 (s,
2H), 5.18 (s, 2H, Ha). 13C NMR (100 MHz, CDCl3): δ = 148.7, 146.7, 140.0, 136.3, 135.2, 129.1, 127.9,
126.1, 122.1, 121.5, 120.1, 120.0, 112.9, 109.8, 108.6, 102.2, 102.1, 101.9, 41.2. HRMS:m/z (ESI-TOF,
[M+H]+) calcd for C19H16N3O2: 318.1243; found: 318.1238.
Acknowledgments
We are grateful to the referees for helpful and supportive comments. TÜBİTAK (Turkish Scientific and
Technological Research Council, grant no. 211T037) and Abant İzzet Baysal University, Directorate of
Research Projects Commission (BAP grant no. 2011.03.03.377) are gratefully acknowledged for
financial support.
References
1. Earl, J. C.; Mackney, A. W. J. Chem. Soc. 1935, 899-900.
2. Azarifar, D.; Bosra, H. G.; Zolfigol,M.-A.; Tajbaksh, M. Heterocycles 2006, 68, 175-181.
3. Browne, D. L.; Harrity, J. P. A. Tetrahedron 2010, 66, 553-568; Ollis, W. D.; Ramsden, C. A. Adv.
Heterocycl. Chem. 1976, 19, 1-122.
4. Foster, R. S.; Adams, H.; Jakobi, H.; Harrity, J. P. A. J. Org. Chem. 2013, 78, 4049-4064 and
references therein. Delaunay, T.; Genix, P.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Org.
Lett. 2010, 12, 3328-3331.
5. Takayuki, N.; Susumu, N.; Kiyoshi,T.; Kenji, M.; Kei-Ichi, F. Hiroshi, K. J. Antibiotics 1968, 21,
300-305.
6. Upadhya, K. G.; Badami, B.V.; Puranik, G. S. Arch. Pharm.(Weinheim) 1980, 313, 684-688.

ACCEPTED MANUSCRIPT
23
7. (a) Lamberth, C. Heterocycles 2007, 71, 1467-1502; (b) Eicher,T.; Hauptmann, S.; Speicher, A.
(Eds.), The Chemistry of Heterocycles, 2nd Ed., Wiley, New York, 2003, p 179.
8. Adams, J. L.; Gallagher, T.; Osifo, I. K. PCT Int. Appl WO9856377, 1998; Chem. Abstr. 1999, 130,
52415.
9. Fink, B. E.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999,
6, 205-219.
10. Tsuji, K.; Nakamura, K.; Konishi, N.; Tojo, T.; Ochi, T.; Senoh, H.; Matsuo, M. Chem. Pharm. Bull.
1997, 45, 987-995.
11. Kudo, N.; Furuta, S.; Tanigushi, M.; Endo, T.; Sato, K. Chem. Pharm. Bull. 1999, 47, 857-868.
12. Yıldırım, M.; Dürüst, Y. Tetrahedron 2011, 67, 3209-3215.
13. Dürüst, Y.; Yıldırım, M.; Fronczek, C. F.; Fronczek, F. R. Monatsh. Chem. 2012, 143, 127-138.
14. Dürüst, Y.; Sağırlı, A.; Fronczek, F. R. Mol. Divers. 2011, 15, 799-808.
15. Dürüst, Y.; Karakuş¸ H. ; Kaiser, M.; Tasdemir, D. Eur. J. Med. Chem. 2012, 48, 296-304.
16. Kim, S. H.; Tran, M. T.; Ruebsam, F.; Xiang, A. X.; Ayida, B.; McGuire, H.; Ellis, D.; Blazel, J.;
Tran, C. V.; Murphy, D. E.; Webber, S. E.; Zhou, Y. F.; Shah, A. M.; Tsan, M.; Showalter, R. E.; Patel,
R.; Gobbi, A.; LeBrun, L. A.; Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.; Sergeeva, M. V.;
Kirkovsky, L.; Zhao, Q.; Han, Q.; Kissinger, C.R. Bioorg. Med. Chem. Lett. 2008, 18, 4181-4185.
17. Chen, K-X.; Xie, H-Y.; Li, Z-G. Acta Chim. Slov. 2009, 56, 684-693.
18. Villar, R.; Encio, I.; Migliaccio, M.; Gil, M. J.; Martinez-Merino, V. Bioorg. Med. Chem. 2004, 12,
963-968.

ACCEPTED MANUSCRIPT
24
19. Lakshmi, N. V.; Thirumurugan, P.; Jayakumar, C.; Perumal, T. P. Synlett 2010, 955-961.
20. Sauter, F.; Büyük, G.; Jordis, U. Monatsh. Chem. 1974, 105, 869-876.
21. Geneste, P.; Durand, R.; Pioch, D. Tetrahedron Lett. 1979, 4845-4847.
22. Mothe , S. R.; Chan, P. W. H. J. Org. Chem. 2009, 74, 5887-5893.
23. Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Eur. J. Org. Chem. 2004, 695-709.
24. Carrillo, J. R.; Cossio, F. P.; Diaz-Ortiz, A.; Gomez-Escalonilla, M. J.; de la Hoz, A.; Lecea, B.;
Moreno, A.; Prieto, P. Tetrahedron 2001, 57, 4179-4187.
25. Teo, Y.-C.; Yong, .F.-F.; Lim, G. S. Tetrahedron Lett. 2011, 52, 7171-7174.
26. Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 8535-8538.
27. Begtrup, M.; Vedso, P.; Cabildo, P.; Claramunt, R. M.; Elguero, J.; Meutermans, W. Magn. Reson.
Chem. 1992, 30, 455-459.
28. Perrez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Gonzalez-Perez, P.; Perez-Castells, J. Synthesis
2002, 1810-1812.
29. Dadiboyena, S.; Nefzi, A. Eur. J. Med. Chem. 2011, 46, 5258-5275.
30. Delaunay, T.; Es-Sayed, M.; Vors, J.-P.; Monteiro, N.; Balme, G. Eur. J. Org. Chem. 2011, 3837-
3848.
31. Munoz, M. P.; Maria, C.; Sierra, M. A.; Chem. Eur. J. 2012, 18, 4499-4504.
32. Samsoniya, Sh. A.; Ésakiya, N. A.; Suvorov, N. N. Chem.Heterocycl. Compd. 1991, 27, 366-369.