Facile synthesis of alkynyl-, aryl- and ferrocenyl-substituted pyrazoles via Sonogashira and Suzuki–Miyaura approaches

Article abstract of DOI:10.1002/aoc.3516

A concise and efficient synthesis of densely substituted novel pyrazoles with alkynyl, aryl and ferrocenyl functionalities is reported, providing a platform for biological studies. The general strategy involves Sonogashira and Suzuki–Miyaura cross-couplin

Full text of DOI:10.1002/aoc.3516

Full paper
Received: 12 December 2015
Revised: 16 April 2016
Accepted: 20 April 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3516
Facile synthesis of alkynyl-, aryl- and ferrocenyl-
substituted pyrazoles via Sonogashira and
Suzuki–Miyaura approaches
Sedef Karabiyikoglu and Metin Zora*
A concise and efficient synthesis of densely substituted novel pyrazoles with alkynyl, aryl and ferrocenyl functionalities is
reported, providing a platform for biological studies. The general strategy involves Sonogashira and Suzuki–Miyaura cross-
coupling reactions of easily obtainable 5-ferrocenyl/phenyl-4-iodo-1-phenylpyrazoles with terminal alkynes and boronic acids,
respectively. The starting 4-iodopyrazoles were synthesized by electrophilic cyclization of α,β-alkynic hydrazones with molecular
iodine. Sonogashira reactions have been achieved by employing 5 mol% PdCl2(PPh3)2, 5 mol% CuI, excess Et3N and 1.2 equiv. of
terminal alkyne, relative to 4-iodopyrazole, in tetrahydrofuran at 65 °C, while Suzuki–Miyaura reactions have been accomplished
using 5 mol% PdCl2(PPh3)2 and 1.4 equiv. of both boronic acid/ester and KHCO3, with respect to 4-iodopyrazole, in 4:1
dimethylformamide–H2O solution at 110 °C. Both Sonogashira and Suzuki–Miyaura coupling reactions have proven effective
for the synthesis of alkynyl-, aryl- and ferrocenyl-substituted pyrazoles and demonstrated good tolerance to a diverse range of
substituents, including electron-donating and electron-withdrawing groups. These coupling approaches could allow for the rapid
construction of a library of functionalized pyrazoles of pharmacological interest. Copyright © 2016 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web site.
Keywords: pyrazole; ferrocene; alkyne; boronic acid; coupling
ketones, reactions of pyrazolylketones with PCl5 followed by a base
Introduction
and metal-catalysed cross-coupling of halogenopyrazoles with
terminal alkynes (known as Sonogashira reaction).[23,24]
Pyrazoles represent an important class of nitrogen-containing five-
membered heterocycles,[1] which have occupied a unique position
Arylpyrazoles, particularly 1,5-diaryl-substituted pyrazoles, are
in the design and synthesis of novel biologically active agents that
exhibit remarkable medicinal activities.[2] In fact, pyrazoles have a
profound effect on human health since they are present in a wide
range of natural products and drugs used to battle a large number
of diseases and pathophysiological conditions.[3] It has been re-
ported that pyrazoles possess a broad spectrum of pharmacological
and biological properties such as anti-bacterial,[4] anti-depressant,[5]
anti-hyperglycaemic,[6] anti-hypertensive,[7] anti-inflammatory[8]
and antitumor[9] properties. In addition, pyrazoles exist as promi-
nent building blocks in the structures of various leading drugs
(e.g. Celebrex,[10] Viagra[11] and Zometapine[12]) and pesticides
(e.g. Cyenopyrafen,[13] Fenpyroximate[14] and Tebufenpyrad[15]).
In particular, alkynyl-, aryl- and ferrocenyl-substituted pyrazoles
have attracted considerable attention due to their broad spectrum
of biological and pharmaceutical activities. Alkynylpyrazoles are
particularly important for their anti-inflammatory,[16,17] antiviral[18]
and muscarinic[19] properties and cyclooxygenase,[20] 5-lipoxy-
genase,[20] HIV protease[21] and phosphodiesterase[22] inhibitory
activities. They are also highly valuable substrates in organic
syntheses since their triple bonds are very prone to undergo a
variety of reactions, including nucleophilic, electrophilic, radical,
and cycloaddition reactions, allowing further functionalization of
pyrazole derivatives.[23] Alkynylpyrazoles are commonly synthe-
sized by 1,3-dipolar cycloaddition of diazomethane with
1,3-butadiynes, cycloaddition of hydrazines with diacetylenic
especially useful for the treatment of inflammation and
inflammation-connected disorders, including arthritis, as well as
cardiovascular disorders.[25] They are also heat shock protein 90
(HSP90) inhibitors and can be used in the treatment of conditions
mediated by HSP90, including cancer.[26] In addition, they are
potent CCR2 receptor antagonists.[27] Arylpyrazoles are typically
synthesized by the reaction of phenylhydrazine with 1,3-dicarbonyl
compounds or their 1,3-dielectrophilic equivalents including
alkynals and alkynones, 1,3-dipolar cycloaddition of diazoalkanes
and nitrilimines with alkenes and alkynes, and metal-catalysed
cross-coupling of halogenopyrazoles with boronic acids (called
Suzuki–Miyaura reaction).[28,29]
It is noteworthy that owing to its unique structure, membrane-
permeation properties and anomalous metabolism, ferrocene is of-
ten integrated into biologically active molecules to enhance their
potency or generate new medicinal properties.[30] Indeed, many
ferrocene derivatives have proved to be particularly active against
a number of animal and human tumours.[30] In this regard, func-
tionally substituted ferrocenylpyrazoles have great potential for
*
Correspondence to: Metin Zora, Department of Chemistry, Middle East Technical
University, 06800 Ankara, Turkey. E-mail: zora@metu.edu.tr
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.

Karabiyikoglu S. and Zora M.
biological studies and it is crucial to provide new methodologies for
their construction.[31]
afforded Z and E isomers of hydrazone 3 in 54 and 36% yields,
respectively. On the other hand, the same reaction with
phenylpropargyl aldehyde (2) yielded Z isomer of hydrazone 4 as
the major product (81%); the isolation of the minor E isomer was
not attempted as it was not adequately stable and mostly
converted into Z isomer during purification. We next carried out
electrophilic cyclizations of hydrazones 3 and 4 using I2 in the pre-
sence of sodium bicarbonate. When reacted with molecular iodine,
Z and E isomers of hydrazone 3 afforded ferrocenyl-substituted
4-iodopyrazole 5 in 90 and 92% yields, respectively. Iodocyclization
Recently, we have reported the synthesis of α,β-alkynic
hydrazones 3 and 4 from propargyl aldehydes 1 and 2, and their
regioselective conversion into pyrazoles 5 and 6, respectively
(Scheme 1).[32] When treated with molecular iodine in the presence
of sodium bicarbonate, α,β-alkynic hydrazones 3 and 4 undergo
electrophilic cyclization and afford ferrocenyl- and phenyl-
substituted 4-iodopyrazole derivatives 5 and 6, respectively, in high
yields. It is noteworthy that iodine-containing pyrazoles are very
important building blocks for the synthesis of diverse natural pro-
ducts and pharmaceuticals since they can be easily elaborated to
more complex structures by metal-catalysed cross-coupling
reactions. In this regard, Sonogashira[33] and Suzuki–Miyaura[34]
reactions are among the most widely used C–C bond forming reac-
tions, providing efficient routes to alkynylaryl and biaryl
compounds, respectively. In particular, they provide rapid entries
to the libraries of alkynylpyrazoles[35] and biarylpyrazoles.[29]
It has been concluded from structure–activity relationships that
the number of substituents, such as aryl groups, attached to a
potentially bioactive core plays an important role in biological
activities.[36] For instance, the corresponding pyridine derivatives
bearing more aryl groups exhibit stronger biological activity as
compared to those containing fewer aryl groups.[36] Notably, an
increase in the number of substituents via introduction of alkynyl
and aryl functionalities into ferrocenylpyrazoles could result in
beneficial biological properties. We have anticipated that the deco-
ration of a pyrazole core with such functionalities may provide
novel derivatives with much enhanced or totally new medicinal
properties. Although pyrazoles are among the most intensely
studied compounds, to the best of our knowledge, 4-alkynyl/aryl-
5-ferrocenyl-substituted pyrazole derivatives are not known. Our
continued interest[37] in the synthesis of new carbocyclic, heterocy-
clic and ferrocenyl compounds as potential pharmaceuticals and
scaffolds has prompted us to investigate the Sonogashira and
Suzuki–Miyaura cross-coupling reactions of 4-iodopyrazoles 5
and/or 6 with terminal alkynes and boronic acids, respectively.
We herein report the full details of this study.
of
Z isomer of hydrazone 4 produced phenyl-substituted
4-iodopyrazole 6 in 80% yield (Scheme 1).[32]
Subsequently, we investigated the feasibility of metal-catalysed
cross-coupling of 4-iodopyrazoles 5 and 6 with terminal alkynes.
Although there are many possibilities for the choice of catalyst,
co-catalyst and base, one of the most common catalytic systems
for Sonogashira reaction consists of a relatively cheap and highly
stable palladium(II)–triphenylphosphine complex with CuI in an
excess of amine.[33] Accordingly, we chose PdCl2(PPh3)2 as catalyst,
CuI as co-catalyst and Et3N as base. The reactions were carried out
with 5 mol% PdCl2(PPh3)2 and 5 mol% CuI. During the course of
such reactions, in situ generation of copper acetylide could yield
homocoupling product of terminal alkyne when it was exposed
to excessive oxidative agents like oxygen. In order to eliminate
the homocoupling, reactions were run under argon atmosphere
and terminal alkynes were added slowly to the reaction medium
in small portions. This prevented the need for high equivalents of
alkyne; thus, relative to starting 4-iodopyrazole, only 1.2 equiv. of
terminal alkynes was used. Initially, the reaction of 5-ferrocenyl-4-
iodopyrazole 5 with phenylacetylene (7a) was examined (Table 1,
entry 1). The reaction was first performed in tetrahydrofuran
(THF) and dimethylformamide (DMF) at room temperature, but
these reactions did not produce desired products and appro-
ximately 95% of the starting 4-iodopyrazole 5 was recovered with
some decomposition. However, the same reaction in refluxing THF
at 65 °C for 12 h afforded 4-alkynylpyrazole 8a in 66% yield. When
the reaction was conducted in DMF at 110 °C for 12 h, product for-
mation was not observed and 85% of the starting 4-iodopyrazole 5
was recovered along with some decomposition products. After
setting reaction solvent and temperature (THF, 65 °C), the
transformation was tested for 4, 6 and 27 h, which yielded 4-
alkynylpyrazole 8a in 55, 64 and 66% yields, respectively, indicat-
ing that longer reaction time (27 h) did not improve the yield of
8a (66%). Although the reaction time for this particular case was
around 12 h, the reactions with other terminal alkynes required
less or more time as indicated by TLC analyses. In summary, the
reactions were performed in refluxing THF at 65 °C by frequent
TLC monitoring for completion. Results from a systematic study
are given in Table 1.
Results and Discussion
We first prepared the required 4-iodopyrazoles 5 and 6 from the
corresponding propargyl aldehydes 1 and 2 according to our
previous study as shown in Scheme 1.[32] The neat reaction of
ferrocenylpropargyl aldehyde (1) with phenylhydrazine at 80 °C
As evident from Table 1, Sonogashira cross-coupling reactions of
5 were carried out with a variety of terminal alkynes including aryl,
heteroaryl, cycloalkyl and ferrocenyl groups as the alkyne substi-
tuent (Table 1, entries 1–8). All reactions produced 4-alkynyl-5-
ferrocenyl-substituted pyrazole derivatives 8a–h, the yields of
which ranged from 37 to 78%. Notably, the couplings with terminal
alkynes 7e and 7f, bearing alcohol and amine functionalities,
resulted in the formation of the corresponding pyrazole derivatives
8e and 8f, respectively, in good yields (Table 1, entries 5 and 6). By
these Sonogashira reactions, thiophenyl-containing pyrazole 8g
and two-ferrocenyl-bearing pyrazole 8h were also synthesized in
good yields (Table 1, entries 7 and 8). We also carried out the
Scheme 1. Synthesis of 4-iodo-substituted pyrazoles.
cross-coupling reactions of 4-iodo-5-phenylpyrazole 6 with
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Novel alkynyl-, aryl- and ferrocenyl-substituted pyrazoles
Table 1. Synthesis of 4-alkynylpyrazoles from 4-iodopyrazoles
Entry
R1
R2
Time (h)
Product
Yield (%)a
, ,
1b c d
R1 = Fc (5)
R2 = Ph (7a)
12
25
8
8a
8b
8c
8d
8e
8f
66
37
78
44
70
68
62
68
42
36
76
85
54
2
5
R2 = 4-MePh (7b)
3
5
R2 = 4-MeOPh (7c)
4
5
R2 = 4-(Me2N)Ph (7d)
15
14
20
18
12
15
24
16
7
5
5
R2 = 1-hydroxycyclohex-1-yl (7e)
6
5
R2 = 1-aminocyclohex-1-yl (7f)
7
5
R2 = 3-thienyl (7g)
8g
8h
9a
9b
9c
9d
9e
8
5
R2 = Fc (7h)
9
R1 = Ph (6)
7a
7b
7c
7g
7h
10
11
12
13
6
6
6
6
13
aYields are of isolated products.
bWhen the reaction was performed in THF or DMF at room temperature, it did not produce any products and 95% of the starting 4-iodopyrazole 5 was
recovered with some decomposition.
cWhen the reaction was performed in DMF at 110 °C, it did not produce any products and 85% of the starting 4-iodopyrazole 5 was recovered along with
some decomposition.
dWhen the reaction was performed in THF at 65 °C for 4, 6 and 27 h, it afforded 4-alkynylpyrazole 8a in 55, 64 and 66% yields, respectively.
terminal alkynes under same conditions (Table 1, entries 9–13).
These reactions afforded the corresponding 4-alkynyl-5-
phenylpyrazoles 9 in yields ranging from 36 to 85%. In these
reactions, the highest yield (85%) was obtained for the pyrazole
9d bearing a thiophenyl group as the alkyne substituent (Table 1,
entry 12). For the pyrazole derivatives containing the same alkynyl
group, the yields of 4-alkynyl-5-arylpyrazoles were slightly lower
than those of 4-alkynyl-5-ferrocenylpyrazoles except the case of
thiophen-3-ylethynyl group. In brief, the coupling reaction was
general for a diversity of terminal alkynes and tolerated the
presence of aryl, heteroaryl, ferrocenyl and cycloalkyl groups with
electron-withdrawing and electron-donating substituents.
Next, we investigated metal-catalysed coupling reactions of
4-iodopyrazole 5 with boronic acids. It is worth mentioning that
Suzuki–Miyaura reactions have been tested previously with a large
number of solvents, bases and palladium catalysts.[34] Our literature
search revealed that bases in bicarbonate salt form and palladium
catalysts with triphenylphosphine ligands, especially PdCl2(PPh3)2,
work quite effectively in these reactions. In addition, DMF–H2O
combination is one of the most widely used solvent systems in such
reactions.[38] In the light of this knowledge, the condition involving
PdCl2(PPh3)2 as catalyst, KHCO3 as base and 4:1 DMF–H2O as
solvent system was adapted for our Suzuki–Miyaura coupling
reactions. The reactions were performed with 5 mol% PdCl2
(PPh3)2 and 1.4 equiv. of both boronic acid/ester and KHCO3, with
respect to starting 4-iodopyrazole, and by heating at 110 °C. Results
from a systematic study are summarized in Table 2. Initially, the
cross-coupling of 5 was carried out with both phenylboronic acid
(10a) and phenylboronic acid pinacol ester (11a) (Table 2, entries
1 and 2). These reactions afforded the corresponding pyrazole
12a in 72 and 80% yields, respectively. Although boronic ester
11a gave a higher yield of 12a, we preferred to use boronic acids
in other couplings because they are cheaper and more readily avail-
able than boronic esters. As evident from Table 2, the coupling re-
actions were all successful and produced the expected 4-aryl-
5-ferrocenylpyrazole derivatives 12 in good to excellent yields in
most cases. The lowest yield (42%) was obtained for 4-(1H-indol-
6-yl)pyrazole (12e) while the highest yield (99%) was observed for
4-(3-nitrophenyl)pyrazole (12k) (Table 2, entries 6 and 12). Since
the introduction of fluorine-bearing substituents into organic
compounds could result in beneficial biological properties,[39] two
derivatives of fluorine-containing pyrazoles, 12g and 12h, were
synthesized (Table 2, entries 8 and 9). For the same reason,
indole-containing pyrazole derivative 12e was synthesized because
indoles are very important for pharmaceutical and agricultural
applications (Table 2, entry 6).[40] It is noteworthy that during the
reactions, homocoupling of arylboronic acids was not observed
since the experiments were carried out under argon atmosphere
to prevent oxidative homocoupling of boronic acids.[41] Moreover,
according to literature studies,[41] the use of a palladium catalyst
with triphenylphosphine ligands, instead of a palladium salt such
as PdCl2, could have an inhibiting effect on homocoupling of
arylboronic acids. In summary, the coupling reaction was found to
be general for a wide range of boronic acids and tolerated the
presence of aryl groups with electron-withdrawing and electron-
donating substituents. Moreover, Suzuki–Miyaura coupling
Appl. Organometal. Chem. (2016)
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Karabiyikoglu S. and Zora M.
Table 2. Synthesis of 4-arylpyrazoles from 4-iodopyrazoles
Moreover, the synthesized heterocycles have potential to act as
new pharmacophores and scaffolds in medicinal chemistry.
Experimental
General Information
1H NMR and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively. Chemical shifts (δ) are reported in parts per million
(ppm) downfield from an internal trimethylsilane (TMS) reference
or relative to CDCl3 (7.26 and 77.16 ppm in 1H NMR and 13C NMR,
respectively). Coupling constants (J) are reported in hertz (Hz),
and spin multiplicities are presented by the following symbols: s
(singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). DEPT 13C NMR information is given in parentheses as
C, CH, CH2 and CH3. Infrared (IR) spectra were recorded using
attenuated total reflection. Band positions are reported in recipro-
cal centimetres (cmÀ1). MS and high resolution MS (HRMS) were
conducted using electrospray ionization (ESI) with Micro-Tof; m/z
values are reported (for each measurement, the mass scale was
recalibrated with sodium formate clusters, and samples were
dissolved and measured in MeOH or CH3CN). Flash chromatogra-
phy was performed using thick-walled glass columns and ‘flash
grade’ silica (230–400 mesh). TLC was performed using commer-
cially prepared 0.25 mm silica gel plates and visualization was
effected with a short-wavelength UV lamp (254 nm). The relative
proportions of solvents in chromatography solvent mixtures refer
to the volume-to-volume ratio. All commercially available reagents
were used directly without purification unless otherwise stated. All
the solvents used in reactions were distilled for purity. An inert
atmosphere was created by slight positive pressure (ca 0.1 psi) of
argon. All glassware was dried in an oven prior to use. The starting
4-iodopyrazoles 5 and 6 were synthesized according to a previous
study.[32]
Entry
R
Time Product Yield
(h)
(%)a
1
2
3
4
R = Ph (10a)
R = Ph (11a)
4
6
5
7
12a
12a
12b
12c
72
80
65
52
R = 4-EtPh (10b)
R = benzo[d] [1,3]dioxol-5-yl
(10c)
5
R = 3,4,5-trimethoxyphenyl
(10d)
5
12d
78
6
7
8
R = 1H-indole-5-yl (10e)
R = 4-ClPh (10f)
13
6
12e
12f
42
91
80
R = 4-ethoxy-3-
4
12g
fluorophenyl (10g)
R = 3,4,5-trifluorophenyl
(10h)
9
5
5
12h
12i
95
93
10
R = 3-(ethoxycarbonyl)phenyl
(10i)
11
12
R = 2-methoxypyridin-5-yl (10j)
R = 3-NO2Ph (10k)
4
6
12j
94
99
12k
aYields are of isolated products.
reactions of 4-iodopyrazoles (Table 2) usually required shorter
reaction times as compared to their corresponding Sonogashira
coupling reactions (Table 1).
General Procedure for Synthesis of 4-Alkynylpyrazoles 8 and 9
via Sonogashira Coupling Reaction (Table 1)
Conclusions
In a two-neck round-bottom flask equipped with a reflux
condenser, 4-iodopyrazole 5 or 6 (0.220 mmol), PdCl2(PPh3)2
(7.73 mg, 0.011 mmol) and CuI (2.09 mg, 0.011 mmol) were
dissolved in a mixture of triethylamine (1.6 ml) and THF (1 ml) by
vigorous stirring under argon. Meanwhile, separately in a flask
under argon, the corresponding terminal alkyne 7 (0.264 mmol)
was dissolved in THF (1 ml) and added slowly to the first reaction
flask over 1 h. The resulting reaction mixture was then heated to
reflux (65 °C) with stirring. This was continued until TLC revealed
the completion of the reaction. After the reaction was over, the
solvent was evaporated using a rotary evaporator. Crude product
was purified by flash chromatography on silica gel using hexane–
ethyl acetate (9:1) as the eluent, which afforded the corresponding
4-alkynylpyrazole 8 or 9 with yield indicated in Table 1.
In summary, we investigated the Sonogashira and Suzuki–Miyaura
cross-coupling reactions of ferrocenyl- and phenyl-substituted
4-iodopyrazoles, prepared by electrophilic cyclization of the
corresponding α,β-alkynic hydrazones with molecular iodine in
the presence of sodium bicarbonate. Sonogashira reactions of
4-iodopyrazoles were accomplished by employing 5 mol% PdCl2
(PPh3)2, 5 mol% CuI, excess Et3N and 1.2 equiv. of terminal alkyne,
relative to 4-iodopyrazole, in refluxing THF at 65 °C. From these re-
actions, 4-alkynylpyrazoles were formed in 36 to 85% yields. Nota-
bly, in most cases with the same terminal alkyne, 5-ferrocenyl-4-
iodopyrazole yielded the corresponding 4-alkynylpyrazole in higher
yield as compared to 4-iodo-5-phenylpyrazole. On the other hand,
Suzuki–Miyaura reactions of 4-iodopyrazoles were achieved by
using 5 mol% PdCl2(PPh3)2 and 1.4 equiv. of both boronic
acid/ester and KHCO3, with respect to 4-iodopyrazole, in 4:1 DMF–
H2O solution at 110 °C. These reactions produced 4-arylpyrazoles
in 42 to 99% yields. Notably, Suzuki–Miyaura coupling reactions of
4-iodopyrazoles went to completion in shorter times than their
corresponding Sonogashira coupling reactions. Both coupling
reactions were found to be general for a diverse range of substrates
including electron-withdrawing and electron-donating substi-
tuents. In conclusion, the chemistry developed here is very versatile
and practical and accommodates various functional groups.
5-Ferrocenyl-1-phenyl-4-(phenylethynyl)-1H-pyrazole (8a)
1H NMR (CDCl3): 7.73 (s, 1H in pyrazole), 7.56–7.54 (m, 2H, Ph),
7.35–7.25 (m, 8H, Ph), 4.40 (br s, 2H, Fc), 4.14 (br s, 2H, Fc), 4.04 (s,
5H, Fc). 13C NMR (CDCl3): 143.6 (C–N in Ph), 143.5 (CH in pyrazole),
140.4 (C in pyrazole attached to Fc), 131.2 (CH, Ph), 129.0 (CH, Ph),
128.6 (CH, Ph), 128.5 (CH, Ph), 128.0 (CH, Ph), 126.6 (CH, Ph), 124.0
(C, Ph), 102.5 (C in pyrazole attached to alkyne), 93.4 (C in CꢀC
attached to Ph), 82.9 (C in CꢀC attached to pyrazole), 73.1 (C, Fc),
70.0 (CH, Fc), 68.9 (CH, Fc), 68.6 (CH, Fc). IR (neat): 3729 (m), 3698
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Novel alkynyl-, aryl- and ferrocenyl-substituted pyrazoles
56
25
(m), 3054 (w), 2228 (vw), 1554 (m), 1495 (s), 1398 (m), 859 (m), 762
(s), 693 (s). Anal. Calcd for C27H20FeN2 (%): C, 75.71; H, 4.71; N, 6.54.
Found (%): C, 75.56; H, 4.67; N, 6.53; MS (ESI, m/z): 451.09 [M + Na]+,
[M + H]+, found: 472.1443; calcd for C29H FeN3: 471.1398 [M]+,
found: 471.1389.
1-((5-Ferrocenyl-1-phenyl-1H-pyrazol-4-yl)ethynyl)cyclohexanol (8e)
428.09 [M]+. HRMS (ESI): calcd for C27H FeN2Na: 451.0874
56
20
[M + Na]+, found: 451.0868; calcd for C27H FeN2: 428.0976 [M]+,
1H NMR (CDCl3): 7.65 (s, 1H in pyrazole), 7.38–7.37 (m, 3H, Ph), 7.29–
7.27 (m, 2H, Ph), 4.40 (s, 2H, Fc), 4.16 (s, 2H, Fc), 4.08 (s, 5H, Fc), 2.24
(br s, 1H, OH), 2.07–2.02 (m, 2H in C6H10), 1.74–1.53 (m, 6H in C6H10),
1.56–1.55 (m, 1H in C6H10), 1.35–1.25 (m, 1H in C6H10). 13C NMR
(CDCl3): 143.8 (CH in pyrazole), 143.4 (C–N in Ph), 140.5 (C in
pyrazole attached to Fc), 129.1 (CH, Ph), 128.7 (CH, Ph), 126.8 (CH,
Ph), 101.8 (C in pyrazole attached to alkyne), 97.1 (C in CꢀC
attached to C6H10), 73.2 (C, Fc), 70.2 (CH, Fc), 69.3 (C in CꢀC
attached to pyrazole), 69.0 (CH, Fc), 68.5 (CH, Fc), 40.1 (CH2 overlap-
ping with C(OH) in C6H10), 25.3 (CH2), 23.3 (CH2). IR (neat): 3725 (w),
3354 (br), 3095 (w), 2930 (vs), 2854 (m), 2218 (w), 1736 (m), 1596
(m), 1505 (s), 1402 (s), 1381 (s), 1255 (m), 1067 (s), 966 (s), 767 (s),
693 (s). Anal. Calcd for C27H26FeN2O (%): C, 72.01; H, 5.82; N, 6.22.
Found (%): C, 71.99; H, 5.92; N, 5.80. MS (ESI, m/z): 449.16
56
20
found: 428.0971.
5-Ferrocenyl-1-phenyl-4-(p-tolylethynyl)-1H-pyrazole (8b)
1H NMR (CDCl3): 7.84 (s, 1H in pyrazole), 7.55 (d, 2H, J = 7.9 Hz in
tolyl), 7.48–7.46 (m, 3H, Ph), 7.41–7.39 (m, 2H, Ph), 7.25 (d, 2H,
J = 7.9 Hz in tolyl), 4.56 (s, 2H, Fc), 4.29 (s, 2H, Fc), 4.20 (s, 5H, Fc),
2.44 (s, 3H, CH3). 13C NMR (CDCl3): 143.4 (C–N in Ph), 143.3 (CH in
pyrazole), 140.4 (C in pyrazole attached to Fc), 138.2 (C in tolyl
attached to CH3), 131.1 (CH, Ph), 129.3 (CH, Ph), 129.0 (CH, Ph),
128.5 (CH, Ph), 126.5 (CH, Ph), 121.0 (C, Ph), 102.8 (C in pyrazole
attached to alkyne), 93.5 (C in CꢀC attached to tolyl), 82.0 (C in
CꢀC attached to pyrazole), 73.5 (C, Fc), 70.2 (CH, Fc) 69.0 (CH, Fc),
68.8 (CH, Fc), 21.6 (CH3). IR (neat): 3733 (m), 3698 (w), 3059 (vw),
2988 (br), 2916 (br), 1500 (s), 1398 (m), 1078 (w), 815 (m), 767 (m),
694 (m). Anal. Calcd for C28H22FeN2 (%): C, 76.03; H, 5.01; N, 6.33.
Found (%): C, 75.80; H, 5.39; N, 6.19. MS (ESI, m/z): 465.10
[M + H]+. HRMS (ESI): calcd for C27H FeN2O: 449.1514 [M + H]+,
54
27
found: 449.1554.
1-((5-Ferrocenyl-1-phenyl-1H-pyrazol-4-yl)ethynyl)cyclohexanamine (8f)
[M + Na]+, 442.11 [M]+. HRMS (ESI): calcd for C28H FeN2Na:
56
22
56
22
1H NMR (CDCl3): 7.63 (s, 1H in pyrazole), 7.38–7.36 (m, 3H, Ph),
7.29–7.26 (m, 2H, Ph), 4.38 (s, 2H, Fc), 4.12 (s, 2H, Fc), 4.03 (s, 5H,
Fc), 2.00–1.96 (m, 2H, NH2), 1.70–1.52 (m, 8H in C6H10), 1.28–1.15
(m, 2H in C6H10). 13C NMR (CDCl3): 143.9 (CH in pyrazole), 142.8
(C–N in phenyl), 140.6 (C in pyrazole attached to Fc), 129.1 (CH,
Ph), 128.7 (CH, Ph), 126.8 (CH, Ph), 102.2 (C in pyrazole attached to
alkyne), 75.8 (C in CꢀC attached to C6H10), 73.1 (C, Fc), 70.0 (CH,
Fc), 68.8 (CH, Fc), 68.2 (CH, Fc), 60.4 (C in CꢀC attached to pyrazole),
40.6 (C–NH2 in C6H10); 25.5 (CH2 in C6H10), 23.5 (CH2 in C6H10), 14.2
(CH2 in C6H10). IR (neat): 3284 (w), 3090 (w), 2927 (vs), 2852 (s), 2222
(w), 1596 (s), 1504 (s), 1381 (m), 1105 (m), 1001 (m), 967 (m), 817 (s),
766 (s), 693 (s). Anal. Calcd for C27H27FeN3 (%): C, 72.17; H, 6.06; N,
9.35. Found (%): C, 71.99; H, 6.21; N, 8.23. MS (ESI, m/z): 448.17
465.1030 [M + Na]+, found: 465.1025; calcd for C28H FeN2:
442.1132 [M]+, found: 442.1127.
5-Ferrocenyl-4-((4-methoxyphenyl)ethynyl)-1-phenyl-1H-pyrazole (8c)
1H NMR (CDCl3): 7.72 (s, 1H in pyrazole), 7.49 (d, 2H, J = 8.7 Hz in
methoxyphenyl), 7.36–7.35 (m, 3H, Ph), 7.29–7.27 (m, 2H, Ph), 6.87
(d, 2H, J = 8.7 Hz in methoxyphenyl), 4.41 (s, 2H, Fc), 4.16 (s, 2H,
Fc), 4.06 (s, 5H, Fc), 3.78 (s, 3H, OCH3). 13C NMR (CDCl3): 159.5 (C in
methoxyphenyl attached to OCH3), 143.4 (CH in pyrazole), 143.3
(C–N in Ph), 140.4 (C in pyrazole attached to Fc), 132.7 (CH in
methoxyphenyl), 129.0 (CH, Ph), 128.5 (CH, Ph), 126.5 (CH, Ph),
116.2 (C in methoxyphenyl), 114.3 (CH in methoxyphenyl), 102.9
(C in pyrazole attached to alkyne), 93.2 (C in CꢀC attached to
methoxyphenyl), 81.2 (C in CꢀC attached to pyrazole), 73.3 (C,
Fc), 70.0 (CH, Fc), 68.7 (CH, Fc), 68.6 (CH, Fc), 55.4 (OCH3). IR (neat):
3057(w), 2969 (w), 2839 (w), 1896 (vw), 1603 (s), 1498 (vs), 1398
(s), 1286 (s), 1245 (vs), 1175 (s), 1027 (s), 966 (s), 878 (m). Anal.
Calcd for C28H22FeN2O (%): C, 73.37; H, 4.84; N, 6.11. Found (%):
[M + H]+. HRMS (ESI): calcd for C27H FeN3: 448.1674 [M + H]+,
54
28
found: 448.1718.
5-Ferrocenyl-1-phenyl-4-(thiophen-3-ylethynyl)-1H-pyrazole (8g)
1H NMR (CDCl3): 7.72 (s, 1H in pyrazole), 7.50 (d, 1H, J = 2.3 Hz in
thiophene), 7.36–7.34 (m, 3H, Ph), 7.29–7.26 (m, 2H in phenyl
overlapping with 1H in thiophene), 7.20 (d, 1H, J = 4.8 Hz in
thiophene), 4.40 (s, 2H, Fc), 4.16 (s, 2H, Fc), 4.07 (s, 5H, Fc). 13C
NMR (CDCl3): 143.6 (C–N in Ph), 143.4 (CH in pyrazole), 140.3 (C in
pyrazole attached to Fc), 129.7 (CH, aromatic), 129.0 (CH, aromatic),
128.5 (CH, aromatic), 127.9 (CH, aromatic), 126.5 (CH, aromatic),
125.7 (CH, aromatic), 123.0 (C in thiophene), 102.5 (C in pyrazole
attached alkyne), 88.5 (C in CꢀC attached to thiophene), 82.1 (C
in CꢀC attached to pyrazole), 73.3 (C, Fc), 70.1 (CH, Fc), 69.0 (CH,
Fc), 68.7 (CH, Fc). IR (neat): 3725 (m), 3691 (m), 2988 (s), 2921 (s),
1489 (s), 1399 (m), 1063 (w), 867 (w), 777 (m), 753 (m), 687 (m).
Anal. Calcd for C25H18FeN2S (%): C, 69.13; H, 4.18; N, 6.45. Found
C, 73.19; H, 5.25; N, 6.20. MS (ESI, m/z): 481.09 [M + Na]+, 458.10
56
[M]+. HRMS (ESI): calcd for C28H FeN2ONa: 481.0979 [M + Na]+,
22
56
found: 481.0974; calcd for C28H FeN2O: 458.1082 [M]+, found:
22
458.1076.
4-((5-Ferrocenyl-1-phenyl-1H-pyrazol-4-yl)ethynyl)-N,N-dimethylaniline (8d)
1H NMR (CDCl3): 7.82 (s, 1H in pyrazole), 7.54 (d, 2H, J = 8.7 Hz in an-
iline), 7.47–7.44 (m, 3H, Ph), 7.39–7.37 (m, 2H, Ph), 6.77 (d, 2H,
J = 8.7 Hz in aniline), 4.54 (s, 2H, Fc), 4.25 (s, 2H, Fc), 4.18 (s, 5H,
Fc), 3.05 (s, 6H, N(CH3)2). 13C NMR (CDCl3): 150 (C in aniline attached
to N(CH3)2), 143.3 (CH in pyrazole), 142.9 (C–N in Ph), 140.5 (C in
pyrazole attached to Fc), 132.4 (CH in aniline), 129.0 (CH, Ph),
128.4 (C, Ph), 126.5 (CH, Ph), 112.1 (CH in aniline), 103.4 (C in
pyrazole attached to alkyne), 94.2 (C in CꢀC attached to Ph), 80.2
(C in CꢀC attached to pyrazole), 73.6 (C, Fc), 70.0 (CH, Fc), 68.7
(CH, Fc), 68.6 (CH, Fc), 40.3 (CH3 in N(CH3)2) (one aromatic carbon
peak is missing due to overlap). IR (neat): 3831 (w), 3722 (s), 3698
(m), 2988 (s), 2922 (s), 1744 (vw), 1599 (vw), 1219 (vw), 1066 (m),
796 (vw), 668 (m). Anal. Calcd for C29H25FeN3 (%): C, 73.89; H, 5.35;
N, 8.91. Found (%): C, 73.71; H, 4.64; N, 8.17. MS (ESI, m/z): 472.14
(%): C, 69.06; H, 4.45; N, 6.49. MS (ESI, m/z): 457.04 [M + Na]+,
56
434.05 [M]+. HRMS (ESI): calcd for C25H FeN2SNa: 457.0438
18
[M + Na]+, found: 457.0433; calcd for C25H FeN2S: 434.0540 [M]+,
56
18
found: 434.0535.
5-Ferrocenyl-4-(ferrocenylethynyl)-1-phenyl-1H-pyrazole (8h)
1H NMR (CDCl3): 7.69 (s, 1H in pyrazole), 7.35–7.27 (m, 5H, Ph), 4.54
(s, 2H, Fc), 4.44 (s, 2H, Fc), 4.28 (s, 5H, Fc), 4.25 (s, 2H, Fc), 4.17 (s, 2H,
Fc), 4.13 (s, 5H, Fc). 13C NMR (CDCl3): 143.4 (CH in pyrazole), 143.2
(C–N in Ph), 140.4 (C in pyrazole attached to Fc), 129.0 (CH, Ph),
[M + H]+, 471.13 [M]+. HRMS (ESI): calcd for C29H FeN3: 472.1476
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26
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Karabiyikoglu S. and Zora M.
1,5-Diphenyl-4-(thiophen-3-ylethynyl)-1H-pyrazole (9d)
128.5 (CH, Ph), 126.6 (CH, Ph), 103.2 (C in pyrazole attached to
alkyne), 92.0 (C in CꢀC attached to Fc), 78.8 (C in CꢀC attached
to pyrazole), 73.6 (C, Fc), 71.2 (CH, Fc), 70.2 (CH, Fc), 70.0 (CH, Fc),
69.0 (CH, Fc), 68.9 (CH, Fc), 68.7 (CH, Fc), 66.7 (C, Fc). IR (neat):
3725 (m), 3599 (w), 3099 (m), 2988 (m), 2903 (m), 2231 (w), 1595
(s), 1497 (s), 1398 (s), 1105 (s), 1000 (s), 965 (s), 816 (s), 767 (s), 695
(s). Anal. Calcd for C31H24Fe2N2 (%): C, 69.44; H, 4.51; N, 5.22. Found
(%): C, 69.33; H, 4.54; N, 4.73. MS (ESI, m/z): 559.05 [M + Na]+, 536.06
1H NMR (CDCl3): 7.81 (s, 1H in pyrazole), 7.32–7.29 (m, 3H, aromatic),
7.24–7.20 (m, 8H, aromatic), 7.15 (dd, 1H, J = 4.0, 3.0 Hz in thio-
phene), 7.0 (dd, 1H, J = 5.0, 1.0 Hz in thiophene). 13C NMR (CDCl3):
144.2 (C–N in Ph), 143.0 (CH in pyrazole), 140.0 (C in pyrazole
attached to Ph), 130.0 (CH, aromatic), 129.7 (CH, aromatic), 129.2
(CH, aromatic), 129.1 (C, aromatic), 128.9 (CH, aromatic), 128.6 (CH,
aromatic), 128.3 (CH, aromatic), 127.9 (CH, aromatic), 125.5 (CH,
aromatic), 125.4 (CH, aromatic), 122.7 (C, aromatic), 104.7 (C in
pyrazole attached to alkyne), 86.9 (C in CꢀC attached to thiophene),
80.9 (C in CꢀC attached to pyrazole). IR (neat): 3614 (vw), 3566 (vw),
3096 (br), 2923 (m), 2851 (m), 2586 (vw), 2215 (vw), 1592 (s), 1498
(vs), 1440 (s), 1386 (s) 960 (s), 771 (s), 761 (s). Anal. Calcd for
C21H14N2S (%): C, 77.27; H, 4.32; N, 8.58. Found (%): C, 77.06; H,
4.65; N, 8.72. MS (ESI, m/z): 327.10 [M + H]+. HRMS (ESI): calcd for
C21H15N2S: 327.0951 [M + H]+, found: 327.1014.
[M]+. HRMS (ESI): calcd for C31H Fe2N2Na: 559.0536 [M + Na]+,
56
24
56
24
found: 559.0531; calcd for C31H Fe2N2: 536.0638 [M]+, found:
536.0634.
1,5-Diphenyl-4-(phenylethynyl)-1H-pyrazole (9a)
1H NMR (CDCl3): 7.84 (s, 1H in pyrazole), 7.35–7.33 (m, 5H, Ph),
7.28–7.20 (m, 10H, Ph). 13C NMR (CDCl3): 144.1 (C–N in Ph), 142.8
(CH in pyrazole), 139.8 (C in pyrazole attached to Ph), 131.3 (CH,
Ph), 129.6 (CH, Ph), 129.0 (CH, Ph), 128.9 (CH, Ph), 128.7 (C, Ph),
128.4 (CH, Ph), 128.3 (CH, Ph), 128.0 (CH, Ph), 127.7 (CH, Ph), 125.1
(CH, Ph), 123.6 (C, Ph), 104.5 (C in pyrazole attached to alkyne),
91.6 (C in CꢀC attached to Ph), 81.4 (C in CꢀC attached to
pyrazole). IR (neat): 3693 (w), 3058 (m), 2929 (w), 2223 (m), 1967
(w), 1596 (s), 1495 (s) 1441 (s), 1387 (s), 1063 (m), 962 (m), 907
(s),751 (s), 730 (s), 688 (s). Anal. Calcd for C23H16N2 (%): C, 86.22; H,
5.03; N, 8.74. Found (%): C, 86.00; H, 5.51; N, 8.65. MS (ESI, m/z):
321.14 [M + H]+. HRMS (ESI): calcd for C23H17N2: 321.1386
[M + H]+, found: 321.1442.
4-(Ferrocenylethynyl)-1,5-diphenyl-1H-pyrazole (9e)
1H NMR (CDCl3): 7.78 (s, 1H in pyrazole), 7.33–7.17 (m, 10H, Ph), 4.38
(s, 2H, Fc), 4.14 (s, 2H, Fc), 4.10 (s, 5H, Fc). 13C NMR (CDCl3): 143.8
(C–N in Ph), 142.8 (CH in pyrazole), 140.0 (C in pyrazole attached
to Ph), 129.6 (CH, Ph), 129.2 (C, Ph), 129.0 (CH, Ph), 128.7 (CH, Ph),
128.3 (CH, Ph), 127.7 (CH, Ph), 125.1 (CH, Ph), 105.1 (C in pyrazole
attached to alkyne), 90.2 (C in CꢀC attached to Fc), 71.5 (CH, Fc),
70.1 (CH, Fc), 70.0 (CH, Fc), 65.8 (C, Fc) (one alkyne carbon peak is
missing due to overlap). IR (neat): 3648 (vw), 3069 (m), 2225 (w),
1594 (s), 1494 (vs), 1442 (s), 1384 (vs) 961 (s), 762 (vs), 691 (s). Anal.
Calcd for C27H20FeN2 (%): C, 75.71; H, 4.71; N, 6.54. Found (%): C,
75.59; H, 4.79; N, 6.12. MS (ESI, m/z): 427.11 [M + H]+. HRMS (ESI):
1,5-Diphenyl-4-(p-tolylethynyl)-1H-pyrazole (9b)
calcd for C27H FeN2: 427.1095 [M + H]+, found: 427.1136.
54
21
1H NMR (CDCl3): 7.83 (s, 1H in pyrazole), 7.35–7.32 (m, 2H, Ph), 7.27–
7.22 (m, 10H, Ph), 7.04 (d, 2H, J = 7.9 Hz in tolyl), 2.26 (s, 3H, CH3). 13
C
NMR (CDCl3): 144.0 (C–N in Ph), 142.8 (CH in pyrazole), 139.8 (C in
pyrazole attached to Ph), 138.1 (C in tolyl attached to CH3), 131.2
(CH, Ph), 129.5 (CH, Ph), 129.0 (CH, Ph), 128.9 (CH, Ph), 128.7 (C,
Ph), 128.3 (CH, Ph), 127.7 (CH, Ph), 125.2 (CH, Ph), 120.5 (C, Ph),
104.7 (C in pyrazole attached to alkyne), 91.7 (C in CꢀC attached
to tolyl), 80.5 (C in CꢀC attached to pyrazole), 21.5 (CH3) (one
aromatic CH carbon peak is missing due to overlap). IR (neat):
3733 (m), 3703 (m), 2988 (s), 2919 (s), 2237 (vw), 1593 (m), 1498
(s), 1442 (m), 1382 (s), 818 (s), 761 (m), 691 (s). Anal. Calcd for
C24H18N2 (%): C, 86.20; H, 5.43; N, 8.38. Found (%): C, 86.04; H,
5.64; N, 7.31. MS (ESI, m/z): 335.16 [M + H]+. HRMS (ESI): calcd for
C24H19N2: 335.1543 [M + H]+, found: 335.1605.
General Procedure for Synthesis of
4-Aryl-5-ferrocenylpyrazoles 12 via Suzuki–Miyaura Coupling
Reaction (Table 2)
In a two-neck round-bottom flask equipped with a reflux con-
denser, 5 (100 mg, 0.220 mmol), the corresponding boronic acid
10 or boronic acid ester derivative 11 (0.308 mmol), PdCl2(PPh3)2
(7.73 mg, 0.011 mmol) and KHCO3 (30.84 mg, 0.308 mmol) were di-
ssolved in a mixture of DMF (8 ml) and H2O (2 ml) under argon, and
the resulting reaction mixture was heated at 110 °C with stirring.
This was continued until TLC revealed the completion of the reac-
tion. Upon completion, the solvent was evaporated, first using a
rotary evaporator, then with a high-vacuum pump equipped with
two serially connected traps immersed in liquid nitrogen. The
obtained crude product was purified by flash chromatography on
silica gel using hexane–ethyl acetate (9:1) as the eluent, which
afforded the corresponding 4-aryl-5-ferrocenylpyrazole 12 with
yield indicated in Table 2.
4-((4-Methoxyphenyl)ethynyl)-1,5-diphenyl-1H-pyrazole (9c)
1H NMR (CDCl3): 7.81 (s, 1H in pyrazole), 7.33–7.31 (m 2H, Ph),
7.25–7.20 (m, 10H, Ph), 6.74 (d, 2H, J = 8.7 Hz in methoxyphenyl),
3.70 (s, 3H, OCH3). 13C NMR (CDCl3): 159.4 (C in methoxyphenyl
attached to OCH3), 143.8 (C–N in Ph), 142.7 (CH in pyrazole),
139.8 (C in pyrazole attached to Ph), 132.7 (CH, Ph), 129.6 (CH,
Ph), 129.0 (CH, Ph), 128.9 (CH, Ph), 128.7 (C, Ph), 128.3 (CH, Ph),
127.7 (CH, Ph), 125.2 (CH, Ph), 116.0 (C, Ph), 114.0 (CH, Ph),
105.0 (C in pyrazole attached to alkyne), 91.5 (C in CꢀC attached
to methoxyphenyl), 79.8 (C in CꢀC attached to pyrazole), 55.3
(OCH3). IR (neat): 3838 (vw), 3614 (vw), 3055 (w), 2836 (w), 1605
(s), 1496 (s), 1439 (s), 1383 (s), 1251 (s), 1173 (s), 960 (m), 825
(s), 694 (s). Anal. Calcd for C24H18N2O (%): C, 82.26; H, 5.18; N,
7.99. Found (%): C, 82.16; H, 5.29; N, 7.36. MS (ESI, m/z): 351.16
[M + H]+. HRMS (ESI): calcd for C24H19N2O: 351.1492 [M + H]+,
found: 351.1555.
5-Ferrocenyl-1,4-diphenyl-1H-pyrazole (12a)
1H NMR (CDCl3): 7.58 (s. 1H in pyrazole), 7.46–7.44 (m, 2H, Ph), 7.40–
7.37 (m, 2H, Ph), 7.34–7.30 (m, 6H, Ph), 4.03 (s, 2H, Fc), 4.00 (s, 2H, Fc),
3.63 (s, 5H, Fc). 13C NMR (CDCl3): 141.0 (C–N in Ph), 140.9 (CH in
pyrazole), 137.7 (C in pyrazole attached to Fc), 134.3 (C, Ph), 130.5
(CH, Ph), 128.8 (CH, Ph), 128.2 (CH, Ph), 128.0 (CH, Ph), 127.3 (CH,
Ph), 126.5 (CH, Ph), 123.3 (C in pyrazole attached to Ph), 75.24 (C,
Fc), 70.2 (CH, Fc), 69.4 (CH, Fc), 68.4 (CH, Fc). IR (neat): 3727 (w),
3627 (w), 3106 (vw), 1597 (w), 1497 (s), 1377 (m), 1106 (m), 999
(m), 863 (m), 818 (m), 754 (s), 690 (s). Anal. Calcd for C25H20FeN2
(%): C, 74.27; H, 4.99; N, 6.93. Found (%): C, 74.09; H, 5.18; N, 6.83.
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2016)

Novel alkynyl-, aryl- and ferrocenyl-substituted pyrazoles
MS (ESI, m/z): 403.11 [M + H]+. HRMS (ESI): calcd for C25H FeN2:
54
5H, Fc). 13C NMR (DMSO-d6): 140.7 (C–N in Ph), 140.6 (CH in
pyrazole), 136.4 (C in pyrazole attached to Fc), 135.1 (C in indole
attached to pyrazole), 128.7 (CH, Ph), 127.8 (CH, Ph), 127.6 (CH,
Ph), 126.3 (CH in indole), 125.8 (CH in indole), 124.2 (C in pyrazole
attached to indole), 124.1 (C in indole), 123.6 (CH in indole), 121.4
(C in indole), 110.9 (CH in indole), 101.2 (CH in indole), 75.2 (C, Fc),
69.6 (CH, Fc), 68.8 (CH, Fc), 67.9 (CH, Fc). IR (neat): 3727 (s), 3698
(s), 3627 (s), 3182 (s), 2988 (vs), 2900 (s), 1407 (m), 1309 (m), 1083
(m), 967 (m), 809 (m), 767 (m), 663 (m). Anal. Calcd for C27H21FeN3
(%): C, 73.15; H, 4.77; N, 9.48. Found (%): C, 73.00; H, 4.90; N, 8.66.
21
403.1095 [M + H]+, found: 403.1105.
4-(4-Ethylphenyl)-5-ferrocenyl-1-phenyl-1H-pyrazole (12b)
1H NMR (CDCl3): 7.56 (s, 1H in pyrazole), 7.34 (d, 2H, J = 7.6 Hz in
ethylphenyl), 7.32–7.30 (m, 5H, Ph), 7.22 (d, 2H, J = 7.6 Hz in
ethylphenyl), 4.05 (s, 2H, Fc), 4.02 (s, 2H, Fc), 3.67 (s, 5H, Fc), 2.65
(q, 2H, J = 7.6 Hz, CH2), 1.22 (t, 3H, J = 7.6 Hz, CH3). 13C NMR (CDCl3):
143.4 (CH in pyrazole), 141.0 (C–N in Ph), 140.9 (C in ethylphenyl
attached to CH2CH3), 137.5 (C in pyrazole attached to Fc), 131.4
(C, Ph), 130.4 (CH, Ph), 128.7 (CH, Ph), 127.9 (CH, Ph), 127.6 (CH,
Ph), 126.5, (CH, Ph), 123.3 (C in pyrazole attached to Ph), 75.6 (C,
Fc), 70.3 (CH, Fc), 69.5 (CH, Fc), 68.5 (CH, Fc), 28.7 (CH2), 15.7
(CH3). IR (neat): 3928 (w), 3659 (w), 3094 (m), 2962 (s), 2228 (m),
1596 (s), 1499 (vs), 1374 (s), 1107 (s), 951 (s), 820 (s), 762 (s), 728
(s), 693 (s). Anal. Calcd for C27H24FeN2 (%): C, 75.01; H, 5.60; N,
6.48. Found (%): C, 74.90; H, 5.70; N, 6.02. MS (ESI, m/z): 431.14
MS (ESI, m/z): 442.12 [M + H]+. HRMS (ESI): calcd for C27H FeN3:
54
22
442.1204 [M + H]+, found: 442.1227.
4-(4-Chlorophenyl)-5-ferrocenyl-1-phenyl-1H-pyrazole (12f)
1H NMR (CDCl3): 7.54 (s, 1H in pyrazole), 7.42–7.32 (m, 9H, Ph), 4.12
(s, 2H, Fc), 4.03 (s, 2H, Fc), 3.75 (s, 5H, Fc). 13C NMR (CDCl3): 140.9
(C–N in Ph), 140.7 (CH in pyrazole), 133.1 (C in pyrazole attached
to Fc), 132.8 (C–Cl in chlorophenyl), 131.5 (CH in chlorophenyl),
128.8 (CH, Ph), 128.4 (CH, Ph), 128.3 (CH, Ph), 126.7 (CH, Ph),
126.1 (C, Ph), 121.9 (C in pyrazole attached to chlorophenyl),
74.7 (C, Fc), 70.0 (CH, Fc), 69.3 (CH, Fc), 68.5 (CH, Fc). IR (neat):
3929 (vw), 3737 (vw), 3095 (w), 2230 (vw), 1948 (vw), 1595 (s),
1550 (s), 1498 (vs), 1381 (s), 1088 (s), 952 (s), 822 (vs), 765 (s)
694 (s). Anal. Calcd for C25H19ClFeN2 (%): C, 68.44; H, 4.37; N,
6.38. Found (%): C, 68.26; H, 4.59; N, 7.67. MS (ESI, m/z): 437.07
[M + H]+. HRMS (ESI): calcd for C25H20Cl54FeN2: 437.0706 [M + H]+,
found: 437.0717.
[M + H]+. HRMS (ESI): calcd for C27H FeN2: 431.1408 [M + H]+,
54
25
found: 431.1436.
4-(Benzo[d] [1,3]dioxol-5-yl)-5-ferrocenyl-1-phenyl-1H-pyrazole (12c)
1H NMR (CDCl3): 7.54 (s, 1H in pyrazole), 7.38–7.29 (m, 5H, Ph), 6.93
(d, 1H, J = 1.2 Hz in benzodioxolyl attached to C and C–O), 6.91 (dd,
1H, J = 8.0, 1.6 Hz in benzodioxolyl attached to C and CH), 6.85 (d,
1H, J = 8.0 Hz in benzodioxolyl attached to CH and C–O), 5.96 (s,
2H, CH2), 4.05 (s, 2H, Fc), 3.96 (s, 2H, Fc), 3.72 (s, 5H, Fc). 13C NMR
(CDCl3): 147.8 (C in benzodioxolyl attached to C–O), 147.3 (C in
benzodioxolyl attached to C–O), 141.4 (C–N in Ph), 141.3 (CH in
pyrazole), 137.9 (C in pyrazole attached to Fc), 129.2 (CH, Ph),
128.5 (CH, Ph), 128.4 (C in benzodioxolyl), 127.0 (CH, Ph), 124.1
(CH in benzodioxolyl), 123.0 (C in pyrazole attached to
benzodioxolyl), 111.3 (CH in benzodioxolyl), 108.5 (CH in
benzodioxolyl), 101.6 (CH2), 75.5 (C, Fc), 70.3 (CH, Fc), 69.7 (CH, Fc),
68.8 (CH, Fc). IR (neat): 3726 (m), 3697 (m), 3627 (m), 2988 (s),
2892 (s), 1596 (w), 1473 (s), 1371 (s), 1230 (s), 1033 (s), 810 (s), 762
(s), 696 (s). Anal. Calcd for C26H20FeN2O2 (%): C, 69.66; H, 4.50; N,
6.25. Found (%): C, 69.51; H, 4.56; N, 5.68. MS (ESI, m/z): 447.10
4-(4-Ethoxy-3-fluorophenyl)-5-ferrocenyl-1-phenyl-1H-pyrazole (12g)
1H NMR (CDCl3): 7.55 (s, 1H in pyrazole), 7.37–7.28 (m, 5H, Ph), 7.20
(dd, 1H, J = 10.0, 2.0 Hz in fluorophenyl), 7.12 (d, 1H, J = 8.4 Hz in
fluorophenyl), 6.99–6.95 (m, 1H in fluorophenyl), 4.1 (q, 2H,
J = 7.2 Hz, CH2), 4.04 (br s, 2H, Fc), 3.93 (br s, 2H, Fc), 3.68 (s, 5H,
Fc), 1.42 (t, 3H, J = 7.2 Hz, CH3). 13C NMR (CDCl3): 150.4 (d, C–F,
J = 245.8 Hz in fluorophenyl), 144.4 (d, C–O, J = 10.8 Hz in
fluorophenyl attached to C–F), 139.2 (C–N in Ph), 139.0 (CH in
pyrazole), 135.9 (C in pyrazole attached to Fc), 127.0 (CH, Ph),
126.3 (CH, Ph), 125.5 (d, CH, J = 5.9 Hz in fluorophenyl attached to
CH and C–O), 124.8 (CH, Ph), 124.2 (d, CH, J = 3.3 Hz in fluorophenyl
attached to C and CH), 119.9 (C in fluorophenyl attached to
pyrazole), 116.4 (d, CH, J = 18.5 Hz in fluorophenyl attached to
C–F and C), 112.7 (C in pyrazole attached to fluorophenyl), 73.0 (C,
Fc), 68.1 (CH, Fc), 67.4 (CH, Fc), 66.6 (CH, Fc), 63.3 (OCH2), 13.1
(CH3). IR (neat): 3726 (m), 2986 (m), 2924 (m), 1566 (m), 1514 (s),
1474 (s), 1262 (s), 1128 (s), 1037 (s), 967 (m), 824 (m), 775 (s), 701
(s). Anal. Calcd for C27H23FFeN2O (%): C, 69.54; H, 4.97; N, 6.01.
Found (%): C, 69.36; H, 5.02; N, 5.52. MS (ESI, m/z): 465.13
[M + H]+. HRMS (ESI): calcd for C27H24F54FeN2O: 465.1263
[M + H]+, found: 465.1281.
[M + H]+. HRMS (ESI): calcd for C26H FeN2O2: 447.0994 [M + H]+,
54
21
found: 447.1021.
5-Ferrocenyl-1-phenyl-4-(3,4,5-trimethoxyphenyl)-1H-pyrazole (12d)
1H NMR (CDCl3): 7.68 (s, 1H in pyrazole), 7.49–7.42 (m, 5H, Ph), 6.72
(s, 2H in trimethoxyphenyl), 4.16 (s, 2H, Fc), 4.10 (s, 2H, Fc), 3.95 (s,
3H, OCH3), 3.94 (s, 6H, OCH3), 3.81 (s, 5H, Fc). 13C NMR (CDCl3):
152.9 (C–O in trimethoxyphenyl), 141.0 (CH in pyrazole), 140.6
(C–N in phenyl), 137.5 (C in pyrazole attached to Fc), 129.7 (C in
trimethoxyphenyl), 128.8 (CH, Ph), 128.2 (CH, Ph), 126.7 (CH, Ph),
123.2 (C in pyrazole attached to Ph), 107.8 (CH, Ph), 75.1 (C, Fc),
70.1 (CH, Fc), 69.4 (CH, Fc), 68.5 (CH, Fc), 61.1 (OCH3), 56.3
(OCH3) (one aromatic C–O carbon peak is missing due to overlap).
IR (neat): 3726 (m), 3698 (m), 3627 (m), 2985 (br), 1581 (s), 1409 (s),
1243 (s), 1123 (vs), 1013 (m), 819 (m), 774 (m), 663 (m). Anal. Calcd
for C28H26FeN2O3 (%): C, 68.03; H, 5.30; N, 5.67. Found (%): C,
67.86; H, 5.87; N, 6.01. MS (ESI, m/z): 495.13 [M + H]+, 494.12
5-Ferrocenyl-1-phenyl-4-(3,4,5-trifluorophenyl)-1H-pyrazole (12h)
1H NMR (CDCl3): 7.54 (s, 1H in pyrazole), 7.38–7.32 (m, 5H, Ph), 7.05
(br s, 2H in trifluorophenyl), 4.12 (s, 2H, Fc), 3.94 (s, 2H, Fc), 3.74 (s,
5H, Fc). 13C NMR (CDCl3): 150.9 (ddd, C–F, J = 249.3, 9.0 and 3.9 Hz
in trifluorophenyl attached to C–F and CH) 140.7 (C–N in Ph),
140.2 (CH in pyrazole), 139.5 (dt, C–F, J = 245.0 and 4.5 Hz in
trifluorophenyl attached to 2 C–F), 130.4 (C in pyrazole attached
to Fc), 128.9 (CH, Ph), 128.8 (C in fluorophenyl attached to pyrazole),
128.6 (CH, Ph), 126.9 (CH, Ph), 120.2 (C in pyrazole attached to
trifluorophenyl), 113.9–114.1 (m, CH in trifluorophenyl), 74.3 (C,
Fc), 70.0 (CH, Fc), 69.5 (CH, Fc), 69.0 (CH, Fc). IR (neat): 3726 (m),
3697 (m), 3628 (m), 3090 (w), 2988 (s), 1526 (s), 1408 (s), 1231 (m),
[M]+. HRMS (ESI): calcd for C28H FeN2O3: 495.1371 [M + H]+,
56
27
56
26
found: 495.1331; calcd for C28H FeN2O3: 494.1293 [M]+, found:
494.1291.
6-(5-Ferrocenyl-1-phenyl-1H-pyrazol-4-yl)-1H-indole (12e)
1H NMR (DMSO-d6): 11.17 (s, 1H, NH), 7.71 (br s, 1H in pyrazole), 7.68
(s, 1H, aromatic), 7.51–7.36 (m, 8H, aromatic), 7.26–7.23 (m, 1H,
aromatic), 4.14 (t, 2H, J = 2.0, Fc), 4.01 (t, 2H, J = 2.0 Hz, Fc), 3.65 (s,
Appl. Organometal. Chem. (2016)
Copyright © 2016 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

Karabiyikoglu S. and Zora M.
1046 (s), 846 (m), 754 (m), 695 (m). MS (ESI, m/z): 457.08 [M + H]+.
HRMS (ESI): calcd for C25H18F534FeN2: 457.0813 [M + H]+, found:
457.0840.
Acknowledgments
We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, grant no. 110 T113) and the Research Fund of
Middle East Technical University (METU, grant no. BAP-2011-07-
02-00-01) for financial support of this research, and Research Assis-
tant Yilmaz Kelgokmen for technical support.
Ethyl 3-(5-ferrocenyl-1-phenyl-1H-pyrazol-4-yl)benzoate (12i)
1H NMR (CDCl3): 8.29 (s, 1H in benzoate), 8.13 (d, 1H, J = 7.6 Hz
in benzoate), 7.74–7.72 (m, 2H in pyrazole and benzoate), 7.59–
7.55 (m, 1H in benzoate), 7.48–7.41 (m, 5H, Ph), 4.46 (q, 2H,
J = 7.2 Hz, OCH2), 4.14 (s, 2H, Fc), 4.04 (s, 2H, Fc), 3.75 (s, 5H,
Fc), 1.45 (t, 3H, J = 7.2, CH3). 13C NMR (CDCl3): 166.5 (C=O),
140.9 (C–N in Ph), 140.7 (CH in pyrazole), 138.0 (C in pyrazole at-
tached to Fc), 134.6 (C in phenyl attached to C=O), 134.5 (CH,
Ph), 131.4 (CH, Ph), 130.5 (C, Ph), 128.8 (CH, Ph), 128.3 (CH, Ph),
128.2 (CH, Ph), 128.1 (CH, Ph), 126.6 (CH, Ph), 122.1 (C in pyrazole
attached to benzoate), 74.7 (C, Fc), 69.9 (CH, Fc), 69.2 (CH, Fc),
68.4 (CH, Fc), 61.1 (OCH2), 14.4 (CH3). IR (neat): 3925 (w), 3726
(w), 3628 (w), 3094 (m), 2978 (s), 2230 (m), 1714 (vs), 1499 (s),
1367 (s), 1257 (vs), 1104 (s), 908 (s), 757 (s), 726 (vs), 691 (s). Anal.
Calcd for C28H24FeN2O2 (%): C, 70.60; H, 5.08; N, 5.88. Found (%):
References
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54
25
(ESI): calcd for C28H FeN2O2: 475.1307 [M
+
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1H NMR (CDCl3): 8.37 (s, 1H in pyridine ortho to N), 7.72 (d, 1H,
J = 7.6 Hz in pyridine para to N), 7.66 (s, 1H in pyrazole), 7.43–7.40
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C
NMR (CDCl3): 163.4 (C–O in pyridine), 147.5 (CH in pyridine ortho
to N), 140.8 (CH in pyrazole), 140.4 (C–N in Ph), 138.1 (C in pyrazole
attached to Fc), 128.8 (CH, Ph), 128.1 (CH, Ph), 126.5 (CH, Ph), 123.1
(C in pyridine attached to pyrazole), 119.1 (C in pyrazole attached to
pyridine), 110.3 (CH in pyridine meta to N), 74.7 (C, Fc), 70.0 (CH, Fc),
69.2 (CH, Fc), 68.5 (CH, Fc), 53.6 (OCH3) (one CH carbon peak is miss-
ing due to overlap). IR (neat): 3726 (m), 3698 (m), 3627 (m), 2988 (s),
2900 (m), 1564 (m), 1477 (m9, 1289 (s), 1017 (s), 948 (m), 810 (m),
668 (m). Anal. Calcd for C25H21FeN3O (%): C, 68.98; H, 4.86; N, 9.65.
Found (%): C, 68.89; H, 4.90; N, 8.83. MS (ESI, m/z): 434.12
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54
22
found: 434.1201.
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1H NMR (CDCl3): 8.34 (s, 1H in nitrophenyl), 8.18 (d, 1H, J = 7.2 Hz
in nitrophenyl), 7.76–7.74 (m, 1H in nitrophenyl), 7.67 (br s, 1H in
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(s), 1081 (m), 809 (m), 768 (m), 683 (m). Anal. Calcd for
C
25H19FeN3O2 (%): C, 66.83; H, 4.26; N, 9.35. Found (%): C,
66.76; H, 4.36; N, 8.49. MS (ESI, m/z): 448.10 [M + H]+. HRMS
54
25 20
(ESI): calcd for C
448.0981.
H
FeN3O2: 448.0946 [M + H]+, found:
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. (2016)

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