Synthesis of ferrocenyl pyrazoles by the reaction of 3-ferrocenylpropynal with hydrazinium salts

Article abstract of DOI:10.1016/j.jorganchem.2007.10.035

Synthesis of ferrocenyl-substituted pyrazoles via the reaction between 3-ferrocenylpropynal and hydrazinium salts is described. Depending upon the substitution pattern of hydrazine derivative, the reaction affords 1-alkyl/aryl-5-ferrocenylpyrazoles and/or

Full text of DOI:10.1016/j.jorganchem.2007.10.035

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Journal of Organometallic Chemistry 693 (2008) 145–154
www.elsevier.com/locate/jorganchem
Synthesis of ferrocenyl pyrazoles by the reaction
of 3-ferrocenylpropynal with hydrazinium salts
a,
a
b,1
*
˘
Metin Zora , Ayßse Nur Pinar , Mustafa Odabaßsoglu
,
Orhan Buyukgungor c,1, Gunseli Turgut
d
¨ ¨
¨
¨
¨
a
Department of Chemistry, Faculty of Arts and Sciences, Middle East Technical University, 06531 Ankara, Turkey
Department of Chemistry, Faculty of Arts and Sciences, Ondokuz Mayıs University, 55139 Kurupelit Samsun, Turkey
b
c
Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, 55139 Kurupelit Samsun, Turkey
d
Department of Chemistry, Faculty of Arts and Sciences, Akdeniz University, 07058 Antalya, Turkey
Received 23 August 2007; received in revised form 19 October 2007; accepted 19 October 2007
Available online 26 October 2007
Abstract
Synthesis of ferrocenyl-substituted pyrazoles via the reaction between 3-ferrocenylpropynal and hydrazinium salts is described.
Depending upon the substitution pattern of hydrazine derivative, the reaction affords 1-alkyl/aryl-5-ferrocenylpyrazoles and/or 1-
alkyl/aryl-3-ferrocenylpyrazoles. Structures of 5-ferrocenyl-1-phenyl-1H-pyrazole, 1-benzyl-5-ferrocenyl-1H-pyrazole and 2-(3-ferro-
cenylpyrazol-1-yl)ethanol were identified by X-ray crystallography.
ꢀ 2007 Elsevier B.V. All rights reserved.
Keywords: Ferrocene; Pyrazole; Hydrazine; Propynal; Cyclization; Condensation
1. Introduction
with enhanced or unexpected biological activity which is
absent or less manifest in the parent molecule [3,4]. Owing
to its unique structure, different membrane-permeation
behavior and anomalous metabolism, ferrocene is often
integrated into a compound in order to obtain unexpected
or enhanced biological activities [3,4]. Thus, in recent years,
substantial effort has been devoted to the synthesis of new
ferrocene derivatives since the properly functionalized
derivatives could be potential antitumor substances [5,6].
Although pyrazoles are among the most intensely studied
compounds [7–9], ferrocenyl-substituted derivatives are rel-
atively less explored [10,11]. In this regard, the reactions of
acetylenic ketones (alkynones) with hydrazines have been
frequently used to synthesize pyrazole derivatives [8,9].
However, analogous reactions between acetylenic alde-
hydes (alkynals) and hydrazines are almost unknown since,
to the best of our knowledge, there is only one example of
such reaction [9]. It has been reported that the microwave-
assisted reaction of 3-phenylpropynal with phenylhydr-
azine provided 1,3- and 1,5-diphenylpyrazoles in 58% and
28% yields, respectively [9]. As a part of our general
The rapid spread of cancer has sparked an intense chem-
ical search for new structure leads which may be of use in
designing novel antitumor drugs. In this regard, pyrazoles
have been the focus of a large number of investigations
in the design and synthesis of novel biologically active
agents that show remarkable anticancer activities [1]. Pyra-
zoles have been studied for over a century as an important
class of heterocyclic compounds and still continue to
attract considerable attention due to the wide range of
medicinal activities they possess, such as analgesic, antimi-
crobial, antiviral, anti-inflammatory, hypoglycemic, anti-
hypertensive and antitumor properties [1,2]. Recent studies
have shown that substitution of an aromatic nucleus of
such structures with a ferrocene unit can lead to products
*
Corresponding author. Tel.: +90 312 2103213; fax: +90 312 2103200.
E-mail address: zora@metu.edu.tr (M. Zora).
Authors to whom inquiries concerning the X-ray analysis should be
1
directed.
0022-328X/$ - see front matter ꢀ 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.10.035

146
M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
involvement in ferrocene containing potential pharmaceu-
ticals, we have investigated the reaction of 3-ferrocenylpro-
pynal (1) with hydrazinium salts (2) since it provides an
easy access to ferrocenyl pyrazoles 3 and/or 4 (Table 1)
[12]. We herein report the results of this study.
Ethynylferrocene was prepared from acetylferrocene
according to a well-known literature procedure [14]. Ace-
tylferrocene is easily obtainable in large quantities from
ferrocene according to a standard protocol [15]. Hydrazini-
um salts (2) were all commercially available, except (2-
hydroxyethyl)hydrazinium dichloride (2C) which was pre-
pared according to a standard procedure [16].
2. Results and discussion
2.1. Synthesis of starting materials
2.2. Synthesis of ferrocenyl pyrazoles 3 and 4
3-Ferrocenylpropynal (1) was synthesized from ethynyl-
ferrocene by a Vilsmeier-Haack-type formylation [13].
The reactions were carried out in refluxing dioxane
(Condition A) or methanol (Condition B) with a mole
Table 1
3
5
Reaction of 3-ferrocenylpropynal (1) with hydrazinium salts 2
N
N1
1
N
C C CHO
R
R-NH-NH2.xHCl (2)
5
3
N
Fe
Fe
Fe
+
R
Condition A or B
3 (1,5-isomer)
4 (1,3-isomer)
1
Entrya
R
x
Products (isolated yield, %)
Condition Ab
Condition Bc
A
B
C
D
a
H
Ph
2
1
2
2
3A (47)
3A (70)
3B (45) + 4B (14)
3C (6) + 4C (19)
3D (63)
3B (70) + 4B (20)
3C (31) + 4C (25)
3D (46) + 4D (30)
CH2–CH2–OH
CH2–Ph
Entry letters define R group for compounds 2, 3 and 4, and x for compound 2.
Condition A: dioxane, 100 ꢁC, 8 h.
Condition B: CH3OH, 65 ꢁC, 5 h.
b
c
PATHWAY A
O
R-NH-NH (2)
2
H
N R
NH
-H O
2
N
Fc
Fc
N
H
Fc
Fc
R
5
4
O
PATHWAY B
H
R-NH-NH (2)
2
N
Fc C C CHO
NH
N
2
N
R
6
-H O
2
1
R
3
PATHWAY C
R-NH-NH (2)
N
NH
R
2
N
Fc
N
Fc
-H O
2
R
7
3
Scheme 1.

M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
147
ratio of ferrocenylpropynal (1) to hydrazinium salt (2)
of about 1:1.5, and the products were isolated by flash
chromatography. The results are summarized in Table 1.
Hydrazinium salts, instead of hydrazines, were employed
in these reactions since they gave relatively higher yields
of pyrazoles. According to our recent study, (2-formyl-1-
chlorovinyl)ferrocene reacted with hydrazine derivatives
to give pyrazoles, and we found the reactions in refluxing
dioxane to give better results [11]. It is for the reason
that the reactions between 3-ferrocenylpropynal (1) and
hydrazinium salts (2) were initially carried out in reflux-
ing dioxane (Condition A). However, in this condition,
Fig. 1. ORTEP diagram of 5-ferrocenyl-1-phenyl-1H-pyrazole (3B). Ellipsoids are drawn at 20% probability.
Fig. 2. ORTEP diagram of 1-benzyl-5-ferrocenyl-1H-pyrazole (3D). Ellipsoids are drawn at 20% probability.

148
M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
pyrazole derivatives were obtained in relatively low
yields. The same reactions were then performed in differ-
ent solvents and refluxing methanol (Condition B) was
found to shorten the reaction time with higher yields
(Table 1).
As seen from Table 1, the reactions between 3-ferroce-
nylpropynal (1) and hydrazinium salts (2) yielded two
kinds of pyrazoles, namely 1-alkyl/aryl-5-ferrocenylpyraz-
oles (3) and 1-alkyl/aryl-3-ferrocenylpyrazoles (4), which
we will refer to as 1,5- and 1,3-isomers, respectively.
1,5- and 1,3-isomers of these types of pyrazoles can easily
be identified on the basis of their 13C NMR spectra [11].
In general, the C5 peak in 1,5-isomer is relatively upfield
and resonates near 140 ppm while the corresponding C3
peak in 1,3-isomer is comparatively downfield and
appears around 150 ppm (see Table 1 for atom number-
ing). Furthermore, in 1,5-isomer, the absolute value of
chemical shift difference between C5 and C3 carbons is
Fig. 3. ORTEP diagram of 2-(3-ferrocenylpyrazol-1-yl)ethanol (4C). Ellipsoids are drawn at 20% probability.
Table 2
Crystallographic data and structure refinement parameters for 3B, 3D and 4C
3B
3D
4C
Empirical formula
Formula weight
Crystal size (mm)
Temperature (K)
Crystal system
Space group
C
328.19
0.470 · 0.380 · 0.260
293(2)
Orthorhombic
Pca21
19H16FeN2
C20H18FeN2
342.21
0.640 · 0.570 · 0.440
293(2)
C15H16FeN2O
296.15
0.780 · 0.423 · 0.210
296(2)
Monoclinic
P21/c
9.3038(17)
14.0340(3)
10.6563(16)
90.000(0)
110.482(13)
90.000(0)
1303.4(4)
4
Triclinic
ꢀ
P1
˚
a (A)
21.999(2)
5.9827(6)
11.4051(9)
90.000(0)
90.000(0)
90.000(0)
1501.1(2)
4
1.452
1.001
Mo Ka/0.71073
27.06
9.2923(5)
10.7911(6)
16.9299(9)
75.493(4)
89.605(4)
75.870(4)
1591.12(15)
4
1.429
0.948
Mo Ka/0.71073
27.90
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
3
˚
V (A )
Z
Dx (g cmꢀ3
)
1.509
1.149
Mo Ka/0.71073
26.00
l (Mo Ka) (mmꢀ1
)
˚
Radiation/wavelength (A)
hmax (ꢁ)
Index range (hkl)
Reflections measured
Independent reflections (Rint
Reflections with I > 2r(I)
Number of parameters
Number of restraints
R[F2 > 2r(F2)]
ꢀ22/27, ꢀ7/7, ꢀ14/14
ꢀ12/12, ꢀ14/14, ꢀ22/22
ꢀ11/11, ꢀ17/17, ꢀ13/13
7738
30561
15701
)
3217
2645
199
1
0.0399
0.1236
1.201
0.882, ꢀ0.750
7544
6232
415
0
0.028
0.0759
1.050
0.198, ꢀ0.351
2563
2270
172
0
0.0251
0.0660
1.046
0.217, ꢀ0.268
wR(F2)
Goodness-of-fit (F2)
Maximum, minimum Dq (e/A )
3
˚

M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
149
generally smaller than that between respective C3 and C5
carbons in 1,3-isomer [11], i.e. jDd(C5–C3)1,5-isomerj <
jDd(C3–C5)1,3-isomerj.
2.3. Crystal structures of 5-ferrocenyl-1-phenyl-1H-pyrazole
(3B), 1-benzyl-5-ferrocenyl-1H-pyrazole (3D) and
2-(3-ferrocenylpyrazol-1-yl)ethanol (4C)
The reaction between ferrocenylpropynal (1) and hydra-
zine dihydrochloride (2A) under both conditions led to for-
mation of a pyrazole derivative, which was tentatively
identified as 5-ferrocenylpyrazole (3A) (entry A). It is note-
worthy to mention that owing to annular tautomerism,
pyrazoles can exist in two tautomeric forms such as 3A
and 4A [17]. Proton transfer in pyrazoles is a formal
[1,5]-hydrogen shift and the barriers for such processes in
both solid state and solution are about 10–14 kcal/mol
[17c]. As we noted previously [11], we were unable to get
a well-resolved 13C NMR spectrum from this compound
at both 25 and ꢀ15 ꢁC to determine its tautomeric identity.
In fact, pyrazole 3A is a known compound [10c] but specific
spectroscopic data (such as 13C NMR data) to distinguish
it from its tautomer 4A has not been reported. Our efforts
to differentiate these tautomers spectroscopically from each
other are continuing.
The reaction of ferrocenylpropynal (1) with phenylhydr-
azine dihydrochloride (2B) afforded 5-ferrocenyl-1-phenyl-
pyrazole (3B) and 3-ferrocenyl-1-phenylpyrazole (4B)
(entry B). In both conditions, pyrazole 3B was isolated as
the major product. The reaction between ferrocenylpropy-
nal 1 and (2-hydroxyethyl)hydrazinium dichloride (2C) [16]
led to formation of 2-(5-ferrocenylpyrazol-1-yl)ethanol
(3C) and 2-(3-ferrocenylpyrazol-1-yl)ethanol (4C) (entry
C). Interestingly, in Condition A, pyrazole 4C was
obtained as the major product of the reaction while in Con-
dition B, pyrazole 3C was the major one. On the other
hand, the reaction of ferrocenylpropynal (1) with benzylhy-
drazine dihydrochloride (2D) produced 1-benzyl-5-ferro-
cenylpyrazole (3D) and/or 1-benzyl-3-ferrocenylpyrazole
(4D) depending upon the condition employed (entry D).
In Condition B, pyrazole 3D was isolated as the major
product of the reaction. Note that the tautomeric assign-
ments of these pyrazole isomers were based on both the
chemical shifts and chemical shift differences of corre-
sponding C3 and C5 carbons, as mentioned earlier [11].
The structures of ferrocenyl pyrazoles 3B, 3D and 4C were
also elucidated by X-ray analysis.
The structures of pyrazoles 3B, 3D and 4C were deter-
mined by X-ray crystal analysis as well. ORTEP diagrams
of 3B, 3D and 4C are shown in Figs. 1–3, respectively. Note
that although two molecules are present in the asymmetric
unit of 3D, only one molecule is shown in Fig. 2 for clarity.
Details of cell data, X-ray data collection, structure solu-
tion and refinement are summarized in Table 2. Selected
bond distances and angles are given in Table 3. A complete
list of atomic coordinates, bond distances and angles,
anisotropic thermal parameters, hydrogen atom coordi-
nates for these structures have been deposited and are
available upon request (see Section Appendix A).
The most striking feature for these structures is the
deviation of the substituted cyclopentadienyl (Cp) and
Table 3
˚
Selected bond distances (A), bond angles (ꢁ) and torsion angles (ꢁ) for 3B,
3D and 4Ca
3B
3D
4C
C1–Fe1
C1–C2
C1–C5
C1–C11
C2–C3
C3–C4
2.064(4)
1.413(6)
1.448(6)
1.444(6)
1.427(6)
1.405(7)
1.402(7)
2.028(4)
1.358(4)
1.385(5)
1.385(6)
1.321(6)
1.422(4)
NA
2.0460(14)
1.425(2)
1.425(2)
1.464(2)
1.415(2)
1.408(3)
1.421(2)
2.0484(17)
1.3552(19)
1.375(2)
1.384(3)
1.313(2)
1.4414(19)
NA
2.0449(16)
1.427(2)
1.428(2)
1.462(2)
1.418(3)
1.416(3)
1.418(3)
2.0393(19)
1.337(2)
1.404(2)
1.364(3)
1.336(2)
NA
C4–C5
C6–Fe1
C11–N1
C11–C12
C12–C13
C13–N2
C14–N1
C15–O1
N1–N2
1.410(2)
1.3585(19)
1.365(4)
1.3637(18)
C2–C1–C11
C11–C1–Fe1
C11–N1–N2
C12–C11–C1
C13–N2–N1
C13–C12–C11
C14–C15–O1
C15–C14–N1
N1–C11–C1
128.8(4)
129.3(3)
112.5(3)
132.1(3)
104.1(3)
105.7(3)
NA
122.48(14)
130.41(10)
112.26(13)
128.49(14)
104.21(14)
105.76(15)
NA
128.43(15)
125.43(11)
104.84(13)
127.37(16)
111.87(14)
105.22(15)
109.05(15)
NA
For the formation of pyrazoles 3 (1,5-isomer) and 4 (1,3-
isomer), three mechanistic pathways are possible as illus-
trated in Scheme 1. In pathways A and B, the reaction
occurs via a conjugate addition of hydrazine 2 to ferroce-
nylpropynal 1, followed by cyclization and/or cyclocon-
densation of the resulting b-hydrazinoenones 5 and 6.
However, in pathway C, the reaction happens via conden-
sation of hydrazine 2 with ferrocenylpropynal 1, followed
by cyclization through conjugate addition of the resulting
a,b-unsaturated hydrazone 7. It is noteworthy that path-
way A leads to 1,3-pyrazole isomer 4 while pathways B
and C go to 1,5-pyrazole isomer 3. It seems that depending
upon the substitution pattern of hydrazine derivative 2, one
pathway or more than one pathway can be functioning
during the course of the reaction.
119.3(3)
122.6(3)
113.90(12)
126.00(13)
122.07(15)
C1–C11–N1–C14
C2–C1–C11–N1
C5–C1–C11–C12
C5–C1–C11–N1
C15–C14–N1–C11
C15–C14–N2–C13
C15–C14–N1–C11
C15–C14–N1–N2
C15–C14–N2–N1
C2–C1–C11–N1
C5–C1–C11–N1
N1–C14–C15–C16
N2–C14–C15–O1
ꢀ1.5(6)
ꢀ43.8(6)
ꢀ46.9(7)
133.1(4)
117.3(4)
NA
117.3(4)
ꢀ64.7(5)
NA
ꢀ43.8(6)
133.1(4)
179.9(4)
NA
3.7(2)
NA
156.31(15)
148.51(17)
ꢀ29.5(2)
89.17(18)
NA
89.17(18)
ꢀ84.20 (17)
NA
156.31(15)
ꢀ29.5(2)
175.42(14)
NA
ꢀ12.9(3)
ꢀ10.7(3)
168.70(15)
NA
94.4(2)
NA
NA
ꢀ81.4(2)
ꢀ12.9(3)
168.70(15)
NA
ꢀ69.0(2)
a
NA, not applicable.

150
M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
pyrazolyl (Py) rings from coplanarity depending upon ste-
ric effects, resulting interruption of the conjugation
between these aromatic moieties. This deviation is
45.36(2)ꢁ in 3B, 26.85(11)ꢁ and 33.52(6)ꢁ in 3D, and
11.87(12)ꢁ in 4C. The deviation angle increases in the order
of 4C < 3D < 3B depending upon the steric hindrance
between Fc group and the substituent (2-hydroxyethyl,
benzyl or phenyl) on N1 or N2 atom of pyrazolyl residue.
The maximum steric interaction is observed between the Fc
and Ph groups of 3B (Fig. 1), and as a result, Ph ring in this
compound is tilted from the pyrazolyl ring plane by an
angle of 64.95(2)ꢁ as well, severely interrupting the conju-
gation. This is further supported by the dihedral angle of
57.6(2)ꢁ between the Ph and substituted Cp ring planes.
It is noteworthy that the conjugation between aromatic
moieties of 4C is largely maintained as compared to those
of 3B and 3D. Noticeably, pyrazolyl and phenyl rings in
the molecules of 3D are nearly perpendicular with an angle
of 87.67(6)ꢁ and 83.90(6)ꢁ although these rings are
separated by a methylene unit (Fig. 2). Another important
structural characteristic is that, in 4C, pyrazolyl and
hydroxyl groups on C14 and C15 atoms, respectively,
adopt a gauche conformation in the solid state, as indicated
by the N2–C14–C15–O1 angle of ꢀ69.0(2)ꢁ, although
C14 and C15 atoms exist in a staggered conformation
(Fig. 3).
the substituted and unsubstituted Cp ring centroids,
respectively. However, in 4C, Fc group exists in a notice-
ably distorted eclipsed conformation as indicated by the
average C–Cgs–Cgas–C torsion angle of 19.74(6)ꢁ. On the
other hand, in all structures, the centroids of Cp rings are
equidistant from Fe atom since the Fe–Cgs and Fe–Cgas
˚
distances are in the range of 1.641(9)–1.654(15) A, and
the Cgs–Fe–Cgas angles are between 177.65(7)ꢁ and
178.85(7)ꢁ. The C–C bond distances in Cp rings alter from
˚
1.379(8) to 1.448(6) A, while Fe–C bond lengths vary
˚
between 2.024(2) and 2.064(4) A, all of which are as
expected [6i,10m,10n,10o,10p].
In terms of crystal packing, each compound shows dif-
ferent molecular arrangement, which are stabilized by C–
H. . .N or O–H. . .N intermolecular hydrogen bonds, and/
or C–H. . .p interactions. The molecules of 3B are stabi-
lized by both C–H. . .N intermolecular hydrogen bonds
and C–H. . .p interactions. In fact, there is a single type
of intermolecular hydrogen bond, [C8–H8. . .N2:H. . .N =
˚
˚
2.694(4) A, C. . .N = 3.407(5) A, C–H. . .O = 137.03(3)ꢁ],
which links the molecules and generate the C(9) chains
along the [001] direction [18] (Fig. 4). In addition, C(9)
chains are connected through C15–H15. . .Cg1i [Cg1 is
˚
the centroid of the C1–C6 ring; H15. . .Cg1 = 3.034 A,
˚
C15. . .Cg1 = 3.884(5) A, C15–H15. . .Cg1 = 152.77ꢁ, (i)
x, y + 1, z], C17–H17. . .Cg2ii [Cg2 is the centroid of the
˚
Bond distances in the pyrazolyl units of these structures
are quite similar. N–N bond distances change from
C6–C10
ring;
H17. . .Cg2 = 3.083 A,
C17. . .Cg2 =
˚
3.662(5) A, C17–H17. . .Cg2 = 122.04ꢁ (ii) x, y, z + 1]
1.359(19) to 1.365(17) A, N–C bond lengths from
and C13–H13. . .Cg3iii [Cg1 is the centroid of the C14–
˚
˚
˚
˚
1.313(2) to 1.358(4) A and C–C bond distances from
C19 ring; H13. . .Cg3 = 2.867 A, C13. . .Cg3 = 3.666(5) A,
C13–H13. . .Cg3 = 144.66ꢁ, (i) 1 ꢀ x, 2 ꢀ y, z + 1/2]
interactions.
˚
1.364(3) to 1.404(2) A (Table 3), which are indicative of
electron delocalization.
Fc group in3B and 3D is almost in the eclipsed confor-
mation since the average C–Cgs–Cgas–C torsion angle var-
ies between ꢀ2.57(3)ꢁ and 3.58(3)ꢁ, where Cgs and Cgas are
On the other hand, the molecules of 3D are stabilized
only by C–H. . .p interactions. Interestingly, C39–H39. . .p
interactions [C39–H39. . .Cg1i; Cg1 is the centroid of the
Fig. 4. Part of the crystal structure of 3B, showing C–H. . .N intermolecular hydrogen bonds and C–H. . .p interactions as dashed lines. H atoms not
involved in hydrogen bonds have been omitted for clarity [Symmetry code: (i) x, 1 ꢀ y, 1 ꢀ z, (ii) x, 1 + y, 1 + z].

M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
151
Fig. 5. A packing diagram of the crystal structure of 3D, showing centrosymmetric R22ð16Þ dimers and C–H. . .p interactions as dashed lines. H atoms not
involved in hydrogen bonds have been omitted for clarity.
Fig. 6. Part of the crystal structure of 4C, showing both O–H. . .N intermolecular hydrogen bonds and C–H. . .p interactions as dashed lines. H atoms not
involved in hydrogen bonds have been omitted for clarity [Symmetry code: (i) x, 3/2 ꢀ y, z ꢀ 1/2].

152
M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
(triplet), q (quartet), m (multiplet). DEPT 13C NMR infor-
mation is given in parenthesis as C, CH, CH2 and CH3.
Infrared spectra were recorded on a Varian 5000 FT-IR
spectrometer. Band positions are reported in reciprocal
centimeters (cmꢀ1). Mass spectra (MS) were obtained on
an Agilent 1100 Series LC MSD spectrometer, using elec-
trospray ionization (ESI) (Fragmentor 100 eV, positive
polarity). Elemental analyses were carried out on a LECO
CHNS-932 instrument. Flash chromatography was per-
formed using thick-walled glass columns and ‘flash grade’
silica (Merck 230–400 mesh). The relative proportion of
solvents in mixed chromatography solvents refers to the
volume:volume ratio. 3-Ferrocenylpropynal (1) [13–15]
and (2-hydroxyethyl)hydrazinium dichloride (2C) [16] were
synthesized according to the known literature procedures.
All other commercially available reagents and reactants
were obtained in reagent grade and used without purifica-
tion. All reaction solvents were distilled and/or dried for
purity according to standard literature procedures. The
inert atmosphere was created by slight positive pressure
(ca. 0.1 psi) of argon.
˚
C21–C25 ring; H39. . .Cg1 = 2.853 A, C39. . .Cg1 =
˚
3.767(2) A, C39–H39. . .Cg1 = 167.53ꢁ, (i) x + 1, y ꢀ 1/2,
z] generate centrosymmetric R22ð16Þ dimers [18] (Fig. 5),
which are linked to each other through C13–H13. . .p inter-
actions [C13–H13. . .Cg2ii; Cg2 is the centroid of the N3/
˚
N4–C33
ring;
H13. . .Cg2 = 2.676 A,
C13. . .Cg2 =
˚
3.561(2) A, C13–H13. . .Cg2 = 159.39ꢁ, (ii) 1/2 ꢀ x, 2 ꢀ y,
z ꢀ 1/2]. Fascinatingly, as seen in Fig. 5, tunnels are
formed inside these dimer heaps, a rare occurrence, which
was not observed in the crystal structures of 3B and 4C.
The molecules of 4C are stabilized by both O–H. . .N
intermolecular hydrogen bonds and C–H. . .p interactions.
Actually, there is a single type of intermolecular hydrogen
˚
bond, [O1–H1. . .N2: H. . .N1 = 2.16(2) A, C. . .N =
2.881(2) A, C–H. . .O = 177.00(3)ꢁ], which connects the
˚
molecules and yields the C(6) chains [18] (Fig. 6). It should
be noted that C(6) chains are linked to each other through
C6–H6. . .Cg1i interactions [Cg1 is the centroid of the C1–
C6 ring; H6. . .Cg1 = 3.094 A, C6. . .Cg1 = 3.853(2) A,
C6–H6. . .Cg1 = 140.00ꢁ, (i) x, 1/2 ꢀ y, 3/2 ꢀ z].
˚
˚
3. Conclusion
4.2. General procedure for the synthesis of ferrocenyl
pyrazoles 3 and 4 (Table 1)
The reaction between 3-ferrocenylpropynal (1) and
hydrazines 2 is investigated in this work, yielding pyrazoles
3 (1,5-isomer) and/or 4 (1,3-isomer). In most cases, 1,5-pyr-
azole isomers 3 have resulted from these reactions as the
single or the major products. The regioselectivity of the
reactions is mainly governed by the nature of the substitu-
ents in hydrazines 2. Owing to the ready availability of
3-ferrocenylpropynal (1) and hydrazines 2, this method
represents a versatile synthesis of ferrocenyl-substituted
pyrazoles 3 and/or 4.
The structures of compounds 3B, 3D and 4C were iden-
tified by X-ray crystal analysis. Depending upon steric
effects, ferrocenyl and pyrazolyl groups in these structures
depart from coplanarity, and, as a result, conjugation
between these aromatic moieties is interrupted to some
extent. The maximum steric interaction is observed
between Fc and Ph groups of 3B, considerably tilting both
from the pyrazolyl ring plane, severely interrupting
conjugation.
To a solution of 3-ferrocenylpropynal (1) (100 mg,
0.420 mmol) in 10 mL of dioxane (Condition A) or metha-
nol (Condition B) under argon was added hydrazine deriv-
ative (2) (1.260 mmol). The resulting mixture was then
heated at reflux for 8 h (Condition A) or 5 h (Condition
B). After the reaction was complete, the mixture was
cooled to 25 ꢁC, and the solvent was removed on a rotary
evaporator. The residue was dissolved in water (20 mL)
and extracted with chloroform (3 · 30 mL). The combined
chloroform layers were dried over magnesium sulfate and
removed in a rotary evaporator. Final purification was
achieved through flash chromatography on silica gel (elu-
ent: hexane/EtOAc from 19:1 to 1:1). The products given
in Table 1 were isolated with the indicated yields.
4.3. Spectral data for products
We have demonstrated that, when treated with hydrazi-
nium salts, acetylenic aldehydes, i.e. alkynals, afford pyra-
zoles, as in the case of acetylenic ketones or alkynones.
We have recently reported the synthesis of ferrocenyl
pyrazoles 3A–D and 4B–C by using a similar method
[11]. Please refer to this study for the spectral data of these
compounds.
4. Experimental
4.3.1. 1-Benzyl-3-ferrocenyl-1H-pyrazole (4D)
4.1. General consideration
1H NMR (CDCl3): d 7.40–7.31 (m, 3H), 7.28 (s, 1H),
7.23 (d, 2H, J = 7.2 Hz), 6.32 (s, 1H), 5.34 (s, 2H), 4.77
(s, 2H), 4.34 (s, 2H), 4.14 (s, 5H); 13C NMR (CDCl3): d
150.8 (C), 137.0 (C), 130.1 (CH), 128.7 (CH), 127.9 (CH),
127.5 (CH), 103.7 (CH), 79.0 (C), 69.6 (CH), 68.5 (CH),
66.7 (CH), 55.8 (CH2); IR (KBr): 3108, 3079, 3030, 2941,
1556, 1497, 1435, 1404, 1303, 1230, 1102, 1060, 1000,
874, 833, 813, 761, 716 cmꢀ1; MS (ESI, m/z): 343.1
[M+H]+, 252.0; Anal. Calc. for C20H18FeN2 with
Nuclear magnetic resonance (1H and 13C) spectra were
recorded on a Bruker Spectrospin Avance DPX400 Ultra-
shield (400 MHz) spectrometer. Chemical shifts are
reported in parts per million (d) downfield from an internal
tetramethylsilane reference. Coupling constants (J values)
are reported in hertz (Hz), and spin multiplicities are indi-
cated by the following symbols: s (singlet), d (doublet), t

M. Zora et al. / Journal of Organometallic Chemistry 693 (2008) 145–154
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0.263 mol CHCl3 incorporation: C, 65.14; H, 4.93; N, 7.50.
Found: C, 65.14; H, 5.62; N, 7.50% [19].
Acknowledgements
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The authors would like to thank the Scientific and Tech-
nical Research Council of Turkey (104T202) and the Re-
search Board of Middle East Technical University
(METU) (BAP-2005-08-16-05 and BAP-2005-07-02-00-
58) for financial support of this research, and the Faculty
of Arts and Sciences, Ondokuz Mayıs University, for the
use of Stoe IPDS II diffractometer (purchased under Grant
F.279 of the University Research Fund).
Vaissermann, M. Huche, G. Jaouen, Chem. Eur. J.
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Appendix A. Supplementary material
CCDC 653294, 653295 and 653296 contain the supple-
mentary crystallographic data for 3B, 3D and 4C. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this
article can be found, in the online version, at
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