Enantiomeric-enriched ferrocenes: Synthesis, chiral resolution, and mathematic evaluation of CD-chiral selector energies with ferrocene-conjugates

Article abstract of DOI:10.3390/molecules22091410

Enantiomeric-enriched ferrocene-modified pyrazoles were synthesized via the reaction of the ferrocene alcohol, (S)-FcCH(OH)CH₃ (Fc = ferrocenyl), with various pyrazoles in acidic conditions at room temperature within several minutes. X-ray structural data for racemic (R,S)-1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (1) and its (S)-enantiomer (S)-1 were determined. A series of racemic pyrazolylalkyl ferrocenes was separated into enantiomers by analytical HPLC on βand γcyclodextrins (CD) chiral stationary phases. The quantum chemical calculations of interaction energies of βCD were carried out for both (R)- and (S)-enantiomers. A high correlation between experimental HPLC data and calculated interaction energies values was obtained.

Full text of DOI:10.3390/molecules22091410

molecules
Article
Enantiomeric-Enriched Ferrocenes: Synthesis, Chiral
Resolution, and Mathematic Evaluation of CD-chiral
Selector Energies with Ferrocene-Conjugates
1
,
ID
1
1
1
Lubov V. Snegur * , Yurii A. Borisov , Yuliya V. Kuzmenko , Vadim A. Davankov ,
Mikhail M. Ilyin , Mikhail M. Ilyin Jr. , Dmitry E. Arhipov , Alexander A. Korlyukov 1,2,
1
1
1
Sergey S. Kiselev 1 and Alexander A. Simenel
1,3
1
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St.,
1
19991 Moscow, Russia; yuaborisov@mail.ru (Y.A.B.); kuzmenko@mail.ru (Y.V.K.);
davank@ineos.ac.ru (V.A.D.); mikhail-ilin2007@yandex.ru (M.M.I.); kotosok@yandex.ru (M.M.I.J.);
arhipov@mail.ru (D.E.A.); alex@xrlab.ineos.ac.ru (A.A.K.); kiss@ineos.ac.ru (S.S.K.);
alexsim@ineos.ac.ru (A.A.S.)
N.I. Pirogov Russian National Research Medical University, 1 Ostrovityanov St., 117997 Moscow, Russia
Moscow Institute of Steel and Alloys National University of Science and Technology, 4 Leninskii Av.,
2
3
1
19049 Moscow, Russia
*
Correspondence: snegur@ineos.ac.ru; Tel.: +7-903-157-8364
Received: 14 July 2017; Accepted: 24 August 2017; Published: 25 August 2017
Abstract: Enantiomeric-enriched ferrocene-modified pyrazoles were synthesized via the reaction
of the ferrocene alcohol, (S)-FcCH(OH)CH (Fc = ferrocenyl), with various pyrazoles in acidic
3
conditions at room temperature within several minutes. X-ray structural data for racemic
(
R,S)-1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (
A series of racemic pyrazolylalkyl ferrocenes was separated into enantiomers by analytical HPLC
on - and -cyclodextrins (CD) chiral stationary phases. The quantum chemical calculations of
interaction energies of -CD were carried out for both (R)- and (S)-enantiomers. A high correlation
1) and its (S)-enantiomer (S)-1 were determined.
β
γ
β
between experimental HPLC data and calculated interaction energies values was obtained.
Keywords: ferrocene; pyrazoles; enantioenriched compounds; enantiomers; X-ray crystallography;
HPLC; cyclodextrin; quantum chemical calculations
1
. Introduction
Enantioselective synthesis is a key process in modern chemistry and is particularly important
in the field of medicinal chemistry, as the different enantiomers or diastereomers of a molecule often
have different biological activities. The thalidomide tragedy in the early 1960s led to much stricter
testing requirements for drugs and pesticides before they can be licensed. It is especially noted into
Pharmacopoeias of many countries or regions [1,2].
The unique properties of organometallic compounds, intermediates between those of classical
inorganic and organic materials, provide new opportunities in medicinal chemistry. A broad variety
of ferrocene compounds are regarded as potential drug candidates for medical treatments [
Such diseases as anemia and ozena can be readily cured with the help of ferrocerone, the first
ferrocene-based drug [ 11]. Many research groups investigated different ferrocene compounds
against malaria, tuberculosis, and particularly cancer [12 20]. The results of electrophysiological
3–8].
1,4,9–
–
in vivo experiments with ferrocenepyrazolyl-based glycine carried out in the CA1 field of the
hippocampus have recently been reported [21].
Efficient synthetic approaches towards ferrocene modifications of organic compounds have
been summarized and analyzed in the recent reviews [22
,23]. For preparing ferrocene-based
Molecules 2017, 22, 1410; doi:10.3390/molecules22091410
www.mdpi.com/journal/molecules

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chiral complexes, multi-step asymmetric synthesizes must be carried out often [24]. This access
to enantiomeric-enriched ferrocene products was well-studied by I. Ugi and co-workers in the early
1
970s [25–27]. To our surprise, biological research upon chiral ferrocene-based individual stereo isomers
has not been realized in detail, excluding the analysis of the effects of ferrocene-based compound
named ferroquine, as an antimalarial agent [28], ferrocene-hormones for specific receptors [29],
and ferrocene-thymine conjugates, which can be used as anticancer agents [30]; all investigated
ferrocene compounds have planar chirality.
In this paper, the development of our ferrocene-devoted works [31
a simple route to enantiomeric-enriched ferrocene-based compounds. The stereogenic center in
-position to the ferrocene moiety, where stabilization by electron-saturated ferrocene occurs, was used for
chiral syntheses by means of the substitution reaction through chiral -ferrocenylalkyl cations (Scheme 1).
–36] are reported. We proposed
α
α
Enantiomeric-enriched (S)-ferrocene-modified pyrazoles were synthesized via the reaction
of the enantioenriched ferrocene alcohol (S)-FcCH(OH)Me (Fc = ferrocenyl) with pyrazoles in
acidic conditions according to the approach previously developed by us for racemic ferrocene
heterocycles [17
) and its (S)-enantiomer (S)-
data and a chiral analytical HPLC technique, (S)-ferrocene pyrazoles were characterized. A series of
racemic (S,R)-ferrocene pyrazoles was separated into enantiomers by analytical HLPC on chiral - or
-cyclodextrins. Quantum chemical calculations of interaction energies of (R)- and (S)-enantiomers of
ferrocene conjugates with -cyclodextrin ( -CD) chiral selector were carried out. A high correlation
E) and experimental HPLC data (separation factor, α)
,31,32]. X-ray structural data for racemic 1N-(3.5-dimethyl pyrazolyl)ethyl ferrocene
(1
1
were obtained. Using a combination of single-crystal X-ray diffraction
β
γ
β
β
between calculated interaction energies (
was obtained.
∆
2
. Results and Discussion
2
.1. Synthesis
The ferrocenylalkylation method for the introduction of ferrocenylalkyl groups into various
nucleophilic substrates was based on the reaction of
amines with nucleophiles [36].
α-(hydroxy)alkyl ferrocenes or ferrocenylalkyl
Imidazoles and pyrazoles, being the central ingredient in many drugs, are often used for chemical
modification by ferrocene for medicinal investigations [22 23 36 37]. Usually the design and synthesis of
,
,
,
ferrocene–heterocycle derivatives either in racemic forms or without stereogenic centers are described.
As initial compounds, ferrocenylalkyl amines and Fc-alcohols are used for the synthesis of target
substances [38–44].
As for enantioenriched ferrocene compounds, this area is much less investigated [45]. Direct
enantiospecific substitution of ferrocene alcohols via acid-catalyzed C-O bond cleavage gives a
variety of ferrocene-modified heterocycles [46]. Recently, it was shown that in the presence of ZnCl2
enantioenriched α-aminoethyl ferrocene, FcCH(CH )NH (96% ee), reacted with N-methylindole and
3 2
◦
parent compounds for 6 h in acetonitrile without extrusion of air and moisture at 100 C, gave the
substitution products in excellent yields and with complete retention of configuration [47]. Much earlier,
A. Togni and co-workers performed the preparation of a great variety of chiral ferrocenes, incorporating a
◦
pyrazole and phosphine by the substitution reaction in acetic acid at 70–90 C for 3–7 h with configuration
retention at the stereogenic center of initial phosphinoferrocenyl amine derivatives [48].
It is known that ferrocene alcohols as racemates, such as (R,S)-FcCH(OH)R, in acidic conditions,
+
form highly kinetic active ferrocenyl carbocations, such as FcC HR [49]. Such primary, secondary,
and tertiary Fc-carbocations as solids were firstly synthesized and characterized by NMR [50] and
+
later X-ray analysis data for permethylated ferrocene carbocation, and (C Me )Fe(C Me )C H was
5
5
5
4
2
reported [51]. Moreover, the density-functional method was used for ab initio calculations of the
+
geometry and total energy of (C Me )Fe(C Me )CH -cation [52]. Chiral FcC HR are known and have
5
5
5
4
2
been extensively used to access various chiral ferrocene derivatives [25,27]. If the stabilization effects

Molecules 2017, 22, 1410
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of the solvents are not significant, Fc-carbocations prepared in situ can easily react with different
nucleophiles, in particular azoles to form ferrocenylalkyl azoles, such as FcCH(R)Az [22]. This idea
was successfully used for stereospecific synthesis here.
In this paper, a simple method for enantioenriched ferrocenylalkyl pyrazoles was developed,
and the stereochemical aspects of ferrocene-containing pyrazoles were studied. We found that (R)-
and (S)-ferrocene alcohols, when interacting with pyrazoles in aqueous-organic media in the presence
of strong inorganic acid HBF , give the corresponding pyrazole-containing ferrocene products, i.e.,
4
FcCH(R)-Pz, in enantiomeric-enriched forms (enantiomeric excess more than 90%, HPLC data). The
complete absence of inversion or racemization at these reaction conditions makes this process a
valuable preparative method for enantioenriched ferrocene-modified compounds. The stabilization of
the carbocation center by electron-rich ferrocene fragment governs the stereoselectivity of the reactions.
This effective strategy has been previously applied for the synthesis of racemic Fc-azoles and Fc-nucleic
bases [15,18,22,32,35,53].
Herein, the one-pot synthesis of enantioenriched ferrocenylethyl 3,5-dimethylpyrazole (S)-
other substituted pyrazoles (S)- , (S)- as well as an unsubstituted pyrazole (S)- was realized (Table 1).
By using (S)-1-ferrocenylethanol and pyrazole, 3,5-dimethylpyrazole (or fluoro-containing pyrazoles)
1 and
3
4
5
and strong acid aqueous HBF in a molar ratio of 1:1:1 in methylene dichloride, and after stirring
4
for a short time at room temperature, the products were synthesized in excellent yields (Scheme 1).
It should be noted that to prevent the oxidation of the final product during the work-up, ascorbic acid
was used. In Table 1 the optical rotation values and enantiomeric excess (HPLC data) are given for
compounds (S)-1−(S)-5.
Scheme 1. Enantiospecific synthesis of (S)-ferrocenylethylpyrazoles. (i) Methylene dichloride,
HBF4 45% water solution, 3,5-dimethylpyrazole (R1 = R2 = CH ), or pyrazoles (R = R2 = H),
3
1
3
-trifluoromethyl-5-methylpyrazole (R = CF , R = CH ), 3,5-di(trifluoromethyl)pyrazoles (R = R =
1 3 2 3 1 2
◦
CF ), 22–25 C, 5 min; ascorbic acid (5–10 mg) was added during the work-up of the product.
3
Table 1. Enantiomeric excess and optical rotation of ferrocene compounds (for formulas see Table 2).
Enantiomeric Excess, ee % (a)
20
Concentration, mole·L−1
No
Molecule
FcCH(CH )-3,5-Me Pz
[α]
D
(
(
(
(
(
S)-1
S)-2
S)-3
S)-4
S)-5
93
97
+78.75
+30.75
+12.00
+14.30
+16.50
0.40 (benzene)
0.60 (methanol)
0.30 (benzene)
0.18 (benzene)
0.70 (benzene)
3
2
FcCH(CH )OH
3
FcCH(CH )-3-CF ,5-CH Pz
not determined
not determined
95
3
3
3
FcCH(CH )-3-CF ,5-CF Pz
3
3
3
FcCH(CH )Pz
3
(a)
Found by HPLC method.
Initial (S)-1-ferrocenylethanol (S)-2 was synthesized from acetylferrocene following the usually
well-reproduced protocol developed by Ugi and co-workers, with some modifications including a

Molecules 2017, 22, 1410
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series of chemical transformations [26
,
27]. According to the analytical HPLC data, 97% enantiomeric
excess (ee) was achieved (see Table 1). It should be noted that enantioenriched 1-ferrocenylethanols
can be prepared by the catalytic reduction of acetylferrocene with good chemical yields and ee [54 55].
,
However, (R)- and (S)-Fc-ethanoles are accessible via Ugi’s classical method. This is the more preferred
synthetic route for our future biological studies as the subsequent medicinal trials demand both (R)-
and (S)-enantiomers, in accordance with Russian Federation Pharmacopoeia [1]. In spite of the fact that
modern ferrocene chemistry is extensively developing, especially in the field of medicine, biological
studies of enantioenriched ferrocene compounds are currently limited [28–30].
2
.2. Enantiomeric Resolution
In this section, racemic ferrocenylethyl pyrazoles were considered. These ferrocene-containing
enantiomers with central chirality were resolved on β- or γ-cyclodextrins as chiral selectors using
the HPLC analytical method. Earlier, this method of separation was successfully applied for
enantiomeric ferrocene compounds carrying different simple substituents [56], as well as for
ferrocenylalkyl azoles [57
and thiopyrimidines [35].
The enantiomeric resolution analytical data are summarized in Table 2. We successfully separated
the five pairs of investigated compounds and . Under the conditions applied, there was no
enantiomeric resolution of compounds and . The recognition mechanism on -CD and -CD
,58] and mercapto benzimidazoles [19], ferrocene-modified pyrimidines [18],
1
,
2
5–7
3
4
β
γ
is apparently connected with the formation of specific hydrogen bonds between the strongly basic
nitrogen atoms of the corresponding pyrazole fragments and the hydrogen atoms of the hydroxyl on
the cavity of cyclodextrins, as in the case of simple ferrocene derivatives such as ferrocenylethanol [56
or ferrocenylalkyl azoles [53,57].
]
Chiral centers in the investigated compounds are represented either by the carbon atom connecting
a ferrocene moiety with a heterocycle ( ), or they are introduced in the substituent of a heterocycle (
and ). Experimental data for compounds and were published earlier [53]. The most efficient HPLC
separation was achieved in the case of compounds
substituents, α = 1.308 for 6 and α = 1.385 for 7 (Table 2).
1
–5
6
7
6
7
6
and
7, with polyfluoro-containing benzimidazoles
Table 2. Enantiomeric resolution of racemic mixtures 1–7 on column Cyclobond I 200 and calculated
data for selectivity energies.
Molecule (a)
Chiral Stationary Phase (b)
No
Separation Factor, α
∆E, kcal/M
1
β-CD
1.059
3.85
FcCH(CH )-3,5-Me Pz
3
2
2
β-CD
1.133
4.89
FcCH(CH )OH
3
3
4
β-CD
β-CD
1.153
1.182
4.94
5.25
FcCH(CH )-3-CF ,5-CH Pz
3
3
3
FcCH(CH )-3-CF ,5-CF Pz
3
3
3

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Table 2. Cont.
Molecule (a)
Chiral Stationary Phase (b)
No
5
Separation Factor, α
∆E, kcal/M
β-CD (c)
1.195
5.58
FcCH(CH )Pz
3
6
7
γ-CD (d)
γ-CD (d)
1.308
1.385
6.20
7.59
(
a)
in the structures means the stereogenic center; (b) Mobile phase, hexane–isopropanol 98:4 (v/v); For compound
(c)
∗
(d)
5
, experimental data were found on modified cyclodextrin, column Cyclobond I 200 SN;
For compounds 6 and 7,
see experimental details in Reference [53].
2
.3. Calculations
Figures 1 and 2 show the structures of
received as the result of energy optimization (top view
N-(3,5-dimethylpyrazolyl)ethyl ferrocene are situated over the torus β-CD.
Table 3 shows the calculated characteristics of -CD complexes with (R)- and (S)-enantiomers,
β
-CD complexes with (R)- and (S)-enantiomers,
β-CD). Attached molecules of enantiomeric
1
β
including the comprehensive energy from the calculation of the DFT B3LYP/LanL2DZ, the computed
values of dipole moments, and the highest occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) energies (a.u.—atomic units).
Table 3. Calculated characteristics of complexes β-CD with R- and S-enantiomers.
System
E, a.u.
µ, D
HOMO, a.u.
LUMO, a.u.
(
(
R)-1-β-CD
S)-1-β-CD
−5167.4437
−5167.4481
4.25
6.25
−0.19354
−0.20897
−0.02009
−0.03714
In Table 2, the experimental analytical HPLC data and the calculated
complexes with 1N-(3,5-dimethylpyrazolyl)ethylferrocene (R)- and (S)-enantiomers as well as other
Fc-compounds are summarized, including ferrocene-based bezimidazoles and . Note that we
failed in resolving fluoro-containing pyrazoleferrocenes and on chiral cyclodextrins. Rather strong
intermolecular hydrogen bonds probably complicate this process. The red-marked values for these
compounds at = 1.153 and = 1.182 (Table 2) were accordingly defined from the linear correlation
∆E energies for β-CD
6
7
3
4
α
α
(Figure 3).
The interaction energy of (S)-enantiomer 1N-(3,5-dimethyl pyrazolyl) ethyl ferrocene (S)-
1
−
1
with
β-CD is 3.85 kcal mol
higher than the interaction energy of the (R)-enantiomer with
β-CD, as it was calculated. Thus, complex
β-CD-(S)-Fc-enantiomer is more stable than complex
β-CD-(R)-Fc-enantiomer. The reason for such differences in energies of interaction,
∆
E, is that the
(
R)-enantiomer-containing complex has only one H-bond connecting the N-heterocyclic atom with
the OH-function of -CD. The bond length N . . . H amounts to 2.057 Å (Figure 1). The complex of
-CD with (S)-Fc-enantiomer has two H-bonds. One bond is formed between the N-pyrazole atom of
pyridine type and the OH-function of -CD. The bond length amounts to 2.116 Å. Another H-bond
connects the Fe-atom with the OH-function of -CD. The bond length Fe . . . H is 2.624 Å. These bonds
β
β
β
β
are marked on Figure 2. These three H-bonds are rather weak [59,60], and therefore racemates with
small ∆E energies were easily separated on cyclodextrins.

Molecules 2017, 22, 1410
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Quantum chemical calculations of hydrogen bonds and energies were made for (R)-,
S)-enantiomers and -cyclodextrins as chiral selectors. The data obtained demonstrate the high
(
β
correlation between the experimental retention factors and the calculated interaction energies (Figure 3).
In conclusion, the combined calculation data and experimental racemic resolution data could be
useful for the determination of the absolute configuration of compounds.
Figure 1. Complex (R)-(3,5-dimethylpyrazolyl)-α-ethyl ferrrocene CD-cyclodextrin (calculated data).
Figure 2. Complex (S)-(3,5-dimethylpyrazolyl)-α-ethyl ferrocene-CD-cyclodextrin (calculated data).

Molecules 2017, 22, 1410
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1
1
1
1
1
1
1
1
.40
.35
.30
.25
.20
.15
.10
.05
3
.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0

E (kcal/Mol)
Figure 3. Correlation between experimental HPLC data (alpha) and ∆E calculated interaction energies
values. α = 0.69862 + 0.09203 ∆E. The multiplier at ∆E is a tangent of the angle inclination of a line.
2
.4. Crystal Structures
We proceeded to crystallize the racemic 1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (
S)-enantiomer (S)- . The molecular structure of is shown in Figure 4. It was found that the domain
consists of blocks containing both the (S)- and (R)-enantiomers in a 1:1 ratio. The
and (S)- are slightly divers due to various experimental conditions. However, the
1) and its
(
1
1
structure of
structures of
1
1
1
discrepancies in the values of bond lengths and angles are negligible.
The value of bond lengths and angles fall in the same range as the bond lengths and angles in the
ferrocene derivatives bearing heterocyclic fragments [18
in the eclipsed conformation that is rather typical for substituted ferrocenes [31
angles are equal to 2.6(2) and 2.7(5) (Ct1 and Ct2 are the centroids of the Cp rings). The molecular
,
19
,
31–
33
,
53]. The cyclopentadienyl ligands are
–
33]. The C2-Ct1-Ct2-C7
structure of
1
in crystal is characterized by the bending of the pyrazole group with respect to the
◦
ferrocenyl moiety. The angle between the mean planes of these fragments is 74.2 .
The absolute configuration definition for compound (S)-1 was made using the Flack parameter;
K = −0.02 and was assigned as (S).
Figure 4. Molecular structure of
Å, and angles ( ), C6-C11 1.509(4); N1-C11 1.470(3); C11-C12 1.527(4); Fe1-C6 2.040(2); N1-N2 1.366(3);
N1-C11-C6 110.5(2); N1-C11-C12 109.5(2); C7-C6-C11 126.4(2); C6-C11-C12 113.1(2).
1 presented in thermal ellipsoids at 50% probability. Selected lengths,
◦

Molecules 2017, 22, 1410
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3
. Experimental Section
3
.1. Methods and Materials
1H- and 13C-NMR spectra were obtained on a Bruker DRX-500 spectrometer (Bruker Billerica, MA,
13
◦
USA) at 500.13 MHz and 125.76 MHz for protons and C, respectively, in CDCl at 30 C. Chemical
3
shifts are given in ppm relative to solvent residual protons. IR spectra were recorded on a UR-20
spectrophotometer (Carl Zeiss, Jena, Germany), using a KBr disk. Electron ionization (EI) mass spectra
were taken on a FINNIGAN POLARIS Q spectrometer (Thermo Fisher Scientific, Waltham, UK) at
◦
7
0 eV, with the temperature of the ion chamber at 250 C. The solvents were purified by standard
techniques. The following chiral columns (250
I 2000), (S)-naphthylcarbamate-derivatized-
×
4.6 mm, 5
µm) were used: β-cyclodextrin (Cyclobond
β
-cyclodextrin (Cyclobond I 2000 SN). Chromatographic
resolution was carried out on an HPLC system (Advanced Separation Thechnologies, Inc., Whippany,
NJ, USA), with a Bruker LC 31 instrument equipped with a UV detector (254 nm); the flow rate was
−
1
1
1
.0 mL
·
min at an ambient temperature. The specific rotation was determined on a Perkin-Elmer
41 polarimeter.
1
-(R,S)-Ferrocenylethanol was synthesized by the reduction of acetylferrocene with LiAlH in THF
4
according to a modified well-known procedure [53
,61]. Initial (S)-N,N-dimethylaminoethylferrocene
for the synthesis of (S)-1-ferrocenylethanol was obtained by the crystallization of racemic amine with
L-tartaric acid [26], and was then transformed into (S)-1-ferrocenylethanol [27]. The synthesis of
ferrocenylalkyl azoles both in racemic and enantiomeric-enriched forms was carried out by previously
described methods [31,33,53]. Initial heterocycles were purchased from Acros Organics and used
without purification. The experimental data for enantiomeric-enriched compounds are summarized in
Table 1.
3
.2. General Procedure
2
0
To a mixture of 1.0 mmol, 0.23 g of (S)-1-ferrocenylethanol, ee 97% (HPLC data), [
α
]
=
D
−
1
+
30.75, 0.60 mol
dichloride, and 0.18 mL of 45% aqueous solution of fluoroboric acid was added under vigorous stirring.
The agitation was continued for 5 min, and then Et O (15 mL), the same amount of cold water, and
·
L
(methanol), 1.0 mmol of the corresponding heterocycle in 1.0 mL of methylene
2
5
–10 mg of ascorbic acid were added to the reaction flask. After vigorous shaking of the mixture, the
organic solution was separated, washed with cold water, the solvent was removed, and the residue
was dried over CaCl in a desiccator.
2
◦
1, yield 92%, 0.28 g, ee 93%, orange crystals, m.p. 76 C,
(
S)-(3,5-Dimethylpyrazolyl)-
α
-ethylferrrocene (S)-
1
H-NMR (CDCl3,
Fc); 4.15 (s, 5H, Fc); 4.20 (s, 1H, Fc); 4.22 (s, 1H, Fc); 5.30 (q, J = 6.8 Hz, 1H, CH); 5.75 (s, 1H, (C-4)Pz).
δ, ppm): 1.83 (d, J = 6.8 Hz, 3H, CH ); 2.20 (s, 3H, CH ); 2.23 (s, 3H, CH ); 4.13 (s, 2H,
3
3
3
1
3
C-NMR (CDCl3, δ, ppm): 11.6 (CH ), 13.7 (CH ), 20.2 (CH ), 53.9 (CH), 66.7 (C H ), 67.3 (C H ), 67.8
3 3 3 5 4 5 4
(
(
C H ), 68.3 (C H ), 68.8 (C H ), 89.9 (ipso-C H ), 105.2 (Pz, C-4), 137.7 (Pz, C-5), 146.6 (Pz, C-3). IR
5
4
5
4
5
5
5
4
−
1
+
KBr,
ν
, cm ): 3010, 2890, 1560, 1470, 1120, 1009, 840, 778, 539, 472. EI-MS, m/z (RI, %): 308 [M] (92).
-ethylferrrocene (S)- , yield 88%, 0.32 g, yellow crystals, m.p.
7 C, H-NMR (CDCl , δ, ppm): 1.85 (d, J = 9.6 Hz, 3H, CH ); 2.25 (s, 3H, CH ); 4.04 (s, 1H, Fc); 4.13
(S)-(3-Trifluoromethyl-5-methylpyrazolyl)-
α
3
◦
1
4
(
3
3
3
13
m, 7H, Fc); 4.21 (s, 1H, Fc); 5.33 (q, J = 9.6 Hz, 1H, CH); 6.23 (s, 1H, (C-4)Pz). C-NMR (CDCl3,
δ,
ppm): 11.5 (CH ), 20.4 (CH ), 55.0 (CH), 66.5 (C H ), 67.4 (C H ), 67.8 (C H ), 68.4 (C H ), 68.9 (C H ),
3
3
5
4
5
4
5
4
5
4
5
5
3
8
1
7
9.3 (ipso-C H ), 103.7 (q, J (C- F) = 1.8 Hz, Pz, C-4), 124.4 (q, J (C-F) = 266.7 Hz, CF ), 138.8 (Pz, C-5),
5 4 3
40.5 (q, J (C- F) = 37.5 Hz, Pz, C-3). IR (KBr,
76, 547, 472. EI-MS, m/z (RI, %): 362 [M] (89).
2
−1
ν
, cm ): 3029, 2898, 1564, 1456, 1265, 1120, 1011, 844,
+
1
(
S)-(3,5-Ditrifluoromethylpyrazolyl)-
α
-ethylferrrocene (S)-
4
, yield 87%, 0.36 g, orange oil, H-NMR (CDCl ,
3
δ
, ppm): 1.88 (d, J = 9.6 Hz, 3H, CH ); 4.14–4.22 (m, 9H, Fc); 5.45 (q, J = 9.6 Hz, 1H, CH); 6.56 (s, 1H,
3
(
C-4)Pz). 13C-NMR (CDCl3,
δ, ppm): 20.6 (CH ), 58.1 (CH), 66.1 (C H ), 67.0 (C H ), 67.7 (C H ),
3 5 4 5 4 5 4
6
8.3 (C H ), 68.9 (C H ), 89.6 (ipso-C H ), 106.3 (m, Pz, C-4), 119.8 (q, J (C-F) = 267 Hz, CF ), 122.4 (q,
5 4 5 5 5 4 3

Molecules 2017, 22, 1410
9 of 13
2
2
J (C-F) = 267 Hz, CF ), 138.2 (q, J (C- F) = 37.5 Hz, Pz, C-5), 141.4 (q, J (C- F) = 37.5 Hz, Pz, C-3). IR
3
−
1
(
KBr,
ν
, cm ): 3010, 2964, 1575, 1510, 1462, 1415, 1396, 1163, 1040, 987, 840, 715, 547, 498. EI-MS, m/z
+
(RI, %): 416 [M] (100).
◦
1
(
(
(
S)-(Pyrazolyl)-
α
-ethylferrrocene (S)-
5, yield 86%, 0.24 g, ee 95%, orange crystals, m.p. 54 C, H-NMR
CDCl3,
s, 1H, (C-4)Pz); 7.30 (s, 1H, Pz); 7.51 (s, 1H, (C-4)Pz). C-NMR (CDCl3,
δ, ppm): 1.86 (d, J = 6.4 Hz, 3H, CH ); 4.17–4.29 (m, 9H, Fc); 5.41 (q, J = 6.8 Hz, 1H, CH); 6.21
3
13
δ
, ppm): 21.4 (CH ), 57.3 (CH),
3
6
6.2 (C H ), 67.9 (C H ), 68.0 (C H ), 68.5 (C H ), 68.9 (C H ), 89.0 (ipso-C H ), 105.0 (Pz, C-4), 126.7
5
4
5
4
5
4
−
5
4
5
5
5
4
1
(Pz), 138.4 (Pz, C-3). IR (KBr,
ν
, cm ): 3115, 2965, 1525, 1411, 1293, 1120, 1045, 968, 853, 720, 665, 538,
+
4
98. EI-MS, m/z (RI, %): 280 [M] (82).
3
.3. Calculations
The calculations of
S)-enantiomers as well as the interaction energies of
performed by the restricted Becke Lee Young Parr modification (RB3LYP) of the density functional
theory [62 64]. The Dunning Hay D95 atomic basis sets were used for the optimization of the
geometry and for the calculation of the interaction energies between -CD and R- and S-enantiomers.
β-cyclodextrin (β-CD), 1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (R)- and
(
β-CD with (R)- and (S)-enantiomers were
−
−
−
–
−
β
3
.4. Crystallography
Single crystals suitable for X-ray diffraction analysis were obtained by recrystallization from
acetone-d compounds and (S)- . X-ray diffraction measurements were carried out using CAD4
1
1
6
Enraf-Nonius and Bruker Smart APEX II diffractometers. The structures were solved by a direct method
2
and refined by the full-matrix least-squares technique against F in an anisotropic approximation.
Hydrogen atoms were located from the difference Fourier maps and refined in rigid body model. All
calculations were performed using the SHELXTL program package [65]. Details of crystallographic
data and experimental conditions are presented in Table 4.
Table 4. Crystallographic data and refinement parameters for the structures 1 and (S)-1.
1
(S)-1
Diffractometer
T, K
Bruker Smart APEX II
120
CAD4 Enraf-Nonius
293
Empirical formula
Formula weight
Crystal system
Space group, Z
Densitycalc. (g·cm 3)
a (Å)
C H FeN
C H FeN
1
7
20
2
17 20
2
308.20
Orthorhombic
P2 2 2 , 4
308.20
Orthorhombic
P2 2 2 , 4
1
1
1
1 1 1
−
1.396
7.8662(5)
8.9661(5)
20.7985(13)
1466.90(15)
60.12
1.346
7.9670(16)
8.9670(18)
21.291(4)
1521.0(5)
49.91
b (Å)
c (Å)
3
V (Å )
θmax ( )
◦
2
F(000)
648
648
Reflections collected
19,371
1649
Independent reflections (R(int)
Number of reflections with I > 2σ(I)
)
4301 (0.0542)
3766
1565 (0.0108)
1364
Parameters
Flack
185
0.467(18)
10.19
184
−0.02(4)
Linear absorption (cm 1)
−
9.83
Goodness-of-fit (GOF)
1.010
0.998
R (I > 2σ(I))
0.0330
0.0698
0.0396
0.1054
1
wR (all reflections)
2
ρ
min/ρmax, e
0.338/−0.397
0.366/−0.661

Molecules 2017, 22, 1410
10 of 13
Bond lengths and angles, thermal parameters, and experimental conditions of the structures
1
and (S)- have been deposited in the Cambridge Crystallographic Data Centre (CCDC Nos. 1491349
1
and 1491350) and can be obtained free of charge via the webpage: http://www.ccdc.cam.ac.uk/
Community/Requestastructure/pages/Requestastructure.aspx.
4
. Conclusions
In summary, we reported an efficient, highly enantiospecific synthesis of chiral pyrazole ferrocenes
via direct substitution under acidic conditions in two-phase media from ferrocene alcohols and
pyrazoles in good yields with very high enantiomeric purity.
Acknowledgments: This work was supported by the Russian Academy of Sciences (Presidium Program
“
Fundamental Sciences for Medicine”), by the Department of Chemistry and Materials Science (Program
Medicinal Chemistry”) and by the Russian Foundation for Basic Research (RFBR No. 14-03-00980, 16-03-00881).
“
Dmitry E. Arhipov and Alexander A. Korlyukov are grateful to ratiopharm GmbH (Ulm) for financial support of
this work. Lubov V. Snegur wishes to thank the reviewers for valuable remarks.
Author Contributions: Lubov V. Snegur suggested the idea of research work and wrote the paper.
Alexander A. Simenel discussed the experimental synthetic data; Yuliya V. Kuzmenko finalized the experimental
work; Yurii A. Borisov and Sergey S. Kiselev preformed mathematic evaluation of ferrocene-CD conjugates;
Dmitry E. Arhipov and Alexander A. Korlyukov were concerned with crystallographic work; Mikhail M. Ilyin,
and Mikhail M. Ilyin, Jr. carried out the HPLC experiments; Vadim A. Davankov revised the manuscript and
discussed the experimental HPLC data. All authors wrote the corresponding part of the paper and approved the
final manuscript.
Conflicts of Interest: All authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 1–7 are available from the authors.
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