Synthesis and Structure of 2-(1Н-Indol-1-yl)-6-ferrocenyl-4-(2-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidine

Article abstract of DOI:10.1134/S1070363218060099

A 2,4,6-trisubstituted pyrimidine including a 2-(1H-indol-1-yl) substituent was synthesized by the reaction of 1-ferrocenyl-3-(2-chloroimidazo[1,2-a]pyridin-3-yl)propanone with 2,5-dimethoxytetrahydrofuran. The structure of the synthesized compound was confirmed by IR and ¹Н NMR spectroscopy, and X-ray diffraction analysis. It has been shown that the ferrocene-containing compounds synthesized in the present work all demonstrate intramolecular charge transfer which is evidenced by the observation of the corresponding absorption bands with λ_max^abs > 480 nm. The oxidation potential of ferrocene (E_ox^Fc) in all the compounds is higher than 700 mV.

Full text of DOI:10.1134/S1070363218060099

ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 6, pp. 1103–1107. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © A.D. Antuf’eva, D.R. Akhmatzyanova, M.V. Dmitriev, E.V. Shklyaeva, G.G. Abashev, 2018, published in Zhurnal Obshchei Khimii,
2
018, Vol. 88, No. 6, pp. 922–926.
Synthesis and Structure
of 2-(1Н-Indol-1-yl)-6-ferrocenyl-
4-(2-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidine
a
b
b
A. D. Antuf’eva , D. R. Akhmatzyanova , M. V. Dmitriev ,
b,c
a–c
E. V. Shklyaeva , and G. G. Abashev *
a
Institute of Technical Chemistry, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences,
ul. Akademika Koroleva 3, Perm, 614013 Russia
*
e-mail: gabashev@psu.ru
b
Perm State National Research University, Perm, Russia
c
Institute of Natural Sciences, Perm State National Research University, Perm, Russia
Received January 15, 2018
Abstract—A 2,4,6-trisubstituted pyrimidine including a 2-(1H-indol-1-yl) substituent was synthesized by the
reaction of 1-ferrocenyl-3-(2-chloroimidazo[1,2-a]pyridin-3-yl)propanone with 2,5-dimethoxytetrahydrofuran.
1
The structure of the synthesized compound was confirmed by IR and Н NMR spectroscopy, and X-ray
diffraction analysis. It has been shown that the ferrocene-containing compounds synthesized in the present
work all demonstrate intramolecular charge transfer which is evidenced by the observation of the
abs
Fc
corresponding absorption bands with λmax > 480 nm. The oxidation potential of ferrocene (Eox) in all the
compounds is higher than 700 mV.
Keywords: indole, 2-aminopyrimidine, ferrocene, 1-azaindolizine, 2,5-dimethoxytetrahydrofuran, Clauson‒Kaas
reaction
DOI: 10.1134/S1070363218060099
Heterocyclic structures incorporating both the pyri-
ferrocene-containing chromophores, we have developed
a different synthetic approach to such compounds. The
key stage of this process is the Clauson–Kaas reaction.
As a result, we obtained a previously unknown
Y-shaped chromophore of DAD' motif, where A is the
central electron-deficient core consisting of the
pyrimidine and 2-chloroimidazo[1,2-a]-pyridine and D
and D' are the electron excessive feroccene and indole
substituents in the 6- and 2-positions of the pyrimidine
ring. The reaction sequence used in the present work is
shown in the Scheme 1.
midine and indole fragments have fairly long been
known. Substituted fused 9Н-pyrimido[4,5-b]indoles
first described by Glushkov et al. [1] are an important
class of such compounds [2, 3]. Pyrimidines, where the
indole fragment is linked to the pyrimidine nucleus via
3
the С atom of the indole ring, have also been reported;
such structures are most commonly synthesized by the
condensation of chalcones with urea or thiourea [4].
Pyrimidines linked to the indole fragment via the
nitrogen atom of the latter, specifically substituted
1
-(pyrimidin-2-yl)-1Н-indoles, are less known; such
structures most frequently contain a substituted indole
fragment. They can be synthesized either by the
reactions of substituted or unsubstituted indoles with
To form the future 1-azaindolizine fragment, we
treated 2-aminopyridine by chloroacetic acid to obtain
2-(2-imino-1,2-dihydropyridin-1-yl)acetic acid 1 [8],
2
-chloropyrimidine under the action of sodium hydride
and the latter was cyclized under the action of POCl
3
in DMF or alkali metal carbonates in DMSO [5] or
PEG 400 by ultrasonication [6] or by Ru-catalyzed
reactions of substituted N-(pyrimidin-2-yl)anilines
with diarylacetylenes [7]. Aimed at preparing new
to obtain 2-chloroimidazo[1,2-а]pyridine 2 [8] and
then aldehyde 3, whose structure was confirmed by X-ray
diffraction analysis [9]. The condensation of adehyde 3
with acetylferrocene gave rise to chalcone 4 [9], which
1
103

1
104
ANTUF’EVA et al.
Scheme 1.
Cl
Cl
O
Cl
N
O
Fc
aa
N
cc
N
bb
H
N
N
NH
CH3
Fe
N
N
N
NH2
O
dd
O
44
OH
1
1
e
e
2
3
2
3
Cl
N
Cl
N
N
N
N
N
'
Fe
MeO
OMe
O
D
D
N
N
Fe
Fe
f f
N
N
N
N
NH2
A
Cl
N
55
N
66
O, 90°C, 5 h; b, POCl
6
6
Reaction conditions: а, ClCH
2
COOH, Et
3
N, H
2
3
, toluene, 110°C, 16 h; c, POCl
3
, DMF, PhCl, 70°C,
5
h; d, 2% NaOH (aq.), reflux for 5 h; e, guanidine sulfate, 50% KOH–EtOH, reflux for 3 h, then H O , (33%), reflux for1 h;
2 2
f, AcOH, reflux, 4 h.
was then used to prepare 4,6-disubstituted 2-amino-
pyrimidine 5. The target product 6 was synthesized by
the Clauson–Kaas reaction (a modified version of the
Paal–Knorr reaction). Depending on the reaction
conditions, the amino group in the 2-position of the
pyrimidine ring can be converted into the pyrrole
imidazole rings and the pyrimidine and pyrrole rings
span the range 3.5–3.7 Å (Fig. 2).
The UV spectra of pyrimidine 6 were studied in com-
parison with those of the starting compounds: chalcone
4
and 2-aminopyrimidine 5. Figure 3 compares the UV
spectra of chloroform solution of compounds 4–6 (the
absorption intensities are normalized). The values of
the absorption maxima, absorption edge and optical
band gaps are summarized in the table. As seen from
these data, compounds 4–6 absorb in the visible
[10–15], indole [15], or carbazole rings [16, 17]. The
potentialities of this reaction was briefly presented by
Husson et al. [18] in their review on the synthetic
applications of 2,5-dimethoxytetrahydrofuran. Pyri-
midine 6 is a bright red crystalline substance. Its com-
position and structure were confirmed by elemental
region; the widest absorption range is inherent to
abs
onset
1
chalcone 4 (λ
600 nm); besides, this very
analysis, IR and Н NMR spectroscopy, and X-ray
compound has also the most intense and long
diffraction analysis (Fig. 1).
abs
max
wavelength absorption maximum (λ 510 nm) arising
Pyrimidine 6 crystallizes in a monoclinic centro-
symmetric space group. The ferrocene fragment has a
geometry typical for such structures, with the two
cyclopentadienyl fragments in an eclipsed conforma-
tion. The pyrimidine ring is planar within 0.01 Å, and
it is almost coplanar with the cyclopentadienyl ring:
the dihedral angle between the pyrimidine and
from the efficient intramolecular charge transfer (ICT).
Furthermore, chalcone 4 has the narrowest optical
opt
band gap (Eg ~2 eV).
We have also studied the electrochemical behavior
of pyrimidine 6 and its parent compounds 4 and 5 by
means of cyclic voltammetry (see table). Figure 4
presents the comparison of voltammograms (CVs) of
pyrimidines 5 and 6 cyclic. All of the obtained CVs
show one reversible oxidation peak associated with the
redox process in the ferrocene fragment. The highest
20 21 22 23 24
С С С С С ring planes is 3.9°. The imidazopyridine
and indole fragments are planar within 0.04 and
0
.03 Å, and the dihedral angles between these ring
planes and the pyrimidine ring lane are 17.9° and 8.7°,
respectively. The main feature of the crystal structure
is that the molecules are packed in stacks, where the
aromatic fragments of adjacent molecules are so close
to each that the resulted distance between them: the
centroid-to-centroid distances between the benzo and
+
Fc/Fc redox potential has been observed for chalcone
4 (740 mV), which is explained by the presence of an
electron-deficient propenone fragment. The CVA of
pyrimidine 6, which contains the indole fragment, displays
the second, weak irreversible one-electron absorption
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018

SYNTHESIS AND STRUCTURE OF 2-(1Н-INDOL-1-YL)-6-FERROCENYL-...
1105
Fig. 1. General view of a molecule of compound 6 in
crystal.
Fig. 2. Crystal packing of molecules of compound 6.
A
λ, nm
Е, V
Fig. 3. Comparison of the (1–3) UV spectra of compounds
Fig. 4. Comparison of the CVAs of compounds (1) 5 and
(2) 6 (с = 0.1 М, MeCN–CH Cl , Et ClO ).
2 2 4 4
–
3
4
–6 in CHCl
3
(с = 1×10 М).
1
ox
–5
wave (E ~1.38 V), associated with the dimer
CHCl (с = 1×10 M). Electrochemical measurements
3
formation due to the oxidation of the indole fragment.
were performed on a Gamry Interface1000 potentiostat
in a three-electrode cell with a сarbositall working
electrode, a platinum auxiliary electrode, and a silver‒
silver chloride reference electrode. In the experiments
we used millimolar solutions of the samples in a
mixture of anhydrous MeCN and CH Cl (4 : 1,
EXPERIMENTAL
The IR spectra were measured on a Perkin‒Elmer
Spectrum Two FTIR spectrometer for suspensions in
mineral oil. The NMR spectra were obtained on a
Varian Mercury Plus300 spectrometer (300 MHz) in
2
2
1
0 mL), background electrolyte Et NClO (с = 0.1 M),
4 4
potential scan rate (vscan) 50 mW/s. Elemental analysis
С, Н) was performed on a Vario EL Cube analyzer.
The iron content was estimated using a Thermo iCE
CDCl , internal reference HMDS. The melting/decom-
3
(
position points were measured by a Mettler Toledo
MP70 instrument. The reaction progress was monitored
and the purity of the synthesized compounds were
controlled by TLC (Sorbfil, Silufol). The mixtures of
compounds and the target products were purified in
silica columns (Alfa-Aesar, Silica gel 60, 0.060–
3
500 adsorption sectrometer.
Acetylferrocene was purified from diacetylferro-
cene by the procedure in [20].
0
2
.2 mm). The UV spectra were run on a Shimadzu UV-
600 spectrophotometer, cell length 10 mm, solvent
3-(2-Chloroimidazo[1,2-a]pyridin-3-yl)-1-ferro-
cenylpropenone (4). A suspension of 2.3 g (0.01 mol)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 6 2018

1
106
ANTUF’EVA et al.
Optical and electrochemical characteristics of compounds 4–6
abs
abs
opt
g
а
Fc
Fc
1
Comp. no.
λ
max, nm
λ
onset, nm
E
, eV
E
ox, mV
E
red, mV
E
ox, mV
4
5
295, 377, 510
607
529
541
2.04
740
720
710
630
610
580
244, 266, 312, 389, 489
262, 306, 355, 481
2.34
2.29
6
1380
a
opt
abs
E
g
= 1240 λonset [19].
3
3
of acetylferrocene and 1.8 g (0.01 mol) of 2-chloro-
pyrrole, J = 3.6), 8.87 d (1Н, indole, J = 8.1), 9.7 m
imidazo[1,2-a]pyridine-3-carbaldehyde 3 in 100 mL of
(1Н, pyrimidine)
2
% NaOH was heated for 2 h, cooled, and poured into
water with ice. The precipitate was filtered off and
purified by column chromatography (eluent hexane–
acetone, 3 : 1). Yield 85%, mp 178–180°С (mp 180°С
X-ray diffraction analysis of compound 6 was
performed on an Xcalibur Ruby diffractometer with a
ССD detector by a standard procedure (ω scanning
[
9]), red crystals.
-Amino-4-(2-chloroimidazo[1,2-a] pyridin-3-yl)-
-ferrocenylpyrimidine (5) was prepared by the proce-
with a 1° step) at 295(2) K with a MoK
α
radiation
(
λ 0.71073 Å) and a graphite monochromator [22]. A
2
dark red needle-like crystal 0.55×0.09×0.03 mm in
dimensions was used. Monoclinic syngony, space
6
dure in [21]. A mixture of 2.5 g (6.5 mmol) of 3-(2-
chloroimidazo[1,2-a]pyridin-3-yl)-1-ferrocenylpro-
penone 4 and 1.57 g (10 mmol) of guanidine sulfate in
group P2 /с, a 12.318(2), b 7.3115(14), c 25.793(4) Å,
1
3
β 97.262(17)°, V 2304.4(8) Å , C H ClFeN , Z 4.
2
9
20
5
Final refinement parameters: R 0.0505, wR 0.1140
1
2
5
0 mL of ethanol was stirred for 15–20 min with 5 mL
of 50% aqueous KОН and refluxed for 3 h. Water,
mL, was then added in small portions under the same
[
for 3800 reflections with I > 2σ(I)], R 0.0805, wR
1 2
0
.1337 (for all 5435 unique reflections), S 1.031.
3
Maximal and minimal residual electron density peaks:
conditions and refluxing was continued for an
additional 1 h. The hot reaction mixture was poured
into water with ice, the precipitate was filtered off,
dried in air, and purified by column chromatography
3
0
.364 and –0.335 ē/Å . Absorption was included
empirically using SCALE3 ABSPACK algorithm [22].
The structure was decoded by a direct method and
refined by full-matrix least squares on F in the
anisotropic approximation for nonhydrogen atoms. The
hydrogen atoms were placed in geometric positions
and refined riding on their carrier atoms isotropically
with dependent thermal parameters. ShELXS-97
2
(eluent hexane–acetone, 1 : 1). Yield 45%, mp 87–89°C,
–
1
dark red crystals. IR spectrum, ν, cm : 3275, 3421
1
(NH ). Н NMR spectrum (CDCl ), δ, ppm (J, Hz):
2
3
3
4
.21 s (5Н, Fc), 4.55 t (2H, Fc, J = 1.8), 4.89 t (2H,
3
Fc, J = 1.8), 5.05 br s (2H, NH ), 6.98 s (1H,
pyrimidine), 7.47 d (2Н, С Н , J = 8.7), 7.61 d (2Н,
С Н , J = 9.0). Found, %: С 59.05; Н 3.64; Fe 12.94.
C H ClFeN . Calculated, %: С 58.70; Н 3.75; Fe 13.00.
2
[23, 24] and OLEX2 program suits [25] were used for
3
6
4
structure solution and refinement. The resulting crystallo-
graphic information was deposited in the Cambridge
Crystallographic Data. Center (CCDC 1845553).
3
6
4
21
16
5
2
-Indolyl-4-(2-chloroimidazo[1,2-a]pyridin-3-yl)-
-ferrocenylpyrimidine (6). A solution of 0.7 g
2 mmol) of 2-aminopyrimidine in 5 mL of glacial
6
(
ACKNOWLEDGMENTS
acetic acid containing 0.5 mL (3.0 mmol) of 2,5-di-
methoxytetrahydrofuran was heated under reflux for
Instrumental investigations were performed using
the equipment acquired at the expense of the Program
for the development of National Research Universities.
4
h, heated, and poured into 150 mL of water with ice.
The precipitate was filtered off and purified by column
chromatography. Yield 48%, mp 104–106°С, dark red
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