Transition metal-free regioselective cross-coupling of azine N-oxides with cymantrenyl lithium

Article abstract of DOI:10.1016/j.jorganchem.2018.06.008

The facile C–C coupling reaction of activated forms of azaaromatics (azine-N-oxides) with cymantrenyl lithium, as a nucleophile, has first been carried out. It has been established that aromatization of intermediate adducts can be realized through either oxidative or eliminative pathways, depending on the structure of the starting azine N-oxide. In particular, the dihydroazinyl intermediates, bearing the additional N(4)-atom relative to the N-oxide group, proved to undergo aromatization through the eliminative pathway. The X-ray studies of 3,6-diphenyl-1,2,4-triazine-5-yl-cymantrene have revealed that it is crystallized in both orthorhombic and monoclinic forms.

Full text of DOI:10.1016/j.jorganchem.2018.06.008

Accepted Manuscript
Transition metal free regioselective cross-coupling of azine N-oxides with cymantrenyl
lithium
Alexandra A. Musikhina, Irina A. Utepova, Oleg N. Chupakhin, Valery N. Charushin,
Pavel A. Slepukhin
PII:
S0022-328X(18)30365-6
10.1016/j.jorganchem.2018.06.008
JOM 20467
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 15 May 2018
Revised Date: 5 June 2018
Accepted Date: 7 June 2018
Please cite this article as: A.A. Musikhina, I.A. Utepova, O.N. Chupakhin, V.N. Charushin, P.A.
Slepukhin, Transition metal free regioselective cross-coupling of azine N-oxides with cymantrenyl
lithium, Journal of Organometallic Chemistry (2018), doi: 10.1016/j.jorganchem.2018.06.008.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Transition metal free regioselective cross-coupling of azine N-oxides with
cymantrenyl lithium
Alexandra A. Musikhinaa, Irina A. Utepovaa,b, Oleg N. Chupakhina,b,1, Valery N. Charushina,b,
Pavel A. Slepukhina,b
a Ural Federal University, Mira str.19, 620002 Ekaterinburg, Russian Federation
b I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences
S. Kovalevskoy str. 22, 620137 Ekaterinburg, Russian Federation
Abstract
The facile C-C coupling of activated azaaromatics forms (azine-N-oxides) with
cymantrenyl lithium, as a nucleophile, has been carried out. Aromatization of nucleophilic
addition intermediate has been found to be depending on the structure of azine N-oxides.
Keywords: Cymantrene, nucleophile, azine-N-oxides, C-C coupling
1. Introduction
During the past two decades, the development of new methods for functionalization
of heteroarenes, especially azaaromatics, by incorporating metallocenyl fragments into
the structure of azines, has become one of the main strategies in bioorganometallic
chemistry [1], since important practical applications of the target organometallic
derivatives. The synthesis of such types of compounds for medicinal chemistry has the
following specific goals: (i) to estimate properties of pharmacophoric heterocyclic
fragment [2] or (ii) to develop systems, bearing an electrochemical [3] or
spectrophotometric [4] tag. It is known, that cyclopentadienyl manganese (I) tricarbonyl
(cymantrene) takes the next place after ferrocene and ruthenocene in the list, counting
number of experimental works in this field [5]. Unique electronic properties and a high IR
activity of CO-groups allow one to use cymantrenes as analytical labels [6] for
immunoassays [7], electro- [8] and photochemical processes [9], as components of
initiating mixtures for polymerization vinyl monomers [10], as well as in bioorganic
chemistry [11] and drug design [12].
1 Corresponding author: E-mail address: chupakhin@ios.uran.ru (O.N. Chupakhin)
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At the same time, there are a limited number of methods to prepare azinyl metallocenes.
They include such principal approaches, as transition metal-catalyzed cross-coupling reactions of
organoelement compounds with heterocyclic halides (or pseudohalides), and construction of a
heteroarene ring on metallocene scaffolds [13].
However, the direct metal-free (non-catalyzed by transition metals) cross-
dehydrogenative coupling (CDC) reaction of azines with the lithium derivatives of
metallocenes appears to be a more atom-efficient approach [14]. In accordance with the
terminology and symbols, suggested by C. K. Ingold [15], the reactions of arenes
(heteroarenes) with organometallic reagents, leading to substitution of hydrogen in
aromatic systems, have to be classified as nucleophilic substitution reactions denoted by
H
H
the symbol SN Ar [16]. The significant difference between SN and conventional SNAr
substitution reactions, accompanied by the departure of good leaving groups (for
example, a halogenide anion) is expressed by adding the “H” symbol.
H
The advantages of the CDC reactions (SN ), which are worth mentioning, are that the latter
require neither metal catalysts, such as palladium, nor the presence of halogen and other
H
auxiliary groups in heteroaromatic substrates [17]. The SN reactions have earlier been
successfully used for the synthesis of hetaryl substituted metallocenes (Scheme 1) [18], including
enantiomerically enriched planar chiral ligands [19].
Previous work
ZnCl
+
Mn
Br
OC
OC
CO
CO
N
N
CO
N
Mn
CO
OC
CO
Li
+
Mn
CO
H
40-80%
This work
Metal free
N+
O-
N
O-
H
Ox
Mn
OC
OC
CO
CO
Li
CO
65-88%
+
Mn
N
OC
CO
N
CO
Metal free
N
N+
O-
H
-H2O
Mn
CO
76-92%
Scheme 1. The synthesis of cymantrenyl azaaromatics.
In this paper, the first time we wish to describe use the transitional metal-free cross-
coupling reaction for modification of the structure of azine N-oxides (an activated form of
azaaromatics) through their reactions with cymantrenyl lithium. Also some characteristic
features of the process, depending on the structure of azines, are supposed to be discussed.
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2. Results and discussion
2.1. Synthesis
A number of mono-, di- and triazine-N-oxides, including their benzo annelated
analogues have been selected as azaaromatic substrates. According to the current concept
[20] on the mechanism of oxidative SNH reactions, the process involves two steps. At the
first step the C-addition of lithium cymantrene
°C, thus giving rise to the σH-adducts
, followed by their hydrolysis into the
corresponding N-hydroxy compounds (Scheme 2) [18c].
2 to an azine N-oxide takes place at -78
3
4
Two mechanisms for aromatization of adducts 3 are considered to be possible (Scheme 2)
[21]. Depending on the structure of the starting azine N-oxides, aromatization of intermediate
adducts can be realized through either oxidative or eliminative pathways. In case of N-oxides 1a-
d a mild oxidation of the adducts 4a-d can be performed by action of 2,3-dichloro-5,6-
dicyanobenzoquinones (DDQ) to give the corresponding products 5a-d (Scheme 2, Path A).
Yields of the reaction products 5a-d proved to be varied from 65% to 88% (Table 1).
Scheme 2. The C-C coupling of azine-N-oxides 1a-g with lithium cymantrene.
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Table 1
Yields of compounds 5a-da
Entry
Azinyl residue
Yield 5, %
1
2
3
4
1-Oxido-quinolin-2-yl (a)
2-Oxido-isoquinolin-1-yl (b)
1-Oxido-pyrimidin-4-yl (c)
2-Oxido-phthalazin-1-yl (d)
88
80
85
65
aThe reactions were carried out using 1.6 M solution of n-BuLi in hexane (0.76 mL, 1.2 mmol), cymantrene
(1.0 mmol), heterocycle-N-oxides 1e-g (1.0 mmol), DDQ (3.8 mmol) in a Schlenk tube under the atmosphere
of argon at -78 °C
.
On the other hand, aromatization of the σH-adducts 4e-g can occur spontaneously
according to the deoxygenative mechanism with elimination of water to afford
compounds 5e-g (Scheme 2, Path B).
An important point is that the formation of products 5a-d is not possible without an
internal oxidant. At the same time, in case of compounds 5e-g the presence of an
oxidizing agent doesn't have any effect on yields of target compounds. This fact can
possibly be explained by the ability of azines 1e-g, bearing the additional N(4)-atom in
the 4-position relative to the N-oxide group, to undergo 1,3-prototropic shift to form the
structure
A (Scheme 3). As a consequent, aromatization of 4e-g proceeds according to the
eliminative mechanism with elimination of water. As for compounds 1a-d, there are no
opportunity to form the structure like
most plausible one.
A, thus making the oxidative mechanism to be the
Moreover, the reaction of phthalazin-2-oxide 1d with lithium cymantrene takes
place with the retention of the N-O moiety, while the parent phthalazine does not react
with the lithium compound 2.
Indeed, yields of 5e-g (76 – 92 %) can be enhanced by approx. 20%, provided N-oxides
are used instead of unactivated azines (60 – 82 %) [18c] (Table 2).
Scheme 3. A plausible mechanism for oxidation of the σH-adducts 3e-g.
H
Attempts to carry out the SN reactions of pyridine-N-oxide or 2,2'-bipyridine-N-oxide
with the cymantrenyl lithium 2 failed, since they didn`t lead to the target products. It can be
explained by a lower electrophilicity of the parent pyridine N-oxide or 2,2'-bipyridine N-oxide,
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which is unsufficient either to react with lithium derivative of cymantrene 2 or/and to stabilize
the intermediate σH-adducts. Instead of it, lithium cymantrene 2 and pyridine N-oxides are
supposed to undergo the re-metallation reaction, thus giving rise to the formation of dimeric
compounds [22]. Also replacement of n-BuLi with t-BuLi, as lithiating agent, didn`t give a
positive result.
Table 2
Yields of compounds 5e-g
Entry
Product
Quinoxaline-2-yl (e)
Yield 5, %a
Yield 5, %b
60 [18c]
1
2
3
76
92
90
3,6-Diphenyl-1,2,4-triazine-5-yl (f)
3-(Pyridine-2-yl)-6-phenyl-1,2,4-
triazine-5-yl (g)
80 [18c]
82 (see SI)
aThe products were isolated from the reactions of cymantrene with N-oxides.
bThe products were isolated from the reactions of cymantrene with unactivated azines.
All azinyl substituted cymantrenes 5 obtained proved to be stable solids, from light
1
brown to dark brown compounds. In the H NMR spectra of 5 the protons resonances,
which are characteristic for mono-substituted cymantrene, are observed as two multiplets
with two-proton intensities at δ 4.9-6.5 ppm, while the signals of heterocyclic protons are
13
observed at δ 7.4-9.0 ppm. In the C NMR spectra the characteristic signal of the CO-
groups is registered at δ 220 ppm. The mass spectra have peaks of the corresponding
molecular ions. In the IR spectra the characteristic absorption bands, corresponding to CO
stretching vibrations of cymantrene (ν = 1900-2020 cm-1) and N-O group (v = 1208-1275
cm-1) (for compounds 5a-d) are observed.
2.2. 1H, 13C, IR, X-ray analysis
Unequivocal evidence for the structure of compounds 5a-d has been obtained by X-ray
analysis. The crystals of 1-oxido-pyrimidin-2-yl-cymantrene 5c (Fig. 2) were obtained by
recrystallization from diethyl ether/methanol mixture.
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Fig. 2. ORTEP structure of 5c with 50% probability thermal ellipsoids. Selected bond
distances (Ǻ) and angles (deg): N(1)-O(4), 1.2997(16); C(8)-C(9), 1.4569(19); O(4)-N(1)-C(9),
123.07(12); C(4)-C(8)-C(9), 130.33(14); O(4)-N(1)-C(12), 117.93(13); N(1)-C(9)-C(8),
120.81(13).
The monoclinic green crystals of 5c have centrosymmetric space group (Fig. 2). The bond
lengths and bond angles are close to the standard ones. The heterocycle is in the plane of the
cyclopentadienyl fragment (Cp). The distance between the manganese atom and Cp plane is
1.768 Å. Moreover, strongly shortened contacts С(7)-Н…О(4) [х, 1-у, z-0.5] indicate the
presence of the weak hydrogen bonds between Cp and oxygen of CO-group of two molecules.
Fig. 3. Fragment of the molecular packing of 1-oxido-pyrimidin-4-yl-cymantrene 5c.
A spatial convergence of CO-groups to an interatomic distance (about ≈3.2 Å, Fig. 3) is
due to the molecules stacking in the crystal and as a consequence the weak π-π interaction of the
groups. In addition, shortened intermolecular C...C contacts of heterocycles fragments are
observed in the crystal.
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Depending on the crystallization conditions, compound 5f could exist in several allotropic
forms (Fig. 4).
Fig. 4. ORTEP structure of 5f with 50% probability thermal ellipsoids. Selected bond distances
(Ǻ) and angles (deg) are presented in Tables S3 and S4 (see Supporting information).
The brown needles of orthorhombic modification of 5f has chiral spatial symmetry group
P212121 (Fig. 5). As a result the crystals are the enantiomers agglomerate. The bond lengths and
valence angles of the molecule are close to the standard ones. The Ph-group at C(3) is
approximately in the plane of the heterocycle (dihedral angle 8 °), at the same time phenyl at
C(6) is angled by 58°. The cyclopentadienyl ring with respect to the plane of the heterocycle is
located by the 10° angle. The fact that the protons of the Cp fragment are able to form shortened
O...H and N...H contacts at 0.1 - 0.2 Å less than the sum of van der Waals radii indicates the
strong polarization of the C-H bonds and the existence of the C-H acidity. Furthermore π- π
stacking of Ph group at C(3) and the Cp fragment of the molecule with the distance C(18)-C(21)
[x-1, y, z] 3.28 Å is observed.
Fig. 5. Fragment of the molecular packing of 3,6-diphenyl-1,2,4-triazine-5-yl-cymantrene
5f (orthorhombic crystal system). H-atoms were omitted for clarity.
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The monoclinic crystals of 5f were isolated as brown prisms (Fig. 6). The crystals have the
centrosymmetric space group P21/c as a racemate of enantiomers. The calculated crystal density
(1.506 g/cm3) is higher than the calculated orthorhombic crystal density (1.475 g/cm3). In
general the geometry of molecules in monoclinic and orthorhombic crystals systems has no
significant differences (Figure 5). In comparison with the orthorhombic system molecule, the
divergence of the measured corresponding bond lengths are about 0.02, which close to a random
measurement error. The Ph-group at C(3) is practically in the plane of the heterocycle, phenyl at
C(6) is angled by 54 °. The Cp fragment with respect to the plane of the heterocycle is located by
the 19° angle.
Fig. 6. Fragment of the molecular packing of 3,6-diphenyl-1,2,4-triazine-5-yl-cymantrene
5f (monoclinic crystal system). H-atoms were omitted for clarity.
The crystalline packing is layered. The layers are oriented in the plane (100). The
intermolecular contact of the C(22)H proton of Cp and O(3)-atom of CO [x, 1.5-y, z-0.5] 2.489
Å is the most significant as an associated with the C-H acidity. There are no other substantially
shortened contacts in the crystal.
3. Conclusion
In summary, we have developed regioselective and simple synthetic approach of
transition metal free cross-coupling of azine-N-oxides and cymantrenyl lithium. The
azinylcymantrenes derivatives could be produced in good yields under mild reaction
conditions. It has been found that aromatization of intermediate σH-adducts depends on
the structure of the starting azine N-oxides, and can be realized in both oxidative and
eliminative modes.
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4. Experimental
4.1. Methods and materials
All reactions were carried out under argon using the standard Schlenk techniques. The 1H-
NMR (400 MHz) and 13C-NMR (100 MHz) spectra were recorded on a NMR spectrometer (400
MHz). Chemical shifts are given in δ values (ppm) using TMS as the internal standard and
CDCl3, acetone-d6 as the solvents. Electrospray mass spectra were recorded in positive mode
with maXis impact high resolution Q-TOF mass spectrometer in 50-2500 Da mass range by
direct infusion of sample solutions in methanol using kdScientific syringe pump at 120 uL/hr
flow rate. Modified instrument settings of a pre-installed method Direct_Infusion_100-1000
were used. Mass calibration was performed using ES-TOF G1969-85000 tuning mix or lithium
acetate in MeOH/ACN/water mixture by HPC or Enhanced Quadratic methods. All data were
collected and analyzed with Compass for oTof series 1.7/DataAnalysis 4.2 software package.
The IR spectra were recorded using Fourier-transform infrared spectrometer equipped with a
diffuse reflection attachment. The elemental analysis was carried out on automated analyzer. The
course of the reactions was monitored by TCL on 0.25 mm silica gel plates (Merck 60F 254).
The column chromatography was performed on silica gel (Silica gel 60, 0.063-0.200 mm (70-
230 mesh)). Cymantrene was purchased from Aldrich. Starting heterocyclic-N-oxides were
prepared according to the published procedure [21, 23].
4.2. General Procedure
4.2.1. Synthesis of 5a-d
1.6 M Solution of n-BuLi in hexane (0.76 mL, 1.2 mmol) was added to solution of
cymantrene (1.0 mmol) in anhydrous THF (5 mL) under the atmosphere of argon at -78 °C.
After 40 minutes stirring of the reaction mixture the solution of corresponding heterocycle-N-
oxides 1a-d (1.0 mmol) in anhydrous THF (7 mL) was added. After stirring the reaction mixture
at -78 °C for 1.5 hours and then for an hour at room temperature, solution of DDQ (3.8 mmol) in
hydrous THF (10 mL) was added. Finally, the reaction mixture was filtrated off through the
neutral alumina and was purified on silica gel (using appropriate solvent as the eluent). The
solution was concentrated under reduce pressure. Finally, the reaction mixture was purified on
silica gel. The eluate was concentrated to dryness in vacuo.
4.2.2. Synthesis of 5e-g
1.6 M Solution of n-BuLi in hexane (0.76 mL, 1.2 mmol) was added to solution of
cymantrene (1.0 mmol) in anhydrous THF (5 mL) under the atmosphere of argon at -78
°C. After 40 minutes stirring of the reaction mixture the solution of corresponding
heterocycle-N-oxides 1e-g (1.0 mmol) in anhydrous THF (7 mL) was added. After
stirring the reaction mixture at -78 °C for 1.5 hours and then for an hour at room
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temperature. The reaction mixture was purified on silica gel (using appropriate solvent as
the eluent). The eluate was concentrated to dryness under reduce pressure.
The physicochemical characteristics of quinoxaline-2-yl-cymantrene 7e and 3,6-
diphenyl-1,2,4-triazine-5-yl-cymantrene 5f match with the literature [18c].
Experimental data for 5a-d and 5g are summarized in Tables 3 and 4.
4.3. X-ray data collection
Crystallographic data for 5c and 5f: Yellow single crystals of 5c and 5f were obtained
by crystallization from diethyl ether. X-ray diffraction analysis was performed on X-ray
diffractometer Xcalibur S equipped with CDD detector (Mo-Kα graphite-monochromated
radiation, λ = 0.71073 Å for 5c, λ = 1.54184 Å for 5f (monoclinic crystal system) and λ =
1.54180 for 5f (orthorhombic crystal system), ω-scanning technique, the scanning step was 1°
and the exposure time per frame of 10 s at 295(2) K. Analytical absorption correction was used
in the reflection intensities [24]. The structure was solved by the direct method and refined
applying the full matrix least-squares against F2 with anisotropic displacement parameters for
hkl
all non-hydrogen atoms using the SHELX97 program package [25]. All hydrogen atoms were
located in different electron density maps and refined using a riding model with fixed thermal
parameters.
4.3.1. Crystal Data of compounds 5c
C12H4MnN2O4, M =298.14, monoclinic, a = 15.8561(10) Å, b = 12.1148(5) Å, c =
12.5676(14) Å, β = 101.543(7)°, V = 2325.0(3) Å3, space group C2/c, Z = 8, ꢀ(Mo Kα) = 1.146
mm-1, 8645 reflections measured, 3495 unique (Rint = 0.0190) which were used in all
calculations. The final wR2= 0.068 (all data) and R1= 0.0294 (I>2σ(I)). Largest diff. peak/hole
0.814/0.677 e Å-3.
4.3.2. Crystal Data of compounds 5f (monoclinic crystal system)
C23H14MnN3O3, M =435.31, monoclinic, a = 16.749(9) Å, b = 9.748(5) Å, c =
12.489(5) Å, β = 109.67(4)°, V = 1920.1(16) Å3, space group P2(1)/c, Z = 4, ꢀ(Mo Kα) = 5.856
mm-1, 16633 reflections measured, 3261 unique (Rint = 0.0920) which were used in all
calculations. The final wR2= 0.1187 (all data) and R1= 0.0507 (I>2σ(I)). Largest diff. peak/hole
0.406/-0.465 e Å-3.
4.3.3. Crystal Data of compounds 5f (orthorhombic crystal system)
C23H14MnN3O3, M =435.31, orthorhombic, a = 7.319(6) Å, b = 15.607(3) Å, c =
17.158(9) Å, β = 90.00°, V = 1960.0(18) Å3, space group P212121, Z = 4, ꢀ(Mo Kα) = 5.736 mm-
1, 7212 reflections measured, 2958 unique (Rint = 0.0603) which were used in all calculations.
The final wR2= 0.1097 (all data) and R1= 0.0455 (I>2σ(I)). Largest diff. peak/hole 0.237/-0.294 e
Å-3.
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Table 3
Rf, IR, Elemental Analysis, ESI-MS and Melting Points Data for 5a-d,g
Rf (eluent)
0.1 (CH2Cl2)
IR (ν, cm-1)
2015, 1920
(CO); 1597,
1564, 1518
(N-O)
Elemental analysis
Found: C, 58.59; H,
3.08; N, 3.83
Calc for C17H10MnNO4:
C, 58.81; H, 2.90; N,
4.03
Found: C, 58.80; H,
3.18; N, 3.98
Calc for C17H10MnNO4:
C, 58.81; H, 2.90; N,
4.03
Found: C, 48.37; H,
2.17; N, 9.51
Calc for C12H7MnN2O4:
C, 48.32; H, 2.35; N,
9.40
Found: C, 55.65; H,
2.83; N, 8.04
Calc for C16H9MnN2O4:
C, 55.19; H, 2.61; N,
8.05
ESI-MS, m/z (%)
[M+H]+:=348.0061
(59.2%)
M.p., °C
143
5a
5b
5c
5d
5g
0.15
2014, 1906
[M+H]+:=348.0067
(36.2%)
166
147
154
180
(hexane:EtOAc, (CO); 1584,
1:1)
1556, 1504
(N-O)
0.5 (EtOAc)
2018, 1917
(CO); 1585,
1527, 1506
(N-O)
[M+H]+: 298.9861
(96.2%)
0.2
2013, 1910
[M+H]+: 349.0014
(5.1%)
(hexane:EtOAc, (CO); 1613,
1:1)
1583, 1549
(N-O)
0.3 (EtOAc)
2015, 1944,
1911 (CO)
Found: C, 61.62; H,
3.53; N, 9.81
[M+H]+: 437.0428
(29.5%)
Calc for C22H13MnN4O3:
C, 60.55; H, 2.98; N,
12.84
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Table 4
1H and 13C NMR Data for 5a-d,ga
1H NMR data
13C NMR data
4.92 (m, 2H, C5H4), 6.10 (m, 2H, C5H4), 82.67, 86.69 (CH-Cp); 90.98 (C-Cp); 117.25;
7.46-7.79 (m, 5H, Quin), 8.78 (m, 1H, 120.13; 120.26; 124.90; 128.15; 128.67;
5a
5b
5c
3-H)
129.00; 130.87; 142.86; 224.3 (CO)
4.98 (m, 2H, C5H4), 5.64 (m, 2H, C5H4), 81.92, 89.52 (CH-Cp); 100.13 (C-Cp);
7.59 (m, 3H, Isoquin), 7.79 (m, 1H, 122.99; 124.90; 127.63; 128.20; 128.95;
Isoquin), 8.20-8.24 (m, 2H, Isoquin)
129.33; 137.63; 137.75; 138.64; 224.64 (CO)
4.94 (m, 2H, C5H4), 6.02 (m, 2H, C5H4), 83.26 (CH-Cp); 85.38 (C-Cp); 87.11 (CH-
7.35 (s, 1H, Pyrim), 8.09 (s, 1H, Pyrim), Cp); 117.59; 142.19; 149.37; 151.44; 223.38
8.96 (s, 1H, Pyrim)
(CO)
5db 4.99 (m, 2H, C5H4), 5.68 (m, 2H, C5H4), 69.19 (C-Cp); 83.57, 90.42 (CH-Cp); 121.46;
7.67 (m, 1H, Phthal), 7.84 (m, 1H, 124.18; 129.02; 129.32; 130.59; 132.82;
3
Phthal), 7.92-7.94 (br.d, 1H, J = 8.0 134.78; 152.59; 225.72 (CO)
3
Hz, Phthal), 8.20-8.22 (br.d, 1H, J =
8.0 Hz, Phthal), 9.02 (s, 1H, 3-H)
4.78 (m, 2H, C5H4), 5.27 (m, 2H, C5H4), 83.27, 88.16 (CH-Cp); 91.74 (C-Cp); 124.19,
7.49 (m, 1H, 2-Py), 7.58-7.62 (m, 5H, 125.62, 127.29, 129.25, 129.30, 129.65;
Ph), 7.92 (m, 1H, 2-Py), 8.58 (m, 1H, 2- 130.27, 135.39; 137.21; 150.58; 151.67;
5g
Py), 8.91 (m, 1H, 2-Py)
152.87; 155.44; 160.82; 223.19 (CO)
a Spectra were recorded in DMSO-d6
b 13C NMR spectrum for 5d was recorded in acetone-d6
Acknowledgments
We are grateful for financial supports from the Russian Science Foundation (Project № 14-
13-01177) and the Russian Foundation for Basic Research (Project No. 16-33-00554).
Appendix A. Supplementary data
It contains 1H and 13C NMR spectra for compounds 5a-g and procedure for the synthesis of
5g. Crystallographic data for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre, CCDC 1813572, 1813979, 1813571 for compounds 5c, 5f
(monoclinic crystal system) and 5f (orthorhombic crystal system), respectively.
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References
[1]
(a) G. Jaouen, A. Vessieres, Pure Appl. Chem. 57 (1985) 1865–1874;
(b) C.G. Riordan, Bioorganometallic chemistry (Themed issue), Dalton Trans. 22
(2009) 4261–4384;
(c) Bioorganometallics, (Ed.: G. Jaouen), Wiley-VCH, Weinheim, Germany, 2006,
465 p.;
(d) E. A. Hillard, G. Jaouen, Organometallics 30 (2011) 20–27;
(e) R. Mahato, W. Tai, K. Cheng, Adv. Drug Delivery Rev. 63 (2011) 659–670;
(f) B. Wang, T. Siahaan, R. Solerto, Drug Delivery: Principles and Applications,
Wiley-Interscience, Hoboken, 2005, 448 p.;
(g) V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Prodrugs:
Challenges and Rewards Springer, New York, 2007.
[2]
[3]
A. Pejović, I. Damljanović, D. Stevanović, M. Vukićević, S. B. Novaković, G. A.
Bogdanović, N. Radulović, R. D. Vukićević, Polyhedron 31 (2012) 789–795.
(a) B. Maity, M. Roy, B. Banik, R. Majumdar, R. R. Dighe, A. R. Chakravarty,
Organometallics 29 (2010) 3632–3641;
(b) B. Maity, S. Gadadhar, T. K. Goswami, A. A. Karande, A. R. Chakravarty, J.
Chem. Soc., Dalton Trans. 40 (2011) 11904–11913;
(c) B. Balaji, B. Banik, P. K. Sasmal, B. Maity, R. Majumdar, R. R. Dighe and A. R.
Chakravarty, Eur. J. Inorg. Chem. (2012) 126–135.
[4]
[5]
M. Salmain, K. L. Malisza, S. Top, G. Jaouen, M. - C. Sénéchal-Tocquer, D.
Sénéchal, B. Caro, Bioconjugate Chem. 5 (1994) 655–659.
(a) I.A. Utepova, O.N. Chupakhin, V.N. Charushin, Heterocycles 76 (2008) 39–72;
(b) I.A. Utepova, A.A. Musikhina, O.N. Chupakhin, Russ. Chem. Bull., Int. Ed.
65(11) (2016) 2523–2558.
[6]
(a) K. Lam, W.E. Geiger, J. Organomet. Chem. 817 (2016) 15–20;
(b) T.R. Johnson, B.E. Mann, J.E. Clark, R. Foresti, C.J. Green, R. Montterlini,
Angew. Chem. Int. Ed. 42 (2003) 3722–3729;
(c) H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. (2009) 4292–
4298;
(d) S.D. Lepore, A. Khoram, D.C. Bromfield, P. Cohn, V. Jairaj, M.A. Silvestri, J.
Org. Chem. 70 (2005) 7443–7446;
(e) Z. Zhang, S.D. Lepore, Tetrahedron Lett. 43 (2002) 7357–7360;
(f) H. Graden, N. Kann, Curr. Org. Chem. 9 (2005) 733–763;
13

ACCEPTED MANUSCRIPT
(g) L.M. Dorozhkin, V.A. Nefedov, A.G. Sabelnikov, V.G. Sevastjanov, Sens.
Actuators B 99 (2004) 568–570.
[7]
(a) M. Hromadová, M. Salmain, N. Fischer-Durand, L. Pospisil, G. Jaouen,
Langmuir 22 (2006) 506–511;
(b) M. Hromadová, M. Salmain, R. Sokolova, L. Pospisil, G. Jaouen, J. Organomet.
Chem. 668 (2003) 17–24.
[8]
[9]
D.I. Bezuidenhout, B. van der Westhuizen, P.J. Swarts, T. Chattergoon, O.Q. Munro,
I. Fernández, J.C. Swarts, Chem. Eur. J. 20 (2014) 4974–4985.
(a) T.T. To, C.B. Duke III, C.S. Junker, C.M. O'Brien, C.R. Ross II, C.E. Barnes,
C.E. Webster, T.J. Burkey, Organometallics 27 (2008) 289–296;
(b) E.J. Heilweil, J.O. Johnson, K.L. Mosley, P.P. Lubet, C.E. Webster, T.J. Burkey,
Organometallics 30 (2011) 5611–5619;
(c) E.S. Kelbysheva, M.G. Ezernitskaya, T.V. Strelkova, Y.A. Borisov, A.F.
Smol'yakov, Z.A. Starikova, F.M. Dolgushin, A.N. Rodionov, B.V. Lokshin, N.M.
Loim, Organometallics 30 (2011) 4342–4353;
(d) L.N. Telegina, M.G. Ezernitskaya, I.A. Godovikov, K.K. Babievskii, B.V.
Lokshin, T.V. Strelkova, Y.A. Borisov, N.M. Loim, Eur. J. Inorg. Chem. (2009),
3636–3643;
(e) T.T. To, E.J. Heilweil, C.B. Duke III, K.R. Ruddick, C.E. Webster, T.J. Burkey,
J. Phys. Chem. A 133 (2009) 2666–2676;
(f) G.R. Letterman, C.B. Duke III, T.T. To, T.J. Burkey, C.E. Webster,
Organometallics 33 (2014) 5928–5931;
(g) C.B. Duke III, R.G. Letterman, J.O. Johnson, J.W. Barr, S. Hu, C.R. Ross II, C.E.
Webster, T.J. Burkey, Organometallics 33 (2014) 485–497;
(h) L. Li, G. Zhang and Z. Pang, J. Organomet. Chem. 695 (2010) 588–594;
(i) E.S. Kelbysheva, L.N. Telegina, A.N. Rodionov, T.V. Strelkova, M.G.
Ezernitskaya, B.V. Lokshin, N.M. Loim, Eur. J. Inorg. Chem. (2016) 3767–3773.
[10] R.M. Islamova, S.V. Nazarova, I.A. Utepova, A.A. Musikhina, O.N. Chupakhin,
Dokl. Chem. 446 (2012) 215–219.
[11] (a) C. Mari, S. Mosberger, N. Llorente, S. Spreckelmeyer, G. Gasser, Inorg. Chem.
Front. 3 (2016) 397–405;
(b) M. Wenzel, M. Patra, C. H. R.Senges, I. Ott, J. J. Stepanek, A. Pinto, P.
Prochnow, C. Vuong, S. Langklotz, N. Metzler-Nolte, J.E. Bandow, ACS Chemical
Biology 8(7) (2013) 1442–1450.
14

ACCEPTED MANUSCRIPT
[12] T. Dallagi, M. Saidi, A. Vessières, M. Huché, G. Jaouen, S. Top, J. Organomet.
Chem. 734 (2013) 69–77.
[13] I.S. Kovalev, D.S. Kopchuk, G.V. Zyryanov, V.L. Rusinov, O.N. Chupakhin, V.N.
Charushin, Russ. Chem. Rev. (Engl. Transl.) 84(12) (2015) 1191–1225.
[14] O.N. Chupakhin, V.N. Charushin, Pure Appl. Chem. 89(8) (2017) 1195–1208.
[15] C.K. Ingold, Structure and Mechanism in Organic. Chemistry, 2nd ed., Cornell
University Press, Ithaca, New York, 1969, 835 p.
[16] O.N. Chupakhin, V.N. Charushin, H. van der Plas, Nucleophilic Aromatic
Substitution of Hydrogen, Academic Press., San Diego, New York, 1994, 367 p.
[17] (a) Y. Araki, K. Kobayashi, M. Yonemoto, Y. Kondo, Org. Biomol. Chem. 9 (2011)
78–80;
(b) K. Inamoto, Y. Araki, S. Kikkawa, M. Yonemoto, Y. Tanaka, Y. Kondo, Org.
Biomol. Chem. 9 (2011) 4438–4441.
[18] (a) O.N. Chupakhin, I.A. Utepova, I.S. Kovalev, V.L. Rusinov, Z.A. Starikova, Eur.
J. Org. Chem. 5 (2007) 857–862;
(b) I.A. Utepova, A.E. Lakhina, M.V. Varaksin, I.S. Kovalev, V.L. Rusinov, P.A.
Slepukhin, M.I. Kodess, O.N. Chupakhin, Russ. Chem. Bull. (Int. Ed.) 57 (2008)
2156–2161;
(c) I.A. Utepova, A.A. Musikhina, O.N. Chupakhin, P.A. Slepukhin, Organometallics
30 (2011) 3047–3053;
(d) O.N. Chupakhin, M.V. Varaksin, I.A. Utepova, V.L. Rusinov, Arkivoc VI (2009)
208–220.
[19] (a) I.A. Utepova, O.N. Chupakhin, P.O. Serebrennikova, A.A. Musikhina, V.N.
Charushin, J. Org. Chem. 79 (2014) 8659–8667;
(b) A.A. Musikhina, I.A. Utepova, P.O. Serebrennikova, O.N. Chupakhin, V.N.
Charushin, Russ. J. Org. Chem. (Engl. Transl.) 49 (2013) 1191–1194.
[20] V. Charushin, O. Chupakhin, Metal free C-H functionalization of aromatics.
Nucleophilic displacement of hydrogen, in: B.U.W. Maes, J. Cossy, S. Polanc (Eds.),
The Series Topics in Heterocyclic Chemistry, vol. 37, Springer, Switzerland, 2014,
283 p.;
[21] D.N. Kozhevnikov, V.L. Rusinov, O.N. Chupakhin, Adv. Heterocycl. Chem. 82
(2002) 261–305.
[22] I.S. Kovalev, V.L. Rusinov, O.N. Chupakhin, Chem. Heterocycl. Compd. 45(2)
(2009) 176–181.
[23] H. Yamanaka, T. Sakamoto, S. Niitsuma, Heterocycles 31(5) (1990) 923–967.
15

ACCEPTED MANUSCRIPT
[24] R.C. Clark, J.S. Reid, Acta Crystallorg., Sect. A. 51 (1995) 887–897.
[25] G.M. Sheldrick, Acta Crystallorg., Sect. A. 64 (2008) 112–122.
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Highlights:
•
•
•
New azinylcymantrenes derivatives have been synthesized.
Their structures were confirmed by means of single-crystal X-ray diffraction.
Aromatization of ntermediate can be realized in both oxidative and eliminative modes.