Indole-3-carbaldehydes Arylhydrazones as Multisite C-Nucleophiles in the Reactions with Quinazoline

Article abstract of DOI:10.1134/S1070363220090030

Abstract: C,C-Coupling of indole-3-carbaldehyde arylhydrazones with quinazoline in trifluoroacetic acid has occurred at position 5 or 7′ of the hydrazone molecule and has afforded the σ-adducts. The C,C-coupling has been accompanied by a change in the E-configuration of the C=N bond of the starting hydrazones to the Z-configuration in the formed quinazoline trifluoroacetyl hydrazides.

Full text of DOI:10.1134/S1070363220090030

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 9, pp. 1601–1610. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 9, pp. 1337–1348.
Indole-3-carbaldehydes Arylhydrazones as Multisite
C-Nucleophiles in the Reactions with Quinazoline
Yu. A. Azeva,*, O. S. Koptyaevaa, O. S. Eltsova, Yu. A. Yakovlevaa, A. N. Tsmokalyuka,
A. V. Ivoilovaa, E. A. Seliverstovaa, T. A. Pospelovaa, and V. A. Bakuleva
a Ural Federal University, Yekaterinburg, 620002 Russia
*e-mail: azural@yandex.ru
Received April 15, 2020; revised April 15, 2020; accepted April 25, 2020
Abstract—C,C-Coupling of indole-3-carbaldehyde arylhydrazones with quinazoline in trifluoroacetic acid has
occurred at position 5 or 7′ of the hydrazone molecule and has afforded the σ-adducts. The C,C-coupling has been
accompanied by a change in the E-configuration of the C=N bond of the starting hydrazones to the Z-configuration
in the formed quinazoline trifluoroacetyl hydrazides.
Keywords: arylhydrazones, indole-3-carbaldehydes, C,C-coupling, quinazoline, trifluoro hydrazides
DOI: 10.1134/S1070363220090030
Quinazoline core is a part of natural alkaloids [1, 2].
The derivatives of quinazoline include the compounds
revealing various types of biological activity, including
antimicrobial, antiallergic, hypotonic, antiviral [3],
antitumor [4], and radioprotective [5] ones.
present, atom economic processes that correspond to the
principles of green chemistry are the most promising
[11]. The reactions of nucleophilic C‒C coupling are
among them, since they can proceed under conditions of
acid catalysis (without the use of metal catalysts) and are
theoretically waste-free [12, 13].
The addition of C-nucleophiles at 3-methyl-
quinazolinium iodide yielding 4-substituted 3,4-di-
hydroquinazolines has been reported [6]. Furthermore,
it has been found that unsubstituted quinazoline
reacts with indole, 5-methyl-2-phenylpyrazol-3-one,
1,3-dimethylbarbituric acid, and pyrogallol in the presence
of an acid, resulting in the 4-σ-adducts [7]. The examples
of quinazoline arylation with 1,3,5-trimetoxybenzene,
1-(4-metoxybenzylidene)-2-phenylhydrazine, and
o-phenylenediamines have been described [8].
In this study, phenylhydrazones of indole-3-
carbaldehydes 3а–3e were used as nucleophiles which
were prepared by short-term heating of indole-3-carbal-
dehydes 1a, 1b with phenylhydrazines 2a–2d in aqueous
ethanol in the presence of HCl (Scheme 1).
The structure of the obtained compounds was
1
confirmed using Н and 13С NMR spectroscopy,
1
mass spectrometry, and the 2D experiments: H‒13C
1
gHSQC/gHMBC and H‒15N gHMBC. In the case of
arylhydrazones, the Е-configuration of the C=N bond
is thermodynamically favorable, as confirmed by X-ray
diffraction analysis [14, 15].
Efficient quinazoline-based drugs can be prepared via
varying the substituents (pharmacophore fragments) in
these compounds, which allows tuning of their physico-
chemical properties (hydrophilicity and lipophilicity),
bioavailability, and activity.
Heating of quinazoline 4 with hydrazones 3a–3c
in trifluoroacetic acid (TFA) gave compounds 5a–5c
(Scheme 2).
Indole core is a constituent of tryptophane and
its metabolites as well as certain natural alkaloids
and antibiotics [9]. Indole derivatives have revealed
antitumor, antiviral, antiinflammatory, antidepressant,
and other types of activity [10].
The structure of compounds 5a–5c was confirmed
by the data of 1H, 13C, and 19F NMR spectroscopy, mass
spectrometry, and 2D correlation spectroscopy (1H‒13C
gHMBC/gHSQC and 2D 1H‒15N gHMBC).
We continue to develop methods for the synthesis
of biologically active derivatives of quinoxaline [7]. At
It was found that the С5 atom of the indole part of the
hydrazone 3a–3c molecule was added at the С4′ atom of
1601

1602
AZEV et al.
Scheme 1.
Scheme 2.
quinazoline. That fact was confirmed by the presence of
the characteristic cross peaks of the interaction between
the С7a atom with the broadened signal of the Н4 proton
in compounds 5 were observed as two-proton doublets
revealing spin-spin interaction and recognized from
the cross-interactions with the nitrogen atom in the 2D
1H–15N gHMBC spectrum.
1
and the H6 atom doublet in the 2D H–13C HMBC
spectrum of compound 5a. If the alternative addition of
the nucleophile at the С6 atom of the indole fragment
took place, the interaction of the С7a atom with the Н4
hydrogen atom doublet would be observed.
1Н NMR spectra of compounds 5a–5c contained a
characteristic singlet of the Н4′′ proton (6.25‒6.26 ppm)
at the sp3-hybridized С4′′ quinazoline atom, the 13С NMR
signal of which was observed at 54.14‒54.61 ppm. The
signals of the H5′ and Н6′ protons of the aryl substituent
Acylation of the intermediate A with TFA occurred
at the N3′ atom, as confirmed by significant downfield
shift of the N3′ atom signal in the 15N NMR spectrum.
The chemical shift of that nitrogen atom in the spectrum
of the starting hydrazone 3a was 155.43 ppm, compared
to 215.5 ppm for the acylation product (thifluoroacetyl
hydrazide 5a). The proton signals of the NH groups of
the indole and quinazoline moieties were retained in the
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INDOLE-3-CARBALDEHYDES ARYLHYDRAZONES AS MULTISITE C-NUCLEOPHILES
1603
Scheme 3.
Scheme 4.
1Н NMR spectra of compound 5a. Hence, the acylation
occurred at the nitrogen atom of the hydrazine fragment.
N‒H∙∙∙O=C hydrogen bond was determined from the
13C NMR spectrum without proton decoupling. Since
an intramolecular hydrogen bond was formed in the
molecule, it could be assumed that compounds 5c‒5c in
DMSO-d6 had a molecular conformation in which the
C=N bond was in Z-configuration.
1
The 2D H–13C gHMBC spectra of the acylation
products 5a–5c contained strong cross-peaks between
the quartet signal of the С8′ atom of the trifluoroacetyl
group and the broadened signal of the N1H proton at
155.4 ppm (5a, JСF = 36.7 Hz). Moreover, the 2hJ(C8′H1)=
3.2 Hz value resulting from the stable intramolecular
Synthesis of the trifluoroacetyl derivatives 5c‒5c
likely occurred in several stages. Hydrazones 3a–3c
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1604
AZEV et al.
Scheme 5.
were first added at quinazoline 4 to form intermediate
A. Further acylation of the molecule started with the
addition of TFA at the С=N bond (intermediate B),
followed by the intramolecular rearrangement affording
the N-acetyl intermediate C. Subsequent dehydration of
intermediate C gave compounds 5a–5c with the hydrogen
bond between the carbonyl group of the trifluoroacetyl
fragment and the NH group of the indole moiety closing
the 9-membered pseudo cycle (Scheme 3).
the broadened signal of the N1H group proton, evidencing
the formation of the intramolecular N‒H∙∙∙O=C hydrogen
bond. The presence of the intramolecular hydrogen bond
in the molecule suggested that the obtained compounds
6a, 6b in DMSO-d6 took the conformation with the C=N
bond in the Z-configuration, as in adducts 5.
Similarly to adducts 5, the formation of the
trifluoroacetyl quinazoline derivatives 6 (Scheme 4)
likely involved the stages of addition of hydrazone to
quinazoline and acylation of the adduct with TFA at
the N3′H group closing the 9-membered pseudo cycle
via the trifluoroacetyl group and the NH proton of the
indole moiety.
In contrast to compounds 3a–3c, addition of
hydrazines 3d, 3e (R1 = H, CH3;R2 = H) to the quinazoline
core occured at С7′-position to yield adducts 6a, 6b
(Scheme 4).
Mass spectra of compounds 6 contained the molecular
Hence, thestudyofreactivityofindole-3-carbaldehydes
phenylhydrazones 3a‒3e towards quinazoline 4 in acidic
medium revealed two active С-nucleophilic sites in the
hydrazone molecules: the С7′ atom of the phenyl fragment
and the С5 atom of the indole moiety. Since the addition
to quinazoline in the absence of a substituent in position
7′ of the phenyl fragment (compounds 3d, 3e) occurred
via the С7′ atom, higher nucleophilicity of that site in
comparison with the С5 atom could be suggested.
ions corresponding to the products of addition of the
hydrazone molecule at the quinazoline core. The Н
1
NMR spectrum contained the singlet of the proton at
the quinazoline sp3-hybridized С4′′ atom, at 6.24 ppm.
Two doublets of the aromatic protons at 7.61 and
7.92 ppm (6a) confirmed the addition of hydrazones 3d,
3e at compound 4 via the para-position of the phenyl
group. Since the signal of the NH proton of the indole
moiety in adducts 6 was preserved, acylation apparently
took place in the hydrazine part of the molecule.
Since the С,С-coupling was accompanied by the
acylation of the hydrazone NH group, we expected
that heating of the starting hydrazones 3 in TFA should
also lead to their acylation into hydrazide 7; that was
confirmed in the experiment: heating of hydrazones
1
The 2D H–13C gHMBC spectra of adducts 6a, 6b
(like those of compounds 5) contained strong cross-
peaks between the quartet signal of the С8′ atom of
trifluoroacetyl group at 155.9 ppm (6a, 2JСF = 36.3 Hz) and
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INDOLE-3-CARBALDEHYDES ARYLHYDRAZONES AS MULTISITE C-NUCLEOPHILES
1605
3d, 3e in TFA gave the trifluoroacyl derivatives 7a, 7b
(Scheme 5).
The structure of the acylation products 7a, 7b was
1
confirmed by the data of Н, 13С, 15N, and 19F NMR
spectroscopy including the 2D correlation experiments
(1H–13C HSQC/HMBC). Since the spectra of compounds
7a, 7b contained the signals of the indole NH protons,
the acylation evidently occurred at the hydrazine part
Field strength, Gauss
1
of the molecule. The 2D H–13C HMBC spectra of the
Fig. 1. Experimental (1) and calculated (2) ESR spectra of
cation-radical of compound 3b in acetonitrile.
products, similarly to the cases of compounds 5 and 6,
contained strong cross-peaks between the quartet signal
2
of the trifluoroacetyl carbon atom (155.4 ppm, JСF
=
whereas the effect of the electron-accepting substituents
was the opposite. The highest oxidation potentials were
observed for trifluoroacetyl hydrazides 7a, 7b.
36.7 Hz) and the indole N1H proton (11.01 ppm), marking
the spin-spin interaction via the hydrogen bond.
The obtained hydrazides 7 were not involved in the
С,С-coupling with quinazoline 4: compounds 7 were
isolated unchanged upon heating of quinazoline 4 with
hydrazides 7a, 7b in TFA. Inertness of hydrazides 7 in the
С,С-coupling reaction showed that the first stage of the
described process occurred as the addition of hydrazones
3 to quinazoline, followed by acylation.
Since the curves of electrochemical oxidation of
the hydrazones and hydrazides were similar, it could
be suggested that they reflected similar process. The
wave of oxidation of the considered compounds likely
corresponded to the single-electron transfer. That
suggestion was confirmed by linear correlation between
the oxidation potential and the calculated data on the
electron affinity of cations of compounds 3 and 7
(Table 2).
During the study of the hydrazones reactivity, the
electron-donor properties of the considered molecules
were assessed by means of voltammetry. The sensitivity
of the compounds to oxidation (the hydrazones fragment
NH‒N=CH is readily oxidized [16]) can be used to
describe their nucleophilicity.
The study of the reactivity features of the reactions of
compound 3b in trifluoroacetic acid revealed the electron
spin resonance (ESR) signal evidencing the single-
electron transfer yielding the cation-radical. It could be
suggested that the donor-acceptor interaction occurs in the
molecule of hydrazone 3b in the presence of an acceptor
(tetrabutylammonium fluoride), affording a cation-radical
(Scheme 6). The calculated ESR spectrum of the cation-
Electrochemical oxidation of compounds 3a‒3e and
7a, 7b led to the appearance of a single strong peak in
the voltammogram. The introduction of electron-donating
substituents in the molecule of hydrazones 3 noticeably
reduced the potential of the first oxidation wave (Table 1),
Table 1. Oxidation potentials of hydrazones 3a–3e and hydrazides 7a, 7b in acetonitrile
R
R1
3a
3b
3c
CН3
F
3d
H
H
3e
CН3
H
7a
7b
CН3
NO2
0.811
CН3
CН3
0.500
CН3
NO2
0.908
CН3
CН3
0.892
R2
Eo, V
0.581
0.625
0.588
Table 2. Energy of oxidation and cations electron affinity of compounds 3a–3e and 7a, 7b in acetonitrile
cat
EA
Comp. no.
EOx, V
0.811
0.470
0.581
0.625
0.588
0.870
0.860
E
, eV
Eopt, eV
–26873
–22377.5
–24008
–20237.5
–21307.6
–39127.8
–34632.7
E
, eV
c at
opt
3a
3b
3c
3d
3e
7a
7b
–26867.9
–22372.9
–24003.3
–20232.7
–21302.9
–39122
5.006898
4.680361
4.761995
4.843629
4.761995
5.768817
5.714394
–34627
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

1606
AZEV et al.
Scheme 6.
radical of compound 3b was in good accordance with the
solution of compound 3b, that with the lowest oxidation
experimental one (Fig. 1).
potential.
The adducts at the N3 site were not formed in the
reaction (at least, they were not detected in the reaction
products), due to weakness of the C–N bond. The
formation of stable adducts was possible upon the
interaction of quinazoline 4 with C-nucleophilic sites С2,
С5, and С7′ of hydrazones 3. Localization of the electron
density at the С7′ atom and spatial availability of the latter
led to the formation of the adducts at that site (Fig. 2a).
Spatial shielding of the С7′ and С2 sites (in hydrazones
3a–3c) emerged the nucleophilic properties of the С5 atom
with the highest occupancy of the HOMO-1 and HOMO-2
levels (Fig. 2b). Indeed, the С5 and C7′ nucleophilic sites
were involved in the С,С-coupling of hydrazones 3 with
quinazoline 4.
It is known that the radical processes are fast and
occur under mild conditions, but the С,С-coupling of
hydrazones 3 with quinazoline 4 at room temperature was
not observed using 1H NMR spectroscopy. Characteristic
NMR signals of the adducts 5 and 6 appeared in the
spectrum upon keeping of the reaction mixture in a
spectrometer cell during 30 h at 50°С. Evidently, the
radical species did not appear at the coordinate of the
considered reactions.
To elucidate the nucleophilic sites in the molecules
of the studied compounds, we performed the quantum-
chemical simulations and determined the localization
of the electron density in the highest orbitals. Using
compound 3d as an example, we simulated the electron
density in three HOMO levels with close energy
eigenvalues.
Analysis of the structure of hydrazones 3 suggested
that the localization of the negative charge at the positions
С5 and C7′ of the hydrazones was due to the conjugation of
the π-electrons of the aromatic nuclei with the electrons
of the amino groups of molecules 3. Deactivation of both
nucleophilic sites in the molecule of hydrazide 7 was
due to the effect of the electron-accepting trifluoroacetyl
group. Calculation of the eigenvalues of energy (eV)
Visual analysis of the obtained data (Fig. 2) revealed
that the highest electron density was localized at the N3
atom of the hydrazone 3d molecule. That was reflected
in the strongest electron-donating activity of the N sites
and determined the oxidation potential of the hydrazone
as well as the formation of the stable cation-radical in a
ꢀɚꢁꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢂꢀEꢁ
Fig. 2. Electron density distribution in the molecule of compound 3b: (a) HOMO, (b) HOMO-1, HOMO-2.
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INDOLE-3-CARBALDEHYDES ARYLHYDRAZONES AS MULTISITE C-NUCLEOPHILES
1607
and occupancy of the molecular orbitals (Fig. 3) in the
molecule of the trifluoroacetyl derivative 7a showed that
the HOMO energy of that molecule was significantly
lower than that of the non-acylated compound 3d:
Localization of the electron density at the С5 and С7′
atoms of compounds 7a, 7b was not revealed (Fig. 3),
explaining the inertness of molecules 7a, 7b as
С-nucleophiles.
Fig. 3. Electron density distribution in the molecule of
compound 7a (HOMO).
Trifluoroacetyl hydrazides 7 showed the highest
oxidation potentials (Table 1) among the considered
compounds, meaning that the electron-donor properties
of those derivatives were less prominent in comparison
with hydrazones 3. That was likely the reason of the
inertness of compounds 7a, 7b towards С,С-coupling
with quinazoline 4.
Switzerland; background electrolyte: tetrabutylammonium
tetrafluoroborate, “special pure” grade, Panreac, Spain in
acetonitrile, “special pure” grade, Kriokhrom, Russia).
Cyclic voltammograms were recorded in a linear mode
with potential scanning rate 100 mV/s.
In summary, phenylhydrazones of indole-3-carbal-
dehydes were multisite С-nucleophiles which could be
used in the C,C-coupling reactions for the preparation
of various derivatives of quinazoline promising in view
of their biological activity. The С,С-coupling of the
hydrazones was accompanied by the acylation of the NH
group of the hydrazone fragment with TFA, changing
the Е-configuration of the C=N hydrazone bond to the
Z-configuration.
Electron affinity energy of cations of the studied
hydrazones in gas phase was determined accounting for
solvation in acetonitrile. The simulation was performed in
the scope of the density functional theory using the B3LYP
exchange-correlation potential in the 6-31G++(d, p)
basis set [17,18] implemented in GAUSSIAN09 software
[19]. The coefficient of determination for the linear
regression of the electron affinity with respect to oxidation
potential (R2) equaled 0.84.
EXPERIMENTAL
Quantum-chemical simulation of the ESR spectrum of
the compound 3b cation-radical was performed via DFT
with geometry optimization using the B3LYP method
in the 6-31+G(d) basis set. The superfine interaction
constants were calculated via the UB3LYP method in
the IGLO-III basis [20]. The simulations were performed
using ORCA 4.01 software [21]. Simulation of the ESR
spectra was performed using EasySpin software [22].
Commercial chemicals (Sigma Aldrich, Merck) were
used as received. The reactions progress was monitored
by TLC on silica gel plates (Merck).
1H, 19F, 13С, and 15N NMR spectra of the solutions
in DMSO-d6 were recorded using Bruker AVANCE
NEO-600 and AVANCE-400 spectrometers. 1Н and 19
F
chemical shifts were measured with respect to the internal
references—tetramethylsilane and trichlorofloromethane,
respectively and those of 13С were determined with
reference to the solvent signal (DMSO-d6). Mass spectra
(EI) were registered using a MicrOTOF-Q instrument
(Bruker Daltonics), ionization potential being 75 eV
at 250°С. High-resolution mass spectra (electrospray
ionization) were obtained using an Agilent 6545 Q-TOF
LC-MS instrument (Agilent Technologies, USA).
Compound 3d was prepared as described elsewhere
[23].
Synthesis of hydrazones 3a–3c, 3e (general proce-
dure). A solution of 0.5 mmol of 2-methyl-1Н-indole-
3-carbaldehyde 1a, 1b in 3 mL of ethanol was added to
a solution of 0.5 mmol of the corresponding hydrazine
2a–2d and 0.02 mL of conc. НСl in 3 mL of water. The
obtained mixture was refluxed during 3‒5 min and cooled.
The hydrazone precipitate was filtered off and dried.
Cyclic voltammetry measurements were performed
using a μAutolab Type III potentiostat-galvanostat
(Metrohm, Switzerland) in a standard three-electrode
cell (working electrode: glassy carbon disk pressed
in fluoroplastic, d = 2.5 mm, Metrohm, Switzerland;
auxiliary electrode: glassy carbon rod, Metrohm,
Switzerland;referenceelectrode:silverchloride, Metrohm,
2-Methyl-3-{(Е)-[2-(4-nitrophenyl)hydrazinyl-
idene]methyl}-1H-indole (3a). Yield 59%, mp 288–
1
289°С. H NMR spectrum (600 MHz), δ, ppm: 2.54 s
(3H, CH3), 7.09 br. s (2H, H4′), 7.12‒7.15 m (2H, H5,
H6), 7.33‒7.37 m (1H, H7), 8.12‒8.17 m (3H, H4, H5′),
8.34 s (1H, H1′), 10.98 s (1H, N3′H), 11.47 s (1H, N1H).
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AZEV et al.
13C NMR spectrum (151 MHz), δC, ppm: 108.08 (C3),
110.56 (C5′), 111.41 (C7), 120.86 (C5), 121.11 (C4),
122.23 (C6), 125.68 (С3a), 126.93 (C6′), 136.18 (C7a),
137.38 (C7′), 139.65 (C2), 140.25 (C1′), 151.31 (C4′).
15N NMR spectrum (61 MHz), δN, ppm: 144.79 (N1),
155.43 (N3′), 303.13 (N2′). Mass spectrum, m/z (Irel,
%): 294 (100) [M]+, 157 (86), 130 (64). Mass spectrum
(HRMS ESI-MS), m/z: 295.1203 [M + H]+ (calculated
for C16H15N4O2: 295.1190).
(C2), 118.04 (C3), 129.91 (C3a), 130.99 (C4), 127.76 (C5),
127.49 (C6), 127.78 (C7), 132.84 (C7a), 139.22 (C1′),
139.44 (Ci), 124.4 (Co), 129.27 (Cm), 127.67 (Cp), 115.98
(CF3), 155.28 (C=O). 15N NMR spectrum (61 MHz), δN,
ppm: 126.8 (N1), 305 (N3′), 218.5 (N3′). Mass spectrum,
m/z (Irel, %): 249 (100) [M]+.
Synthesis of trifluoroacetyl hydrazides 5a–5c
(general procedure). A mixture of 0.5 mmol of
quinazoline 4 and 0.5 mmol of the corresponding
hydrazone 3a–3c in 3 mLof TFAwas refluxed during 65‒
70 h. The solvent was evaporated off; the residue was
suspended in 2 mL of water, filtered off, and dried.
2-Methyl-3-{(Е)-[2-(4-methylphenyl)hydrazinyl-
idene]methyl}-1H-indole (3b). Yield 61%, mp 143–
1
144°C. H NMR spectrum (600 MHz), δ, ppm: 2.21 s
(3H, CH3), 2.51 s (3H, C2CH3), 6.94 d (2H, H4′, J =
7.9 Hz), 7.03 d (2H, H5′, J = 8.1 Hz), 7.10 d. d (2Н, H5,
H6, J = 5.9, 3.1 Hz), 7.31 d. d (1H, H7, J = 5.6, 3.4 Hz),
8.15 s (2H, H1′, H4), 9.64 br. s (1H, N3′H), 11.23 s (1H,
N1H). 13C NMR spectrum (151 MHz), δC, ppm: 108.79
(C3), 111.14 (C7), 111.85 (C5′), 120.25 (C5), 121.02 (C4),
121.77 (C6), 125.88 (С3a), 126.24 (C7′), 129.96 (C6′),
134.61 (C1′), 136.08 (C7a), 136.76 (C2), 144.58 (C4′). 15N
NMR spectrum (61 MHz), δN, ppm: 140.1 (N3′), 140.5
(N1), 311.7 (N2′). Mass spectrum, m/z (Irel, %): 263 (100)
[M]+, 157 (68), 130 (41). Mass spectrum (HRMS ESI-
MS), m/z: 264.1506 [M + H]+ (calculated for C17H18N3:
264.1495).
4-(2-Methyl-3-{(Z)-[2-(4-nitrophenyl)-2(2,2,2-
trifluoroacetyl)hydrazinylidene]methyl}1Н-indol-5-
yl)-1,4-dihydroquinazolin-3-ium 2,2,2-trifluoroacetate
1
(5a). Yield 68%, mp 143–144°C. H NMR spectrum
(600 MHz), δ, ppm: 2.29 s (3H, H8), 6.26 s (1H, H4′′), 7.13 d
(1H, H5′′, J = 7.6 Hz), 7.20 d (1H, H8′′, J = 7.9 Hz), 7.24 t
(1H, H6′′, J = 7.5 Hz), 7.37 t (1Н, H7′′, J = 7.6 Hz), 7.50 d
(2Н, H7, J = 8.0 Hz), 7.53 s (1H, H4), 7.55 d (1Н, H6,
J = 8.1 Hz), 7.76 s (1H, H1′), 7.87 d (2Н, H5′, J = 9.0 Hz),
8.41 d (2Н, H6′, J = 8.9 Hz), 8.56 s (1H, H2′′), 11.12 s (2H,
N1H, N3′′H), 12.39 s (1H, COOH). 13C NMR spectrum
(151 MHz), δC, ppm: 12.22 (C8), 54.61 (C4′′), 116.39
(CF3, J = 288.7 Hz), 117.61 (C8′′), 119.67 (C3), 121.93
(C4a′′), 124.75 (2C5′), 125.51 (2C6′), 127.62 (C6), 127.86
(C6′′), 128.60 (C5′′), 128.72 (C7), 129.86 (C8a′′), 130.05
(C7′′), 130.24 (C3a), 130.46 (C4), 133.64 (C7a), 137.63
(C2), 141.26 (C1′), 142.44 (C5), 144.73 (C4′), 146.25 (C7′),
2-Methyl-3-{(E)-[2-(4-fluorophenyl)hydrazinyl-
idene]methyl}-1H-indole (3c). Yield 68%, mp
1
133‒134°C. H NMR spectrum (600 MHz), δ, ppm:
2.51 s (3H, CH3), 6.98‒7.02 m (2H, H5, H6), 7.05‒7.11 m
(4H, H5′, H6′), 7.29‒7.33 m (1H, H7), 8.11‒8.14 m (1H,
H4), 8.15 s (1H, H1′), 9.75 s (1H, N3H), 11.23 s (1H,
N1H). 13C NMR spectrum (151 MHz), δC, ppm: 108.65
(C3), 111.16 (C7), 111.83 (C5′), 120.98 (C5), 121.81 (C4),
122.34 (C6), 125.84 (C3a), 126.75 (C7′), 128.40 (C6′),
135.17 (C1′), 136.07 (C7a), 136.98 (C2), 143.52 (C4′). 19F
NMR spectrum (565 MHz): δF ‒127.76 ppm. 15N NMR
spectrum (61 MHz), δN, ppm: 142.2 (N3′), 147.4 (N1),
315.2 (N2′). Mass spectrum, m/z (Irel, %): 267 (100) [M]+,
157 (69), 130 (51). Mass spectrum (HRMS ESI-MS), m/z:
268.1255 [M + H]+ (calculated for C16H15FN3: 268.1245).
2
149.20 (C2′′), 155.83 (COCF3, J = 36.3 Hz), 158.39 q
(COOH, 2J = 31.6 Hz). 19F NMR spectrum (565 MHz),
δF, ppm: ‒73.53, ‒74.00. 15N NMR spectrum (61 MHz),
δN, ppm: 126.1 (N1”, N3′′), 215.5 (N1, N3′), 304.2 (N2′),
369.2 (NO2). Mass spectrum, m/z (Irel, %): 520 (15) [M]+,
390 (31), 131 (100). Mass spectrum (HRMS ESI-MS),
m/z: 521.1565 [M + H]+ (calculated for C26H20F3N6O3:
521.1543).
4-(2-Methyl-3-{(Z)-[2-(4-methylphenyl)-2(2,2,2-
trifluoroacetyl)hydrazinylidene]methyl}-1Н-indol-5-
yl)-1,4-dihydroquinazolin-3-ium 2,2,2-trifluoroacetate
1
2-Methyl-3-[(Е)-(2-phenylhydrazinylidene]-1Н-
indole (3e). Yield 59%, mp 192‒193°С (mp 192‒193°С
[21]). 1H NMR spectrum (600 MHz), δ, ppm: 2.49 s (3H,
CH3), 6.67 t. t (1H, Hp, J = 7.3, 1.2 Hz), 7.03 d. d (2H,
Ho, J = 8.5, 1.2 Hz), 7.08‒7.12 m (2H, H5, H6), 7.21 d. d
(2H, Hm, J = 8.5, 7.3 Hz), 7.31 m (1H, H7), 8.15 m (1H,
H4), 8.17 s (1H, H1′), 9.78 br. s (1H, N3′H), 11.23 s (1H,
N1H). 13C NMR spectrum (151 MHz), δC, ppm: 136.06
(5b). Yield 71%, mp 118–119°C. H NMR spectrum
(400 MHz), δ, ppm: 2.15 s (3H, H8), 2.39 s (3H, H7′), 6.25 s
(1H, H4′′), 7.13 d (1Н, H5′′, J = 8.0 Hz), 7.20 d (1Н, H8′′,
J = 8.0 Hz), 7.24 t (1Н, H6′′, J = 8.0 Hz), 7.42‒7.30 m
(4H, H4,6,7,7′′), 7.87 d (2Н, H5′, J = 8.0 Hz), 7.60 s (1H,
H1′), 8.41 m (2H, H6′), 8.55 s (2H, H2′′), 11.06 s (2H,
N1H, N3′′H), 12.35 s (1H, COOH). 13C NMR spectrum
(101 MHz), δC, ppm: 11.24 (C8), 20.57 (C8′), 54.14
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INDOLE-3-CARBALDEHYDES ARYLHYDRAZONES AS MULTISITE C-NUCLEOPHILES
1609
(C4′′), 111.33 (CF3, J = 284.6 Hz), 117.10 (C3), 117.39
(2C5′), 117.79 (C8′′), 121.45 (C4a′′), 122.55 (C6), 124.36
(2C6′), 126.64 (C6′′), 127.35 (C5′′), 128.15 (C7), 129.33
(C8a′′), 129.71 (C3a), 130.44 (C7′′), 130.97 (C7a), 132.98
(C4), 136.19 (C2), 136.95 (C1′), 137.35 (C5), 138.86
(C4′), 141.84 (C2′′), 148.70 (C7′), 155.67‒154.96 m
(COCF3), 158.13‒157.77 m (COOH). 19F NMR spectrum
(376 MHz), δF, ppm: ‒73.65, ‒74.00. 15N NMR spectrum
(61 MHz), δN, ppm: 128.3 (N1”, N3′′), 221.7 (N1, N3′),
300.6 (N2′). Mass spectrum, m/z (Irel, %): 489 (38) [M]+,
359 (32), 131 (100). Mass spectrum (HRMS ESI-MS),
m/z: 490.1872 [M + H]+ (calculated for C27H23F3N5O:
490.1849).
7.20‒7.24 m (2H, H6′′, H7′′), 7.37 t (1Н, H5, J = 7.7 Hz),
7.41 d (1Н, H4, J = 6.7 Hz), 7.43‒7.45 m (2H, H6,7), 7.61 d
(2Н, H5′, J = 8.4 Hz), 7.69 d (2Н, H8′′, J = 7.6 Hz), 7.92 d
(2Н, H6′, J = 8.4 Hz), 7.98 s (1H, H1′), 8.57 s (1H, H2′′),
8.80 s (1H, H2), 11.18 s (2H, N1H, N3′′H), 12.37 s (1H,
COOH). 13C NMR spectrum (151 MHz), δC, ppm: 54.61
(C4′′), 116.39 (CF3, J = 288.7 Hz), 117.59 (C8′′), 119.17
(C3), 121,42 (C6′), 122.42 (C4a), 126.86 (C7), 127.83
(C6′′), 128.22 (C7′), 128.60 (C5′), 128.73 (C5′′), 129.34
(C7′′), 129.48 (C4), 129.82 (C8a), 130.07 (C3a), 131.90
(C7a), 132.0 (C4′), 139.89 (C7), 140.54 (C5), 141.1 (C6),
2
149.14 (C2′′), 156.00 (COCF3, J = 36.3 Hz), 158.44 q
(COOH, 2J = 30.7 Hz). 19F NMR spectrum (376 MHz), δF,
ppm: ‒73.50, ‒74.12. 15N NMR spectrum (61 MHz), δN,
ppm: 126.9 (N1′, N3′′), 218.6 (N1, N3′), 301.6 (N2′). Mass
spectrum, m/z (Irel, %): 461(20) [M]+, 369 (11), 131 (100).
2-Methyl-4-{3-[2-(4-fluorophenyl)-2(2,2,2-
trifluoroacetyl)hydrazinylidene]methyl}-1Н-indol-5-
yl)-1,4-dihydroquinazolin-3-ium 2,2,2-trifluoroacetate
1
(5c). Yield 65%, mp 123–124°C. H NMR spectrum
4-(4-{2-[(Z)-(2-Methyl-1Н-indol-3-yl)methylidene]-
1-(2,2,2-trifluoacetyl)hydrazinyl}phenyl)-1,4-dihyd-
roquinazolin-3-ium 2,2,2-trifluoroacetate (6b). Yield
(400 MHz), δ, ppm: 2.16 s (3H, H8), 6.25 s (1H, H4′′),
7.13 d (1Н, H5′′, J = 8.0 Hz), 7.20 d (1Н, H8′′, J = 8.0 Hz),
7.25 t (1Н, H6′′, J = 8.0 Hz), 7.44‒7.35 m (4H, H4,6,7,7′′),
7.55‒7.50 d. d (2Н, H6′, J = 14.4, 2.8 Hz), 7.56 d (2Н,
H5′, J = 8.0 Hz), 7.63 s (1H, H1′), 8.55 s (2H, H2′′), 11.08 s
(2H, N1H, N3′′H), 12.32 s (1H, COOH). 13C NMR
spectrum (101 MHz), δC, ppm: 11.14 (C8), 54.14 (C4′′),
116.19 (CF3, J = 286.3 Hz), 117.10 (C8′′), 117.54 (C3),
121.44 (C4a′′), 126.43‒126.97 m (2C6′, 2C5′), 127.43 (C6),
127.72‒127.83 m (C5′′, C6′′), 128.16 (C7), 129.35 (C8a′′),
129.56 (C7′′), 129.88 (C3a), 130.33 (C4), 130.89‒131.03 m
(C7′), 133.03 (C4′), 135.77 (C7a), 136.49 (C2), 139.16
(C1′), 141.86 (C5), 148.69 (С2′′), 154.97‒155.64 m
(COCF3), 157.59‒158.18 m (COOH). 19F NMR spectrum
(376 MHz), δF, ppm: ‒73.55, ‒74.01, ‒114.01. 15N
NMR spectrum (61 MHz), δN, ppm: 127.5 (N1”, N3′′),
218.1 (N1, N3′), 302.5 (N2′). Mass spectrum, m/z (Irel,
%): 493 (35) [M]+, 363 (18), 131 (100). Mass spectrum
(HRMS ESI-MS), m/z: 494.1619 [M + H]+ (calculated
for C26H19F4N5O: 494.1598).
1
55%, mp 121‒122°C. H NMR spectrum (400 MHz),
δ, ppm: 2.21 s (3H, CH3), 6.28 s (1H, H4′′), 7.11 d (1H,
СНAr, J = 7.4 Hz), 7.24 m (2H, CHAr), 7.38 t (1Н, СНAr,
J = 7.7 Hz), 7.44 s (5H, 4CHindole + CHAr), 7.63 s (3H,
CHAr), 7.64 s (1H, H1′), 8.57 s (1H, H2′′), 11.03 m (2H,
NH), 12.37 br. s (1H, COOH). 13C NMR spectrum (151
MHz), δC, ppm: 11.34 (СH3), 55.96 (C4′′), 115.33 (CF3,
J = 147.38 Hz), 118.06 (C8′′), 119.17 (C3), 123.08 (C6′),
124.11 (C4a), 124.53 (C7), 127.50 (C6′′), 127.67 (C7′),
127.74 (C5′), 127.78 (C5′′), 127.95 (C7′′), 129.85 (C8a),
130.97 (C4), 132.86 (C7a), 136.05 (C3a), 138.50 (C4′),
138.87 (C7), 138.87 (C5), 144.98 (C6), 146.48 (C2′′),
2
155.30 (COCF3, J = 36.5 Hz), 158.17 q (COOH, J =
30.9 Hz). 19F NMR spectrum (376 MHz), δF, ppm: ‒73.72,
‒74.07. Mass spectrum, m/z (Irel, %): 475 (27) [M]+, 345
(25), 131 (100).
Compounds 7a, 7b (general procedure). A solution
of 0.3 mmol of hydrazone 3d, 3e in 2 mL of TFA was
heated during 45‒50 h. The solvent was evaporated off
in vacuum; the residue was suspended in 2 mL of water
and adjusted to рН = 7‒8 with aqueous ammonia. The
precipitate was filtered off, washed with 2 mL of water,
and dried.
Trifluoroacetyl hydrazides 6a, 6b (general proce-
dure). A mixture of 0.5 mmol of quinazoline 4 and
0.5 mmol of the corresponding hydrazone 3d, 3e in
3 mL of TFA was refluxed during 65‒70 h. The solvent
was evaporated off in vacuum; the residue was suspended
in 2 mL of water, filtered off, and dried.
2,2,2-Trifluoro-N′-[(Z)-1H-indol-3-ylmethylidene]-
N-phenylacetohydrazide (7a). Yield 55%, mp 154‒
155°С. 1H NMR spectrum (600 MHz), δ, ppm: 7.34 t. t
(1H, Hп, J = 7.5, 1.0 Hz), 7.39 m (1H, H6), 7.43‒7.46 m
(2H, H5, H6), 7.54 d. d (2H, Hm, J = 8.6, 7.5 Hz), 7.70 m
(1H, H4), 7.85 d. d (2H, Hz, Ho, J = 8.6, 1.0 Hz), 7.97 s
4-(4-{2-[(Z)-1H-Indol-3-ylmethylidene]-1-(2,2,2-
trifluoroacetyl)hydrazinyl}phenyl)-1,4-dihyd-
roquinazolin-3-ium 2,2,2-trifluoroacetate (6a). Yield
1
51%,mp 112‒113°C. H NMR spectrum (600 MHz),
δ, ppm: 6.24 s (1H, H4′′), 7.07 d (1Н, H5′′, J = 7.4 Hz),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 9 2020

1610
AZEV et al.
(1H, H1′), 8.78 s (1H, H2), 11.15 s (1H, N1H). 13C NMR
spectrum (151 MHz), δC, ppm: 116.08 (CF3, J = 288.6 Hz),
118.22 (Co), 120.64 (C3), 126.19 (C2), 126.49 (Cп), 127.57
(C6), 128.18 (C5), 128.18 (C7), 129.08 (C4), 129.64 (Cm),
131.36 (C7a), 139.39 (Ci), 139.7 (C1′), 155.52 (C=O, J =
36.2 Hz).19F NMR spectrum (470 MHz): δF ‒74.52 ppm.
Mass spectrum, m/z (Irel, %): 331 (100) [M]+, 262 (44).
11. Anastas, P.T. and Warner, J.C., Green Chemistry Theory
and Practice, New York: Oxford University Press, 1998,
p. 516.
12. Charushin, V.N. and Chupakhin, O.N., Topics in Heterocy-
clic Chemistry, Switzerland: Springer, 2014, no. 37, p. 1.
13. Makosza, M. and Wojciechowski, K., Topics in Heterocy-
clic Chemistry, Switzerland: Springer, 2014, no. 37, p. 50.
14. Zabaleta, N., Uria, U., Reyes, E., Carrillo, L., and Vi-
cario, J.L., Chem. Commun., 2018, vol. 54, p. 8905.
https://doi.org/10.1039/C8CC05311A
15. Tung, T., Tezcan, H., San, M., Bueykguengoer, O., and
Yagbasan, R., Acta Crystallogr. (C), 2003, vol. 59, p. 528.
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2,2,2-Trifluoro-N′-[(Z)-(2-methyl-1H-indol-3-yl)-
methylidene]-N-phenylacetohydrazide (7b). Yield
64%, mp 164‒165°C. 1H NMR spectrum (500 MHz), δ,
ppm: 2.21 s (3H, CH3), 7.43‒7.47 m (5H, H4, H5, H6, H7,
Hp), 7.52 d. d (2H, Ho, J = 8.5, 1.4 Hz), 7.57 d. d (2H, Hm,
J = 8.5, 7.2 Hz), 7.63 s (1H, H1′), 10.99 s (1H, N1H). 13C
NMR spectrum (151 MHz), δC, ppm: ‒115.98 (CF3, J =
288.8 Hz), 118.04 (C3), 124.4 (Co), 127.49 (C6), 127.67
(Cp), 127.76 (C5), 127.78 (C7), 129.27 (Cm), 130.99
(C4), 136.06 (C2), 132.84 (C7a), 139.22 (C1′), 139.44
(Ci), 155.28 (C=O, J = 36.2 Hz). 19F NMR spectrum
(376 MHz): δF ‒74.45 ppm. Mass spectrum, m/z (Irel, %):
345 (80) [M]+, 276 (100).
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Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G.,
Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fuku-
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Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C.,
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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