Synthesis of Aminophenylpolycarbonitriles from Arylidenemalononitriles by the Michael Reaction

Article abstract of DOI:10.1134/S1070363220080289

Abstract: The reactions of arylidenemalononitriles with malononitrile, methyl cyanoacetate and cyanoacetamide yielded aminophenyldi- and tricarbonitriles. Formation of these compounds occurs through the dehydrocyanation step of the corresponding aminohexe

Full text of DOI:10.1134/S1070363220080289

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 8, pp. 1573–1577. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 8, pp. 1304–1308.
SHORT
COMMUNICATIONS
Synthesis of Aminophenylpolycarbonitriles
from Arylidenemalononitriles by the Michael Reaction
M. A. Maryasova,*, V. V. Davydovaa, O. E. Nasakina, S. A. Shteingoltsb, and O. A. Lodochnikovab
a I.N. Ulyanov Chuvash State University, Cheboksary, 428015 Russia
b A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of the Russian Academy of Sciences,
Kazan, 420088 Russia
*e-mail: marsikprovisor@mail.ru
Received February 20, 2020; revised February 20, 2020; accepted February 27, 2020
Abstract—The reactions of arylidenemalononitriles with malononitrile, methyl cyanoacetate and cyanoacetamide
yielded aminophenyldi- and tricarbonitriles. Formation of these compounds occurs through the dehydrocyanation
step of the corresponding aminohexenepolycarbonitriles.
Keywords: arylidenemalononitriles, malononitrile, aminophenylcarbonitriles, 4-aminocyclohex-4-ene-1,1,3,3,5-
pentacarbonitrile, SK2 inhibitors
DOI: 10.1134/S1070363220080289
Cycloaddition reactions are widely used in organic
synthesis. The Michael reaction can also be used to obtain
cyclic products [1–3]. Previously, 4-aminocyclohex-
4-ene-1,1,3,3,5-pentacarbonitriles have been obtained
by reacting malononitrile with two equivalents of
arylidenemalononitrile in the presence of a base [4].
Structurally similar compounds have been also prepared
through the reaction of malononitrile with levulinic and
succinic aldehydes [5].
diseases) [6]. In addition, a number of compounds
with an aminophenylcarbonitrile moiety exhibit anti-
inflammatory [7, 8] and antimicrobial activity [9].
In order to optimize the methods for the synthesis
of this type of polycarbonitrile compounds, we
studied the reactions of vinylidene cyanide 1а and
arylidenemalononitriles 1b–1e with malononitrile
2а, cyanoacetamide 2b, and methyl cyanoacetate 2c
(Scheme 1). The reactions were carried out in ethanol in
the presence of triethylamine with heating (40–50°С) for
3–4 h.As a result, the corresponding aminophenyldi- and
-tricarbonitriles 4a–4h were obtained in 55–84% yields.
Aminophenylpolycycarbonitriles are precursors of
inhibitors or modulators of protein kinase SK2 activity,
which are used to treat tumor diseases, infections,
degenerative processes (Alzheimer’s and Parkinson’s
Scheme 1.
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MARYASOV et al.
Scheme 2.
In the case of the reaction of vinylidene cyanide
of NH2 groups (3187–3557 cm–1), conjugated cyano
groups (2189–2235 cm–1), С=O (1660–1783 cm–1), NH
(1636 cm–1) and С=С moieties (1518–1727 cm–1). In
the 1H NMR spectra, the signals of NH2 protons appear
at 3.45–5.54 and 7.39–8.04 ppm (4e, 4f). The signals
of the protons of the COONH2 fragment are recorded
in the range of 7.71–8.29 ppm; the signals at 3.28 and
3.82 ppm correspond to the COOCH3 and OCH3 groups,
respectively. The 13C NMR spectra are characterized by
the presence of signals from the carbon atoms of the cyano
groups in the range of 110.7–118.0 ppm and signals from
the C=O groups in the range of 162.1–165.2 ppm.
1а with malononitrile 2а, 4-aminocyclohex-4-ene-
1,1,3,3,5-pentacarbonitrile 3а was initially isolated,
which was subsequently easily oxidized to 2-aminobenzo-
1,3,5-tricarbonitrile 4а. This confirms the fact that
in the case of arylidenemalononitriles 1b–1e, the
reaction proceeds through the stage of formation of
aminocyclohexenecarbonitriles followed by dehydro-
cyanation.
Structure of compound 3а was confirmed by the
single crystal X-ray diffraction analysis (Fig. 1). The
X-ray diffraction data obtained by us at 150 K are
generally similar to those obtained earlier at 293 K [10].
In the crystal, the six-membered ring of the molecule is
in the six-membered envelope conformation: the С2–6
atoms are in one plane, the C1 atom is out off this plane.
In the crystal, hydrogen bonds are observed with the
participation of hydrogen atoms of the amino group and
nitrogen atoms of the cyano groups.
When arylidenemalononitrile 1c reacted with methyl
cyanoacetate 2b, an alternative course of the reaction was
observed. Thus, 6-amino-4-(4-methoxyphenyl)-2-oxo-
2H-pyran-3,5-dicarbonitrile 5 was obtained (Scheme 2).
1
Structure of compound 5 was confirmed by H, 13C
NMR, IR spectroscopy, and mass spectrometry methods.
In summary, a simple and convenient method for the
synthesis of aminophenylpolycarbonitriles, potential
inhibitors of protein kinase SK2, was developed.
Structure of compounds 4a–4h was proved by 1H, 13C
NMR, IR spectroscopy and mass spectrometry. The IR
spectra of compounds 4а–4h contain absorption bands
EXPERIMENTAL
The reaction progress and the purity of the synthesized
compounds were monitored by thin-layer chromatography
on Sorbfil plates (eluent—ethyl acetate, development
with UV light, iodine vapor, or thermal decomposition).
Melting points were determined on an Optimelt MPA100
apparatus. IR spectra were recorded on an FSM-1202
Fourier spectrometer from a thin layer (suspension in
1
mineral oil). H and 13C NMR spectra were recorded
on a Bruker DRX-500 spectrometer (500 and 125 MHz,
respectively) using DMSO-d6 as the solvent. Mass
spectra were recorded on a Bruker Ultraflex MALDI-
TOF instrument. Elemental analysis was performed on
a varioMicrocube CHN analyzer.
Fig. 1. General view of the molecule of 3a in the crystal
(CCDC 1978850).
X-Ray diffraction analysis of the crystal of compound
3a was carried out on a Bruker Smart APEX II CCD
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SYNTHESIS OF AMINOPHENYLPOLYCARBONITRILES
1575
automatic diffractometer [graphite monochromator,
λ(MoKα) = 0.71073 Å, ω-scanning, 150 K]. Structure
was solved by a direct method and refined first in the
isotropic and then in the anisotropic approximation using
the SHELXL-2017/1 program [11]. Semi-empirical
absorption accounting was carried out using the SADABS
software package. H(C) hydrogen atoms were placed into
geometrically calculated positions and included into the
refinement using the rider model. H(N) hydrogen atoms
were identified from the difference series of electron
density and refined isotropically. All calculations were
performed using the WinGX program [12].
temperature for 3–4 h.After cooling to room temperature,
the mixture was acidified with a diluted solution of
sulfuric or hydrochloric acid. The precipitate was filtered
off, washed with 2 mL of cooled ethanol and dried.
2-Aminobenzene-1,3,5-tricarbonitrile (4a). Yield
55%, mp 203–205°C (EtOH). IR spectrum, ν, cm–1: 3346
br (NH), 2204 s (C≡N), 1650 br (NH), 1623 m (C=С). 1H
NMR spectrum, δ, ppm: 7.67 s (2Н, СН), 3.45 br. s (2Н,
NH2). 13C NMR spectrum, δC, ppm: 155.1 (C2), 136.3 (С4,
С6), 116.1 (С5СN), 115.3 (C1CN, C3CN), 88.4 (C5), 85.1
(C1, C3). Mass spectrum, m/z (Irel, %): 168 (100) [M]+.
Found, %: C 63.95; H 2.12; N 34.05. C9H4N4. Calculated,
%: C 64.28; H 2.40; N 33.32.
Crystals of compound 3a are pale yellow, prismatic,
monoclinic, C11H6N6, M 222.22, a = 14.204(5) Å, b =
6.5700 (18) Å, c = 12.157 (4) Å, β = 115.104 (18)°, V =
1027.4 (5) Å3, dcalc = 1.437 g/cm3, μ(Mo) = 0.096 mm–1,
Z = 4, space group P21/c. Scanning angle interval is
3.17° < θ < 26.65°. 8457 reflections were measured, of
which 2234 were independent, 1693 of which were with
I ≥ 2σ. Final values of divergence factors are: R = 0.0427
for the observed reflections and Rw = 0.1052 (for all
reflections), the fitting parameter is 1.013. The maximum
and minimum peaks of the residual electron density are
0.262 and –0.197 e/Å3. The structure was deposited at the
Cambridge Crystallographic Database (CCDC 1978850).
5′-Amino-[1,1′:3′,1′′-terphenyl]-2′,4′,6′-
tricarbonitrile (4b). Yield 62%, mp 305–307°C (EtOH).
IR spectrum, ν, cm–1: 3300, 3212 br (NH), 2213, 2192 s
(C≡N), 1650 br (NH), 1562 m (C=C). 1H NMR spectrum,
δ, ppm: 7.52 t (6Н, СН, JHH = 3.3 Hz), 7.44 d (2Н, СН,
JHH = 2.2 Hz), 7.43–7.41 m (2Н, СН), 5.54 br. s (2Н,
NH2). 13C NMR spectrum, δC, ppm: 161.4 (C5), 157.8
(C1 C3), 156.7 (C1C1′, C3C1′′), 135.0 (C3′, C5′, C3′′, C5′′),
,
130.2 (C2′, C6′, C2′′, C6′′), 128.7 (C4′, C4′′ , 128.3 (C2),
)
115.4 (C4CN, C6CN), 115.2 (C2CN), 85.9 (C4, C6). Mass
spectrum, m/z (Irel, %): 320 (0.5) [M]+, 321 (2.3) [M +
H]+. Found, %: C 79.15; H 3.02; N 16.35. C21H12N4.
Calculated, %: C 78.73; H 3.78; N 17.49.
4-Aminocyclohex-4-ene-1,1,3,3,5-pentacarbonitrile
(3а). To a mixture of 4 mmol of vinylidene cyanide
1а and 2 mmol of malononitrile 2а in 5 mL of cooled
diethyl ether was added 1 drop of diluted and cooled
triethylamine. The formed precipitate was immediately
filtered off and washed with 2 mL of cooled diethyl
ether. The precipitate was filtered off and dried. When
stored in air, it turns yellow and partially tarred. Upon
recrystallization, compound 4а is formed. Yield 34%,
mp 110–111°C (EtOH). IR spectrum, ν, cm–1: 3355 br
(NH), 2268, 2201 s (C≡N), 1647 br (NH), 1623 m (C=С).
1H NMR spectrum, δ, ppm: 3.63 s (2Н, СН2), 3.24 br. s
5′-Amino-4,4′′-dimethoxy-[1,1′:3′,1′′-terphenyl]-
2′,4′,6′-tricarbonitrile (4c). Yield 56%, mp 284–285°C
(EtOH). IR spectrum, ν, cm–1: 3306, 3203 br (NH), 2216,
2189 s (C≡N), 1727, 1650 br (NH), 1620 m (C=C). 1H
NMR spectrum, δ, ppm: 7.41 d (4Н, СН, JHH = 8.5 Hz),
7.07 d (4Н, СН, JHH = 8.6 Hz), 5.41 br. s (2Н, NH2), 3.82 s
(6Н, ОСН3). 13C NMR spectrum, δC, ppm: 161.3 (C4′,
C4′′), 160.9 (C5), 157.1 (C1, C3), 156.5 (C1C1′, C3C1′′),
130.2 (C2′, C6′, C2′′, C6′′), 126.7 (C3′, C5′, C3′′, C5′′), 115.4
(C4CN, C6CN), 114.0 (C2CN), 86.0 (C2), 81.4 (C4, C6),
55.4 [(OCH3)2]. Mass spectrum, m/z (Irel, %): 380 (1.0)
[M]+, 381 (3.9) [M + H]+. Found, %: C 70.95; H 5.44;
N 15.82. C23H16N4O2. Calculated, %: C 72.62; H 4.24;
N 14.73.
(1Н, NH2), 3.19 s (2H, CH2), 3.14 br. s (1Н, NH2). 13
C
NMR spectrum, δC, ppm: 143.9 (C4), 117.4 (C5CN),
113.6 (C3(CN)2), 112.2 (C1(CN)2), 69.8 (C5), 34.4 (C2),
32.0 (C6), 31.1 (C3), 28.2 (C1). Mass spectrum, m/z (Irel,
%): 222 (1.3) [M]+. Found, %: C 58.52; H 3.64; N 35.48.
C11H6N6. Calculated, %: C 59.46; H 2.72; N 37.82.
5′-Amino-4,4′′-dihydroxy-[1,1′:3′,1′′-terphenyl]-
2′,4′,6′-tricarbonitrile (4d). Yield 59%, mp 310–312°C
(EtOH). IR spectrum, ν, cm–1: 3352 br (NH), 3152 w
(OH), 2216 s (C≡N), 1641 (NH), 1605, 1565 m (C=C).
General procedure for the synthesis of compounds
4а–4h, 5. To a suspension of 4 mmol of the corresponding
nitrile 1а–1e in 5–7 mL of ethanol were added 2 mmol of
malononitrile 2а–2c and 2–3 drops of triethylamine. The
resulting mixture was heated to 40–50°С and stirred at this
1H NMR spectrum, δ, ppm: 7.29 d (4Н, СН, JHH
=
8.64 Hz), 6.87 d (4Н, СН, JHH = 8.6 Hz), 5.23 br. s (2Н,
NH2), 5.23 s (2Н, ОН). 13C NMR spectrum, δC, ppm:
161.6 (C4′, C4′′), 159.5 (C5), 157.0 (C1, C3), 156.5 (C1C1′,
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MARYASOV et al.
C3C1′′), 130.4 (C2′, C6′, C2′′, C6′′), 125.0 (C3′, C5′, C3′′, C5′′),
115.5 (C4CN, C6CN), 115.4 (C2CN), 85.9 (C2), 81.3 (C4,
C6). Mass spectrum, m/z (Irel, %): 352 (0.5) [M]+, 353
(2.2) [M + H]+. Found, %: C 72.03; H 3.82; N 15.04.
C21H12N4O2. Calculated, %: C 71.58; H 3.43; N 15.90.
Methyl 5′-amino-2′,6′-dicyano-[1,1′:3′,1′′-
terphenyl]-4′-carboxylate (4h). Yield 58%, mp
144–143°C (EtOH). IR spectrum, ν, cm–1: 3355, 3193 br
(NH), 2197 s (C≡N), 1745 w (C=O), 1666 br (NH),
1597 m (C=C). 1H NMR spectrum, δ, ppm: 7.45–7.35 m
(10Н, С6Н5), 6.81 s (2Н, NН2), 3.28 s (3Н, ОCН3). 13
C
5′-Amino-2′,6′-dicyano-4,4′′-dinitro-[1,1′:3′,1′′-
terphenyl]-4′-carboxamide (4e). Yield 71%, mp 180–
181°C (EtOH). IR spectrum, ν, cm–1: 3440, 3342, 3220 br
(NH), 2223 s (C≡N), 1692 s (C=O), 1622 br (NH),
1606, 1518 m (C=C). 1H NMR spectrum, δ, ppm: 8.37 d
(2H, СН, JHH = 8.9 Hz), 8.29 s (2Н, CONH2),8.11 d (2Н,
СН, JHH = 8.9 Hz), 8.04 br. s (1H, NH2), 7.90 br. s (1H,
NH2). 13C NMR spectrum, δC, ppm: 162.1 (CONH2),
148.8 (C5), 148.3 (C1, C3), 148.2 (C1C1′, C3C1′′), 136.1
(C4′, C4′′), 131.0 (C2′, C6′, C2′′, C6′′), 124.2 (C3′, C5′, C3′′,
C5′′), 124.1 (C4), 115.8 (C6CN), 115.7 (C2CN), 110.7 (С2),
90.7 (С6). Mass spectrum, m/z (Irel, %): 428 (2.7) [M]+,
429 (1.0) [M + H]+. Found, %: C 59.54; H 3.92; N 17.18.
C21H12N6O5. Calculated, %: C 58.88; H 2.82; N 19.62.
NMR spectrum, δC, ppm: 165.2 (COOCH3), 162.4 (C5 ,
)
135.8 (C1), 134.3 (C3), 129.5 (C1C1′), 129.2 (C3′, C5′, C3′′,
C5′′), 129.0 (C3C1′′), 128.9 (C2′, C6′, C2′′, C6′′), 128.7 (C4′,
C4′′), 128.4 (C4), 118.0(C6CN), 117.0 (C2CN), 89.4 (С2),
74.1 (C6), 53.4 (OCH3). Mass spectrum, m/z (Irel, %):
353 (1.5) [M]+, 354 (2.4) [M + H]+. Found, %: C 72.21;
H 3.72; N 11.02. C22H15N3O2. Calculated, %: C 74.78;
H 4.28; N 11.89.
6-Amino-4-(4-methoxyphenyl)-2-oxo-2H-pyran-
3,5-dicarbonitrile (5). Yield 55%, mp 152–153°C
(EtOH). IR spectrum, ν, cm–1: 3301, 3206 br (NH), 2220,
2191 s (C≡N), 1638 w (C=O), 1612 br (NH), m 1568
(C=C). 1H NMR spectrum, δ, ppm: 7.40 d (2, СН, JHH
=
8.8 Hz), 7.06 d (2Н, СН, JHH = 8.5 Hz), 4.83 br. s (2H,
NH2), 3.82 s (3Н, ОСН3). 13C NMR spectrum, δC, ppm:
161.0 (C4), 160.7 (C6), 158.0 (C4′), 156.9 (C2), 130.2
(C2′, C6′), 126.9 (C4C1′), 115.7 (C5CN), 115.4 (C3CN),
114.0 (C3′, C5′), 85.9 (C3), 81.3 (C5), 55.4 (OCH3). Mass
spectrum, m/z (Irel, %): 267 (100.0) [M]+. Found, %: C
64.02; H 4.64; N 13.56. C14H9N3O3. Calculated, %: C
62.92; H 3.39; N 15.72.
5′-Amino-2′,6′-dicyano-[1,1′:3′,1′′-terphenyl]-4′-
carboxamide (4f). Yield 84%, mp 270–271°C (EtOH).
IR spectrum, ν, cm–1: 3452, 3339 br (NH), 2213 s (C≡N),
1748 s (C=O), 1638 br (NH), 1606 m (C=C). 1H NMR
spectrum, δ, ppm: 7.76 br. s (2Н, СONH2), 7.53 t (6Н, СН,
JHH = 3.2 Hz), 7.49 d (2Н, СН, JHH = 2.4 Hz), 7.47–7.46 m
(2Н, СН), 7.39 br. s (2H, NH2). 13C NMR spectrum, δC,
ppm: 162.6 (CONH2), 159.8 (С5), 156.7 (C1, C3), 156.5
(C1C1′, C3C1′′), 134.7 (C3′, C5′, C3′′, C5′′), 130.3 (C2′, C6′,
C2′′, C6′′), 128.7 (C4′, C4′′), 128.0 (С4), 116.2 (C6CN),
115.4 (C2CN), 88.7 (С2), 74.8 (С6). Mass spectrum, m/z
(Irel, %): 338 (1.2) [M]+, 339 (0.5 [M + H]+. Found, %:
C 75.32; H 4.74; N 15.12. C21H14N4O. Calculated, %: C
74.54; H 4.17; N 16.56.
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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