Knoevenagel Reactions of Indole-3-carbaldehyde. Synthesis of 3-Substituted Indole Derivatives

Article abstract of DOI:10.1134/S1070428018120060

The Knoevenagel condensations of 1H-indole-3-carbaldehyde with various CH acids gave a number of substituted 3-(1H-indol-3-yl)acrylonitriles and acrylamides which were alkylated to afford the corresponding N-alkyl derivatives. The latter were used as Michael acceptors in the synthesis of 4H-pyran, pyridine, 5,6,7,8-tetrahydroquinoline, and [1,3]thiazolo[3,2-a]pyridine derivatives containing an indole fragment.

Full text of DOI:10.1134/S1070428018120060

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1777–1784. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © V.D. Dyachenko, I.O. Matusov, I.V. Dyachenko, V.G. Nenajdenko, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54,
No. 12, pp. 1763–1770.
Knoevenagel Reactions of Indole-3-carbaldehyde.
Synthesis of 3-Substituted Indole Derivatives
V. D. Dyachenkoa, I. O. Matusova, I. V. Dyachenkoa, and V. G. Nenajdenkob*
a Taras Shevchenko Lugansk National University, ul Oboronnaya 2, Lugansk, 92703 Ukraine
b Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
*e-mail: nenajdenko@gmail.com
Received September 5, 2018; revised September 5, 2018; accepted September 7, 2018
Abstract—The Knoevenagel condensations of 1H-indole-3-carbaldehyde with various CH acids gave
a number of substituted 3-(1H-indol-3-yl)acrylonitriles and acrylamides which were alkylated to afford the
corresponding N-alkyl derivatives. The latter were used as Michael acceptors in the synthesis of 4H-pyran,
pyridine, 5,6,7,8-tetrahydroquinoline, and [1,3]thiazolo[3,2-a]pyridine derivatives containing an indole
fragment.
DOI: 10.1134/S1070428018120060
Many physiologically active natural compounds
contain an indole fragment [1, 2], which stimulates
researchers’ interest in indole derivatives. We pre-
viously reported an unusual transformation of piperidi-
nium 3-cyano-5-ethoxycarbonyl-4-(1H-indol-3-yl)-6-
methyl-1,4-dihydropyridine-2-thiolate in boiling acetic
acid, which involved cleavage of the C–C bond
between the indole and dihydropyridine fragments [3].
In this work we studied the condensation of 1H-indole-
3-carbaldehyde (1) with CH acids 2a–2f and 3, alkyla-
tion of the condensation products, and behavior of the
alkyl derivatives as Michael acceptors.
1H-Indole-3-carbaldehyde (1) reacted with CH
acids 2a–2f and 3 in ethanol at room temperature in the
presence of a catalytic amount of morpholine to give
the corresponding Knoevenagel condensation prod-
ucts, 3-(1H-indol-3-yl)prop-2-enamides 4a–4f and
4-(1H-indol-3-ylmethylidene)-3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one (5) (Scheme 1). Compounds like 4
and 5 were synthesized previously by reactions of
3-aminomethylideneindoles with CH acids in a mix-
ture of ethanol and acetic acid [4], on heating in
ethanol in the presence of potassium hydroxide [5] or
L-proline [6], under solvent-free conditions in the pres-
ence of piperidine under microwave irradiation at
160°C [7], or at 85°C in the presence of 4-dimethyl-
aminopyridine [8].
nitrile (6) in DMF in the presence of morpholine at
20°C led to the formation of 2-(1H-indol-3-ylmethyli-
dene)malononitrile (7) as a result of exchange of meth-
ylene components [9, 10] (Scheme 1, a). Substituted
acrylonitrile 7 was also synthesized independently, by
directly reacting 1H-indole-3-carbaldehyde (1) with
malononitrile (6) in ethanol at 20°C in the presence of
morpholine (Scheme 1, b).
The alkylation of 1H-indoles 4a–4f and 7 with
alkyl halides 8a–8e in DMF in the presence of an equi-
molar amount of potassium hydroxide at 20°C regio-
selectively afforded the corresponding N-alkyl deriva-
tives, 3-(1-alkyl-1H-indol-3-yl)prop-2-enenitriles 9a–
9g, despite the presence of two other more nucleo-
philic centers in their molecules, C2 of malononitrile
[11] and amide nitrogen atom [12].
The Michael reaction of substituted acrylonitrile 9a
with dimedone 10 in DMF at 20°C in the presence of
a catalytic amount of morpholine produced the expect-
ed [13–15] 5,6,7,8-tetrahydro-4H-chromene derivative
11 (Scheme 1).
Taking into account ambiguous behavior of 3-al-
kenylindoles 4 in the Michael reaction, we synthesized
2-cyano-3-(1H-indol-3-yl)prop-2-enethioamide (12) by
condensation of 1H-indole-3-carbaldehyde (1) with
cyanothioacetamide (13) in ethanol in the presence of
morpholine at 20°C and studied its behavior as
Michael acceptor toward carbon-centered nucleophiles
Compounds 4 and 5 can be regarded as Michael
acceptors. However, the reaction of 4a with malono-
1777

DYACHENKO et al.
1778
Scheme 1.
CHO
R
R
8a
RCH2CN (2a–2f)
CN
CN
N
N
N
H
H
Z
1
4a–4f
9a–9g
O
O
ZCH2Hlg
(8a–8e)
Me
Me
6
O
H2C(CN)2 (6) –2a
N
Ph
Me
b
N
10
a
3
N
H2C
Ph
N
O
CN
CN
CN
N
Me
Me
N
N
H
O
NH2
Me
O
H
5
7
11
2, 4, R = cyclo-C3H5NHC(O) (a), Me(CH2)6OC(O) (b), 1,3-thiazol-2-ylcarbamoyl (c), PhCH2NHC(O) (d), Furan-2-ylmethyl-
carbamoyl (e), (CN)2C=C(NH2) (f); 8, Hlg = Br, Z = CH2=CH (a); Hlg = Cl, Z = H2NCO (b); Hlg = I, Z = H (c); Hlg = Cl, Z =
EtOC(O) (d), Ph (e); 9, R = CN, Z = CH2=CH (a), Ph (b), EtOC(O) (c), H (d), H2NCO (e); Z = CH2=CH, R = Me(CH2)6OC(O) (f);
cyclo-C3H5NHC(O) (g).
(Scheme 2). Thioamide 12 was synthesized previously
from the same initial compounds in anhydrous ethanol
at room temperature using piperidine or triethylamine
as catalyst [16]; however, neither spectral nor
physicochemical characteristics of the product were
given in [16].
bromoethane (22) instead of 8b followed essentially
the same path, but sulfide 23 underwent in situ intra-
molecular alkylation to produce thiazolopyridine 24
which is promising as intermediate products for the
synthesis of medicines and ensembles of heterocycles
[21–26] (Scheme 2).
The reaction of 12 with Meldrum’s acid (14) in
boiling ethanol in the presence of N-methylmorpholine
involved exchange of methylene components to give
compound 15. In contrast, the condensation of 12 with
dimedone 10 under similar conditions followed the
path typical of (arylmethylidene)cyanothioacetamides
[17–19], leading to hexahydroquinoline derivative 16
(Scheme 2).
We also studied reactions of 3-(1H-indol-3-yl)-2-
cyanoprop-2-enethioamide (12) with enamines. The
reaction of 12 with 4-(cyclopent-1-en-1-yl)morpholine
(17) afforded compound 18 as a result of the Stork
reaction [20] (alkylation of enamines with alkenes).
The three-component condensation of thioamide 12
with ethyl 3-(morpholin-4-yl)but-2-enoate (19) and
2-chloroacetamide (8b) in ethanol at 20°C led to the
formation of dihydropyridine derivative 20 through
intermediate morpholinium salt 21 which was isolated
by us previously [3]. Analogous reaction with 1,2-di-
The structure of all isolated compounds was unam-
biguously proved by a set of physicochemical methods
(see Experimental). The IR spectra of substituted
acrylamides 4a–4f characteristically showed absorp-
tion bands due to stretching vibrations of the N–H,
C≡N, and C=O groups at 3310–3408, 2195–2202, and
1
1665–1708 cm–1, respectively. In the H NMR spectra
of N-alkylindoles 9a–9g we observed signals from
aromatic protons and NCH2 and CH= groups at
δ 5.03–5.66 and 8.59–8.66 ppm, respectively. In the
1H NMR spectrum of substituted 1,4-dihydropyridine
20, signals of protons of the SCH2 group appeared as
two doublets at δ 3.62 and 3.77 ppm with a geminal
2
coupling constant J of 14.9 Hz. Analogous pattern
was observed by us previously in the spectra of
partially hydrogenated 2-(alkylsulfanyl)pyridines
[27–29]; presumably, the SCH2 protons become
nonequivalent due to restricted rotation of the
SCH2C(O)NH2 fragment.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

KNOEVENAGEL REACTIONS OF INDOLE-3-CARBALDEHYDE.
1779
Scheme 2.
O
O
O
Me
O
O
Me
O
14
Me
Me
–13
O
N
O
H
15
S
H2N
CN
CN
NH
S
NH2
1
10
NC
Me
Me
S
N
H
N
O
13
12
H
16
S
Me
O
O
N
CN
NH
N
OEt
17
O
19
N
H
18
S
NH2
S
CN
NH
O
CN
NH2
8b
NH
Me
O
Me
COOEt
COOEt
N
H
HN
21
20
BrCH2CH2Br (22)
Br
S
S
CN
CN
NH
N
Me
COOEt
Me
COOEt
HN
HN
23
24
EXPERIMENTAL
The IR spectra were recorded in mineral oil on
an IKS-40 spectrometer. The H and C NMR spectra
were measured on a Varian VXR-400 spectrometer at
399.97 and 100 MHz, respectively, using DMSO-d6 as
solvent and tetramethylsilane as internal standard. The
mass spectra were obtained using an Agilent 1100
Series LC/MSD instrument (electron impact, 70 eV;
samples were introduced as solutions in acetic acid).
The elemental compositions were determined with
a Perkin Elmer CHN analyzer. The melting points
were measured on a Kofler hot stage. The progress of
reactions and the purity of the isolated compounds
were monitored by TLC on Silufol UV-254 plates
using acetone–hexane (3:5) as eluent; spots were
1
13
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

DYACHENKO et al.
1780
visualized by treatment with iodine vapor and under
UV light.
(Irel 100%) [M + 1]+. Found, %: C 61.12; H 3.33;
N 18.89. C15H10N4OS. Calculated, %: C 61.21; H 3.42;
N 19.04. M 294.3.
Compounds 4a–4f (general procedure). A mixture
of 1.5 g (10 mmol) 1H-indole-3-carbaldehyde (1) and
10 mmol of CH acid 4a–4f in 20 mL of ethanol
containing 3 drops of morpholine was stirred for 4 h at
20°C. The mixture was left to stand for 24 h, and the
precipitate was filtered off and washed with ethanol
and hexane.
N-Benzyl-2-cyano-3-(1H-indol-3-yl)prop-2-en-
amide (4d). Yield 2.4 g (79%), yellow powder,
mp 212–214°C (from BuOH). IR spectrum, ν, cm–1:
1
3305 (NH), 2200 (C≡N), 1670 (C=O). H NMR spec-
trum, δ, ppm: 4.47 s (2H, CH2), 7.02–7.49 m (7H,
H
H
arom), 7.53 d (1H, Harom, J = 8.1 Hz), 7.93 d (1H,
arom, J = 7.8 Hz), 8.51 s (1H, 2-H), 8.55 s (1H, CH=),
2-Cyano-N-cyclopropyl-3-(1H-indol-3-yl)prop-2-
enamide (4a). Yield 2.1 g (82%), light yellow cotton-
like solid, mp 205–207°C (from BuOH). IR spectrum,
ν, cm–1: 3300 (NH), 2195 (C≡N), 1668 (C=O).
1H NMR spectrum, δ, ppm: 0.60 br.s (2H, CH2),
0.69 br.s (2H, CH2), and 2.77 br.s (1H, CH) (C3H5);
7.21–7.28 m (2H, Harom), 7.54 d (1H, Harom, J =
7.1 Hz), 7.92 d (1H, Harom, J = 6.8 Hz), 8.31 br.s (1H,
CONH), 8.40 s (1H, 2-H), 8.44 s (1H, CH=), 12.31 br.s
(1H, NH). 13C NMR spectrum, δC, ppm: 6.3 (2C), 23.7,
98.3, 110.0, 113.2, 118.9, 119.1, 121.9, 123.7, 127.6,
130.5, 136.4, 142.2, 164.0. Mass spectrum: m/z 252.0
(Irel 100%) [M + 1]+. Found, %: C 71.58; H 5.14;
N 16.66. C15H13N3O. Calculated, %: C 71.70; H 5.21;
N 16.72. M 251.3.
8.85 br.s (1H, CONH), 12.36 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 43.5, 97.7, 110.1, 113.2, 118.9,
119.2, 122.0, 123.7, 127.3, 127.7, 127.8 (2C), 128.8
(2C), 130.8, 136.5, 139.9, 142.8, 162.7. Mass spec-
trum: m/z 302.2 (Irel 100%) [M + 1]+. Found, %:
C 75.66; H 4.91; N 13.80. C19H15N3O. Calculated, %:
C 75.73; H 5.02; N 13.94. M 301.4.
2-Cyano-N-(furan-2-ylmethyl)-3-(1H-indol-3-yl)-
prop-2-enamide (4e). Yield 2.3 g (80%), yellow
powder, mp 221–223°C (from dioxane). IR spectrum,
ν, cm–1: 3313 (NH), 2196 (C≡N), 1666 (CONH).
1H NMR spectrum, δ, ppm: 4.42 d (2H, NCH2, J =
5.5 Hz), 6.30 s (1H, 3′-H), 6.41 s (1H, 4′-H), 7.22–
7.28 m (2H, Harom), 7.55 d (1H, Harom, J = 7.7 Hz),
7.59 s (1H, CH=), 7.92 d (1H, Harom, J = 8.1 Hz),
8.45 s (1H, 5′-H), 8.49 s (1H, 2-H), 8.77 t (1H, NHCO,
Heptyl 2-cyano-3-(1H-indol-3-yl)prop-2-enoate
(4b). Yield 2.1 g (68%), yellow plates fluorescing
under UV light, mp 107–109°C (from EtOH). IR spec-
trum, ν, cm–1: 3310 (NH), 2200 (C≡N), 1708 (C=O).
1H NMR spectrum, δ, ppm: 0.85 t (3H, Me, J =
6.7 Hz), 1.13–1.43 m (8H, CH2), 1.66 t (2H, CH2, J =
7.1 Hz), 4.22 t (2H, OCH2, J = 6.5 Hz), 7.23–7.32 m
(2H, Harom), 7.56 d (1H, Harom, J = 7.7 Hz), 7.94 d (1H,
Harom, J = 7.5 Hz), 8.55 s (1H, 2-H), 8.57 s (1H, CH=),
12.57 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
14.0, 22.1, 25.4, 28.2, 28.4, 31.2, 65.4, 92.4, 110.0,
113.1, 118.1, 118.6, 122.2, 123.7, 127.0, 132.8, 136.4,
146.7, 163.4. Mass spectrum: m/z 311.2 (Irel 100%)
[M + 1]+. Found, %: C 73.40; H 7.05; N 8.95.
C19H22N2O2. Calculated, %: C 73.52; H 7.14; N 9.02.
M 310.4.
13
J = 5.5 Hz), 12.34 br.s (1H, NH). C NMR spectrum,
δC, ppm: 36.8, 97.6, 107.6, 110.0, 111.0, 113.2, 118.9,
119.1, 122.0, 123.7, 127.7, 130.8, 136.5, 142.5, 142.8,
152.6, 162.6. Mass spectrum, m/z 292.0 (Irel 100%)
[M + 1]+. Found, %: C 69.92; H 4.38; N 14.29.
C17H13N3O2. Calculated, %: C 70.09; H 4.50; N 14.43.
M 291.9.
2-Amino-4-(1H-indol-3-yl)buta-1,3-diene-1,1,3-
tricarbonitrile (4f). Yield 1.8 g (70%), yellow crys-
tals, mp 242–244°C (from dioxane). IR spectrum, ν,
cm–1: 3408, 3396, 3311 (NH, NH2), 2196 (C≡N), 1638
1
(δNH2). H NMR spectrum, δ, ppm: 7.19–7.33 m (2H,
Harom), 7.57 d (1H, Harom, J = 7.5 Hz), 7.97 d (1H,
Harom, J = 7.2 Hz), 8.40 s (1H, 2-H), 8.56 s (1H, CH=),
8.74 br.s and 8.85 br.s (1H each, NH2), 12.52 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 48.6, 92.8, 110.6,
113.4, 116.2, 116.7, 117.7, 119.2, 122.4, 124.1, 127.7,
132.0, 136.5, 146.3, 166.6. Mass spectrum: m/z 260.1
(Irel 100%) [M + 1]+. Found, %: C 69.36; H 3.60;
N 27.04. C15H9N5. Calculated, %: C 69.50; H 3.50;
N 27.00. M 259.3.
2-Cyano-3-(1H-indol-3-yl)-N-(1,3-thiazol-2-yl)-
prop-2-enamide (4c). Yield 2.1 g (72%), yellow
powder, mp 225–227°C (from BuOH). IR spectrum, ν,
1
cm–1: 3312 (NH), 2202 (C≡N), 1669 (C=O). H NMR
spectrum, δ, ppm: 7.12–7.32 m (4H, Harom), 7.34–
7.61 m (2H, Harom), 8.04 br.s (1H, CONH), 8.57 s
(1H, 2-H), 8.85 s (1H, CH=), 12.53 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 91.3, 97.8, 110.4, 113.3,
113.7, 119.0, 119.1, 122.3, 123.9, 128.0, 131.6, 135.1,
136.5, 143.9, 163.7. Mass spectrum: m/z 295.0
4-(1H-Indol-3-ylmethylidene)-3-methyl-
1-phenyl-1H-pyrazol-5-(4H)-one (5) was synthesized
in a similar way from aldehyde 1 and 1.74 g (10 mmol)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

KNOEVENAGEL REACTIONS OF INDOLE-3-CARBALDEHYDE.
1781
of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (3). Yield
2.3 g (77%), bright red crystals, mp 225–227°C (from
BuOH); published data [4]: mp 235–236°C. IR spec-
trum, ν, cm–1: 3300 (NH), 1665 (C=O). 1H NMR spec-
trum, δ, ppm: 2.41 s (3H, Me), 7.16 t (1H, Harom, J =
7.0 Hz), 7.31 d (2H, Harom, J = 7.8 Hz), 7.43 t (2H,
C 77.10; H 4.82; N 18.08. C15H11N3. Calculated, %:
C 77.23; H 4.75; N 18.01. M 233.3.
2-(1-Benzyl-1H-indol-3-ylmethylidene)malono-
nitrile (9b). Yield 2.2 g (79%), yellow cotton-like
material, mp 186–188°C (from AcOH). IR spectrum:
1
ν 2218 cm–1, sh (C≡N). H NMR spectrum, δ, ppm:
Harom, J = 7.5 Hz), 7.59 d (1H, Harom, J = 7.0 Hz),
5.66 s (2H, CH2), 7.21–7.38 m (7H, Harom), 7.62 d (1H,
Harom, J = 5.5 Hz), 8.06 d (1H, Harom, J = 5.5 Hz),
8.66 s (1H, 2-H), 8.69 s (1H, CH=). 13C NMR spec-
trum, δC, ppm: 50.8, 70.5, 110.9, 112.4, 116.1, 116.3,
119.9, 123.5, 124.6, 127.9, 128.0 (2C), 128.4, 129.3
(2C), 135.8, 136.7, 136.7, 152.4. Mass spectrum:
m/z 284.2 (Irel 100%) [M + 1]+. Found, %: C 80.41;
H 4.75; N 14.84. C19H13N3. Calculated, %: C 80.54;
H 4.62; N 14.83. M 283.4.
8.01 d (2H, Harom, J = 7.8 Hz), 8.10 s (1H, 2-H), 8.16 d
(1H, Harom, J = 6.8 Hz), 9.82 s (1H, CH=), 12.66 br.s
(1H, NH). Mass spectrum: m/z 302.1 (Irel 100%)
[M + 1]+. Found, %: C 75.65; H 4.88; N 13.80.
C19H15N3O. Calculated, %: C 75.73; H 5.02; N 13.94.
M 301.4.
2-(1H-Indol-3-ylmethylidene)malononitrile (7).
a. A mixture of 2.1 g (10 mmol) of compound 4a,
0.66 g (10 mmol) of malononitrile (6), and 0.87 mL
(10 mmol) of morpholine in 25 mL of DMF was
stirred for 2 h at 20°C. The mixture was left to stand
for 24 h and was then diluted with an equal volume of
water. The precipitate was filtered off and washed with
water, ethanol, and hexane. Yield 1.3 g (69%), yellow
crystals, mp 218–220°C (from EtOH); published data
[6]: mp 223°C.
Ethyl 2-[3-(2,2-dicyanoethenyl)-1H-indol-1-yl]-
acetate (9c). Yield 2.1 g (76%), light yellow cotton-
like material, mp 199–200°C (from dioxane); sublimes
at 170°C. IR spectrum, ν, cm–1: 2212 sh (C≡N), 1714
(C=O). 1H NMR spectrum, δ, ppm: 1.28 t (3H, Me, J =
7.0 Hz), 4.19 q (2H, OCH2, J = 7.0 Hz), 5.36 s (2H,
NCH2), 7.19–7.32 m (2H, Harom), 7.50 d (1H, Harom, J =
7.5 Hz), 7.98 d (1H, Harom, J = 7.8 Hz), 8.59 s (1H,
2-H), 8.64 s (1H, CH=). Mass spectrum: m/z 280.1
(Irel 100%) [M + 1]+. Found, %: C 68.72; H 4.55;
N 14.93. C16H13N3O2. Calculated, %: C 68.81; H 4.69;
N 15.05. M 279.3.
b. A mixture of 1.5 g (10 mmol) of aldehyde 1,
0.66 g (10 mmol) of malononitrile (6), and 3 drops of
morpholine in 25 mL of ethanol was stirred for 2 h at
20°C. The mixture was left to stand for 24 h, and the
precipitate was filtered off and washed with ethanol
and hexane. Yield 1.5 g (80%); the melting point and
spectral parameters of the product were identical to
those of a sample of 7 prepared as described in a.
2-(1-Methyl-1H-indol-3-ylmethylidene)malono-
nitrile (9d). Yield 1.7 g (82%), yellow crystals
fluorescing under UV light, mp 174–176°C (from di-
oxane). IR spectrum: ν 2206 cm–1, sh (C≡N). 1H NMR
spectrum, δ, ppm: 3.97 s (3H, Me), 7.22–7.34 m (2H,
Harom), 7.53 d (1H, Harom, J = 7.7 Hz), 7.97 d (1H,
Harom, J = 8.0 Hz), 8.46 s (1H, 2-H), 8.51 s (1H, CH=).
Mass spectrum: m/z 208.0 (Irel 100%) [M + 1]+. Found,
%: C 75.27; H 4.33; N 20.40. C13H9N3. Calculated, %:
C 75.35; H 4.38; N 20.27. M 207.2.
Compounds 9a–9g (general procedure). Alkyl
halide 8a–8e, 10 mmol, and 10% aqueous potassium
hydroxide, 5.6 mL (10 mmol), were added in succes-
sion with stirring at 20°C to a mixture of 10 mmol of
substituted indole 4a–4f or 7 and 30 mL of DMF. The
mixture was stirred for 4 h and left to stand for 24 h.
The mixture was diluted with an equal volume of
water, and the precipitate was filtered off and washed
with water, ethanol, and hexane.
2-[3-(2,2-Dicyanoethenyl)-1H-indol-1-yl]acet-
amide (9e). Yield 2.0 g (79%), light yellow cotton-like
material fluorescing under UV light, mp 275–277°C
(from dioxane). IR spectrum, ν, cm–1: 3411, 3382,
3305 (NH2), 2202 sh (C≡N), 1667 (CONH2). 1H NMR
spectrum, δ, ppm: 5.03 s (2H, CH2), 7.23–7.31 m (3H,
Harom, NH2), 7.47 d (1H, Harom, J = 7.6 Hz), 7.73 br.s
(1H, NH2), 7.80 d (1H, Harom, J = 7.3 Hz), 8.52 s (1H,
2-H), 8.59 s (1H, CH=). Mass spectrum: m/z 251.1
(Irel 100%) [M + 1]+. Found, %: C 67.04; H 3.89;
N 22.44. C14H10N4O. Calculated, %: C 67.19; H 4.03;
N 22.39. M 250.3.
2-[1-(Prop-2-en-1-yl)-1H-indol-3-ylmethylidene]-
malononitrile (9a). Yield 1.75 g (75%), light green
needles, mp 111–113°C (from AcOH). IR spectrum:
1
ν 2208 cm–1, sh (C≡N). H NMR spectrum, δ, ppm:
5.05 d (2H, CH2, J = 4.5 Hz), 5.18 d (1H, =CH2,
Jtrans = 17.1 Hz), 5.26 d (1H, =CH2, Jcis = 10.2 Hz),
5.83–6.16 m (1H, CH2=CH), 7.24–7.31 m (2H, Harom),
7.55 d (1H, Harom, J = 7.2 Hz), 8.00 d (1H, Harom, J =
7.5 Hz), 8.51 s (1H, 2-H), 8.60 s (1H, CH=). Mass
spectrum, m/z 234.1 (Irel 100%) [M + 1]+. Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

DYACHENKO et al.
1782
8.2 Hz), 7.37 t (1H, Harom, J = 7.9 Hz). Mass spectrum:
Heptyl 2-cyano-3-[1-(prop-2-en-1-yl)-1H-indol-
m/z 374.2 (Irel 100%) [M + 1]+. Found, %: C 73.80;
H 6.18; N 11.34. C23H23N3O2. Calculated, %: C 73.97;
H 6.21; N 11.25. M 373.5.
3-yl)prop-2-enoate (9f). Yield 2.4 g (67%), light yel-
low needles fluorescing under UV light, mp 64–65°C
(from AcOH). IR spectrum, ν, cm–1: 2205 (C≡N), 1711
(C=O). 1H NMR spectrum, δ, ppm: 0.90 t (3H, Me, J =
6.7 Hz), 1.25–1.49 m (8H, CH2), 1.72 t (2H, CH2, J =
7.1 Hz), 4.27 t (2H, OCH2, J = 6.6 Hz), 5.04 d (2H,
NCH2, J = 5.5 Hz), 5.18 d (1H, =CH2, Jtrans = 17.0 Hz),
5.27 d (1H, =CH2, Jcis = 11.4 Hz), 6.00–6.18 m (1H,
CH=), 7.25–7.31 m (2H, Harom), 7.55 d (1H, Harom, J =
7.1 Hz), 7.87 d (1H, Harom, J = 7.8 Hz), 8.48 s (1H,
2-H), 8.54 s (1H, CH=). Mass spectrum: m/z 351.2
(Irel 100%) [M + 1]+. Found, %: C 75.31; H 7.35;
N 8.07. C22H26N2O2. Calculated, %: C 75.40; H 7.48;
N 7.99. M 350.5.
2-Cyano-3-(1H-indol-3-yl)prop-2-enethioamide
(12). A mixture of 1.5 g (10 mmol) of aldehyde 1, 1.0 g
(10 mmol) of cyanothioacetamide (13), and 3 drops of
morpholine in 30 mL of ethanol was stirred for 5 h at
20°C. The precipitate was filtered off and washed with
ethanol and hexane. Yield 2.0 g (85%), yellow crystals,
mp 174–176°C (from EtOH) [3].
5-(1H-Indol-3-ylmethylidene)-2,2-dimethyl-1,3-
dioxane-4,6-dione (15). A mixture of 2.3 g (10 mmol)
of thioacrylamide 12, 1.4 g (10 mmol) of Meldrum’s
acid (14), and 1.1 mL (10 mmol) of N-methylmor-
pholine was refluxed for 2 h. After cooling, a solid
crystallized from the mixture and was filtered off and
washed with ethanol and hexane. Yield 1.8 g (68%),
light yellow crystals, mp 234–235°C (from EtOH). IR
2-Cyano-N-cyclopropyl-3-[1-(prop-2-en-1-yl)-
1H-indol-3-yl]prop-2-enamide (9g). Yield 2.1 g
(71%), yellow cotton-like material fluorescing under
UV light, mp 235–237°C (from BuOH). IR spectrum,
ν, cm–1: 3300 (NH), 2212 (C≡N), 1667 (CONH).
1H NMR spectrum (CDCl3), δ, ppm: 0.65 br.s (2H,
CH2), 0.89 br.s (2H, CH2), and 2.89 br.s (1H, CH)
1
spectrum, ν, cm–1: 3314 (NH), 1718 (C=O). H NMR
spectrum, δ, ppm: 1.72 s (6H, Me), 7.33–7.41 m (2H,
Harom), 7.62 d (1H, Harom, J = 8.1 Hz), 7.91 d (1H,
Harom, J = 7.8 Hz), 8.75 s (1H, 2-H), 9.34 s (1H, CH=),
12.90 br.s (1H, NH). Mass spectrum: m/z 270.0
(Irel 100%) [M – 1]+. Found, %: C 66.31; H 4.79;
N 5.22. C15H13NO4. Calculated, %: C 66.42; H 4.83;
N 5.16. M 271.3.
(C3H5); 4.84 s (2H, NCH2), 5.18 d (1H, =CH2, Jtrans
=
17.3 Hz), 5.32 d (1H, =CH2, Jcis = 9.8 Hz), 5.94–
6.11 m (1H, CH=CH2), 6.26 br.s (1H, NH), 7.11–
7.23 m (3H, Harom), 7.88 m (1H, Harom), 8.36 s (1H,
13
2-H), 8.66 s (1H, CH=). C NMR spectrum, δC, ppm:
6.8 (2C), 23.4, 49.9, 95.2, 110.7, 118.6, 119.0, 119.3,
122.3, 122.5, 123.8, 128.5, 131.6, 132.5, 136.2, 144.0,
163.2. Mass spectrum: m/z 292.1 (Irel 100%) [M + 1]+.
Found, %: C 74.05; H 5.90; N 14.32. C18H17N3O.
Calculated, %: C 74.21; H 5.88; N 14.42. M 291.4.
4-(1H-Indol-3-yl)-7,7-dimethyl-5-oxo-2-sulfanyli-
dene-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile
(16). A mixture of 2.3 g (10 mmol) of amide 12, 1.4 g
(10 mmol) of dimedone 10, and 1.1 mL (10 mmol) of
N-methylmorpholine in 25 mL of DMF was stirred for
4 h at 20°C and was left to stand for 24 h. The mixture
was diluted with an equal volume of water and left to
stand for 48 h, and the precipitate was filtered off and
washed with water, ethanol, and hexane. Yield 2.4 g
(69%), yellow crystals, mp 310°C (decomp., from
AcOH). IR spectrum, ν, cm–1: 3315, 3164 (NH), 2229
2-Amino-7,7-dimethyl-5-oxo-4-[1-(prop-2-en-1-
yl)-1H-indol-3-yl]-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (11). A mixture of 2.3 g (10 mmol) of
acrylonitrile 9a, 1.4 g (10 mmol) of dimedone 10, and
3 drops of morpholine in 30 mL of DMF was stirred
for 2 h at 20°C. The mixture was left to stand for 24 h,
diluted with an equal volume of water, and left to stand
for 24 h more. The precipitate was filtered off and
washed with water, ethanol, and hexane. Yield 2.9 g
(77%), light yellow crystals, mp 180–182°C (from
BuOH). IR spectrum, ν, cm–1: 3411, 3382, 3310 (NH2),
1
(C≡N), 1690 (C=O), 1208 (C=S). H NMR spectrum,
δ, ppm: 0.98 s (3H, Me), 1.12 s (3H, Me), 2.23 d and
2.55 d (1H each, CH2, 2J = 16.0 Hz), 2.96 d and 3.05 d
(1H each, CH2, 2J = 16.2 Hz), 6.89–6.93 m (1H, Harom),
7.11–7.19 m (2H, Harom), 7.44 d (1H, Harom, J =
7.9 Hz), 7.74 s (1H, 2′-H), 11.62 br.s (1H, N1′H),
14.14 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
27.3, 28.3, 32.1, 40.1, 51.9, 110.6, 112.2, 115.9, 117.0,
117.3, 119.1, 119.9, 121.7, 126.1, 127.3, 136.2, 149.4,
159.0, 180.1, 192.3. Mass spectrum: m/z 348.0
(Irel 100%) [M + 1]+. Found, %: C 69.01; H 5.14;
N 11.95. C20H17N3OS. Calculated, %: C 69.14; H 4.93;
N 12.09. M 347.4.
1
2195 (C≡N), 1714 (C=O), 1633 (δNH2). H NMR
spectrum, δ, ppm: 0.92 s (3H, Me), 1.08 s (3H, Me),
2.06 d and 2.18 d (1H each, CH2, 2J = 16.1 Hz), 3.11 s
(2H, CH2), 4.49 s (1H, 4-H), 4.74 d (2H, NCH2, J =
5.2 Hz), 5.01 d (1H, =CH2, Jtrans = 17.1 Hz), 5.14 d
(1H, =CH2, Jcis = 10.2 Hz), 5.84–6.13 m (1H, CH=),
6.66 br.s (2H, NH2), 6.97 t (1H, Harom, J = 7.9 Hz),
7.07 br.s (2H, 2′-H, Harom), 7.29 d (1H, Harom, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

KNOEVENAGEL REACTIONS OF INDOLE-3-CARBALDEHYDE.
1783
4-(1H-Indol-3-yl)-2-sulfanylidene-2,5,6,7-tetra-
hydro-1H-cyclopenta[b]pyridine-3-carbonitrile (18)
was synthesized in a similar way from thioamide 12
and 1.5 g (10 mmol) of 4-(cyclopent-1-en-1-yl)mor-
pholine (17). Yield 2.3 g (78%), yellow powder,
mp 287–289°C. IR spectrum, ν, cm–1: 3162 (NH),
potassium hydroxide was added, and the mixture was
stirred for 1 h and left to stand for 24 h. The mixture
was diluted with an equal volume of water, and the
precipitate was filtered off and washed with water,
ethanol, and hexane. Yield 2.6 g (72%), yellow
crystals, mp 174–176°C (from BuOH). IR spectrum, ν,
1
1
2212 (C≡N), 1210 (C=S). H NMR spectrum, δ, ppm:
cm–1: 3328 (NH), 2197 (C≡N), 1716 (C=O). H NMR
2.01 t (2H, CH2, J = 7.6 Hz), 2.55–2.68 m (2H, CH2),
2.96 t (2H, CH2, J = 8.0 Hz), 7.13 t (1H, Harom, J =
7.4 Hz), 7.21 t (1H, Harom, J = 8.0 Hz), 7.39 d (1H,
spectrum, δ, ppm: 1.05 t (3H, Me, J = 6.5 Hz), 2.43 s
(3H, Me), 3.95 t (2H, OCH2, J = 6.5 Hz), 4.17 t (2H,
NCH2, J = 7.7 Hz), 4.25 t (2H, SCH2, J = 7.7 Hz),
4.92 s (1H, 7-H), 7.00 t (1H, Harom, J = 7.8 Hz), 7.04–
7.16 m (2H, Harom, 2′-H), 7.37 d (1H, Harom, J =
7.8 Hz), 7.44 d (1H, Harom, J = 7.5 Hz), 10.95 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 14.4, 17.0, 28.5,
33.9, 52.5, 60.0, 78.6, 104.5, 112.2, 119.1, 119.3,
119.6, 120.7, 121.4, 123.8, 126.0, 137.1, 144.2, 152.0,
167.6. Mass spectrum: m/z 364.2 (Irel 100%) [M – 1]+.
Found, %: C 65.66; H 5.20; N 11.62. C20H19N3O2S.
Calculated, %: C 65.73; H 5.24; N 11.50. M 365.5.
H
arom, J = 8.0 Hz), 7.51 t (1H, Harom, J = 7.4 Hz), 7.84 s
(1H, 2′-H), 12.02 br.s (1H, N1′H); no pyridine NH
signal was observed, presumably because of fast H–D
exchange. Mass spectrum, m/z 292.0 (Irel 100%)
[M + 1]+. Found, %: C 69.94; H 4.46; N 14.53.
C17H13N3S. Calculated, %: C 70.08; H 4.50; N 14.42.
M 291.4.
Ethyl 6-(2-amino-2-oxoethylsulfanyl)-5-cyano-
4-(1H-indol-3-yl)-2-methyl-1,4-dihydropyridine-3-
carboxylate (20). A mixture of 2.3 g (10 mmol) of
amide 12 and 2 g (10 mmol) of enamine 19 in 30 mL
of ethanol was stirred for 5 h at 20°C. 2-Chloroacet-
amide (8b), 0.94 g (10 mmol), was then added, and the
mixture was stirred for 2 h and left to stand for 24 h.
The mixture was diluted with an equal volume of
water, and the precipitate was filtered off. Yield 2.8 g
(71%), colorless plates, mp 218–220°C (from BuOH).
IR spectrum, ν, cm–1: 3372, 3330, 3205 (NH, NH2),
2196 (C≡N), 1681 (C=O, ester), 1669 (C=O, amide).
1H NMR spectrum, δ, ppm: 1.09 t (3H, Me, J =
7.1 Hz), 2.25 s (3H, Me), 3.62 d and 3.77 d (1H each,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 18-53-06006 Az_a, 16-29-10669 ofi_m).
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