Synthesis and Biological Activity of Substituted Spiro[chromene-4,3′-indoles] and Spiro[indole-3,4′-quinolines]

Article abstract of DOI:10.1134/S1070428018120254

New substituted spiro[chromene-4,3′-indoles] and spiro[indole-3,4′-quinolines] have been synthesized in 35–65% yields by one-pot regioselective three-component condensation of N-substituted isatins with two active methylene compounds.

Full text of DOI:10.1134/S1070428018120254

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1860–1863. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © S.A. Pogosyan, M.V. Pogosyan, L.R. Aleksanyan, A.S. Safaryan, A.G. Arakelyan, 2018, published in Zhurnal Organicheskoi Khimii,
2018, Vol. 54, No. 12, pp. 1845–1848.
SHORT
COMMUNICATIONS
Synthesis and Biological Activity of Substituted
Spiro[chromene-4,3′-indoles] and Spiro[indole-3,4′-quinolines]
S. A. Pogosyana,* M. V. Pogosyana, L. R. Aleksanyana, A. S. Safaryana, and A. G. Arakelyana
a Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
*e-mail: safar.pogosyan@gmail.com
Received January 19, 2018; revised October 19, 2018; accepted October 24, 2018
Abstract—New substituted spiro[chromene-4,3′-indoles] and spiro[indole-3,4′-quinolines] have been synthe-
sized in 35–65% yields by one-pot regioselective three-component condensation of N-substituted isatins with
two active methylene compounds.
DOI: 10.1134/S1070428018120254
We previously synthesized a series of spiro hetero-
cycles containing an oxodihydroindole fragment [1, 2].
Interest in these compounds is determined by the
possibility of extending their synthetic potential. The
synthesis of some spiro[indole-3,4′-quinolines] under
microwave irradiation has been reported [3, 4]. In con-
tinuation of these studies, we have developed a new
procedure for the synthesis of analogous spiro com-
pounds by domino reaction of isatins with two CH
acids in the presence of a catalytic amount of a base. In
order to estimate the scope of the new preparative
procedure, we used as starting compounds N-substi-
tuted isatins 1a–1g and resorcinol (2) and ethyl cyano-
acetate (3) or malononitrile (4) and 3,3-dimethyl-5-
anilinocyclohexan-1-one (5). The condensation of
isatin with two other components containing an active
methylene group followed the cascade cyclization
path, leading to regioselective formation of spiro-fused
oxoindole derivatives 6a–6f and 7a–7f.
The antibacterial activity of compounds 6a–6f and
7a–7f was assayed by the agar diffusion method [5] at
a bacterial load of 20×106 CFU/mL. The test cultures
HO
O
NH2
OH
O
OEt
COOEt
O
NC
+
+
O
N
O
N
OH
R
R
1a–1f
2
3
6a–6f
Me
Me
Ph
N
O
NH2
O
CN
1a–1e, 1g
+
+
O
NC
CN
Me
Me
Ph
N
R
N
H
4
5
7a–7f
1, 6, R = H (a), Me (b), Et (c), Pr (d), PhCH2 (e), CH2=CHCH2 (f), Bu (g); 7, R = H (a), Me (b), Et (c), Pr (d), Bu (e), PhCH2 (f).
1860

SYNTHESIS AND BIOLOGICAL ACTIVITY
1861
were gram-positive S. aureus and gram-negative
Sh. flexneri and E. coli. The compounds to be tested
and reference drug were dissolved in DMSO at a dilu-
tion of 1:20. Petri dishes containing an agar nutrient
medium were inoculated with the test cultures, and
a 0.1-mL sample of a solution of 6a–6f or 7a–7f or
reference drug was applied thereonto. The results were
evaluated as the diameter (d, mm) of the inhibition
zone after incubation for 24 h in a thermostat. The
reference drug was furazolidone [6].
1H NMR spectrum, δ, ppm: 0.72 t (3H, CH2CH3, J =
7.1 Hz), 3.20 s (3H, NCH3), 3.69 q (2H, OCH2, J =
7.1 Hz), 6.28 d (1H, 5-H, J = 8.6 Hz), 6.33 d.d (1H,
6-H, J = 8.6, 2.4 Hz), 6.42 d (1H, 8-H, J = 2.4 Hz),
6.83–6.91 m (3H) and 7.11–7.20 m (1H) (4′-H, 5′-H,
6′-H, 7′-H), 7.70 br.s (2H, NH2), 9.33 s (1H, OH).
Found, %: C 65.56; H 4.47; N 7.65. C20H18N2O5. Cal-
culated, %: C 65.57; H 4.37; N 7.65.
Ethyl 2-amino-1′-ethyl-7-hydroxy-2′-oxo-1′,2′-
dihydrospiro[chromene-4,3′-indole]-3-carboxylate
(6c). Yield 4.5 g (64%), mp 262–263°C, Rf 0.6. IR
spectrum, ν, cm–1: 3399 (OH), 3297 (NH2), 1682
Compounds 6a–6d showed no antibacterial activity,
and the activity of 6e and 6f was low (inhibition zone
10–13 mm against 24–25 mm for the reference drug).
We also examined the antiradical activity of com-
pounds 6a–6f by the DPPH assay (reaction with
2,2′-diphenyl-1-picrylhydrazyl) at ratios of 1:1, 1:2,
and 1:4 in methanol. The measurements were per-
formed by spectrophotometry over a period of 20 min
[7]. The tested compounds displayed almost no anti-
radical activity. Increase of the 6–DPPH ratio from 1:1
to 4:1 did not change their ability to trap the stable
radical to an appreciable extent.
1
(C=O), 1642 (C=O), 1609 (C=C). H NMR spectrum,
δ, ppm: 0.68 t (3H, OCH2CH3, J = 7.1 Hz), 1.31 t (3H,
NCH2CH3, J = 7.1 Hz), 3.58–3.71 m and 3.75–3.89 m
(2H each, NCH2, OCH2), 6.27 d (1H, 5-H, J = 8.6 Hz),
6.34 d.d (1H, 6-H, J = 8.6, 2.3 Hz), 6.43 d (1H, 8-H,
J = 2.3 Hz), 6.84–6.92 m (3H) and 7.12–7.18 m (1H)
(4′-H, 5′-H, 6′-H, 7′-H), 7.70 br.s (2H, NH2), 9.34 s
(1H, OH). Found, %: C 66.32; H 5.37; N 7.39.
C21H20N2O5. Calculated, %: C 66.31; H 5.27; N 7.36.
Ethyl 2-amino-7-hydroxy-2′-oxo-1′-propyl-1′,2′-
dihydrospiro[chromene-4,3′-indole]-3-carboxylate
(6d). Yield 4.3 g (55%), mp 260–262°C, Rf 0.6. IR
spectrum, ν, cm–1: 3410 (OH), 3303 (NH2), 1685
(C=O), 1642 (C=O), 1610 (C=C), 1608 (C=C).
1H NMR spectrum, δ, ppm: 0.68 t (3H, OCH2CH3, J =
7.1 Hz), 1.04 t (3H, CH2CH2CH3, J = 7.4 Hz), 1.69–
1.82 m (2H, NCH2CH2); 3.44–3.53 m (1H), 3.58–
3.69 m (1H), and 3.72–3.84 m (2H) (NCH2, OCH2);
6.27 d (1H, 5-H, J = 8.6 Hz), 6.33 d.d (1H, 6-H, J =
8.6, 2.3 Hz), 6.43 d (1H, 8-H, J = 2.3 Hz), 6.83–6.92 m
(3H) and 7.12–7.18 m (1H) (4′-H, 5′-H, 6′-H, 7′-H),
7.70 br.s (2H, NH2), 9.32 s (1H, OH). Found, %:
C 67.02; H 5.57; N 7.11. C22H22N2O5. Calculated, %:
C 67.00; H 5.58; N 7.11.
Compounds 6 and 7 (general procedure). Isatin
1a–1g, 20 mmol, was dissolved in 80 mL of ethanol,
20 mmol of resorcinol (2), 20 mmol of ethyl cyanoace-
tate (3) [or 20 mmol of 5-anilino-3,3-dimethylcyclo-
hexan-1-one (5) and 20 mmol of malononitrile (4)],
and 2 mL of triethylamine were added, and the mixture
was refluxed for 2 h with stirring. The solvent was
partially distilled off (40 mL), the residue was cooled,
and the precipitate was filtered off and recrystallized
from ethanol.
Ethyl 2-amino-7-hydroxy-2′-oxo-1′,2′-dihydro-
spiro[chromene-4,3′-indole]-3-carboxylate (6a).
Yield 4.5 g (64%), mp 306–308°C, Rf 0.6. IR spec-
trum, ν, cm–1: 3410 (OH), 3310 (NH2), 3170 (NH),
1699 (C=O), 1660 (C=O), 1630 (C=C), 1616 (C=C).
1H NMR spectrum, δ, ppm: 0.78 t.d (3H, CH3, J =
7.1 Hz ), 3.75 m (2H, OCH2), 6.35 d.d (1H, 6-H, J =
8.6, 2.4 Hz), 6.41 d (1H, 8-H, J = 2.4 Hz), 6.44 d (1H,
7-H, J = 8.6 Hz), 6.75–6.84 m (3H) and 7.04 t (1H, J =
7.4, 1.6 Hz) (4′-H, 5′-H, 6′-H, 7′-H), 7.64 br.s (2H,
NH2), 9.28 s (1H, OH), 10.08 s (1H, NH). Found, %:
C 64.72; H 4.52; N 7.97. C19H16N2O5. Calculated, %:
C 64.74; H 4.54; N 7.95.
Ethyl 2-amino-1′-benzyl-7-hydroxy-2′-oxo-1′,2′-
dihydrospiro[chromene-4,3′-indole]-3-carboxylate
(6e). Yield 4.7 g (60%), mp 273–275°C, Rf 0.62. IR
spectrum, ν, cm–1: 3398 (OH), 3202 (NH2), 1692
(C=O), 1677 (C=C), 1625 (C=C), 1608 (C=C).
1H NMR spectrum, δ, ppm: 0.54 t (3H, CH3, J =
7.1 Hz), 3.42–3.53 m and 3.74–3.83 m (1H each,
OCH2), 4.68 d and 5.03 d (1H each, NCH2, J =
15.2 Hz), 6.24 d (1H, 5-H, J = 8.6 Hz), 6.32 d.d (1H,
6-H, J = 8.6, 2.3 Hz), 6.45 d (1H, 8-H, J = 2.3 Hz);
6.81–6.93 m (3H) and 7.05–7.11 m (1H) (4′-H, 5′-H,
6′-H, 7′-H), 7.23–7.46 m (5H, Ph), 7.73 br.s (2H,
NH2), 9.35 s (1H, OH). Found, %: C 70.60; H 4.97;
N 6.36. C26H22N2O5. Calculated, %: C 70.59;
H 4.98; N 6.34.
Ethyl 2-amino-7-hydroxy-1′-methyl-2′-oxo-1′,2′-
dihydrospiro[chromene-4,3′-indole]-3-carboxylate
(6b). Yield 4.1 g (54%), mp 312–314°C, Rf 0.65. IR
spectrum, ν, cm–1: 3396 (OH), 3288, 3144 (NH2), 1699
(C=O), 1660 (C=O), 1630 (C=C), 1626 (C=C).
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POGOSYAN et al.
1862
Ethyl 2-amino-7-hydroxy-2′-oxo-1′-(prop-2-en-
2′-Amino-1-ethyl-7′,7′-dimethyl-2,5′-dioxo-1′-
phenyl-1,2,5′,6′,7′,8′-hexahydro-1′H-spiro[indole-
3,4′-quinoline]-3-carbonitrile (7c). Yield 5.1 g (58%),
mp 320–322°C, Rf 0.66. IR spectrum, ν, cm–1: 3465,
3315, 3212 (NH2), 2179 (C≡N), 1717, (C=O), 1653
1-yl)-1′,2′-dihydrospiro[chromene-4,3′-indole]-3-
carboxylate (6f). Yield 5.02 g (64%), mp 258–260°C,
Rf 0.45. IR spectrum, ν, cm–1: 3399 (OH ), 3297 (NH2),
1682 (C=O), 1650 (C=O), 1642 (C=C), 1609 (C=C).
1H NMR spectrum, δ, ppm: 0.69 t (3H, CH3, J =
7.1 Hz), 3.60–3.73 and 3.75–3.87 m (2H, OCH2),
4.14 d.d.t and 4.47 d.d.t (2H, NCH2, J = 15.8, 5.8,
1.2 Hz), 5.27 d.q (1H, =CH2, J = 10.2, 1.4 Hz),
5.41 d.q (1H, =CH2, J = 17.2, 1.4 Hz), 5.91 d.d.t (1H,
CH=CH2, J = 17.2, 1.4, 5.8 Hz), 6.30 d (1H, 5-H, J =
8.6 Hz), 6.35 d.d (1H, 6-H, J = 8.6, 2.3 Hz), 6.44 d
(1H, 8-H, J = 2.3 Hz), 6.82–6.93 m (3H) and 7.09–
7.15 m (1H) (4′-H, 5′-H, 6′-H, 7′-H), 7.70 br.s (2H,
NH2), 9.34 s (1H, OH). 13C NMR spectrum, δC, ppm:
13.33, 42.08, 48.65, 57.73, 57.97, 73.10, 102.04,
107.47, 111.66, 112.30, 117.26, 121.85, 122.47,
126.52, 126.58, 126.82, 132.06, 138.60, 142.29,
148.11, 161.23, 178.53. Found, %: C 67.34; H 5.09;
N 7.14. C22H20N2O5. Calculated, %: C 67.35; H 5.10;
N 7.14.
1
(C=O), 1620 (C=C), 1590 (C=C). H NMR spectrum,
δ ppm: 0.89 s and 0.97 s (3H each, 7′-CH3), 1.30 t (3H,
CH2CH3, J = 7.1 Hz), 1.84 d and 2.14 d (1H each, 6′-H
or 8′-H, J = 17.2 Hz), 1.93 d and 2.11 d (1H each, 8′-H
or 6′-H, J = 15.9 Hz), 3.67–3.85 m (2H, NCH2),
6.86 br.d (1H, 7-H, J = 7.6 Hz), 6.97 d.d.d (1H, 5-H,
J = 7.6, 7.3, 0.7 Hz), 7.15 d.d (1H, 4-H, J = 7.3,
1.2 Hz), 7.21 t.d (1H, 6-H, J = 7.6, 1.2 Hz), 7.44–
7.52 m and 7.53–7.64 m (5H, Ph). Found, %: C 73.96;
H 5.95; N 12.78. C27H25N4O2. Calculated, %: C 73.97;
H 5.94; N 12.79.
2′-Amino-7′,7′-dimethyl-2,5′-dioxo-1′-phenyl-1-
propyl-1,2,5′,6′,7′,8′-hexahydro-1′H-spiro[indole-
3,4′-quinoline]-3-carbonitrile (7d). Yield 4.8 g
(53%), mp 313–316°C, Rf 0.53. IR spectrum, ν, cm–1:
3415, 3153 (NH2), 2179 (C≡N), 1707, (C=O), 1653
1
(C=O), 1620 (C=C), 1590 (C=C). H NMR spectrum,
2′-Amino-7′,7′-dimethyl-2,5′-dioxo-1′-phenyl-
1,2,5′,6′,7′,8′-hexahydro-1′H-spiro[indole-3,4′-
quinoline]-3-carbonitrile (7a). Yield 3.1 g (44%),
mp 322–324°C, Rf 0.45. IR spectrum, ν, cm–1: 3428,
3318 (NH2), 3220 (NH), 2187 (C≡N), 1716 (C=O),
1696 (C=O), 1620 (C=C), 1590 (C=C). 1H NMR spec-
trum, δ, ppm: 0.90 s and 0.96 s (3H each, 7′-CH3),
1.84 d and 2.12 d (1H each, 6′-H or 8′-H, J = 17.2 Hz),
1.96 d and 2.12 d (1H each, 8′-H or 6′-H, J = 16.0 Hz),
5.06 br.s (2H, NH2); 6.80 m, 6.98 m, 6.89 m, and 7.07–
7.13 m (4H, 4-H, 5-H, 6-H, 7-H), 7.46 m and 7.57–
7.64 m (5H, Ph), 10.12 s (1H, NH). Found, %:
C 73.18; H 5.33; N 13.65. C25H22N4O2. Calculated, %:
C 73.16; H 5.36; N 3.67.
δ, ppm: 0.89 s and 0.96 s (3H each, 7′-Me), 1.05 t (3H,
CH2CH3, J = 7.4 Hz), 1.70–1.83 m (2H, NCH2CH2,
J = 7.5 Hz), 1.84 d and 2.13 d (1H each, 6′-H or 8′-H,
J = 17.2 Hz), 1.93 d and 2.11 d (1H each, 8′-H or 6′-H,
J = 15.9 Hz), 3.55–3.75 m (2H, NCH2), 5.08 s (2H,
NH2), 6.85 br.d (1H, 7-H), 6.96 d.d.d (1H, 5-H, J =
7.6, 7.3, 0.6 Hz), 7.14 d.d (1H, 4-H, J = 7.3, 1.2 Hz),
7.19 t.d (1H, 6-H, J = 7.6, 1.2 Hz), 7.44–7.52 m
and 7.54–7.64 m (5H, Ph). Found, %: C 74.35;
H 6.18; N 12.33. C28H28N4O2. Calculated, %: C 74.34;
H 6.19; N 12.34.
2′-Amino-1-butyl-7′,7′-dimethyl-2,5′-dioxo-1′-
phenyl-1,2,5′,6′,7′,8′-hexahydro-1′H-spiro[indole-
3,4′-quinoline]-3-carbonitrile (7e). Yield 4.3 g (36%),
mp 310–312°C, Rf 0.62. IR spectrum, ν, cm–1: 3415,
3193 (NH2), 2181 (C≡N), 1697, (C=O), 1630 (C=O),
2′-Amino-1,7′,7′-trimethyl-2,5′-dioxo-1′-phenyl-
1,2,5′,6′,7′,8′-tetrahydro-1′H-spiro[indole-3,4′-
quinoline]-3-carbonitrile (7b). Yield 5.2 g (62%),
mp 325–327°C, Rf 0.61. IR spectrum, ν, cm–1: 3437,
3326 (NH2), 2185 (C≡N), 1717 (C=O), 1642 (C=O),
1
1620 (C=C), 1590 (C=C). H NMR spectrum, δ, ppm:
0.89 s and 0.96 s (3H, 7′-CH3), 1.01 t (3H, CH2CH3,
J = 7.3 Hz), 1.43–1.56 m (2H, CH2CH3), 1.66–1.76 m
(2H, NCH2CH2), 1.84 d and 2.13 d (1H each, 6′-H or
8′-H, J = 17.2 Hz), 1.93 d and 2.11 d (1H each, 8′-H or
6′-H, J = 15.9 Hz), 3.57–3.77 m (2H, NCH2), 5.07 s
(2H, NH2), 6.84 br.d (1H, 7-H), 6.96 d.d.d (1H, 5-H,
J = 7.6, 7.3, 0.8 Hz), 7.14 d.d (1H, 4-H, J = 7.3,
1.2 Hz), 7.19 t.d (1H, 6-H, J = 7.6, 1.2 Hz), 7.44–
7.52 m and 7.54–7.64 m (5H, Ph). Found, %: C 74.70;
H 6.49; N 12.04. C28H28N4O2. Calculated, %: C 74.68;
H 6.48; N 12.07.
1
1620 (C=C), 1590 (C=C). H NMR spectrum, δ, ppm:
0.89 s and 0.96 s (3H each, 7′-CH3), 1.84 d and 2.13 d
(1H each, 6′-H or 8′-H, J = 17.1 Hz), 1.94 d and 2.09 d
(1H each, 8′-H or 6′-H, J = 15.9 Hz), 3.22 s (3H,
NCH3), 5.11 br.s (2H, NH2), 6.86 br.d (1H, 7-H, J =
7.6 Hz), 6.98 d.d.d (1H, 5-H, J = 7.33, 7.3, 0.8 Hz),
7.15 d.d (1H, 4-H, J = 7.3, 1.2 Hz), 7.22 t.d (1H, 6-H,
J = 7.6, 1.2 Hz), 7.44–7.52 m and 7.54–7.65 m (5H,
Ph). Found, %: C 73.56; H 5.65; N 13.25. C26H24N4O2.
Calculated, %: C 73.58; H 5.66; N 13.21.
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SYNTHESIS AND BIOLOGICAL ACTIVITY
1863
benzene–ethanol, 5:2; spots were visualized by treat-
ment with iodine vapor). The melting points were
measured on a Boetius melting point apparatus.
2′-Amino-1-benzyl-7′,7′-dimethyl-2,5′-dioxo-1′-
phenyl-1,2,5′,6′,7′,8′-hexahydro-1′H-spiro[indole-
3,4′-quinoline]-3-carbonitrile (7f). Yield 3.9 g (39%),
mp 326–328°C, Rf 0.60. IR spectrum, ν, cm–1: 3466,
3303, 3200 (NH2), 2194 (C≡N), 1708 (C=O), 1630
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1
(C=O), 1620 (C=C), 1590 (C=C). H NMR spectrum,
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δ, ppm: 0.92 s and 0.99 s (3H, 7′-CH3), 1.88 d (1H,
6′-H or 8′-H, J = 17.3 Hz), 2.00 d (1H, 8′-H or 6′-H,
J = 15.5 Hz), 2.17 d (1H, 8′-H or 6′-H, J = 15.5 Hz),
2.17 d (1H, 6′-H or 8′-H, J = 17.2 Hz), 4.92 d and
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C6H4, J = 7.6, 1.0 Hz), 7.07 t.d (1H, C6H4, J = 7.3,
1.3 Hz), 7.16–7.34 m (4H, Harom), 7.46–7.65 m (7H,
Harom). Found, %: C 76.7; H 5.6; N 11.3. C32H28N4O2.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018