Synthesis of fused 2′-amino-3′-R-spiro-[indole-3,4′- pyran]-2(1H)-ones

Article abstract of DOI:10.1134/S1070428008120117

An efficient one-pot procedure has been proposed for the synthesis of fused 2′-amino-3′-R-spiro-[indole-3,4′-pyran]-2(1H)-ones via base-catalyzed three-component condensation of isatins with the corresponding nitriles and 1,3-diketones.

Full text of DOI:10.1134/S1070428008120117

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1789–1794. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © L.A. Shemchuk, V.P. Chernykh, R.G. Red’kin, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12,
pp. 1816–1821.
Synthesis of Fused 2′-Amino-3′-R-spiro-
[indole-3,4′-pyran]-2(1H)-ones
L. A. Shemchuk, V. P. Chernykh, and R. G. Red’kin
Natsional Pharmaceutical University, ul. Pushkinskaya 53, Khar’kov, 61002 Ukraine
e-mail: ruslan_red@ukr.net
Received May 3, 2007
Abstract—An efficient one-pot procedure has been proposed for the synthesis of fused 2′-amino-3′-R-spiro-
[indole-3,4′-pyran]-2(1H)-ones via base-catalyzed three-component condensation of isatins with the corre-
sponding nitriles and 1,3-diketones.
DOI: 10.1134/S1070428008120117
The goal of the present study was to synthesize
derivatives of 2-oxoindole with a view to obtain new
melatonin analogs containing spiro-fused 4H-pyran
and 2-oxoindole rings and an aminoethyl pharmaco-
phoric group incorporated into the pyran ring. Spiro-
cyclic systems possessing 2-oxoindole and pyran frag-
ments have been found in the nature, in particular as
alstonisine alkaloids isolated from Alstonia plants,
which exhibit mainly cholinolytic and anti-inflam-
matory effects [1, 2]. Synthetic 4H-pyran derivatives,
including spirocyclic ones, are widely known as bio-
logically active substances possessing versatile phar-
macological activity [3, 4]. Among these, melatonin
analogs lacking indole fragment were also found [5].
droxyethyl)amine gave the corresponding 2-amino-3-
R-5,6,7,8-tetrahydrospiro[chromene-4,3′-indole]-
2′,5(1′H,4H)-diones Va−Vh or 2-amino-3-R-7,7-di-
methyl-5,6,7,8-tetrahydrospiro[chromene-4,3′-indole]-
2′,5(1′H,4H)-diones VIa−VIi (Scheme 1).
Replacement of cyclic 1,3-diketones by acetyl-
acetone (VII) in the condensation with isatin Ia and
malononitrile (IIa) or ethyl cyanoacetate (IIb) in the
presence of tris(2-hydroxyethyl)amine in ethanol
(short heating or reflux for 2 h) also resulted in
2′-amino-2-oxo-3′-R-1,2-dihydrospiro[indole-3,4′-pyr-
an] derivatives VIIIa and VIIIb (Scheme 1).
When 2-(2-oxoindol-3-ylidene)malononitriles
IXa−IXd or ethyl 2-(2-oxoindol-3-ylidene)cyanoace-
tate derivatives IXe−IXh were used as α-cyanoethyl-
ene component in the Michael reactions with 1,3-dicar-
bonyl compounds III, IV, and VII on prolonged
heating in boiling ethanol in the presence of a catalytic
amount of tris(2-hydroxyethyl)amine, we obtained the
same fused 4H-pyran derivatives V, VI, and VIII.
Obviously, compounds IX are key intermediates in the
three-component condensation of isatins with CH-ac-
tive nitriles and 1,3-diketones, which is consistent with
the generally accepted mechanism of such reactions.
Spirocyclic systems in which the spiro-carbon atom
occupies position 3 in 2-oxoindole and position 4 in
2-amino-4H-pyran were poorly studied. Reactions of
2-(2-oxoindol-3-ylidene)malononitrile with dimedone
and cyclohexane-1,3-dione were reported [6–8]; how-
ever, no systematic studies on such compounds were
performed.
Different methods for the synthesis of 2-amino-4H-
pyran are known [9], but the most important is Michael
addition of carbonyl compounds to electron-deficient
ethylenes possessing a cyano group [10]. We followed
an analogous approach to synthesize 2′-amino-3′-R-
spiro[indole-3,4′-pyran]-2(1H)-ones.
Compounds IXa−IXd were synthesized by con-
densation of isatins Ia−Ie with malononitrile (IIa), and
esters IXe−IXh were obtained by heating isatins Ia−Ie
with ethyl cyanoacetate (IIb) in boiling ethanol in the
presence of an equimolar amount of tris(2-hydroxy-
ethyl)amine according to the procedure described in
[11]. In the three-component condensation of N-(mor-
pholinomethyl)isatin (X) with cyclic 1,3-diketones III
Three-component condensation of isatins Ia−Ie
with malononitrile (IIa) or ethyl cyanoacetate (IIb)
and cyclic 1,3-diketone, cyclohexane-1,3-dione (III) or
dimedone (IV), on heating for a short time in ethanol
in the presence of an equimolar amount of tris(2-hy-
1789

SHEMCHUK et al.
1790
Scheme 1.
O
R2
R1
R3
R3
N
OH
O
III, IV
O
R4
R3
R3
NH2
O
Va–Vh, VIa–VIi
III, IV
NC
R4
O
O
R2
R2
+
R4CH2CN
O
N
R1
N
R1
Ia–Ie
IIa, IIb
IXa–IXh
VII
O
O
R2
R1
N
Me
Me
O
VII
O
R4
Me
NH2
O
Me
VIIIa, VIIIb
I, R1 = H, R2 = H (a); R1 = H, R2 = Me (b); R1 = Me, R2 = H (c); R1 = PhCH2, R2 = H (d); R1 = H, R2 = Br (e); II, R4 = CN (a),
CO2Et (b); III, R3 = H; IV, R3 = Me; V, R1 = R2 = R3 = H, R4 = CN (a); R1 = R3 = H, R2 = Me, R4 = CN (b); R1 = Me, R2 = R3 = H,
R4 = CN (c); R1 = PhCH2, R2 = R3 = H, R4 = CN (d); R1 = R2 = R3 = H, R4 = CO2Et (e); R1 = R3 = H, R2 = Me, R4 = CO2Et (f); R1 =
Me, R2 = R3 = H, R4 = CO2Et (g); R1 = PhCH2, R2 = R3 = H, R4 = CO2Et (h); VI, R1 = R2 = H, R3 = Me, R4 = CN (a); R1 = H, R2 =
R3 = Me, R4 = CN (b); R1 = R3 = Me, R2 = Br, R4 = CN (c); R1 = R3 = Me, R2 = H, R4 = CN (d); R1 = PhCH2, R2 = H, R3 = Me, R4 =
CN (e); R1 = R2 = H, R3 = Me, R4 = CO2Et (f); R1 = H, R2 = R3 = Me, R4 = CO2Et (g); R1 = R3 = Me, R2 = H, R4 = CO2Et (h); R1 =
PhCH2, R2 = H, R3 = Me, R4 = CO2Et (i); VIII, R1 = R2 = H, R4 = CN (a); R1 = R2 = H, R4 = CO2Et (b); IX, R1 = R2 = H,
R4 = CN (a); R1 = H, R2 = Me, R4 = CN (b); R1 = Me, R2 = H, R4 = CN (c); R1 = PhCH2, R2 = H, R4 = CN (d); R1 = R2 = H, R4 =
CO2Et (e); R1 = H, R2 = Me, R4 = CO2Et (f); R1 = Me, R2 = H, R4 = CO2Et (g); R1 = PhCH2, R2 = H, R4 = CO2Et (h).
Thus three-component condensation of isatins with
cyanomethylene compounds and 1,3-diketones
smoothly occurs under mild conditions in the presence
of an equimolar amount of tris(2-hydroxyethyl)amine
to give the corresponding fused 2-amino-3′-R-spiro-
[indole-3,4′-pyran]-2(1H)-ones in high yield.
and IV or acetylacetone (VII), the same products as
in the reaction with Ia (compounds Va, Ve, VIa, VIf,
VIIIa, and VIIIb) were isolated even at room tem-
perature (Scheme 2).
Elimination of the morpholinomethyl residue from
isatin X which is capable of acting as reactive Mannich
base was also observed previously. Compound X read-
ily reacts with 1,3-diketones even at room temperature
[12]. We failed to isolate the corresponding products,
but this assumption is confirmed by the fact that the
yield of 4H-pyrans decreased from 70–90 to 30−45%.
EXPERIMENTAL
The 1H NMR spectra were measured from solutions
in DMSO-d6 on a Varian M-200 spectrometer
(200 MHz) using tetramethylsilane as internal refer-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SYNTHESIS OF FUSED 2′-AMINO-3′-R-SPIRO[INDOLE-3,4′-PYRAN]-2(1H)-ONES
1791
Scheme 2.
III
O
Va, Ve
O
IV
N
N
+
RCH2CN
VIa, VIf
VII
O
VIIIa, VIIIb
X
IIa, IIb
ence. The IR spectra were recorded in KBr on
a Bruker Tensor-27 spectrophotometer. The mass spec-
tra (electron impact, 70 eV) were obtained on a Varian
1200L mass spectrometer with direct sample admis-
sion into the ion source heated to 50–150°C. The prog-
ress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 plates.
N 10.98. C20H16N2O3. Calculated, %: C 65.62; H 4.72;
N 10.93.
2-Amino-3′-R-spiro[indole-3,4′-pyran]-2(1H)-
ones Va–Vh, VIa–VIi, VIIIa, and VIIIb (general
procedure). a. Isatin Ia−Ie, 1 mmol, was dissolved in
10 ml of ethanol, and 0.066 g (1 mmol) of malononi-
trile or 0.11 ml (1 mmol) of ethyl cyanoacetate,
1 mmol of 1,3-diketone III, IV, or VII, and 0.13 ml
(1 mmol) of tris(2-hydroxyethyl)amine were added. In
the condensations with malononitrile, the mixture was
stirred, heated to the boiling point, and left to stand at
room temperature for crystallization. In the condensa-
tions with ethyl cyanoacetate, the mixture was heated
for 2 h under reflux and left to stand for 24 h in a re-
frigerator. The precipitate was filtered off, washed first
with boiling hexane and then with ethanol, and dried.
Initial 2-(2-oxoindol-3-ylidene)malononitriles
IXa−IXd and ethyl 2-(2-oxoindol-3-ylidene)cyano-
acetates IXe−IXh were synthesized according to the
procedure described in [11]. Compounds IXa, IXc,
IXe, and IXg were reported in [13, 14].
2-(5-Methyl-2-oxo-2,3-dihydro-1H-indol-3-
ylidene)malononitrile (IXb). Yield 89%, mp 185°C
(decomp.). IR spectrum, ν, cm–1: 3257, 3108, 2231,
1
2110, 1731, 1620, 1584, 1466, 1341. H NMR spec-
trum, δ, ppm: 3.42 s (3H, CH3), 6.98–7.1 m (3H,
b. A mixture of 1 mmol of 2-(2-oxo-2,3-dihydro-
1H-indol-3-ylidene)malonitrile IXa−IXd or ethyl
cyano(2-oxo-2,3-dihydro-1H-indol-3-ylidene)acetate
IXe−IXh, 1 mmol of the corresponding 1,3-diketone,
and 0.13 ml (1 mmol) of tris(2-hydroxyethyl)amine in
15 ml of ethanol was heated for 1 (compounds
IXa−IXd) or 3−4 h (IXe−IXf) and was then treated as
described above in a.
Harom), 11.25 s (1H, NH). Found, %: C 68.70; H 3.26;
N 20.06. C12H7N3O. Calculated, %: C 68.89; H 3.37;
N 20.09.
2-(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yli-
dene)malononitrile (IXd). Yield 90%, mp 200−203°C
(decomp.). IR spectrum, ν, cm–1: 3030, 2227, 1719,
1
1612, 1592, 1496, 1469. H NMR spectrum, δ, ppm:
4.93 s (2H, CH2), 7.05–7.95 m (9H, Harom). Found, %:
C 75.59; H 3.85; N 14.70. C18H11N3O. Calculated, %:
C 75.78; H 3.89; N 14.73.
2-Amino-2′,5-dioxo-1′,2′,5,6,7,8-hexahydrospiro-
[chromene-4,3'-indole]-3-carbonitrile (Va). Yield
0.26 g (84%), mp 290°C (decomp.). H NMR spec-
1
trum, δ, ppm: 1.90 t (2H, CH2), 2.20 m (2H, CH2),
2.57 t (2H, CH2), 6.75 d (1H, Harom), 6.85 t (1H, Harom),
7.0 d (1H, Harom), 7.12 t (1H, Harom), 7.21 s (2H, NH2,
D2O), 10.35 s* (1H, NH, D2O). Mass spectrum, m/z
(Irel, %): 307 (19.7) [M]+, 281 (7.9) [M − 26]+, 262
(26.6) [M − 45]+, 252 (11.2) [M − 55]+, 251 (100) [M −
56]+, 250 (28.4) [M − 57]+, 236 (7.6) [M − 71]+, 210
(16.0) [M − 97]+, 209 (36.4) [M − 98]+, 195 (30.8)
[M − 109]+, 194 (11.4) [M − 113]+, 179 (7.8) [M −
128]+, 151 (8.2) [M − 156]+, 127 (7.0) [M − 180]+.
Found, %: C 66.63; H 4.18; N 13.82. C17H13N3O3. Cal-
culated, %: C 66.44; H 4.26; N 13.67.
Ethyl cyano(5-methyl-2-oxo-2,3-dihydro-1H-
indol-3-ylidene)acetate (IXf). Yield 71%, mp 198°C.
IR spectrum, ν, cm–1: 3267, 2988, 2213, 1716, 1622,
1576, 1485. H NMR spectrum, δ, ppm: 1.31 t (3H,
CH3), 2.22 s (3H, CH3), 2.48 q (2H, CH2), 6.74 d (1H,
1
Harom), 7.27 d (1H, Harom), 7.90 s (1H, Harom), 10.94 s
(1H, NH). Found, %: C 65.44; H 4.70; N 10.98.
C14H12N2O3. Calculated, %: C 65.62; H 4.72; N 10.93.
Ethyl (1-benzyl-2-oxo-2,3-dihydro-1H-indol-3-
ylidene)cyanoacetate (IXh). Yield 72%, mp 225°C
(decomp.). IR spectrum, ν, cm–1: 3028, 2227, 2213,
1
1719, 1622, 1578, 1469. H NMR spectrum, δ, ppm:
1.35 t (3H, CH3), 2.52 q (2H, CH2), 4.90 s (2H, CH2),
7.10–7.95 m (9H, Harom). Found, %: C 65.44; H 4.70;
* Hereinafter, the position of signals marked with an asterisk
may vary.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SHEMCHUK et al.
1792
2-Amino-5′-methyl-2′,5-dioxo-1′,2′,5,6,7,8-hexa-
ylate (Vf). Yield 0.24 g (64%), mp 257°C (decomp.).
1H NMR spectrum, δ, ppm: 0.80 t (2H, CH3), 1.85 t
(2H, CH2), 2.20 m (5H, CH2, CH3), 2.65 t (2H, CH2),
3.70 q (2H, CH2), 6.55 d (1H, Harom), 6.65 s (1H,
Harom), 6.80 d (1H, Harom), 7.80 s* (2H, NH2, D2O),
10.05 s* (1H, NH, D2O). Mass spectrum, m/z (Irel, %):
368 (35.5) [M]+, 313 (6.9) [M − 55]+, 312 (35.5) [M −
56]+, 313 (6.9) [M − 55]+, 296 (13.7) [M − 72]+, 295
(100) [M − 73]+, 267 (7.4) [M − 101]+, 238 (6.9)
[M − 130]+, 190 (5.3) [M − 178]+. Found, %: C 65.49;
H 5.32; N 7.76. C20H20N2O5. Calculated, %: C 65.21;
H 5.47; N 7.60.
hydrospiro[chromene-4,3′-indole]-3-carbonitrile
(Vb). Yield 0.22 g (69%), mp 287°C (decomp.).
1H NMR spectrum, δ, ppm: 1.85 t (2H, CH2), 2.25 m
(2H, CH2, CH3), 2.57 t (2H, CH2), 6.65 d (1H, Harom),
6.78 s (1H, Harom), 6.92 d (1H, Harom), 7.20 s* (2H,
NH2, D2O), 10.27 s* (1H, NH, D2O). Mass spectrum,
m/z (Irel, %): 321 (100) [M]+, 295 (9.9) [M − 26]+, 265
(30.9) [M − 56]+, 264 (8.1) [M − 57]+, 224 (9.2) [M −
97]+, 223 (16.8) [M − 98]+, 208 (5.2) [M − 113]+.
Found, %: C 67.03; H 4.68; N 13.12. C18H15N3O3. Cal-
culated, %: C 67.28; H 4.71; N 13.08.
Ethyl 2-amino-1′-methyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carbox-
ylate (Vg). Yield 0.27 g (72%), mp 289–291°C.
1H NMR spectrum, δ, ppm: 0.68 t (2H, CH3), 1.80 t
(2H, CH2), 2.12 m (2H, CH2), 2.63 t (2H, CH2), 3.05 s
(3H, CH3), 3.63 q (2H, CH2), 6.82 m (3H, Harom), 7.15 t
(1H, Harom), 7.89 s* (2H, NH2, D2O). Mass spectrum,
m/z (Irel, %): 369 (7.2) [M + 1]+, 368 (29.1) [M]+ , 312
(37.8) [M − 56]+, 296 (15.8) [M − 72]+, 295 (100) [M −
73]+, 267 (30.9) [M − 102]+, 253 (16.1) [M − 115]+,
239 (38.3) [M − 129]+, 238 (76.5) [M − 130]+, 296
(15.8) [M − 72]+, 235 (8.2) [M − 133]+, 210 (14.1)
[M − 158]+, 181 (12.6) [M − 187]+, 154 (7.6) [M −
214]+. Found, %: C 64.99; H 5.62; N 7.84.
C20H20N2O5. Calculated, %: C 65.21; H 5.47; N 7.60.
2-Amino-1′-methyl-2′,5-dioxo-1′,2′,5,6,7,8-hexa-
hydrospiro[chromene-4,3′-indole]-3-carbonitrile
(Vc). Yield 0.29 g (92%), mp 250°C (decomp.).
1H NMR spectrum, δ, ppm: 1.75 t (2H, CH2), 2.45 m
(2H, CH2), 2.57 t (2H, CH2), 3.35 s (3H, CH3), 6.90–
7.15 m (3H, Harom), 7.25 s* (2H, 1H, Harom, NH2, D2O).
Mass spectrum, m/z (Irel, %): 322 (7.1) [M +1]+, 321
(41.4) [M]+, 295 (7.8) [M − 26]+, 265 (100) [M − 56]+,
255 (15.9) [M − 66]+, 223 (28.7) [M − 98]+, 180 (7.2)
[M − 141]+, 154 (6.2) [M − 167]+. Found, %: C 67.11;
H 4.81; N 13.14. C18H15N3O3. Calculated, %: C 67.28;
H 4.71; N 13.08.
2-Amino-1′-benzyl-2′,5-dioxo-1′,2′,5,6,7,8-hexa-
hydrospiro[chromene-4,3′-indole]-3-carbonitrile
1
(Vd). Yield 0.37 g (94%), mp 290–292°C. H NMR
Ethyl 2-amino-1′-benzyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carbox-
ylate (Vh). Yield 0.28 g (65%), mp 247−250°C
spectrum, δ, ppm: 1.80 t (2H, CH2), 2.25 m (2H, CH2),
2.70 t (2H, CH2), 4.85 s (2H, CH2), 6.90 t (1H, Harom),
7.10 m (2H, Harom), 7.30 m (5H, Harom), 7.50 s* (2H,
1H, Harom, NH2, D2O). Found, %: C 72.47; H 4.53;
N 10.72. C24H19N3O3. Calculated, %: C 72.53; H 4.82;
N 10.57.
1
(decomp.). H NMR spectrum, δ, ppm: 0.52 t (2H,
CH3), 1.75 t (2H, CH2), 2.45 m (2H, CH2), 2.35 t (2H,
CH2), 3.45 q (2H, CH2), 4.72 s (2H, CH2), 6.65 d (1H,
Harom), 6.85 t (1H, Harom), 6.95 d (1H, Harom), 7.10 t
(1H, Harom), 7.30 m (3H, Harom), 7.60 d (1H, Harom),
7.93 s* (2H, NH2, D2O). Mass spectrum, m/z (Irel, %):
444 (13.4) [M]+, 428 (8.4) [M − 16]+, 400 (28.1) [M −
44]+, 399 (100) [M − 45]+, 388 (28.1) [M − 56]+, 381
(17.2) [M − 63]+, 361 (7.2) [M − 83]+, 335 (7.6) [M −
109]+, 400 (28.1) [M − 44]+, 309 (14.7) [M − 135]+,
280 (9.8) [M − 164]+, 230 (8.9) [M − 214]+, 223 (22.8)
[M − 221]+, 204 (9.6) [M − 240]+, 195 (23.3) [M −
249]+, 168 (12.6) [M − 276]+, 128 (9.3) [M − 316]+.
Found, %: C 70.37; H 5.52; N 6.41. C26H24N2O5. Cal-
culated, %: C 70.26; H 5.44; N 6.30.
Ethyl 2-amino-2′,5-dioxo-1′,2′,5,6,7,8-hexahydro-
spiro[chromene-4,3′-indole]-3-carboxylate (Ve).
1
Yield 0.24 g (67%), mp 230°C (decomp.). H NMR
spectrum, δ, ppm: 0.75 t (2H, CH3), 1.80 t (2H, CH2),
2.20 m (2H, CH2), 2.60 t (2H, CH2), 3.75 q (2H, CH2),
6.60−6.90 m (3H, Harom), 7.10 t (1H, Harom), 7.80 s*
(2H, NH2, D2O), 10.10 s* (1H, NH, D2O). Mass spec-
trum, m/z (Irel, %): 354 (30.8) [M]+, 299 (9.7) [M −
55]+, 298 (63.5) [M − 56]+, 282 (16.1) [M − 72]+, 281
(100) [M − 73]+, 263 (8.3) [M − 91]+, 253 (21.4) [M −
101]+, 252 (7.3) [M − 102]+, 236 (7.3) [M − 118]+, 225
(5.3) [M − 129]+, 224 (11.7) [M − 130]+. Found, %:
C 64.08; H 5.29; N 8.06. C19H18N2O5. Calculated, %:
C 64.40; H 5.12; N 7.91.
2-Amino-7,7-dimethyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carboni-
trile (VIa). Yield 0.32 g (95%), mp 285°C (decomp.);
published data [7]: mp 285–286°C. 1H NMR spectrum,
δ, ppm: 1.02 s [6H, C(CH3)2], 2.10 s (2H, CH2), 2.58 s
Ethyl 2-amino-5′-methyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carbox-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SYNTHESIS OF FUSED 2′-AMINO-3′-R-SPIRO[INDOLE-3,4′-PYRAN]-2(1H)-ONES
1793
(2H, CH2), 6.78 d (1H, Harom), 6.85 t (1H, Harom),
6.98 d (1H, Harom), 7.15 t (1H, Harom), 7.23 s* (2H,
NH2, D2O), 10.40 s* (1H, NH, D2O). Found, %:
C 68.23; H 5.19; N 12.76. C19H17N3O3. Calculated, %:
C 68.05; H 5.11; N 12.53.
2-Amino-1′-benzyl-7,7-dimethyl-2′,5-dioxo-
1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-indole]-
3-carbonitrile (VIe). Yield 0.36 g (85%), mp 285°C
1
(decomp.). H NMR spectrum, δ, ppm: 1.0 d [6H,
C(CH3)2], 2.15 q (2H, CH2), 2.60 s (2H, CH2), 4.89 s
(2H, CH2), 6.65 d (1H, Harom), 6.95 t (1H, Harom),
7.12 m (2H, Harom), 7.30 m (5H, 3H, Harom, NH2, D2O),
7.50 d (1H, Harom). Mass spectrum, m/z (Irel, %): 425
(7.7) [M]+, 397 (14.2) [M − 28]+, 362 (9.0) [M − 63]+,
334 (19.9) [M − 91]+, 316 (13.3) [M − 109]+, 285 (7.6)
[M − 140]+, 251 (9.7) [M − 174]+, 238 (23.0) [M −
187]+, 236 (56.5) [M − 189]+, 234 (100) [M − 191]+,
224 (7.2) [M − 201]+, 219 (28.1) [M − 206]+, 206
(14.8) [M − 219]+, 189 (26.8) [M − 236]+, 170
(11.8) [M − 255]+, 139 (11.6) [M − 286]+, 114 (12.4)
[M − 311]+. Found, %: C 73.28; H 5.55; N 10.08.
C26H23N3O3. Calculated, %: C 73.39; H 5.45; N 9.88.
2-Amino-5′,7,7-trimethyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carboni-
trile (VIb). Yield 0.32 g (92%), mp 255°C (decomp.).
1H NMR spectrum, δ, ppm: 1.0 s [6H, C(CH3)2], 2.10 s
(2H, CH2), 2.50 s (5H, CH2, CH3), 6.60 d (1H, Harom),
6.75 s (1H, Harom), 6.90 d (1H, Harom), 7.18 s* (2H,
NH2, D2O), 10.35 s* (1H, NH, D2O). Mass spectrum,
m/z (Irel, %): 350 (19.1) [M]+, 349 (100) [M]+, 323
(16.7) [M − 26]+, 304 (33.8) [M − 45]+, 265 (55.6)
[M − 84]+, 250 (13.3) [M − 99]+, 223 (37.9) [M − 126]+,
220 (11.4) [M − 129]+, 192 (21.8) [M − 157]+, 177
(7.5) [M − 172]+, 153 (8.2) [M − 196]+. Found, %:
C 68.51; H 5.52; N 12.09. C20H19N3O3. Calculated, %:
C 68.75; H 5.48; N 12.03.
Ethyl 2-amino-7,7-dimethyl-2′,5-dioxo-1′,2′,5,6,-
7,8-hexahydrospiro[chromene-4,3′-indole]-3-carbox-
ylate (VIf). Yield 0.24 g (63%), mp 263°C (decomp.).
IR spectrum, ν, cm–1: 3372, 3235, 3181, 3115, 2986,
2-Amino-5′-bromo-7,7-dimethyl-2′,5-dioxo-
1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-indole]-
3-carbonitrile (VIc). Yield 0.27 g (65%), mp 275°C
1
2959, 2900, 1714, 1689, 1616, 1526, 1472. H NMR
1
spectrum, δ, ppm: 0.78 t (3H, OCH2CH3), 1.0 d [6H,
C(CH3)2], 2.05 s (2H, CH2), 2.60 s (2H, CH2), 3.70 q
(2H, OCH2), 6.65−6.85 m (3H, Harom), 7.05 t (1H,
(decomp.). H NMR spectrum, δ, ppm: 1.05 s [6H,
C(CH3)2], 2.20 s (2H, CH2), 2.57 s (2H, CH2), 6.70 d
(1H, Harom), 6.85 s (1H, Harom), 7.30 m (3H, 1H, Harom
,
H
arom), 7.85 s* (2H, NH2, D2O), 10.12 s* (1H, NH,
NH2, D2O), 10.55 s* (1H, NH, D2O). Mass spectrum,
m/z (Irel, %): 415 (13.2) [M + 1]+, 414 (8.9) [M]+, 413
(15.8) [M − 1]+, 372 (14.4) [M − 42]+, 371 (19.6) [M −
43]+, 329 (100) [M − 85]+, 328 (15.7) [M − 86]+, 303
(14.3) [M − 111]+, 287 (27.8) [M − 127]+, 261 (8.4)
[M − 153]+, 217 (14.5) [M − 197]+, 194 (20.8) [M −
220]+, 165 (20.6) [M − 249]+, 140 (31.2) [M − 274]+,
139 (16.1) [M − 275]+, 127 (8.8) [M − 287]+. Found,
%: C 55.31; H 4.09; N 10.22. C19H16BrN3O3. Calculat-
ed, %: C 55.09; H 3.89; N 10.14.
D2O). Found, %: C 66.16; H 5.94; N 7.51. C21H22N2O5.
Calculated, %: C 65.96; H 5.80; N 7.33.
Ethyl 2-amino-5′,7,7-trimethyl-2′,5-dioxo-
1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-indole]-
3-carboxylate (VIg). Yield 0.27 g (69%), mp 272°C
1
(decomp.). H NMR spectrum, δ, ppm: 0.80 t (3H,
OCH2CH3), 1.0 d [6H, C(CH3)2], 2.05 s (2H, CH2),
2.10 s (5H, CH2, CH3), 3.70 q (2H, OCH2), 6.52 d (1H,
H
arom), 6.65 s (1H, Harom), 6.80 d (1H, Harom), 7.80 s*
(2H, NH2, D2O), 10.02 s* (1H, NH, D2O). Found, %:
C 66.73; H 6.19; N 7.22. C22H24N2O5. Calculated, %:
C 66.65; H 6.10; N 7.07.
2-Amino-1′,7,7-trimethyl-2′,5-dioxo-1′,2′,5,6,7,8-
hexahydrospiro[chromene-4,3′-indole]-3-carbo-
nitrile (VId). Yield 0.26 g (75%), mp 265–267°C.
1H NMR spectrum, δ, ppm: 1.0 d [6H, C(CH3)2],
2.10 s (2H, CH2), 2.60 s (2H, CH2), 3.10 s (3H, CH3),
6.90−7.10 m (3H, Harom), 7.25 m (2H, 1H, Harom, NH2,
D2O). Mass spectrum, m/z (Irel, %): 349 (7.7) [M]+, 323
(10.6) [M − 26]+, 306 (6.0) [M − 43]+, 283 (6.0) [M −
66]+, 283 (6.0) [M − 66]+, 265 (100) [M − 66]+, 264
(24.5) [M − 85]+, 255 (6.0) [M − 94]+, 250 (9.9) [M −
99]+, 283 (6.0) [M − 66]+, 240 (67.8) [M − 109]+, 238
(34.8) [M − 111]+, 237 (59.3) [M − 112]+, 222 (9.0)
[M − 127]+, 194 (9.0) [M − 155]+. Found, %: C 68.11;
H 5.61; N 12.12. C20H19N3O3. Calculated, %: C 68.75;
H 5.48; N 12.03.
Ethyl 2-amino-1′,7,7-trimethyl-2′,5-dioxo-
1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-indole]-
3-carboxylate (VIh). Yield 0.32 g (82%), mp 205°C
1
(decomp.). H NMR spectrum, δ, ppm: 0.68 t (3H,
OCH2CH3), 0.98 d [6H, C(CH3)2], 2.05 q (2H, CH2),
2.65 t (2H, CH2), 3.05 s (3H, CH3), 3.65 q (2H,
OCH2), 6.80 m (3H, Harom), 7.13 t (1H, Harom), 7.90 s*
(2H, NH2, D2O). Mass spectrum, m/z (Irel, %): 396
(29.0) [M]+, 323 (100) [M − 73]+, 312 (28.3) [M − 84]+,
295 (18.7) [M − 101]+, 283 (6.0) [M − 66]+, 250 (8.6)
[M − 146]+, 211 (9.7) [M − 185]+, 168 (6.6) [M − 228]+,
140 (6.9) [M − 256]+. Found, %: C 66.84; H 6.24;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SHEMCHUK et al.
1794
N 7.12. C22H24N2O5. Calculated, %: C 66.65; H 6.10;
N 7.07.
D2O), 10.25 s* (1H, NH, D2O). Found, %: C 63.15;
H 5.30; N 8.18. C18H18N2O5. Calculated, %: C 63.15;
H 5.30; N 8.18.
Ethyl 2-amino-1′-benzyl-7,7-dimethyl-2′,5-dioxo-
1′,2′,5,6,7,8-hexahydrospiro[chromene-4,3′-indole]-
3-carboxylate (VIi). Yield 0.37 g (78%), mp 289°C
REFERENCES
1
(decomp.). H NMR spectrum, δ, ppm: 0.50 t (3H,
1. Rahman, A., Silva, W.S.J., Alvi, K.A., and De
OCH2CH3), 1.0 d [6H, C(CH3)2], 2.05 q (2H, CH2),
2.50 t (2H, CH2), 3.50 q (2H, OCH2), 4.80 q (2H,
CH2), 6.65 d (1H, Harom), 6.82 t (1H, Harom), 6.90 d
(1H, Harom), 7.15 t (1H, Harom), 7.30 m (3H, Harom),
7.6 d (2H, Harom), 7.80 s* (2H, NH2, D2O). Found, %:
C 70.97; H 5.91; N 6.01. C28H28N2O5. Calculated, %:
C 71.17; H 5.97; N 5.93.
Silva, K.T.D., Phytochemistry, 1987, vol. 26, p. 865.
2. Rahman, A., Qureshi, M.M., Muzaffar, A., and De
Silva, K.T.D., Heterocycles, 1988, vol. 27, p. 725.
3. Peterson, A.C. and Cook, J.M., J. Org. Chem., 1995,
vol. 60, p. 120.
4. Abdelrazek, F.M., Metz, P., and Farrag, E.K., Arch.
Pharm. Pharm. Med. Chem., 2004, vol. 337, p. 482.
5′-Acetyl-2′-amino-6′-methyl-2-oxo-1,2-dihydro-
spiro[indole-3,4′-pyran]-3′-carbonitrile (VIIIa).
5. Pickering, H., Sword, S., Vonhoff, S., Jones, R., and
Sugden, D., Brit. J. Pharmacol., 1996, vol. 119, p. 379.
1
Yield 0.19 g (64%), mp 240°C (decomp.). H NMR
6. Dworczak, R., Sterk, H., Kratky, C., and Junek, H.,
spectrum, δ, ppm: 2.05 s (3H, CH3), 2.25 s (3H,
COCH3), 6.65 d (1H, Harom), 6.90 t (1H, Harom), 7.05 d
(1H, Harom), 7.15 m (3H, 1H, Harom, NH2, D2O),
10.35 s* (1H, NH, D2O). Mass spectrum, m/z (Irel, %):
295 (8.9) [M]+, 279 (5.4) [M − 16]+, 266 (6.9) [M − 29]+,
254 (8.0) [M − 41]+, 253 (23.8) [M − 42]+, 252 (66.2)
[M − 43]+, 224 (10.2) [M − 71]+, 210 (100) [M − 85]+,
207 (15.1) [M − 88]+, 194 (6.9) [M − 101]+, 179 (10.1)
[M − 116]+, 154 (8.3) [M − 141]+. Found, %: C 65.27;
H 4.62; N 14.14. C16H13N3O3. Calculated, %: C 65.08;
H 4.44; N 14.23.
Chem. Ber., 1989, vol. 122, p. 1323.
7. Abdel-Latif, F.F., Mashaly, M.M., and El-Gawish, E.H.,
J. Chem. Res., Miniprint, 1995, no. 5, p. 1220.
8. Al-Omran, F., El-Ghamry, I., and Elnagdi, M.H., Org.
Prep. Proced. Int., 1998, vol. 30, no. 3, p. 363.
9. Sharanin, Yu.A. and Goncharenko, M.P., Zh. Org.
Khim., 1988, vol. 24, no. 2, p. 460.
10. Klokol, G.V., Krivokolysko, S.G., Dyachenko, V.D., and
Litvinov, V.P., Khim. Geterotsikl. Soedin., 1999,
p. 1363.
11. Harley-Manson, J. and Inleby, R., J. Chem. Soc., 1958,
p. 3639.
Ethyl 5′-acetyl-2′-amino-6′-methyl-2-oxo-1,2-
dihydrospiro[indole-3,4′-pyran]-3′-carboxylate
(VIIIb). Yield 0.22 g (65%), mp 235°C (decomp.).
1H NMR spectrum, δ, ppm: 065 t (3H, OCH2CH3),
1.80 s (3H, CH3), 2.05 s (3H, COCH3), 3.65 q (2H,
OCH2), 6.65 d (1H, Harom), 6.80 t (1H, Harom), 6.98 d
(1H, Harom), 7.05 t (1H, Harom), 7.72 s* (1H, NH2,
12. Gupta, R.P. and Narayana, N.L., Pharm. Acta Helv.,
1997, vol. 72, p. 43.
13. Daisley, R.W. and Walker, J., Eur. J. Med. Chem., 1979,
vol. 14, p. 47.
14. Long, D.R., Richards, C.G., and Ross, M.S.F., J. Hetero-
cycl. Chem., 1978, vol. 15, p. 633.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008