Synthesis of pyrrolo[2,3-H]quinolines from 4-amino-2,3-dimethyl-and 4-amino-1,2,3-trimethylindoles

Article abstract of DOI:10.1007/s10593-007-0163-1

A study was carried out on the reactions of 4-amino-2,3-dimethyl-and 4-amino-1,2,3-trimethylindoles with acetylacetone, dibenzoylmethane, ethyl acetoacetate, ethyl trifluoroacetoacetate, and ethyl oxaloacetate. Methods were developed for the synthesis of a series of substituted pyrrolo-[2,3-h] quinolines.

Full text of DOI:10.1007/s10593-007-0163-1

Chemistry of Heterocyclic Compounds, Vol. 43, No. 8, 2007
SYNTHESIS OF PYRROLO[2,3-h]QUINOLINES FROM 4-AMINO-
2,3-DIMETHYL- AND 4-AMINO-1,2,3-TRIMETHYLINDOLES
S. A. Yamashkin, E. A. Oreshkina, and N. V. Zhukova
A study was carried out on the reactions of 4-amino-2,3-dimethyl- and 4-amino-1,2,3-trimethylindoles
with acetylacetone, dibenzoylmethane, ethyl acetoacetate, ethyl trifluoroacetoacetate, and ethyl
oxaloacetate. Methods were developed for the synthesis of a series of substituted pyrrolo-
[2,3-h]quinolines.
Keywords: acetylacetone, ethyl acetoacetate, dibenzoylmethane, 4-amino-2,3-dimethyl- and 4-amino-
1,2,3-trimethylindoles, substituted pyrrolo[2,3-h]quinolines, ethyl trifluoroacetoacetate, ethyl oxaloacetate.
In work on the development of methods for the synthesis of pyrroloquinolines with potential biological
activity, reactions of 4-amino-2,3-dimethyl- (1) and 4-amino-1,2,3-trimethylindoles (2) with β-dicarbonyl
compounds have not yet been studied.
NH2
Me
R1CH2COR2
Me
N
R
1, 2
O
O
NH
NH
Me
Me
HO
F3C
O
R1 = CF3CO
R2 = OEt
F3C
+
Me
Me
N
N
R
R
7a, 8
7
R2
CO2Et
N
NH
Me
Me
R1
EtO2C
Me
Me
N
N
H
R
3–6, 9a
9b
1 R = H; 2 R = Me; 3 R = H, R1 = MeCO, R2 = Me; 4 R = R2 = Me, R1 = MeCO; 5 R = H, R1 = PhСO, R2 = Ph;
6 R = Me, R1 = PhСO, R2 = Ph; 7, 7a (mixture) R = H; 8 R = Me; 9 R = H, R1 = R2 = CO2Et
__________________________________________________________________________________________
N. P. Ogarev Mordovsk State University, Saransk 430000, Russia; e-mail: biotech@moris.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1234-1242, August, 2007. Original article submitted
March 13, 2006.
1044
0009-3122/07/4308-1044©2007 Springer Science+Business Media, Inc.

TABLE 1. 1H NMR Spectra of Compounds 3-16
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
3
1.80 (3Н, s, =C–CH3); 2.00 (3Н, s, О=С–СН3); 2.13 (3Н, s, 3–СН3); 2.28 (3Н, s, 2–СН3);
5.22 (1Н, s, =CH); 6.71 (1Н, d, J5,6 = 8, Н-5); 6.94 (1Н, t, J5,6,7 = 8, Н-6);
7.15 (1Н, d, J7,6 = 8, Н-7); 10.91 (1Н, s, 4-NН); 12.51 (1Н, s, Н-1)
4
1.80 (3Н, s, =C–CH3); 2.00 (3Н, s, О=С-СН3); 2.18 (3Н, s, 3–СН3); 2.31 (3Н, s, 2–СН3);
3.65 (3Н, s, 1–СН3); 5.23 (1Н, s, =CH); 6.76 (1Н, d, J5,6 = 8, Н-5);
7.05 (1Н, t, J5,6,7 = 8, Н-6); 7.30 (1Н, d, J7,6 = 8, Н-7); 12.51 (1Н, s, 4-NН)
5
2.34 (3Н, s, 3-СН3); 2.48 (3Н, s, 2-СН3); 6.08 (1Н, d, J5,6 = 8, Н-5); 6.21 (1Н, s, =CH);
6.64 (1Н, t, J5,6,7 = 8, Н-6); 6.97 (1Н, d, J7,6 = 8, Н-7); 7.29-7.60 (10Н, m, 2C6H5);
10.90 (1Н, s, Н-1); 13.25 (1Н, s, 4-NН)
6
2.36 (3Н, s, 3-СН3); 2.50 (3Н, s, 2-СН3); 3.65 (3Н, s, 1-СН3);
6.12 (1Н, d, J5,6 = 8, Н-5); 6.22 (1Н, s, =CH); 6.70 (1Н, t, J5,6,7 = 8, Н-6);
7.10 (1Н, d, J6,7 = 8, Н-7); 7.37-7.55 (10Н, m, 2C6H5); 13.27 (1Н, s, 4-NН)
8
2.29 (3H, s, 9-CH3); 2.42 (3H, s, 8-CH3); 2.86 (1Н, d, J3Н,3Н' = 15, Н-3);
3.03 (1Н, d, J3Н',3Н = 15, Н'-3); 3.61 (3H, s, 7-CH3); 6.80 (1H, s, 4-OH);
7.12 (1Н, d, J5,6 = 7, Н-5); 7.28 (1Н, d, J6,5 = 7, Н-6); 9.05 (1Н, s, NН)
9a
0.94 (3Н, t, J = 7, СООСН2СН3 chelate); 1.24 (3Н, t, J = 7, СООСН2СН3);
2.30 (3Н, s, 3-СН3); 2.34 (3Н, s, 2-СН3); 4.05 (2Н, q, J = 7, СООСН2СН3 chelate);
4.15 (2Н, q, J = 7, СООСН2СН3); 5.14 (1Н, s, =СН.); 6.30 (1Н, d, J5,6 = 8, Н-5);
6.85 (1Н, t, J5,6,7 = 8, Н-6); 7.04 (1Н, d, J7,6 = 7, Н-7); 10.05 (1Н, s, 4-NН);
10.86 (1Н, s, Н-1)
9b
1.24 (3Н, t, J = 7, 2-СООСН2СН3); 2.20 (3Н, s, 3-СН3); 2.34 (3Н, s, 2-СН3);
4.15 (2Н, q, J = 7, 2-СООСН2СН3); 4.71 (2Н, s, –СН2–); 6.09 (1Н, d, J5,6 = 8, Н-5);
6.48 (1Н, d, J7,6 = 8, Н-7); 6.63 (1Н, t, J5,6,7 = 8, Н-6); 10.27 (1Н, s, Н-1)
10
11
2.35 (3Н, s, 8-СН3); 2.60 (6Н, s, 2-, 4-СН3); 2.65 (3Н, s, 9-СН3); 7.08 (1Н, s, Н-3);
7.45 (1Н, d, J6,5 = 8, Н-6); 7.51 (1Н, d, J5,6 = 8, Н-5); 11.15 (1Н, s, Н-7)
2.38 (3Н, s, 8-СН3); 2.62 (3Н, s, 4-СН3); 2.64 (3Н, s, 2-СН3); 2.72 (3Н, s, 9-СН3);
3.76 (3Н, s, 7-СН3); 7.10 (1Н, s, Н-3); 7.57 (1Н, d, J6,5 = 8, Н-6);
7.64 (1Н, d, J5,6 = 8, Н-5)
12
13
2.44 (3Н, s, 8-СН3); 2.84 (3Н, s, 9-СН3); 7.36 (1Н, d, J5,6 = 8, Н-5);
7.48 (1Н, t, J = 7, 4-Нp-Ph); 7.52 (1Н, d, J6,5 = 8, Н-6);
7.55-7.65 (7Н, m, 4-Но-, m-Ph, 6-Нm-, p-Ph); 7.88 (1Н, s, Н-3); 8.40 (1Н, d, J = 7, 2-Но-Ph);
11.38 (1Н, s, Н-7)
2.45 (3Н, s, 8-СН3); 2.85 (3Н, s, 9-СН3); 3.80 (3Н, s, 7-СН3);
7.42 (1Н, d, J5,6 = 8, Н-5); 7.48 (1Н, t, J = 7, 4Hp-Ph);
7.50-7.53 (7Н, m, 4-Но-, m-Ph, 2-Нm-, p-Ph); 7.70 (1Н, d, J6,5 = 8, Н-6);
7.87 (1Н, s, Н-3); 8.40 (2Н, d, J = 7, 2-Но-Ph
)
14
2.35 (3Н, s, 8-СН3); 2.58 (3Н, s, 9-СН3); 3.75 (3Н, s, 7-СН3); 6.80 (1Н, s, Н-3);
7.38 (1Н, d, J5,6 = 8, Н-5); 7.45 (1Н, d, J6,5 = 8, Н-6); 10.10 (1Н, s, Н-1)
15
2.33 (3Н, s, 8-СН3); 2.52 (3Н, s, 9-СН3); 6.80 (1Н, s, Н-3);
7.30 (2Н, br. s, J5,6 = 8, Н-5,6); 10.11 (1Н, s, Н-1); 11.44 (1Н, s, Н-7)
16А
1.29 (3Н, t, J = 7, 2-СООСН2СН3); 2.19 (3Н, s, 8-СН3); 2.70 (3Н, s, 9-СН3);
4.38 (2Н, q, J = 7, 2-СООСН2СН3); 7.44 (1Н, s, Н-3); 7.55 (1Н, d, J5,6 = 8, Н-5);
7.70 (1Н, d, J6,5 = 8, Н-6); 11.24 (1Н, s, Н-7); 11.34 (1Н, s, 4-ОН)
16В
1.29 (3Н, t, J = 7, 2-СООСН2СН3); 2.16 (3Н, s, 8-СН3); 2.58 (3Н, s, 9-СН3);
4.94 (2Н, q, J = 7, 2-СООСН2СН3); 6.64 (1Н, s, Н-3);
7.32 (1Н, d, J5,6 = 8, Н-5); 7.72 (1Н, d, J6,5 = 8, Н-6); 9.73 (1Н, s, Н-1); 11.50 (1Н, s, Н-7)
We have found that amines 1 and 2 react upon heating with acetylacetone (at ~139°C) and
dibenzoylmethane (at ~180°C) to give enamino ketones 3-6.
1
The H NMR spectra of enamino ketones 3-6 given in Table 1 show singlets for two methyl groups (3
and 5) or three methyl groups (4 and 6) of the indole fragment, vinyl proton (=CH), 4-NH, H-1 (3 and 5), two
doublets for H-5, H-7, and a triplet for H-6 with J = 8 Hz. The spectra of 3 and 4 also show singlets for the
COCH3 and =CCH3 methyl groups. The spectra of 5 and 6 also show multiplets for two phenyl substituents. The
UV spectra of 3-6 are typical for indolylenamino ketones [1].
1045

TABLE 2. UV and Mass Spectra of Compounds 3-16
Com-
pound
UV spectrum
max, nm log ε
Mass spectrum, m/z (Irel, %)
λ
3
227 314
4.45 4.21 242 [М]+ (100), 227 (31), 225 (55), 212 (11), 211 (11),
200 (13), 199 (72), 197 (11), 186 (13), 185 (99), 184 (79),
183 (33), 182 (13), 170 (48), 169 (13), 159 (20), 158 (19),
144 (23), 143 (20), 115 (14), 114 (14)
4.46 4.23 256 [М]+ (61), 241 (11), 213 (40), 199 (60), 198 (62), 184 (48),
183 (18), 173 (19), 158 (22), 157 (12), 143 (12), 128 (14),
4
229 318
120 (24), 116 (13), 115 (26), 99 (27), 98 (25), 84 (31), 43 (100)
5
224 344
226 345
4.54 4.18 366 [М]+ (25), 261 (39), 247 (34), 246 (23), 159 (11), 158 (11),
145 (11), 144 (11), 115 (14), 105 (77), 77 (100), 51 (16)
4.45 4.09 380 [М]+ (9), 275 (27), 261 (34), 260 (30), 173 (11), 158 (11),
6
105 (57), 77 (100)
7, 7а
298 [М]+ (33), 279 (13), 257 (13), 229 (100), 187 (67),
160 (82), 159 (93), 69 (82)
8
232 305
4.53 3.93 312 [М]+ (27), 244 (15), 243 (100), 225 (10), 173 (30)
9a
223 280
345
4.47 4.08 330 [М]+ (48), 284 (9), 257 (63), 256 (20). 211 (54), 210 (41),
3.90
209 (26), 183 (100), 170 (57), 143 (33), 115 (33), 77 (20),
57 (20), 43 (30)
10
11
12
13
14
15
16
227 265
339
4.45 4.35 224 [М]+ (100), 223 (70), 209 (24), 112 (21)
3.90
236 266
342
4.45 4.36 238 [М]+ (89), 237 (49), 223 (100), 224 (17), 181 (13), 119 (44)
3.96
224 245
295 360
4.45 4.56 348 [М]+ (100), 347 (35), 174 (37), 77 (33)
4.33 3.97
225 248
270 365
4.55 4.68 362 [М]+ (100), 361 (26), 348 (11), 347 (48), 181 (87),
4.54 4.11 180 (26), 173 (39), 77 (54)
4.52 4.42 294 [М]+ (100), 293 (87), 279 (48), 147 (26), 69 (25)
218 240
281 345
4.33 3.83
215 234
281 340
4.48 4.31 280 [М]+ (100), 279 (83), 265 (37), 69 (45)
4.27 3.78
240 284
380
4.72 4.17 284 [М]+ (50), 211 (22), 210 (100), 182 (70), 181 (48),
3.85
167 (12), 154 (28), 127 (20), 115 (14), 77 (27), 63 (20), 45 (28)
The decomposition of the molecular ions of enamines 3-6 upon electron impact proceeds through two
major pathways: elimination of Me(Ph)CO· or Me(Ph)COCH2 to give fragment ions [M–Me(Ph)CO]+ and [M–
Me(Ph)COCH2]+ respectively. These results indicate that in the gas phase, the compounds studied are found in at
least two forms: imino and enamino ketone (Table 2).
A mixture of products is formed in the reaction of aminoindole 1 and ethyl 4,4,4-trifluoroacetoacetate
upon heating in benzene at reflux with catalytic amounts of acetic acid. Acording to the 1H NMR spectrum this
mixture contains acyclic amide 7 (probably in different tautomeric forms) and a cyclic amide 7a. Amides 7 and
7a were not isolated as pure compounds. The formation of a mixture of 7 and 7a was supported by the mass
spectrum. The [M–69]+ peak (100%), corresponding to the loss of the CF3 radical from the molecular ion, was
the strongest peak in the spectrum. This is the major decomposition pathway, as noted previously for cyclic
amides obtained from 6-aminoindoles [1]. The strong [M–138]+ peak (82%) corresponds to the loss of
trifluorodiketene from the amide molecular ion to give the corresponding aminoindole. This decomposition
pathway was observed for the described acyclic amides.
In contrast to the case of amide 1, cyclic amide 8 is the product of the reaction of amine 2 with ethyl
1
trifluoroacetate. The H NMR spectrum of amide 8 has signals for the methyl groups at positions 7, 8, and 9,
signal for 4-OH, and two AB doublets for H-5 and H-6. The protons of the methylene group also appear as two
doublets (at 2.86 and 3.03 ppm) with coupling constant 15 Hz. The nonequivalence of the H-3 protons is
attributed to the effect of differently positioned CF3 and OH groups at the asymmetric C(4) atom. The strongest
1046

peak in the mass spectrum of 8 is found for the fragmentation ion with m/z 243 corresponding to the loss of the
CF3 radical from the molecular ion, leading to the stable protonated pyrrolo[2,3-h]quinolinedione system. This
finding also supports the assigned cyclic structure for 8. The formation of cyclic amides was also observed for
other 1-methylaminoindoles upon reaction with ethyl trifluoroacetate [1] and attributed to enhanced reactivity of
the benzene ring carbon atoms in the indole system due to the effect of the N–Me group.
The analogous reaction of aminoindole 1 with ethyl oxaloacetate under the same conditions, in contrast
to the reaction with ethyl trifluoroacetate, gives the diethyl ester of (4-amino-2,3-dimethylindolyl)fumaric acid
1
(9). H NMR spectroscopy in DMSO-d6 indicated that ~20% imine form of 9 (lack of signals for vinyl and
amine protons and presence of a signal for methylene group protons) exists along with ~80% enamine form
(presence of singlets for =CH and 4-NH protons). The two triplets and two quartets for the protons of the
ethoxycarbonyl groups in the spectrum also indicate the condensation of 4-amino-2,3-dimethylindole due to the
ketone group of ethyl oxaloacetate to give enamine 9. The structure and composition of 9 were supported by the
mass spectrum, in which the strongest peak with m/z 183 (100%) corresponds to the consecutive elimination of
the ethoxycarbonyl radical, EtOH molecule, and CO molecule from the molecular ion.
Products 3-8 were then studied under conditions of acid cyclization. Enamino ketones 3-6 in
trifluoroacetic acid give the expected pyrroloquinolines 10-13.
R1
N
Me
CF3CO2H
R1
3–6
Me
N
R
10–13
10 R = H, R1 = Me; 11 R = R1 = Me; 12 R = H, R1 = Ph; 13 R = Me, R1 = Ph
The 1H NMR spectra of 10 and 11 showed singlets for 2-CH3, 4-CH3, 8-CH3, 9-CH3, H-3, and H-7 (10)
and 7-CH3 (11) as well as doublets for H-5 and H-6. The spectra of 12 and 13 lack signals for 2-CH3 and 4-CH3
characteristic for pyrroloquinolines 10 and 11 but display multiplets for phenyl group protons.
Amides (7, 7a) and 8 differ in their behavior under acid cyclization conditions. Thus, while methylated
amide 8 is converted over 3.5 h into the corresponding pyrroloquinoline 14, heating the mixture of 7 and 7a in
trifluoroacetic acid at reflux for 30 h does not lead to complete cyclization. Only the use of more vigorous
conditions (ZnCl2, 140°C) gives pure pyrroloquinoline 15.
O
NH
Me
F3C
(7, 7a), 8
Me
N
14, 15
R
14 R = Me; 15 R = H
The 1H NMR spectra of 14 and 15 show two (15) or three (14) methyl group signals, signal for aromatic
proton H-3, as well as singlets for H-7 (for 15) and H-1 and two doublets for H-5 and H-6. The mass spectra of
pyrroloquinolines 14 and 15 display molecular ion peaks at m/z 294 (100%) and 280 (100%), respectively, and
fragment peaks only for [M–H]+ (83 and 87%) and [M–CH3]+ (37 and 48%), which indicates stability of the
molecule toward electron impact.
1047

The product of the condensation of 4-amino-2,3-dimethylindole with ethyl oxaloacetate 9 is converted to
pyrroloquinoline 16 upon heating in diphenyl at reflux.
CO2Et
N
CO2Et
NH
Me
Me
9
HO
O
Me
Me
N
N
H
H
A
B
16
1
The H NMR spectrum of 16 in DMSO-d6 indicates that this compound exists as a 3:1 mixture of two
tautomeric forms: hydroxyquinoline form A and quinolone form B (according to the proton integral intensities).
The spectra of both forms have a triplet and quartet for the 2-CO2Et group, signals for 8-CH3, 9-CH3, H-3, and
H-7, two doublets for H-5 and H-6, as well as singlets for the 4-OH proton (for form A) and H-1 (for form B). In
TABLE 3. Physicochemical Characteristics of 3-6 and 8-16
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Rf *
mp, °C *2
Yield, %
С
Н
М
3
4
5
6
8
C15H18N2O
74.23
74.35
74.88
74.97
81.72
81.94
81.71
82.07
57.51
57.69
65.21
65.44
80.20
80.32
80.44
80.63
7.65
7.49
7.98
7.86
6.29
6.05
6.80
6.36
4.96
4.84
6.92
6.71
7.34
7.19
7.72
7.61
242
242
256
256
366
366
380
380
312
312
330
330
224
224
238
238
348
348
362
362
294
294
280
280
0.48
0.61
0.61
0.68
0.76
0.48
0.56
0.42
0.77
0.83
0.54
0.47
0.43
96-97
100-101
152-153
150-51
206-207
113
53
39
45
41
50
27
67
77
79
91
95
76
47
C16H20N2O
C25H22N2O
C26H24N2O
C15H15F3N2O2
C18H22N2O4
C15H16N2
9
10
158
11
12
13
14
15
16
C16H18N2
196-197
274-275
204-205
237-238
266-267
273
C25H22N2
86.00
86.17
—
5.91
5.79
—
C26H22N2
C15H13F3N2O
C14H11F3N2O
C16H16N2O3
61.03
61.22
59.54
60.00
67.49
67.59
4.67
4.45
4.46
3.96
5.69
5.67
284
284
_______
Elution systems: 3:1 benzene-ethyl acetate for 3, 4, 10, 11,
*
1:1 benzene-ethyl acetate for 8 and 15, 10:1 benzene-ethyl acetate for 9,
and 1:2 benzene-ethyl acetate for 14, chloroform with traces of methanol
for 5, 6, 12, 13, and 16.
*2 Crystallization solvents: petroleum ether for 3, 4, 9, chloroform for 5, 6,
benzene-petroleum ether for 8, 10, 14, 15, ethanol for 11, 12, hexane for
13, and ethanol for 16.
1048

addition, the differences in the spectra of tautomers A and B entail different chemical shifts for the signals of
monotypic protons. Thus, the signal for H-3 for form A appears at lower field than the analogous signal for
form B (∆δ = 1 ppm). The assignment of the proton signals to a specific form was accomplished by a
1
comparative analysis of the calculated H NMR spectra of tautomers A and B as well as the experimental
spectral characteristics of 10-15.
The mass spectrum of pyrroloquinoline 16 shows a molecular ion peak [M]+ (55%). The two strongest
peaks in this spectrum are found for ions with m/z 210 (100%) and 182 (70%), corresponding to the consecutive
elimination of HCO2Et and CO from the molecular ion.
Thus, we studied the behavior of 4-aminoindoles 1 and 2 in reactions with acetylacetone,
dibenzoylmethane, ethyl trifluoroacetate, and ethyl oxaloacetate and developed syntheses for the corresponding
pyrrolo[2,3-h]quinolines. In evaluating the reactivity of these amines in the first step of the reaction with the
dicarbonyl component, we should note their relative inertness in comparison with all substituted 5- and
6-aminoindoles and 7-amino-2,3-dimethylindole [2, 3], whose condensation with acetylacetone and
dibenzoylmethane proceeds upon heating (139-180°C) over 0.5-1.5 h. Completion of these reactions under the
same conditions for 4-aminoindoles requires 2-7 h. The 3-methyl group in 1 and 2 probably shields the amine
nitrogen atom, similar to the N–CH3 group in 7-amino-1,2,3-trimethylindole. Thus, formation of an enamine
from this aminoindole is known to be more difficult than from 7-amino-2,3-dimethylindole [3]. Since the
charges on the amino group nitrogen atoms in 1 and 2 are similar (0.066 and 0.059, respectively) as indicated by
quantum-chemical calculations, the lower activity of 4-amino-1,2,3-trimethylindole (2) in comparison with
4-amino-2,3-dimethylindole (1) should be attributed to a steric effect of the three methyl groups.
The difficulties in the cyclization of enamines 4 and 6, in light of their strong basicity, are probably a
result of the presence of forms protonated at C(3) in trifluoroacetic acid. This leads to a diminution in the
reactivity of indole C(5) for the electrophilic closure of the pyridine ring. Similarly, vigorous conditions are also
required for the cyclization of acyclic amide 7. On the other hand, the aromatization of cyclic amides 7a and 8
proceeds smoothly upon heating in trifluoroacetic acid at reflux. The thermal cyclization of enamine 9 also
proceeds without the participation of acid, which is further support for our hypotheses given above.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker DRX 500 spectrometer at 500 MHz in DMSO-d6 with
TMS as the internal standard. The mass spectra were taken on a Finnigan MAT Incos-50 mass spectrometer with
direct sample inlet into the ion chamber and 70 eV ionization voltage. The electronic absorption spectra were
taken on a Specord spectrophotometer in ethanol. The products were purified by column chromatography and
preparative thick-layer chromatography on an unattached layer of neutral, Brockmann grade-I or II activity
alumina. The reaction course and purity of the products were monitored by thin-layer chromatography on
Silufol UV-254 plates with benzene-ethyl acetate as the eluent.
The physicochemical characteristics of 3-6 and 8-16 are given in Table 3.
PM3 semiempirical quantum-chemical calculations were carried out for 1 and 2 (RHF, algorithm, Polak
Ribiere; RMS gradient: 0.01 kcal/Å·mol) using the HyperChem 7.0 program package.
(Z)-4-[(2,3-Dimethyl-1H-indol-4-yl)amino]pent-3-en-2-one (3). A mixture of 4-amino-2,3-dimethyl-
indole (1) (0.40 g, 2.50 mmol) and acetylacetone (3 ml) was heated at reflux for 2 h. Excess acetylacetone was
then distilled off in vacuum. The residue was dissolved in benzene-petroleum ether and filtered hot through 2 cm
alumina. The filtrate was cooled. The precipitate formed of enamine 3 was filtered off. Recrystallization from
petroleum ether gave enamine 3 (0.32 g).
(Z)-4-[(1,2,3-Trimethyl-1H-indol-4-yl)amino]pent-3-en-2-one (4) was obtained analogously from
4-amino-1,2,3-trimethylindole (2) (0.30 g, 1.72 mmol) after heating at reflux for 2.5 h. Recrystallization of the
crude product from petroleum ether gave enamine 4 (0.17 g).
1049

(Z)-3-[(2,3-Dimethyl-1H-indol-4-yl)amino]-1,3-diphenyl-2-propen-1-one (5).
A
mixture of
aminoindole 1 (0.16 g, 0.99 mmol) and dibenzoylmethane (0.33 g, 1.48 mmol) was maintained for 2.5 h at
180-185°C. At the end of the reaction as indicated by thin-layer chromatography, 5 was isolated by preparative
thick-layer chromatography on alumina with chloroform as the eluent. The yield of 5 was 0.16 g.
(Z)-3-[(1,2,3-Trimethyl-1H-indol-4-yl)amino]-1,3-diphenyl-2-propen-1-one (6) was obtained
analogously from aminoindole 2 (0.45 g, 2.59 mmol) and dibenzoylmethane (1.16 g, 5.17 mmol) after heating
for 7 h at 180-185°C. The yield of 6 was 0.35 g.
4-Hydroxy-7,8,9-trimethyl-4-trifluoromethyl-1,2,3,4-tetrahydro-2H-pyrrolo[2,3-h]quinolin-
2-one (8). A mixture of aminoindole 2 (0.40 g, 2.29 mmol) and ethyl 4,4,4-trifluoroacetoacetate (0.45 g,
2.44 mmol) in absolute benzene (200 ml) in the presence of a catalytic amount of glacial acetic acid was heated
at reflux for 21 h with a Dean–Stark trap. After all the aminoindole had been consumed in the reaction as
indicated by thin-layer chromatography, the volume of the reaction mixture was reduced to 50 ml by distilling
off benzene. The precipitate formed of amide 8 was filtered off, washed with benzene, and recrystallized from
petroleum ether to give amide 8 (0.36 g).
Diethyl Ester of [(2,3-Dimethyl-1H-indol-4-yl)amino]fumaric Acid (9) was obtained analogously
from aminoindole 1 (0.595 g, 3.72 mmol) and ethyl oxaloacetate (0.7 g, 3.72 mmol) after heating for 44 h. The
crude product was recrystallized from 3:1 benzene–petroleum ether to give compound 9 (0.334 g).
2,4,8,9-Tetramethyl-7H-pyrrolo[2,3-h]quinoline (10). Enamine 3 (0.14 g, 0.58 mmol) in a 10-fold
excess of trifluoroacetic acid was heated for 4 h at reflux. At the end of the reaction as indicated by thin-layer
chromatography, the reaction mixture was poured into 12% aqueous ammonia containing ice. The precipitate
formed was filtered off, repeatedly washed with water, and dried in the air. The crude product was recrystallized
from benzene-petroleum ether to give compound 10 (0.086 g).
2,4,7,8,9-Pentamethyl-7H-pyrrolo[2,3-h]quinoline (11) was obtained analogously from enamine 4
(0.16 g, 0.63 mmol) after heating for 6 h. The crude product was recrystallized from aqueous ethanol to give
compound 11 (0.114 g).
8,9-Dimethyl-2,4-diphenyl-7H-pyrrolo[2,3-h]quinoline (12) was obtained analogously from
enamine 5 (0.067 g, 0.18 mmol) after heating for 5 h. The crude product was recrystallized from ethanol to give
compound 12 (0.05 g).
7,8,9-Trimethyl-2,4-diphenyl-7H-pyrrolo[2,3-h]quinoline (13) was obtained analogously from
enamine 6 (0.120 g, 0.32 mmol) after heating for 10 h. The yield of 13 was 0.1 g.
7,8,9-Trimethyl-4-trifluoromethyl-1,7-dihydro-2H-pyrrolo[2,3-h]quinolin-2-one (15). A mixture of
aminoindole 1 (0.22 g, 1.38 mmol) and ethyl 4,4,4-trifluoroacetoacetate (0.26 g, 1.39 mmol) in absolute
benzene (200 ml) in the presence of a catalytic amount of glacial acetic acid was heated at reflux for 17 h with a
Dean-Stark trap. After all the aminoindole had been consumed in the reaction as indicated by thin-layer
chromatography, the volume of the reaction mixture was reduced to 50 ml by distilling off benzene. The
precipitate formed was filtered off and washed with benzene. The mixture of 7 and 7a and a 10-fold excess of
ZnCl2 was heated at 140-145°C for 2 h. At the end of the reaction as indicated by thin-layer chromatography, the
reaction mixture was treated with 10-12% aqueous ammonia. The precipitate formed was filtered off, washed
repeatedly with warm water, and dried in the air. The crude product was recrystallized from benzene to give
compound 15 (0.203 g).
2-Ethoxycarbonyl-4-hydroxy-8,9-dimethyl-7H-pyrrolo[2,3-h]quinoline (A) and 2-Ethoxycarbonyl-
8,9-dimethyl-4-oxo-4,7-dihydro-7H-pyrrolo[2,3-h]quinoline (B) (16). Enamine 9 (0.15 g, 0.45 mmol) was
added to diphenyl (5 ml) heated at reflux. The mixture was heated at reflux for 15 min. At the end of the
reaction as indicated by thin-layer chromatography, the still warm reaction mixture was poured into petroleum
ether. The precipitate formed was filtered off and washed repeatedly with hot petroleum ether to remove
diphenyl. The crude product was recrystallized from ethanol to give compound 16 (0.06 g).
1050

REFERENCES
1.
2.
3.
S. A. Yamashkin, E. A. Oreshkina, I. S. Romanova, and M. A. Yurovskaya, Khim. Geterotsikl. Soedin.,
1529 (2005). [Chem. Heterocycl. Comp., 41, 1280 (2005)].
A. N. Kost, S. A. Yamashkin, and L. G. Yudin, Khim. Geterotsikl. Soedin., 770 (1977). [Chem.
Heterocycl. Comp., 13, 624 (1977)].
S. A. Yamashkin and I. A. Batanov, Khim. Geterotsikl. Soedin., 58 (1995). [Chem. Heterocycl. Comp.,
31, 50 (1995)].
1051