Synthesis of functionally substituted pyrrolo[2,3-g]- and pyrrolo[3,2-f]quinolines from 5-amino-2-phenyl- and 5-amino-1-methyl-2-phenylindoles

Article abstract of DOI:10.1023/B:COHC.0000008264.35326.20

The behavior of 5-amino-2-phenyl- and 5-amino-1-methyl-2-phenylindoles in reactions with acetoacetic, trifluoroacetoacetic, and ethoxymethylenemalonic esters, leading to the preparation of pyrrolo[2,3-g]- and pyrrolo[3,2-f]quinolines with functional substituents has been studied.

Full text of DOI:10.1023/B:COHC.0000008264.35326.20

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
SYNTHESIS OF FUNCTIONALLY SUBSTITUTED
g
f
PYRROLO[2,3- ]- AND PYRROLO[3,2- ]QUINOLINES
FROM 5-AMINO-2-PHENYL- AND 5-AMINO-
1-METHYL-2-PHENYLINDOLES
S. A. Yamashkin1, G. A. Romanova1, I. S. Romanova1, and M. A. Yurovskaya2
The behavior of 5-amino-2-phenyl- and 5-amino-1-methyl-2-phenylindoles in reactions with
acetoacetic, trifluoroacetoacetic, and ethoxymethylenemalonic esters, leading to the preparation of
pyrrolo[2,3-g]- and pyrrolo[3,2-f]quinolines with functional substituents has been studied.
Keywords: 5-amino-2-phenylindole, 5-amino-1-methyl-2-phenylindole, acetoacetic ester, trifluoro-
acetoacetic ester, ethoxymethylenemalonic ester, functionally substituted pyrrolo[2,3-g]quinolines,
functionally substituted pyrrolo[3,2-f]quinolines.
We discovered previously that the thermal condensation of 5-amino-2-phenyl- (1) and 5-amino-1-
methyl-2-phenylindoles (2) with acetylacetone and dibenzoylmethane leads to the corresponding enamino
ketones which cyclize in trifluoroacetic acid into a mixture of pyrroloquinolines of angular and linear structure
[1]. Wlile continuing investigations in this direction we have studied the reaction of 1 and 2 with acetoacetic,
trifluoroacetoacetic, and ethoxymethylenemalonic esters with the aim of developing methods for the synthesis
of functionally substituted pyrrolo[2,3-g]- and pyrrolo[3,2-f]quinolines.
It turned out that the interaction of amines 1 and 2 with the esters listed above, as in the case of
1,3-diketones, goes with the participation of only the amino group, although reaction at the β-position of the
pyrrole ring is not excluded. Such reactions are known for example for derivatives of 2-aminoindole [2].
Mixtures of the E- and Z-isomers of aminocrotonates 3 and 4 are obtained on heating aminoindoles 1
and 2 with acetoacetic ester in absolute benzene with catalytic quantities of glacial acetic acid.
O
O
H
N
H
N
O
H2N
R
OEt
R
N
R1
1, 2
Ph
N
R1
N
R1
Ph
Ph
O
O
R
OEt
3–6
7, 8
1 R1 = H, 2 R1 = Me, 3 R = Me, R1 = H, 4 R = R1 = Me, 5, 7 R = CF3, R1 = H,
6, 8 R = CF3, R1 = Me
__________________________________________________________________________________________
1
Mordovian State Pedagogical University, Saransk 430007, Russia; e-mail: mgpi@si.moris.ru.
2 Moscow M. V. Lomonosov State University, Moscow 119899, Russia; e-mail: yumar@org.chem.msu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii., No. 9, pp. 1354-1363, September, 2003. Original
article submitted December 20, 2002.
1188
0009-3122/03/3909-1188$25.00©2003 Plenum Publishing Corporation

According to the integrated intensity of the signals of the characteristic protons in the 1H NMR spectrum
of compound 3 (Table 1) in DMSO-d6 solution the ratio of the Z- and E-forms was 3.5:1. Assignment to the Z-
and E-forms was based on the differences in chemical shift of the signals of certain protons. The signal of the
N–H proton of the enamine fragment for the Z-form, due to interaction with the ethoxycarbonyl group, was
displaced by 2 ppm towards low field compared with the signal of this proton in the E-form. This influence is
also felt on the chemical shifts of the ethoxy group protons, the difference of which for the Z- and E-forms was
0.12 ppm. Due to the influence of the ethoxycarbonyl group the signal of the protons of the β-methyl group was
displaced towards low field by 0.45 ppm in the E-form.
An analogous picture is also observed for indolylaminocrotonate 4, the ratio of the Z- and E-isomers for
which, according to data of 1H NMR spectra, was 3:1. The results obtained are in agreement with the data of the
crotonates formed with other aminoindoles previously investigated by us [3, 4].
In difference to the unfluorinated analog trifluoroacetoacetic ester reacts with amines 1 and 2 under the
same conditions with the participation not only of the carbonyl but also of the ethoxycarbonyl group. The
corresponding Z-enamines 5 and 6 and amides 7 and 8 were isolated in ratios of 1:4 (5 and 7) and 1:3 (6 and 8).
The corresponding enamines and amides were separated chromatographically in an aluminum oxide thin layer.
In the 1H NMR spectrum of indolylaminocrotonate 5 signals were observed for the protons of the ethoxy group
(1.30 and 4.19), the vinylic proton (5.2), the phenyl group protons, the aromatic protons 4-, 6-, and 7-H, and the
N–H group proton of the enamine (9.81 ppm) and the pyrrole fragments. The fluorinated aminocrotonate 5,
unlike the unfluorinated enamine 3, exists exclusively in the Z-form, which follows from a comparison of the
chemical shifts of the protons of the ethoxy group, and of the vinylic and amine protons. Analogous regularities
were observed in the spectrum of indolylaminocrotonate 6, which also indicates its Z-structure.
In the mass spectra of compounds 5 and 6, apart from the molecular ion peak, there was a peak for the
[M-46]+ ion, which was the most intense for enamine 6. Loss of a molecule of ethyl alcohol, characteristic of the
majority of indolylaminocrotonates, leads to the formation of the molecular ion of the corresponding
pyrroloquinolones 17 and 18 (see below for interpretation of structures), because the mass spectral breakdown
of the latter and the further breakdown picture of enamines 5 and 6 are the same. The UV spectra of both the
fluorinated and unfluorinated indolylaminocrotonates 3-6 contain the same absorption bands, which indicates
the similarity of their structure.
Regretably, IR spectroscopy proved to be uninformative when studying the structure of
enaminocarbonyl compounds and amides of the indole series. As was shown by us previously in [5] the band for
the stretching vibrations of the conjugated carbonyl group in such systems was displayed in the area for
conjugated double bond vibrations (1600-1620 cm-1).
The predominant formation of amides in the reactions of aminoindoles 1 and 2 with fluorinated
acetoacetic ester, unlike with acetoacetic ester itself, is probably linked with the acceptor influence of the
trifluoromethyl group, which increases the reactivity of the ester grouping. Confirmation of the formation of
amides 7 and 8 was the absence from their 1H NMR spectra of signals for the ethoxy group protons. The number
of hydrogen atoms in the molecules of the amides obtained corresponds to the total integrated intensity of the
protons in the spectra. A clear assignment of the available signals was hindered by the existence in the solution
(DMSO-d6–CCl4, 1:3) of the amides in a minimum of three forms: carbonyl, enolic, and as cyclization products.
This is also confirmed by a chromatographic check. In connection with this, the amides were not characterized
as individual compounds, although their molecular weights measured mass-spectrometrically corresponded to
calculated values.
Aminoindoles 1 and 2 react with ethoxymethylenemalonic ester on boiling in ethyl alcohol with the
formation of the corresponding (5-indolylaminomethylene)malonates 9 and 10.
1189

OEt
O
CH O
H
N
H
EtO
OEt
1, 2
N
R
Ph
O
O
OEt
OEt
9, 10
9 R = H, 10 R = Me
In the 1H NMR spectra of malonates 9 and 10 multiplet signals were observed for the protons of the two
ethoxy groups, singlet signals for the protons 1-H (9), CH3 (10), and proton 3-H, a multiplet for the aromatic
protons, and two doublets for the vinylic and amino protons of the enamine fragment with coupling constant
15 Hz, which unequivocally confirms their anti disposition in structures 9 and 10.
On heating amides 7 and 8 in trifluoroacetic acid the pyrroloquinolines 11-13 are formed with linear
linking of the rings.
R1
H
O
N
CF3CO2H
7, 8
N
R
Ph
CF3
11–13
11 R = R1 = H, 12 R = Me, R1 = H, 13 R = Me, R1 = CF3CO
1
The linear structure of compounds 11-13 is confirmed unequivocally by H NMR spectra, in which
singlet signals were observed for the protons at 1-H (11), CH3 (12, 13), 3-H (11, 12), 4-, 7-, and 9-H. The picture
of an ABC system for the protons of the phenyl group for compound 13 differed somewhat from the remainder
(two triplet signals are in superimposition), seemingly due to the influence of the trifluoroacetyl group located
close to it. The trifluoroacetyl group also displaces the 4-H proton signal towards low field by 0.77 ppm. The
structure of compound 13 is also confirmed by the mass spectrum in which there is a peak for the molecular ion
and the most intense peak in the spectrum is for the [M-69]+ ion. This character of the mass spectral
decomposition is explained by the presence in the molecule of the trifluoroacetyl group [6].
Amides of 5-indolyltrifluoroacetic acid under conditions of acid catalysis even with a free position of
the β pyrrole ring are cyclized with the participation of position 6 and not 4, which leads to a linearly
constructed pyrroloquinoline, unlike the same nonfluorinated amides which are converted under analogous
conditions predominantly into pyrroloquinolines of angular structure [3]. Such an anomaly must probably be
explained by the large steric requirements of the trifluoromethyl group compared with methyl. The peri
substituents (methyl and hydrogen) do not create stress in the angular pyrroloquinoline and the formation of the
latter with a trifluoromethyl group and hydrogen in the peri positions is found to be difficult.
Under the action of dimethyl sulfate compounds 11 and 12 are readily converted into pyrroloquinoline
14 methylated at both nitrogen atoms.
Me
O
N
Me2SO4
Me2SO4
12
11
N
Ph
CF3
Me
14
1190

TABLE 1. Physicochemical and Spectral Characteristics of the Compounds Obtained
Found, %
——————
UV spectrum
λmax, nm
log ε
Com-
pound
Empirical
foprmula
Rf
mp, °С
Yield,
%
1Н NMR spectrum, δ, ppm (J, Hz)
Calculated, %
(system)
(solvent)
С
3
Н
4
M+
5
1
2
6
7
8
9
10
11
58
С20Н20N2O2
74.75 6.12
74.98 6.29
320
320
0.71
(C)
160-162
(light
210
225
350
4.19
4.32
4.48
3
(Е) 1.13 (3Н, t, J = 7, ОСН2СН3); 2.37 (3Н, s, α-СН3);
3.90 (2Н, q, J = 7, ОСН2СН3); 4.75 (1Н, s, Н vin.);
6.78 (1Н, s, 3-Н); 7.45 (8Н, m, 4-, 6-, 7-H, Ph); 8.07 (1Н, s,
N–Н amin.); 11.36 (1Н, s, 1-Н) (Z) 1.25 (3Н, t, J = 7, ОСН2СН3);
1.93 (3Н, s, α-СН3); 4.07 (2Н, q, J = 7, ОСН2СН3);
4.57 (1Н, s, Н vin.); 6.78 (1Н, s, 3-Н);
petroleum)
7.45 (8Н, m, 4-, 6-, 7-Н, Ph); 10.23 (1Н, s,
N–Н amin.); 11.40 (1Н, s, 1-Н)
С21H22N2O2
75.28 6.75
75.42 6.63
334
334
0.84
(C)
139-141
(light
(Е) 1.13 (3Н, t, J = 7, О–СН2СН3); 2.38 (3Н, s, α-СН3);
3.77 (3Н, s, 1-СН3); 3.93 (2Н, q, J = 7, О–СН2СН3);
4.75 (1Н, s, Н vin.); 6.50 (1Н, s, 3-Н);
4
5
petroleum)
7.28 (8Н, m, 4-, 6-, 7-H, Ph); 8.09 (1Н, s, N–Н amin.)
α
(Z) 1.26 (3Н, t, J = 7, О–СН2СН3); 1.93 (3Н, s, -СН3);
3.77 (3Н, s, 1-СН3); 4.10 (2Н, q, J = 7, ОСН2СН3);
4.58 (1Н, s, Н vin.); 6.50 (1Н, s, 3-Н);
7.27 (8Н, m, 4-, 6-, 7-Н, Ph); 10.26 (1Н, s, N–Н amin.)
C20H17F3N2O2
64.26 4.41
64.17 4.58
374
374
0.82
(B)
175-176
(Z) 1.30 (3Н, t, J = 7, ОСН2–СН3); 4.19 (2Н, q, J = 7,
210
230
315
4.47
4.37
4.58
15*
(heptane)
О–СН2СН3); 5.20 (1Н, s, Н vin.); 6.74 (1Н, s, 3-Н);
6.93 (1Н, d, J = 8, 7-Н); 7.28 (1Н, t, J = 8, р-Н, Рh);
7.35 (1Н, s, 4-Н); 7.35 (1Н, d, J = 8, 6-Н); 7.41 (2Н, t, m-Н, Рh);
7.80 (2Н, d, о-Н, Рh); 9.81 (1Н, s, N–Н amin.); 11.42 (1Н, s, 1-Н)

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
11
C21H19F3N2O2
64.71 4.70
64.94 4.93
388
388
0.71
(A)
128-129
(Z) 1.33 (3Н, t, J = 7, О–СН2СН3); 3.80 (3Н, s, 1-СН3);
4.20 (2Н, q, J = 7, ОСН2–СН3); 5.22 (1Н, s, Н vin.);
6.48 (1Н, s, 3-Н); 7.04 (1Н, d, J = 8, 7-Н); 7.36 (1Н, d, J = 8,
6-Н); 7.40 (1Н, s, 4-Н); 7.40 (1Н, t, J = 8, р-Н, Рh);
7.48 (2Н, t, J = 8, m-Н, Рh); 7.53 (2Н, d, J = 8, о-Н, Рh);
9.83 (1Н, s, N–Н amin.)
1.30 (6Н, m, 2 ОСН2СН3); 4.21 (4Н, m, 2 ОСН2СН3);
6.89 (1Н, s, 3-Н); 7.38 (8Н, m, 4-, 6-, 7-Н, Рh);
8.44 (1Н, d, J = 15, Н vin.); 10.77 (1Н, d, J = 15, Н amin.);
11.49 (1Н, s, 1-Н)
1.33 (6Н, m, 2 ОСН2СН3); 3.77 (3Н, s, 1-СН3);
4.22 (4Н, m, 2 ОСН2СН3); 6.53 (1Н, s, 3-Н);
7.34 (8Н, m, 4-, 6-, 7-Н, Рh); 8.46 (1Н, d, J = 15, Н vin.);
10.92 (1Н, d, J = 15, N–Н amin.)
6.73 (1Н, s, 3-Н); 6.84 (1-Н, s, 7-Н); 7.33 (1Н, t, J = 8, р-Н, Рh);
7.45 (2Н, t, J = 8, m-Н, Рh); 7.52 (1Н, s, 4-Н); 7.76 (1Н, s, 9-Н);
7.84 (2Н, d, J = 8, о-Н, Рh); 11.48 (1Н, s, 1-Н); 11.80 (1Н, s, 5-Н)
3.84 (3Н, s, 1-Н); 6.55 (1Н, s, 3-Н); 6.77 (1Н, s, 7-Н);
7.45 (1Н, t, J = 8, р-Н, Рh); 7.51 (2Н, t, J = 8, m-Н, Рh);
7.56 (1Н, s, 4-Н); 7.58 (2Н, d, J = 8, о-Н, Рh);
7.64 (1Н, s, 9-Н); 11.93 (1Н, s, 1-Н)
3.65 (3Н, s, 1-Н); 6.86 (1Н, s, 7-Н); 7.48 (2Н, d, о-Н, Рh);
7.57 (3Н, m, m-, p-Н, Рh); 7.74 (1Н, s, 9-Н); 8.33 (1Н, s, 4-Н);
12.14 (1Н, s, 5-Н)
210
225
300
4.36
4.40
4.50
13*2
6
9
(heptane)
С22H22N2O4
С23H24N2O4
69.90 5.61
69.83 5.86
378
378
0.46
(B)
163-164
207
227
333
4.37
4.30
4.51
43
66
70.21 6.31
70.39 6.16
392
392
0.59
(C)
106-108
> 300
208
225
320
4.57
4.54
4.65
10
C18H11F3N2O
C19H13F3N2O
65.92 3.21
65.86 3.38
328
328
0.41
(D)
11
12
66.45 3.76
66.67 3.83
342
342
0.42
(F)
282-283
230
250
364
4.61
4.70
4.52
28
22
(aq. alcohol)
C21H12F6N2O2
57.30 2.85
57.54 2.76
438
438
0.68
(G)
> 300
220
238
4.51
4.43
3.39
4.35
4.18
13
(alcohol)
272 (sh)
317
330
C20H15F3N2O
C18H14N2O
67.26 4.10
67.41 4.24
356
356
0.74
(G)
263-264
(alcohol)
3.75 (3Н, s, 5-СН3); 3.86 (3Н, s, 1-СН3); 6.68 (1Н, s, 3-Н);
6.89 (1Н, s, 7-Н); 7.47 (1Н, t, J = 8, р-Н, Рh);
7.53 (2Н, t, J = 8, m-Н, Рh); 7.59 (2Н, d, J = 8, о-Н, Рh);
7.67 (1Н, s, 4-Н); 7.71 (1Н, s, 9-Н)
230
250
356
4.51
4.60
4.41
56
58
14
15
78.65 5.21
78.81 5.14
274
274
0.63
(J)
>300
2.37 (3Н, s, 7-СН3); 5.93 (1Н, s, 8-Н); 7.24 (1Н, d, J = 8, 4-Н);
7.30 (1Н, t, J = 8, р-Н, Рh); 7.46 (2Н, t, J = 8, m-Н, Рh);
7.66 (1Н, d, J = 8, 5-Н); 7.86 (2Н, d, о-Н, Рh);
207,
230
4.32
4.36
4.11
4.15
4.23
(alcohol)
252 (sh)
301
7.90 (1Н, s, 1-Н); 11.35 (1Н, s, 6-Н); 11.71 (1Н, s, 3-Н)
360

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
11
43
C19H16N2O
79.21 5.45
79.14 5.59
288
288
0.61
(J)
228-230
(alcohol)
2.37 (3Н, s, 7-СН3); 3.85 (3Н, s, 3-СН3); 5.93 (1Н, s, 8-Н);
7.32 (1Н, d, J = 8, 4-Н); 7.43 (1Н, t, J = 8, р-Н, Рh);
7.52 (2Н, t, J = 8, m-Н, Рh); 7.61 (2Н, d, J = 8, о-Н Рh);
7.69 (1Н, s, 1-Н); 7.77 (1Н, d, J = 8, 5-Н); 11.36 (1Н, s, 6-Н)
208
223
254
294
345
4.46
4.45
4.26
4.18
4.26
16
C18H11F3N2O
C19H13F3N2O
65.38 3.42
65.86 3.38
328
328
0.44
(E)
>300
7.19 (1Н, s, 8-Н); 7.26 (1Н, t, J = 8, р-Н, Рh);
209
226
280
350
210
227
274
345
4.40
4.29
4.14
4.10
4.42
4.39
4.37
4.18
80
93
17
18
(alcohol)
7.43 (2Н, t, J = 8, m-Н, Рh); 7.64 (1Н, d, J = 8, 4-Н);
7.71 (1Н, s, 1-Н); 7.86 (1Н, d, J = 8, 5-Н);
7.89 (2Н, d, J = 8, о-Н, Рh); 11.40 (1Н, s, 6-Н); 11.90 (1Н, s, 3-Н)
66.38 3.75
66.67 3.83
342
342
0.69
(E)
282-283
3.97 (3Н, s, 3-СН3); 7.22 (1Н, s, 8-Н);
7.40 (1Н, t, J = 8, р-Н, Рh); 7.45 (1Н, s, 1-Н);
7.50 (2Н, t, J = 8, m-Н, Рh); 7.61 (2Н, d, J = 8, о-Н, Рh);
7.76 (1Н, d, J = 8, 4-Н); 7.91 (1Н, d, J = 8, 5-Н);
11.43 (1Н, s, 6-Н)
(aq. alcohol)
C20H16N2O3
C21H18N2O3
71.95 4.96
72.28 4.85
332
332
0.38
(K)
>300
1.31 (3Н, t, J = 7, ОСН2СН3); 4.28 (2Н, q, J = 7, ОСН2СН3);
207
228
4.24
4.23
4.05
4.10
4.03
4.23
4.32
4.04
4.23
4.18
56
48
19
20
(alcohol)
7.36 (1Н, d, J = 8, 4-Н); 7.60 (5Н, m, о-Н, Рh);
7.80 (1Н, d, J = 8, 5-Н); 8.04 (1Н, s, 1-Н);
276 (sh)
303
8.44 (1Н, s, 7-Н); 11.90 (1Н, s, 3-Н); 12.25 (1Н, s, 9-ОН)
370
72.61 5.31
72.82 5.24
346
346
0.20
(H)
263-265
(alcohol)
1.32 (3Н, t, J = 7, ОСН2СН3); 3.87 (3Н, s, 3-СН3);
4.26 (2Н, q, J = 7, ОСН2СН3); 7.41 (1Н, d, J = 8, 4-Н);
7.46 (1Н, t, J = 8, р-Н, Рh); 7.54 (2Н, t, J = 8, m-Н, Рh);
7.63 (2Н, d, J = 8, о-Н, Рh); 7.73 (1Н, s, 1-Н); 7.88 (1Н, d,
J = 8, 5-Н); 8.43 (1Н, s, 7-Н); 12.15 (1Н, s, 9-ОН)
206
227
267
303
357
_______
* Overall yield of enamine and amide was 82%.
*2 Overall yield of enamine and amide was 56%.

The 1H NMR spectrum of compound 14 differs from the spectra of pyrroloquinolines 11 and 12 by the
absence of the N–H signals and by the presence of two singlet signals for the protons of the N-methyl groups.
The UV spectra of pyrroloquinolines 11, 12, and 14 are characterized by four absorption bands and are
practically identical.
Compound 13 is formed together with pyrroloquinoline 12 by acylation of the latter in the β-position of
the pyrrole ring with trifluoroacetic acid. The nucleophilicity of the β-position is probably somewhat increased
due to the presence of the methyl group.
High temperature (250-280°C) cyclization of indolylaminocrotonates 3-6 and indolylmethylene-
malonates 9, 10 leads to pyrroloquinolines 15-20 of angular structure.
R2
R1
O
HN
3–6, 9, 10
Ph
N
R
15–20
15 R = R2 = H, R1 = Me, 16 R = R1 = Me, R2 = H, 17 R = R2 = H, R1 = CF3;
18 R = Me, R2 = H, R1 = CF3, 19 R = R1 = H, R2 = CO2Et, 20 R = Me, R1 = H, R2 = CO2Et
On boiling compounds 3 and 4 in biphenyl the pyrroloquinolines 15 and 16 are formed, the product of
the alternative cyclization at position 6 was not detected. The angular connection of the rings in compounds 15
1
and 16 is confirmed by the presence in the H NMR spectra of two doublets for the 4-H and 5-H protons
(J = 8 Hz) and also the low field position of the signal for the 1-H proton (for compound 15), found in the
position peri to the γ-oxygen atom of the pyridone ring. Pyrroloquinolines 15 and 16 are stable towards electron
impact, consequently the most intense peaks in their mass spectra are the molecular ions with m/z 274 and 288
respectively. The presence of peaks for [M-CO]+ ions points in favor of a γ-quinolone structure for the
compounds. The UV spectra of compounds 15 and 16 are practically identical, which confirms their similar
structure.
Like crotonates 3 and 4 their fluorinated analogs 5 and 6 are converted on boiling in biphenyl into the
corresponding trifluoromethyl-substituted angular pyrroloquinolines 17 and 18. The same regularities are
observed in the spectral characteristics as for compounds 15 and 16.
Thermal cyclization of indolylmalonates in dowtherm (250°C) also leads to the formation of angular
1
pyrroloquinolines 19 and 20. This is confirmed by the presence in the H NMR spectra of the obtained
compounds of signals for the protons of the ethoxy group, singlet signals for the 3-H protons (compound 19),
3-CH3 (compound 20), and the 1-, 7-H, and 9-OH protons. Unlike compounds 15-18 pyrroloquinolines 19 and
20 are in the γ-hydroxyquinoline form, which was confirmed by the presence of a singlet signal for the
α-pyridine proton (7-H), and also by the character of the mass spectral decomposition. In the mass spectra of
pyrroloquinolines 19 and 20 the most intense signal was the [M-46]+ peak, which corresponds to elimination of
a molecule of alcohol from the molecular ion. Such fragmentation is characteristic for o-ethoxycarbonylphenols.
EXPERIMENTAL
The NMR spectra were recorded on Bruker DRX-500 (500 MHz) and Bruker AM-300 (300 MHz)
instruments in DMSO-d6 (compounds 3, 4, 9, 10, 15, 16, 19, 20) and DMSO-d6–CCl4, 1:3 (compounds 5-8,
11-14, 17, 18), internal standard was TMS. The mass spectra were obtained on a Finnigan MAT INCOS-50
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mass spectrometer with direct insertion of samples into the ion source at an ionization energy of 70 eV.
Electronic spectra were recorded on a Specord spectrophotometer in ethanol. Purification of reaction products
was carried out by column chromatography, and also preparatively on Al2O3 plates (neutral, Brockmann grade I
and II). A check on the course of reactions and the purity of the compounds obtained was effected by TLC on
Silufol UV-254 plates in the systems benzene (A), benzene–ethyl acetate, 8:1 (B), 5:1 (C), 3:2 (D), 3:1 (E), 1:1
(F), 2:1 (G), ethyl acetate (H), ethyl acetate–methanol, 5:2 (I), 3:1 (J), and 5:1 (K).
The physicochemical and spectral characteristics of the compounds obtained are given in Table 1. The
preparation of the initial aminoindoles 1 and 2 is described in [1].
Ethyl Ester of (E,Z)-3-[(2-Phenyl-1H-5-indolyl)amino]crotonic Acid (3). A solution of 5-amino-2-
phenylindole 1 (0.57 g, 2.74 mmol) and acetoacetic ester (0.3579 g, 2.75 mmol) in absolute benzene (100 ml) in
the presence of traces of glacial acetic acid was heated for 28 h with a Dean–Stark apparatus. At the end of the
reaction (check by TLC) the benzene was distilled off. The compound obtained was purified by passing a
boiling benzene solution through a layer (2-3 cm) of aluminum oxide. Yield 0.51 g.
Ethyl Ester of (E,Z)-3-[(1-Methyl-2-phenyl-1H-5-indolyl)amino]crotonic Acid (4) was obtained
analogously from 5-amino-1-methyl-2-phenylindole (2) (1.04 g, 4.68 mmol) and acetoacetic ester (0.634 g,
4.88 mmol), heating for 19-20 h. Yield 0.8 g.
Ethyl Ester of 4,4,4-Trifluoro-3-[(2-phenyl-1H-5-indolyl)amino]crotonic Acid (5) and
N-(2-Phenyl-1H-5-indolyl)amide of 4,4,4-Trifluoro-3-oxobutyric Acid (7). A solution of compound 1
(0.79 g, 3.8 mmol) and trifluoroacetoacetic ester (0.85 g, 4.62 mmol) in absolute benzene was boiled in the
presence of catalytic amounts of glacial acetic acid for 40 h (chromatographic control) with a Dean–Stark
apparatus. The benzene was distilled off at the end of the reaction. The solid residue (a mixture of enamine 5
and amide 7) of weight 1.233 g was boiled in heptane. The hot solution of enamine 5 was filtered from the
undissolved solid and passed through a layer (1 cm) of aluminum oxide. Yield was 0.22 g. The solid not
dissolving in heptane is amide 7 (yield 0.874 g), purified by recrystallization from alcohol with active carbon.
The compound obtained was not homogeneous according to chromatographic analysis. The overall integrated
1
intensity of protons in the H NMR spectrum corresponds to the amide structure. Mass spectrum: found
346 [M]+; calculated: M = 346.
Ethyl Ester of 4,4,4-Trifluoro-3-[(1-methyl-2-phenyl-1H-5-indolyl)aminocrotonic Acid (6) and
N-(1-Methyl-2-phenyl-1H-5-indolyl)amide of 4,4,4-Trifluoro-3-oxobutyric Acid (8) were obtained
analogously from compound 2 (1.14 g, 5.14 mmol) and trifluoroacetoacetic ester (1.1 g, 5.98 mmol) but heating
was carried out for 50 h. Aminocrotonate 6 was purified by passing a boiling solution in a mixture of hexane
and benzene through a layer (1 cm) of aluminum oxide. Yield 0.265 g. The solid insoluble in heptane was amide
8. The substance was purified by passing a boiling solution in a mixture of benzene and heptane through a layer
(1 cm) of aluminum oxide. Recrystallization was from heptane. Yield was 0.68 g. The overall integrated
1
intensity of protons in the H NMR spectrum corresponded to the amide structure. Mass spectrum: found
360 [M]+; calculated: M = 360.
Diethyl Ester of 2-[(2-Phenyl-1H-5-indolyl)aminomethylene]malonic Acid (9). A mixture of
compound 1 (0.468 g, 2.25 mmol) and ethoxymethylenemalonic ester (0.52 g, 2.4 mmol) in ethyl alcohol (5 ml)
was boiled for 1 h 30 min. The solid precipitated after cooling was filtered off, and washed with cold alcohol.
Yield 0.37 g.
Diethyl Ester of 2-[(1-Methyl-2-phenyl-1H-5-indolyl)aminomethylene]malonic Acid (10) was
obtained analogously from compound 2 (0.5 g, 2.25 mmol) and ethoxymethylenemalonic ester (0.52 g,
2.4 mmol). Yield 0.58 g.
2-Phenyl-8-trifluoromethyl-5,6-dihydro-1H-pyrrolo[2,3-g]quinol-6-one (11). Amide 7 (0.3 g,
0.87 mmol) was boiled in trifluoroacetic acid (5 ml) for 3 h. The reaction mass was then poured into 12%
aqueous ammonia with ice. The precipitated solid was filtered off and washed many times with water. The
substance was purified in a binder-free thick layer of aluminum oxide in ethyl acetate. Yield 0.216 g.
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1-Methyl-2-phenyl-8-trifluoromethyl-5,6-dihydro-1H-pyrrolo[2,3-g]quinol-6-one (12) and
1-Methyl-2-phenyl-3-trifluoroacetyl-8-trifluoromethyl-5,6-dihydro-1H-pyrrolo[2,3-g]quinol-6-one (13)
were obtained analogously from amide 8 (0.292 g, 0.811 mmol), but heating was carried out for 5 h. The
obtained mixture of substances 12 and 13 was separated in a binder-free thick layer of aluminum oxide in the
system benzene–ethyl acetate, 1:2. Yield of pyrroloquinoline 12 0.077 g. Yield of pyrroloquinoline 13 0.077 g.
1,5-Dimethyl-2-phenyl-8-trifluoromethyl-5,6-dihydro-1H-pyrrolo[2,3-g]quinol-6-one (14). A. A
solution of pyrroloquinoline 11 (0.15 g, 0.457 mmol) and an excess of dimethyl sulfate and potassium hydroxide
in acetone was heated for 1 h. At the end of the reaction the acetone was distilled off, and the reaction mass
diluted with water. The precipitated solid was filtered off. Yield 0.09 g.
B. Compound 14 was obtained analogously from pyrroloquinoline 12, heating for 2 h.
7-Methyl-2-phenyl-6,9-dihydro-3H-pyrrolo[3,2-f]quinol-9-one (15). Aminocrotonate 3 (0.64 g,
2 mmol) in biphenyl was boiled for 30 min. The cooled reaction mixture was poured into petroleum ether. The
precipitated solid was filtered off, and washed with hot hexane. Yield 0.32 g.
3,7-Dimethyl-2-phenyl-6,9-dihydro-3H-pyrrolo[3,2-f]quinol-9-one (16) was obtained analogously
from aminocrotonate 4 (0.67 g, 2 mmol). Yield 0.25 g.
2-Phenyl-7-trifluoromethyl-6,9-dihydro-3H-pyrrolo[3,2-f]quinol-9-one
(17)
was
obtained
analogously from aminocrotonate 5 (0.188 g, 0.503 mmol) heating for 15 min. Yield 0.133 g. The substance
obtained was purified in a binder-free thick layer of aluminum oxide in a mixture of benzene–ethyl acetate, 3:1.
3-Methyl-2-phenyl-7-trifluoromethyl-6,9-dihydro-3H-pyrrolo[3,2-f]quinol-9-one (18) was obtained
analogously from aminocrotonate 6 (0.13 g, 0.335 mmol). Yield 0.103 g.
Ethyl Ester of 9-Hydroxy-2-phenyl-3H-pyrrolo[3,2-f]quinoline-8-carboxylic Acid (19). A solution
of aminomethylenemalonate 9 (0.57 g, 1.5 mmol) in dowtherm was boiled for 30 min. The cooled reaction
mixture was poured into petroleum ether. The precipitated solid was filtered off, and washed many times with
hot hexane. Pyrroloquinoline 19 (0.28 g) was isolated.
Ethyl Ester of 9-Hydroxy-3-methyl-2-phenyl-3H-pyrrolo[3,2-f]quinoline-8-carboxylic Acid (20)
was obtained analogously from aminomethylenemalonate 10 (0.59 g, 1.5 mmol). Yield 0.25 g.
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S. A. Yamashkin, Khim. Geterotsikl. Soedin., 1520 (1992).
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S. A. Yamashkin, L. G. Yudin, and A. N. Kost, Khim. Geterotsikl. Soedin., 493 (1983).
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