Heterocyclization of 2-acyl-3-indolylacetic acids using hydrazine. Synthesis of 2,3-dihydro-2-oxo-5-R1-1H-[1,2]diazepino[4,5-b]indoles

Article abstract of DOI:10.1007/s10593-009-0322-7

The heterocyclization of 2-acetyl-3-indolylacetic acid hydrazones and its amides, in contrast to similar derivatives of phenylacetic acid, does not lead to 2,3-dihydro-2-oxo-5-R¹-1H-[1,2]diazepino-[4,5-b]indoles but rather to 2-aminoindolo[2,3-

Full text of DOI:10.1007/s10593-009-0322-7

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
HETEROCYCLIZATION OF 2-ACYL-
3-INDOLYLACETIC ACIDS USING
HYDRAZINE. SYNTHESIS OF 2,3-DIHYDRO-
2-OXO-5-R1-1H-[1,2]DIAZEPINO[4,5-b]INDOLES
V. S. Tolkunov1*, A. B. Eresko1, A. I. Khizhan1, O. V. Shishkin2,
G. V. Palamarchuk2, and S. V. Tolkunov1
The heterocyclization of 2-acetyl-3-indolylacetic acid hydrazones and its amides, in contrast to similar
derivatives of phenylacetic acid, does not lead to 2,3-dihydro-2-oxo-5-R1-1H-[1,2]diazepino-
[4,5-b]indoles but rather to 2-aminoindolo[2,3-c]pyridin-3(2H)-one or azines of 2-acetyl-3-indolyl-
acetic acid. 2,3-Dihydro-2-oxo-5-R1-1H-[1,2]diazepino[4,5-b]indoles were obtained by the reaction of
1-alkylaminoacetylindolo[2,3-c]pyrilium perchlorates and of methyl esters of 2-acetyl- and 2-propionyl-
3-indolylacetic acid with hydrazine hydrate.
Keywords: 2-aminoindolo[2,3-c]pyridin-3(2H)-one, hydrazine hydrate, hydrazones of 2-acetyl-
3-indolylacetic acid, 2,3-dihydro-2-oxo-5-R1-1H-[1,2]diazepino[4,5-b]indoles.
Interest in derivatives of 2,3-benzodiazepines is related to the broad spectrum of their biological action
on the central nervous system [1-7]. Some 2,3-benzodiazepines have been found to be tranquilizers and
anticonvulsants [2-4]. The tranquilizer, Tofizopam, a 2,3-benzodiazepine, has found use in clinical practice [1].
Considerable attention has been given to the synthesis and study of the pharmacological properties of diazepines
condensed with various heterocyclic systems [3, 4, 6].
A number of pathways have been reported for the synthesis of derivatives of 2,3-benzo-4-diazepinones
based on the reaction of 2-aroyl-4,5-dimethoxyphenylacetic acids with hydrazine [2, 8-10]. 3H-[1,2]Diaze-
pino[5,6-b]indoles were obtained by the cyclization of the ethyl esters of 2-formyl- and 2-acetyl-2-indolylacetic
acids using hydrazine hydrate [11-13].
We have recently shown that the reaction of 2-acetylbenzo[b]furan-3-acetic acid as well as its ester and
amide derivatives with hydrazine hydrate leads not to the corresponding benzofurodiazepines but rather to
2-aminobenzofuro[2,3-c]pyridin-3(2H)-ones or azines of 2-acetylbenzo[b]furan-3-acetic acid [14].
_______
* To whom correspondence should be addressed, e-mail: s_tolkunov@yahoo.com.
1L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
83114 Donetsk, Ukraine.
2STC Institute for Single Crystals, National Academy of Sciences of Ukraine, 61001 Kharkiv, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 907-917, June, 2009. Original
article submitted March 21, 2008.
726
0009-3122/09/4506-0726©2009 Springer Science+Business Media, Inc.

In the present work, we studied pathways to the synthesis of diazepino[4,5-b]indoles by the reaction of
3-R1,R2-aminoindolo[2,3-c]pyrilium salts with hydrazine hydrate and the heterocyclization of derivatives of
2-acetyl-3-indolylacetic acid 1a as well as ester and amide derivatives of 1a with hydrazine hydrate.
Heating 2-acetyl-3-indolylacetic acid (1a) and 2-propionyl-3-indolylacetic acid (1b) with hydrazine
hydrate in ethanol or heating their sodium salts in water with subsequent acidification by adding acetic acid lead
to amines 2a and 2b, which are also obtained upon heating 1-methyl- and 1-ethyl-3-hydroxyindolo-
[2,3-c]pyrilium borofluoride at reflux with hydrazine hydrate. In contrast to 2-acetylbenzo[b]furan-3-acetic acid,
decarboxylation does not occur in formation of the azines.
CH2CO2H
CH2CO2H
N2H4
O
R
N
H
N
H
N
R
2
1a,b
2a,b
N2H4
OH
+
–
O
BF4
N
H
R
3a,b
1–3 a R = Me, b R = Et
The reaction of keto acid 1a with phenylhydrazine in ethanol leads to the phenylhydrazone of
2-acetyl-3-indolylacetic acid (4). Heterocyclization of phenylhydrazone 4 was carried out by the action of
dicyclohexylcarbodiimide (DCC). The product isolated was 1-methyl-2-phenylaminoindolo[2,3-c]pyridin-
3(2H)-one (5).
CH2CO2H
O
PhNHNH2
DCC
1a
N
N
H
N
NNHPh
Me
NH
Ph
H
Me
4
5
In previous work [15], we have shown that heating 3-arylamino-1-methylindolo[2,3-c]pyrilium
perchlorates or arylamides of 2-acetyl-3-indolylacetic acids with hydrazine hydrate in ethanol gives exclusively
hydrazones of the arylamides of 2-acetyl-3-indolylacetic acids 6. Hydrazinolysis of the amides does not occur
even upon prolonged heating of the reaction mixture at reflux [15]. We discovered that subsequent
heterocyclization of hydrazones 6 proceeds only in acidic media. Heating hydrazones 6a and 6b in acetic acid at
reflux gave 2-aryl-1-methylindolo[2,3-c]pyridin-3(2H)-ones 7a and 7b. This reaction is probably related to the
hydrolysis of hydrazones 6a and 6b and subsequent acid-base catalysis, leading to 2-aryl derivatives 7a and 7b
[15]. Hydrazones 6a and 6b are converted in trifluoroacetic acid into 2-amino-1-methylindolo[2,3-c]pyridin-
3(2H)-ones 9.
Acetylhydrazones 8a and 8b obtained by treating the corresponding hydrazones 6a and 6b with acetyl
chloride in THF in the presence of triethylamine in acetic as well in trifluoroacetic acids cyclize to give
2-acetylamino-1-methylindolo[2,3-c]pyridin-3(2H)-one (9b), which was also obtained by heating hydrazones 6a
and 6b directly with acetic anhydride.
727

CH2CONHAr
O
AcOH
Ac2O
N
N
N
H
6a,b
N
H
NH2
Ar
Me
Me
7a,b
Et3N AcCl
CH2CONHAr
O
CF3CO2H
N
N
R
N
H
NHAc
N
H
N
H
Me
Me
8a,b
9a,b
6–8 а Ar = 4-MeC6H4, b Ar = 4-MeОC6H4; 9 а R = Н, b R = Ac
2-Dimethylamino-1-methyl(ethyl)(morpholino)indolo[2,3-c]pyrilium perchlorates 10a-c react with
hydrazine hydrate in ethanol similarly to 3-arylaminoindolo[2,3-c]pyrilium salts, i.e., to give the hydrazones of the
dimethylamide(morpholide) of 2-acetyl(propionyl)indolyl-3-acetic acid 11a-c. The heterocyclization of hydrazones
11a-c both in acetic acid and trifluoroacetic acid leads to already reported 2-amino-1-methylindolo-
[2,3-c]pyridin-3(2H)-one (9a) and 2-amino-1-ethylindolo[2,3-c]pyridin-3(2H)-one (9c).
CH2CONR2R3
NR2R3
O
AcOH
N2H4
+
O
NNH2
N
N
N
NH2
–
N
H
N
R1
ClO4
H
H
R1
R1
10a–c
11a–c
9a,c
9 a R1 = Me, c R1 = Et; 10, 11 a R1 = R2 = R3 = Me, b R1 = Me, R2+R3 = (CH2CH2O)2,
c R1 = Et, R2+R3 = (CH2CH2O)2
In contrast to 3-arylamino- and 3-dialkylaminopyrilium perchlorates 10-10c, 3-acetylamino-1-methyl-
indolo[2,3-c]pyrilium perchlorate (12a) and 3-acetylamino-1-ethylindolo[2,3-c]pyrilium perchlorate (12b) react
with hydrazine hydrate to give 2,3-dihydro-2-oxo-5-R1-1H-[1,2]diazepino[4,5-b]indoles 13a and 13b along with
traces of 2-amino derivatives 9a and 9c. Diazepino[4,5-b]indole 13a was also obtained by cyclization of the
O
CH2CO2Me
CH2CO2Me
N2H4
NH
+
O
N
N
N
H
N
N
H
H
R1
R1
Me
2
14a
13a
2c
H
N
O
R1
N2H4
+
NH
+
9a,c
O
O
–
N
H
N
N
R1
H
R1
ClO4
12a,b
13a,b
12–14 a R1 = Me, b R1 = Et
728

methyl ester of 2-acetyl-3-indolylacetic acid 14a with hydrazine hydrate. In this case, GC/MS analysis of the
reaction mixture obtained in the conversion of ester 14a showed the presence of the azine of the methyl ester of
2-acetyl-3-indolylacetic acid 2c.
1
The H NMR spectra of diazepines 13a and 13b display singlets for H-5 at 3.56 ppm and NHCO at
10.6 ppm, indicating that these compounds exist as lactams. We should note that, according to Monge et al. [13],
isomeric 1-methyl-3H-[1,2]diazepino[5,6-b]indole exists in DMSO solution as a lactim.
The structure of 5-ethyl-2,3-dihydro-2-oxo-1H-[1,2]diazepino[4,5-b]indole (13b) was established by
X-ray diffraction structural analysis (Fig. 1). The seven-membered heterocycle is in boat conformation. Atoms
C(8), C(10), and N(3) deviate from the mean-square plane of the remaining ring atoms by 0.62, 0.57, and
0.64 Å, respectively. The angle between the C(7)–C(8)–C(10)–C(11) and C(8)–C(9)–N(2)–N(3) planes is 60.6°.
The ethyl group is markedly twisted relative to the plane of the indole fragment; the N(1)–C(11)–C(10)–C(12)
and C(11)–C(10)–C(12)–C(13) torsion angles are -27.9(1)° and -54.6(1)°, respectively.
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C
C
H
Cl
N
2а
2b
2c
C24H22N4O4
C26H26N4O4
C26H26N4O4
66.88
66.97
68.03
68.11
68.25
68.11
5.08
5.15
5.79
5.72
5.61
5.72
—
—
—
13.10
13.02
12.28
12.22
12.11
12.22
235-236
172-173
78
80
32
237-238
(decomp.)
4
C18H17N3O2
C18H15N3O
C19H20N4O2
C21H22N4O2
C21H22N4O3
C12H11N3O
70.25
70.34
74.63
74.72
67.98
67.84
69.71
69.59
66.58
66.65
67.42
67.59
5.62
5.58
5.29
5.23
5.81
5.99
6.23
6.12
5.75
5.86
5.39
5.20
—
—
—
—
—
—
13.75
13.67
14.65
14.52
16.76
16.65
15.36
15.46
14.91
14.80
19.54
19.71
163-164
246-247
185-186
265-266
256-257
282-283
74
67
93
89
89
5
6b
8а
8b
9a
92 (A),
83 (B)
9b
9c
C14H13N3O2
C13H13N3O
65.97
65.87
5.10
5.13
—
—
16.55
16.46
264-265
(decomp.)
87
68.60
68.71
5.66
5.77
18.59
18.49
258-259
(decomp.)
90
10a
10b
10c
11а
11b
11c
12a
C14H15ClN2O5
C16H17ClN2O6
C17H19ClN2O6
C14H18N4O
51.55
51.46
52.21
52.11
53.45
53.34
64.98
65.09
64.06
63.98
64.79
64.95
51.13
51.26
4.53
4.63
4.54
4.65
5.08
5.00
7.12
7.02
6.63
6.71
7.29
7.05
4.10
3.99
10.80
10.85
9.55
9.61
9.19
9.26
—
—
—
—
8.71
8.57
7.69
7.60
7.44
7.32
21.75
21.69
18.75
18.65
17.69
17.82
8.66
8.54
>300
86
90
78
73
76
80
44
>300
292-293
204-205
230-231
224-225
C16H20N4O2
C17H22N4O2
C14H13BF4N2O2
211-212
(decomp.)
12b
13a
13b
C16H17BF4N2O2
C12H11N3O
53.81
53.96
4.93
4.81
—
—
—
7.75
7.87
189-190
(decomp.)
40
67.70
67.59
5.11
5.20
19.79
19.71
270
(decomp.)
47 (A),
52 (B)
C13H13N3O
68.84
68.71
5.64
5.77
18.38
18.49
218-219
54 (A)
729

The configuration of the nitrogen atom of the amide fragment departs somewhat from planar. The sum
of the bond angles centered at N(2) is 358°.
Fig. 1. Molecular structure of 5-ethyl-2,3-dihydro-2-oxo-1H-[1,2]diazepino-
[4,5-b]indole (13b) from X-ray diffraction structural analysis data.
The molecules in crystalline 13 form centrosymmetric dimers by means of intermolecular hydrogen
bonding N(2)–H(2A)···O(1)' (-x, 1-y, -z) (H···O, 2.11 Å; N-H···O, 178°). The dimers form chains along the 1 0 0
crystallographic axis due to intermolecular hydrogen bonding N(1)–H(1A)···O(1)' (x+1, y, z) (H···O, 1.99 Å, N–
H···O angle 173°). Adjacent dimer chains are connected to each other by weak C–H···π bonds between the C(8)–
H(8A) group and π-system of the benzene ring of the adjacent molecule (H(8A)···C(4) bond length is 2.76 Å, the
sum of the van der Waals radii is 2.87 Å [16]).
EXPERIMENTAL
1
The H NMR spectra were taken on a Gemini-200 spectrometer at 200 MHz and a Bruker DRX500
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; the ionizing electron energy was 70 eV. The LC/MS spectra were
taken on an Agilent 1100 LC/MSD VL using atmospheric pressure chemical ionization (APCI).
Chromatographic column parameters: 50 mm length, 4.6 mm diameter, ZORBAX SB-C18 stationary phase,
95:5 acetonitrile–water solvent, 0.1% trifluoroacetic acid, gradient elution, solvent inlet rate 3.0 ml/min. The
preparative chromatography of the compounds was carried out on Merck 60 silica gel.
The characteristics of the products are given in Tables 1-3.
X-ray Diffraction Structural Analysis. Triclinic crystals of 13b were grown from 3:1 chloroform–aceto-
nitrile, C13H13N3O. Unit cell parameters at 293 K: a = 7.4495(4), b = 7.8021(5), c = 10.30798(6) Å, α = 102.876(5),
–
β = 94.570(5), γ = 100.536(5)°, V = 569.65(6) Å3, M = 227.26, Z = 2, space group P , dcalc = 1.325 g/cm3,
1
r
µ(MoKα) = 0.087 mm-1, F(000) = 240. The X-ray diffraction structural analysis of the compound 13b was carried
out at 20°C on an Xcalibur-3 diffractometer using MoKα radiation, CCD detector, graphite monochromator,
ω-scanning, 2θmax = 60°. A total of 8233 reflections were measured, of which 3296 were independent (Rint = 0.021).
730

TABLE 2. 1H NMR Spectra of Compounds Synthesized
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
2а
2b
2c
4
2.51 (3Н, s, СН3C=N); 4.09 (2Н, s, СН2); 7.07 (1H, t, J = 8.0, H-6);
7.17 (1Н, t, J = 8.0, Н-5); 7.44 (1Н, d, J = 8.0, H-7); 7.58 (1Н, d, J = 8.0, H-4);
11.28 (1H, s, NH); 12.12 (1H, s, СООH)
1.15 (3Н, t, J = 7.4, СН3СН2); 3.08 (3Н, q, J = 7.4, СН3СН2); 4.09 (2Н, s, СН2);
7.02 (1H, t, J = 8.0, H-6); 7.16 (1Н, t, J = 8.0, Н-5); 7.43 (1Н, d, J = 8.0, H-7);
7.55 (1Н, d, J = 8.0, H-4); 11.21 (1H, s, NH); 12.03 (1H, s, СООH)
2.53 (3Н, s, СН3C=N); 3.64 (1H, s, ОСH3); 4.15 (2Н, s, СН2); 7.07 (1H, t, J = 8.0, H-6);
7.20 (1Н, t, J = 8.0, H-5); 7.43 (1Н, d, J = 8.0, H-7); 7.61 (1Н, d, J = 8.0, H-4);
11.24 (1H, s, NH)
2.37 (3Н, s, СН3C=N); 3.97 (2Н, s, СН2); 6.73 (1Н, t, J = 6.0, Н-4');
6.95 (1H, t, J = 8.0, H-6); 7.06 (1Н, t, J = 8.0, Н-5); 7.18-7.29 (4Н, m, Н arom.);
7.36 (1Н, d, J = 8.0, H-7); 7.46 (1Н, d, J = 8.0, H-4); 9.13 (1Н, s, NH);
10.84 (1H, s, 1-NH); 11.97 (1H, s, СООH)
5
2.68 (3Н, s, 1-СН3); 6.63 (2Н, d, J = 7.6, Н-2',6'); 6.87 (1Н, t, J = 7.6, Н-4');
7.06 (1H, t, J = 8.0, H-7); 7.15 (2Н, t, J = 7.6, Н-3',5'); 7.33 (1Н, d, J = 8.0, H-8);
7.45 (1H, t, J = 8.0, H-6); 7.97 (1Н, d, J = 8.0, H-5); 9.03 (1Н, s, NH); 10.75 (1H, s, 9-NH)
6b
2.26 (3Н, s, СН3C=N); 3.71 (3Н, s, 4'-ОСН3); 3.78 (2Н, s, СН2);
6.72 (4Н, d, J = 9.0, H-3',5'); 6.83 (2Н, s, NН2); 6.98 (1Н, t, J = 7.6, H-6);
7.06 (1Н, t, J = 7.6, H-5); 7.30 (1Н, d, J = 7.6, H-7); 7.43 (2Н, d, J = 9.0, H-2',6');
7.62 (1Н, d, J = 7.6, H-4); 10.48 (1Н, s, CONH); 10.91 (1Н, s, 1-NH)
8а
2.16 (6Н, s, COСН3 и 4'-СН3); 2.40 (3Н, s, СН3C=N); 3.89 (2Н, s, СН2);
7.00 (2Н, d, J = 8.6, H-3',5'); 7.08 (1Н, t, J = 7.7, H-6); 7.15 (1Н, t, J = 7.7, H-5);
7.39 (1Н, d, J = 7.7, H-7); 7.44 (2Н, d, J = 8.6, H-2',6'); 7.78 (1Н, d, J = 7.7, H-4);
10.29 (1Н, s, СН3CONH); 10.89 (1Н, s, СН2CONH); 11.38 (1Н, s, 1-NH)
8b
2.19 (3Н, s, COСН3); 2.41 (3Н, s, СН3C=N); 3.70 (3Н, s, 4'-ОСН3); 3.91 (2Н, s, СН2);
6.68 (2Н, d, J = 8.6, H-3',5'); 7.04 (1Н, t, J = 7.4, H-6); 7.11 (1Н, t, J = 7.4, H-5);
7.34 (1Н, d, J = 7.4, H-7); 7.52 (2Н, d, J = 8.6, H-2',6'); 7.84 (1Н, d, J = 7.4, H-4);
10.15 (1Н, s, СН3CONH); 10.70 (1Н, s, СН2CONH); 11.07 (1Н, s, 1-NH)
9а
9b
9c
2.67 (3Н, s, 1-СН3); 6.40 (2Н, s, NH2); 6.88 (1Н, s, H-4); 7.03 (1Н, t, J = 7.6, H-7);
7.31 (1Н, d, J = 7.6, H-8); 7.43 (1Н, t, J = 7.6, H-6); 7.97 (1Н, d, J = 7.6, H-5);
10.68 (1Н, s, 9-NH)
2.08 (3Н, s, COСН3); 2.42 (3Н, s, 1-СН3); 6.88 (1Н, s, H-4); 7.01 (1Н, t, J = 8.0, H-7);
7.27 (1Н, d, J = 8.0, H-8); 7.45 (1Н, t, J = 8.0, H-6); 7.97 (1Н, d, J = 8.0, H-5);
10.48 (1Н, s, CONH); 10.79 (1Н, s, 9-NH)
1.32 (3Н, t, J = 7.6, 1-СН2СН3); 3.13 (3Н, q, J = 7.6, 1-СН2СН3); 5.97 (2Н, s, NH2);
6.71 (1Н, s, Н-4); 6.93 (1Н, t, J = 8.2, H-7); 7.21 (1Н, d, J = 8.2, H-8);
7.28 (1Н, t, J = 8.2, H-6); 7.79 (1Н, d, J = 8.2, H-5); 10.30 (1Н, s, 9-NH)
2.85 (3Н, s, 1-СН3); 3.37 (6Н, s, N(СН3)2); 7.20 (1Н, t, J = 8.0, H-7); 7.41 (1Н, d, J = 8.0, H-8);
7.63 (1Н, t, J = 8.0, H-6); 7.69 (1Н, s, H-4); 8.21 (1Н, d, J = 8.0, H-5); 11.43 (1Н, s, 9-NH)
10а
10b
2.83 (3Н, s, 1-СН3); 3.57–3.89 (8Н, m, morpholine); 7.22 (1Н, t, J = 8.0, H-7);
7.44 (1Н, d, J = 8.0, H-8); 7.66 (1Н, t, J = 8.0, H-6); 7.71 (1Н, s, H-4);
8.22 (1Н, d, J = 8.0, H-5); 11.52 (1Н, s, 9-NH)
10c
11а
11b
11c
1.33 (3Н, t, J = 7.3, 1-СН2СН3); 2.89 (3Н, q, J = 7.3, 1-СН2СН3); 3.30 (6Н, s, N(СН3)2);
7.12 (1Н, t, J = 8.0, H-7); 7.32 (1Н, d, J = 8.0, H-8); 7.54 (1Н, t, J = 8.0, H-6);
7.60 (1Н, s, H-4); 8.09 (1Н, d, J = 8.0, H-5); 11.28 (1Н, s, 9-NH)
2.11 (3Н, s, СН3C=N); 2.88 (3Н, s, NСН3); 3.04 (3Н, s, NСН3); 3.99 (2Н, s, СН2);
5.99 (2Н, s, NН2); 6.89 (1Н, t, J = 8.0, H-6); 7.02 (1Н, t, J = 8.0, H-5);
7.29 (1Н, d, J = 8.0, H-7); 7.44 (1Н, d, J = 8.0, H-4); 10.59 (1Н, s, 1-NH)
2.09 (3Н, s, СН3C=N); 3.36–3.53 (8Н, m, morpholine); 4.01 (2Н, s, СН2);
6.28 (2Н, s, NН2); 6.91 (1Н, t, J = 7.8, H-6); 7.02 (1Н, t, J = 7.8, H-5);
7.30 (1Н, d, J = 7.8, H-7); 7.47 (1Н, d, J = 7.8, H-4); 10.81 (1Н, s, 1-NH)
1.05 (3Н, t, J = 7.3, 1-СН2СН3); 2.63 (3Н, q, J = 7.3, 1-СН2СН3);
3.32–3.51 (8Н, m, morpholine); 4.01 (2Н, s, СН2); 6.48 (2Н, s, NН2);
6.89 (1Н, t, J = 8.0, H-6); 7.00 (1Н, t, J = 8.0, H-5); 7.28 (1Н, d, J = 8.0, H-7);
7.47 (1Н, d, J = 8.0, H-4); 10.78 (1Н, s, 1-NH)
13а
2.44 (3Н, s, 5-СН3); 3.56 (2Н, s, 1-СН2); 7.13 (1Н, t, J = 8.1, H-8);
7.26 (1Н, t, J = 8.1, H-9); 7.44 (1Н, d, J = 8.1, H-7); 7.71 (1Н, d, J = 8.1, H-10);
10.64 (1Н, s, CONH); 11.49 (1Н, s, 6-NH)
13b
1.19 (3Н, t, J = 7.3, 5-СН2СН3); 2.85 (3Н, q, J = 7.3, 5-СН2СН3); 3.48 (2Н, s, 1-СН2);
7.05 (1Н, t, J = 8.0, H-8); 7.17 (1Н, t, J = 8.0, H-9); 7.38 (1Н, d, J = 8.0, H-7);
7.59 (1Н, d, J = 8.0, H-10); 10.23 (1Н, s, CONH); 11.13 (1Н, s, 6-NH)
731

TABLE 3. Mass Spectra of Compounds Synthesized
Com-
pound
m/z (Irel, %)*
2а
2b
2с
5
430 [M] (30), 342 (70), 171 (40), 155 (10), 129 (15), 63 (15), 44 (100)
370 (20), 341 (15), 185 (40), 169 (17), 155 (15), 130 (13), 77 (9), 44 (100)
459 [M + 1]+ (100)
289 [M] (30), 197 (41), 169 (65), 127 (12), 101 (13), 93 (100), 77 (16), 65 (30),
51 (12), 42 (28)
9b
255 [M] (100), 238 (15), 213 (48), 197 (50), 184 (41), 169 (30), 154 (25),
127 (20), 115 (10), 101 (13), 77 (15), 51 (11), 43 (53)
213 [M] (100), 197 (12), 184 (100), 169 (10), 154 (16), 128 (13)
13а
_______
*The strongest peaks are given. The mass spectrum for 2c was obtained by
HPLC/MSD method.
The structure was solved by the direct method and refined for F2 by the full-matrix method of least
squares anisotropically for the non-hydrogen atoms using the SHELXTL program package [17]. The positions
of the hydrogen atoms were found in the electron density difference map and refined isotropically. The final
divergence factors: wR2 = 0.095 for 7900 reflections (R1 = 0.035 for 2315 reflections with F > 4σ(F), S = 0.947.
The atomic coordinates, geometric parameters of the molecule, and crystallographic data are deposited at the
Cambridge Crystallographic Data Center (CCDC deposit 673,503).
Samples of 2-acetyl-3-indolylacetic acid (1a), 2-propionyl-3-indolylacetic acid (1b), and their methyl
esters 14a and 14b were obtained according to Plieninger et al. [18].
Preparation of Azines of 2-Acetyl-3-indolylacetic Acid (2a) and 2-Propionyl-3-indolylacetic
acid (2b) (General Method). A. Hydrazine hydrate (2.5 g, 50 mmol) was added to a solution of 1a or 1b
(10 mmol) in aqueous sodium bicarbonate, heated at reflux for 1 h, cooled, and made acidic by adding acetic
acid to pH < 7. The precipitate formed was filtered off and washed with ethanol and water; compound 2a was
crystallized from aqueous DMSO, while compound 2b was crystallized from methanol.
B. A mixture of corresponding 1-methyl- (3a) or 1-ethyl-3-hydroxyindolo[2,3-c]pyrilium borofluoride
(3b) (10 mmol) [18] and hydrazine hydrate (2.5 g, 50 mmol) in methanol (30 ml) was heated at reflux for 1 h
and cooled. Crystals of compounds 2a or 2b were filtered off and washed with ethanol and water.
Phenylhydrazone of 2-Acetyl-3-indolylacetic Acid (4). Phenylhydrazine (1.62 g, 15 mmol) was added
to a solution of compound 1a (2.3 g, 10 mmol) in 2-propanol and heated at reflux for 1 h. After cooling, the
precipitate formed was filtered off, washed with cold 2-propanol, and crystallized from methanol.
1-Methyl-2-phenylaminoindolo[2,3-c]pyridin-3(2H)-one (5).) Dicyclohexylcarbodiimide (0.72 g,
3.5 mmol) was added to a solution of compound 4 (1 g, 3.1 mmol) in methylene chloride (20 ml) and stirred for
5 h. Dicyclohexylurea was filtered off and washed with methylene chloride. The filtrate was evaporated and the
residue was crystallized from 2-propanol.
Hydrazone of 4-Methylphenylamide of 2-Acetyl-3-indolylacetic Acid (6a) was prepared from
1-methyl-3-(4-methylphenylamino)indolo[2,3-c]pyrilium perchlorate [15].
Hydrazone of 4-Methoxyphenylamide of 2-Acetyl-3-indolylacetic Acid (6b) was prepared from
1-methyl-3-(4-methoxyphenylamino)indolo[2,3-c]pyrilium perchlorate [15] analogously to compound 6a.
Hydrazone 6b was crystallized from methanol.
2-(4-Methoxyphenylamino)-1-methylindolo[2,3-c]pyridin-3(2H)-one (7a) was prepared by heating
hydrazone 6a in glacial acetic acid at reflux for 2 h. This product was spectrally identical to previously prepared
samples [15] and a mixed probe did not give a depressed melting point.
732

2-(4-Methoxyphenylamino)-1-methylindolo[2,3-c]pyridin-3(2H)-one (7b) was obtained by heating
hydrazone 6b in glacial acetic acid for 2 h. The product was spectrally identical to previously prepared samples
[15] and a mixed probe did not give a depressed melting point.
N-Acetylhydrazone of 4-Methylphenylamide of 2-Acetyl-3-indolylacetic Acid (8a). Acetyl chloride
(0.157 g, 2 mmol) was added with stirring and cooling solution of hydrazone 6a (0.64 g, 2 mmol) and
triethylamine (0.3 ml) in THF, stirred for 1 h, brought to reflux, cooled, and poured into water. The precipitate
was filtered off and crystallized from DMSO.
N-Acetylhydrazone of 4-Methoxyphenylamide of 2-Acetylbenzo[b]furan-3-acetic Acid (8b) was
obtained from hydrazone 6b analogously to compound 8a. This product was crystallized from DMSO.
2-Amino-1-methylindolo[2,3-c]pyridin-3(2H)-one (9a). A. A solution of 1 g hydrazones of aryl-
amides of 2-acetyl-3-indolylacetic acid 6a or 6b was heated at reflux for 1 h in trifluoroacetic acid (20 ml).
Then, trifluoroacetic acid was removed in vacuum and water (50 ml) was added. The remaining trifluoroacetic
acid was neutralized by adding ammonium hydroxide to bring the pH to >7. The precipitate formed was filtered
off, washed with water, and crystallized from ethanol.
B. Amino ketone 9a was obtained by a procedure analogous to method A using hydrazones of
alkylamides of 2-acetyl-3-indolylacetic acid 11a or 11b and acetic acid.
The samples of amino ketone 9a obtained by methods A and B were spectrally identical and a mixed
probe did not give a depressed melting point.
2-Acetylamino-1-methylindolo[2,3-c]pyridin-3(2H)-one (9b). A. Acetic anhydride (0.2 g, 4 mmol)
was added to a solution of hydrazone 6a (0.96 g, 3 mmol) in THF. The solution was brought to reflux, cooled,
and poured into water. The precipitate formed was filtered off and crystallized from 2-propanol.
B. N-Acetylhydrazone of 4-methylphenylamide of 2-acetyl-3-indolylacetic acid (8a) (0.38 g, 1 mmol) was
dissolved in acetic acid (20 ml) and heated at reflux for 1 h. The solution was cooled and 50 ml water was added.
The acetic acid was neutralized by adding 10% ammonium hydroxide to bring the pH to >7. The precipitate formed
was filtered off, washed with water, and crystallized from 2-propanol. Samples of compound 9b obtained by
methods A and B are spectrally identical and a mixed probe did not give a depressed melting point.
2-Amino-1-ethylindolo[2,3-c]pyridin-3(2H)-one (9c) was obtained from hydrazone 11c analogous to
compound 9a (method B) and crystallized from 2-propanol.
3-Dimethylamino-1-methylindolo[2,3-c]pyrilium Perchlorate (10a) was obtained according to our
reported method [19] by the cyclization of the dimethylamide of 2-acetyl-3-indolylacetic acid [18].
1-Methyl-3-morpholinoindolo[2,3-c]pyrilium Perchlorate (10b) was obtained according to our
reported procedure [19] by the cyclization of the morpholide of 2-acetyl-3-indolylacetic acid [18].
1-Ethyl-3-morpholinoindolo[2,3-c]pyrilium Perchlorate (10c) was obtained according to our reported
procedure [19] by the cyclization of the morpholide of 2-propionylindolyl-3-acetic acid [18].
Hydrazone of Dimethylamide of 2-Acetyl-3-indolylacetic Acid (11a). 60% Hydrazine hydrate (5 ml)
was added to a suspension of pyrilium perchlorate 10a (10 mmol) in 2-propanol (50 ml) and heated at reflux for
1.5 h. After cooling, 50 ml water was added. The precipitate was filtered off, washed with water, and
crystallized from 2-propanol.
Hydrazone of Morpholide of 2-Acetyl-3-indolylacetic Acid (11b) was obtained from 1-methyl-3-morpho-
linoindolo[2,3-c]pyrilium perchlorate (10b) analogously to hydrazone 11a and crystallized from 2-propanol.
Hydrazone of Morpholide of 3-Propionyl-3-indolylacetic Acid (11c) was obtained from
perchlorate 10c analogously to hydrazone 11a and crystallized from 2-propanol.
3-Acetylamino-1-methylindolo[2,3-c]pyrilium Perchlorate (12a) was obtained by the acylation of
3-indolylacetonitrile using acetic anhydride in the presence of boron trifluoride etherate according to a
procedure analogous to the method of Dorofeenko et al. [20].
3-Acetylamino-1-ethylindolo[2,3-c]pyrilium Perchlorate (12b) was obtained by the acylation of
3-indolylacetonitrile using propionic anhydride in the presence of boron trifluoride etherate according to a
procedure analogous to the method of Dorofeenko et al. [20].
733

2-Oxo-2,3-dihydro-5-R-1H-[1,2]diazepino[4,5-b]indoles 13a and 13b. A. 98% Hydrazine hydrate
(5 ml) was added to a suspension of corresponding pyrilium perchlorate 12a or 12b (10 mmol) in 2-propanol
(50 ml) and heated at reflux for 30 min. After cooling, 50 ml water was added and the excess hydrazine was
neutralized by adding acetic acid to bring the pH to <7. The mixture was extracted with chloroform. The extract
was washed with water and the solvent was removed. Indoles 13a and 13b were purified by preparative
chromatography. Product 13a, Rf 0.13, was eluted with 20:1 chloroform–methanol, while product 13b, Rf 0.45,
was eluted with 3:1 chloroform–acetonitrile.
B. 98% Hydrazine hydrate (0.75 ml)was added to a solution of keto acid methyl ester 14a [18] (5 mmol)
in 2-propanol (50 ml) and heated at reflux for 2 h. After cooling, water (30 ml) was added and excess hydrazine
was neutralized by adding acetic acid to bring the pH to <7. The precipitate formed was filtered off and washed
with water. Products 13a and 2c were separated by preparative chromatography using 20:1 chloroform–
methanol as the eluent. Product 2c, Rf 0.43, was crystallized from ethanol.
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734