Indole derivatives. 141. Synthesis and investigation of new 2-arylindoles

Article abstract of DOI:10.1023/A:1012439205723

2-(Diphenylmethan-4-y1)- and 2-(dibenzyl-4-y1)indo1es have been synthesized by the Fischer reaction. Reactions carried out included azo coupling, formylation, and nitrosation. The corresponding 3-substituted derivatives were obtained.

Full text of DOI:10.1023/A:1012439205723

Chemistry of Heterocyclic Compounds, Vol. 37, No. 7, 2001
INDOLE DERIVATIVES.
141. SYNTHESIS AND INVESTIGATION
OF NEW 2-ARYLINDOLES*
Sh. A. Samsoniya, I. Sh. Chikvaidze, T. G. Narindoshvili, and N. N. Suvorov
2-(Diphenylmethan-4-yl)- and 2-(dibenzyl-4-yl)indoles have been synthesized by the Fischer reaction.
Reactions carried out included azo coupling, formylation, and nitrosation. The corresponding
3-substituted derivatives were obtained.
Keywords: arylindoles, indolization, azo coupling, formylation, nitrosation.
2-Phenylindole and its derivatives, which possess specific properties, constitute an important group of
indole compounds of considerable interest from the point of view of various areas of science and technology
[2,3], including medicine [4-6].
With the purpose of searching for new indole derivatives with useful properties, we have synthesized
2-(diphenylmethan-4-yl)indole (5) and 2-(dibenzyl-4-yl)indole (6) from phenylhydrazones 3 and 4 by the
Fischer reaction.
The arylindoles 5 and 6 were obtained from the corresponding ketones 1 and 2 and phenylhydrazine in
polyphosphoric acid (PPA) at 100 and 110°C without isolation of the intermediate hydrazones 3 and 4. The
yields of these compounds after purification were 25 and 40% respectively.
4
O
3
2
5
6
A
B
1
X
C
CH3
N
X
7
H
1, 2
5, 6
to
C6H5NH–NH2
PPA
CH3
C
X
N
H
N
3, 4
'
1
2'
1, 3, 5 X = CH2; 2, 4, 6 X = CH2–CH2
_______
* For part 140 see [1].
__________________________________________________________________________________________
I. Javakhishvili Tbilisi State University, Tbilisi 380028, Georgia; e-mail: shsam@mmc.net.ge.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 899-905, July, 2001. Original article
submitted July 30, 1999.
0009-3122/01/3707-0827$25.00©2001 Plenum Publishing Corporation
827

In the 1H NMR spectrum of 2-(diphenylmethan-4-yl)indole (5) (Table 1) the signals of the 4-H and 7-H
protons of the indole fragment were recorded as a doublet of doublets at 7.50 and 7.35 ppm respectively. The
signals for the 5-H and 6-H protons (6.97 and 7.07 ppm) were displayed as a triplet of doublets. The signal of
the 3-H proton was displayed as a doublet at 6.82 ppm. The low field signal at 11.45 ppm was assigned by us to
the NH proton. The protons of the first nucleus of the diphenylmethane give two doublet signals at 7.77 and
7.31 ppm, characteristic of protons of para-disubstituted benzenes, the latter partially overlapping the multiplet
of protons of the second benzene ring. The singlet for the protons of the bridge methylene group is displayed at
3.97 ppm.
The 1H NMR spectrum of 2-(dibenzyl-4-yl)indole (6) (Table 1) resembled the spectrum of
2-(diphenylmethane-4-yl)indole (5). The singlet signal (2.92 ppm) of the bridge group protons –CH2–CH2–
corresponded to four protons in intensity. Identical values for the chemical shifts of these protons and the
absence of spin coupling may, in our opinion, be explained by an identical degree of shielding from the side of
the aromatic nuclei.
The azo coupling reaction has been studied for arylindoles 5 and 6 with benzenediazonium chloride and
its p-Cl, p-NO2, p-COOH, p-COOCH3, and p-SO2NH2 derivatives. Best results were achieved when carrying out
the reaction in dilute solution at pH 6-7 (Table 2). Formylation of 2-arylamines according to Vilsmeier–Haack
was carried out at 40°C in 70-75% yield.
Nitrosation of arylindoles 5 and 6 in acetic acid at 20°C leads to the formation of nitroso compounds 21
and 22 (yellow crystals) in almost quantitative yield.
A'
B'
–
+
N
N
R
R
N2Cl
X
N
H
7–18
O
C
H
POCl3
DMF
5, 6
X
X
N
H
19, 20
N
OH
NaNO2
CH3CO2H
N
21, 22
1, 3, 5, 7–12, 19, 21 X = CH2; 2, 4, 6, 13–18, 20, 22 X = CH2–CH2; 7, 13 R = H;
8, 14 R = Cl; 9, 15 R = NO2; 10, 16 R = SO2NH2; 11, 17 R = COOCH3; 12, 18 R = COOH
A hypsochromic shift of the long wave maximum of 31 and 20 nm was observed in the electronic
spectra of azo compounds 8 and 14 (Figs. 1 and 2) compared with the analogous maximum of the benzeneazo
derivatives 7 and 13. A bathochromic shift of this maximum was observed in the spectra of compounds 9-12 and
15-18, the value of which grew with an increase in the electron-withdrawing nature of the substituent of the
diazo component. It is evident that the character of the absorption in the spectra of compounds 8 and 14 is
changed due to the positive mesomeric effect of the chlorine atom.
828

TABLE 1. Spectral Characteristics for Compounds 5-22
Com-
IR spectrum,
UV spectrum,
1H NMR spectrum, ppm*
4
J, Hz
pound
ν, cm-1
λ
max, nm (log ε)
1
2
3
5
3425 (NH)
214 (4.48); 247 (4.28);
315(4.42)
11.45 (1H, s, NH); 6.82 (1H, d, 3-H); 7.50 (1H, d, 4-H); 6.97 (1H, dt, 5-H);
7.07 (1H, d, 6-H); 7.35 (1H, d, 7-H); 7.77 (2H, d, AH); 7.31 (2H, d, BH);
7.20-7.32 (5H, m, С6Н5); 3.97 (2H, s, CH2)
J
J
13 = 1.73; J46 = J57 = 1.16;
45 = J67 = 8.11; JAB = 8.11
5
3452 (NH)
210 (4.40); 247 (4.18);
315 (4.30)
11.45 (1H, s, NH); 6.84 (1H, d, 3-H); 7.50 (1H, d, 4-H); 6.98 (1H, dt, 5-H);
7.06 (1H, dt, 6-H); 7.38 (1H, d, 7-H); 7.76 (1H, d, AH); 7.30 (2H, d, BH);
7.18-7.28 (5H, m, C6H5); 2.92 (4H, s, CH2CH2)
J
J
13 = 1.36; J46 = J56 = 1.14;
45 = J67 = 8.0; JAB = 7.96
6
3455 (NH);
1460 (N=N)
209 (4.43); 253 (4.27);
300 (4.35); 406 (4.44)
12.30 (1H, s, NH); 8.48 (1H, d, 4-H); 7.20-7.56 (11H, 5-H÷7-H, B'H, C'H, C6H5);
7.80 (2H, d, AH); 7.47 (2H, d, BH); 8.10 (2H, d, A'H); 4.05 (2H, s, CH2)
8.62 (1H, s, NH); 7.92 (1H, d, 4-H); 7.20-7.39 (12H, m, 5-H÷7-H, AH, BH, С6Н5);
7.44 (2H, d, A'H); 7.81 (2H, d, B'H); 4.06 (2H, s, CH2)
J
J
AB = 7.52; JA'B' = 7.96
7
8
9
45 = 7.52
3420 (NH);
211 (4.56); 254 (4.40);
J
A'B' = 8.40
1425 (N=N)
302 (4.50); 375 (4.26)
3345 (NH);
1420 (N=N);
1330 (NО2)
209 (4.34); 289 (4.24);
465 (4.21)
12.61 (1H, s, NH); 8.60 (1H, d, 4-H); 7.21-7.49 (7H, m, 5-H, 6-H, C6H5); 7.63 (1H, d, 7-H);
J
J
AB = 8.0; J67 = J45 = 8.0
8.21 (2H, d, AH); 7.58 (2H, d, BH); 8.03 (2H, d, A'H); 8.44 (2H, d, B'H); 4.05 (2H, s, CH2)
A'B' = 8.11
3325 (NH);
1450 (N=N);
1360 (SО2)
3340 (NH);
1700 (CO);
1420 (N=N)
3400 (NH);
1680 (CO);
1410 (N=N)
210 (4.57); 254 (4.44);
299 (4.56);
12.47 (1H, s, NH); 8.48 (1H, d, 4-H); 7.20-7.34 (7H, m, 5-H, 6-H, С6Н5); 7.51 (1H, d, 7-H);
7.91 (2H, d, AH); 7.89 (2H, d, BH); 8.10 (2H, d, A'H); 7.48 (2H, d, B'H); 7.41 (2H, s, NH2);
4.06 (2H, s, CH2)
12.47 (1H, s, NH); 8.48 (1H, d, 4H); 7.20-7.34 (7H, m, 5-H, 6-H, C6H5); 7.51 (1H, d, 7-H);
8.10 (2H, d, AH); 7.48 (2H, d, BH); 8.10 (2H, d, A'H); 7.88 (2H, d, B'H); 3.88 (3H, s, CН3);
4.06 (2H, s, CH2)
12.46 (1H, s, NH); 8.49 (1H, d, 4-H); 7.20-7.34 (7H, m, 5-H, 6-H, C6H5); 7.51 (1H, d, 7-H);
8.07 (2H, d, AH); 7.49 (2H, d, ВH); 8.10 (2H, d, A'H); 7.87 (2H, d, B'H); 12.99 (1H, s, OH);
4.06 (2H, s, CН2)
J
J
AB = 7.96; JA'B' = 8.4
10
11
12
13
45 = 7.08
416.6 (4.52)
211 (4.49); 250 (4.31);
J
J
A'B' = 8.4; JAB = 7.96
308 (4.41); 426 (4.13)
45 = 7.08
211 (4.51); 255 (4.31);
303 (4.40);
J
AB = 8.4; JA'B' = 8.84
416.6 (4.35)
3400 (NH);
208 (4.67); 250 (4.48);
12.32 (1H, s, NH); 8.48 (1H, d, 4-H); 7.20-7.34 (11H, 5H÷7-H, B'H, C'H, C6H5);
J
J
AB = 7.52; JA'B' = 8.40
1455 (N=N)
298 (4.57); 400 (4.39)
7.81 (2H, d, AH); 7.48 (2H, d, BH); 8.08 (2H, d, A'H); 2.98 (4H, s, CH2CH2)
45 = 7.96

TABLE 1 (continued)
1
2
3
4
5
3460 (NH);
1430 (N=N)
3360 (NH);
1420 (N=N);
1320 (NO2)
3300 (NH);
1430 (N=N);
1370 (SО2)
3300 (NH);
1690 (CO);
1410 N=N)
209 (4.58); 252 (4.39);
300 (4.44); 380 (4.36)
—
—
14
207 (4.43); 286 (4.21);
8.76 (1H, s, NH); 8.63 (1H, d, 4-H); 7.18-7.48 (8H, m, 5-H÷7-H, C6H5); 7.96 (2H, d, AH);
J
A'B' = 8.88
15
16
17
18
265 (4.14)
7.32 (2H, d, BH); 7.93 (2H, d, A'H); 8.35 (2H, d, B'H); 3.70 (4H, s, CH2-CH2)
210 (4.54); 252 (4.36);
303 (4.41);
12.49 (1H, s, NH); 8.49 (2H, d, 4-H); 7.20-7.32 (7H, m, 5-H, 6-H, C6H5); 7.51 (1H, d, 7-H);
7.96 (2H, d, AH); 7.91 (2H, d, BH); 8.08 (2H, d, A'H); 7.48 (2H, d, B'H); 7.43 (2H, s, NH2);
2.99 (4H, s, CH2CH2)
12.51 (1H, s, NH); 8.62 (1H, d, 4H); 7.27-7.45 (7H, m, 5-H, 6-H, C6H5); 7.62(1H, d, 7-H);
8.17 (2H, d, AH); 7.59 (2H, d, BH); 8.22 (2H, d, A'H); 7.98 (2H, d, B'H); 4.00 (3H, s, CH3);
3.15 (4H, s, CH2CH2)
12.48 (1H, s, NH); 8.50 (1H, d, 4-H); 7.51 (1H, d, 7-H); 7.19-7.32 (7H, m, 5-H, 6-H, C6H5);
8.09 (2H, d, AH); 7.49 (2H, d, BH); 8.09 (2H, d, A'H); 7.86 (2H, d, B'H); 12.99 (1H, s, OH);
2.98 (4H, s, CH2CH2)
J
J
A'B' = 8.4; JAB = 8.84
45 = 7.96
416.6 (4.35)
210 (4.73); 254 (4.58);
J
A'B' = 8.0; J45 = 7.52
303 (4.63); 426 (4.60)
3450 (NH);
1670 (CO);
1420 (N=N)
210 (4.55); 252 (4.36);
303 (4.41);
J
AB = 8.4; J45 = 7.96
416.6 (4.36)
3140 (NH);
212 (4.41); 225 (4.32);
10.01 (1H, s, NH); 8.34 (1H, d, 4-H); 7.05-7.41 (8H, m, 5-H÷7-H, C6H5); 7.49 (2H, d, AH);
J
J
AB = 8.4
19
20
1620 (CO)
261 (4.54); 318 (4.22)
7.28 (2H, d, BH); 8.78 (1H, s, CHO); 4.04 (2H, s, CH2)
3150 (NH);
1630 (CO)
211 (4.46); 226 (4.41);
260 (4.40); 317 (4.06)
10.10 (1H, s, NH); 8.44 (1H, d, 4-H); 7.40 (1H, t, 5-H); 7.21-7.37 (7H, m, 6-H, 7-H, C6H5);
7.58 (2H, d, AH); 7.20 (2H, d, BH); 8.62 (1H, s, CHO); 3.01 (2H, t, 2'-CH2);
3.03 (2H, t, 1'-CH2)
AB = 7.6; J1'2' = 11.0
3300-3600;
209 (4.31); 225 (3.97);
268 (4.42)
13.81 (1H, s, OH); 8.20 (1H, d, 4-H); 7.25-7.58 (7H, m, 5-H, 6-H, C6H5); 7.48 (1H, d, 7-H);
J
J
AB = 8.0; J45 = 8.0
21
22
br. p (ОН)
8.31 (2H, d, AH); 7.64 (2H, d, BH); 4.21 (2H, s, CН2)
3300-3600;
210 (4.33); 225 (3.99);
13.76 (1H, s, OH); 8.10 (1H, d, 4-H); 7.15-7.33 (6H, m, 5-H, С6Н5); 7.46 (1H, t, 6-H);
7.53 (1H, d, 7-H); 8.18 (2H, d, AH); 7.38 (2H, d, BH); 2.96 (2H, t, 2'-CH2);
2.94 (2H, t, 1'-CH2)
AB = 7.96; J1'2' = 12.0
br. p (ОН)
269 (4.53)
_______
* The spectra of compounds 5-7, 9-13, 16-18, 21, and 22 were taken in DMSO-d6, and of 8, 15, 19, and 20 in CHCl3.

log
ε
Fig. 1. Electronic spectra of compounds 5 (1), and 7-12 (2-7).
log
ε
Fig. 2. Electronic spectra of compounds 6 (1) and 13-18 (2-7).
In the IR spectra of compounds 12-18 (Table 1) there were characteristic absorption bands for the N=N
group at 1410-1460 cm-1.
1
In the H NMR spectra of compounds 7-22 (Table 1) there were no signals for the 3-H protons of the
initial arylindoles. The values of the chemical shifts and the multiplicity of the remaining protons were in
1
accordance with the proposed structures of 7-22. In the H NMR spectra of the 3-formyl and 3-nitroso
derivatives 20 and 22 (Table 1) the signals of the bridge ethylene group were displayed as two triplets at 3.03,
3.01 and 2.96, 2.94 ppm respectively. In our opinion this is caused by the strong electron-withdrawing influence
of the formyl and nitroso groups leading to a reduction in the degree of shielding of the 1-CH2 group. A similar
picture was not observed in the remaining derivatives of this arylindole 7-18, 19, and 21, probably due to the
lower influence of the substituent in position 3.
831

TABLE 2. Characteristics of the Synthesized Compounds 5-22
Found, %
——————
Com-
Empirical
Yield, %
(color)
mp, °С,
Rf
Calculated, %
pound formula
C
H
N
С21H17N
89.1
6.10
6.00
4.80
4.90
151-152
204-205
132-133
82-83
0.38a
0.31a
0.59b
0.61c
0.54c
0.75d
0.55c
0.71e
0.58f
0.71b
0.74f
0.74d
0.51c
0.78d
0.85g
0.83g
0.73h
0.72h
25
5
89.00
(colorless)
C22H19N
88.8
6.40
4.80
38
6
88.9
6.40
4.70
(colorless)
С27H21N3
83.10
83.70
5.50
5.45
10.81
10.85
95
7
(orange)
C27H20ClN3
C27H20N4O2
C27H22N4O2S
C29H23N3O2
C28H21N3O2
C28H23N3
76.10
4.76
9.89
95
8
76.80
4.74
9.96
(orange)
74.90
75.00
4.60
4.62
13.10
12.96
249-250
171-172
190-191
241-242
131-132
124-125
261-262
200-201
180-181
248-249
179-180
211-212
220-221
259-260
95
9
(red)
69.48
4.80
11.97
90
10
11
12
13
14
15
16
17
18
19
20
21
22
69.53
4.74
12.01
(red)
77.90
78.20
5.38
5.16
9.41
9.43
85
(red)
78.00
4.84
9.80
89
77.96
4.87
9.74
(red)
83.81
83.79
5.68
5.70
10.39
10.47
95
(orange)
C28H22ClN3
C28H22N4O2
C28H24N4O2S
C30H25N3O2
C29H23N3O2
C22H17NO
C23H19NO
C21H16N2O
C22H18N2O
77.20
5.01
9.59
95
77.15
5.05
9.64
(orange)
75.12
75.33
4.97
4.93
10.72
10.76
95
(red)
69.90
5.01
9.95
90
70.00
5.00
10.00
(red)
78.61
78.43
5.25
5.41
9.21
89
9.15
(red)
78.40
5.11
8.12
8.09
85
78.20
5.16
(red)
88.89
88.88
5.71
5.72
4.70
70
4.72
(colorless)
88.73
6.12
4.50
4.52
75
88.74
6.11
(colorless)
80.77
80.76
5.13
5.11
8.97
95
8.98
(yellow)
80.98
5.52
8.58
8.57
96
80.97
5.53
(yellow)
_______
* Systems for chromatography: a) hexane–ether, 12 : 1; b) hexane–ether, 3 : 2;
c) benzene; d) benzene–ether, 1 : 1; e) benzene–ether, 1 : 3; f) benzene–
hexane, 1 : 3; g) benzene–acetone, 5 : 1; h) benzene–ether, 6 : 1.
EXPERIMENTAL
The IR spectra were recorded on a UR 20 instrument in nujol, the UV spectra on a Specord
spectrophotometer in ethanol, and the 1H NMR spectra on a Bruker AM 400 spectrometer, internal standard was
TMS. A check on the progress of reactions and the purity of compounds with determination of Rf values was
carried out on Silufol UV 254 plates.
2-(Diphenylmethan-4-yl)indole (5). A mixture of ketone 1 (2.12 g, 10 mmol), phenylhydrazine
hydrochloride (1.59 g, 11 mmol), and polyphosphoric acid (PPA) (40 g) was heated to 100°C and stirred for
30 min. The mixture was cooled and poured into water (150 ml). The solid was filtered off, washed with water
to pH 7, and dried. The product was recrystallized from heptane.
832

2-(Dibenzyl-4-yl)indole (6) was obtained analogously to compound 5 from ketone 2 (2.24 g, 10 mmol)
at 110°C.
General Method of Synthesis of 3-Arylazo Derivatives of 2-(Diphenylmethan-4-yl)indole and
2-(Dibenzyl-4-yl)indole (7-18). A solution of indole derivative 5 or 6 (1 mmol) in a mixture of isopropyl
alcohol (160 ml) and dioxane (60 ml) was cooled to 0°C and a solution obtained by diazotizing the aniline
derivative (4 mmol) was added dropwise, maintaining pH 6-7 by adding sodium acetate. The reaction mixture
was stirred at 0-5°C for 30 min and diluted with water (600 ml). The precipitated solid was filtered off, washed
with water, and dried.
2-(Diphenylmethan-4-yl)-3-formylindole (19). Phosphorus oxychloride (0.35 ml, 4 mmol) was added
dropwise during 30 min with stirring to cold freshly distilled dimethylformamide (2.3 ml, 30 mmol). The
solution obtained was stirred for 10 min at 20-25°C, cooled to 0°C, and a solution of 2-(diphenylmethan-4-yl)-
indole 5 (0.28 g, 1 mmol) in DMF (1 ml) was slowly introduced maintaining the temperature at 0-5°C. The
reaction mixture was stirred for 1 h at 40°C, crushed ice (4 g) was added, and then a 20% solution of sodium
hydroxide (15 ml) with vigorous stirring. The mixture was carefully heated to boiling and slowly cooled. The
precipitated solid was filtered off, washed with water to pH 7, and dried. The solid was recrystallized from
alcohol.
2-(Dibenzyl-4-yl)-3-formylindole (20) was obtained analogously to compound 19 from 2-(dibenzyl-4-
yl)indole 6 (0.32 g, 1 mmol).
2-(Diphenylmethan-4-yl)-3-nitrosoindole (21). Sodium nitrite (0.43 g, 5 mmol) was added to a
solution of indole 5 (0.28 g, 1 mmol) in glacial acetic acid (25 ml). The mixture was stirred at room temperature
for 30 min and poured into water (200 ml). The precipitated solid was filtered off, washed with water to pH 7,
and dried. The product was recrystallized from ethyl acetate.
2-(Dibenzyl-4-yl)-3-nitrosoindole (22) was obtained analogously to compound 21 from 2-(dibenzyl-4-
yl)indole 6 (0.32 g, 1 mmol).
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833