Indole derivatives. 142. Some properties of [4-(2-indolyl)phenyl] phenylmethane and 1-[4-(2-indolyl)phenyl]-2-phenylethane

Article abstract of DOI:10.1023/B:COHC.0000033533.33043.f9

The reactions of 2-arylindoles with strong electrophiles take place with significant resin formation. It was shown that electrophilic substitution is directed into the indole ring and into the side chain. 1,7-Migration of the substituent is observed in the investigated systems.

Full text of DOI:10.1023/B:COHC.0000033533.33043.f9

Chemistry of Heterocyclic Compounds, Vol. 40, No. 4, 2004
INDOLE DERIVATIVES. 142.* SOME PROPERTIES
OF [4-(2-INDOLYL)PHENYL]PHENYLMETHANE AND
1-[4-(2-INDOLYL)PHENYL]-2-PHENYLETHANE
I. Sh. Chikvaidze, Sh. A. Samsoniya, and T. G. Narindoshvili
The reactions of 2-arylindoles with strong electrophiles take place with significant resin formation. It
was shown that electrophilic substitution is directed into the indole ring and into the side chain.
1
,7-Migration of the substituent is observed in the investigated systems.
Keywords: arylindoles, rearrangement, nitration, N-alkylation.
Earlier [1] we reported on the synthesis of new 2-arylindoles and their reactions with weak electrophiles
(
azocoupling, formylation, and nitrosation), as a result of which the corresponding 3-substituted derivatives are
formed.
In the present communication we describe the nitration, bromination, alkylation, and 1,7-migration of
the substituent in these 2-arylindoles.
It is known that the nitration reaction of the simplest indoles is ambiguous on account of complications
caused by the strong acids used as components of the usual nitrating mixtures [2, 3].
For the nitration of [4-(2-indolyl)phenyl]phenylmethane (1) we used a KNO –H SO mixture at 0°C and
3
2
4
a Ac O–50% HNO mixture at 2-7°C. In both cases there was considerable resinification of the reaction mixture.
2
3
From the each obtained multicomponent mixtures we were able to isolate and characterize two compounds, i.e.,
2
, 3 and compounds 4 and 5, with yields of 18, 31, 19, and 39% respectively (Scheme 1).
In the strongly acidic medium the formation of the product from cleavage of the side chain of compound
can be explained by protonation of the nearest 2-phenyl ring, and this probably favors removal of the benzyl or
2
p-nitrobenzyl group. In a weakly acidic medium the reaction is characterized by higher selectivity. Substitution
in [4-(2-indolyl)phenyl]phenylmethane takes place at the positions of the indole ring that are rich in electron
density.
1
In the H NMR spectra of the three 5-nitro derivatives 2-4 there are signals characteristic of the 4-, 6-,
and 7-H protons of 5-substituted indole. We assigned doublets at 8.52 (compound 2), 8.51 (compound 3), and
8
.27 ppm (compound 4) with J = 2 Hz to the 4-H protons and doublets at 7.41 (compound 2), 7.53 (compound
m
3
), and 7.68 ppm (compound 4) with J = 8 Hz to the 7-H protons. The signals of the 6-H protons appear in the
o
form of quadruplets at 8.00 (2), 7.98 (3), and 7.89 ppm (4), while the signals of the 3-H protons appear in the
form of singlets at 7.20 (2), 7.21 (3), and 7.06 ppm (4). The analogous signal of the 3-H proton is absent in the
spectrum of compound 5. In the spectrum of compound 3 the presence of two pairs of doublets at 7.55, 8.16 and
at 7.40 and 7.84 ppm (J = 8 Hz), which we assigned to the protons of the 4,4'-disubstituted diphenylmethane,
o
_
*
_
______
For Communication 141, see [1].
_________________________________________________________________________________________
Iv. Javakhishvili Tbilisi State University, Tbilisi 0128, Georgia; e-mail: shsam@wanex.net. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 524-529, April, 2004. Original article submitted
February 24, 2003.
4
30
0009-3122/04/4004-0430©2004 Plenum Publishing Corporation

Scheme 1
O N
2
N
H
2
3
KNO3
O N
2
H SO4
2
CH2
NO2
N
H
CH2
N
H
1
O N
2
CH2
CH2
N
H
Ac O
2
4
HNO3
NO2
N
H
5
2
and also singlet signals for the NH and CH groups at 12.22 and 4.16 ppm respectively, confirms conclusively
the proposed structure. In the spectra of compounds 2, 4, and 5 there are multiplets for the terminal
monosubstituted phenyl rings (Table 1).
The alkylation of the indole 1 and 1-[4-(2-indolyl)phenyl]-2-phenylethane 6 was carried out by the
method described in [4] under the conditions of phase-transfer catalysis. During benzylation of the indole 1 the
1
,3-dibenzylation product 7 was unexpectedly obtained.
RX
(
CH2)n
Cat. / 50% KOH
N
H
1
, 6
R'
(
CH2)n
N
R
7
–9
Me, R' = H;
7
R = R' = CH
2
Ph; 8 R = CH
2
Ph, R' = H; 9 R = CH
2
CH
2
1
, 7, 9 n = 1, 6, 8 n = 2; X = Cl, Br
1
The H NMR spectrum of compound 7 does not contain a signal for the 3-H proton, and the signals for
the protons of the N–CH and 3-CH groups appear in the form of two singlets in the region of 5.23 and
2
2
3
.99 ppm respectively (Table 1).
In the mass spectrum of compound 7 maximum intensity is observed in the molecular ion peak at 464,
the fragmentation of which takes place with successive removal of the two benzyl groups.*
_
*
______
The m/z values are given with the relative intensities at the maximum ion current in parentheses.
4
31

TABLE 1. The Spectral Data of the Compounds
Com-
pound
IR spectrum,
ν, cm
UV spectrum,
λmax, nm (log ε)
1
-
1
Н NMR spectrum, δ, ppm
J, Hz
2
3400 (NH),
520, 1335
NO
207 (4.30),
230 (4.09) sh,
297 (4.40)
7.20 (1H, d, 3-H); 7.41 (1H, d, 7-H);
7.48-7.58 (3H, m, HPh); 7.98 (2H, d,
A-H); 8.00 (1H, dd, 6-H); 8.52 (1H,
d, 4-H); 12.21 (1H, s, NH)
J
J
J
46 = 2.00;
13 = 1.35;
67 = 7.20
1
(
2
)
3
3390 (NH),
510, 1340
NO
207 (4.50),
220 (4.00) sh,
300 (4.54)
4.16 (2H, s, CH
2
); 7.12 (1H, d, 3-H);
J
J
J
J
46 = 2.20;
13 = 1.37;
AB = 7.84;
A,B' = 8.72
1
(
7.40 (2H, d, B-H); 7.53 (1H, d, 7-H);
7.55 (2H, d, A'-H); 7.84 (2H, d,
A-H); 7.98 (1H, dd, 6-H);
2
)
8
1
.16 (2H, d, B'-H); 8.51 (1H, d, 4-H);
2.22 (1H, s, NH)
4
5
7
3395 (NH),
525, 1345
NO
210 (4.61),
257 (4.41),
377 (4.21)
4.01 (2H, s, CH
2
); 7.06 (1H, d, 3-H);
J
J
J
J
46 = 1.90;
67 = 8.80;
AB = 8.22;
13 = 1.48
1
(
7.24-7.31 (5H, m, HPh'); 7.38 (1H, d,
B-H); 7.68 (1H, d, 7-H); 7.84 (1H, d,
A-H); 7.89 (1H, d, 6-H); 8.27 (1H, d,
2
)
4
-H); 12.21 (1H, s, NH)
12.66 (1H, s, NH); 8.21 (1H, d, 4-H);
4.05 (2H, s, CH ); 7.30-7.43 (10H,
m, 5-, 7-, 13-H, HPh');
3400 (NH),
515, 1337
NO
209 (4.95),
261 (4.61),
333 (4.47)
J
AB = 8.20
1
2
(
2
)
7
1
.67 (2H, d, A-H); 8.21 (1H, d, 4-H);
2.66 (1H, s, NH)
—
213 (4.51),
7.36 (1H, d, 4-H); 6.96 (1H, dt,
5-H); 7.07 (1H, dt, 6-H); 7.32 (1H,
d, 7-H); 7.17 (2H, d, A-H); 6.83 (2H,
J
J
J
o
= 7.96;
= 0.88;
2
3
27 (4.52),
01 (4.16)
m
AB = 7.92
2
d, B-H); 5.29 (2H, s, N–CH );
7
3
.08-7.33 (15H, m, HPh', HPh'', HPh''');
.99 (2H, s, C(3)–CH
2
); 3.98 (2H, s,
CH
3.05 (4H, s, CH
N–CH ); 6.74 (1H, s, 3-H); 7.14 (2H,
d, B-H); 7.22-7.41 (13H, m, 5-, 7-H,
Ph', HPh''); 7.46 (2H, d, A-H);
7.77 (1H, dd, 4-H)
0.64 (3H, t, CH ); 1.56 (2H, sextet,
CH ); 4.02 (2H, s, CH ); 4.13 (2H, t,
N–CH ); 6.46 (1H, s, 3-H); 7.03 (1H,
t, 5-H); 7.14 (1H, t, 6-H);
.17-7.53 (5H, m, HPh'); 7.36 (2H, d,
B-H); 7.45 (2H, d, A-H); 7.50 (1H, d,
-H); 7.53 (1H, d, 4-H)
2.93 (4H, s, CH CH ); 4.32 (2H, s,
); 6.80 (1H, d, 6-H); 6.84
(1H, d, 3-H); 6.91 (1H, t, 5-H);
2
)
8
9
—
—
214 (4.55),
2
CH
2
), 5.47 (2H, s,
J
J
J
AB = 8.40;
45 = 8.40;
46 = 2.0
2
2
2
3
18 (4.52) sh,
27 (4.64),
41 (4.51) sh,
00 (4.44)
2
H
209 (4.58),
3
J
J
J
67 = 7.92;
AB = 7.96;
45 = 1.32
2
2
2
22 (4.53) sh,
38 (4.37) sh,
97 (4.26)
2
2
2
7
7
1
4
3410 (NH)
210 (4.61),
2
2
J
J
J
J
45 = 7.52;
13 = 2.24;
56 = 7.08;
AB = 8.40
2
3
49 (4.33),
11 (4.39)
C(7)–CH
2
7
7
1
.15-7.33 (12H, m, B-H, HPh', HPh'');
.36 (1H, d, 4-H); 7.83 (2H, d, A-H);
1.09 (1H, s, NH)
–
PhCH Ph
–
PhMe
92
2
–CH Ph
+
2
M
464 (34)
204 (3.85)
113 (2.32)
3
72 (4.05)
–
–168
–91
–
CN
1
78 (4.89)
–
26
During propylation of the same arylindole 1 with propyl bromide under analogous conditions a single
reaction product, [4-(1-propyl-2-indolyl)phenyl]phenylmethane (9), was obtained.
Alkylation of the 2-arylindoles 1 and 6 with benzyl chloride under Friedel–Crafts conditions led to
complete resinification of the reaction mixture.
4
32

In both cases bromination with dioxane dibromide in dioxane gave complex mixtures of products.
Earlier we reported that when a mixture of N-benzylphenylhydrazine and certain ketones was heated in
polyphosphoric acid the corresponding N-unsubstituted indoles and their 7-benzyl derivatives were formed
instead of the expected 2-substituted N-benzylindoles [5, 6]. We obtained a similar result during the synthesis of
the N-benzyl derivatives 8 and 12.
O
Me
C
Me
C
R + Ph
N
NH2
Ph
N
N
R
CH Ph
CH Ph
1
0, 11
2
2
R
R
1, 6
+
N
H
N
CH Ph
CH Ph
2
2
8
, 12
1
3, 14
1
0, 12, 13 R = C Н CH Ph; 8, 11, 14 R = C H (CH ) Ph
6
4
2
6
4
2 2
Compounds 6 and 14 were likewise obtained when 1-[4-(N-benzyl-2-indolyl)phenyl]-2-phenylethane
was treated in polyphosphoric acid at 125°C, indicating 1,7-migration of the substituent.
In the IR spectrum of the 7-benzyl derivative 14 there is a band characteristic of the indole NH group in
-
1
the region of 3410-3430 cm , which is absent in the spectrum of the corresponding N-benzyl derivative 8.
(CH2)2
N
H
6
8
(CH2)2
N
H
CH Ph
2
14
1
The position to which the benzyl group migrates was established by comparing the H NMR spectra of
the N-benzyl derivative 8 and the product from migration of the benzyl group 14 (Table 1). In particular, the
spectrum of 1-[4-(1-benzyl-2-indolyl)phenyl]-2-phenylethane (8) does not contain a signal for the 1-H proton. A
signal in the form of a doublet of doublets at 7.77 ppm can be assigned to the 4-H proton, while the signals for
the 5-, 6-, and 7-H protons are included in the multiplet at 7.22-7.41 ppm.
1
In the H NMR spectrum of 1-[4-(7-benzyl-2-indolyl)phenyl]-2-phenylethane (14) a signal for 1-H
appears at 11.09 ppm, while the signal of the 7-H proton disappears. The signal for 6-H appears at 6.80 ppm in
the form of a doublet, the signal for 5-H appears at 6.91 ppm in the form of a triplet, and the signal for 4-H
appears at 7.36 ppm in the form of a doublet. In addition, for compounds 8 and 14 there are signals in the form
of two doublets characteristic of the A-H and B-H protons of p-disubstituted benzenes, singlets for the bridging
group (CH CH ), and signals for the protons of the benzyl group. In the mass spectrum of compound 14
2
2
maximum intensity is observed in the peak of the molecular ion at 387.
4
33

TABLE 2. The Characteristics of the Compounds
Found, %
Calculated, %
H
M,
Com-
pound
Empirical
formula
——————
Yield,
%
Found, %
R
f
*
mp, °С
——————
C
N
Calculated, %
2
3
4
5
7
8
9
C
C
C
C
C
C
C
C
14
21
21
21
35
29
24
29
H
10
H
15
H
16
H
16
H
29
H
25
H
23
H
25
N
2
N
3
N
2
N
2
N
N
N
N
O
2
O
4
O
2
O
2
70.71
4.38
4.20
4.21
4.02
4.72
4.88
4.69
4.88
6.12
6.26
6.22
6.46
7.23
7.08
6.37
6.46
11.61
11.76
11.22
11.26
8.32
8.54
8.65
8.54
3.18
3.02
3.45
3.62
4.22
4.31
3.48
3.62
238
238
373
373
328
328
328
328
463
463
387
387
—
325
0.46
0.41
0.64
0.35
0.58
0.50
0.50
0.56
194-195
218-219
157-158
167-168
129-130
114-115
97-98
19
31
19
39
45
47
49
7
0.59
67.68
7.56
6
76.91
6.83
7
76.95
6.83
7
90.08
0.71
9
89.72
9.92
8
88.41
8.62
8
2
1
4
89.95
9.92
387
387
139-140
*
8
_
*
______
System for chromatography: hexane–ether, 1:1 (compounds 2-5);
benzene–hexane, 1:3 (compounds 7 and 8); heptane (compound 9);
hexane–ether, 6:1 (compound 14).
2
*
Yield 6% (by method B) and 18% (by method A).
EXPERIMENTAL
The IR spectra were recorded in Vaseline oil on a UR-20 instrument. The UV spectra were obtained in
1
ethanol on a Specord spectrometer. The H NMR spectra were obtained on a Bruker AM-400 spectrometer at
4
00 MHz with TMS as internal standard. The mass spectra were obtained on an MS-Varian, Mat-311, EL-MS
spectrometer at 70 eV.
The reactions and the purity of the compounds were monitored and the R values were determined on
f
Silufol UV-254 plates.
-Nitro-2-phenylindole (2) and [4-(5-Nitro-2-indolyl)phenyl](4-nitrophenyl)methane (3). A
5
solution of potassium nitrate (0.44 g, 5.2 mmol) in sulfuric acid (5 ml) was slowly added dropwise to a
suspension of [4-(2-indolyl)phenyl]phenylmethane (0.2 g, 0.7 mmol) in sulfuric acid (10 ml), cooled to -2°C,
while keeping the temperature at 0°C. The reaction mixture was stirred for 5 min and poured onto crushed ice
(
100 g). The product was extracted with ethyl acetate, and the extract was washed with an aqueous solution of
sodium carbonate and with water and dried with sodium sulfate. The mixture was separated on a column of
silica gel with 6:1 hexane–ether as eluent. We isolated 0.03 g of compound 2 and 0.082 g of compound 3 in the
form of yellow crystals.
[
4-(5-Nitro-2-indolyl)phenyl]phenylmethane (4) and [4-(3-Nitro-2-indolyl)phenyl]phenylmethane
5). 50% Nitric acid (0.07 ml, 1.4 mmol) and then a solution of [4-(2-indolyl)phenyl]phenylmethane (1) (0.19 g,
.67 mmol) in acetic anhydride (5-7 ml) were added dropwise to acetic anhydride (25 ml), cooled to 0°C, while
(
0
keeping the temperature at 0°C. The reaction mixture was stirred at 5-7°C for 30 min, poured onto ice (100 g),
and extracted with ether. The extract was washed with an aqueous solution of sodium carbonate and with water
and dried with sodium sulfate. The mixture was separated on a column of silica gel (hexane–ether, 4:1). We
isolated 0.04 g of compound 4 and 0.85 g of compound 5 in the form of yellow crystals.
4
34

[
4-(1,3-Dibenzyl-2-indolyl)phenyl]phenylmethane (7). To a solution of the indole 1 (0.28 g, 1 mmol)
in benzene (30 ml) we added a 50% aqueous solution of potassium hydroxide (5 ml), tetrabutylammonium
bromide (0.035 g), and benzyl chloride (0.63 g, 5 mmol). The mixture was stirred at 60°C for 4 h, cooled, diluted
with water, and extracted with benzene. The extract was washed with water and dried with sodium sulfate. The
mixture was separated on a column of silica gel (heptane). We isolated 0.21 g of compound 7 in the form of
colorless crystals.
1
-[4-(1-Benzyl-2-indolyl)phenyl]-2-phenylethane (8). This compound was obtained by the method
described for compound 7 from 1-[4-(2-indolyl)phenyl]-2-phenylethane (6) (0.30 g, 1 mmol) and benzyl
chloride (0.63 g, 5 mmol). We isolated 0.18 g of compound 8 as colorless crystals.
[
4-(1-Propyl-2-indolyl)phenyl]phenylmethane (9). This compound was obtained by the method
described for compound 7 from the indole 1 (0.28 g, 1 mmol) and propyl bromide (0.62 g, 5 mmol). We isolated
.16 g of compound 9 in the form of colorless crystals.
-[4-(2-Indolyl)phenyl]-2-phenylethane (6) and 1-[4-(7-Benzyl-2-indolyl)phenyl]-2-phenylethane
0
1
(
14). A. A mixture of 4-acetyldiphenylmethane (11) (2.24 g, 10 mmol), N-benzylphenylhydrazine hydrochloride
(
2.57 g, 10 mmol), and polyphosphoric acid (50 g) was stirred at 100-110°C for 45 min. The mixture was cooled
and poured as a thin stream into water (200 ml). The product was extracted with ether, and the extract was
washed with water and dried. The mixture was separated on a column of silica gel (heptane–ether, 50:1). We
isolated 0.7 g (18%) of compound 14 and 1.18 g (40%) of compound 6 in the form of colorless crystals.
B. A mixture of compound 8 (0.15 g, 0.3 mmol) and polyphosphoric acid (7 ml) was stirred at 125°C for
3
0 min. The mixture was cooled and poured into water (30 ml). The precipitate was filtered off, washed with
water, and dried. The mixture was separated on a column of silica gel (heptane–ether, 20:1). We isolated 0.16 g
6%) of compound 14 in the form of colorless crystals.
(
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.
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3
4
.
.
.
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6
.
.
Sh. A. Samsoniya, I. Sh. Chikvaidze, and E. O. Gogrichiani, Khim. Geterotsikl. Soedin., 1146 (1994).
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4
35