A novel and efficient method for the synthesis of unsymmetrical diindolylmethanes and heterocyclic(indolyl)alkanes

Article abstract of DOI:10.1055/s-2008-1067217

3-Alkylated indoles, obtained from a three-component reaction of indole, aldehyde, and N,N-dimethylbarbituric acid, undergo an elimination-addition reaction with another indole molecule or heterocyclic nucleophile giving unsymmetrical diindolylmethanes or heterocyclic(indolyl)alkanes in the absence of a catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067217

PAPER
2891
A Novel and Efficient Method for the Synthesis of Unsymmetrical
Diindolylmethanes and Heterocyclic(indolyl)alkanes
Synthesis of
Diindolyl
o
and
H
eteroc
h
yclic(indoly
i
l)metha
t
ne
s
L. Deb, Pulak J. Bhuyan*
Medicinal Chemistry Division, North East Institute of Science & Technology (Formerly RRL), Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 2 April 2008; revised 6 May 2008
workers13 reported the synthesis of unsymmetrical 3,3¢-di-
indolylmethanes from the reaction of indoles with (1H-in-
dol-3-yl)(alkyl)methanols catalyzed by ammonium
cerium(IV) nitrate and ultrasound. Although the yields of
Abstract: 3-Alkylated indoles, obtained from a three-component
reaction of indole, aldehyde, and N,N-dimethylbarbituric acid, un-
dergo an elimination–addition reaction with another indole mole-
cule or heterocyclic nucleophile giving unsymmetrical
diindolylmethanes or heterocyclic(indolyl)alkanes in the absence of the products were good, the reaction took a long time to
go to completion. Recently Csaky and co-workers14 have
a catalyst.
synthesized unsymmetrical 3,3¢-diindolylmethanes from
gramine using an expensive catalyst, moreover, the proce-
dure was operationally difficult.
Key words: unsymmetrical diindolylmethanes, indole, 3-alkylated
indole, anticancer
OH
OH
3,3¢-Diindolylmethane (DIM) is a major digestive product
of indole-3-methanol, a potential anticancer component of
cruciferous vegetables.1 3,3¢-Diindolylmethane is a potent
activator of the immune response system in vivo.2 It acti-
vates and potentiates interferon-gamma signaling in hu-
man cells3 and its use as supplement in human increases
the 2-hydroxylation of estrogen metabolites.4 It reduces
the growth of breast cancer cells by 95%.5 3,3¢-Diindolyl-
methane exhibits potent antiproliferative and antiandro-
genic properties in androgen-dependent human prostate
cancer cells.6 Its various potent anticancer properties have
lead to the National Cancer Institute of the United States
beginning clinical trials of 3,3¢-diindolylmethane as a
therapeutic for numerous forms of cancer. Recently it was
found that 3,3¢-diindolylmethane A (Figure 1) worked as
HIV-1 integrase inhibitor.7 Vibrindole A, a metabolite of
the marine bacterium Vibrio parahaemolyticus (isolated
from the toxic mucus of the boxfish Ostracion cubicus),
has been demonstrated to exhibit antibacterial activity.8
Compound C has growth inhibitory activity on prostate
cancer cell lines.9 Compound D was reported to act as a
nonsteroidal aromatase inhibitor against breast cancer.10
Me
N
H
N
H
N
H
N
H
[A]
Vibrindole A
[B]
Me Me
CO2Et
EtO2C
N
N
N
H
H
[C]
N
Br
N
F
Et
[D]
Figure 1
Recently we reported15 the synthesis of some novel 3-
alkylated indoles utilizing equimolar amounts of indole,
aldehyde, and N,N-dimethylbarbituric acid in one pot un-
der thermal and solvent-free conditions. In the reaction we
also observed the formation of small amounts of di-
indolylmethanes for which a mechanism was proposed.
That interesting observation encouraged us to explore the
utility of the reaction for the preparation of unsymmetrical
diindolylmethanes 3 from the reaction of 3-alkylated in-
doles 1 and indoles 2 (Scheme 1).
Symmetrical diindolylalkanes can readily be synthesized
by Lewis or protic acid catalyzed indole–aldehyde con-
densation reactions,11 but the synthesis of unsymmetrical
3,3¢-diindolylmethanes have a number of drawbacks and
limitations.12 Vallee and co-workers12a reported the first
synthesis of unsymmetrical 3,3¢-diindolylmethanes, but
the procedure was complex. Chakrabarty et al.12b reported
another method for the preparation of such 3,3¢-diindolyl-
methanes through the Michael reaction of 3-(2-nitrovi-
nyl)indole with indoles. However, the method was limited
to 2,2-bis(indol-3-yl)-1-nitroethane derivatives. Ji and co-
The 3-alkylated indoles 1 were prepared from the reaction
of indoles, aldehydes, and N,N-dimethylbarbituric acid.15
Then equimolar amounts of 3-alkylated indole 1a and in-
dole 2a were refluxed in ethanol–water for 30 minutes to
afford, after workup, diindolylmethane 3a in excellent
SYNTHESIS 2008, No. 18, pp 2891–2898
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.08.2008
DOI: 10.1055/s-2008-1067217; Art ID: P04708SS
© Georg Thieme Verlag Stuttgart · New York

2892
M. L. Deb, P. J. Bhuyan
PAPER
H
O
R
+
R2
O
R2
O
R1
R1
Me
N
R3
Me
N
N
O
N
O
N
O
H
N
O
H
N
H
Me
1
H
Me
O
1
R
2
∆
R3
EtOH–H2O
R2
R1
N
H
via SN2 reaction
2
R2
N
H
O
R3
R1
O
R
Me
O
N
+
via elimination–addition
N
H
N
H
O
N
R2
O
Me
R3
R1
3
Me
N
4
+
Scheme 1
N
N
H
N
O
O
H
Me
yield. The N,N-dimethylbarbituric acid (4) eliminated
during the reaction was isolated and identified. With suit-
able conditions established for the reaction, compounds
3b–o were synthesized by utilizing various 3-alkylated in-
doles 1a–i with indoles 2a–f and characterized (Table 1).
3
4
Scheme 2
nonbenzenoid canonical form whereas in case of 3-alky-
lated indoles the intermediate retained the aromaticity of
the benzene ring. When unsubstituted (indol-3-ylmeth-
yl)barbituric acid derivative 1j was used (Table 1, entry
16), the reaction did not occur, as the barbituric acid moi-
ety could not be eliminated even after an extended period
of reflux. This can reasonably be explained by the fact that
unlike aromatic aldehydes and aliphatic aldehydes con-
taining an a-hydrogen, the intermediate is not stabilized
by either resonance or hyperconjugation. This fact strong-
ly supports our proposed mechanism. Thus the reactivity
is in the order of R2 = aromatic > aliphatic > hydrogen.
The reactions were then studied in various other solvents
(e.g., MeOH, MeCN, toluene, CHCl3 etc.) and also in the
absence of solvent, however, the reactions proceeded
smoothly only in methanol. A few drops of water to the re-
action mixture accelerated the reaction considerably with
improved yields of the products.
We also studied the effect of substituents in the phenyl
(R2), indole (R1), and barbituric acid moiety. It was found
that an electron-donating group on the phenyl ring accel-
erated the reactions. 5-Bromo-1H-indole and 1-methyl-
1H-indole had least reactivity. When 3-alkylated indoles
1 bearing barbituric acid (instead of N,N-dimethylbarbitu-
ric acid) were used, the products were obtained easily with
a shorter reaction time. However, it is very difficult to pre-
pare substrates, the 3-alkylated indoles bearing barbituric
acid, due to their very low solubility.
Compounds like 3a and 3b were also synthesized easily
by the reverse process that is from the reaction of 1d,e
(where the indole moiety contains a methyl group at the 2-
or 5-position) with indole (acting as a nucleophile). How-
ever, the preparation of compounds 1 of this type is very
difficult because the elimination–addition process is so
fast that it gives symmetrical diindolylmethanes (in case
of 5- or 2-methylindole) as the major compound.
A plausible mechanism for the reaction is outlined in
Scheme 2. The mechanism is an elimination–addition
mechanism. First the barbituric acid moiety eliminates
from the 1 and then the indole molecule (nucleophile) at-
tacks the C=C–C=N system of the intermediate 3-alky-
lidene-3H-indolium giving the desired diindolylmethane.
The rate enhancement of the reaction in protic solvents is
due to the coordination of the solvent to the nitrogen atom
of the intermediate, which makes it more electrophilic to-
wards the nucleophile. The protic solvent also helps in the
elimination process of barbituric acid making it a good
leaving group by loose coordination with the carbonyl ox-
ygen.
In order to broaden the scope of this reaction, the reactiv-
ity of 1a with other heterocyclic nucleophiles 5a–e were
also studied and this gave a series of heterocyclic(in-
dolyl)alkane derivatives 6a–e in satisfactory yields
(Table 2). The structures of the compounds were deter-
mined from spectroscopic data and elemental analysis.
Thus, the reaction of 1a and 5a in refluxing ethanol–water
1
gave 6a in 85% yield in 30 minutes. The H NMR spec-
trum of compound 6a shows the chemical shift for the me-
thyl protons attached to the pyrazolone ring at d = 2.36
and for the NH proton of the indole moiety at d = 9.55.
The mass spectrum (HRMS) shows molecular ion peak at
380.1654 [M + H]+.
Longer reaction times were required for 2-alkylated in-
dole 1h (Table 1, entries 13 and 14) as in this cases the ni-
trogen in the intermediate could interact only via a
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

PAPER
Synthesis of Diindolyl- and Heterocyclic(indolyl)methanes
2893
Table 1 Synthesis of Unsymmetrical Diindolylmethanes 3
Entry
1
2
Producta 3
Time
(min)
Yieldb
(%)
Ph
O
Ph
Me
N
N
N
N
1
30
82
82
61
72
62
75
63
88
Me
N
H
N
H
N
O
O
N
H
N
H
Me
Ph
2a
Me
3a
1a
1a
1a
1a
Ph
O
Me
Me
Me
2
3
4
5
6
7
8
30
55
85
55
30
30
30
N
N
H
N
O
O
H
N
H
N
H
2b
2c
Me
3b
Ph
Ph
O
Me
N
N
H
N
N
O
O
N
H
Me
Me
Me
3c
Ph
O
Ph
Me
H
N
Me
N
H
N
H
N
O
O
N
H
Me
Ph
Me
2d
3d
Ph
O
Br
Me
Br
N
N
H
N
H
N
O
O
N
H
N
H
2e
2a
Me
3e
1a
1b
4-Tol
O
4-Tol
Me
Me
N
Me
N
H
N
H
N
O
O
N
H
N
H
Me
3f
(4-NO2)H4C6
C6H4(4-NO2)
O
Me
N
Me
N
H
N
N
O
O
N
N
H
Me
H
H
2a
2a
Me
3g
1c
Ph
O
Ph
Me
Me
Me
N
Me
N
H
N
N
O
O
N
N
Me
H
H
H
Me
3h
1d
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

2894
M. L. Deb, P. J. Bhuyan
PAPER
Table 1 Synthesis of Unsymmetrical Diindolylmethanes 3 (continued)
Entry
1
2
Producta 3
Time
(min)
Yieldb
(%)
Ph
O
O
Ph
Me
H
Me
N
N
9
75
50
65
80
70
67
55
48
N
H
N
H
N
O
Me
Me
N
H
Me
2d
2a
Me
3i
1e
Ph
O
Ph
Br
Me
Br
N
10
11
12
Me
N
H
N
H
N
O
O
N
H
N
Me
Ph
H
Me
3j
1f
Ph
O
Br
Br
Me
N
N
N
N
H
N
O
O
N
H
Me
Me
Me
2c
2a
3k
1f
Ph
O
Ph
O
Me
N
Me
N
H
N
H
N
N
O
N
Me
Me
Me
Me
3l
1g
1h
1h
Me
N
H
N
Me
Me
O
O
13
14
90
90
58
66
N
N
H
N
H
N
H
Me
4-Tol
4-Tol
O
2f
3m
Me
N
Me
Me
H
N
Me
O
O
N
Me
N
H
N
H
N
H
Me
4-Tol
Me
4-Tol
Me
O
O
2a
3n
Me
O
N
15
16
60
75
Me
N
H
N
H
N
O
N
H
N
H
Me
2a
2f
Me
3o
1i
1j
O
Me
O
N
–
–
–
N
H
N
H
N
O
Me
a All reactions were performed on a 1 mmol scale.
b Isolated yields.
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

PAPER
Synthesis of Diindolyl- and Heterocyclic(indolyl)methanes
2895
NMR and 13C NMR spectra were recorded on Bruker Avance-DPX
300 MHz and 75 MHz FT NMR in CDCl3 using TMS as an internal
standard. LR-MS were recorded in Bruker Daltonics ESQUIRE
3000 LC ESI ion trap mass spectrometer and HRMS were obtained
with a MALDI-TOF instrument. Elemental analyses were per-
formed on Perkin Elmer-2400 spectrometer. Analytical TLC and
column chromatography were performed using E. Merck alumi-
num-backed silica gel plates coated with silica gel G and E. Merck
silica gel (100–200 mesh); petroleum ether = PE. Melting points
(uncorrected) were determined on a Buchi B-540 apparatus.
Table 2 Synthesis of (Heterocyclic)(indolyl)alkanes from [(Indol-
3-yl)(phenyl)methyl]barbituric Acid Derivative 1a and Various Nu-
cleophiles
Entry Nucleophile 5
Producta 6
Time Yieldb
(h) (%)
Ph
Me
Me
N
1
0.5 85c
O
N
N
N
O
Indole, aldehydes, and substituted barbituric acids were purchased
from Aldrich Chemical Co. and other commercially available re-
agents were used without further purification.
N
H
Ph
Ph
5a
6a
Ph
H
N
Diindolylmethanes 3; General Procedure
Equimolar amounts of 3-alkylated indole 1 (1 mmol) and indole 2
(1 mmol) were added to a round-bottomed flask containing EtOH–
H2O (9:1, 6 mL) and refluxed for the time indicated in Table 1. The
solvent was then removed under reduced pressure and the desired
product 3 separated by column chromatography (15% EtOAc–PE);
in some instances crystalline product appeared and filtration only
gave the pure product.
2
3
1
45
N
H
N
H
5b
6b
Ph
O
O
N
Me
O
Me
N
N
1.5 50
3-[(1H-Indol-3-yl)(phenyl)methyl]-2-methyl-1H-indole (3a)
White shining crystals; yield: 275 mg (82%); mp 221–222 °C; Rf =
0.75 (15% EtOAc–PE).
H2N
N
N
H
O
H2N
Ph
Me
Me
5c
6c
IR (KBr): 3413 (NH stretch), 3394 (NH stretch), 3054 (w), 2928
(w), 1459 (s), 1353 (m), 744 (s), 700 cm–1 (m).
1H NMR (300 MHz, DMSO-d6): d = 2.24 (s, 3 H), 5.91 (s, 1 H), 6.68
(s, 1 H), 6.83–6.85 (d, J = 7.38 Hz, 1 H), 6.91–7.02 (m, 2 H), 7.11–
7.17 (q, J = 7.35 Hz, 3 H), 7.22–7.27 (m, 5 H), 7.63 (s, 1 H), 7.83
(s, 1 H), 9.39 (s, 1 H, NH), 9.48 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 14.11, 44.91, 112.44, 115.62,
116.22, 122.48, 123.25, 123.98, 124.53, 124.70, 126.01, 126.25,
127.33, 129.12, 131.65, 133.47, 133.61, 133.83, 134.55, 139.95,
140.72, 141.66.
N
4
5
1
40
N
H
N
N
H
N
H
5d
6d
Ph
O
O
O
OH
O
2.5 48c
HRMS: m/z [M + H]+ calcd for C24H20N2: 337.1628; found:
337.1613.
O
N
H
5e
6e
a All reactions were performed on a 1 mmol scale.
b Isolated yields.
3-[(1H-Indol-3-yl)(phenyl)methyl]-5-methyl-1H-indole (3b)
Light brown powder; yield: 275 mg (82%) ; mp 98–101 °C; Rf =
0.74 (15% EtOAc–PE).
c In both cases we obtained a single isomer.
IR (CHCl3): 3407 (NH stretch), 3398 (NH stretch), 3055 (w), 2928
(w), 1456 (s), 1351 (m), 744 (s), 701 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 2.49 (s, 3 H), 5.90 (s, 1 H), 6.66
(s, 1 H), 6.69 (s, 1 H), 6.91–7.0 (m, 3 H), 7.14–7.26 (m, 4 H), 7.35–
7.43 (m, 5 H), 7.83 (s, 1 H, NH), 7.91 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 15.45, 44.93, 113.31, 115.88,
116.27, 122.55, 123.71, 123.98, 124.53, 124.72, 126.01, 126.31,
127.56, 129.12, 131.61, 133.47, 133.69, 133.86, 134.56, 139.95,
140.80, 141.67.
In conclusion, we have reported a very simple, novel, and
efficient method for the synthesis of unsymmetrical di-
indolylmethanes and some (heterocyclic)(indolyl)alkanes
in moderate to excellent yields. It is interesting to note that
no catalyst is required in the entire course of the reaction.
The effect of solvents in the reaction was studied and pro-
tic solvents were found most suitable for the reaction.
Moreover, all the reactions proceed smoothly in aqueous
ethanol and do not require anhydrous conditions. The
eliminated N,N-dimethylbarbituric acid, is an inexpen-
sive, nontoxic compound and can be recycled. The pre-
sented method for the preparation of this important class
of diindolylmethanes, which is much superior to the exist-
ing methods, is a valuable addition to the chemistry of in-
doles.
HRMS: m/z [M + H]+ calcd for C24H20N2: 337.1628; found:
337.1639.
3-[(1H-Indol-3-yl)(phenyl)methyl]-1-methyl-1H-indole (3c)
White powder; yield: 205 mg (61%); mp 187–188 °C; Rf = 0.81
(15% EtOAc–PE).
IR (CHCl3): 3410 (NH stretch), 3055 (w), 2919 (w), 1456 (s), 1013
(m), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 3.50 (s, 3 H), 5.77 (s, 1 H), 6.38
(s, 1 H), 6.46 (s, 1 H), 6.86–6.91 (t, J = 7.65 Hz, 3 H), 7.02–7.18 (m,
5 H), 7.22–7.29 (m, 4 H), 7.42 (s, 1 H), 8.25 (s, 1 H, NH).
All chemicals including solvent used for reactions without drying.
All reagents and solvents were of reagent grade. All IR spectra were
recorded on Perkin Elmer system-2000 FTIR spectrometer. H
1
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

2896
M. L. Deb, P. J. Bhuyan
PAPER
13C NMR (75 MHz, CDCl3): d = 33.20, 40.68, 109.70, 111.61,
118.64, 119.22, 119.75, 120.26, 120.48, 120.60, 122.02, 122.43,
124.22, 126.67, 127.59, 127.99, 128.80, 128.85, 129.28, 137.17,
137.95, 141.79.
3 H), 7.14–7.29 (m, 5 H), 7.36–7.39 (d, J = 8.1 Hz, 2 H), 8.06 (s, 1
H, NH), 8.09 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.78, 44.27, 115.33, 116.25,
117.63, 122.22, 124.00, 124.35, 124.45, 124.61, 126.11, 126.29,
127.29, 128.44, 128.94, 131.97, 132.86, 134.51, 136.69, 140.19,
141.54, 147.94.
MS: m/z = 335.5 [M – H]+.
2-[(1H-Indol-3-yl)(phenyl)methyl]-3-methyl-1H-indole (3d)
Pink powder; yield: 242 mg (72%); mp 194–195 °C; Rf = 0.77 (15%
EtOAc–PE).
HRMS: m/z [M + H]+ calcd for C24H19N3O2: 382.4102; found:
382.4126.
IR (CHCl3): 3417 (NH stretch), 3409 (NH stretch), 3055 (w), 2923
(w), 1456 (s), 744 cm–1 (s).
2-Methyl-3-[(5-methyl-1H-indol-3-yl)(phenyl)methyl]-1H-in-
dole (3h)
White solid; yield: 308 mg (88%); mp 217–218 °C; Rf = 0.74 (15%
EtOAc–PE).
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 5.91 (s, 1 H), 6.64
(s, 1 H), 7.08–7.17 (m, 4 H), 7.21–7.33 (m, 4 H), 7.55–7.58 (d,
J = 7.42 Hz, 3 H), 7.85 (s, 2 H), 8.09 (s, 1 H, NH), 8.18 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.59, 45.37, 112.36, 115.69,
116.22, 122.36, 123.28, 123.99, 124.59, 124.72, 126.01, 126.28,
127.32, 129.03, 131.66, 133.49, 133.55, 133.84, 134.55, 139.96,
140.71, 141.62.
IR (KBr): 3410 (NH stretch), 3387 (NH stretch), 3057 (w), 2929
(w), 1456 (s), 743 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 2.48 (s, 3 H), 5.91
(s, 1 H), 6.66 (s, 1 H), 6.97–7.0 (d, J = 7.33 Hz, 2 H), 7.08–7.13 (t,
J = 7.91 Hz, 3 H), 7.24–7.32 (m, 4 H), 7.35–7.42 (m, 3 H), 8.11 (s,
1 H, NH), 8.24 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.37, 20.41, 42.54, 109.78,
111.13, 114.27, 116.44, 119.20, 122.49, 124.39, 124.71, 126.10,
126.44, 127.29, 128.47, 128.99, 132.12, 132.80, 134.51, 136.64,
138.11, 140.19, 141.34.
MS: m/z = 337.9 [M + H]+.
5-Bromo-3-[(1H-indol-3-yl)(phenyl)methyl]-1H-indole (3e)
White powder; yield: 248 mg (62%); mp 161–163 °C; Rf = 0.71
(15% EtOAc–PE).
IR (CHCl3): 3410 (NH stretch), 3393 (NH stretch), 3056 (w), 2921
(w), 1456 (s), 1159 (m), 744 cm–1 (s).
MS: m/z = 351.8 [M + H]+.
2-Methyl-3-[(3-methyl-1H-indol-2-yl)(phenyl)methyl]-1H-in-
dole (3i)
Pink powder; yield: 245 mg (70%); mp 175–177 °C; Rf = 0.78 (15%
EtOAc–PE).
1H NMR (300 MHz, CDCl3): d = 5.76 (s, 1 H), 6.49–6.50 (d,
J = 3.38 Hz, 2 H), 6.95–6.99 (t, J = 6.90 Hz, 2 H), 7.06–7.13 (m, 3
H), 7.16–7.26 (m, 3 H), 7.44–7.47 (d, J = 8.51 Hz, 2 H), 7.72 (s, 2
H), 8.39 (s, 1 H, NH), 8.57 (s, 1 H, NH).
IR (KBr): 3416 (NH stretch), 3404 (NH stretch), 3058 (w), 2928
(w), 1456 (s), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H), 2.29 (s, 3 H), 5.89
(s, 1 H), 6.87–6.90 (d, J = 7.18 Hz, 2 H), 7.08–7.18 (m, 5 H), 7.26–
7.29 (t, J = 7.44 Hz, 2 H), 7.52–7.55 (d, J = 7.40 Hz, 2 H), 7.96 (s,
2 H), 8.31 (s, 1 H, NH), 8.38 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 9.27, 13.05, 41.39, 112.31, 115.60,
116.75, 121.98, 123.11, 123.77, 124.59, 124.71, 126.42, 126.76,
127.09, 128.86, 131.04, 134.44, 134.58, 135.97, 137.11, 139.96,
141.63, 142.54.
13C NMR (75 MHz, CDCl3): d = 40.43, 111.63, 112.98, 113.06,
119.67, 119.74, 120.28, 122.47, 122.70, 124.08, 125.23, 125.33,
126.81, 127.32, 128.81, 129.07, 129.17, 135.65, 137.10, 143.98.
MS: m/z = 401.3 ([M + H]+, 79Br, 100), 403.3 ([M + H]+, 81Br, 98).
HRMS: m/z [M + H]+ calcd for C23H17N279Br: 401.0576; found:
401.0558.
3-[(1H-Indol-3-yl)(4-methylphenyl)methyl]-2-methyl-1H-in-
dole (3f)
White shining crystals; yield: 262 mg (75%); mp 198–199 °C; Rf =
0.74 (15% EtOAc–PE).
MS: m/z = 351.4 [M + H]+.
IR (CHCl3): 3410 (NH stretch), 3402 (NH stretch), 3056 (w), 2927
(w), 1456 (s), 743 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H), 2.32 (s, 3 H), 5.83
(s, 1 H), 6.62 (s, 1 H), 6.98–7.0 (d, J = 7.17 Hz, 2 H), 7.05–7.08 (d,
J = 7.79 Hz, 2 H), 7.11–7.20 (m, 4 H), 7.29–7.40 (m, 4 H), 8.19 (s,
1 H, NH), 8.28 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.98, 21.22, 44.67, 114.07,
116.04, 123.27, 123.56, 124.06, 124.81, 124.89, 125.02, 126.36,
126.74, 128.61, 128.93, 132.03, 132.41, 133.20, 133.52, 133.89,
136.38, 140.40, 142.35.
3-[(5-Bromo-1H-indol-3-yl)(phenyl)methyl]-2-methyl-1H-in-
dole (3j)
Light orange powder; yield: 277 mg (67%); mp 188–191 °C; Rf =
0.65 (15% EtOAc–PE).
IR (CHCl3): 3417 (NH stretch), 3405 (NH stretch), 3056 (w), 2927
(w), 1456 (s), 1168 (m), 743 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H), 5.89 (s, 1 H), 6.66
(s, 1 H), 6.94–6.95 (d, J = 6.13 Hz, 2 H), 7.01–7.09 (m, 3 H), 7.13–
7.24 (m, 4 H), 7.35–7.37 (d, J = 7.24 Hz, 3 H), 8.14 (s, 1 H, NH),
8.19 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 17.27, 42.56, 109.98, 111.23,
113.36, 116.17, 122.24, 123.28, 124.11, 124.75, 126.34, 126.81,
127.12, 127.43, 128.65, 130.43, 133.31, 134.57, 138.10, 140.03,
141.54, 142.56.
MS: m/z = 351.7 [M + H]+.
3-[(1H-Indol-3-yl)(4-nitrophenyl)methyl]-2-methyl-1H-indole
(3g)
Yellowish crystals; yield: 240 mg (63%); mp 207–209 °C; Rf = 0.63
(15% EtOAc–PE).
MS: m/z = 415.2 ([M + H]+, 79Br, 100), 417.5 ([M + H]+, 81Br, 98).
IR (CHCl3): 3414 (NH stretch), 3398 (NH stretch), 3056 (w), 2927
(w), 1512 (s), 1456 (s), 1355 (m), 743 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H), 5.88 (s, 1 H), 6.69
(s, 1 H), 6.90–6.93 (d, J = 7.29 Hz, 2 H), 7.01–7.07 (q, J = 8.28 Hz,
3-[(5-Bromo-1H-indol-3-yl)(phenyl)methyl]-1-methyl-1H-in-
dole (3k)
Pink powder; yield: 227 mg (55%); mp 211–213 °C; Rf = 0.68 (15%
EtOAc–PE).
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

PAPER
Synthesis of Diindolyl- and Heterocyclic(indolyl)methanes
2897
IR (CHCl3): 3413 (NH stretch), 3056 (w), 2927 (w), 1456 (s), 1165
(m), 743 cm–1 (s).
HRMS: m/z [M + H]+ calcd for C26H24N2: 365.1941; found:
365.1967.
1H NMR (300 MHz, CDCl3): d = 3.50 (s, 3 H), 5.78 (s, 1 H), 6.66
(s, 1 H), 6.69 (s, 1 H), 6.99–7.02 (d, J = 7.22 Hz, 2 H), 7.05–7.10 (t,
J = 7.43 Hz, 3 H), 7.13–7.21 (m, 4 H), 7.35–7.38 (d, J = 7.55 Hz, 3
H), 8.14 (s, 1 H, NH).
3-[1-(1H-Indol-3-yl)ethyl]-2-methyl-1H-indole (3o)
Red powder; yield: 205 mg (75%); mp 143–145 °C; Rf = 0.65 (15%
EtOAc–PE).
IR (CHCl3): 3414 (NH stretch), 3396 (NH stretch), 3056 (w), 2965
(w), 2931 (w), 1456 (s), 744 (s) cm–1.
13C NMR (75 MHz, CDCl3): d = 33.67, 41.86, 109.91, 111.28,
113.36, 115.98, 122.06, 123.29, 124.18, 124.55, 126.37, 126.83,
127.12, 127.47, 128.76, 130.13, 132.88, 134.51, 138.10, 140.21,
141.55, 142.32.
MS: m/z = 415.0 ([M + H]+, 79Br, 100), 417.0 ([M + H]+, 81Br, 100).
HRMS: m/z [M + H]+ calcd for C24H19N281Br: 417.0732; found:
1H NMR (300 MHz, CDCl3): d = 1.84–1.86 (d, J = 7.13 Hz, 3 H),
2.33 (s, 3 H), 4.62–4.69 (q, J = 7.08 Hz, 1 H), 6.75 (s, 1 H), 6.96–
7.0 (m, 2 H), 7.25–7.27 (d, J = 6.98 Hz, 2 H), 7.31–7.34 (d, J = 8.14
Hz, 2 H), 7.41–7.44 (d, J = 7.92 Hz, 2 H), 7.92 (s, 1 H, NH), 8.15
(s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 17.09, 25.80, 32.79, 115.17,
115.96, 120.67, 123.69, 123.99, 124.21, 124.61, 125.48, 125.96,
126.35, 126.70, 132.18, 132.94, 135.13, 140.22, 141.60.
417.0714.
1-Methyl-3-[(2-methyl-1H-indol-3-yl)(phenyl)methyl]1H-in-
dole (3l)
Pink powder; yield: 168 mg (48%); mp 224–226 °C; Rf = 0.78 (15%
MS: m/z = 275.3 [M + H]+.
EtOAc–PE).
3-[(Heterocyclic)(phenyl)methyl]-1H-indoles 6; General Proce-
dure
IR (CHCl3): 3411 (NH stretch), 3056 (w), 2933 (w), 1456 (s), 1013
(m), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 3 H), 3.58 (s, 3 H), 5.88
(s, 1 H), 6.50 (s, 1 H), 6.84–7.03 (m, 4 H), 7.15–7.17 (d, J = 6.53
Hz, 2 H), 7.20–7.24 (t, J = 7.38 Hz, 4 H), 7.29–7.31 (d, J = 7.40 Hz,
3 H), 8.18 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 17.13, 37.55, 44.12, 114.0, 114.99,
118.92, 122.29, 123.56, 123.87, 124.35, 124.85, 125.51, 126.32,
128.61, 130.73, 132.74, 132.95, 133.34, 133.68, 136.39, 140.05,
142.22.
Equimolar amounts of 3-alkylated indole 1a (1 mmol) and hetero-
cyclic nucleophile 5 (1 mmol) were taken in a round-bottomed flask
containing EtOH–H2O (9:1, 6 mL) and refluxed for 0.5 to 2.5 h. The
solid product that appeared was filtered off and purified by recrys-
tallization (EtOH–CHCl3); in the case of 6b it was separated by col-
umn chromatography (12% EtOAc–PE).
4-[(1H-Indol-3-yl)(phenyl)methyl]-5-methyl-2-phenyl-2,4-dihy-
dro-3H-pyrazol-3-one (6a)
White powder; yield: 322 mg (85%); mp 233–234 °C; Rf = 0.45
(25% EtOAc–PE).
MS: m/z = 373.3 [M + Na]+.
IR (KBr): 3405 (NH stretch), 3056 (w), 2925 (w), 1621 (s), 1561
(s), 1456 (s), 771 cm–1 (s).
2-[(1H-Indol-3-yl)(4-methylphenyl)methyl]-3-methyl-1H-in-
dole (3m)
1H NMR (300 MHz, DMSO-d6): d = 2.36 (s, 3 H), 3.63–3.66 (d,
J = 8.24 Hz, 1 H), 5.62–5.64 (d, J = 8.19 Hz, 1 H), 6.76 (s, 1 H),
6.96–7.0 (t, J = 7.23 Hz, 2 H), 7.12–7.17 (t, J = 7.41 Hz, 3 H), 7.22–
7.29 (m, 3 H), 7.34–7.40 (m, 2 H), 7.62–7.74 (m, 4 H), 9.55 (s, 1 H,
NH).
13C NMR (75 MHz, DMSO-d6): d = 13.46, 45.77, 54.58, 111.23,
113.65, 117.61, 118.12, 121.43, 121.59, 122.74, 124.38, 125.57,
125.93, 127.89, 131.23, 132.90, 134.27, 139.29, 141.44, 146.45,
161.76.
Straw colored powder; yield: 203 mg (58%); mp 154–156 °C; Rf =
0.62 (15% EtOAc–PE).
IR (CHCl3): 3410 (NH stretch), 3388 (NH stretch), 3061 (w), 2931
(w), 1456 (s), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3 H), 2.32 (s, 3 H), 5.88
(s, 1 H), 6.55 (s, 1 H), 6.98–7.00 (d, J = 7.37 Hz, 2 H), 7.06–7.17
(m, 4 H), 7.20–7.24 (t, J = 7.34 Hz, 2 H), 7.34–7.37 (d, J = 8.18 Hz,
2 H), 7.54–7.56 (d, J = 6.98 Hz, 2 H), 7.99 (s, 1 H, NH), 8.09 (s, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 9.02, 21.52, 40.40, 111.07, 111.58,
118.14, 118.68, 119.36, 120.16, 121.36, 122.75, 124.35, 127.15,
128.79, 128.88, 129.68, 130.01, 135.37, 136.31, 136.60, 137.09,
139.42.
HRMS: m/z [M + H]+ calcd for C25H21N3O: 380.1686; found:
380.1654.
Anal. Calcd for C25H21N3O: C, 79.15; H, 5.54; N, 11.08. Found: C,
79.10; H, 5.61; N, 11.17.
MS: m/z = 351.5 [M + H]+.
3-[Phenyl(1H-pyrrol-2-yl)methyl]-1H-indole (6b)
Brown semisolid; yield: 122 mg (45%); Rf = 0.68 (15% EtOAc–
PE).
2-Methyl-3-[(3-methyl-1H-indol-2-yl)(4-methylphenyl)meth-
yl]-1H-indole (3n)
Brown powder; yield: 240 mg (66%); mp 183–185 °C; Rf = 0.62
(15% EtOAc–PE).
IR (CHCl3): 3425 (NH stretch), 3405 (NH stretch), 3060 (w), 1456
(s), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 5.22 (s, 1 H), 6.11–6.15 (m, 2 H),
6.63–6.68 (m, 2 H), 7.09–7.12 (d, J = 7.44 Hz, 3 H), 7.24–7.28 (t,
J = 7.19 Hz, 2 H), 7.34–7.47 (m, 4 H), 7.92 (s, 1 H, NH), 8.10 (s, 1
H, NH).
13C NMR (75 MHz, CDCl3): d = 44.26, 106.43, 109.0, 113.51,
115.13, 118.35, 121.47, 121.84, 124.42, 125.98, 126.46, 127.81,
128.08, 131.35, 132.91, 137.23, 141.98.
IR (CHCl3): 3410 (NH stretch), 3393 (NH stretch), 3058 (w), 2931
(w), 1456 (s), 744 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.13 (s, 3 H), 2.20 (s, 3 H), 2.30
(s, 3 H), 5.87 (s, 1 H), 6.89–6.91 (d, J = 7.58 Hz, 2 H), 7.04–7.12
(m, 4 H), 7.20–7.23 (d, J = 7.99 Hz, 2 H), 7.52–7.59 (m, 4 H), 7.69
(s, 1 H, NH), 7.94 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 9.18, 12.37, 21.57, 39.46, 107.97,
110.94, 111.25, 112.29, 118.72, 119.43, 119.51, 120.14, 121.53,
128.44, 128.79, 129.64, 129.91, 132.90, 135.42, 135.78, 136.35,
136.46, 139.28.
MS: m/z = 295.5 [M + Na]+.
Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York

2898
M. L. Deb, P. J. Bhuyan
PAPER
6-Amino-5-[(1H-indol-3-yl)(phenyl)methyl]-1,3-dimethylpyri-
midine-2,4(1H,3H)-dione (6c)
Colorless crystal; yield: 180 mg (50%); mp 254–256 °C; Rf 0.60
(40% EtOAc–PE).
Acknowledgement
The authors thank Dr. P. G. Rao, the Director, NEIST, Jorhat for
providing the facilities to perform the work. M.L.D. thanks CSIR
(India) for the award of a Senior Research Fellowship.
IR (KBr): 3411(s), 3397 (s), 3355 (m), 2951 (w), 1659 (s), 1499 (s),
1456 (s), 771 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 3.32 (s, 3 H), 3.34 (s, 3 H), 5.02
(s, 1 H), 6.34 (s, br s, 2 H, NH2), 6.67 (s, 1 H), 6.84–6.87 (d, J = 7.65
Hz, 2 H), 7.04–7.09 (t, J = 7.43 Hz, 2 H), 7.19–7.37 (m, 5 H), 8.25
(s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 28.61, 28.73, 57.85, 78.54, 114.41,
119.05, 120.45, 122.36, 123.71, 124.26, 127.43, 128.41, 128.80,
136.54, 138.82, 140.23, 151.44, 155.91, 163.20.
References
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MS: m/z 361.3 [M + H]+.
Anal. Calcd for C21H20N4O2: C, 70.00; H, 5.55; N, 15.55. Found: C,
70.11; H, 5.63; N, 15.48.
3-[(1H-Imidazol-4-yl)(phenyl)methyl]-1H-indole (6d)
White solid; yield: 109 mg (40%); mp 292–294 °C; Rf = 0.30 (60%
EtOAc–PE). Due to solubility problems, the 13C NMR spectrum of
this compound could not be taken
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IR (KBr): 3442 (br s), 3413 (s), 2955 (w), 1456 (s), 743 cm–1 (s).
1H NMR (300 MHz, DMSO-d6): d = 5.87 (s, 1 H), 6.68 (s, 1 H), 6.79
(s, 1 H), 7.02–7.07 (t, J = 7.29 Hz, 3 H), 7.16–7.19 (d, J = 7.54 Hz,
2 H), 7.33–7.41 (m, 3 H), 7.52–7.54 (d, J = 7.18 Hz, 2 H), 9.34 (s,
1 H, NH), 9.49 (s, 1 H, NH).
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(9) Ling, J.; Wan-Ru, C. US 68,00,655, 2004.
(10) (a) Lézé, M.-P.; Le Borgne, M.; Marchand, P.; Loquet, D.;
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Le Baut, G.; Hartmann, R. W.; Palzer, M. Bioorg. Med.
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MS: m/z = 272.4 [M – H]+.
Anal. Calcd for C18H15N3: C, 79.12; H, 5.49; N, 15.38. Found: C,
79.18; H, 5.54; N, 15.46.
(11) (a) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G.; Prabhakar,
A.; Kunwar, A. C. Tetrahedron Lett. 2003, 44, 2221.
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1959. (c) Ji, S.-J.; Wang, S.-Y.; Zhang, Y.; Loh, T.-P.
Tetrahedron 2004, 60, 2051. (d) Koshima, H.; Matsuaka,
W. J. Heterocycl. Chem. 2002, 39, 1089. (e) Chakrabarty,
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3-[(1H-Indol-3-yl)(phenyl)methyl]-2H-1-benzopyran-2,4(3H)-
dione (6e)
Yellow shining crystal; yield: 176 mg (48%); mp 248–250 °C; Rf =
0.40 (50% EtOAc–PE).
IR (KBr): 3409 (NH stretch), 2931 (w), 1747 (s, OC=O), 1717 (s,
C=O), 1456 (s), 1235 (s), 744 cm–1 (s).
1H NMR (300 MHz, DMSO-d6): d = 4.14 (d, J = 6.14 Hz, 1 H), 5.53
(d, J = 6.19 Hz, 1 H), 6.66 (s, 1 H), 7.08–7.11 (d, J = 7.41 Hz, 2 H),
7.14–7.23 (m, 3 H), 7.29–7.34 (t, J = 7.14 Hz, 3 H), 7.54–7.63 (m,
5 H), 9.95 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): d = 51.23, 58.52, 111.31, 113.62,
118.44, 121.33, 122.39, 124.21, 124.57, 126.78, 126.89, 128.41,
133.56, 137.53, 137.98, 138.34, 140.41, 141.71, 154.12, 165.79,
197.23.
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Anal. Calcd for C24H17NO3: C, 78.47; H, 4.63; N, 3.81. Found: C,
78.44; H, 4.71; N, 3.89.
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Synthesis 2008, No. 18, 2891–2898 © Thieme Stuttgart · New York