Efficient hexamethylenetetramine-bromine (HMTAB)-Catalyzed synthesis of bis(indolyl)methanes in water

Article abstract of DOI:10.1081/SCC-200063977

An efficient, facile, and environmentally friendly electrophilic substitution reaction of indoles with various aldehydes and ketones proceeded smoothly in water using the hexamethylenetetramine-bromine complex to afford the corresponding bis(indolyl)metha

Full text of DOI:10.1081/SCC-200063977

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Efficient
Hexamethylenetetramine‐Bromine
(HMTAB)‐Catalyzed Synthesis of
Bis(indolyl)methanes in Water
Mohammad Bagher Teimouri a & Houri Mivehchi b
a Petrochemical Department, Iran Polymer and
Petrochemical Institute, Tehran, Iran
b Novel Drug Delivery Systems Department, Iran
Polymer and Petrochemical Institute, Tehran, Iran
Version of record first published: 15 Aug 2006.
To cite this article: Mohammad Bagher Teimouri & Houri Mivehchi (2005):
Efficient Hexamethylenetetramine‐Bromine (HMTAB)‐Catalyzed Synthesis of
Bis(indolyl)methanes in Water, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:13, 1835-1843
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Synthetic Communicationsw, 35: 1835–1843, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200063977
Efficient Hexamethylenetetramine-Bromine
(HMTAB)-Catalyzed Synthesis of
Bis(indolyl)methanes in Water
Mohammad Bagher Teimouri
Petrochemical Department, Iran Polymer and Petrochemical Institute,
Tehran, Iran
Houri Mivehchi
Novel Drug Delivery Systems Department, Iran Polymer and
Petrochemical Institute, Tehran, Iran
Abstract: An efficient, facile, and environmentally friendly electrophilic substitution
reaction of indoles with various aldehydes and ketones proceeded smoothly in water
using the hexamethylenetetramine–bromine complex to afford the corresponding
bis(indolyl)methanes in excellent yields. This method provides several advantages
such as being environmentally friendly, giving high yields, and having simple
workup procedure. Water was chosen as a cheap, nontoxic, green solvent.
Keywords: Carbonyl compounds, electrophilic substitution, hexamethylenetetramine–
bromine, indole, water
INTRODUCTION
Bisindoles constitute important class of compounds because of their existence
in bioactive metabolites.[1] In recent years the biological activity of bisindoles
has been intensively studied. For example, diindolylmethane (DIM) has been
gaining increasing importance because of its potent anticarcinogenic proper-
ties.[2] Bis(indolyl)methane derivatives affect the central nervous system
Revised in Poland February 14, 2005
Address correspondence to Mohammad Bagher Teimouri, Petrochemical Depart-
ment, Iran Polymer and Petrochemical Institute, P.O. Box 14965-115, Tehran, Iran.
E-mail: m.teimouri@ippi.ac.ir
1835

1836
M. B. Teimouri and H. Mivehchi
and so are used as tranquilizers. The wide-ranging biological activities associ-
ated with bisindole derivatives, both naturally occurring and synthetic, ensure
that the synthesis of these compounds remains a topic of current interest.[3]
Generally, bis(indolyl)methanes are prepared by the condensation of indoles
with various carbonyl compounds in the presence of either protic or Lewis
acids.[4–6] Most of the previously reported methods suffer from several
drawbacks such as low yields, expensive and highly toxic solvents and
catalysts, long reaction times, complex reaction mixtures, and deactivation
or decomposition of many Lewis acids by nitrogen-containing reactants.
However, these problems were overcome to some extent by recently
reported methods employing molecular iodine [7] and N-bromosuccinimide.[8]
Hence, a more efficient and practical alternative using an inexpensive and
environmentally friendly reagent is still warranted.
In the past decade, the use of aqueous media in organic synthesis has
attracted much attention for environmental, economical, and safety reasons,
and has shown unique reactivities and selectivities that are not observed for
reactions in organic media.[9] The role of water was explained by introducing
the concept of hydrophobic effects in organic reactions.[10] So far, various
efficient catalytic reactions in water have been developed such as the
Diels–Alder reaction, aldol condensation, the Claisen rearrangement, the
Michael addition, the Mannich reaction, radical addition reaction and
Grignard-type additions, allylation reactions, and the benzoin conden-
sation.[11] This article shows that electrophilic substitutions of indoles with
substituted benzaldehydes in the presence of catalytic amount of hexamethy-
lenetetramine–bromine complex can successfully take place in water as a
cheap, nontoxic, green solvent.
RESULTS AND DISCUSSION
Hexamethylenetetramine–bromine complex is readily prepared by adding
bromine to a chloroform solution of hexamethylenetetramine. This yellow-
orange, nonhygroscopic, homogeneous solid, stable at room temperature, is
not affected by exposure to light, air, or water and has no offensive odor of
bromine or amine. This complex is transformed during reaction into easily
removable products and presents a convenient alternative to other N-bromo
reagents such as N-bromosuccinimide.
In an earlier work, the HMTAB has been used for oxidation of primary
and secondary alcohols to aldehydes and ketones, respectively.[12] Also,
mechanistic aspects of the oxidation of diols[13] by HMTAB have been
described. Furthermore, this complex has recently been used for selective
regeneration of carbonyl compounds from oximes and toslylhydrazones.[14]
As part of our research to develop a green chemistry by synthesis of target
molecules in an aqueous medium,[15] and in continuation of our interest
on chemistry of hexamethylenetetramine–bromine,[16] we now report the

Synthesis of Bis(indolyl)methanes
1837
HMTAB-catalyzed condensation reaction of indoles and various carbonyl
compounds (Scheme 1).
The condensation reaction of indoles with aromatic or aliphatic aldehydes
or ketones in the presence of HMTAB in water proceeds well, giving
bis(indolyl)methanes in good yield at 758C. The results are summarized in
Table 1, which shows the scope and generality of the present method with
respect to various carbonyl compounds and indole derivatives.
CONCLUSION
In summary, the paper describes a facile and highly efficient procedure for
the preparation of bis(indolyl)methanes through the hexamethylenetetra-
mine-bromine-catalyzed electrophilic substitution reactions of indoles with
aldehydes and ketones in water. The notable features of this procedure are
neutral and mild reaction conditions, improved yields, easy workup, environ-
mentally friendliness, and use of water as an ideal reaction medium.
EXPERIMENTAL
All products are known compounds and were identified by comparison of
their physical, spectral (IR, 1H NMR, and mass spectra), and elemental
analysis data with those of authentic samples.[5–7] Melting points were
measured on a Bu¨chi 535 apparatus and are uncorrected. Elemental
analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass
spectra were recorded on a Finnigan-Mat 8430 mass spectrometer operating
at an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu
1
IR-470 spectrometer. H NMR spectra were recorded on a Bruker DRX-400
Avance spectrometer at 400.13 MHz with CDCl3 as solvent. All reagents
and solvents used in this work are commercial materials and were
purchased from Fluka (Buchs, Switzerland) or Merck and were used
without further purification. Hexamethylenetetramine–bromine complex
was prepared according to published procedure.[16a]
Scheme 1.

1838
M. B. Teimouri and H. Mivehchi

Synthesis of Bis(indolyl)methanes
1839

1840
M. B. Teimouri and H. Mivehchi
General Procedure for Synthesis of Bis(indolyl)methanes
A mixture of aldehyde or ketone (1.0 mmol), indole (2.0 mmol), and HMTAB
(0.1 g) in water (20 mL) was heated at 758C for the appropriate time (Table 1).
After completion of the reaction (monitored by TLC) and cooling to room
temperature, the mixture treated with aq. Na2S2O3 solution (5%, 10 mL)
and the product was filtered off and washed with water (3 ꢀ 10 mL). The
crude products were dried and crystallized from ethyl acetate–hexane (1 : 3)
to give 3.
3-[(3,4-Dimethoxyphenyl)(1H-indol-3-yl)methyl]-1H-indole (3a): Mp
1
199–2008C; IR (KBr) (nmax, cm21): 3450, 1625, 1479, 1221, 760; H NMR
(CDCl3, 400 MHz): dH ¼ 3.70 and 3.81 (6 H, 2 s, 2 OMe), 5.75 (1 H, s,
Ar-CH), 6.71 (2 H, d, J ¼ 2.5 Hz), 6.80 (2 H, d, J ¼ 8.0 Hz), 6.86 (1 H, s),
6.89 (2 H, d, J ¼ 8.0 Hz), 7.07 (2 H, t, J ¼ 8.0 Hz), 7.31 (4 H, t,
J ¼ 8.0 Hz), 10.43 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 382
(Mþ, 100), 265 (17), 244 (41), 69 (32); anal. calcd. for C25H22N2O2
(382.46): C, 78.51; H, 5.80; N, 7.32%. Found: C, 78.60; H, 5.84; N, 7.31%.
3-[1H-Indol-3-yl(4-methoxyphenyl)methyl]-1H-indole
(3b):
Mp
188–1908C; IR (KBr) (nmax, cm21): 3427, 1609, 1512, 1451, 1234, 733; H
NMR (CDCl3, 400 MHz) dH ¼ 3.77 (3 H, s, OMe), 5.84 (1 H, s, Ar-CH),
6.65 (2 H, s), 6.81 (2 H, d, J ¼ 8.2 Hz,), 7.03 (2 H, t, J ¼ 7.3 Hz), 7.18 (2 H,
t, J ¼ 7.3 Hz), 7.20 (2 H, s), 7.34–7.42 (4 H, m), 7.91 (2 H, br s, 2 NH)
ppm; MS (EI, 70 eV) (m/z, %): 352 (Mþ, 100), 338 (42), 238 (35), 207
(18), 131 (55); anal. calcd. for C24H20N2O (352.43): C, 81.79; H, 5.72; N,
7.95%. Found: C, 81.85; H, 5.78; N, 8.01%.
1
3-[1H-Indol-3-yl(4-hydroxyphenyl)methyl]-1H-indole (3c): Mp 121–
1238C; IR (KBr) (nmax, cm21): 3466, 3371, 1644, 1579, 1375, 761; 1H NMR
(CDCl3, 400 MHz): dH ¼ 5.53 (1 H, s, Ar-CH), 6.72 (2 H, s), 7.19–7.29
(8 H, m), 7.45 (2 H, d, J ¼ 8.2 Hz), 7.56 (2 H, d, J ¼ 8.2 Hz), 7.64 (1 H, s,
OH), 7.93 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 338 (Mþ, 100),
321 (22), 246 (32), 131 (55), 77 (25); anal. calcd. for C23H18N2O (338.40):
C, 81.63; H, 5.36; N, 8.28%. Found: C, 81.70; H, 5.41; N, 8.30%.
3-[1H-Indol-3-yl(4-methylphenyl)methyl]-1H-indole (3d): Mp 95–978C;
1
IR (KBr) (nmax, cm21): 3419, 1607, 1504, 1221, 778; H NMR (CDCl3,
400 MHz): dH ¼ 2.34 (3 H, s, CH3), 5.82 (1 H, s, Ar-CH), 6.66 (2 H, d,
J ¼ 2.5 Hz), 6.97 (2 H, t, J ¼ 7.6 Hz), 7.08 (2 H, d, J ¼ 7.6 Hz), 7.20–7.30
(6 H, m), 7.37 (2 H, d, J ¼ 7.6 Hz), 7.90 (2 H, br s, 2 NH) ppm; MS (EI,
70 eV) (m/z, %): 336 (Mþ, 100), 245 (51), 219 (40), 144 (18), 119 (9), 69
(27); anal. calcd. for C24H20N2 (336.43): C, 85.68; H, 5.99; N, 8.33%.
Found C, 85.56; H, 5.93; N, 8.26%.
3-[1H-Indol-3-yl(phenyl)methyl]-1H-indole (3e): Mp 90–928C; IR (KBr)
(nmax, cm21): 3422, 3051, 1622, 1588, 1103, 751; 1H NMR (CDCl3,

Synthesis of Bis(indolyl)methanes
1841
400 MHz): dH ¼ 5.90 (1 H, s, Ar-CH), 6.63 (2 H, d, J ¼ 2.2 Hz), 7.03 (2 H, t,
J ¼ 7.2 Hz), 7.19–7.35 (11 H, m), 7.94 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV)
(m/z, %): 322 (Mþ, 100), 245 (66), 205 (34), 122 (40), 105 (12), 77 (19); anal.
calcd. for C23H18N2 (322.40): C, 85.68; H, 5.63; N, 8.69%. Found: C, 85.75;
H, 5.70; N, 8.74%.
3-[(4-Chlorophenyl)(1H-indol-3-yl)methyl]-1H-indole (3f): Mp 76–778C;
1
IR (KBr) (nmax, cm21): 3421, 3046, 1481, 1443, 1079, 1009, 742; H NMR
(CDCl3, 400 MHz): dH ¼ 5.86 (1 H, s, Ar-CH), 6.83 (2 H, s), 7.02 (2 H, t,
J ¼ 8.2 Hz), 7.19 (2 H, t, J ¼ 8.2 Hz), 7.23–7.37 (8 H, m), 8.01 (2 H, br s,
2 NH) ppm; MS (EI, 70 eV) (m/z, %): 356 (Mþ, 100), 322 (11), 246 (55),
241 (38), 126 (31), 111 (23), 77 (15); anal. calcd. for C23H17ClN2 (356.85):
C, 77.41; H, 4.80; N, 7.85%. Found: C, 77.44; H, 4.76; N, 7.80%.
3-[(3,4-Chlorophenyl)(1H-indol-3-yl)methyl]-1H-indole (3g): Mp 153–
1558C; IR (KBr) (nmax, cm21): 3477, 1611, 1466, 1245, 1017, 766; 1H
NMR (CDCl3, 400 MHz): dH ¼ 5.84 (1H, s), 6.75 (2H, d, J ¼ 2.2 Hz), 6.84
(1H, m,), 6.89 (2 H, m), 6.93–7.09 (4 H, m), 7.18 (1H, s), 7.26 (2 H, t,
J ¼ 8.2 Hz), 7.36 (1H, s), 7.80 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z,
%): 390 (Mþ, 100), 274 (67), 245 (54), 204 (14), 176 (10), 117 (17), 77 (9);
anal. calcd. for C23H16Cl2N2 (391.29): C, 70.60; H, 4.12; N, 7.16%. Found:
C, 70.66; H, 4.17; N, 7.74%.
3-[1H-Indol-3-yl(3-nitrophenyl)methyl]-1H-indole (3h): Mp 217–2198C;
1
IR (KBr) (nmax, cm21): 3462, 3036, 1601, 1548, 1233, 1010, 762; H NMR
(CDCl3, 400 MHz): dH ¼ 5.96 (1H, s, Ar-CH), 6.64 (2 H, d, J ¼ 2.4 Hz),
6.86 (2 H, t, J ¼ 8.2 Hz), 7.06 (2 H, t, J ¼ 8.2 Hz), 7.26 (2 H, d,
J ¼ 8.2 Hz), 7.31 (2 H, d, J ¼ 8.2 Hz), 7.45 (2 H, m), 8.07 (2 H, d,
J ¼ 8.2 Hz), 10.08 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 367
(Mþ, 100), 245 (36), 204 (7), 160 (8), 122 (24), 97 (33), 69 (51); anal.
calcd. for C23H17N3O2 (367.40): C, 75.19; H, 4.66; N, 11.44%. Found: C,
75.30; H, 4.70; N, 11.51%.
3-[(4-Methoxyphenyl)(2-methyl-1H-indol-3-yl)methyl]-2-methyl]-1H-
indole (3i): Mp 99–1018C; IR (KBr) (nmax, cm21): 3374, 1556, 1326, 1289,
1
748; H NMR (CDCl3, 400 MHz): dH ¼ 2.05 (6 H, s, CH3), 3.72 (3 H, s,
OCH3), 5.85 (1 H, s, Ar-CH), 6.69 (2 H, t, J ¼ 7.3 Hz), 6.83 (4 H, m), 6.90
(2 H, t, J ¼ 7.1 Hz), 7.09 (2 H, d, J ¼ 8.0 Hz), 7.21 (2 H, d, J ¼ 7.9 Hz),
10.71 (2 H, s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 380 (Mþ, 100), 365
(77), 273 (21), 247 (76), 217 (51), 162 (83), 147 (96), 122 (26), 69 (68);
anal. calcd. for C26H24N2O (380.48): C, 82.08; H, 6.36; N, 7.36%. Found:
C, 82.22; H, 6.42; N, 7.29%.
3-[Cyclohexyl(1H-indol-3-yl)methyl]-1H-indole (3j): Mp 137–1398C; IR
1
(KBr) (nmax, cm21): 3441, 3043, 1614, 1276, 1045, 768; H NMR (CDCl3,
400 MHz): dH ¼ 1.21–1.88 (10 H, m), 2.25 (1 H, m), 4.46 (1 H, m), 6.95
(2 H, d, J ¼ 2.5 Hz), 7.04 (2 H, m), 7.15 (2 H, m), 7.26 (2 H, d, J ¼ 8.2 Hz),

1842
M. B. Teimouri and H. Mivehchi
7.45 (2 H, d, J ¼ 8.2 Hz), 7.88 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV)
(m/z, %): 328 (Mþ, 51), 245 (72), 130 (14), 83 (75), 43 (21); anal. calcd.
for C23H24N2 (328.45): C, 84.11; H, 7.36; N, 8.53%. Found: C, 84.20; H,
7.39; N, 8.61%.
3-[1-(1H-Indol-3-yl)hexyl]-1H-indole (3k): Mp 67–698C; IR (KBr) (nmax
,
cm21): 3426, 3041, 1611, 1441, 1346, 1105, 776; 1H NMR (CDCl3,
400 MHz): dH ¼ 0.83 (3 H, t, J ¼ 7.1 Hz), 1.24–1.33 (6 H, m), 2.26 (2 H,
m), 4.62 (1 H, t, J ¼ 7.1 Hz), 6.86 (2 H, d, J ¼ 2.3 Hz), 7.03 (2 H, t,
J ¼ 8.1 Hz), 7.17 (2 H, t, J ¼ 8.1 Hz), 7.36 (2 H, d, J ¼ 8.1 Hz), 7.51 (2 H,
d, J ¼ 8.1 Hz), 7.85 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 316
(Mþ, 82), 245 (100), 206 (14), 199 (54), 156 (72), 149 (46), 118 (26), 43
(22); anal. calcd. for C22H24N2 (316.44): C, 83.50; H, 7.64; N, 8.85%.
Found: C, 83.55; H, 7.68; N, 8.87%.
3-[1-(1H-Indol-3-yl)-1-phenylethyl]-1H-indole (3l): Mp 188–1908C; IR
(KBr) (nmax, cm21): 3426, 3023, 1628, 1437, 721; 1H NMR (CDCl3,
400 MHz): dH ¼ 2.22 (3 H, s, CH3), 6.57 (1 H, s, Ar-CH), 7.37–7.48 (13 H,
m), 7.80 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %): 336 (Mþ, 80),
260 (100), 246 (27), 159 (15), 77 (43); anal. calcd. for C24H20N2 (336.42):
C, 85.68; H, 5.99; N, 8.33%. Found: C, 85.76; H, 6.04; N, 8.35%.
3-[1-(1H-Indol-3-yl)cyclohexyl]-1H-indole (3m): Mp 117–1198C; IR (KBr)
1
(nmax, cm21): 3426, 3044, 1603, 1442, 1345, 1104, 733; H NMR (CDCl3,
400 MHz): dH ¼ 1.48–1.52 (6 H, m), 1.84 (4 H, m), 2.26 (1 H, m), 4.27
(1 H, d, J ¼ 9.4 Hz), 7.01–7.21 (6 H, m), 7.34 (2 H, d, J ¼ 5.9 Hz), 7.55
(2 H, d, J ¼ 7.2 Hz), 7.95 (2 H, br s, 2 NH) ppm; MS (EI, 70 eV) (m/z, %):
314 (Mþ, 75), 286 (100), 246 (16), 207 (29), 199 (34), 83 (22), 43 (32);
anal. calcd. for C22H22N2 (314.42): C, 84.04; H, 7.05; N, 8.91%. Found: C,
83.96; H, 6.98; N, 9.00%.
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