View Article Online / Journal Homepage / Table of Contents for this issue

Infrared-assisted eco-friendly selective synthesis of

diindolylmethanes

Guillermo Penieres-Carrillo,*a José Guadalupe García-Estrada,a José Luis

Gutiérrez-Ramíreza and Cecilio Alvarez-Toledanob

a FES Cuautitlán-UNAM, Av. 1 de mayo s/n, Cuautitlán Izcalli, Estado de México, C.P.
54740, México. E-mail: penieres@servidor.unam.mx
b Instituto de Química-UNAM, Circuito Exterior, Ciudad Universitaria, Coyoacán, México

D.F., C.P. 04510, México

Published on 08 May 2003. Downloaded by Yale University Library on 25/07/2013 12:07:56.

Received 8th November 2002

First published as an Advance Article on the web 8th May 2003

An alternative and environmentally benign pathway for selective synthesis of aryl-3,3A-diindolylmethanes from
indole and several aromatic aldehydes is described. The electrophilic aromatic substitution (EAS) reactions are
achieved with good yield and short reaction time employing infrared irradiation as energy source and a bentonitic
clay as catalyst and reaction medium, in solvent-free reaction conditions.

Introduction
Actually, diindolymethanes are very important chemical com-
pounds with potential pharmaceutical activity. One of these
compounds, diindolymethane (DIM), has been the subject of
much research and it is proposed that DIM has potential uses in
promoting healthier estrogen metabolism, breast cancer preven-
tion, control of cervical dysplasia,1 a strong anti-proliferative
effect in human endometrial cancer cells2 and many others.
Several methods are available for the preparation of 3,3A-
diindolylmethanes. Kamal and Qureshi3 obtained it from the
reaction of either indole or 2-methylindole with aldehydes
under controlled pH with a 10 day reaction time, but in some
reactions the desired compound was not obtained. In the same
way, Bergman and coworkers4 reported the synthesis of the title
compounds under acidic reaction conditions with the formation Scheme 1
of cyclooligomeric compounds in moderate yields, and Jackson
and coworkers5 reported the synthesis of DIM in moderate to
good yields under acidic reaction conditions. After the recrystallization purification process, spectroscopic
In recent years we have been engaged in designing alternative identification revealed the 3,3A-diindolylmethane structure of
synthetic strategies with an environmentally benign approach, the reaction product. Then, we took this reaction time as a
utilising a bentonitic clay as catalyst or reaction medium and reference for the other substituted benzaldehyde reactions.
alternative energy sources, such as microwaves, infrared or The obtained yield for each used benzaldehyde is given in
ultrasound, in solvent-free reaction conditions applied to several Table 1.
organic reactions.6 With this synergetic methodology we have
found in many cases that the reactions are cleaner, with high
selectivity, an easy experimental work-up and with very
important economic advantages. Green Context
Our continuing interest in the Green Chemistry postulates
prompted us to develop a convenient alternative synthesis of Diindolylmethanes are an important class of organic com-
several aryl-3,3A-diindolylmethanes from indole and aromatic pounds with numerous pharmaceutical applications. Sev-
aldehydes in the presence of a bentonitic clay, using infrared eral synthetic strategies are available but these suffer from
energy in the absence of solvent, outlined in Scheme 1. drawbacks including long reaction periods and hazardous
conditions. Here a new, more environmentally benign
pathway to aryl-3,3A-diindolylmethanes is described. This
involves the avoidance of solvents, short reaction times
Results and discussion through the use of infrared irradiation as the energy source
and the use of an inexpensive and natural clay catalyst. Thus
Firstly, we looked at the effectiveness of the proposed strategy through the combination of several items in the clean
by the reaction of benzaldehyde with indole. At 15 minutes technology toolkits a much improved, reduced environ-
reaction time the highest yield of a single reaction product was mental impact synthesis to an important class of compounds
detected and after this time no significant changes were is achieved. JHC
observed by thin layer chromatography.

DOI: 10.1039/b211011c Green Chemistry, 2003, 5, 337–339 337

This journal is © The Royal Society of Chemistry 2003
 View Article Online

Table 1 Condensation of aromatic aldehydes with indole, formation of diindolylmethanes

Isolated
Entry Aldehyde Product Melting point/°C yield (%)

1 125–127 75
Published on 08 May 2003. Downloaded by Yale University Library on 25/07/2013 12:07:56.

2 83–85 70

3 191–193 70

4 166–168 55

5 203–204 85

6 102–104 82

7 265–266 93

8 221–223 (Dec.) 96

These results show a regular chemical behavior according to
the substituent on the phenyl group; that is, with electron-
releasing groups (Me, OMe, Me2N, Me) in the para position the
electrophilic character of the carbonylic carbon is expected to
be smaller for the EAS reaction, while with electron-with-
drawing groups (CHO, CN, NO2) although they are in the meta
position the electrophilic character of the same carbonylic
carbon is increased and this effect is clearly more enhanced with
the nitro group in the para position
Finally, as another purpose of the present work it is important
to point out the reaction with the terephthalaldehyde (entry 5),
since under both the reaction conditions and stoichiometric

338 Green Chemistry, 2003, 5, 337–339


quantities used only a single aldehyde function was reacted and
with the mild experimental work-up it was not altered.
In conclusion, we found an alternative and selective method
to diindolylmethanes synthesis in good yields which is achieved
under solvent-free reaction conditions and short reaction times
with the use of a cheap bentonitic clay and infrared energy.
Experimental
A typical experimental procedure is as follows. To a mixture of
Published on 08 May 2003. Downloaded by Yale University Library on 25/07/2013 12:07:56.
indole (1.0 g, 8.54 mmol) and benzaldehyde (0.45 g, 4.27
mmol) was added the bentonitic clay (4 g). The reaction mixture
was IR irradiated with a commercial IR lamp (250 W),
according to the methodology reported by Pool and Teuben,7
for 15 minutes (after this reaction time no changes were
detected by thin layer chromatography), and the temperature
reached during the reaction was 180 °C.8 Then, to the produced
reaction mixture a 1 : 1 water–methanol mixture was added for
recrystallization purposes. The pure product was identified by
both nuclear magnetic resonance (1H, 13C) and mass spectrome-
try. Selected data for phenyl-3,3A-diindolylmethane (1): HR-MS
M 322.1464 g mol21 observed (322.1470 g mol21 estimated)
for a molecular formula C23H18N2. Pink solid; yield: 75%; mp
125–127 °C (methanol–water 1 : 1); EIMS (r.a.): m/z 322 (M+,
100), 321 (34), 245 (52); 1H NMR (300 MHz, CDCl3) d ppm:
9.98 (s, 2H), 7.82 (s, 2H), 7.35–6.95 (m, 13H), 5.87 (s, 1H); 13C
NMR (75 MHz, CDCl3) d ppm: 144.0, 136.7, 129.1, 128.7,
128.2, 126.1, 123.5, 121.9, 119.9, 119.6, 119.2, 111.0, 40.1.
View Article Online
Acknowledgements
The authors wish to thank Rocío Patiño, Luis Velasco and
Francisco J. Pérez for their technical assistance. G. Penieres
wishes to acknowledge support from CONACYT Project
35593E.
References
1 D. Z. Chen, M. Qi, K. J. Auborn and T. H. Carter, J. Nutr., 2001, 131,
3294.
2 H. Leong, G. L. Firestone and L. F. Bjeldanes, Carcinogenesis, 2001,
22, 1809.
3 A. Kamal and A. Qureshi, Tetrahedron, 1963, 19, 513.
4 J. Bergman, S. Högberg and J. Lindström, Tetrahedron, 1970, 26,
3347.
5 A. H. Jackson, N. Prasitpan, P. V. Shannon and A. C. Tinker, J.
Chem. Soc. Perkin Trans. 1, 1987, 2543.
6 G. Penieres, C. Alvarez, K. Franco, O. García and O. Espinoza,
Heterocyclic Commun., 1996, 2, 359; G. Penieres, J. G. García, J. M.
Aceves, F. Delgado and R. Miranda, Heterocyclic Commun., 1996, 2,
401; M. Jiménez, A. Navarro, J. L. Eusebio, C. Alvarez, O. García
and G. Penieres, Steroids, 1997, 62, 500; G. Penieres, V. Soto, C.
Alvarez, O. García and J. G. García, Heterocyclic Commun., 1998, 4,
31; J. Gómez-Lara, R. Gutiérrez-Pérez, G. Penieres-Carrillo, J. G.
López-Cortés, A. Escudero-Salas and C. Alvarez-Toledano, Synth.
Commun., 2000, 30, 2713; F. Delgado, A. C. Cano, O. García, J. G.
Alvarado, L. Velasco, C. Alvarez and H. Rudler, Synth. Commun.,
1992, 22, 2125; G. Penieres, J. M. Aceves, A. Flores, G. Mendoza, O.
García and C. Alvarez, Heterocyclic Commun., 1997, 3, 507.
7 G. Pool and J. Teuben, ACS Symp. Ser., 1987, 357, 30.
8 The same reaction was also performed using an oil bath at the same
temperature and reaction time. After the recrystallization process the
obtained yield was similar to the infrared method, but with great
amounts of pollution vapors produced from the hot oil.
Green Chemistry, 2003, 5, 337–339 339