SYNTHETIC APPROACHES FOR BIS (INDOLYL) METHANES

SYNTHETIC APPROACHES FOR BIS (INDOLYL) METHANES

Partha Pratim Kaishap* and Chandrajit Dohutia

Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh- 786004, Assam, India

ABSTRACT:Indole ring system is the most important heterocycle available in natural compounds. Owing to great structural diversity, the indole ring system has become an important structural requirement in many pharmaceutical agents. Indole has been widely identified as a privileged structure or pharmacophore, with its presence in over 3000 natural isolates which are known to possess broad spectrum of biological activities and pharmaceutical applications. The bis (indolyl) methane derivatives are found to be very active compounds in pharmacy field. They are found in cruciferous plants and are known to promote beneficial oestrogen metabolism and induce apoptosis in human cancer cells. In recent years, a lots of bis (indolyl) methane derivatives have been synthesized and found to possess promising biological activities including anticancer, antimicrobial, antifungal, analgesic, anti-inflammatory, anthelmintic, cardiovascular activities. In the present review several synthetic schemes of these compounds are discussed involving non-toxic catalyst and providing high yields.

Bis (indolyl) Methanes, Indole, Aldehyde, Catalyst, Carbonyl Compounds

INTRODUCTION: Bis (indolyl) methanes, indole and their derivatives are known as important intermediates in organic synthesis and pharma-ceutical chemistry and exhibit various physiological properties. Indole ring system is the most important heterocycle available in natural compounds. Owing to great structural diversity of biologically active indoles, it is not surprising that the indole ring system has become an important structural requirement in many pharmaceutical agents. Indole has been widely identified as a privileged structure or pharmacophore, with its presence in over 3000 natural isolates ¹ which are known to possess broad spectrum of biological activities and pharmaceutical applications ².

Indomethacin and tenidap are indole derivatives found to possess anti-inflammatory activity with analgesic and anti-pyretic properties. They inhibit production of ecosanoids by inhibition of cyclo-oxygenase (COX) and thereby reduce oedema. Several indole derivatives are reported to have anti microbial activity.

Bis (indolyl) methanes are found in cruciferous plants and are known to promote beneficial oestrogen metabolism and induce apoptosis in human cancer cells ³. Bis (indolyl) methanes have received much attention in recent years ⁴.

Such compounds are prone to develop interesting bio activity and find useful applications as breast cancer preventive⁵ and anti- bacterial agents ⁶. Hong et al. ⁷ and Kedmi et al. ⁸ reported recently the potential beneficial effects of 3, 3-biindolyl methanes on the proliferation and induction of apoptosis in human prostate and breast cancer cells.

Bis(Indolyl) methane derivatives have been reported to possess promising biological activities including antipyretic, antifungal,  anti-inflammatory, ant-helmintic, cardiovascular, anticonvulsant, anti-microbial and selective COX-2 inhibitory activities ⁹. Therefore synthesis of bis (indolyl) moiety has become interesting target for the synthetic organic chemist in view of their immense biological and pharmaceutical activities.

The lead indole derivatives reported in this literature are bis (indolyl) methane. The method of synthesis involves both one step as well as multistep synthesis. Several methods have been reported in this literature for the preparation of bis (indolyl) methanes from indoles and carbonyl compounds using protic acids ¹⁰ and Lewis acids ¹¹. Fischer in 1886 prepared 3, 3-bis (indolyl) methanes for the first time which was a mere acid catalyzed Friedel-Crafts reaction between indole and carbonyl compounds, generally aldehydes and ketones.

The acid catalyzed reaction of electron rich heterocyclic compounds such as indole and pyroles with p-dimethyl aminobenzaldehyde is known as the Ehrlich test ¹². Generally 3,3`-bis (indolyl) methanes  are synthesized by an analogous reaction to the Ehrlich test, where indole reacts with aliphatic or aromatic aldehydes or ketones in the presence of an acid catalyst to produce azafulvenium salt which undergoes further addition reaction with a second indole molecule to produce bis (indolyl) methanes.

Mechanism of the Reaction:
The common route for the synthesis of bis (indolyl) methanes is electrophilic substitution reaction of indoles with the aromatic or aliphatic aldehyde and ketones catalyzed by protic acids or Lewis acids. However, Lewis acids are required in excess because it is destroyed by the presence of even small amount of moisture or when trapped by nitrogen present in heterocycles.

In recent years, synthesis of this class of molecules under mild conditions have been reported with promoters such as SnCl_2.2H₂O ¹³, TCBDA ¹⁴, PCBS ¹⁵, Silica H₂SO₄ ¹⁶, P₂O₅/SiO₂ ¹⁷, SbCl₃ ¹⁸, Alum ¹⁹ etc.

There are various type of method including solvent free, microwave synthesis for the synthesis of bis (indolyl) methanes have been reported in the literature.

Synthetic Schemes

The common route for the synthesis of bis (indolyl) methanes is electrophilic substitution reaction of indoles with the aromatic or aliphatic aldehyde and ketones catalyzed by protic acids or Lewis acids. However, Lewis acids are required in excess because it is destroyed by the presence of even small amount of moisture or when trapped by nitrogen present in heterocycles.

In recent years, synthesis of this class of molecules under mild conditions have been reported with promoters such as SnCl_2.2H₂O ¹³, TCBDA ¹⁴, PCBS ¹⁵, Silica H₂SO₄ ¹⁶, P₂O₅/SiO₂ ¹⁷, SbCl₃ ¹⁸, Alum ¹⁹ etc.

There are various type of method including solvent free, microwave synthesis for the synthesis of bis (indolyl) methanes have been reported in the literature

CONCLUSION: This review gives an overview of a number of synthetic procedures using various catalysts, used to form a biologically rich bis (indolyl) methanes moiety. This paper may be helpful for further research work for the development of better medicinal agents and newer compounds containing bis (indolyl) moiety.

ACKNOWLEDGEMENT: The authors are thankful to Prof. Dipak Chetia of Department of Pharm. Sciences, Dibrugarh University for his kind support and help.

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