SYNTHETIC APPROACHES FOR BIS (INDOLYL) METHANES
HTML Full TextSYNTHETIC 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.
Keywords: |
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 SnCl2.2H2O 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 SnCl2.2H2O 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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Article Information
8
1312-1322
460KB
1815
English
IJPSR
Partha Pratim Kaishap* and Chandrajit Dohutia
Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh- 786004, Assam, India
pk6511@gmail.com
24 December, 2012
13 March, 2013
29 March, 2013
http://dx.doi.org/10.13040/IJPSR.0975-8232.4(4).1312-22
01 April, 2013