Clay Catalyzed Reactions of Indole and its Methyl Derivatives with α , β-unsaturated Carbonyl Compounds

Electrophilic substituons reactions of indole and 1-methylindole with methyl propiolate in the presence of K-10 montmorillonite were obtained the formation of the corresponding methyl 3,3bis(indolyl)propanoates. The reaction of 1,3-dimethylindole with methyl propiolate was given methyl 3,3bis(1,3-dimethyl-1H-indol-2-yl)propanoate, methyl 1,5-dimethyl-1H-benzo[b]azepine-3-carboxylate and methyl 3,3,3-tris(1,3-dimethyl-1H-indol-2-yl)propanoate. The reaction of 1,3-dimethylindole with 2cyclopentenone was yielded a typical addition product, similarly the reaction of indole and 1-methylindole with 2-cyclopentenone were concluded the expected addition products only.


INTRODUCTION
Indole and its derivatives are components of drugs founded in many pharmaceutical compounds 1−4 and are crucial building blocks for biologically active compounds. 5,6The Michael addition of indoles to α,βunsaturated carbonyl compounds are an useful reaction for medicinal chemistry applications.−13 Trisindolyl amines are reported to be important intermediates for the development of new drugs with potential ironchelating abilities. 14However, for years, many synthetic methods for the preparation of the biologically important, diindolyl 15−22 and trisindolylalkanes, 23−27 have been reported and most of these procedures either in strong acidic conditions, 28,29 expensive reagents and catalysts involved 30−35 or they were carried out under dry conditions using microwaves 36,37 and ultrasound accelerated methods. 38nvironmentally, Benign chemical processes using less hazardous catalysts has become a primary goal in synthetic organic chemistry.In this work, the reactions of indole, 1-methylindole and 1,3-dimethylindole with methyl propiolate and 2-cyclopentenone in dichloromethane under mild conditions using K-10 montmorillonite as catalyst is described.The reactions of indole and methyl-substituted indoles with α,β-unsaturated carbonyl compounds with an initial attack at the preferred 3-position of the indoles were followed by rearrangement to the 2-position.This type of rearrangement has been previously reported by Jackson et al. 39−41 Treatment of indole(1) and 1-methylindole(2) with methyl propiolate in dichloromethane in the presence K10 montmorillonite, occurred just at that position to give methyl 3,3-di(1H-indol-2-yl)propanoate(4) and 3,3-bis(1-methyl-1H-indol-2-yl)propanoate(5) (Scheme 1).The C 3 atom in the indole molecule is the most active in electrophilic substitution processes. 23,31In the molecule of 1,3-dimethylindole(3), because the 3position is occupied by methyl group, from the addition reaction of 1,3-dimethylindole(3) to methyl propiolate in dichloromethane and K-10 Montmorllonite catalyst were obtained three different products in one pot;   8) respectively (Scheme 2).Substituted benzoazepines possess a broad spectrum of biological activities. 42They are of moderate size giving rise to their potential as ligands for receptors and offer semi-restricted conformational flexibility allowing considerable scope for selective binding with a range of functional groups. 14Benzoazepine type compounds were previously synthesized from the 2-methoxyindole and dimethyl pyrroles in 1966. 43It is worth mentioning that in previous work, 44 we have reported the synthesis of dimethyl 2-(2-methyl-1H-methylindol-3-yl)maleate and dimethyl 2-methyl-1H-1-benzazopine-3,4-dicarboxylate from the reaction of 2-metylindole with dimethyl acetylenedicarboxylate.From the reaction 1,3-dimethylindole and dimethyl acetylenedicarboxylate were isolated dimethyl 1,5-dimethyl-1H-1-benzoazepine-3,4dicarboxylate.In 1,3-dimethylindole with methylpropiolate reaction as a successful example of the ring expansion was obtained methyl 1,5-dimethyl-1H benzo[b]azepin-3-carboxylate (7).
Indole(1), 1-methylindole(2) and 1,3-Dimethylindole(3) was also reacted with 2-cyclopentenone under the same conditions and in this reaction, it is yielded only Michael addition products (Scheme 3).We have found that Montmorillonite smoothly catalyzes in these reactions leading to two C-C bonds and thus affording the desired products in one pot.

EXPERIMENTAL Material
All chemicals were purchased from Merck, Fluka and Sigma-Aldrich and Montmorillonite K-10 clay was purchased from Fluka AG, Switzerland.TLC was carried out on aluminum sheets precoated with silica gel 60 F 254 (Merck), and the spots were visualized with UV light (λ = 254 nm).Column chromatography was conducted on silica gel 60 (40−63 μm).The melting points were determined on an Electrotermal A 9100 melting point apparatus.The NMR spectra were recorded on a Bruker DPX-400 spectrometer.Chemical shifts are reported in parts per million relative to CHCl 3 ( 1 H: δ = 7.27), CDCl 3 ( 13 C: δ = 77.0ppm) and CCl 4 ( 13 C: δ = 96.4ppm).The IR spectra were measured in KBr on a Jasco FTIR 300E spectrometer.The mass spectra were run on an LC/MS, AGILENT 1100 MSD system.The elemental compositions were determined using a LECO CHNS-932 analyzer.

Synthesis of 3-(1-methyl-1H-indol-3-yl)cyclopentanone(10)
4 g of Montmorillonite was added in to a mixture of 8 mmol of 1-methylindole and 4 mmol of 2cyclopentenone in 40 mL dicloromethane.The mixture was refluxed for 4 h and the reaction product was flash chromatographed using ethylacetate / petroleum ether
Substituted benzoazepines possess a broad spectrum of biological activities, as the benzoazepine ring is a major fragment of a series of alkaloids. 33,47However, when the resonate was further attacked by a second molecule of 1,3-dimethyl indole, the reaction was also proceeded with the attack at the 3-position followed by rearrangement to the 2-position to give the methyl 3,3-bis(1,3dimethyl-1H-indol-2-yl)propanoate(6) at higher yield.Jackson et al have previously reported similar type of rearrangement. 41The methyl 3,3,3-tris(1,3-dimethyl-1H-indol-2-yl)propano-ate( 8) was obtained at lower yield.The reaction of indole and 1-methylindole with methyl propiolate gave only diindolyl products and no cyclization or trisindolyl products were observed (Scheme 1).

CONCLUSION
−47 The reaction is a typical Michael type 1,4-addition or conjugate addition of resonance-stabilized carbanions of the methyl propiolate.The reaction of indole and 1methylindole with methyl propiolate could afford addition products and bisindolyl products only (Scheme 1).However, Montmorillonite smoothly catalyzes these reactions leading to two C-C bonds.The use of clay in these reactions was found to be very attractive, because of its environmental compatibility.Many protic acids and Lewis acids that are used in these reactions are sometimes deactivated.When Lewis acids are used, the excess acid can liberate as harmful mixtures to the eco system.