Formation of indole trimers in Vilsmeier type reactions

The reaction of indole with the complex formed from 1,3-dimethylimidazolidin-2-one or N -methyloxindole with phosphorus oxychloride (phosphoryl chloride), was studied. In similar reactions of five-membered tertiary amide rings, 3-(1-alkyl-pyrrolidin-2-ylidene)-3 H -indoles or ring opening products were obtained but in these cases, new products N 1 ,N 2 -dimethyl-N 1 -[tri-(1 H -indol-3-yl)methyl]ethane-1,2-diamine and N -methyl-2- (3,3,3-tri-(1 H -indol-3-yl)propyl)aniline as trimers of indole were obtained


Introduction
The reaction of indole with the Vilsmeier reagent, followed by base, is the classic and very efficient method for the 3-formylation of indoles. 1 3-Acylindoles can be obtained from Vilsmeier reaction of indole and tertiary amides in combination with phosphorus oxychloride. 2However, when 1-methylpyrrolidin-2-one is used as the cyclic amide component, 3-(1-methylpyrrolidin-2-ylidene)-3H-indole (1) is the product, without formation of an amino ketone product (2) (Scheme 1). 3,4Compound 1 contains an intriguing combination of enamine and imine (as part of a 3H-indole) groups in conjugation.Usually the primary products, resulting from the Vilsmeier-Haack acylation, are hydrolyzed immediately without isolation of the intermediate iminium salts. 5Iminium chemistry is the basis of an important formylation reaction of aromatic and heteroaromatic ring systems.Iminium salts and their neutral relatives, the imines, have found importance in the synthesis of heterocyclic ring systems. 6They react as electrophiles with electron-rich systems such as indoles. 7The iminium ion has a short lifetime in water and it is known to have an even shorter lifetime in the presence of a strong nucleophilic reagent. 8ndole derivatives are widely distributed in nature and are known as an important class of heterocyclic compounds and bioactive intermediates in pharmaceutical industry. 9Various derivatives of indole have been synthesized to study their bioactivity.Thus di-and tri-indolylmethanes are well known, and the electrophilic substitution reaction of indoles with carbonyl compounds is an important method for their preparation.Bis(indolyl)methanes promote beneficial estrogen metabolism and induce apoptosis in human cancer cells. 102][13][14][15] Many simple indoles and bisindoles have been shown to have interesting biological activities. 16,17It is reported that triindolylmethane cations could be used as the acceptors of hydride ions. 18However, there is no report on the biological activity of triindoles, especially, triindolylmethanes.

Results and Discussion
Our interest in this type of reaction promoted us to test the use of 1,3-dimethylimidazolidin-2-one (3) and N-methyloxindole (4).When 1,3-dimethylimidazolidin-2-one, instead of 1-methylpyrrolidin-2-one, was reacted with phosphorus oxychloride at -10 to 0 °C, an active complex was obtained that took a different path in its reaction with indole.The expected products ( 5) or ( 6) by analogy were not formed, but instead reaction proceeded to a trimer of indole with structure 7 (Scheme 2).Identification and confirmation of the product structure (7) was carried out using various spectroscopic methods.In the 1 H-NMR spectrum, the -NH signals of indole rings and secondary amine, in a 3 to 1 ratio, were observed as single peaks at δ 10.77 ppm and δ 9.72 ppm respectively, which disappeared on addition a few drops of D 2 O.The UV absorption spectrum of the compound was similar to that of indole.The base peak in its mass spectrum was observed at m/z 447.A peak at m/z 331.13 belongs to the stable fragment ion (8), which ARKAT USA, Inc results by loss of an indole unit and is stabilized by conjugation with two indole rings on one side and a nitrogen atom on the other.We also studied the reaction of N-methyloxindole (4) as a tertiary cyclic amide with phosphorus oxychloride and indole.Although it is commercially available, we prepared it from isatin. 25In this method, isatin was first N-methylated using methyl iodide and then N-methyloxindole (4) was obtained in high yield by reduction with a Wolff-Kishner procedure. 26reatment of N-methyloxindole with indole under Vilsmeier reaction conditions produced N-methyl-2- In the 1 H-NMR spectrum of 9, signals for the N-methyl, methylene and the NH of the indole rings were observed at δ 2.18, δ 3.71 and δ 4.47 ppm respectively.The main peak in the mass spectrum was observed at m/z 480.A suggested mechanism of this reaction is shown in Scheme 4.

Conclusions
In conclusion, we have reported a simple and convenient method for the synthesis of tri-(1H-indol-3-yl) derivatives by Vilsmeier-type reactions of indole with 1,3-dimethylimidazolidin-2-one and N-methyloxindole.

Experimental Section
General.Melting points were taken on a Philip Harris C4954718 apparatus.Infrared spectra were recorded on a Thermo Nicolet (Nexus 670) Fourier transform (FT) infrared spectrometer, using sodium chloride cells and measured in KBr pellets. 1 H (300 MHz) and 13 C (75.5 MHz) NMR spectra were recorded on a Bruker 300 spectrometer using TMS as the internal reference.Mass spectra were recorded on Agilent 6890-N-Network-GC-system.Analytical thin-layer chromatography's (TLC) were carried out on Merck silica gel 60 F 254 aluminum sheets and detection was made with the help of a UV lamp (λ 254 nm).The ultraviolet spectra were recorded with a Perkin Elmer Lambda 25 UV device.Microanalyses were performed on a Leco Analyzer 932.N 1 ,N 2 -Dimethyl-N 1 -[tri-(1H-indol-3-yl)methyl]ethane-1,2-diamine (7).To 1,3-dimethylimidazolidin-2-one (3) (4 mL, 0.04 mol) cooled in an ice bath was added POCl 3 (4.08 g, 0.026 mol) with stirring during 30 min.The temperature was maintained at -10-0 °C.The mixture was stirred an additional 10 min, and then a solution of indole (2.80 g, 0.024 mol) in 1,3-dimethylimidazolidine-2-one (4 mL, 0.04 mol) was added slowly during 2 h.The temperature rose to 45 °C.The mixture was heated at 80 °C for 3 h, and then mixed with water (100 mL).Some sediment began to form on dropwise addition of H 2 O.The solid was filtered off and washed with water.

Scheme 4 .
Scheme 4. Proposed mechanism for the synthesis of compound 9 from the reaction of N-methyloxindole (4) with phosphorus oxychloride and indole.