One-pot, regioselective synthesis of functionalized indole derivatives: a three-component domino reaction of arylamine, arylglyoxal, and 4-hydroxycoumarin or 4-hydroxy-6-methyl-2-pyrone

A metal free, one-pot tandem synthetic routes for functionalized indole derivatives has been established. An efficient three-component reaction was designed with incorporation of Knoevenagel condensation followed by inter-, and intramolecular nucleophilic addition reaction in one-pot under mild condition. The structural diversities of the synthesized compounds have been confirmed spectroscopically, by IR, 1 H-and 13 C NMR, and elemental analyses which agree with the proposed structures.


Introduction
The indole motifs are one of the most important and abundant nitrogen-containing heterocyclic compounds found in important natural products, various functional molecules, and pharmaceuticals. 1 Indole analogs are very interesting to organic and medicinal chemists due to their biological activities, such as, anti-inflammatory A, 2 antimicrobial B, 3 antioxidant C, 4 and antibacterial D activity (Figure 1). 5 In addition, many indole derivatives have exhibited high cytotoxic activity against breast, esophageal, colonic, lung, and stomach tumor cell lines. 6,7Moreover, indole cores can be found in the structure of different drugs such as sumatriptan, 8 reserpine, 9 and lotronex. 10On the other hand, among indole and its structural analogs, especially indolyl chromene and indolyl pyran derivatives, are found in a large number of pharmacological activities, such as antibacterial E, 11 antimicrobial F, 12,13 anticancer G, 14 antioxidant H, 15,16 and antifungal I activities (Figure 2). 17Therefore, studies on strategies for the synthesis of indole derivatives have received high importance in organic synthesis.In this regard, there are many traditional methods for the preparation of indole derivatives including Fischer reaction, 18,19 Bischler reaction, 20 Reissert reaction, 21 Bartoli reaction, 22 and Leimgruber-Batcho reaction. 234][35][36] Most of these protocols appear to suffer from some drawbacks such as tedious experimental procedures, difficult reaction conditions, multiple synthetic steps, low yields, and usage of expensive catalysts and reagents.Therefore, the development of more economic, convenient and efficient approaches to the regioselective synthesis of substituted indoles under mild conditions is still an attractive proposition.In continuation of our previous works on the application of arylglyoxal in synthesis of heterocyclic compounds, 37,38 we herein report new synthetic strategy for the domino arylamine, arylglyoxal, and 4hydroxycoumarin or 4-hydroxy-6-methyl-2-pyrone yielding the synthesis of functionalized indole derivatives with high yields.
As can be seen from Table 2, the nature of the arylamine, the arylglyoxal, and the 1,3-dicarbonyl compounds was important.When the arylamine derivatives especially with electron-donating groups, the arylglyoxal derivatives with electron-withdrawing groups, and the 1,3-dicarbonyl compounds such as 4hydroxycoumarin were employed, a higher yield was achieved.All the synthesized compounds were unknown, and were characterized by 1 H and 13 C NMR, IR, CHN analysis and melting points.For instance, the 1 H NMR spectrum of the compound 4a consisted of one singlet at δ = 2.65 ppm for the three hydrogens of the methyl group.A singlet that integrated for three protons was observed at δ = 3.33 ppm for the methoxy protons.The aromatic protons resonated in the region δ = 6.29-7.49ppm, and a broad singlet that integrated for one hydrogen was observed at δ = 9.71 ppm for the hydroxyl proton.A broad singlet at δ = 10.52 ppm for the proton of the nitrogen group.The 13

Conclusions
In summary, we have reported the development of a facile synthesis of functionalized indol derivatives using a one-pot, three-component process through Knoevenagel condensation followed by inter-, and intramolecular nucleophilic addition reaction.Using this method, we were able to assemble a wide range of indol derivatives with good to excellent yields in a single step.The salient feature of our protocol is high atom-economy, operational simplicity, easy work-up, and easily available precursors.

Experimental Section
General.All chemicals were purchased from Aldrich and Merck with high-grade quality, and used without any purification.All melting points were obtained by Barnstead Electrothermal 9200 apparatus and are uncorrected.The reactions were monitored by TLC and all yields refer to isolated products.NMR spectra were obtained on a Varian 500 MHz spectrometer ( 1 H NMR at 500 MHz, 13 C NMR at 125 MHz) in DMSO using TMS as an internal standard.Infrared spectra were recorded on a Bruker FT-IR Equinax-55 spectrophotometer in KBr with absorption in cm -1 .Elemental analyses were performed using a Carlo Erba EA 1108 instrument.All products were characterized by their spectral and physical data.
General procedure for the synthesis of compounds 4a-i.A mixture of arylamine 1 (1.5 mmol) and arylglyoxal 2 (1.5 mmol) was stirred in 15 mL of ethanol at reflux for 2 h. to give iminone.Then, 4-hydroxycoumarin 3 (1.0 mmol) was added, and obtained mixture was refluxed for 8 h.After completion of the reaction, determined by TLC, the solvent was removed under reduced pressure, and the resulting crude product was purifed by washing with diethyl ether then, by simple filtration and washing with cold ethyl acetate to give the pure compounds 4a-i (78-94%).General procedure for the synthesis of compounds 6a-f.

Table 1 .
Optimization of the reaction conditions a Reaction conditions: solvent was 15 mL, reaction time was 10 h.b Isolated yields.c Reaction time was 24 h.