Conjugate Addition of Indoles to α,β-Unsaturated Ketones Using a Brønsted Acid Ionic Liquid as an Efficient Catalyst

The Brønsted acid ionic liquid [PyN(CH2)4SO3H][p-CH3PhSO3] has been reported as an efficient catalyst for the Michael addition reaction of indoles to α,β-unsaturated ketones. Satisfactory results were obtained, with excellent yields and a simple experimental procedure. The catalyst could be recycled and reused up to three times without any noticeable decrease in the catalytic activity.


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Therefore, to avoid these limitations, the introduction of a more efficient method affording higher yields is needed. In recent years, ionic liquids (ILs) have attracted increasing interest in the context of Green Chemistry owing to their advantageous properties such as negligible vapor pressure, high chemical stability, etc. ILs have gone far beyond the role of solvent, showing their significant importance as new catalysts in controlling the reactions in which they participate [18,19]. Recently, the synthesis of ''task-specific'' ILs with special functions according to the requirement of a particular reaction has become an attractive field [20,21]. To the best of our knowledge, there have been no reports on the use of Brønsted acid ionic liquids as catalysts for Michael additions of indoles. Herein we wish to report for the first time a novel, environment-friendly and efficient methodology for the synthesis of βindolylketones by the reaction of indoles and α,β-unsaturated ketones using the SO 3 [9][10][11][12][13][14]. It was clear that the highest yield was produced when the reaction time was 6 h, although the yield did not improve to any greater extent when the reaction time was increased from 4 h to 6 h. For the purpose of saving energy, we therefore chose 4 h as the reaction time. Hence, the best condition employs 0.1:1:1 mole ratio of [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ], indole and chalcone at 80 °C for 4 h using acetonitrile as solvent.
When optimizing the reaction conditions, the recycling of the catalyst in the reaction of indole and chalcone was investigated. After the separation of products, ethyl acetate was added to the filtrate, which split into two layers. The upper ethyl acetate layer contained unreacted raw material. The lower aqueous layer included the ionic liquid. The lower layer was concentrated on a rotary evaporator at 80 °C for 1 h under vacuum to remove excess solvent. [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] could be recovered easily and directly reused in subsequent runs. As shown in Table 1, the desired product was obtained in 97, 93, 90% yields after 1-3 runs, respectively (entry 12 b ). This indicated that the ionic liquid [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] was an efficient and recyclable catalyst for the conjugated addtion of indoles to α, β-unsaturated ketones. To explore the generality and scope of this method, a wide variety of substituted indoles and α,βunsaturated ketones were reacted with 10 mol% of [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] catalyst under the optimized experimental conditions to afford the corresponding β-indolylketones in excellent yields. ( Table 2). The results obtained indicated that the electron donating or withdrawing groups at the indole ring did not seem to affect the reaction significantly in terms of yields, nor do aromatic rings of α,βunsaturated ketones.
A plausible mechanism for the conjugate addition of indoles to chalcones is proposed in Scheme 2.

Conclusions
In conclusion, we have described for the first use of the Brønsted acid ionic liquid [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] as an efficient catalyst for the synthesis of β-indolylketones. The procedure reported here has the advantages of mild reaction conditions, high yields of products, operational simplicity and catalyst recyclability.

General
All compounds were characterized by IR, 1 H-NMR spectra and elemental analysis. The IR spectra were obtained as potassium bromide pellets with a FTS-40 spectrometer (BIO-RAD, U.S.A). The 1 H-NMR spectra were obtained on a Varian Inova-400 spectrometer using DMSO-d 6 as solvent and TMS as an internal standard; chemical shifts are given in ppm. Elemental analyses (C, H, N) were performed on a Perkin-Elmer Analyzer 2400. Melting points were determined using a Büchi B-540 instrument. All melting points are uncorrected. The Brønsted acid ionic liquid [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] was synthesized according to previous literature [22].

General procedure for the synthesis of β-indolylketones
A mixture of indole or substituted indole (2 mmol), α,β-unsaturated ketone (2 mmol) and [PyN(CH 2 ) 4 SO 3 H][p-CH 3 PhSO 3 ] (0.2 mmol) was refluxed at 80 °C in acetonitrile (10 mL) for 4 h with stirring. The completion of the reaction was monitored by TLC. After cooling, the reaction mixture was poured onto crushed ice (30 g). The resulting precipitate was filtered under suction, and then recrystallized from ethanol to afford the pure product. The results are summarized in Tables 2. All products (except 3e, 3g, 3i, 3j, 3m) are known compounds, which were characterized by mp, IR, 1 H-NMR spectra, elemental analyses.