Brønsted acidic ionic liquid-promoted direct C3-acylation of N-unsubstituted indoles with acid anhydrides under microwave irradiation

A green and efficient pathway for the synthesis of 3-acylindoles using a Brønsted acidic ionic liquid as a catalyst has been developed for the first time. The C3-acylation of N-unsubstituted indoles with acid anhydrides affords the desired products in good to excellent yields with high regioselectivity under microwave irradiation. Moreover, the Brønsted acidic ionic liquid can be recycled up to four times without significant loss of catalytic activity.


Preparation of [(4-SO 3 H)BMIM]HSO 4 ionic liquid
[(4-SO 3 H)BMIM]HSO 4 ionic liquid has been prepared by two steps: formation of the zwitterionic intermediate and subsequent protonation by concentrated sulphuric acid. However, these methods suffered from some drawbacks such as low yields and long reaction times. 36,37,[57][58][59][60] Thus, the ultrasound irradiation was chosen to improve the reaction efficiency for the synthesis of [(4-SO 3 H)BMIM]HSO 4 . It should be noted that the two-step procedure provided [(4-SO 3 H)BMIM]HSO 4 in excellent yield within very short reaction time under solvent-free sonication (please see ESI, Tables S1 and S2 †). The structure of ionic liquid was characterized by NMR, FT-IR, and HR-MS (ESI). The ionic liquid is hygroscopic but moisture-stable and should be constantly stored in a desiccator.

Effect of reaction time and temperature for the C3propionylation of indole
The catalytic activity of the prepared [(4-SO 3 H)BMIM]HSO 4 was evaluated for the Friedel-Cras acylation of indoles with acid anhydrides under solvent-free microwave irradiation. To optimize the reaction conditions, the reaction of indole and propionic anhydride under microwave irradiation was conducted as a model reaction. Initially, the Friedel-Cras propionylation of indole in the presence of [(4-SO 3 H)BMIM]HSO 4 (25 mol%) under microwave irradiation at 60 C for 5 min was employed to prepare the desired product. To our surprise, the model reaction afforded the propionylindole in 46% yield with 100% regioselectivity in C3-position, and no impurity was found in TLC and GC (Table 1, entry 1). Aer screening the reaction conditions, we determined the optimal conditions at 100 C for 5 min for the formation of the corresponding product in 92% yield ( Table 1, entry 3). The control experiments were also carried out under conventional heating and ultrasound irradiation, but only a trace amount of 3-propionylindole was detected.
Effect of reaction time and amount of catalyst for the C3propionylation of indole Next, the amount of catalyst was varied from 5 to 100 mol% to study its effect on the yield of product. The results were presented in Table 2. The desired product was not detected in the absence of the catalyst (Table 2, entry 1). As only a small catalyst loading of 5 mol% was introduced to the reaction mixture, the desired product straightforwardly formed with a detectable yield of 35% (Table 2, entry 2). The best yield was obtained in 92% yield in the presence of 25 mol% of [(4-SO 3 H)BMIM]HSO 4 ionic liquid under solvent-free microwave irradiation at 100 C for 5 min ( Table 2, entry 4).

Effect of acylating reagents for the C3-propionylation of indole
With optimal reaction conditions in hand, we extended the current method to other acid anhydrides such as acetic, butyric, isobutyric, pivalic, and benzoic anhydride. The results were presented in Table 3. The desired products were obtained in good to excellent yields (65-92%) with over 95% selectivity in C3-position. The low yields of pivalic and benzoic anhydride were obtained under current method presumably due to steric effect (Table 3, entries 5 and 6). Interestingly, no 1,3-diacylated and polymerized products were obtained under current method. The selectivity to C3-acylation can be rationalized based on the electron-donating resonance from the lone pair on the nitrogen atom to C3 through C2, giving rise to a partially negative charge on C3. The resonance pathway via benzene ring to end up with a partially negative charge on C2 is disfavored because it destroys the aromaticity of the benzene ring. The higher reactivity of C3-center over unsubstituted-NH moiety in this method can be attributed to the assumption that a so electrophile as acid anhydride preferably attacks to a so nucleophilic C3-position rather than a hard center as unsubstituted-NH moiety. We also experimentally tested this hypothesis by conducting the same reaction in which a typical hard electrophile, benzoyl chloride, was employed as acylation reagent instead of acid anhydrides. As expected, the N-benzoylated product was selectively formed in the yield of 80%.

Investigation on recycling of [(4-SO 3 H)BMIM]HSO 4 ionic liquid for the C3-propionylation of indole
The reusability of [(4-SO 3 H)BMIM]HSO 4 ionic liquid was carried out in the model reaction at 100 C for 5 min under microwave irradiation. The results were reported in Table 5. Four consecutive runs were tested with less reduction in the catalytic activity. FT-IR spectra of fresh and recovered [(4-SO 3 H)BMIM] HSO 4 conrmed that the structure of ionic liquid kept unchanged.

Mechanism of C3-acylation of indoles by [(4-SO 3 H)BMIM] HSO 4 ionic liquid
Based on the previous literatures, we propose a plausible mechanism depicted in Scheme 1.

Chemicals, supplies, and instruments
All starting materials were purchased from Sigma-Aldrich and immediately used without further purication. Silica gel 230-400 mesh (for ash chromatography) and TLC plates were obtained from Merck. Microwave irradiation was used on a CEM Discover BenchMate. GC-MS spectra were performed on an Agilent GC System 7890 equipped with a mass selective detector Agilent 5973N. FT-IR spectra were analyzed by a Bruker Vertex 70. 1 H and 13 C NMR spectra were recorded on a Bruker Advance 500. HRMS (ESI) data were performed on Bruker micrOTOF-QII MS at 80 eV (please see in ESI, † Section S1).

Preparation of [(4-SO 3 H)BMIM]HSO 4 catalyst under solventfree sonication
The two-step procedure for the synthesis of ionic liquids from 1methylimidazole, 1,4-butane sultone, and sulfuric acid under ultrasound irradiation were reported in the Section S2 (please see ESI †).

General procedure for Friedel-Cras acylation of indole
Indole (1.0 mmol, 0.117 g), propionic anhydride (1.0 mmol, 0.130 g) and [(4-SO 3 H)BMIM]HSO 4 (25 mol%) was heated under microwave irradiation at 100 C for 5 min in a CEM Discover apparatus. The completion of the reaction was checked by TLC and GC. The mixture was then extracted with diethyl ether (5 Â 5 mL). The organic layer was decanted, washed with aqueous NaHCO 3 (2 Â 15 mL), water (15 mL) and brine (15 mL), and dried with Na 2 SO 4 . The solvent was removed under vacuum. The crude product was puried by silica gel chromatography using ethyl acetate-hexane (1 : 9). The puried product was then characterized by 1 H and 13 C NMR, GC-MS or HR-MS (ESI).

Recycling of [(4-SO 3 H)BMIM]HSO 4
The recycling of [(4-SO 3 H)BMIM]HSO 4 was also carried out under microwave irradiation in the model reaction between indole and propionic anhydride. Aer completion of the reaction, diethyl ether was used to extract the reaction mixture until both starting materials and products were entirely separated from the ionic liquid.

Conclusions
In summary, we have developed a green and efficient method using [(4-SO 3 H)BMIM]HSO 4 as an effective catalyst for the highly regioselective C3-acylation of N-unsubstituted indoles with acid anhydrides. Remarkably, the accelerated microwaveassisted Friedel-Cras acylation catalyzed by [(4-SO 3 H)BMIM] HSO 4 was reported for the rst time. Furthermore, the [(4-SO 3 H) BMIM]HSO 4 possesses several advantages including mild preparation from commercially available materials, easy handling, and recyclability without loss of reactivity. Finally, it provides a simple, facile, and efficient alternative to the existing synthetic methods of 3-acylindoles.

Conflicts of interest
There are no conicts to declare.