Ultrasound-accelerated arylthiomethylation of indole via multicomponent reaction in water catalyzed by acetic acid

Multicomponent reactions (MCRs) play an important role to create the molecular complexity in a one-step process. Based on the mechanism and process of Mannich-type reactions in the synthesis of Grammin, arylthiomethylation reactions of indole were performed by using three components: indole, p-thiocresol and a solution of formaldehyde (36%) under two activation conditions, e.g. magnetic stirring and ultrasonic irradiation. The main product, 3-(p-tolylthiomethyl)-1H-indole, was obtained in a moderate yield (54%) under short irradiation (40 minutes) by probe sonicator.


INTRODUCTION
Mannich reaction classified into multicomponent reactions (MCRs), has been fairly extensively investigated, while there are few studies using thiols in place of amines for Mannich-type reaction, namely alkylthiomethylation and arylthiomethylation.The latter has been used widely in organic chemistry, especially in total synthesis of natural products, e.g.sesquiterpenes and antibiotics [1][2][3][4][5].
In pursuit of our work on the analogue of the Mannich reaction, we report the arylthiomethylation involving indole, p-thiocresol and the solution of formaldehyde (36 %) to produce 3-(ptolylthiomethyl)-1H-indole under the assistance of ultrasound irradiation in comparison with the on under magnetic stirring (Fig. 1).According to our literature review on the three-component reaction of indole, alkanethiol/arenethiol and formaldehyde, it was found that only one article described the yield around 25 % of desired products obtained for six-day magnetic stirring [8].

Instrumentation
Ultrasonic irradiation was performed by means of a probe sonicator GE130-41505L with 1/8" (3 mm) stepped microtip, operating at frequency 20 kHz.GC/MS analyses were performed on Agilent 7890A apparatus equipped with HP 5MS capillary column (30 m x250 m x0.25 m) and 5973C VL MSD with Triple-Axis Detector, detector and injector temperature at 250 o C, gas carrier (Helium) at 11.104 mL/min (total flow), and oven temperature programme as follows: started at initial temperature is 50 o C (maintained 2 min), increased 10 o C/min up to 300 o C (maintained 4 min).GC analyses were performed on Agilent 6890N apparatus equipped with capillary column (30 m x320 m x0.25 m), detector and injector temperature at 250 o C, gas carrier (Nitrogen) at 1.0 mL/min (total flow), and oven temperature programme as follows: started at initial temperature is 80 o C (maintained 1 min), increased 25 o C/min up to 230 o C (maintained 1 min) and continued increasing up to 300 o C (maintained 2 min).NMR spectra were recorded on Bruker 500 NMR spectrometer at 500 MHz ( 1 H) and 125 MHz ( 13 C).

Chemicals
All commercially available chemicals used were purchased from Aldrich and analyzed for authenticity and purity by GC/MS prior to use.
General procedure of arylthiomethylation of indole with p-thiocresol and the solution of formaldehyde (36 %) into 3-(p-tolylthiomethyl)-1Hindole under ultrasound irradiation p-Thiocresol (0.248 g, 2.0 mmol) was added into the 25 mL two-neck pear flask containing 6 mL of water, then glacial acetic acid (0.180 g, 3 mmol), the formaldehyde (2.0 mmol, 36 % aq.) and the indole (0.351 g, 3.0 mmol) were added successively.The flask was equipped with the ultrasound probe and irradiated at a suitable amplitude for a specific period of time.Subsequently, 7 mL of water was added and the pH was adjusted to pH 11-13 by 20 % NaOH solution.The reaction mixture was extracted with dichloromethane (4 x 15 mL).The combined extracts were washed with water until pH 8, and then dried (anhydrous Na 2 SO 4 ).After removal of the solvent by rotatory evaporation, the crude product was analysed by GC or GC/MS.The product was isolated by flash column chromatography (4-7 g silica gel, Davisil, grade 710, 4-20 m, 60 A, 99 %) using as eluent a mixture of hexane and ethyl acetate (9:1 v/v).

RESULTS AND DISCUSSION
At the beginning of this work, the reactions of indole, p-thiocresol and the solution of formaldehyde without using catalyst were performed under magnetic stirring for 2.5 h.The results showed that the three-component reactions in the absence of the catalyst did not take place.This led us to test several catalysts such as CH 3 COOH, NiCl 2 .6H 2 O, Mg-Al Hydrotalcite, and KF/Al 2 O 3 (wt.40 %) for this arylthiomethylation.Consequently, it was noticeable that acetic acid played a crucial role in our multicomponent reaction (Table 1).
A series of experiments with different molar ratios between p-thiocresol and acetic acid, as well as p-thiocresol and indole, was carried out to improve the reaction yield (Entries 1-5, Table 2).The optimum yield was observed when 3.0 mmol of acetic acid was utilized as catalyst; whereas the excessive amount of this acidic catalyst led to a remarkable reduction of product yield owing to the deactivation of indole ring from the protonation of nitrogen atom under acidic media.a The reactions with a fixed amount of formaldehyde (2.0 mmol) and p-thiocresol (2.0 mmol) were conducted by magnetic stirring at room temperature.b Yields were calculated based on GC-FID analyses.c The reactions with a fixed amount of formaldehyde (2.0 mmol) and p-thiocresol (2.0 mmol) were assisted by probe sonicator with amplitude at 64 micrometer.
In the next step, the reaction time was investigated under two activation methods.In the first series of arylthiomethylation of indole, the mixture of reactants were allowed to react under magnetic stirring for 1.5 h, 2.5 h, 3.5 h and 24 h at room temperature (Entries 4, 6-8, Table 2).In the second series, some reactions performed under the ultrasound irradiation were compared with those above (Entries 9-12, Table 2).We first investigated the effect of ultrasonic amplitudes at 48 m, 64 m, 80 m, 96 m, and 128 m on the yield of desired indole.The results demonstrated that the most efficient amplitude to accelerate this reaction was at 64 m (Fig. 2).The comparison of the experiments activated by two methods showed that a maximum yield of 4 obtained by the three-component reaction with acetic acid as catalyst reached 54 % after forty-minute ultrasound irradiation, while it was 53 % after three and half hour magnetic stirring.It could be explained that the disruption of the phase boundary, owing to a formation of extremely fine emulsions from the mixture of immiscible liquids under ultrasonic irradiation, increased the interfacial contact area between the reactant layers [10].

Table 1 .
Effect of the catalyst nature on the arylthiomethylation of indole with p-thiocresol and the solution of formaldehyde a b Yields were calculated based on GC-FID analysis.

Table 2 .
Influence of reaction conditions on the yield of 3-(p-tolylthiomethyl)-1H-indole a