Green and efficient technique for the three component synthesis of 2-aminothiophenes using ball-milling method through Gewald reaction

In this paper, a simple, green, and efficient approach was used to the synthesis of various 2aminothiophenes derivatives with excellent yields (97%) in a short reaction time under ball milling technique without any solvent and any catalyst through Gewald reaction. A direct condensation of an equimolar amount of an ethyl acetoacetat/2-butanone, malononitrile/ethyl cynoacetate, and elemental sulfur under ball milling offered 2-aminothiophenes derivatives in


INTRODUCTION
Highly substituted thiophene derivatives have attracted considerable attention due to their importance in pharmaceutical and industrial fields.[1][2][3][4][5][6][7][8] The substituted 2-aminpthiophenes are reported to possess various biological activities such as adenosine receptor A3 inhibitors [9], phosphatase PTP1B inhibitors [10] and serotonin receptor subtype 5-HT1A inhibitors.[11] Several methods were reported in the literature for the synthesis of these heterocycles.[12−18] Nevertheless, the application of these methods with organic solvents and different catalysts leads to low yields of 2-aminpthiophenes with long reaction durations.Scholars have also increasingly focused on reduction of any source of pollution.Thus, efficient, clean, and flexible synthesis methods must be developed.
The present research paper investigates a high-yielding one-pot three-component synthesis of 2-aminpthiophene derivatives using ball-milling technique under solvent-and catalyst-free conditions.

RESULTS AND DISCUSSION
As a continuation of our research interest on the applications of ball milling in organic synthesis [37,38], we report in this paper an eco-friendly, effective, and high-yield synthesis of 2-aminothiophene derivatives via a Gewald three component reaction.In this technique, ethyl acetoacetate/2-butanone, malonitrile/ethyl cynoacetate and elemental sulfur are directly placed in a simple planetary ball mill under solvent-and catalyst-free conditions (Scheme 1).

Scheme 1. 2-aminothiophene derivatives synthesis using planetary ball milling technique
To optimize the conditions for the synthesis of 2-aminothiophenes, we placed ethyl acetoacetate (0.02 mol), malonitrile (0.02 mol), and elemental sulfur (0.02 mol) (with a total mass of 4.56 g) in a tempered vial.We subsequently added 22.80 g of balls (ratio of the ball weight to the reagent weight is equal to 5) [37].The progress of the reaction was monitored every 10 min of the milling cycle via thin-layer chromatography (TLC).2-aminothiophene (3a) yield was low at low rotation speed of 250 rpm, whereas 2-aminothiophene (3a) yield was high after a short reaction time at 750 rpm (Table 1).Similar conditions were applied to different reactions, and all the synthesized products were obtained in the same time (30 min).

CONCLUSION
We described a simple, operational, and green one-pot synthesis of 2-aminothiophens (Table 2) via a Gewald three component reaction using the ball milling technique.This economical and eco-friendly method can be used to synthesize all products in a short period of time and with high yields.

EXPERIMENTAL PART 1. Materials and Techniques
The ball mill used in this study was a Planetary Micro Mill PULVERISETTE 7 classic line with 10 cm 3 stainless steel vials.Melting points were determined using the Stuart Melting point apparatus SMP10.The IR spectra were obtained using an FT-IR-Tensor 27 spectrometer in KBr pellets.The 1 H and 13 C NMR spectra were determined using a BRUKER 300 NMR spectrometer in CDCL3 with TMS as the internal standard.Chemical shifts are expressed as δ ppm units.The progress of all reactions was monitored via TLC on silica gel 60 (Merck) by using a chloroform-ethanol system.

General Procedure for the Synthesis of Pyridine Compound 3a
A mixture of ethyl acetoacetate (0.02 mol), malonitrile (0.02 mol), and elemental sulfur (0.02 mol) with a total mass equal to 4.56 g was placed in tempered vials with 22.80 g of tempered balls (ratio of the ball weight to the reagent weight is equal to 5).The vials were closed and then placed in a Planetary Micro Mill PULVERISETTE 7 classic line.Crude compound 3a was obtained after 30 min of milling time and purified via recrystallization in ethyl acetate.

Table . 1
Comparison of the effect of different rotation speeds conditions for the condensation of ethyl acetoacetate (1a), malonitrile (2a) and elemental sulfur.