Abstract
In this paper, a simple, green, and efficient approach was used to the synthesis of various 2-aminothiophenes 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 acetoacetate/acetyl acetone, malononitrile/ethyl cynoacetate, and elemental sulfur under ball milling offered 2-aminothiophenes derivatives in 30 min at 750 rpm.
Highlights
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
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)
Operational, and green one-pot synthesis of 2-aminothiophens (Table 2) via a Gewald three component reaction using the ball milling technique
Summary
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] the application of these methods with organic solvents and different catalysts leads to low yields of 2-aminpthiophenes with long reaction durations. The use of the ball milling technique in organic synthesis has gained increasing attention over the last decades [19,120]. Ball milling is used to synthesize various types of organic compounds for the preparation of phosphorus ylides [21], reductive benzylation of malononitrile [22], functionalization of Knoevenagel condensations [23], functionalization of fullerenes [24], coordination polymers [25], synthesis of nitrones [26], protection of diols/diamines [27], Suzoku-type reaction [28], synthesis of functionalized indan-1,3-diones [29], aldol reaction [30,31], Heck-type reactions [32,33], symmetrical and unsymmetrical thioureas [34], pyrano pyrimidine-dione synthesis [35], functionalized 2- amino-3-cyano-4H-pyrans [36], and synthesis of thioxo- and oxo-pyrimidine-5-carbonitriles [37]
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