Organic Preparations and Procedures International | 2019
Facile Synthesis and Anticancer Activity of Novel 4-Aminothieno[2,3-d]pyrimidines and Triazolothienopyrimidines
Abstract
Thienopyrimidines play important roles in numerous biological activities. They are known to display multiple therapeutic properties, such as anti-inflammatory, antimicrobial, antiproliferative, antidiabetic and analgesic activities. They are structural analogs of biogenic purines and can be considered as potential nucleic acid antimetabolites. Consequently, preparation of thienopyrimidine derivatives with interesting biological activities has attracted particular attention and a variety of methods for the synthesis of thienopyrimidines have been developed. The most common method for synthesis of 4-aminothieno[2,3-d]pyrimidines involves the thermal ring closure of 2-(benzoylthioureido)thiophene-3-carbonitriles effected by sodium hydroxide in an ethanol–water mixture, followed by the addition of alkyl halides. In continuation of our interest in synthesizing biologically active heterocyclic compounds, we therefore designed a simple and facile synthesis of key reactant 2. Tetrahydrobenzo[b]thiophene derivative A was reacted with chloroacetyl chloride, furnishing the corresponding N-chloroacetylamino derivative 1 by a modified procedure of Sauter et al. (Scheme 1). Compound 1 was treated with ammonium thiocyanate in refluxing ethanol, affording the compound 2 rather than the 2-imino-4-oxothiazolidine derivative 3 (Scheme 1). In the infrared spectrum of the product, the appearance of strong absorption bands for the NH2 group at 3296 and 3134 cm 1 and the carbonyl ester group at 1735 cm 1 along with the absence of any absorption band for the nitrile group is in agreement with the structure 2 and ruled out the 2-imino-4-oxothiazolidine derivative 3. Moreover, in the H-NMR spectrum of compound 2, the appearance of a broad signal attributable to the NH2 protons at d 6.8 ppm and a quartet at d 4.12 ppm and a triplet at d 1.19 ppm confirmed the outcome of the cyclization reaction. Hydrazinolysis of compound 2 using hydrazine hydrate (1:1) in refluxing ethanol afforded colorless crystals which were identified as acetohydrazide 4 (Scheme 2). A number of novel 4-aminothieno[2,3-d]pyrimidines were then synthesized using the acid hydrazide 4 and treatment with different C-electrophiles. Thus, refluxing compound 4