Synthesis and Characterization of Novel Coumarin Incorporated Isatins and Some Urea Analogs

Abstract

Isatin and coumarin are two heterocyclic molecules of tremendous importance in medicinal chemistry. Current research in this field suggests that hybridization of biologically active molecules is a novel strategy to generate robust pharmacophores and to solve resistance problems. In this context, a variety of novel coumarin incorporated isatins (290-302) & (303-312) have been synthesized and structurally characterized. The reaction of 4-hydroxy coumarin and epichlorohydrin in dry acetone in the presence oftriethylamine as base, provided 4-(oxiran-2-ylmethoxy)-2H-chromen-2-one (265) in 73% yield which was further reacted with isatin in DMF solvent containing NaH base to afford coumarin incorporated isatin intermediate (266) in 61 % yield. This intermediate was then reacted with a series ofthiosemicarbazides (267-279) and hydrazides (280-289) to furnish targeted thiosemicarbazones (290-302) and hydrazones (303-312) of coumarin incorporated isatin in good to excellent yields. Urea functionality is a part of various clinically approved therapies and numerous bioactive compounds. The hydrogen bonding capability of urea with proteins and receptor targets make it an important functionality to be included in drug design for establishing the key drug-target interactions and tuning the drug-like properties. Hence, the interest in the urea derivatives is ever growing especially in the field of medicinal chemistry. In view of this importance, a variety of new urea derivatives namely, N-allylureas (313-320), 0- allylureas (321-328) and indolines (329-330) have been synthesized and characterized. The reaction of N-allylaniline and o-allylaniline with a series of isocyanates in dry dichloromethane at room temperature afforded N-allylureas (313-320) and o-allylureas (321-328) in 74-89% and 73-91% yields, respectively. Interestingly, the o-allylurea bearing trifluoromethyl and nitro substituents (322) and (324) react with o-allyl aniline in the presence of catalytic amounts of silica gel to afford respective indo lines (329-330) in 89% and 84 % yields respectively. This reaction most probably proceeds on the surface of silica gel that promotes intramolecular amination by a nucleophilic attack on terminal alkene, followed by internal proton transfer to give cyclized products. The electro cyclization of N-allyl urea analogs was also carried out to afford a series of cyclic urea derivatives (331-335) in good to excellent yields using 9-1 OmA current and in the presence