Synthesis and Reactions of 3-(2-Chloromethyl-carbonylamino)tetrachloroquinazolin-2,4-dione

A series of tetrachloroquinazolin-2,4-dione derivatives were synthesized using appropriate synthetic route and characterized by IR, 1H NMR, MS, and elemental analysis. The synthesized compounds were evaluated for their preliminary in vitro antibacterial activity towards Salmonella typhi, Staphylococcus aureus, and Bacillus cereus. 1. Introduction Pyrimidine and quinazoline derivatives have occupied a unique position in medicinal chemistry; the pyrimidine ring is present in a large number of biological important compounds [1] such as alkaloids, drugs, and agrochemicals. Furthermore, pyrimidine and condensed pyrimidines have received much attention over the years because of their interesting biological and pharmacological properties as sedatives [2] and antibacterial [3–8], antimalarial [2], analgesic [2, 4, 7], anti-inflammatory [2, 3, 7], anticonvulsant [8], antipyretic [5], antiparasitic [5], antifungal [6, 9], antitoxic [10], antiviral [8, 10, 11], anticancer [12–15], and DNA-binding activities [14]. This encouraged us to develop new synthetic route for the synthesis of new quinazoline derivatives by introducing a heterocyclic moiety directly or through side chain in position 3 starting with 3-(2-chloromethylcarbonylamino)tetrachloro-quinazolin-2,4-dione 2. We anticipated that these novel heterocyclic compounds would possess certain pharmacological activities. 2. Results and Discussion The reaction sequences employed for synthesis of the target compounds are shown in Scheme 1, and their physical properties are depicted in Table 1. The key intermediate in the present study, 3-(2-chloromethylcarbonylamino)tetrachloroquinazolin-2,4-dione 2, was prepared by the reaction of 3-aminotetrachloroquinazolin-2,4-dione [16] 1 with chloroacetyl chloride. Reaction of the starting compound 2 with potassium isothiocyanate gave 3. It was expected that the imino group could be hydrolyzed but ammonia odour was not detected during the reaction. The preparation of 4a,b was achieved by the reaction of compound 2 with urea and/or thiourea under basic condition. Compound 5 was synthesized by heating compound 2 with piperidine in dioxane. Table 1: Physical properties and elemental analysis data. Scheme 1 The reaction of compound 2 with potassium isothiocyanate may proceed according to the mechanism (Dimroth-type rearrangement) [17] shown in Scheme 2. Scheme 2 Formation of compounds 4a and 4b may proceed according to the mechanism shown in Scheme 3. Scheme 3 3. Biological Activity Salmonella typhi, Staphylococcus aureus, and Bacillus cereus were obtained from the Faculty of