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

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)tetrachloroquinazolin-2,4-dione 2. We anticipated that these novel heterocyclic compounds would possess certain pharmacological activities.


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.
The reaction of compound 2 with potassium isothiocyanate may proceed according to the mechanism (Dimrothtype rearrangement) [17] shown in Scheme 2.
Formation of compounds 4a and 4b may proceed according to the mechanism shown in Scheme 3.

Biological Activity
Salmonella typhi, Staphylococcus aureus, and Bacillus cereus were obtained from the Faculty of Veterinary Medicine, Pathology Department.The three kinds of selected bacteria were grown on the appropriate media.
The two most active compounds tested are compounds 2 and 5.The activity of these compounds against all microorganisms tested showed positive reactions as indicated by zone of inhibition (Table 2); this may be due to four and five chlorine atoms [18], respectively.Compound 1 has approximately the same antibacterial activity against Staph.areus and Bacillus cereus.Compound 1 did not show any inhibition activity against Salmonella typhi.However, 1 showed a moderate antibacterial effect compared to other compounds, and this may be due to the tetrachloro pyrimidine [19][20][21].

Experimental
Scheme 1

Table 1 :
Electron impact mass spectra were obtained at 70 ev using a GCMS sp.1000 Shimadzu.Elemental analyses were carried out at the Microanalysis Unit at Cairo University.The purity of the compounds was detected by TLC.Physical properties and elemental analysis data.