N-phosphorylated nitrogen mustards; Preparation of 2-chloroethyl-and bis(2-chloroethyl)-amides with the benzodiazaphosphorinone ring system

Article abstract of DOI:10.1080/10426509708043542

The reaction of isatoic acid anhydride 1 with NaH/BrCH₂CH₂Cl furnished the N-(2-chloroethyl) substituted derivative 2, which was allowed to react with methylamine to form N-(2-chloroethyl)-N'-methylanthranilamide 3. Treatment of 3 with PCl₃ furnished the 1,3,2-diazaphosphorin-4-one 4, which reacted with bis(2-chloroethyl) amine hydrochloride to form the P-bis(2-chloroethyl)amino derivative 5 by substitution at phosphorus. Oxidation of 5 with the hydrogen peroxide/urea 1:1 adduct led to the phosphoryl species 6. The σ⁴P-derivative 7 was formed by hydrolysis of 4 with small amounts of water. Treatment of the P-chloro derivative 8 with (CH₃)₃SiOCH₃ furnished the methoxy-substituted compound 9, which formed the phosphoryl derivative 10 upon reaction with SO₂Cl₂. The previously known bis(2-chloroethyl)amino-substituted 1,3,2-benzodiazaphosphorin-4-on-2-oxide 11 was synthesized by reaction of 10 with bis(2-chloroethyl)amine hydrochloride/triethylamine. The P-2-chloroethylamino-substituted derivative 12 was obtained by treatment of 8 with 2-chloroethylamine hydrochloride/triethylamine. The structures of 3, 4 and 5 were confirmed by single crystal X-ray structure determination. In 3 the molecules are linked into chains by hydrogen bonds of the form N-H...O=C between amide groups. The heterocycles of 4 and 5 display half-boat conformation with the P atom out of plane.