SYNTHESIS AND PROPERTIES OF 5-(1,2-DIHALOETHYL)-2'-DEOXYURIDINES AND RELATED ANALOGS

The regiospecific reaction of 5-vinyl-3',5'-di-O-acetyl-2'-deoxyuridine (2) with HOX (X = Cl, Br, I) yielded the corresponding 5-(1-hydroxy-2-haloethyl)-3',5'-di-O-acetyl-2'-deoxyuridines 3a-c. Alternatively, reaction of 2 with iodine monochloride in aqueous acetonitrile also afforded 5-(1-hydroxy-2-iodoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (3c). Treatment of 5-(1-hydroxy-2-chloroethyl)- (3a) and 5-(1-hydroxy-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (3b) with DAST (Et2NSF3) in methylene chloride at 40-degrees gave the respective 5-(1-fluoro-2-chloroethyl) (6a, 74%) and 541-fluoro-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6b, 65%). In contrast, 5-(1-fluoro-2-iodoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6e) could not be isolated due to its facile reaction with methanol, ethanol or water to yield the corresponding 5-(1-methoxy-2-iodoethyl)- (6c), 5-(1-ethoxy-2-iodoethyl) (6d) and 5-(1-hydroxy-2-iodoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (3c). Treatment of 5-(1-hydroxy-2-chloroethyl)- (3a) and 541-hydroxy-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (3b) with thionyl chloride yielded the respective 541,2-dichloroethyl)- (6f, 85%) and 241 'Chloro-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6g, 50%), whereas a similar reaction employing the 541-hydroxy-2-iodoethyl)- compound 3c afforded 541-methoxy-2-iodoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6c), possibly via the unstable 541-chloro-2-iodoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine intermediate 6h. The 541-bromo-2-chloroethyl)- (6i) and 5-(1,2-dibromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6j) could not be isolated due to their facile conversion to the corresponding 541-ethoxy-2-chloroethyl)- (6k) and 541-ethoxy-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6l). Reaction of 5-(1-hydroxy-2-bromoethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (3b) with methanolic ammonia, to remove the 3',5'-di-O-acetyl groups, gave 2,3-dihydro-3-hydroxy-542'-deoxy-bea-D-ribofuranosyl)-furano[2,3-d]pyrimidine-6(5H)-one (8). In contrast, a similar reaction of 541-fluoro-2-chloroethyl)-3',5'-di-O-acetyl-2'-deoxyuridine (6a) yielded (E)-542-chlorovinyl)-2'-deoxyuridine (lb, 23%) and 542'-deoxy-beta-D-ribofuranosyl)furano[2,3-d]pyrimidin-6(5H)-one (9, 13%). The mechanisms of the substitution and elimination reactions observed for these 541,2-dihaloethyl)-3',5'-di-O-acetyl-2'-deoxyuridines are described.