Synthesis and properties of 5‐(1,2‐dihaloethyl)‐2′‐deoxyuridines and related analogues

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 (Et 2 NSF 3 ) in methylene chloride at ‐40° gave the respective 5‐(1‐fluoro‐2‐chloroethyl)‐ ( 6a , 74%) and 5‐(1‐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 5‐(1‐hydroxy‐2‐bromoethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine ( 3b ) with thionyl chloride yielded the respective 5‐(1,2‐dichloroethyl)‐ ( 6f , 85%) and 5‐(1‐chloro‐2‐bromoethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine ( 6g , 50%), whereas a similar reaction employing the 5‐(1‐hydroxy‐2‐iodoethyl)‐ compound 3c afforded 5‐(1‐methoxy‐2‐iodoethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine ( 6c ), possibly via the unstable 5‐(1‐chloro‐2‐iodoethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine intermediate 6h . The 5‐(1‐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 5‐(1‐ethoxy‐2‐chloroethyl)‐ ( 6k ) and 5‐(1‐ethoxy‐2‐bromoethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine ( 61 ). 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‐5‐(2′‐deoxy‐β‐D‐ribofuranosyl)‐furano[2,3‐ d ]pyrimidine‐6(5 H )‐one ( 8 ). In contrast, a similar reaction of 5‐(1‐fluoro‐2‐chloroethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridine ( 6a ) yielded ( E )‐5‐(2‐chlorovinyl)‐2′‐deoxyuridine ( 1b , 23%) and 5‐(2′‐deoxy‐β‐D‐ribofuranosyl)furano[2,3‐ d ]pyrimidin‐6(5 H )‐one ( 9 , 13%). The mechanisms of the substitution and elimination reactions observed for these 5‐(1,2‐dihaloethyl)‐3′,5′‐di‐ O ‐acetyl‐2′‐deoxyuridines are described.