Nucleic acid related compounds. 34. Non-aqueous diazotization with tert-butyl nitrite. Introduction of fluorine, chlorine, and bromine at C-2 of purine nucleosides

Abstract

Treatment of 2,6-diamino-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (1c) with tert-butyl nitrite (TBN) in 60% anhydrous hydrogen fluoride/pyridine at −20 °C gave 2-fluoroadenosine triacetate (2) in 48% yield. Analogous treatment of the acetylated 2-amino-6-fluoropurine nucleoside (1a) gave the 2,6-difluoro compound (3a) in 63% yield. Anhydrous ammonia in 1,2-dimethoxy-ethane converted 3a → 2 without ammonolysis of the acetate groups. The overall conversion of 1a → 3a → 2 without isolation of 3a proceeded in 80% yield. Similar diazotization of the 2-amino-6-chloro nucleoside (1b) in HF/pyridine gave the 2-fluoro-6-chloro analogue (3b) in 89% yield. Treatment of 1b with TBN and pyridine hydrochloride in dichloromethane (77%) or TBN and antimony trichloride in 1,2-dichloroethane (84%) gave the 2,6-dichloropurine nucleoside (4b). The latter conditions converted 1a to the 2-chloro-6-fluoro product (4a) in 77% yield. Conversions of 1a and 1b to the 2-bromo-6-fluoro (5a, 67%) and 2-bromo-6-chloro (5b, 78%) analogues were effected using TBN and antimony tribromide in dibromomethane.