Nucleic Acid Related Compounds. 116. Nonaqueous Diazotization of Aminopurine Nucleosides. Mechanistic Considerations and Efficient Procedures with tert-Butyl Nitrite or Sodium Nitrite^,1

Abstract

Nonaqueous diazotization-dediazoniation of two types of aminopurine nucleoside derivatives has been investigated. Treatment of 9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-2-amino-6-chloropurine (1) with SbCl(3)/CH(2)Cl(2) was examined with benzyltriethylammonium (BTEA) chloride as a soluble halide source and tert-butyl nitrite (TBN) or sodium nitrite as the diazotization reagent. Optimized yields (>80%) of the 2,6-dichloropurine derivative were obtained with SbCl(3). Combinations with SbBr(3)/CH(2)Br(2) gave the 2-bromo-6-chloropurine product (>60%), and SbI(3)/CH(2)I(2)/THF gave the 2-iodo-6-chloropurine derivative (>45%). Antimony trihalide catalysis was highly beneficial. Mixed combinations (SbX(3)/CH(2)X'(2); X/X' = Br/Cl) gave mixtures of 2-(bromo, chloro, and hydro)-6-chloropurine derivatives that were dependent on reaction conditions. Addition of iodoacetic acid (IAA) resulted in diversion of purine radical species into a 2-iodo-6-chloropurine derivative with commensurate loss of other radical-derived products. This allowed evaluation of the efficiency of SbX(3)-promoted cation-derived dediazoniations relative to radical-derived reactions. Efficient conversions of adenosine, 2'-deoxyadenosine, and related adenine nucleosides into 6-halopurine derivatives of current interest were developed with analogous combinations.

Synthesis and Biological Evaluation of 2',3'-Didehydro-2',3'-Dideoxy-9-Deazaguanosine, a Monophosphate Prodrug and Two Analogues, 2',3'-Dideoxy-9-Deazaguanosine and 2',3'-Didehydro-2',3'-Dideoxy-9-Deazainosine

“…Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane in anhydrous THF gave a number of complicated products along with compound 4, which was isolated in 10-15% yield by silica gel column chromatography. The results were consistent with reports [18,19] that diazotization of electron-deficient heterocyclic SCHEME 2 Synthesis of the mononucleotide prodrug of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, 2',3'-dideoxy-9-deazaguanosine, and 2'3'-didehydro-2',3'-dideoxy-9-deazainosine. amines was problematic and multiple decomposition pathways were possible for transient purinediazonium species, which led to the various complicated products.…”

Synthesis of N6,N6‐Dialkyladenine Nucleosides Using Hexaalkylphosphorus Triamides Produced in Situ

“…[6] In order to circumvent some of the problems associated with access to electrophilic nucleoside precursors, non-aqueous diazotization methods have been developed. [7] Nevertheless, newer and simpler methods are needed for the synthesis of N -modified adenine nucleosides.…”

Straightforward Pyrimidine Ring Construction: A Versatile Tool for the Synthesis of Nucleobase and Nucleoside Analogues

“…In order to avoid side reactions on protected alcohol functions, sugar moiety deprotection was first examined (Scheme 7). Classical basic and nucleophilic conditions [19][20][21] could not be used as they would result in structural modifications on the pyrimidine moiety by methylsulfanyl substitution. Surprisingly, complete deacetylation of 44a took place quantitatively in methanolic medium.…”

“…In order to avoid side reactions on protected alcohol functions, sugar moiety deprotection was first examined (Scheme 7). Classical basic and nucleophilic conditions [19][20][21] could not be used as they would result in Scheme 7. O-Deprotection of the sugar moiety.…”