and co-workers have improved conversions of 6-chloropurine
nucleosides into the more SNAr-reactive 6-fluoro analogues.5
Ve´liz and Beal have reported deoxygenative chlorination and
bromination of 2′,3′,5′-tri-O-acetylinosine.6
analogous addition of the large and very weakly basic iodide
and elimination of triphenylphosphine oxide should be
significantly less favorable. The highly activated 6-[(phos-
phonium)oxy] intermediate should be susceptible to addition
of external nitrogen nucleophiles followed by elimination
of Ph3PdO.
Treatment of 5′-O-TBDMS-2′,3′-O-isopropylideneinosine
with I2/Ph3P/EtN(i-Pr)2 in the presence of a secondary
aliphatic amine (morpholine or piperidine) in toluene for ∼1
h at ambient temperature gave quantitative conversion (TLC)
into the 6-(morpholin-4-yl or piperidin-1-yl) products, which
were isolated as solid white foams (98-99%) by silica
column chromatography. Other initial reactions and displace-
ments were explored with this protecting group combination
for convenience in manipulation and isolation (excellent
yields in all cases). Similar treatment of 2′,3′,5′-tri-O-
acetylinosine (1a) (Scheme 1) with (morpholine or piperi-
Classical methods for C6 functionalization of purine
nucleosides include deoxygenative chlorination of sugar-
protected derivatives of inosine with phosphorus oxychloride
(POCl3) in the presence of a tertiary aromatic amine or with
Vilsmeier-Haack reagent combinations [(POCl3 or SOCl2)/
DMF/CHCl3].9 These procedures give reasonable yields of
6-chloropurine ribonucleoside derivatives, but the acidic
conditions (in situ generation of HCl) and temperatures
normally employed result in cleavage of the glycosyl bond
of the sensitive 2′-deoxynucleoside derivatives. Robins and
Basom10 developed the first practical transformation of 2′-
deoxyinosine into 6-chloro-9-(2-deoxy-â-D-erythro-pento-
furanosyl)purine and its 6-fluoro analogue, but careful
attention to explicit experimental conditions10b (SOCl2/DMF/
CH2Cl2) is required to obtain the reported yields. Diazoti-
zation-bromodediazoniation has been applied with 2′-
deoxyadenosine,2a,3b,c,11 but modest yields (∼60%) were
reported. Deoxygenative thiation with P4S10 or Lawesson’s
reagent has been used to convert inosine derivatives into
purine-6-thione nucleosides,9 but these procedures cause
major glycosyl bond cleavage with 2′-deoxy analogues.
Elaboration of 2′-deoxyadenosine and related systems into
their 6-(1,2,4-triazol-4-yl) derivatives, which undergo SNAr,
has been described.12 However, no comparably mild and
efficient procedures have been reported for conversion of
2′-deoxyinosine into nucleoside derivatives with a group at
C6 that undergoes ready substitution. We now describe such
methodology.
Scheme 1a
We chose a modified Appel combination13 of elemental
iodine and triphenylphosphine to generate a reactive phos-
phonium intermediate. Attack of O6 at phosphorus would
a (a) Morpholine/I2/Ph3P/EtN(i-Pr)2/CH2Cl2; (b) NaOMe/MeOH;
(c) piperidine/I2/Ph3P/EtN(i-Pr)2/CH2Cl2; (d) (i) imidazole/I2/Ph3P/
EtN(i-Pr)2/toluene/95 °C; (ii) NH3/MeOH; (e) piperidine/60 °C; (f)
PhCH2NH2/75-80 °C; (g) NaH/PhCH2SH/DMF.
produce a purine 6-[(triphenylphosphonium)oxy] iodide
complex (with absorption of hydrogen iodide by Hu¨nig’s
base). It was recently noted6 that sources of positive bromine
or chlorine (NBS or CX4) with P(NMe2)3 allowed SNAr
replacement of O6 [as OdP(NMe2)3] with halide to generate
6-halopurine ribonucleosides, but we had reasoned that
dine)/I2/Ph3P/EtN(i-Pr)2 in CH2Cl2 for ∼1 h at ambient
temperature also gave quantitative conversions (TLC). The
acetyl intermediates were deprotected (NaOMe/MeOH), and
products were purified by anion-exchange chromatography
to give 6-(morpholin-4-yl or piperidin-1-yl)-9-(â-D-ribofura-
nosyl)purine [2a (94%) or 3a (96%), respectively]. Treatment
of 1a with imidazole/I2/Ph3P/EtN(i-Pr)2 in toluene at 95 °C
for 50 min gave the 6-(imidazol-1-yl) intermediate, which
was deprotected (NH3/MeOH) to give 6-(imidazol-1-yl)-9-
(â-D-ribofuranosyl)purine (4a, 87%). SNAr reactions were
effected readily with 4a and alkoxides or alkylthiolates at
ambient temperature and primary or secondary amines at
elevated temperatures. For example, 4a in benzylamine at
(9) Srivastava, P. C.; Robins, R. K.; Meyer, R. B., Jr. In Chemistry of
Nucleosides and Nucleotides; Townsend, L. B., Ed.; Plenum: New York,
1988; Vol. 1, pp 113-281.
(10) (a) Robins, M. J.; Basom, G. L. Can. J. Chem. 1973, 51, 3161-
3169. (b) Robins, M. J.; Basom, G. L. In Nucleic Acid Chemistry: ImproVed
and New Synthetic Procedures, Methods, and Techniques; Townsend, L.
B., Tipson, R. S., Eds.; Wiley: New York, 1978; Part Two, pp 601-606.
(11) Nair, V.; Richardson, S. G. J. Org. Chem. 1980, 45, 3969-3974.
(12) Miles, R. W.; Samano, V.; Robins, M. J. J. Am. Chem. Soc. 1995,
117, 5951-5957.
(13) (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811. (b)
Castro, B. R. Org. React. 1983, 29, 1-162.
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