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SUN AND HOSMANE
nucleosides such as Ara-A (arabinofuranosyladenine), ddA (2ꢁ,3ꢁ-dideoxyade-
nosine), and cordycepin (3-deoxyadenosine) that are known to be potent anti-
tumor and/or antiviral agents (1) or that are used as important research tools for
antiviral and anticancer studies (2).
The majority of literature reports on the synthesis of 9-benzyladenine
(Beilstein Registry No. (BRN) 226270) employ alkylation of adenine with
either benzyl chloride or benzyl bromide in the presence of a base such as sodium
or potassium hydroxide, ethoxide, hydride, or carbonate, and a solvent such as
dimethylformamide, ethanol, or water, at a temperature ranging from 30–100◦C.
However, the main problem with such direct alkylation is the formation of a
mixture of alkylated products that are often difficult or tedious to separate. For
example, a reported (3) alkylation describes the presence of five other products in
the reaction mixture besides 9-benzyladenine, whose yield was only 12%. These
other products included 1-benzyladenine, 3-benzyladenine, 7-benzyladenine, 1,9-
dibenzyladenine, and 3,7-dibenzyladenine. While synthesis of 9-benzyladenine
from condensation of an appropriate imidazole (4) or a pyrimidine derivative (5)
with formic acid (4) or formamide (5) have been reported, the necessary imidazole
or pyrimidine starting materials are themselves difficult or laborious to prepare,
require multistep synthesis, or suffer from poor yields. We report herein an easy,
efficient, and convenient synthesis of the target 9-benzyladenine from the readily
available and inexpensive starting materials.
Our initial efforts focused on the synthesis of the necessary imidazole precur-
sor (5) (Scheme 1). An examination of the literature revealed that there are three
major routes available for accessing 5: (a) condensation of the reagent methyl
N-dicyanomethylmethanimidate (4) with benzylamine (6), (b) condensation of
diaminomaleonitrile (6) with benzyl isocyanide (7), and (c) condensation of 2-
amino-2-cyanoacetamide with (N,N-dimethylaminomethylene)benzylamine (8).
Our attempts to repeat the above three procedures revealed shortcomings in each.
While the required precursor for Method A, namely 2-aminomalononitrile (3),
is now commercially available as a tosylate salt (Aldrich or Lancaster), the key
reagent N,N-dicyanomethylmethanimidate (4), prepared from 3, suffered from ex-
treme moisture sensitivity, short life span, and the necessity for more than usual
precautions in storage and handling. Method B, on the other hand, suffered from
inconsistent results, and when successful, gave only poor yields. Method C ne-
cessitated the elaborate synthesis of the intermediate 2-amino-2-cyanoacetamide
(11) that is highly unstable and reactive, and is not commercially available.
Our synthesis of the target 9-benzyladenine (I), via intermediate 5, employs
the commercially available, relatively inexpensive, and stable diaminomaleoni-
trile (6) (Scheme 2). The latter was converted to the corresponding imidate 13
by reaction with triethyl orthoformate (9). Compound 13 was obtained as a solid
in 85% yield, and was recrystallized into colorless needles from a mixture of
diethyl ether-benzene. It is reasonably stable, and could be stored for months un-
der normal protection (desiccator) from atmospheric moisture. The reaction of 13