A model study for a novel synthetic approach to 2-carboxyinosines

Article abstract of DOI:10.1016/S0040-4039(00)01725-1

A model study for a novel approach to the synthesis of 2-carboxyinosines has been described. The synthesis of 9-benzyl-2-carboxyhypoxanthine (I), a model for 2-carboxyinosine, was achieved in four steps starting from 1-benzyl-5-nitroimidazole-4-carboxylic acid. Also reported is the synthesis of 9-benzyl-2,2-bis(ethoxycarbonyl)hypoxanthine (II). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01725-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9713–9717
A model study for a novel synthetic approach to
2-carboxyinosines†
Vasanthakumar Rajappan and Ramachandra S. Hosmane*
Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland,
Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA
Received 7 August 2000; revised 26 September 2000; accepted 28 September 2000
Abstract
A model study for a novel approach to the synthesis of 2-carboxyinosines has been described. The
synthesis of 9-benzyl-2-carboxyhypoxanthine (I), a model for 2-carboxyinosine, was achieved in four steps
starting from 1-benzyl-5-nitroimidazole-4-carboxylic acid. Also reported is the synthesis of 9-benzyl-2,2-
bis(ethoxycarbonyl)hypoxanthine (II). © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: hypoxanthines; 2-substitution; 2,2-disubstitution; 2-carboxyhypoxanthine; 2,2-dicarboxylic acid ester.
There has been continued biomedical interest in the synthesis of analogues of inosine
substituted at the 2-position with a functional group that is a member of the carboxylic acid
family, including the parent carboxylic acid moiety,1 a carboxamide group,2 a nitrile,1,3 an
imidate,1 or an ester functionality.4 Also reported are inosines or 2%- or 3%-deoxyinosines or
hypoxanthines substituted with a carboxaldehyde or a ketone group at the 2-position.3,5 Most of
these reported methods involve direct functional group transformations of nucleosides. While
the use of nucleosides has an advantage in that it forgoes the glycosylation step, it nevertheless
suffers from extensive protection and deprotection steps of not only the heterocyclic moiety, but
also of the sugar hydroxyls. This is especially true in case of 2-substituted purines since the
formation of a CꢀC bond by direct nucleophilic displacement reaction, for example, of a 2-halo
substituent by cyanide anion, has largely been unsuccessful.1,2 This often necessitates
organometallic reactions that call for stringent requirements of protection/deprotection steps,
such as the Stille coupling6 between an organic iodide and tri-n-butyl cyanide in the presence of
tetrakis(triphenylphosphine)palladium. Thus, the reported conversion of guanosine into 2-
cyano-3%-deoxyinosine, an analogue of the naturally occurring antibiotic cordycepin,7 involved
ten synthetic steps.3 Although sulfonylmethyl1 and sulfonylphenyl2 groups at the purine 2-posi-
tion have been reported to be far better leaving groups than the corresponding halogen
substituents, the attempted direct displacement reactions by a cyanide or other carbanions on
* Corresponding author.
†
This paper is dedicated to Professor Nelson J. Leonard on the occasion of his 84th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01725-1

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the sulfonyl substituents failed on both guanosine1 and inosine.2 The explanation given for these
failures is that the dissociable N-1 proton in either guanosine or inosine, especially at a
reasonably high temperature that is normally employed for such displacement reactions
(ꢀ100°C in DMF), renders the C-2 position less susceptible for nucleophilic attack.1,2 The
support for such a notion came from the successful nucleophilic displacement reactions with
2-sulfonylalkyl or 2-sulfonylaryl derivatives of either adenosine1 or 6-methoxypurine.2
We report here an alternative short approach to the synthesis of 2-substituted hypoxanthines.
The synthesis of 9-benzyl-2-carboxyhypoxanthine (I), described herein, is a heterocyclic model
for 2-carboxyinosine. Since the parent carboxylic acid group can be conveniently converted to
other members of the carboxylic acid family as well as to aldehydes and ketones employing
conventional chemical methods, the synthesis is potentially versatile. Also reported here is the
synthesis of 2,2-diester-substituted analogue II that was obtained by mere change of solvent in
the final ring-closure step. Although the initial purpose of its synthesis was to confirm the
anticipated mechanism of formation of I, compound II is apparently a good precursor to a wide
variety of 2,2-disubstituted analogues of hypoxanthine and inosine, which may otherwise be
difficult to prepare by usual synthetic methods.
The synthesis of target I was achieved in four steps commencing from 1-benzyl-5-nitroimida-
zole-4-carboxylic acid (1)8 (Scheme 1). Condensation of 1 with diethylaminomalonate, mediated
by 1,1%-carbonyldiimidazole (CDI), yielded diethyl 2-[N-(1-benzyl-5-nitroimidazolyl-4-car-
1
bonyl)amino]malonate (2) in 93% yield, mp 88°C; H NMR (300 MHz, DMSO-d6) l 9.27–9.29
(d, J=7.2 Hz, 1H, NH, ex./w. D2O), 8.28 (s, 1H, CH), 7.10–7.83 (m, 5H, ArꢀH), 5.54 (s, 2H,
NCH2), 5.22–5.24 (d, JNHꢀCH=7.2 Hz, 1H, CH), 4.18 (q, 4H, 2×CH2), 1.20 (t, 6H, 3×CH3);
Anal. C, H, N.9 The reaction of 2 with bromine in the presence of sodium hydride in
dimethylformamide, followed by treatment with potassium phthalimide, afforded diethyl 2-
phthalimido-2-[N-(1-benzyl-5-nitroimidazolyl-4-carbonyl)amino]malonate (3) in 92% yield, mp
1
83–85°C; H NMR (300 MHz, DMSO-d6) l 9.06 (s, 1H, NH), 8.26 (s, 1H, CH), 7.92 (m, 4H,
ArꢀH), 7.35 (m, 5H, ArꢀH), 5.48 (d, 2H, NCH2), 4.30 (q, 4H, 2×CH2), 1.10 (t, 6H, 2×CH3);
Anal. C, H, N.9 This reaction is presumed to proceed (Scheme 2) via base-catalyzed bromination
of the side-chain malonate moiety to produce 6, followed by dehydrohalogenation to form the
imine intermediate 7. The latter would readily react with the phthalimide anion to produce 3.
The nitro group of 3 was reduced by catalytic transfer hydrogenation10 using cyclohexene and
palladium on charcoal, which gave diethyl 2-phthalimido-2-[N-(5-amino-1-benzylimidazolyl-4-
1
carbonyl)amino]malonate (4) in 45% yield, mp 162–164°C; H NMR (300 MHz, DMSO-d6) l
9.22 (s, 1H, NH), 8.19 (s, 1H, CH), 7.59–7.18 (m, 9H, phenyl H), 5.94 (s, 2H, NH2), 5.10 (s, 2H,
NCH2), 4.22 (q, 4H, 2×CH2), 1.15 (t, 6H, 2×CH3); Anal. C, H, N.9 Finally, the target
9-benzyl-2-carboxyhypoxanthine (I) was prepared in 78% yield by heating 4 at 70°C for 10
minutes in anhydrous dimethyl sulfoxide containing slightly more than two equivalents of
1
sodium hydride; H NMR (300 MHz, DMSO-d6) l 13.56 (br, s, 1H, CO2H), 8.43 (s, 1H, NH),
8.12 (s, 1H, CH), 7.38–7.21 (m, 5H, ArꢀH), 5.05 (s, 2H, CH2); Anal. C, H, N.9

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Scheme 1.
Scheme 2.

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The conversion of 4 into I is believed to go through an imine intermediate 8 (Scheme 3),
formed by base-catalyzed elimination of phthalimide, followed by ring-closure to produce II in
situ. The latter undergoes facile nucleophilic displacement by the dimsyl anion present in the
medium with concomitant elimination of carbon dioxide to form a ketene-type intermediate 9.
The aqueous work-up of 9 to produce 10, accompanied by spontaneous aromatization of the
latter by loss of molecular hydrogen, yields the target 2-carboxyinosine analogue I. The support
for the speculated mechanism came from the ring-closure reaction of 4 carried out in a solvent
that is non-nucleophilic or is incapable of forming a nucleophilic species by reaction with
sodium hydride, such as the dimsyl anion mentioned above. Accordingly, when the final
ring-closure of 4 was carried out in dimethylformamide instead of dimethyl sulfoxide as the
1
solvent, it gave 9-benzyl-2,2-bis(ethoxycarbonyl)hypoxanthine (II), mp 166–171°C; H NMR
(300 MHz, DMSO-d6) l 10.06 (s, 1H, NH), 9.57 (s, 1H, NH), 8.23 (s, 1H, CH), 7.42 (m, 5H,
ArꢀH), 5.18 (s, 2H, CH2), 4.18 (q, 4H, 2×CH2), 1.62 (t, 6H, 2×CH3); Anal. C, H, N.9 The
speculated intermediacy of II in the conversion of 4 to I was further corroborated by a separate
treatment of the isolated II with sodium hydride in dimethyl sulfoxide under identical reaction
conditions as used for 4“I conversion, which indeed afforded I.
Scheme 3.
Acknowledgements
The research was supported by a grant from the National Institutes of Health (cCA 71079).
The mass spectra were run at the MSU-NIH Mass Spectral Facility, supported by an NIH grant
(cP41 RR00480).

9717
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