C6 substitution of inosine using hexamethylphosphorous triamide in conjunction with carbon tetrahalide or N-halosuccinimide

Article abstract of DOI:10.1016/S0040-4039(00)00051-4

Herein we report the facile conversion of 2',3',5'-tri-O- acetylinosine to three different nucleoside analogs via reaction of hexamethylphosphorous triamide and an organic halide. Acetyl-protected 6-bromopurine riboside, 6- chloropurine riboside and N⁶,N⁶-dimethyladenosine can each be prepared in good yield from 2',3',5'-tri-O-acetylinosine, HMPT and halide. The major product of the reaction is determined by the identity of the halide used and the reaction temperature. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00051-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1695–1697
C6 substitution of inosine using hexamethylphosphorous triamide
in conjunction with carbon tetrahalide or N-halosuccinimide†
∗
Eduardo A. Véliz and Peter A. Beal
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, USA
Received 22 November 1999; accepted 30 December 1999
Abstract
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Herein we report the facile conversion of 2 ,3 ,5 -tri-O-acetylinosine to three different nucleoside analogs via
reaction of hexamethylphosphorous triamide and an organic halide. Acetyl-protected 6-bromopurine riboside,
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-chloropurine riboside and N ,N -dimethyladenosine can each be prepared in good yield from 2 ,3 ,5 -tri-O-
acetylinosine, HMPT and halide. The major product of the reaction is determined by the identity of the halide used
and the reaction temperature. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: halogenation; inosine; HMPT; 6-halopurine.
Nucleoside analogs substituted on the purine ring have potential impact in a number of research
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areas including understanding the biological effects of DNA damaging reagents, mechanistic
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analysis of nucleoside metabolizing enzymes, and in the development of antibacterial or antiviral
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chemotherapeutics. We became interested in the preparation of these compounds in our ongoing studies
of RNA-editing adenosine deaminases, where the use of purine analogs will be valuable in helping to
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define the deamination reaction mechanism.
Purine derivatives halogenated at C6 are useful intermediates in the synthesis of a variety of nucleoside
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analogs via substitution or cross coupling reactions of the halopurine. Herein, we wish to report a new,
simple and efficient procedure for the preparation of 6-bromopurine riboside (2), 6-chloropurine riboside
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3) and N ,N -dimethyladenosine (4) from the reaction of 2 ,3 ,5 -tri-O-acetylinosine (1) and hexameth-
ylphosphorous triamide (HMPT) in conjunction with either carbon tetrahalide or N-halosuccinimide.
The Appel protocol (Ph P/CCl ) and its variations (Ph P/Y, Y=CBr , Br , I , NBS) have been widely
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used in the generation of alkyl halides from alcohols and are well documented in the literature.
Furthermore, these protocols have been applied to the synthesis of iminoyl halides from secondary
amides and γ-lactams. Thus, we believed that regioselective halogenation of the purine ring may
be possible using this approach and a ribose-protected inosine as the starting material. Our primary
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∗
†
Corresponding author. Tel: (801) 585-9719; e-mail: beal@chemistry.chem.utah.edu (P. A. Beal)
Dedicated to the memory of Angela Chanis P.
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040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00051-4
tetl 16331

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motivation was the investigation of new methods to prepare 6-bromopurine riboside, given the well-
documented reactivity of bromides in metal-catalyzed coupling reactions using Pd, Zn or Cu. However,
when we attempted to prepare this compound using PPh /CBr and inosine 1, only starting material
3
4
was recovered. This lack of reactivity was observed with either acetonitrile (ACN) or dichloromethane
DCM) as solvent at room temperature or reflux. Recently, Sugimoto et al. reported the halogenation of
(
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hydroxyheterocycles by the action of PPh and N-halosuccinimide. When we applied this procedure,
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however, again only unreacted starting material was recovered.
We reasoned that a more nucleophilic phosphine might be required for the formation of the inter-
mediate phosphonium species from inosine. Therefore, the reaction was carried out with HMPT. A
rapid disappearance of inosine 1 was observed upon addition of HMPT and CBr at room temperature.
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3
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Analysis of the reaction mixture by P NMR indicated that HMPT had been converted to a new
compound with a chemical shift consistent with an aryloxyphosphonium salt. When the phosphonium
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salt formed from inosine 1/HMPT/CBr was treated with 5 equiv. of LiBr at 70°C for 5 h, the bromo
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derivative 2 was isolated in 65% yield. LiBr was more effective as an external halide source than
tetrabutylammonium bromide (TBAB), as addition of TBAB led to a more modest yield (Fig. 1). We also
found that if NBS was used instead of CBr (2.5 equiv. HMPT, 3.0 equiv. NBS), the reaction proceeded
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to product in higher yield (79%) with fewer colored by-products, simplifying purification.
Fig. 1. Formation of C6-substituted purine analogs11
We attempted a similar procedure to prepare the 6-chloropurine 3. Inosine 1 was allowed to react with
HMPT/CCl in ACN or DCM. Again, the starting material was rapidly consumed and after heating
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at reflux, the 6-chloro derivative 3 was isolated in 96% yield. Interestingly, when this reaction was
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repeated at room temperature using 2.0 equiv. of HMPT and 1.1 equiv. of either CBr or CCl , N ,N -
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4
dimethyladenosine 4 was formed as the major product in good yield. Products arising from reaction of
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dimethylamine liberated from HMPT have been observed previously.
Because of its ease of formation and apparent reactivity at higher temperatures to external nucleophiles,
the inosine oxyphosphonium salt may provide a new route to purine analogs and these experiments are
underway in our laboratories.
In summary, this study provides a simple, efficient procedure to prepare the important synthetic inter-
mediates 6-bromopurine riboside and 6-chloropurine riboside from inosine. In addition, minor modifica-
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tions of the reaction conditions leads to the formation of 2 ,3 ,5 -tri-O-acetyl-N ,N -dimethyladenosine
in good yield. Further refinements and extensions of this protocol are being investigated and will be
reported as events merit.
Typical procedure: To a cold (−20°C) solution of 1 and CBr (or NBS) in dry ACN, HMPT was added
4
dropwise. After addition, the cold bath was removed and the reaction mixture stirred at rt for 0.5 h. Then,
LiBr was added and the mixture was heated (see Table 1) for 5 h. The mixture was concentrated under

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reduced pressure and then purified by flash column chromatography (2% MeOH:CHCl ) to afford the
3
halogenated product.
Table 1
References
1
2
3
4
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. Wallace, S. S.; Van Houten, B. V.; Kow, Y. W. Ann. New York Acad. Sci. 1994, 726, 1.
. Kati, W. M.; Acheson, S. A.; Wolfenden, R. Biochemistry 1992, 31, 7356.
. Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley: New York, 1979.
. Yi-Brunozzi, H. Y.; Easterwood, L. M.; Kamilar, G. M.; Beal, P. A. Nucleic Acids Res. 1999, 27, 2912.
. For substitution reactions, see: (a) Trivedi, B. K. In Nucleic Acid Chemistry. Part 4; Townsend, L. B.; Tipson, R. S., Eds.;
Wiley: New York, 1991; pp. 269–273. (b) Bridges, A. J. ibid pp. 230–239. (c) Robins, M. J.; Basom, G. L. Can. J. Chem.
1
973, 51, 3161 and references cited therein. Coupling reactions: (1) Cu-catalyzed: Hocek, M.; Holy, A. Collect. Czech.
Chem. Commun. 1999, 64, 229 and references cited therein. (2) Pd-catalyzed: Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.;
Martin, J. Q. J. Am. Chem. Soc. 1999, 121, 6090. (3) Zn-catalyzed: (a) Stevenson, T. M.; Prasad, A. S. B.; Citineni, J. B.;
Knochel, P. Tetrahedron Lett. 1996, 37, 8375. (b) Prasad. A. S. B.; Stevenson, T. M.; Citineni, J. B.; Nyzam, V.; Knochel, P.
Tetrahedron 1997, 53, 7237. (c) Véliz, E. A.; Beal, P. A. Unpublished results.
6
7
8
9
. Castro, B. R. Org. React. 1983, 29, 1 and references cited therein.
. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801 and references cited therein.
. He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397 and references cited therein.
. Sugimoto, O.; Mori, M.; Tanji, K. Tetrahedron Lett. 1999, 40, 7477.
0. For salt formation, the mixture was stirred at rt for 0.5 h. 31P NMR (121 MHz, CH
1
3
CN, 85% H
: 48.51 ppm; (c) HMPT+CBr +1: 35.37 ppm. P NMR resonance
reported for an aryloxyphosphonium salt: 38.5 ppm, Ramirez, F.; Patwardhan, A. V.; Smith, C. P. J. Am. Chem. Soc. 1965,
7, 4973.
1. Compounds 2 and 3 gave spectroscopic data as reported values. Compound 4 gave satisfactory analytical spectroscopic
3 4
PO as external standard)
3
1
resonances: (a) HMPT: 25.33 ppm; (b) HMPT+CBr
4
4
8
1
3
1
1
13
data ( H and C NMR, MS, and HRMS).
1
1
2. Hans, J. J.; Driver, R. W.; Burke, S. D. J. Org. Chem. 1999, 64, 1430 and references cited therein.
3. Nair, V.; Richardson, S. G. J. Org. Chem. 1980, 45, 3969.