Synthesis and reactions of 2-chloro- and 2-tosyloxy-2′-deoxyinosine derivatives

Article abstract of DOI:10.1021/jo050847j

Convenient syntheses of 2-chloro- and 2-tosyloxy-2′-deoxyinosine as their tert-butyldimethylsilyl ethers are described. Both compounds can be synthesized via a common route and rely on commercially available 2′-deoxyguanosine. The present method leading t

Full text of DOI:10.1021/jo050847j

Synthesis and Reactions of 2-Chloro- and
2-Tosyloxy-2′-deoxyinosine Derivatives
Narender Pottabathini,† Suyeal Bae,†,‡ Padmanava Pradhan,† Hoh-Gyu Hahn,‡
Heduck Mah,*,§ and Mahesh K. Lakshman*,†
Department of Chemistry, The City College and The City University of New York, 138th Street at Convent
Avenue, New York, New York 10031-9198, Organic Chemistry Laboratory, Korea Institute of Science and
Technology, P.O. Box 131, Cheongryang, Seoul 136-791, Korea, and Department of Chemistry,
Kyonggi University, Suwon 442-760, Korea
lakshman@sci.ccny.cuny.edu
Received April 26, 2005
Convenient syntheses of 2-chloro- and 2-tosyloxy-2′-deoxyinosine as their tert-butyldimethylsilyl
ethers are described. Both compounds can be synthesized via a common route and rely on
commercially available 2′-deoxyguanosine. The present method leading to the chloro nucleoside is
operationally simpler compared to previously reported glycosylation techniques where isomeric
products were obtained. Both electrophilic nucleosides can be used for the preparation of
N-substituted 2′-deoxyguanosine analogues via displacement of the leaving groups, and a comparison
of their reactivities shows the chloro analogue to be superior. Interestingly, a Pd catalyst-mediated,
two-step, one-pot conversion of an allyl-protected chloro nucleoside intermediate to the final modified
2′-deoxyguanosine derivatives is also feasible. On the basis of these observations, initial assessments
of Pd-catalyzed aryl amination as well as a C-C cross-coupling have also been performed with the
chloro and tosyloxy nucleoside substrates. Results indicate a potentially high synthetic utility of
2-chloro-2′-deoxyinosine and in many instances this derivative can supplant the bromo and fluoro
analogues that are more cumbersome to prepare or are not readily available.
Introduction
There are two approaches to the syntheses of 2-halo-
2′-deoxyinosines. One is fusion chemistry, which has been
utilized to prepare 2-fluoro-2′-deoxyinosine (as the O6-
The introduction of leaving groups into positions 2 and
6 of purine nucleosides produces reactive, electrophilic
nucleosides that can be further manipulated via nucleo-
philic displacement mechanisms. An abundance of these
types of transformations is available in the literature,
and N-modified adenine and guanine nucleosides can also
be prepared via these methods.1 Due to their lability,
synthesis of halo purine deoxynucleosides can be prob-
lematic. Among the electrophilic C-2-functionalized 2′-
deoxyinosine nucleoside analogues, the fluoro, chloro, and
bromo derivatives have been reported in the literature.
On the other hand, a 2-iodo-2′-deoxyinosine derivative
has been stated to be unstable.2
(1) For some examples, please see: (a) Srivastava, P. C.; Robins, R.
K.; Meyer, R. B., Jr. In Chemistry of Nucleosides and Nucleotides:
Townsend, L. B., Ed.; Plenum Press: New York, 1988; Chapter 2, pp
113-280. (b) Robins M. J.; Uznan´ski B. Can. J. Chem. 1981, 59, 2601-
2607. (c) Trivedi, B. K. Nucleosides Nucleotides 1988, 7, 393-402. (d)
Trivedi, B. K.; Bruns, R. F. J. Med. Chem. 1989, 32, 1667-1673. (e)
Cosstick, R.; Douglas, M. E. J. Chem. Soc., Perkin Trans. 1 1991, 1035-
1040. (f) van der Wenden, E. M.; von Frijtag Drabbe Ku¨nzel, J. K.;
Mathoˆt, R. A. A.; Danhof, M.; IJzerman, A. P.; Soudijn, W. J. Med.
Chem. 1995, 38, 4000-4006. (g) Robins, M. J.; Basom, G. L. Can. J.
Chem. 1973, 51, 3161-3169. (h) Lakshman, M.; Lehr, R. E. Tetrahe-
dron Lett. 1990, 31, 1547-1550. (i) Chaturvedi, S.; Lakshman, M. K.
Carcinogenesis 1996, 17, 2747-2752. (j) Kim, S. J.; Jajoo, H. K.; Kim,
H.-Y.; Zhou, L.; Horton, P.; Harris, C. M.; Harris, T. M. Bioorg. Med.
Chem. 1995, 3, 811-822. (k) Ferentz, A. E.; Verdine, G. L. Nucleosides
Nucleotides 1992, 11, 1749-1763. (l) Gao, H.; Fathi, R.; Gaffney, B.
L.; Goswami, B.; Kung, P.-P.; Rhee, Y.; Jin, R.; Jones, R. A. J. Org.
Chem. 1992, 57, 6954-6959. (m) Samano, V.; Miles, R. W.; Robins,
M. J. J. Am. Chem. Soc. 1994, 116, 9331-9332. (n) Gerster, J. F.;
Robins, R. K. J. Am. Chem. Soc. 1965, 87, 3752-3759.
* M.K.L.: Tel (212) 650-7835. Fax (212) 650-6107.
† The City College and The City University of New York.
‡ Korea Institute of Science and Technology.
§ Kyonggi University.
(2) De Riccardis, F.; Johnson, F. Org. Lett. 2000, 2, 293-295.
10.1021/jo050847j CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/04/2005
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J. Org. Chem. 2005, 70, 7188-7195

2-Chloro and 2-Tosyloxy-2′-deoxyinosine Derivatives
benzyl derivative) from 2-fluoro-6-benzylpurine and 1,3,5-
tri-O-acetyl-2-deoxy-â-D-erythro-pentofuranose.3 Simi-
larly, 2-bromo-2′-deoxyinosine has been synthesized by
a condensation between 2-bromohypoxanthine and 1-
chloro-2-deoxy-3,5-di-O-p-toluoyl-R-D-erythro-pentofuran-
ose.4 In many cases, the glycosylation reaction can
produce isomeric products that need separation. A second
approach is nonaqueous diazotization-halogenation that
alleviates many problems due to its reliance on the
commercially available â-anomers of nucleosides. Gener-
ally, such procedures not only are operationally simple
but also provide a more facile access to halo nucleosides
compared to glycosylation techniques.5 Such nonaqueous
diazotization has therefore provided routes to 2-fluoro-
2′-deoxyinosine derivatives (O6-protected6 and unpro-
tected7) as well as those of 2-bromo-2′-deoxyinosine (O6-
protected8).
catalyzed reactions17 at the C-2 position of purine nucleo-
sides and because of the lack of a convenient route to
2-chloro- and 2-tosyloxy-2′-deoxyinosine derivatives, we
decided to develop their syntheses. We also reasoned that
both compounds could be prepared from common inter-
mediates. Therefore, this paper describes a simple route
to 2-chloro-2′-deoxyinosine and the first synthesis of the
corresponding C-2 tosyloxy analogue. Since neither com-
pound has been studied in detail, the relative reactivities
of the two electrophilic nucleosides have been evaluated
in direct displacement reactions with amines, and an
initial assessment of their utilities for Pd-mediated
transformations has also been made. As elaborated later,
there are distinct advantages to the described syntheses
and compounds.
Results and Discussion
Synthesis of 2-chloro-2′-deoxyinosine as well as a
limited study on its use in displacement reactions with
amines have been reported in the literature.9-12 In these
reports, the synthesis of the chloro nucleoside relied upon
the glycosylation technique. Briefly, the sodium salt of
2,6-dichloropurine was allowed to react with 1-chloro-2-
deoxy-3,5-di-O-p-toluoyl-R-D-erythro-pentofuranose to yield
2,6-dichloro-9-(2-deoxy-3,5-di-O-p-toluoyl-â-D-erythro-pento-
furanosyl)purine.13 Although this reaction proceeded in
good yield (72%), the desired N-9 nucleoside (59%)
required chromatographic separation from the N-7 iso-
mer (13%).13 In this context, it is noteworthy that
synthesis of the relatively labile chloro sugar required
for the glycosylation from 2-deoxy-D-ribose is a nontrivial,
multistep procedure.14 Once the required N-9 2,6-dichlo-
ropurine nucleoside isomer was obtained, the C-6 chloride
was selectively replaced with an allyloxy group. This step
also produced deprotection of the sugar hydroxyls that
were reprotected after deallylation to afford the necessary
2-chloro-2′-deoxyinosine derivative.9-11
Our synthesis commenced with the silylation of 2′-
deoxyguanosine (1). Conversion of 2 to 3a was ac-
complished via the Mitsunobu reaction.7 Although we
have reported a two-step conversion of 2 to 3a that
circumvents the Mitsunobu reaction,18 the presence of
excess benzyl alcohol in this procedure renders product
purification somewhat difficult on a large scale. For the
diazotization-chlorination, we initially chose conditions
analogous to those reported for the bromination.8 Halo-
genation of 3a with SbCl3/tert-BuONO in CH2Cl219 at -10
°C was low yielding (∼15%). More recently, the use of
TMSCl and CH3COCl has been reported for the haloge-
nation of several nucleosides.20 This procedure is opera-
tionally simple and was attempted in the present case.
Diazotization-chlorination of 3a with TMSCl/tert-BuONO
in CH2Cl2 at -10 °C was again disappointing (∼20% yield
of 4a).21 In trying to understand the difficulty faced in
the present case, we realized that TMSI had been utilized
for the cleavage of nucleoside methyl ethers.22 On this
basis we surmised that one potential problem in reactions
of 3a could reside with the O6-benzyl group, which could
be susceptible to cleavage by TMSCl. Therefore, we chose
further experimentation with the O6-allyl derivative 3b.
Due to the lower boiling point of allyl alcohol compared
to benzyl alcohol, it was generally more convenient to
prepare 3b via a two-step method we have previously
Among nonhalo, electrophilic 2′-deoxyinosine ana-
logues, the C-2 triflate is known, albeit only as its O6-
protected derivatives, which have been used in displace-
ment reactions with amines.15,16 As described later, O6-
protection may be detrimental to displacement reactions
at the C-2 position. Due to our interest in studying metal-
(3) Robins, M. J.; Robins, R. K. J. Org. Chem. 1969, 34, 2160-2163.
(4) Jhingan, A. K.; Meehan, T. Synth. Commun. 1992, 22, 3129-
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(6) (a) Lee, H.; Hinz, M.; Stezowski, J. J.; Harvey, R. G. Tetrahedron
Lett. 1990, 31, 6773-6776. (b) Woo, J.; Sigurdsson, S. T.; Hopkins, P.
B. J. Am. Chem. Soc. 1993, 115, 3407-3415.
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Chem., Int. Ed. Engl. 1993, 32, 404-406. (b) Edwards, C.; Boche, G.;
Steinbrecher, T.; Scheer, S. J. Chem. Soc., Perkin Trans. 1 1997, 1887-
1893.
(16) Cooper, M. D.; Hodge, R. P.; Tamura, P. J.; Wilkinson, A. S.;
Harris, C. M.; Harris, T. M. Tetrahedron Lett. 2000, 41, 3555-3558.
(17) For our recent reviews, please see: (a) Lakshman, M. K. J.
Organomet. Chem. 2002, 653, 234-251. (b) Lakshman, M. K. Curr.
Org. Synth. 2005, 2, 83-112.
(7) (a) Harris, C. M.; Zhou, L.; Strand, E. A.; Harris, T. M. J. Am.
Chem. Soc. 1991, 113, 4328-4329. (b) Zajc, B, Lakshman, M. K.; Sayer,
J. M.; Jerina, D. M. Tetrahedron Lett. 1992, 33, 3409-3412.
(8) Harwood, E. A.; Sigurdsson, S. T.; Edfeldt, N. B. F.; Reid, B. R.;
Hopkins, P. B. J. Am. Chem. Soc. 1999, 121, 5081-5082.
(9) (a) Cook, P. D.; Ramasamy, K. S.; Manoharan, M. U.S. Pat.
5459255, 1995. (b) Miraglia, L. J.; Nero, P.; Graham, M. J.; Monia, B.
P.; Koller, E.; Chiang, M. Y.; Manoharan, M. U.S. Pat. Appl. Publ.
20030203862, 2003.
(18) Lakshman, M. K.; Ngassa, F. N.; Keeler, J. C.; Dinh, Y. Q. V.;
Hilmer, J. H.; Russon, L. M. Org. Lett. 2000, 2, 927-930.
(19) Francom, P.; Janeba, Z.; Shibuya, S.; Robins, M. J. J. Org.
Chem. 2002, 67, 6788-6796.
(20) Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68, 666-669.
(21) 1H NMR for 4a (500 MHz, CDCl3): δ 8.25 (s, 1H, H-8), 7.54 (d,
(10) Ramasamy, K. S.; Bakir, F.; Baker, B.; Cook, P. D. J. Heterocycl.
Chem. 1993, 30, 1373-1377.
2H, J ) 7.0), 7.38-7.31 (m, 3H, Ar-H), 6.43 (app t, 1H, H-1′, Japp
∼
6.3), 5.64 (ABquart, 2H, -OCH2, J ) 12.0), 4.62 (m, 1H, H-3′), 4.00 (app
q, 1H, H-4′, Japp ∼ 3.5), 3.89 (dd, 1H, H-5′, J ) 11.3; 4.0), 3.76 (dd, 1H,
H-5′, J ) 11.5; 3.0), 2.59 (app quint, 1H, H-2′, J ) 13.0; 6.4), 2.43 (ddd,
1H, H-2′, J ) 13.0; 6.4; 4.0), 0.91 and 0.90 (2s, 18H, C(CH3)3), 0.099,
(11) Ramasamy, K. S.; Zounes, M.; Gonzalez. C.; Freier, S. M.;
Lesnik, E. A.; Cummins, L. L.; Griffey, R. H.; Monia, B. P.; Cook, P.
D. Tetrahedron Lett. 1994, 35, 215-218.
(12) Manoharan, M.; Ramasamy, K. S.; Mohan, V.; Cook, P. D.
Tetrahedron Lett. 1996, 37, 7675-7678.
0.086 (2s, 12H, SiCH3). FAB HRMS calcd for C29H46ClN4O4Si2 (M+
H): 605.2746, found 605.2774.
+
(13) Kazimierczuk, Z.; Cottam, H. B.; Revankar, G. R.; Robins, R.
K. J. Am. Chem. Soc. 1984, 106, 6379-6382.
(22) (a) Nair, V.; Turner, G. A.; Chamberlain, S. D. J. Am. Chem.
Soc. 1987, 109, 7223-7224. (b) Nair, V.; Turner, G. A.; Buenger, G.
S.; Chamberlain, S. D. J. Org. Chem. 1988, 53, 3051-3057.
(14) Hoffer, M. Chem. Ber. 1960, 93, 2777-2781.
J. Org. Chem, Vol. 70, No. 18, 2005 7189

Pottabathini et al.
TABLE 1. Reactions of 5a and 5b with Various Aminesa
SCHEME 1. Synthesis of
3′,5′-Bis-O-tert-butyldimethylsilyl 2-Chloro- and
2-Tosyloxy-2′-deoxyinosinea
a Key: (a) TBDMSCl, imidazole, DMF; (b) 3a: PhCH2OH, PPh3,
DEAD, 1,4-dioxane; 3b: ref 18; (c) 4a,b: tert-BuONO, TMSCl,
CH2Cl2, -10 °C (see text for details); 4c: NaNO2, AcOH, H2O-
acetone; (d) p-TsCl, Et3N, CH2Cl2; (e) 5a: see text for details; 5b:
H2, 10% Pd/C, 1:1 THF-MeOH.
reported.18 Through this procedure, 3b was routinely
synthesized on multigram scales with good overall yields
(55-60%). At least in our hands, purification of products
obtained by this route was simpler compared to the
Mitsunobu reaction.
a Reactions were conducted in tert-BuOH at 85 °C. b Performed
with 5 molar equiv of amine. c Performed with 2.5 molar equiv of
amine. d Performed with 7.5 molar equiv of amine. e Performed
with 30 molar equiv of amine. f Reaction was not performed.
Diazotization-chlorination of 3b with TMSCl/tert-
BuONO in CH2Cl2 at -10 °C was much more successful,
and 4b could be routinely obtained in 50-55% yield.
Since allyl group cleavage can be effected under either
Pd or Ni catalysis,23 we needed to determine whether
metal insertion into the C-Cl bond would compete with
allyl deprotection. This is in connection with our previous
studies on C-6 halopurine nucleosides, where a chloro
nucleoside has been shown to be remarkably effective in
Pd-catalyzed cross-coupling reactions.24 For this reason,
we chose to evaluate the debenzylation of 4a under
catalytic hydrogenation conditions. Loss of the halogen
under these conditions could indicate reactivity at this
position. When subjected to hydrogenation with 1 atm
hydrogen pressure and 5% Pd-C, 4a underwent deben-
zylation cleanly with no loss of chlorine, as evidenced by
the presence of a singlet at δ 8.12 ppm in the aromatic
region (89% yield of 5a). These results led us to the
conclusion that metal insertion would not complicate the
deallylation reaction.
morpholine in THF was promising on a small scale;
however, competing reaction of 5a with morpholine was
observed on larger scales even at room temperature.
Similarly, the combination of Pd(PPh3)4 and morpholine
resulted in the morpholino product. Pd2(dba)3/(()-BINAP/
Et2NH2+HCO3- in CH2Cl2 was quite successful, although
variability in both reaction times and yields were ob-
served (60-90%).26 Best results, however, were obtained
with 10% Pd-C, EtOH, Et3N, and 1 atm H2.9 Under these
conditions, deprotection was complete within 30 min, and
5a was obtained in 96% yield after chromatography.
Next, attention was directed toward the synthesis of
the 2-tosyloxy derivative of 2′-deoxyinosine 5b. Conver-
sion of 3a to the hypoxanthine derivative 4c was per-
formed as reported in the literature (67% yield).27 Reac-
tion of 4c with p-TsCl and Et3N in CH2Cl2 afforded 4d
in 97% yield. Finally, catalytic debenzylation of 4d with
10% Pd-C and 1 atm H2 in 1:1 THF-MeOH gave 5b
(47% yield).
Several methods were analyzed for deprotection of the
O6-allyl group in 4b.25 An attempt using Pd(PPh3)4 and
dimedone in THF proved to be impractical, although
product formation was observed. Pd2(dba)3/(()-BINAP/
Although 5a has been used for displacement reactions
with amines, such use has been relatively limited (two
primary10,12 and one secondary11), and 5b has not been
(23) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley-Interscience: New York, 1999; pp 68-74.
(24) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.;
Dinh, Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001,
123, 7779-7787.
(25) Hayakawa, Y.; Kato, H.; Uchiyama, M.; Kajino, H.; Noyori, R.
J. Org. Chem. 1986, 51, 2400-2402.
(26) For preparation of Et2NH2+HCO3-, see: Hayakawa, Y.; Hirose,
M.; Noyori, R. J. Org. Chem. 1993, 58, 5551-5555.
(27) (a) Kodra, J. T.; Benner, S. A. Synlett 1997, 939-940. (b)
Jurczyk, S. C.; Horlacher, J.; Devined, K. G.; Benner, S. A.; Battersby,
T. R. Helv. Chim. Acta 2000, 83, 1517-1524.
7190 J. Org. Chem., Vol. 70, No. 18, 2005

2-Chloro and 2-Tosyloxy-2′-deoxyinosine Derivatives
TABLE 2. Synthesis of N2-Modified 2′-Deoxyguanosine
evidence that a chloride at the C-2 position of a purine
nucleoside can be effectively activated for Pd-catalyzed
amination under suitable conditions (Scheme 2). To
prevent undesired deallylation and to maximize catalytic
activity for amination, an aryl amination reaction was
performed on the O6-benzyl-2-chloro nucleoside 4a.
Under conditions we have utilized in a previous report
on C-N bond formation,24 a reaction of 4a with p-
toluidine was complete within 2 h at 85 °C in 1,2-DME.
The isolated yield of the known compound 7 after
chromatographic purification was 63%.24 Similarly, a
C-C bond-forming reaction was attempted with 4a and
PhB(OH)2 under conditions reported previously.24 This
reaction was complete within 3 h and afforded a 62%
yield of the known C-2 phenyl compound 8.24 Both
unoptimized results clearly demonstrate that a C-Cl
bond at the 2 position of purine nucleosides can be
activated for Pd-catalyzed C-N and C-C bond formation.
Further work in our laboratories is currently focused on
understanding the details of these metal-catalyzed reac-
tions. A C-C cross-coupling reaction of tosylate 4d with
PhB(OH)2 was also attempted. With catalytic systems
derived from various ligands (Xantphos, XPhos, 2-(dicy-
clohexylphosphino)-2′-(N,N-dimethylamino)-1,1′-biphe-
nyl, BINAP, DPPF, and 2-(di-tert-butylphosphino)biphe-
nyl) less than 5% product formation was observed over
96 h. This result also warrants comment based upon our
successful Pd-catalyzed amination28 and C-C cross-
coupling29 reactions of O6-arylsulfonyl 2′-deoxyguanosine
derivatives. It currently appears that the reactivity of a
C-6 sulfonate is quite different from that of the C-2
sulfonate in 4d. The reasons behind this difference are
not immediately obvious and will be evaluated in the
course of our future studies on metal catalysis.
Derivatives via a Two-Step, One-Pot Reactiona
a Reactions were conducted with 1 mol % Pd2(dba)3/2 mol % (()-
BINAP and 5 molar equiv of amine in tert-BuOH at 85 °C.
studied. Therefore, at this stage the effectiveness of 5a
and 5b was tested in displacement reactions with a
diverse set of amines. Previous reactions were conducted
in 2-methoxyethanol solvent at 90 °C, but we chose tert-
BuOH. Results from the reactions of 5a and 5b with
various amines are shown in Table 1.
From Table 1, it is evident that both nucleoside
derivatives do undergo reaction with a variety of amines.
The chloro nucleoside 5a is substantially more effective
under the conditions tested, resulting in good to high
product yields compared to the tosyloxy analogue 5b. It
is plausible, however, that 5b may find other applications
under conditions different from those utilized in this
study. Of note are entries 4 and 5 that involve a sensitive
ketal (perhaps accounting for the lowered yield) and a
substituted piperazine, respectively.
One other aspect of interest that emerged was based
upon the analysis of the deallylation reaction described
earlier. We had observed that use of Pd2(dba)3/(()-
BINAP/morpholine in THF led to not only 5a, but, in
some cases, also competitive formation of 6a. Thus, we
reasoned that cleavage of the allyl group in 4b and
replacement of the chloride could be accomplished as a
two-step, one-pot reaction through the use of Pd2(dba)3/
(()-BINAP/amine in tert-BuOH at 85 °C. Three amines
were tested, and the results of these experiments are
shown in Table 2.
As seen in Table 2, even at low Pd concentration, the
overall yields from this two-step procedure compare very
favorably with the yields from the displacement reaction
(Table 1). Therefore, it is possible that in many instances
this approach will provide a one-step reduction in the
synthesis of such N-substituted nucleosides. An observa-
tion that emerged from this analysis was that the two-
step reactions appeared to be generally faster than the
direct displacement. What is presently unclear is whether
deallylation occurs prior to halide displacement or whether
Pd catalyzes the reactions of 4b and/or 5a in these cases.
However, as described below, we present preliminary
Conclusion
In summary, we have demonstrated that 2-chloro-2′-
deoxyinosine and the corresponding 2-tosyloxy derivative
can be readily synthesized. Among the two, not only is
the chloro derivative useful for direct displacement
reactions but metal-mediated chemistry also appears to
be feasible with this compound. On the basis of the
overall simplicity of the chlorination described, 2-chloro-
2′-deoxyinosine may prove to be a useful substitute for
the bromo and fluoro derivatives, with certain noteworthy
points in this comparison. Synthesis of the bromo ana-
logue, O6-benzyl-2-bromo-3′,5′-bis-O-(tert-butyldimethyl-
silyl)-2′-deoxyinosine, via diazotization-halogenation re-
quires the use of hazardous SbBr3. Further, only this O6-
protected form is currently available via the methodology8
since removal of the O6 protection by catalytic debenz-
ylation could be accompanied by halide cleavage. It has
been reported that attempted direct displacement of
bromide from this protected derivative by n-butylamine
resulted in decomposition of the nucleoside.30 This result
as well as our present work indicate that effective direct
displacement of a leaving group from the C-2 position of
(28) Gunda, P.; Russon, L. M.; Lakshman, M. K. Angew. Chem., Int.
Ed. 2004, 43, 6372-6377. Also see corrigendum: Gunda, P.; Russon,
L. M.; Lakshman, M. K. Angew. Chem., Int. Ed. 2005, 44, 1154.
(29) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J.
H.; Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479-1482.
(30) Harwood, E. A.; Hopkins, P. B.; Sigurdsson, S. T. J. Org. Chem.
2000, 65, 2959-2964.
J. Org. Chem, Vol. 70, No. 18, 2005 7191

Pottabathini et al.
SCHEME 2. Pd-Catalyzed C-N and C-C Bond Formation with 3′,5′-Bis-O-tert-butyldimethylsilyl
2-Chloro-2′-deoxyinosinea
a Key: (a) Pd2(dba)3, 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)-1,1′-biphenyl, K3PO4, p-toluidine, 1,2-DME, 85 °C. (b) Pd(OAc)2,
2-(dicyclohexylphosphino)biphenyl, K3PO4, PhB(OH)2, 1,4-dioxane, 90 °C.
inosine nucleosides may require that the O6 position be
unprotected. O6-Unprotected 2-bromo-2′-deoxyinosine
can be obtained but via glycosylation chemistry where
formation of isomeric product mixtures is a limitation.4
When considering addition-elimination-type reactions,
leaving group ability may also be a factor (in simple aryl
systems F > Cl > Br), and 2-chloro-2′-deoxyinosine may
offer advantages over the bromo analogue. Although the
highly reactive 2-fluoro-2′-deoxyinosine can be prepared
in the O6-unprotected form, HF-pyridine is needed for
its synthesis, which precludes the use of a silylated
precursor and therefore requiring protecting group in-
terconversions and a longer synthesis.7 For these reasons,
it is our expectation that the easily synthesized 2-chloro-
2′-deoxyinosine derivative (5a) will find substantial
synthetic utility. Although in this study the tosyloxy
compound 5b was less reactive compared to 5a, this
stable xanthine derivative may find suitable applications
elsewhere, particularly because the corresponding C-2
triflate is available only in its O6-protected form. Finally,
the synthesis described here may also derive applications
in other fields of research. For instance, 2-chloroinosine
has been utilized to probe the mechanism of inosine
monophosphate dehydrogenase.31 2-Chloroinosine is also
formed in low yield upon diazotization of guanosine in
the presence of NaCl, leading to the hypothesis that
2-chloroinosine could be produced in the human stomach
and may have a unique role in gastric cancer.32 More
recently, 2-chloro-2′-deoxyinosine has been identified as
a metabolite of the clinically used cladribine.33 Thus,
2-chlorohypoxanthine nucleosides needed for various
studies can now be accessed via routes described herein.
Furthermore, the operationally simple direct displace-
ment as well as the two-step, one-pot procedure may also
be applicable to the synthesis of other N-modified gua-
nine nucleosides.
pared by percolating the solvent through a bed of solid
NaHCO3 and basic alumina). All spectra were referenced
to residual CHCl3 in CDCl3. Chemical shifts are reported
in δ parts per million, and coupling constants are in
hertz. The sugar protons are numbered 1′-5′ beginning
at the anomeric carbon and proceeding via the carbon
chain to the primary carbinol carbon. Proton assignments
1
were made on the basis of H-1H COSY and analogy to
known nucleoside derivatives.
O6-Allyl-2-chloro-3′,5′-bis-O-(tert-butyldimethylsi-
lyl)-2′-deoxyguanosine (4b). A solution of tert-butylni-
trite (0.24 mL, 2.1 mmol) in CH2Cl2 (16.4 mL) was cooled
to -10 °C while being stirred. Chlorotrimethylsilane (0.27
mL, 2.1 mmol) was added dropwise to this stirred
solution followed by dropwise addition of a solution of
compound 3b (0.43 g, 0.80 mmol) in CH2Cl2 (7.8 mL). The
reaction mixture was stirred for 2 h at -10 °C, diluted
with CH2Cl2, and extracted twice with water followed by
saturated aqueous NaHCO3. The organic layer was
separated, dried over Na2SO4, and evaporated under
reduced pressure. The resulting yellow oil was applied
to a silica gel column packed in CH2Cl2. Sequential
elution with CH2Cl2, 1% EtOAc in CH2Cl2, and 2% EtOAc
in CH2Cl2 gave 0.23 g (52% yield) of 4b as a clear yellow
1
oil. Rf (5% EtOAc in CH2Cl2) ) 0.5. H NMR (500 MHz,
CDCl3): δ 8.26 (s, 1H, H-8), 6.43 (t, 1H, H-1′, J ) 6.5),
6.18-6.10 (m, 1H, -CHd), 5.48 (ddd, 1H, dCHtrans, J )
17.2; 1.7; 1.2), 5.32 (ddd, 1H, dCHcis, J ) 10.2; 1.6; 1.2),
5.10 (d, 2H, -OCH2, J ) 5.8), 4.70-4.55 (m, 1H, H-3′),
4.00 (app q, 1H, H-4′, Japp ∼ 3.5), 3.89 (dd, 1H, H-5′, J )
11.3; 3.9), 3.77 (dd, 1H, H-5′, J ) 11.3; 3.0), 2.59 (app
quint, 1H, H-2′, J ) 12.8; 6.5), 2.44 (ddd, 1H, H-2′, J )
12.8; 6.5; 4.3), 0.91 (s, 18H, C(CH3)3), 0.10, 0.09 (2s, 12H,
SiCH3). 13C NMR (125 MHz, CDCl3): δ 160.6, 152.8,
152.6, 141.4, 131.8, 120.9, 119.3, 88.1, 84.6, 71.7, 68.5,
62.7, 41.4, 25.9, 25.8, 18.4, 18.0, -4.7, -4.8, -5.4, -5.5.
FAB HRMS calcd for C25H44ClN4O4Si2 (M+ + H) 555.2590,
found 555.2608.
Experimental Section
O6-Benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-
deoxyxanthosine (4c). To a solution of compound 3a
(2.11 g, 3.61 mmol) in acetone (20 mL) were added water
(13 mL), acetic acid (12 mL), and NaNO2 (4.98 g, 72.2
mmol). This reaction mixture was stirred for 4 h at room
temperature and then quenched with saturated aqueous
NaHCO3 (400 mL). The mixture was extracted with ethyl
acetate (2 × 200 mL), and the organic layer was dried
with MgSO4 and evaporated. The resulting yellow oil was
applied to a silica gel column packed in 20% EtOAc in
n-hexane. Sequential elution with 20% EtOAc in n-
hexane and 50% EtOAc in n-hexane gave 1.41 g (67%
Thin-layer chromatography was performed on 250 µm
silica plates, and column chromatographic purifications
were performed on 200-300 mesh silica gel. All other
reagents were obtained from commercial sources and
used without further purification. 1H NMR spectra were
recorded at 500 or 600 MHz, and 13C NMR spectra were
recorded at 125 or 151 MHz in deacidified CDCl3 (pre-
(31) Antonino, L. C.; Wu, J. C. Biochemistry 1994, 33, 1753-1759.
(32) Suzuki, T.; Ide, H.; Yamada, M.; Morii, T.; Makino, K. Biorg.
Med. Chem. 2001, 9, 2937-2941.
(33) Bierau, J.; Leen, R.; van Gennip, A. H.; Caron, H. N.; van
Kuilenburg, A. B. P. J. Chromatogr. B 2004, 805, 339-346.
7192 J. Org. Chem., Vol. 70, No. 18, 2005

2-Chloro and 2-Tosyloxy-2′-deoxyinosine Derivatives
yield) of 4c as a white, foamy solid. Rf (50% EtOAc in
n-hexane) ) 0.5. 1H NMR (500 MHz, CDCl3): δ 11.8 (br,
1H, NH), 7.92 (s, 1H, H-8), 7.51 (d, 2H, J ) 7.0), 7.37-
7.30 (m, 3H, Ar-H), 6.35 (app t, 1H, H-1′, Japp ∼ 5.7),
5.68 (ABquart, 2H, -OCH2, J ) 12.0), 4.56 (app q, 1H, H-3′,
Japp ∼ 4.8), 3.99 (m, 1H, H-4′), 3.94 (dd, 1H, H-5′, J )
11.5; 2.0), 3.81 (dd, 1H, H-5′, J ) 11.5; 2.0), 2.50 (app
CDCl3): δ 8.12 (s, 1H, H-8), 6.34 (t, 1H, H-1′, J ) 6.4),
4.59 (m, 1H, H-3′), 4.05 (app q, 1H, H-4′, Japp ∼ 3.5), 3.86
(dd, 1H, H-5′, J ) 11.4; 3.8), 3.77 (dd, 1H, H-5′, J ) 11.4;
3.3), 2.54 (app quint, 1H, H-2′, J ) 13.1; 6.4), 2.43 (ddd,
1H, H-2′, J ) 13.1; 6.4; 4.1), 0.91, 0.90 (2s, 18H, C(CH3)3),
0.12, 0.09, 0.087, 0.05 (4s, 12H, SiCH3). 13C NMR (125
MHz, CDCl3): δ 158.8, 148.1, 143.8, 138.9, 123.4, 88.1,
84.6, 71.7, 62.6, 41.6, 25.9, 25.7, 18.4, 17.9, -4.7, -4.8,
-5.4, -5.5. FAB HRMS calcd for C22H40ClN4O4Si2 (M+
+ H) 515.2277, found 515.2278. Method B. To a solution
of compound 4b (60 mg, 0.11 mmol) in EtOH (2 mL) was
added Et3N (0.017 mL, 0.12 mmol). To this mixture was
added 10% Pd-C (10 mg), and the mixture was allowed
to stir at 1 atm H2 pressure (balloon) for 30 min at room
temperature. The reaction mixture was filtered and
washed with MeOH (5 mL), and the filtrate was evapo-
rated to dryness. This product was applied to a silica gel
column packed in CH2Cl2. Sequential elution with CH2-
Cl2, 1% MeOH in CH2Cl2, and 2% MeOH in CH2Cl2 gave
0.054 g (96% yield) of 5a as pale yellow, foamy solid.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-O2-(4-methyl-
benzenesulfonyl)-2′-deoxyxanthosine (5b). To a solu-
tion of 4d (0.65 g, 0.88 mmol) in 1:1 THF-MeOH (20 mL)
was added 10% Pd-C (50 mg). The flask was evacuated
and flushed with hydrogen, and this procedure was
repeated three times. The reaction mixture was then
stirred for 3 h under a hydrogen balloon. Upon completion
of the reaction, the mixture was filtered though a plug
of Celite, and the filtrate was evaporated to dryness.
Purification of the crude material by flash chromatogra-
phy on a silica gel column eluted with 20% EtOAc in
MeOH gave 0.27 g (47% yield) of 5b as a white, foam. Rf
(20% EtOAc in MeOH) ) 0.5. 1H NMR (600 MHz, DMSO-
d6): δ 7.94 (s, 1H, H-8), 7.89 (d, 2H, Ar-H, J ) 8.4), 7.42
(d, 2H, Ar-H, J ) 8.4), 6.02 (t, 1H, H-1′, J ) 6.9), 4.45
(m, 1H, H-3′), 3.78 (m, 1H, H-4′), 3.65 (dd, 1H, H-5′, J )
11.1; 6.3), 3.56 (dd, 1H, H-5′, J ) 11.1; 4.5), 2.68 (m, 1H,
H-2′), 2.39 (s, 3H, CH3), 2.12 (ddd, 1H, H-2′, J ) 13.2;
6.3; 3.0), 0.89 and 0.83 (2s, 18H, C(CH3)3), 0.10 and 0.08
(2s, 12H, SiCH3). 13C NMR (151 MHz, DMSO-d6): δ
155.4, 149.1, 146.7, 138.9, 134.2, 130.4, 129.3, 123.9,
117.1, 87.9, 84.2, 72.9, 63.4, 39.0, 26.4, 21.9, 21.8, 18.6,
18.4, -4.1, -4.2, -4.3, -4.8. FAB HRMS calcd for
C29H46N4NaO7SSi2 (M+ + Na) 673.2523, found 673.2544.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-morpholinyl-
2′-deoxyinosine (6a). In a clean, dry vial were placed a
stirring bar and 5a (0.10 g, 0.19 mmol). tert-BuOH (1.5
mL) was added to the vial, followed by morpholine (86
µL, 0.98 mmol). The vial was flushed with N2 and then
sealed, and the mixture was allowed to stir at 85 °C for
24 h. The mixture was then evaporated under reduced
pressure and dried under high vacuum. The crude
product was applied to a silica gel column packed in CH2-
Cl2. Sequential elution with CH2Cl2, 1% MeOH in CH2-
Cl2, and 2% MeOH in CH2Cl2 gave 0.093 g (84% yield) of
6a was as a white foam. Rf (5% MeOH in CH2Cl2) ) 0.38.
1H NMR (500 MHz, CDCl3): δ 11.77 (s, 1H, NH), 7.79
(s, 1H, H-8), 6.25 (app t, 1H, H-1′, J ) 6.9), 4.55 (m, 1H,
H-3′), 3.95 (app q, 1H, H-4′, Japp ∼ 3.5), 3.84-3.75 (m,
10H, 2H-5′, 2 x OCH2, 2 x NCH2), 2.49 (app quint, 1H,
H-2′, J ) 12.8; 7.2; 5.8), 2.32 (ddd, 1H, H-2′, J ) 12.8;
6.9; 3.6), 0.91, 0.90 (2s, 18H, C(CH3)3), 0.1, 0.073, 0.07
(3s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 159.3,
152.6, 150.9, 136.3, 117.3, 87.6, 83.5, 72.06, 72.05, 66.4,
quint, 1H, H-2′, Japp ∼ 5.9), 2.33 (app q, 1H, H-2′, Japp
∼
6.1), 0.93 and 0.90 (2s, 18H, C(CH3)3), 0.13, 0.12 and 0.09
(3s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 162.5,
158.4, 147.5, 136.9, 135.6, 128.6, 128.4, 128.3, 115.0, 87.8,
85.0, 71.0, 69.5, 62.3, 42.1, 26.1, 25.7, 18.5, 18.0, 4.6, -4.9,
-5.3, -5.4. FAB HRMS calcd for C29H47N4O5Si2 (M+
H) 587.3085, found 587.3104.
+
O6-Benzyl-3′,5′-bis-O-(tert-butyldimethylsilyl)-O2-
(4-methylphenylsulfonyl)-2′-deoxyxanthosine (4d).
To a solution of compound 4c (1.37 g, 2.39 mmol) in CH2-
Cl2 (30 mL) was added Et3N (0.33 mL, 2.39 mmol). To
this mixture was added p-TsCl (0.47 g, 2.39 mmol), and
the mixture was allowed to stir for 12 h at room
temperature. Water (15 mL) was added, and the mixture
was stirred for 5 min after which the organic layer was
separated, dried over MgSO4, and evaporated under
reduced pressure to give an oily residue. This product
was purified by flash chromatography on a silica gel
column eluted with 20% EtOAc in n-hexane to give 1.67
g (97% yield) of 4d as a clear, gummy foam. Rf (20%
1
EtOAc in n-hexane) ) 0.2. H NMR (600 MHz, CDCl3):
δ 8.20 (s, 1H, H-8), 7.92 (d, 2H, Ar-H, J ) 8.4), 7.43 (d,
2H, Ar-H, J ) 7.2), 7.35-7.29 (m, 5H, Ar-H), 6.33 (t,
1H, H-1′, J ) 6.3), 5.45 (ABquart, 2H, -OCH2, J ) 12.0),
4.58 (m, 1H, H-3′), 3.99 (app q, 1H, H-4′, Japp ∼ 3.6), 3.85
(dd, 1H, H-5′, J ) 11.4; 4.2), 3.76 (dd, 1H, H-5′, J ) 11.4;
3.6), 2.53 (app quint, 1H, H-2′, Japp ∼ 6.6), 2.42 (s, 3H,
CH3), 2.39 (ddd, 1H, H-2′, J ) 13.2; 6.0; 4.2), 0.93 and
0.90 (2s, 18H, C(CH3)3), 0.112, 0.110 and 0.076 (3s, 12H,
SiCH3). 13C NMR (151 MHz, CDCl3): δ 161.5, 154.0,
152.7, 145.3, 141.5, 135.6, 134.9, 129.7, 128.9, 128.7,
128.6, 128.5, 120.6, 88.4, 85.0, 72.1, 69.5, 63.0, 41.7, 26.1,
26.0, 21.8, 18.6, 18.2, -4.5, -4.6, -5.2, -5.3. FAB HRMS
calcd for C36H53N4O7SSi2 (M+ + H) 741.3174, found
741.3189.
2-Chloro-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-
deoxyinosine (5a): Method A. In an oven-dried 50 mL
flask equipped in with a stirring bar were placed 4b (0.70
g, 1.3 mmol) and Et2NH2+HCO3- (0.95 g, 7.8 mmol). Dry
CH2Cl2 (20 mL) was added slowly via a syringe to this
mixture at room temperature. In a vial a solution of (()-
BINAP (0.014 g, 0.023 mmol) and Pd2(dba)3 (0.01 g, 0.011
mmol) in anhydrous CH2Cl2 (4.5 mL) was prepared. This
catalyst solution was added dropwise via a syringe to the
reaction mixture. The reaction mixture was allowed to
stir at room temperature for 4 h at which time TLC
indicated the reaction to be incomplete. Therefore, an-
other aliquot of (()-BINAP (0.014 g, 0.023 mmol) and
Pd2(dba)3 (0.01 g, 0.011 mmol) in CH2Cl2 (2 mL) was
prepared and added to the mixture. The reaction was
allowed to continue and was complete in 18 h. The
reaction mixture was evaporated under reduced pressure,
and the resulting orange-yellow foam was applied to a
silica gel column packed in CH2Cl2. Sequential elution
with CH2Cl2, 1% MeOH in CH2Cl2, and 2% MeOH in CH2-
Cl2 gave 0.57 g (87% yield) of 5a as pale yellow, foam. Rf
(5% MeOH in CH2Cl2) ) 0.15. 1H NMR (500 MHz,
J. Org. Chem, Vol. 70, No. 18, 2005 7193

Pottabathini et al.
62.9, 45.6, 41.1, 25.9, 25.7, 18.4, 17.9, -4.7, -4.8, -5.4,
-5.5. FAB HRMS calcd for C26H48N5O5Si2 (M+ + H)
566.3194, found 566.3205.
nitrophenyl)piperizine (0.04 g, 0.19 mmol) in tert-BuOH
(0.6 mL) over 2 h. Chromatographically purified (SiO2,
2% MeOH in CH2Cl2) compound 6e was obtained as a
yellow solid (0.039 g, 73% yield). Rf (5% MeOH in CH2-
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-piperidinyl-
2′-deoxyinosine (6b). As described for the synthesis of
6a, 6b was prepared by a reaction between 5a (0.015 g,
0.03 mmol) and piperidine (15 µL, 0.15 mmol) in tert-
BuOH (0.23 mL) over 24 h. Chromatographically purified
(SiO2, 2% MeOH in CH2Cl2) compound 6b was obtained
as a white foam (0.016 g, 98% yield). Rf (5% MeOH-CH2-
1
Cl2) ) 0.32. H NMR (500 MHz, CDCl3): δ 11.93 (br s,
1H, NH), 8.16 (d, 2H, Ar-H, J ) 9.4), 7.86 (s, 1H, H-8),
6.85 (d, 2H, Ar-H, J ) 9.4), 6.30 (app t, 1H, H-1′, J )
6.8), 4.57 (m, 1H, H-3′), 4.07-4.00 (br m, 4H, NCH2), 3.99
(app q, 1H, H-4′, Japp ∼ 3.4), 3.85-3.70 (m, 2H, 2H-5′),
3.64 (t, 4H, NCH2, J ) 5.5), 2.48 (app quint, 1H, H-2′, J
) 13.2; 7.0; 6.1), 2.35 (ddd, 1H, H-2′, J ) 13.2; 6.1; 3.6),
0.93, 0.92 (2s, 18H, C(CH3)3), 0.12, 0.09 (2s, 12H, SiCH3).
13C NMR (125 MHz, CDCl3): δ 159.5, 154.3, 152.2, 151.0,
138.8, 136.4, 125.9, 117.1, 112.5, 87.8, 83.4, 72.1, 62.9,
46.2, 44.5, 41.4, 25.9, 25.7, 18.4, 18.1, -4.6, -4.7, -5.3,
-5.5. FAB HRMS calcd for C32H52N7O6Si2 (M+ + H)
686.3518, found 686.3516.
1
Cl2) ) 0.45. H NMR (500 MHz, CDCl3): δ 11.37 (br s,
1H, NH), 7.71 (s, 1H, H-8), 6.22 (app t, 1H, H-1′, J )
6.9), 4.53 (m, 1H, H-3′), 3.94 (app q, 1H, H-4′, Japp ∼ 3.8),
3.77-3.73 (br m, 2H, 2H-5′), 3.73-3.69 (br m, 4H, NCH2),
2.52 (app quint, 1H, H-2′, J ) 13.2; 7.2; 5.8), 2.30 (ddd,
1H, H-2′, J ) 13.2; 6.8; 3.6), 1.66 (br s, 6H, CH2), 0.90,
0.89 (2s, 18H, C(CH3)3), 0.09, 0.06 (2s, 12H, SiCH3). 13C
NMR (125 MHz, CDCl3): δ 159.3, 152.3, 151.3, 135.9,
116.7, 87.5, 83.5, 72.1, 62.9, 46.6, 40.8, 25.9, 25.7, 25.4,
24.3, 18.4, 17.9, -4.7, -4.8, -5.4, -5.5. FAB HRMS calcd
for C27H50N5O4Si2 (M+ + H) 564.3401, found 564.3411.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-pyrrolidinyl-
2′-deoxyinosine (6c). As described for the synthesis of
6a, 6c was prepared by a reaction between 5a (0.1 g,
0.194 mmol) and pyrrolidine (82 µL, 0.97 mmol) in tert-
BuOH (1.5 mL) over 8 h. Chromatographically purified
(SiO2, 2% MeOH in CH2Cl2) compound 6c was obtained
as a light yellow foam (0.078 g, 73% yield). Rf (5% MeOH
3′,5′-Bis-O-(tert-butyldimethylsilyl)-N2-methyl-N2-
[(2-N,N-dimethylamino)ethyl)]-2′-deoxyguanosine
(6f). As described for the synthesis of 6a, 6f was prepared
by a reaction between 5a (0.04 g, 0.078 mmol) and
N,N,N′-trimethylethylenediamine (76 µL, 0.59 mmol) in
tert-BuOH (0.6 mL) over 8 h. Chromatographically puri-
fied (SiO2, 2% MeOH in CH2Cl2) compound 6f was
obtained as a light yellow foam (0.032 g, 73% yield). Rf
(5% MeOH in CH2Cl2) ) 0.11. 1H NMR (500 MHz,
CDCl3): δ 7.71 (s, 1H, H-8), 6.25 (dd, 1H, H-1′, J ) 6.2;
7.3), 4.54 (m, 1H, H-3′), 3.95 (app q, 1H, H-4′, Japp ∼ 4.3),
3.79-3.72 (m, 2H, 2H-5′, J ) 10.9; 3.9), 3.43 (t, 2H, CH2,
J ) 4.5), 3.14 (s, 3H, CH3), 2.62 (t, 2H, CH2, J ) 4.5),
2.53 (app quint, 1H, H-2′, J ) 13.3; 7.4; 6.0), 2.41 (s, 6H,
N(CH3)2), 2.29 (ddd, 1H, H-2′, J ) 13.3; 6.2; 3.5), 0.90,
0.89 (2s, 18H, C(CH3)3), 0.09, 0.07, 0.06 (3s, 12H, SiCH3).
13C NMR (125 MHz, CDCl3): δ 158.7, 154.2, 150.6, 135.3,
118.0, 87.5, 83.5, 72.2, 63.0, 59.1, 50.8, 45.1, 40.8, 37.8,
25.9, 25.7, 24.3, 8.4, 17.9, -4.7, -4.8, -5.4, -5.5. FAB
HRMS calcd for C27H53N6O4Si2 (M+ + H) 581.3667, found
581.3678.
1
in CH2Cl2) ) 0.32. H NMR (500 MHz, CDCl3): δ 10.54
(br s, 1H, NH), 7.69 (s, 1H, H-8), 6.23 (app t, 1H, H-1′, J
) 6.9), 4.56 (m, 1H, H-3′), 3.95 (app q, 1H, H-4′, Japp
∼
3.7), 3.80-3.75 (br m, 2H, 2H-5′), 3.65-3.61 (br m, 4H,
NCH2), 2.61 (app quint, 1H, H-2′, J ) 13.2; 7.2; 5.8), 2.28
(ddd, 1H, H-2′, J ) 13.2; 6.1; 3.6), 2.03-2.01 (br s, 4H,
CH2), 0.91, 0.90 (2s, 18H, C(CH3)3), 0.10, 0.09, 0.07, 0.06
(4s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 159.2,
151.5, 150.9, 135.7, 116.6, 87.5, 83.8, 72.2, 62.9, 47.3,
40.3, 25.9, 25.7, 25.5, 18.1, 17.9, -4.7, -4.8, -5.53, -5.55.
FAB HRMS calcd for C26H48N5O6Si2 (M+ + H): 550.3245,
found 550.3247.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-N2-propyl-2′-
deoxyguanosine (6g). As described for the synthesis
of 6a, 6g was prepared by a reaction between 5a (0.04 g,
0.078 mmol) and n-propylamine (0.192 mL, 2.34 mmol)
in tert-BuOH (0.6 mL) over 8 h. Chromatographically
purified (SiO2, 2% MeOH in CH2Cl2) compound 6g was
obtained as a whitish yellow foam (0.029 g, 69% yield).
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-(1,4-dioxa-8-
azaspiro[4.5]dec-8-yl)-2′-deoxyinosine (6d). As de-
scribed for the synthesis of 6a, 6d was prepared by a
reaction between 5a (0.04 g, 0.078 mmol) and 1,4-dioxa-
azaspiro[4.5]decane (51 µL, 0.39 mmol) in tert-BuOH (0.6
mL) over 2 h. Chromatographically purified (SiO2, 2%
MeOH in CH2Cl2) compound 6d was obtained as a white
solid (0.027 g, 56% yield). Rf (5% MeOH in CH2Cl2) )
0.28. 1H NMR (500 MHz, CDCl3): δ 11.38 (br s, 1H, NH),
7.86 (s, 1H, H-8), 6.25 (app t, 1H, H-1′, J ) 6.5), 4.54 (m,
1H, H-3′), 4.10-3.95 (m, 4H, OCH2), 3.96 (app q, 1H,
H-4′, Japp ∼ 3.9), 3.88 (t, 4H, NCH2, J ) 5.6), 3.77-3.74
(m, 2H, 2H-5′), 2.49 (app quint, 1H, H-2′, J ) 13.1; 6.9;
6.0), 2.32 (ddd, 1H, H-2′, J ) 13.1; 6.2; 3.6), 1.81 (t, 4H,
CH2, J ) 5.6), 0.91 (s, 18H, C(CH3)3), 0.10, 0.08 (2s, 12H,
SiCH3). 13C NMR (125 MHz, CDCl3): δ 159.3, 152.0,
151.2, 136.0, 116.9, 106.9, 87.6, 83.6, 72.2, 64.4, 63.0,
43.8, 41.1, 34.6, 25.9, 25.7, 18.4, 18.0, -4.6, -4.7, -5.3,
-5.5. FAB HRMS calcd for C29H52N5O6Si2 (M+ + H)
622.3456, found 622.3420.
1
Rf (5% MeOH in CH2Cl2) ) 0.32. H NMR (500 MHz,
CDCl3): δ 12.01 (br s, 1H, NH), 7.70 (s, 1H, H-8), 7.01
(br s, 1H, NH), 6.25 (app t, 1H, H-1′, J ) 6.6), 4.55 (m,
1H, H-3′), 3.98 (app q, 1H, H-4′, Japp ∼ 3.9), 3.80-3.76
(m, 2H, 2H-5′), 3.37 (br m, 2H, -NCH2), 2.56 (app quint,
1H, H-2′, J ) 13.2; 7.1; 5.9), 2.34 (ddd, 1H, H-2′, J ) 13.2;
6.4; 3.5), 2.02 (br s, 2H, -CH2), 1.65 (app q, 2H, CH2, J
) 6.9), 0.93 (t, 3H, CH3, J ) 7.4), 0.92, 0.91 (2s, 18H,
C(CH3)3), 0.11, 0.084, 0.08 (3s, 12H, SiCH3). 13C NMR
(125 MHz, CDCl3): δ 159.7, 152.8, 151.7, 135.5, 116.9,
87.7, 83.9, 72.2, 63.1, 43.0, 40.9, 25.9, 25.7, 22.5, 18.4,
17.9, 11.6, -4.8, -5.4, -5.5. FAB HRMS calcd for
C25H48N5O4Si2 (M+ + H) 538.3245, found 538.3248.
Typical Procedure for the Amination of 5b. In a
dry screw-cap vial, equipped with a stirring bar, were
placed nucleoside sulfonate 5b (0.03 g, 0.046 mmol),
anhydrous tert-BuOH (0.3 mL), and amine (5 molar
equiv). The vial was flushed with argon and sealed with
a Teflon-lined cap, and the mixture was heated at 82-
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-[4-(4-nitro-
phenyl)piperizin-1-yl]-2′-deoxyinosine (6e). As de-
scribed for the synthesis of 6a, 6e was prepared by a
reaction between 5a (0.04 g, 0.078 mmol) and 1-(4-
7194 J. Org. Chem., Vol. 70, No. 18, 2005

2-Chloro and 2-Tosyloxy-2′-deoxyinosine Derivatives
83 °C with stirring. Upon completion of the reaction,
evaporation of the mixture provided the crude products
that were purified by column chromatography on silica
gel as described for the individual compounds above.
MeOH in CH2Cl2, and 2% MeOH in CH2Cl2 afforded
0.043 g (84% yield) of the desired 6a as a white foamy
solid. Data for 6a have been reported above.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-piperidinyl-
2′-deoxyinosine (6b). White foam (0.048 g, 94% yield).
Data for 6b have been reported above.
3′,5′-Bis-O-(tert-butyldimethylsilyl)-2-pyrrolidinyl-
2′-deoxyinosine (6c). Pale yellow foam (0.042 g, 85%
yield). Data for 6c have been reported above.
Typical Procedure for the Two-Step, One-Pot
Reaction of 4a with Amines: Synthesis of 3′,5′-Bis-
O-(tert-butyldimethylsilyl)-2-morpholinyl-2′-deoxyi-
nosine (6a). Compound 4a (0.05 g, 0.09 mmol) was
placed in a clean and dry vial equipped with a stirring
bar. tert-BuOH (0.75 mL) was added followed by the
amine (5 molar equiv), (()-BINAP (1.1 mg, 1.76 µmol),
and finally Pd2(dba)3 (0.7 mg, 0.76 µmol). The reaction
mixture was flushed with N2 and heated at 85 °C for
2.5-4 h with stirring. Upon completion of the reaction
as indicated by TLC, the reaction mixture was evaporated
under reduced pressure and dried under high vacuum.
The product mixture was applied to silica gel column
packed in CH2Cl2. Sequential elution with CH2Cl2, 1%
Acknowledgment. This work has been partially
supported by NSF Grant CHE-0314326, NIH Grant
2S06 GM008168-24S1, and a PSC-CUNY 36 award.
Acquisition of a 500 MHz NMR spectrometer was
funded by NSF Grant CHE-0210295.
Supporting Information Available: Proton NMR spectra
of 4a-d, 5a, 5b, and 6a-g. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO050847J
J. Org. Chem, Vol. 70, No. 18, 2005 7195