Pd-catalyzed C-C bond-forming reactions of thymidine mesitylene sulfonate

Article abstract of DOI:10.1021/jo070843+

(Chemical Equation Presented) Facile synthesis of C-4 aryl pyrimidinone nucleoside analogues from an easily prepared O⁴-arylsulfonate derivative of thymidine is reported. Two O⁴-arylsulfonylthymidine precursors, (4-methylphenyl)sulfo

Full text of DOI:10.1021/jo070843+

Pd-Catalyzed C-C Bond-Forming Reactions of Thymidine
Mesitylene Sulfonate
Soon Bang Kang,†,‡ Erik De Clercq,§ and Mahesh K. Lakshman*,†
Department of Chemistry, The City College and The City UniVersity of New York,
160 ConVent AVenue, New York, New York 10031-9198, and Rega Institute for
Medical Research, Minderbroederstraat 10, B-3000, LeuVen, Belgium
lakshman@sci.ccny.cuny.edu
ReceiVed April 23, 2007
Facile synthesis of C-4 aryl pyrimidinone nucleoside analogues from an easily prepared O4-arylsulfonate
derivative of thymidine is reported. Two O4-arylsulfonylthymidine precursors, (4-methylphenyl)sulfonyl
and (2,4,6-trimethylphenyl)sulfonyl, were prepared and analyzed for their stabilities. Of the two, the
latter possessed suitable stability as well as reactivity for Pd-catalyzed C-C bond-forming reactions
with a variety of arylboronic acids. These reactions at the C-4 position are nontrivial in comparison with
similar reactions at the C-5 position of pyrimidine nucleosides, with hydrolysis of the arylsulfonate
precursor being a competing reaction in some cases. There are pronounced solvent influences in these
reactions, but successful reactions can be attained by careful control of conditions. Many reactions
proceeded efficiently at room temperature, and electron-deficient arylboronic acids can also be cross-
coupled under suitable conditions. Desilylation of these products was also nontrivial, and various conditions
were tested. Finally, antiviral screening was performed with the C-4 aryl pyrimidinone nucleoside
analogues, but none possessed any interesting activity. The study represents the first successful synthesis
of C-4 aryl pyrimidinone nucleoside analogues by cross-coupling of arylboronic acids with an arylsulfonate
derived from a pyrimidine nucleoside, as well as antiviral testing of this new class of compounds.
Introduction
Pd- and Ni-mediated Suzuki-Miyaura reactions of halo or
azolyl nucleoside derivatives with arylboronic acids have
provided facile access to aryl-linked nucleoside analogues.4
Some of these aryl-nucleoside derivatives have shown anti-HCV
as well as cytostatic activity that augments the importance of
synthetic access to such compounds.5 In this relation, we have
been particularly interested in understanding the basis of the
The pharmacological importance and potential pharmaceutical
value of nucleoside analogues has fueled the development of
novel methods for their synthesis as well as the quest for new
compounds.1,2 In this context, metal-catalyzed chemistry offers
new directions for nucleoside modification strategies.3
* Author to whom correspondence should be addressed. Tel: (212) 650-7835,
fax: (212) 650-6107.
(2) (a) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385-423. (b)
Zemlicka, J. Pharmacol. Ther. 2000, 85, 251-266. (c) Ferrero, M.; Gotor,
V. Chem. ReV. 2000, 100, 4319-4347. (d) Huryn, D. M.; Okabe, M. Chem.
ReV. 1992, 92, 1745-1768.
(3) For reviews, please see: (a) Lakshman, M. K. Curr. Org. Synth. 2005,
2, 83-112. (b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. ReV. 2003,
103, 1875-1916. (c) Hocek, M. Eur. J. Org. Chem. 2003, 245-254. (d)
Lakshman, M. K. J. Organomet. Chem. 2002, 653, 234-251.
† The City College.
‡ Guest Researcher from The Korea Institute of Science and Technology.
§ Rega Institute for Medical Research (antiviral testing).
(1) (a) PerspectiVes in Nucleosides and Nucleic Acid Chemistry;
Kisakurek, M. V.; Rosemeyer, H., Eds.; Wiley-VCH: Weinheim, Germany,
2001. (b) Suhadolnik, R. J. Nucleosides as Biological Probes; Wiley: New
York, 1979.
10.1021/jo070843+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
5724
J. Org. Chem. 2007, 72, 5724-5730

C-C Bond Formation With A Thymidine Aryl Sulfonate
SCHEME 1. Synthesis of Two Thymidine O4-Arylsulfonates
catalysis chemistry as well as reactivity patterns and have
reported C-C bond-forming reactions of 6-bromo and chloro-
purine nucleosides6 as well as O6-arylsulfonates of 2′-deoxy-
guanosine.7,8 During the course of our prior work we have
demonstrated that, in contrast to simpler halo aromatic systems,
C-6 chloropurine nucleosides are highly effective coupling
partners in C-C bond-forming reactions with arylboronic acids.6
We have also shown that easily synthesized O6-arylsulfonates
of 2′-deoxyguanosine are particularly important substrates7,8
since the C-6 chlorination of 2′-deoxyguanosine is not trivial.9
We have additionally demonstrated that 2′-deoxyguanosine O6-
arylsulfonates undergo Pd-catalyzed C-C bond-forming reac-
tions with arylboronic acids under mild conditions and at room
temperature, indicating their excellent reactivity and utility.8
On the basis of these results, we were interested in exploring
whether O4-arylsulfonate derivatives of pyrimidine nucleosides
could be utilized for Pd-catalyzed C-C bond-forming reactions
with arylboronic acids. Whereas C-5 modifications via such
cross-coupling are known in the literature,10 to our knowledge,
comparable methods for modification at the C-4 are not.
Introduction of a leaving group into the C-4 position of a
pyrimidine nucleoside places it at the â-position of an R,â-
unsaturated system. Although metal-catalyzed C-C bond-
forming reactions of enol sulfonates (tosylate and triflate)
derived from â-keto amides and lactones with organoboron
derivatives are known,11 we have shown that the chemistry of
simpler molecules is often not applicable to the more complex
nucleosides. Furthermore, while this work was in progress,
Negishi and Stille reactions of some uridine O4-(2,4,6-triiso-
propylphenyl)sulfonate derivatives were reported. That work was
specifically prompted by unsuccessful attempts at Suzuki-
Miyaura and Heck reactions.12
silyl) derivative 1 (TBDMSCl, imidazole, DMF, room temper-
ature, 24 h). Conversion of 1 to the O4-arylsulfonates was
attempted via two methods. Initially, following a literature
procedure, 1 was deprotonated with NaH in THF and allowed
to react with ArSO2Cl (Ar ) 2,4,6-trimethylphenyl and 4-
methylphenyl).13 Although products 2 and 3 were available via
this route, 2 was contaminated with ∼14% of a byproduct that
was thought to be the N-sulfonyl derivative but was not
rigorously characterized. Also, this procedure was not readily
amenable to a larger scale synthesis of 2. An alternative
method14 that utilized Et3N, DMAP in CH2Cl2 for sulfonylation
with ArSO2Cl was found to be more suitable for the preparation
of 2 (Scheme 1).
Since the O4-(2,4,6-trimethylphenyl)sulfonyl thymidine de-
rivative has been stated as being unstable to storage,13 we wanted
to initially ascertain the stabilities of 2 and 3. In solution (CDCl3)
both compounds underwent hydrolysis to 1, and 2 was hydro-
lytically more reactive compared to 3. However, deacidification
and drying of the NMR solvent slowed this hydrolysis (∼26%
at room temperature over 2 weeks), and 2 was stable to storage
in the refrigerator (4-5 °C) for 2 months as a solid. Although
more stable compared to 2, about 40% hydrolysis of 3 occurred
over a 6-month period in the refrigerator (4-5 °C). Overall, 2
was more interesting to us since the relief of steric bulk could
be favorable to the oxidative-addition step in the catalysis
reactions, and the relative hydrolytic reactivity may be reflective
of this. Further, we have had excellent prior results in C-C
bond-forming reactions of the analogous (2,4,6-trimethylphen-
yl)sulfonyl derivative of 2′-deoxyguanosine and arylboronic
acids.7,8
Initial experiments focused on conditions that we have shown
to be successful for Pd-catalyzed C-C bond formation at room
temperature.8 Using the catalyst composed of 10 mol % Pd-
(OAc)2/20 mol % (2-dicyclohexylphosphino)-1,1′-biphenyl, a
reaction of 2 and 2 mol equiv of PhB(OH)2 was conducted at
room temperature in the presence of 2 mol equiv of K3PO4 in
toluene as solvent. This reaction was complete within 15 h and
produced a 95% yield of the C-4 aryl product 4a accompanied
by a trace amount of 1. When the reaction was conducted for
7 h, the yield of 4a dropped to 84% and the amount of 1
increased. When the ligand was changed to 2-(di-tert-butylphos-
phino)-1,1′-biphenyl, the reaction yielded only 6% of 4a, 79%
of 1, and 15% of unreacted 2 (room temperature, 15 h). Use of
Pd(PPh3)4 was also inferior, resulting in 33% of 4a, 19% of 1,
and 48% of 2 remaining unreacted (NMR analysis of the crude
product mixture from a room-temperature reaction after 50 h).
Results and Discussion
Our chemistry commenced with the readily available thymi-
dine that was converted to its 3′,5′-bis-O-(tert-butyldimethyl-
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J. Org. Chem, Vol. 72, No. 15, 2007 5725

Kang et al.
TABLE 1. Pd-Catalyzed C-C Bond-Forming Reactions Leading
(entries 1-6), which was 24-29 °C during the course of the
experimentation. Others (entries 7 and 10) showed progress at
room temperature but were not complete. As we have previously
reported for reactions of O6-[(2,4,6-trimethylphenyl)sulfonyl]-
3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine,8 tetrahy-
dropyran (THP) proved to be an effective solvent for those
reactions that were inefficient in PhMe. Reactions of dibenzo-
furanyl- and 3-methoxyphenylboronic acids proceeded ef-
ficiently in THP at 90 °C (entries 9 and 12) but were less
efficient at 50 °C (entries 8 and 11). Cross-coupling reactions
of electron-deficient arylboronic acids can be generally difficult16
and such boronic acids are also known to undergo competitive
protio-deboronation17,18 as well as dimerization.19 We have seen
that elevated temperatures and the use of THP as solvent
provides reasonable cross-coupling results.8 Consistent with our
expectation, the reaction of 4-acetylphenylboronic acid with 2
in PhMe at room temperature afforded 16% of 4i and 15% of
1 with 69% of 2 remaining unreacted (by 1H NMR of the crude
reaction mixture after 15 h). In PhMe at 90 °C, a yield
improvement was observed (entry 13), but in THP at 90 °C a
77% yield of 4i was obtained (entry 14). Interestingly, 1,4-
dioxane also proved to be a comparably good solvent in this
case (entry 15). With 3-nitrophenylboronic acid, some other
interesting influences were observed. In PhMe at 90 °C, no
product formation occurred whereas in THP a small amount of
product formation was observed, but conversion to 1 predomi-
nated in each case (entries 16 and 17). On the other hand, in
THP at 50 °C reasonably good conversion to 4j was observed
(entry 18). Replacing THP with 1,4-dioxane abolished the
product-forming pathway again resulting in the formation of 1.
With some differences, these solvent effects parallel those
observed in the C-C bond-forming reactions of O6-[(2,4,6-
trimethylphenyl)sulfonyl]-3′,5′-bis-O-(tert-butyldimethylsilyl)-
2′-deoxyguanosine.8 Solvent does seem to play an important
but presently unknown role in these reactions. We feel that
coordinating abilities of solvents as well as solvent basicities
could have subtle but significant influences in these reactions.
We also briefly tested 3 for its reactivity toward PhB(OH)2.
In PhMe at room temperature, after 3 h an 81% yield of 4a
(accompanied by ∼19% 1) was obtained. However, a compa-
rable reaction after 15 h at room temperature yielded 4a in 95%
(and a trace amount of 1). At 50 °C, a 3 h reaction time led to
the isolation of 4a in 87% yield with no detectable formation
of 1. Thus, 2 also appears to be suitably reactive in these
transformations, but a limitation to the use of any specific
precursor could be the stability of the thymidine O4-arylsulfonate
balanced against reactivity.
to C-4 Aryl Pyrimidine Nucleoside Analoguesa
a Reactions were conducted using 10 mol % Pd(OAc)2, 20 mol % (2-
dicyclohexylphosphino)-1,1′-biphenyl, 2 mol equiv K3PO4 and 2 mol equiv
ArB(OH)2 (0.14 M nucleoside concentration). b Isolated yields, unless
specified otherwise. c The amount of 1 produced was determined either by
isolation or from the 1H NMR data of the crude reaction mixture. d On the
basis of 1H NMR, the amount of 1 produced is an approximate estimation
based on integration values relative to 4.
Since these novel thymidine derivatives could potentially
possess antiviral activity, these compounds were desilylated for
testing. The desilylation proved to be nontrivial, and reaction
of 4a with KF (3-6 mol equiv) in MeOH at 50-80 °C resulted
in the formation of some fluorescent byproducts in addition to
the desired desilyl compound 5a. Attempt at milder conditions
through the use of KF and 18-crown-6 in PhMe resulted in no
reaction at room temperature and very slow reaction at elevated
Although Pd(PPh3)4 has been used to catalyze C-C bond
formation of nucleoside derivatives and arylboronic acids,4e,f,5,10b,c
the superiority of (2-dicyclohexylphosphino)-1,1′-biphenyl-based
catalysts for such conversions has been noted by others.15 On
the basis of these initial results, the generality of the transforma-
tion was assessed, and the results are compiled in Table 1.
From the data presented in Table 1 it is clear that substrate
2 can be effectively used for C-C bond formation via Pd
catalysis. Several reactions proceeded well at room temperature
(16) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
(17) Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. J. Am. Chem.
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(19) (a) Yamamoto, Y.; Suzuki, R.; Hattori, K.; Nishiyama, H. Synlett
2006, 1027-1030. (b) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001,
42, 4087-4089.
(15) (a) Meketa, M. L.; Weinreb, S. M. Org. Lett. 2006, 8, 1443-1446.
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5726 J. Org. Chem., Vol. 72, No. 15, 2007

C-C Bond Formation With A Thymidine Aryl Sulfonate
TABLE 2. Methods Evaluated for the Desilylation of 4aa
Detailed compilations of the antiviral results are presented in
Tables 1-5 of the Supporting Information section.
Conclusions
In this paper we have demonstrated that an O4-arylsulfonate
derivative of thymidine is a suitable substrate for the synthesis
of C-4 aryl pyrimidinone nucleoside analogues. To our knowl-
edge, this is the first report on successful Suzuki-Miyaura
reactions at the C-4 position utilizing an arylsulfonate of a
pyrimidine nucleoside. In contrast to facile reactions at the C-5
position, with simpler catalytic systems, reactions at the C-4
are much less trivial. In some cases product formation is
accompanied by small amounts of the hydrolysis product, and
this hydrolysis becomes more significant in cross-coupling
reactions that are less facile. Nevertheless good to excellent
yields were obtained in all reactions studied here. Noteworthy
is the fact that, via a Negishi reaction, a 60% yield of compound
4a has been reported in a reaction time of 3 days.12 The slowness
of this reaction has been linked to the possibility of steric
congestion at the reactive site.12 By contrast, the same compound
is attainable within 15 h at room temperature via the presently
described approach, despite the presence of the C-5 methyl
group adjacent to the reactive center. This is a representation
of the efficiency of the reactions described. In viewing the C-C
bond-forming reactions of nucleoside arylsulfonates in general,
certain common features emerge. Many reactions can be
accomplished at room temperature in toluene. The ligand most
generally applicable is 2-(dicyclohexylphosphino)-1,1′-biphenyl
usually in combination with Pd(OAc)2. Electron-deficient aryl-
boronic acids, as anticipated, are difficult coupling partners.
However, successful reactions in such cases can be attained in
THP.
entry
1
desilylation conditions
result
KF (3 mol equiv),
85% yieldb
MeOH, 70 °C, 40 h
CsF (5 mol equiv),
CH3CN, 90 °C, 15 h
CsF (5 mol equiv),
CH3CN-H2O (10:1),
90 °C, 19 h
2
3
product formation observed,
but several byproducts formedc
quantitative yielda
4
n-Bu4N+F- (10 mol equiv),
AcOH (10 mol equiv), THF,
rt, 24 h
TASF (5 mol equiv),
CH3CN, 0 °C to rt, 20 h
TASF (5 mol equiv),
DMF, 0 °C to rt, 17 h
77% yieldb
5
6
98% yieldb
quantitative yieldb
a
See the Experimental Section for additional examples of desilylations
involving 4d (CsF), 4h, and 4j (both with TASF). b Isolated yield after
chromatographic purification. c Product was not isolated.
temperatures. Therefore, compounds 4a-j were deprotected
with KF (3-6 mol equiv) in MeOH at 70-80 °C, and by
carefully monitoring the reactions 49-85% yield of the purified
products 5a-j were obtained. In contrast to the reasonably
successful desilylation of 4d with KF in MeOH (49% yield),
use of n-BuN4+F- in THF resulted in the formation of several
fluorescent spots. Because of the unanticipated problems
encountered in the desilylation of these products, we subse-
quently briefly investigated conditions for desilylation using 4a
as a model substrate. These incuded the use of CsF in CH3CN
or CH3CN-H2O,20 buffered n-BuN4+F-,21 and tris(dimethyl-
amino)sulfonium difluorotrimethylsilicate (TASF) in DMF.22,23
From the results shown in Table 2, it appeared that TASF in
DMF or CH3CN would be a suitable desilylating agent.
The desilylated compounds were tested for antiviral activity
in three types of cell cultures: human embryonic lung (HEL)
[Herpes simplex virus-1 (KOS), Herpes simplex virus-2 (G),
Vaccinia virus, Vesicular stomatitis virus and Herpes simplex
virus-1 (TK- KOS ACVr)], HeLa [Vesicular stomatitis virus,
Coxsackie virus B4, Respiratory syncytial virus], and Vero
[Parainfluenza-3 virus, Reovirus-1, Sindbis virus, Coxsackie
virus B4 and Punta Toro virus]. Activity was also assayed
against cytomegalovirus and varicella-zoster in human embry-
onic lung (HEL) cells. None of the compounds tested possessed
a significant level of specific or potent antiviral activity. In all
cases the minimal antivirally effective concentration was not
more than 5-fold lower than the minimal cytotoxic concentration
(most had a minimum cytotoxic concentration of g100 µg/mL).
Experimental Section
3′,5′-Bis-O-(tert-butyldimethylsilyl)-O4-[(2,4,6-trimethylphen-
yl)sulfonyl]thymidine (2). 3′,5′-Bis-O-(tert-butyldimethylsilyl)-
thymidine 1 (0.942 g, 2.0 mmol) and DMAP (0.024 g, 0.2 mmol)
were dissolved in 10 mL of dry, distilled CH2Cl2. The solution
was chilled to 0 °C, and Et3N (1.67 mL, 6 mol equiv) was added.
After 30 min at this temperature, 2,4,6-trimethylphenylsulfonyl
chloride (0.744 g, 3.4 mmol) was added. The reaction mixture was
allowed to stir under nitrogen gas at 0 °C for 1 h and then at room
temperature for an additional 30 h. Upon completion, the reaction
mixture was poured into a 1:1 mixture of hexanes-EtOAc (40 mL)
and filtered through a glass funnel. The filter cake was washed
with Et2O, and the filtrate was concentrated to yield a brown-yellow
oil. Chromatography on silica gel using 2:1 hexanes-Et2O yielded
1.170 g of 2 as a white, foamy solid (89% yield). Rf (silica gel, 2:1
1
hexanes-Et2O) ) 0.33. H NMR (500 MHz, CDCl3): δ 7.95 (s,
1H, H-6), 6.97 (s, 2H, Ar-H), 6.90 (t, 1H, H-1′, J ) 6.3), 4.31
(dt, 1H, H-3′, J ) 5.9, 3.3), 3.96 (app q, 1H, H-4′, J ) 2.9), 3.87
(dd, 1H, H-5′, J ) 11.2, 2.4), 3.74 (dd, 1H, H-5′, J ) 11.2, 2.4),
2.75 (s, 6H, CH3), 2.46 (ddd, 1H, H-2′, J ) 13.7, 5.9, 3.9), 2.29 (s,
3H, CH3), 2.03 (s, 3H, CH3), 1.93 (dt, 1H, H-2′, J ) 13.7, 6.5),
0.89, 0.86 (2s, 18H, SiC(CH3)3), 0.09, 0.08, 0.05, 0.04 (4s, 12H,
SiCH3). 13C NMR (125 MHz, CDCl3): δ 166.0, 153.5, 144.0, 143.0,
140.7, 131.9, 131.7, 103.3, 88.3, 87.2, 71.5, 62.5, 42.3, 25.9, 25.7,
21.1, 18.3, 17.9, 12.3, -4.6, -4.9, -5.4. HRMS calculated for
C31H53N2O7SSi2 (M+ + H): 653.3112, found 653.3125.
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Typical Procedure for the Cross-Coupling of 2 with Aryl-
boronic Acids (Step 1 under each compound heading). In an
oven-dried, screw-cap vial equipped with a stirring bar were placed
Pd(OAc)2 (1.4 mg, 6.1 µmol), 2-(dicyclohexylphosphino)-1,1′-
biphenyl (4.3 mg, 12.3 µmol), K3PO4 (26.0 mg, 122.5 µmol), 3′,5′-
J. Org. Chem, Vol. 72, No. 15, 2007 5727

Kang et al.
bis-O-(tert-butyldimethylsilyl)-O4-[(2,4,6-trimethylphenyl)sulfonyl]-
thymidine 2 (40.0 mg, 61.3 µmol), and the arylboronic acid (2 mol
equiv, 122.5 µmol). PhMe or THP or 1,4-dioxane (0.7 mL, see
Results and Discussion for choice of solvent) was added, the vial
was flushed with nitrogen gas and sealed with a Teflon-lined cap,
and the mixture was stirred at a suitable temperature (room
temperature or 50 °C or 90 °C, see Results and Discussion). Upon
completion, the reaction mixture was filtered through Celite, and
the residue was washed with CH2Cl2. Evaporation of the filtrate
provided the crude product mixture that was purified by column
chromatography on silica gel (SiO2, 230-400 mesh) using a suitable
ratio of hexanes-EtOAc. Details are provided under the individual
compound headings. In some cases, the reactions were performed
using 100 mg of 2 by appropriate modifications to stoichiometry
and concentration.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-phenylpyrimidin-2(1H)-
one (5a). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-butyldimethyl-
silyl)-2′-deoxyribofuranosyl]-5-methyl-4-phenylpyrimidin-2(1H)-
one (4a). Chromatography with 10:4 hexanes-EtOAc yielded a
colorless, oily residue. Rf (silica gel, 10:4 hexanes-EtOAc) ) 0.14.
1H NMR (500 MHz, CDCl3): δ 8.08 (s, 1H, H-6), 7.62-7.58 (m,
2H, Ar-H), 7.46-7.42 (m, 3H, Ar-H), 6.33 (t, 1H, H-1′, J )
6.2), 4.40 (dt, 1H, H-3′, J ) 5.9, 3.4), 4.04 (app q, 1H, H-4′, J )
2.9), 3.95 (dd, 1H, H-5′, J ) 11.5, 2.7), 3.80 (dd, 1H, H-5′, J )
11.5, 2.7), 2.65 (ddd, 1H, H-2′, J ) 13.7, 6.4, 3.9), 2.13 (s, 3H,
CH3), 2.11 (dt, 1H, H-2′, J ) 13.7, 6.7), 0.92, 0.90 (2s, 18H, SiC-
(CH3)3), 0.12, 0.11, 0.09, 0.08 (4s, 12H, SiCH3). 13C NMR (125
MHz, CDCl3): δ 174.6, 155.1, 141.9, 138.1, 129.8, 128.5, 128.1,
110.9, 88.5, 87.4, 71.7, 62.7, 42.6, 25.9, 25.8, 18.4, 18.0, 16.6, -4.5,
-4.9, -5.4.
Step 2: Desilylation. To a solution of 4a (18.8 mg, 35.4 µmol)
in MeOH (0.3 mL), was added KF (6.2 mg, 106.2 µmol), and the
reaction mixture was stirred at 70 °C for 40 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give 9.1 mg (85% yield) of 5a
as a colorless, oily residue that upon trituration with Et2O yielded
a white, cottony solid. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.12.
1H NMR (500 MHz, CD3OD): δ 8.58 (s, 1H, H-6), 7.64-7.60
(m, 2H, Ar-H), 7.56-7.49 (m, 3H, Ar-H), 6.27 (t, 1H, H-1′, J )
6.0), 4.44 (dt, 1H, H-3′, J ) 5.9, 4.4), 4.07 (app q, 1H, H-4′, J )
3.7), 3.92 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.81 (dd, 1H, H-5′, J )
12.0, 3.7), 2.60 (ddd, 1H, H-2′, J ) 13.7, 6.2, 4.4), 2.28 (dt, 1H,
H-2′, J ) 13.7, 6.1), 2.17 (s, 3H, CH3). 13C NMR (125 MHz, CD3-
OD): δ 175.2, 155.9, 144.1, 137.8, 130.1, 128.3, 128.2, 112.8, 88.4,
87.8, 70.1, 61.0, 41.5, 15.2. HRMS calculated for C16H19N2O4 (M+
+ H): 303.1345, found: 303.1348.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-[4-(methylsulfanyl)-
phenyl]pyrimidin-2(1H)-one (5b). Step 1: Synthesis of 1-[3′,5′-
bis-O-(tert-butyldimethylsilyl)-2′-deoxyribofuranosyl]-5-methyl-4-
[4-(methylsulfanyl)phenyl]pyrimidin-2(1H)-one (4b). Chromatog-
raphy with 10:3 hexanes-EtOAc yielded a pale yellow, oily residue.
Rf (silica gel, 10:4 hexanes-EtOAc) ) 0.16. 1H NMR (500 MHz,
CDCl3): δ 8.05 (s, 1H, H-6), 7.58 (d, 2H, Ar-H, J ) 8.2), 7.28
(d, 2H, Ar-H, J ) 8.2), 6.32 (t, 1H, H-1′, J ) 6.4), 4.40 (dt, 1H,
H-3′, J ) 6.1, 3.4), 4.03 (app q, 1H, H-4′, J ∼ 3.0), 3.95 (dd, 1H,
H-5′, J ) 11.3, 2.8), 3.80 (dd, 1H, H-5′, J ) 11.3, 2.4), 2.64 (ddd,
1H, H-2′, J ) 13.5, 6.3, 3.9), 2.52 (s, 3H, SCH3), 2.15 (s, 3H,
CH3), 2.10 (dt, 1H, H-2′, J ) 13.4, 6.5), 0.92, 0.90 (2s, 18H, SiC-
(CH3)3), 0.12, 0.11, 0.08, 0.07 (4s, 12H, SiCH3). 13C NMR (125
MHz, CDCl3): δ 173.5, 155.1, 142.1, 141.6, 134.2, 129.2, 125.3,
110.9, 88.4, 87.2, 71.6, 63.6, 42.5, 25.9, 25.7, 18.4, 17.9, 16.9, 15.2,
-4.6, -4.9, -5.4.
impregnated silica gel was loaded onto a silica gel column and
eluted with 15:1 CHCl3-MeOH to give a white solid that upon
trituration with hexanes-EtOAc yielded 32.8 mg (68% yield) of
5b as a pale yellow solid. Rf (silica gel, 10:1 CHCl3-MeOH) )
0.16. 1H NMR (500 MHz, CD3OD): δ 8.55 (s, 1H, H-6), 7.60 (d,
2H, Ar-H, J ) 8.5), 7.38 (d, 2H, Ar-H, J ) 8.5), 6.26 (t, 1H,
H-1′, J ) 6.1), 4.43 (dt, 1H, H-3′, J ) 6.4, 4.4), 4.06 (app q, 1H,
H-4′, J ∼ 3.6), 3.92 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.81 (dd, 1H,
H-5′, J ) 12.2, 3.4), 2.59 (ddd, 1H, H-2′, J ) 13.7, 6.2, 4.4), 2.56
(s, 3H, SCH3), 2.27 (dt, 1H, H-2′, J ) 13.7, 6.1), 2.20 (s, 3H, CH3).
13C NMR (125 MHz, CD3OD): δ 174.3, 155.9, 144.1, 142.7, 133.8,
129.1, 125.2, 112.8, 88.4, 87.7, 70.1, 61.1, 41.5, 15.5, 13.8. HRMS
calculated for C17H21N2O4S (M+ + H): 349.1222, found: 349.1209.
1-(2′-Deoxyribofuranosyl)-4-(4-methoxyphenyl)-5-methylpy-
rimidin-2(1H)-one (5c). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyribofuranosyl]-4-(4-methoxyphenyl)-5-
methylpyrimidin-2(1H)-one (4c). Chromatography with 10:4
hexanes-EtOAc yielded a pale yellow, oily residue. Rf (silica gel,
1
10:4 hexanes-EtOAc) ) 0.10. H NMR (500 MHz, CDCl3): δ
8.03 (s, 1H, H-6), 7.64 (d, 2H, Ar-H, J ) 8.8), 6.95 (d, 2H, Ar-
H, J ) 8.8), 6.33 (t, 1H, H-1′, J ) 6.4), 4.40 (dt, 1H, H-3′, J )
5.9, 3.3), 4.02 (app q, 1H, H-4′, J ∼ 2.7), 3.95 (dd, 1H, H-5′, J )
11.2, 2.9), 3.86 (s, 3H, OCH3), 3.80 (dd, 1H, H-5′, J ) 11.2, 2.4),
2.63 (ddd, 1H, H-2′, J ) 13.5, 6.2, 4.0), 2.17 (s, 3H, CH3), 2.09
(dt, 1H, H-2′, J ) 13.7, 6.5), 0.92, 0.90 (2s, 18H, SiC(CH3)3), 0.12,
0.11, 0.08, 0.07 (4s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3):
δ 173.6, 161.2, 155.2, 141.9, 130.6, 130.2, 113.5, 110.9, 88.3, 87.2,
71.6, 62.6, 55.3, 42.5, 25.9, 25.7, 18.4, 17.9, 17.1, -4.6, -4.9,
-5.4.
Step 2: Desilylation. To a solution of 4c (83.6 mg, 149.1 µmol)
in MeOH (1.0 mL) was added KF (51.9 mg, 834.3 µmol), and the
reaction mixture was stirred at 80 °C for 24 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a white solid that upon
trituration with Et2O yielded 32.0 mg (82% yield) of 5c as a pale
yellow solid. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.15. 1H NMR
(500 MHz, CD3OD): δ 8.52 (s, 1H, H-6), 7.66 (d, 2H, Ar-H, J )
8.5), 7.06 (d, 2H, Ar-H, J ) 8.5), 6.27 (t, 1H, H-1′, J ) 6.0),
4.45-4.42 (m, 1H, H-3′), 4.05 (app q, 1H, H-4′, J ) 3.6), 3.92
(dd, 1H, H-5′, J ) 12.0, 3.2), 3.88 (s, 3H, OCH3), 3.80 (dd, 1H,
H-5′, J ) 12.2, 3.4), 2.58 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9), 2.26
(dt, 1H, H-2′, J ) 13.7, 6.2), 2.22 (s, 3H, CH3). 13C NMR (125
MHz, CD3OD): δ 174.3, 161.9, 155.9, 143.8, 130.5, 129.8, 113.6,
112.8, 88.4, 87.7, 70.1, 61.1, 54.7, 41.5, 15.7. HRMS calculated
for C17H21N2O5 (M+ + H): 333.1450, found: 333.1443.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-(2-naphthyl)pyrimidin-
2(1H)-one (5d). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-butyldi-
methylsilyl)-2′-deoxyribofuranosyl]-5-methyl-4-(2-naphthyl)pyri-
midin-2(1H)-one (4d). Chromatography with 10:4 hexanes-EtOAc
yielded a pale yellow, oily residue. Rf (silica gel, 10:4 hexanes-
EtOAc) ) 0.20. 1H NMR (500 MHz, CDCl3): δ 8.13 (m, 1H, Ar-
H), 8.12 (s, 1H, H-6), 7.91-7.87 (m, 3H, Ar-H), 7.73-7.71 (m,
1H, Ar-H), 7.57-7.51 (m, 2H, Ar-H), 6.36 (t, 1H, H-1′, J )
6.4), 4.42 (dt, 1H, H-3′, J ) 6.1, 3.4), 4.05 (app q, 1H, H-4′, J ∼
2.9), 3.97 (dd, 1H, H-5′, J ) 11.6, 2.8), 3.82 (dd, 1H, H-5′, J )
11.6, 2.4), 2.67 (ddd, 1H, H-2′, J ) 13.4, 6.1, 4.0), 2.20 (s, 3H,
CH3), 2.16 (dt, 1H, H-2′, J ) 13.4, 6.5), 0.94, 0.90 (2s, 18H, SiC-
(CH3)3), 0.14, 0.13, 0.09, 0.08 (4s, 12H, SiCH3). 13C NMR (125
MHz, CDCl3): δ 174.3, 155.1, 142.1, 135.3, 133.8, 132.7, 128.9,
128.8, 127.8, 127.7, 127.2, 126.5, 125.7, 111.2, 88.4, 87.3, 71.6,
62.6, 42.6, 25.9, 25.8, 18.4, 17.9, 16.9, -4.5, -4.9 -5.4.
Step 2: Desilylation. To a solution of 4d (30.5 mg, 52.5 µmol)
in MeOH (0.5 mL) was added KF (9.2 mg, 157.5 µmol), and the
reaction mixture was stirred at 70 °C for 36 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
Step 2: Desilylation. To a solution of 4b (80.0 mg, 138.6 µmol)
in MeOH (1.0 mL) was added KF (48.3 mg, 831.9 µmol), and the
reaction mixture was stirred at 80 °C for 24 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
5728 J. Org. Chem., Vol. 72, No. 15, 2007

C-C Bond Formation With A Thymidine Aryl Sulfonate
eluted with 15:1 CHCl3-MeOH to give a pale yellow residue that
upon trituration with hexanes and then Et2O yielded 9.0 mg (49%
yield) of 5d as a pale yellow powder. Rf (silica gel, 10:1 CHCl3-
Step 2: Desilylation. To a solution of 4f (76.0 mg, 132.2 µmol)
in MeOH (0.8 mL) was added KF (23.0 mg, 396.6 µmol), and the
reaction mixture was stirred at 60 °C for 64 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a pale yellow, oily residue
that upon trituration with Et2O yielded 27.4 mg (60% yield) of 5f
as a pale yellow powder. Rf (silica gel, 10:1 CHCl3-MeOH) )
1
MeOH) ) 0.14. H NMR (500 MHz, CD3OD): δ 8.63 (s, 1H,
H-6), 8.16 (s, 1H, Ar-H), 8.02-7.98 (m, 2H, Ar-H), 7.97-7.94
(m, 1H, Ar-H), 7.73 (dd, 1H, Ar-H, J ) 8.3, 1.5), 7.62-7.57
(m, 2H, Ar-H), 6.30 (t, 1H, H-1′, J ) 6.1), 4.46 (dt, 1H, H-3′, J
) 6.3, 4.5), 4.08 (app q, 1H, H-4′, J ) 3.6), 3.94 (dd, 1H, H-5′, J
) 12.2, 2.9), 3.83 (dd, 1H, H-5′, J ) 12.2, 3.4), 2.62 (ddd, 1H,
H-2′, J ) 13.7, 6.4, 4.4), 2.31 (dt, 1H, H-2′, J ) 13.7, 6.1), 2.24
(s, 3H, CH3). 13C NMR (125 MHz, CD3OD): δ 175.1, 155.9, 144.2,
135.0, 134.2, 133.0, 128.6, 128.5, 128.0, 127.6, 127.4, 126.7, 125.3,
113.1, 88.5, 87.8, 70.1, 61.1, 41.5, 15.4. HRMS calculated for
C20H21N2O4 (M+ + H): 353.1501, found: 353.1491.
1
0.13. H NMR (500 MHz, CD3OD): δ 8.53 (s, 1H, H-6), 7.20
(dd, 1H, Ar-H, J ) 8.0, 1.5), 7.16 (d, 1H, Ar-H, J ) 1.5), 6.95
(d, 1H, Ar-H, J ) 8.5), 6.26 (t, 1H, H-1′, J ) 6.0), 6.06 (s, 2H,
OCH2O), 4.43 (dt, 1H, H-3′, J ) 6.4, 4.4), 4.05 (app q, 1H, H-4′,
J ∼ 3.6), 3.91 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.80 (dd, 1H, H-5′, J
) 12.0, 3.7), 2.58 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9), 2.26 (dt, 1H,
H-2′, J ) 13.7, 6.1), 2.20 (s, 3H, CH3). 13C NMR (125 MHz, CD3-
OD): δ 174.2, 155.9, 149.8, 148.1, 144.0, 131.5, 123.5, 112.7,
108.9, 107.8, 101.9, 88.4, 87.7, 70.1, 61.1, 41.5, 15.6. HRMS
calculated for C17H19N2O6 (M+ + H): 347.1243, found: 347.1221.
1-(2′-Deoxyribofuranosyl)-4-(4-dibenzofuranyl)-5-methylpy-
rimidin-2(1H)-one (5g). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyribofuranosyl]-4-(4-dibenzofuranyl)-5-
methylpyrimidin-2(1H)-one (4g). Chromatography with 10:4
hexanes-EtOAc yielded an off-white, foamy solid. Rf (silica gel,
Desilylation of 4d (39.2 mg, 67.5 µmol) with CsF (51.3 mg,
337.4 µmol) in 10:1 CH3CN-H2O (1.1 mL) at 90 °C over 24 h
gave a 73% yield of 5d after workup and chromatography.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-(1-naphthyl)pyrimidin-
2(1H)-one (5e). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-butyldi-
methylsilyl)-2′-deoxyribofuranosyl]-5-methyl-4-(1-naphthyl)pyri-
midin-2(1H)-one (4e). Chromatography with 10:4 hexanes-EtOAc
yielded a pale yellow, oily residue. Rf (silica gel, 10:4 hexanes-
EtOAc) ) 0.16. 1H NMR (500 MHz, CDCl3): δ 8.16 (s, 1H, H-6),
7.91 (t, 2H, Ar-H, J ) 8.9), 7.61 (d, 1H, Ar-H, J ) 8.2), 7.54-
7.42 (m, 4H, Ar-H), 6.39 (t, 1H, H-1′, J ) 6.4), 4.45 (dt, 1H,
H-3′, J ) 5.8, 3.3), 4.12-4.08 (m, 1H, H-4′), 3.99 (dd, 1H, H-5′,
J ) 11.6, 2.7), 3.83 (dd, 1H, H-5′, J ) 11.6, 2.4), 2.72 (ddd, 1H,
H-2′, J ) 13.4, 6.1, 3.7), 2.19 (dt, 1H, H-2′, J ) 13.4, 6.6), 1.81
(s, 3H, CH3), 0.92, 0.91 (2s, 18H, SiC(CH3)3), 0.123, 0.121, 0.11,
0.10 (4s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 175.9,
155.0, 141.2, 135.7, 133.3, 129.8, 129.3, 128.4, 126.6, 126.1, 125.4,
125.1, 124.9, 112.7, 88.6, 87.6, 71.8, 62.7, 42.6, 25.9, 25.7, 18.3,
17.9, 15.5, -4.6, -4.9, -5.5.
Step 2: Desilylation. To a solution of 4e (82.0 mg, 141.2 µmol)
in MeOH (1.0 mL) was added KF (49.1 mg, 846.0 µmol), and the
reaction mixture was stirred at 80 °C for 24 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a pale yellow residue that
upon trituration with Et2O yielded 27.5 mg (55% yield) of 5e as a
pale yellow powder. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.21.
1H NMR (500 MHz, CD3OD): δ 8.67 (s, 1H, H-6), 8.03-7.98
(m, 2H, Ar-H), 7.63-7.45 (m, 5H, Ar-H), 6.34 (t, 1H, H-1′, J )
6.1), 4.48 (dt, 1H, H-3′, J ) 5.9, 4.5), 4.10 (app q, 1H, H-4′, J )
3.6), 3.95 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.83 (dd, 1H, H-5′, J )
12.2, 3.9), 2.66 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9), 2.36 (dt, 1H,
H-2′, J ) 13.7, 6.1), 1.83 (s, 3H, CH3). 13C NMR (125 MHz, CD3-
OD): δ 176.4, 155.7, 143.7, 135.5, 133.8, 129.9, 129.5, 128.5,
126.9, 126.3, 125.3, 125.1, 124.6, 114.4, 88.5, 88.0, 70.2, 61.1,
41.5, 14.1. HRMS calculated for C20H21N2O4 (M+ + H): 353.1501,
found: 353.1516.
1
10:4 hexanes-EtOAc) ) 0.16. H NMR (500 MHz, CDCl3): δ
8.18 (s, 1H, H-6), 8.05 (dd, 1H, Ar-H, J ) 7.6, 1.2), 7.99 (d, 1H,
Ar-H, J ) 7.3), 7.61 (dd, 1H, Ar-H, J ) 7.6, 1.2), 7.54 (d, 1H,
Ar-H, J ) 8.3), 7.47-7.45 (m, 2H, Ar-H), 7.37 (t, 1H, Ar-H, J
) 7.3), 6.37 (t, 1H, H-1′, J ) 6.5), 4.44 (dt, 1H, H-3′, J ) 6.4,
3.3), 4.08 (app q, 1H, H-4′, J ∼ 2.6), 3.99 (dd, 1H, H-5′, J ) 11.7,
2.4), 3.83 (dd, 1H, H-5′, J ) 11.7, 2.4), 2.70 (ddd, 1H, H-2′, J )
13.9, 6.3, 3.9), 2.19 (dt, 1H, H-2′, J ) 13.7, 6.6), 2.05 (s, 3H, CH3),
0.94, 0.91 (2s, 18H, SiC(CH3)3), 0.14, 0.13, 0.10, 0.096 (4s, 12H,
SiCH3). 13C NMR (125 MHz, CDCl3): δ 171.9, 156.1, 155.1, 152.6,
141.8, 127.8, 127.5, 124.6, 123.8, 123.1, 123.0, 122.9, 122.2, 120.8,
112.8, 111.7, 88.5, 87.6, 71.7, 62.6, 42.6, 25.9, 25.8, 18.4, 18.0,
15.4, -4.5, -4.9, -5.4.
Step 2: Desilylation. To a solution of 4g (70.0 mg, 112.7 µmol)
in MeOH (0.8 mL) was added KF (19.6 mg, 338.2 µmol), and the
reaction mixture was stirred at 70 °C for 33 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a white solid that upon
trituration with Et2O yielded 37.1 mg (84% yield) of 5g as a white,
1
fluffy solid. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.18. H NMR
(500 MHz, CD3OD): δ 8.70 (s, 1H, H-6), 8.21 (dd, 1H, Ar-H, J
) 7.6, 1.2), 8.11 (d, 1H, Ar-H, J ) 6.8), 7.61-7.58 (m, 2H, Ar-
H), 7.55-7.51 (m, 2H, Ar-H), 7.45-7.41 (m, 1H, Ar-H), 6.32
(t, 1H, H-1′, J ) 6.4), 4.48 (dt, 1H, H-3′, J ) 6.4, 4.4), 4.10 (app
q, 1H, H-4′, J ) 3.6), 3.96 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.84 (dd,
1H, H-5′, J ) 12.2, 3.4), 2.65 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9),
2.34 (dt, 1H, H-2′, J ) 13.7, 6.1), 2.07 (s, 3H, CH3). 13C NMR
(125 MHz, 50 °C, CD3OD): δ 172.4, 156.4, 155.8, 152.6, 143.9,
127.8, 127.1, 125.0, 123.7, 123.4, 123.1, 122.5, 122.4, 120.8, 114.2,
111.4, 88.6, 88.1, 70.3, 61.2, 41.5, 13.9 (since the compound
crystallized from MeOH elevated temperature was used for acquir-
ing data). HRMS calculated for C22H21N2O5 (M+ + H): 393.1450,
found: 393.1435.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-[(3,4-methylenedioxy)-
phenyl]pyrimidin-2(1H)-one (5f). Step 1: Synthesis of 1-[3′,5′-
bis-O-(tert-butyldimethylsilyl)-2′-deoxyribofuranosyl]-5-methyl-4-
[(3,4-methylenedioxy)phenyl]pyrimidin-2(1H)-one (4f). Chromatog-
raphy with 10:4 hexanes-EtOAc yielded a light gray solid. Rf (silica
1
gel, 10:4 hexanes-EtOAc) ) 0.14. H NMR (500 MHz, CDCl3):
δ 8.05 (s, 1H, H-6), 7.16 (d, 2H, Ar-H, J ) 8.6), 7.15 (s, 1H,
Ar-H), 6.86 (d, 2H, Ar-H, J ) 8.6), 6.32 (t, 1H, H-1′, J ) 6.3),
6.02 (s, 2H, OCH2O), 4.39 (dt, 1H, H-3′, J ) 6.1, 3.4), 4.03 (app
q, 1H, H-4′, J ∼ 2.9), 3.95 (dd, 1H, H-5′, J ) 11.5, 2.6), 3.80 (dd,
1H, H-5′, J ) 11.5, 2.6), 2.63 (ddd, 1H, H-2′, J ) 13.4, 6.2, 3.9),
2.16 (s, 3H, CH3), 2.07 (dt, 1H, H-2′, J ) 13.4, 6.3), 0.92, 0.89
1-(2′-Deoxyribofuranosyl]-4-(3-methoxyphenyl)-5-methylpy-
rimidin-2(1H)-one (5h). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyribofuranosyl]-4-(3-methoxyphenyl)-5-
methylpyrimidin-2(1H)-one (4h). Chromatography with 2:1 hexanes-
EtOAc yielded a pale yellow, oily product. Rf (silica gel, 10:4
hexanes-EtOAc) ) 0.13. 1H NMR (500 MHz, CDCl3): δ 8.08 (s,
1H, H-6), 7.34 (t, 1H, Ar-H, J ) 8.1), 7.15-7.14 (m, 2H, Ar-
H), 7.00-6.98 (m, 1H, Ar-H), 6.32 (t, 1H, H-1′, J ) 6.3), 4.40
(dt, 1H, H-3′, J ) 6.4, 3.4), 4.04 (app q, 1H, H-4′, J ∼ 2.8), 3.95
(dd, 1H, H-5′, J ) 11.5, 2.7), 3.84 (s, 3H, OCH3), 3.80 (dd, 1H,
(2s, 18H, SiC(CH3)3), 0.12, 0.11, 0.08, 0.07 (4s, 12H, SiCH3). 13
C
NMR (125 MHz, CDCl3): δ 173.5, 155.1, 149.2, 145.6, 142.1,
131.7, 123.5, 110.9, 109.3, 107.9, 101.4, 88.4, 87.3, 71.6, 62.6,
42.5, 25.9, 25.7, 18.4, 18.0, 17.1, -4.6, -4.9, -5.4.
J. Org. Chem, Vol. 72, No. 15, 2007 5729

Kang et al.
H-5′, J ) 11.5, 2.7), 2.65 (ddd, 1H, H-2′, J ) 13.7, 6.4, 3.9), 2.12
(s, 3H, CH3), 2.11 (m, 1H, H-2′), 0.92, 0.90 (2s, 18H, SiC(CH3)3),
0.12, 0.11, 0.08, 0.075 (4s, 12H, SiCH3). 13C NMR (125 MHz,
CDCl3): δ 174.3, 159.4, 154.9, 142.2, 139.0, 129.1, 120.8, 116.1,
113.7, 111.1, 88.5, 87.4, 71.6, 62.6, 55.4, 42.6, 25.9, 25.8, 18.4,
18.0, 16.7, -4.5, -4.9, -5.4.
1-(2′-Deoxyribofuranosyl)-5-methyl-4-(3-nitrophenyl)pyrimi-
din-2(1H)-one (5j). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyribofuranosyl]-5-methyl-4-(3-nitrophenyl)-
pyrimidin-2(1H)-one (4j). Chromatography by sequential elution
with 10:1 and then 1:1 hexanes-EtOAc yielded a colorless, oily
residue. Rf (silica gel, 10:4 hexanes-EtOAc) ) 0.11. 1H NMR (500
MHz, CDCl3): δ 8.47 (br s, 1H, Ar-H), 8.34-8.32 (m, 1H, Ar-
H), 8.20 (s, 1H, H-6), 7.99-7.97 (m, 1H, Ar-H), 7.66 (t, 1H, Ar-
H, J ) 7.8), 6.31 (t, 1H, H-1′, J ) 6.0), 4.41 (dt, 1H, H-3′, J )
5.9, 3.4), 4.06 (app q, 1H, H-4′, J ) 2.8), 3.97 (dd, 1H, H-5′, J )
11.7, 2.4), 3.81 (dd, 1H, H-5′, J ) 11.7, 2.4), 2.67 (ddd, 1H, H-2′,
J ) 13.7, 6.4, 3.9), 2.16 (s, 3H, CH3), 2.11 (dt, 1H, H-2′, J ) 13.7,
6.6), 0.92, 0.90 (2s, 18H, SiC(CH3)3), 0.13, 0.12, 0.09, 0.08 (4s,
12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 171.8, 154.8, 147.9,
143.3, 139.4, 134.7, 129.5, 124.6, 123.6, 110.5, 88.6, 87.6, 71.6,
62.6, 42.6, 25.9, 25.7, 18.4, 18.0, 16.5, -4.5, -4.9, -5.3.
Step 2: Desilylation. To a solution of 4h (59.0 mg, 105.2 µmol)
in MeOH (0.8 mL) was added KF (18.3 mg, 315.6 µmol), and the
reaction mixture was stirred at 70 °C for 33 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a pale yellow, oily residue
that upon trituration with Et2O yielded 24.0 mg (69% yield) of 5h
as an off-white powder. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.12.
1H NMR (500 MHz, CD3OD): δ 8.58 (s, 1H, H-6), 7.42 (t, 1H,
Ar-H, J ) 7.8), 7.17-7.15 (m, 2H, Ar-H), 7.10-7.08 (m, 1H,
Ar-H), 6.27 (t, 1H, H-1′, J ) 6.1), 4.44 (dt, 1H, H-3′, J ) 5.9,
4.5), 4.07 (app q, 1H, H-4′, J ) 3.6), 3.92 (dd, 1H, H-5′, J ) 12.2,
2.9), 3.86 (s, 3H, OCH3), 3.81 (dd, 1H, H-5′, J ) 12.2, 3.9), 2.60
(ddd, 1H, H-2′, J ) 13.7, 6.4, 4.4), 2.27 (dt, 1H, H-2′, J ) 13.7,
6.1), 2.16 (s, 3H, CH3). 13C NMR (125 MHz, CD3OD): δ 175.1,
159.9, 155.8, 144.1, 139.0, 129.4, 120.5, 115.8, 113.7, 112.8, 88.4,
87.8, 70.1, 61.1, 54.7, 41.5, 15.2. HRMS calculated for C17H21N2O5
(M+ + H): 333.1450, found: 333.1432.
Step 2: Desilylation. To a solution of 4j (35.0 mg, 60.8 µmol)
in MeOH (0.5 mL) was added KF (10.6 mg, 182.3 µmol), and the
reaction mixture was stirred at 70 °C for 30 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give a pale yellow solid that
upon trituration with hexanes and then Et2O yielded 9.2 mg (77%
yield) of 5j as a pale yellow solid. Rf (silica gel, 10:1 CHCl3-
1
Desilylation of 4h (53.7 mg. 95.7 µmol) through the use of 1.3
M TASF in DMF (0.37 mL, 131.9 mg, 478.7 µmol) in DMF (1
mL) from 0 °C (2 h) to room temperature over 20 h provided a
79% yield of 5h after workup and chromatography.
MeOH) ) 0.15. H NMR (500 MHz, CD3OD): δ 8.68 (s, 1H,
H-6), 8.52 (br s, 1H, Ar-H), 8.45-8.39 (m, 1H, Ar-H), 8.07-
8.04 (m, 1H, Ar-H), 7.79 (t, 1H, Ar-H, J ) 7.8), 6.27 (t, 1H,
H-1′, J ) 6.1), 4.46-4.43 (m, 1H, H-3′), 4.08 (app q, 1H, H-4′, J
) 3.4), 3.94 (dd, 1H, H-5′, J ) 12.2, 2.9), 3.82 (dd, 1H, H-5′, J )
12.2, 3.9), 2.62 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9), 2.29 (dt, 1H,
H-2′, J ) 13.7, 6.1), 2.20 (s, 3H, CH3). 13C NMR (125 MHz, CD3-
OD): δ 172.5, 155.7, 148.4, 145.0, 139.3, 134.5, 129.8, 124.6,
123.4, 112.6, 88.5, 88.0, 70.0, 61.0, 41.5, 14.9. HRMS calculated
for C16H18N3O6 (M+ + H): 348.1196, found: 348.1198.
Desilylation of 4j (88.8 mg, 154.2 µmol) through the use of 1.3
M TASF in DMF (0.59 mL, 212.5 mg, 771.0 µmol) in DMF (1
mL) from 0 °C (1 h) to room temperature over 24 h provided a
90% yield of 5j after workup and chromatography.
1-(2′-Deoxyribofuranosyl)-4-(4-acetylphenyl)-5-methylpyrimi-
din-2(1H)-one (5i). Step 1: Synthesis of 1-[3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyribofuranosyl]-4-(4-acetylphenyl)-5-
methylpyrimidin-2(1H)-one (4i). Chromatography with 1:1 hexanes-
EtOAc yielded a pale yellow, foamy solid. Rf (silica gel, 1:1
hexanes-EtOAc) ) 0.44. 1H NMR (500 MHz, CDCl3): δ 8.13 (s,
1H, H-6), 8.03 (d, 2H, Ar-H, J ) 8.3), 7.69 (d, 2H, Ar-H, J )
8.3), 6.32 (t, 1H, H-1′, J ) 6.4), 4.40 (dt, 1H, H-3′, J ) 6.5, 3.3),
4.05 (app q, 1H, H-4′, J ∼ 2.8), 3.96 (dd, 1H, H-5′, J ) 11.2, 2.4),
3.80 (dd, 1H, H-5′, J ) 11.7, 2.4), 2.66 (ddd, 1H, H-2′, J ) 13.2,
6.4, 3.4), 2.65 (s, 3H, COCH3), 2.11 (s, 3H, CH3), 2.11 (dt, 1H,
H-2′, J ) 13.2, 6.5), 0.92, 0.90 (2s, 18H, SiC(CH3)3), 0.12, 0.11,
0.09, 0.08 (4s, 12H, SiCH3). 13C NMR (125 MHz, CDCl3): δ 197.6,
173.4, 154.8, 142.7, 142.1, 137.8, 128.8, 128.1, 110.8, 88.5, 87.5,
71.6, 62.6, 42.6, 29.7, 26.7, 25.9, 25.7, 18.4, 18.0, 16.4, -4.5, -4.9,
-5.4.
Antiviral Testing. Methodology used for evaluation of the
antiviral activity listed in Tables 1-5 of the Supporting Information
were performed as per reported procedures.24
Acknowledgment. This work was supported by NIH Grant
S06 GM008168-24S1 (NIGMS) and in part by NSF Grants
CHE-0314326 and CHE-0640417 (M.K.L.). Acquisition of a
mass spectrometer was funded by NSF Grant CHE-0520963
(M.K.L.). Infrastructural support at CCNY via NIH RCMI Grant
G12 RR03060 is also gratefully acknowledged. Drs. P. Pradhan
and S. Bae are thanked for their assistance.
Step 2: Desilylation. To a solution of 4i (93.9 mg, 163.9 µmol)
in MeOH (0.8 mL) was added KF (28.6 mg, 491.7 µmol), and the
reaction mixture was stirred at 60 °C for 30 h. After cooling, silica
gel was added to the reaction mixture and the MeOH was
evaporated under reduced pressure. The resulting compound-
impregnated silica gel was loaded onto a silica gel column and
eluted with 10:1 CHCl3-MeOH to give an off-white solid that upon
trituration with Et2O yielded 47.3 mg (84% yield) of 5i as a yellow
Supporting Information Available: Results of the antiviral
testing, 1H and 13C NMR spectra of compounds 2, 4a-j, and 5a-
j. This information is available free of charge via the Internet at
http://pubs.acs.org.
1
solid. Rf (silica gel, 10:1 CHCl3-MeOH) ) 0.19. H NMR (500
MHz, CD3OD): δ 8.63 (s, 1H, H-6), 8.13 (d, 2H, Ar-H, J ) 8.0),
7.74 (d, 2H, Ar-H, J ) 7.5), 6.27 (t, 1H, H-1′, J ) 6.0), 4.44 (app
q, 1H, H-3′, J ∼ 5.0), 4.07 (app q, 1H, H-4′, J ) 3.6), 3.93 (dd,
1H, H-5′, J ) 12.2, 2.9), 3.81 (dd, 1H, H-5′, J ) 12.2, 3.4), 2.67
(s, 3H, COCH3), 2.61 (ddd, 1H, H-2′, J ) 13.7, 6.4, 4.9), 2.28 (dt,
1H, H-2′, J ) 13.7, 6.1), 2.16 (s, 3H, CH3). 13C NMR (125 MHz,
CD3OD): δ 198.6, 174.2, 155.7, 144.5, 142.1, 138.1, 128.7, 128.3,
112.7, 88.5, 87.9, 70.1, 61.0, 41.5, 25.7, 15.0. HRMS calculated
for C18H21N2O5 (M+ + H): 345.1450, found: 345.1448.
JO070843+
(24) (a) De Clercq, E.; Holy´, A.; Rosenberg, I.; Sakuma, T.; Balzarini,
J.; Maudgal, P. C. Nature 1986, 323, 464-467. (b) De Clercq, E.
Antimicrob. Agents Chemother. 1985, 28, 84-89. (c) De Clercq, E.;
Descamps, J.; Verhelst, G.; Walker, R. T.; Jones, A. S.; Torrence, P. F;
Shugar, D. J. Infect. Dis. 1980, 141, 563-574.
5730 J. Org. Chem., Vol. 72, No. 15, 2007