Synthesis and chemoselective n-and o-alkylation of thiadiazolopyrimidine nucleosides and uridines

Article abstract of DOI:10.1055/s-0029-1216882

A facile and selective N-or O-alkylation of 4-b-D-ribofuranosyl[ 1,2,5]thiadiazolo[3,4-d]pyrmidine-5,7(4H,6H)-dione as well as uridines was accomplished via bimolecular base alkylation or bimolecular nucleophilic substitution reaction controlled by the re

Full text of DOI:10.1055/s-0029-1216882

PAPER
2689
Synthesis and Chemoselective N- and O-Alkylation of Thiadiazolopyrimidine
Nucleosides and Uridines
N-
and O-Alkylati
b
on of
T
hiadia
u
zolopyrimid
g
ine
N
ucleosi
a
des
a
nd U
r
f
Department of Drug Discovery and Development, Division of Pharmaceutical Science, Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayma University, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan
Fax +81(86)2517926; E-mail: nagamatsu@pheasant.pharm.okayama-u.ac.jp
Received 18 March 2009; revised 27 April 2009
and -xanthine, because of their potential biological
Abstract: A facile and selective N- or O-alkylation of 4-b-D-ribo-
activities9 and their activity in enzyme-catalyzed reac-
furanosyl[1,2,5]thiadiazolo[3,4-d]pyrmidine-5,7(4H,6H)-dione as
well as uridines was accomplished via bimolecular base alkylation
or bimolecular nucleophilic substitution reaction controlled by the
tions.10 These results have aroused our continuing interest
in the synthesis of isopurine nucleosides with a ribofura-
reagents. In the presence of 18-crown-6 and anhydrous K2CO3, the nosyl moiety residing on the pyrimidine ring, which
highly chemoselective O-methylation was performed using dimeth-
yl carbonate (DMC) in DMF at 22–25 °C, i.e. the 2¢,3¢-O-isopropy-
would be useful in the treatment of neoplastic and viral
diseases. However, although chemoselective alkylation is
lidene derivatives of 4-b-D-ribofurnosyl[1,2,5]thiadiazolo[3,4-
an effective method for the introduction of alkyl groups at
d]pyrmidine-5,7(4H,6H)-dione, uridine, and 5-bromouridine, un-
different positions on nitrogen or oxygen,11 the chemose-
derwent only the primary alcoholic O-methylation reaction without
lective alkylation of purine and pyrimidine nucleosides
has not been studied intensively.
affecting the NH group of the pyrimidne ring. The novel N-alkylat-
ed derivatives of 4-b-D-ribofurnosyl[1,2,5]thiadiazolo[3,4-d]pyr-
midine-5,7(4H,6H)-dione were also prepared using the appropriate
alkyl halides with a base.
In this paper, we report a facile synthesis of 4-b-D-ribo-
furanosyl[1,2,5]thiadiazolo[3,4-d]pyrimidines, which in-
cludes modifications at the level of heterocyclic base,
such as 6-N-substituted derivatives (I), or of the ribofura-
nosyl moiety such as 5¢-O-methyl derivative (II), as a new
aspect of chemoselective methylation (Figure 1). These
derivatives are structurally related to isoxanthosine and
represent the first examples of these kinds of compounds.
In addition, a chemoselective synthesis of 5¢-O-methyl-
uridine (III) and 5-bromo-5¢-O-methyluridine (IV) is also
reported.
Key words: ribofuranosylthiadiazolopyrimidines, uridines, chemo-
selectivity, alkylations, heterocycles
In the treatment of human viral diseases, purine nucleo-
side analogues have recently emerged as an important
therapeutic agent.1 The majority of purine nucleoside an-
alogues are natural substrates with modifications in the
heterocyclic base. Such base-modified analogues are per-
haps the most obvious target due to the density of accessi-
ble hydrogen-bond donor and acceptor sites that reside on
the heterocycle. These analogues have been used to com-
prehensively map the contribution of functional groups on
conserved purines to hairpin ribozyme activity.2 One of
the simplest strategies for the alteration of a functional
group is methylation. This has the effect of removing the
hydrogen bond from nitrogen or oxygen for the purpose of
introducing minimal steric perturbation. A new alkylated
isopurine nucleoside has recently been isolated from the
marine sponge Tedania digitata and identified as 1-meth-
ylisoguanosine.3,4 The isolation of the same compound
from the digestive glands of a nudibranch has also recent-
ly been reported,5 and it has been shown to possess potent
muscle-relaxant activity as well as exhibiting cardiovas-
cular and anti-inflammatory properties.5–8 Most of the nat-
O
7
O
O
4
1
R
O
5
X
N
N
N
N6
5
HN
O
HN3
2
S 2
S
4
1
6
N
3
N
O
N
O
N
5'
O
O
4'
HO
MeO
MeO
1'
2'
3'
HO OH
HO OH
HO OH
I
II
III X = H
IV X = Br
Figure 1
The desired 4-b-D-ribofurnosyl[1,2,5]thiadiazolo[3,4-
d]pyrimidine-5,7(4H,6H)-dione (5) was synthesized ac-
cording to the preliminary outlined procedure12 with some
modification (Scheme 1). Namely, the reaction of 5¢,6-
anhydro-6-hydroxy-2¢,3¢-O-isopropylideneuridine (1)13
with liquid ammonia, in the presence of ammonium ace-
tate at 50 °C, afforded 6-amino-2¢,3¢-O-isopropylidene-
uridine (2)12 in 40% yield. This reaction was also carried
out in the presence of ammonium chloride, but it was ob-
served that the yield using ammonium acetate as the cata-
lyst gave slightly better yield. Since this amination was
carried out in sealed steel containers for extended times,
urally occurring purine nucleosides possess
a
ribofuranosyl moiety on the imidazole ring. Nevertheless,
there has been increased interest in purine nucleosides
with a ribofuranosyl moiety attached to a nitrogen atom of
the pyrimidine ring, such as 3-b-D-ribofuranosyl-adenine
SYNTHESIS 2009, No. 16, pp 2689–2696
x
x.
x
x
.
2
0
0
9
Advanced online publication: 01.07.2009
DOI: 10.1055/s-0029-1216882; Art ID: F05809SS
© Georg Thieme Verlag Stuttgart · New York

2690
A. M. L. Hossion et al.
PAPER
O
N
O
N
O
O
N
O
N
NOH
NH
N
N
N
HN
O
HN
NH
HN
HN
O
S
S
N
O
O
O
O
N
O
O
O
NH2
O
O
O
ii
iii
i
iv
HO
HO
HO
HO
O
O
O
O
O
O
O
HO
OH
1
2
3
4
5
v
vi
O
N
O
N
O
N
O
N
R
O
R
O
N
S
N
N
N
N
S
N
N
N
N
O
HN
O
N
O
HN
O
S
S
O
O
O
iv
iv
a R = Me
b R = Et
c R = Pr
d R = Bn
HO
MeO
HO
MeO
HO
OH
O
O
O
HO
OH
e R = CH2COOEt
f R = CH2CH2CH2COOCEt
9
8
7a–f
6a–f
Scheme 1 Reagents and conditions: (i) liquid NH3, NH4Cl or AcONH4, 50 °C, 1.5 d; (ii) amyl nitrite, HCl, EtOH–EtOAc, 25 min; (iii)
Na2S2O3·5H2O, 5% aq AcOH, r.t., 1 h; (iv) 0.5 M HCl, MeOH, 50 °C, 4–8 h; (v) alkyl halide (a, MeI; b, EtI; c, n-PrI; d, BnBr; e, BrCH2CO2Et;
f, BrCH2CH2CH2CO2Et), K2CO3, anhyd DMF or acetone, 0 °C→r.t., 10 min→4 h; (vi) Me2CO3, 18-crown-6-ether, K2CO3, anhyd DMF, 22–
25 °C, 1 d.
portions of the starting material decomposed. The reason in 75% yield. In this case, the methylation occurred on the
for the lower yield of this reaction is presumably due to ribofuranosyl moiety instead of on the pyrimidine ring.
the decomposition of the ribose–pyrimidine linkage, since The product 8 was easily deprotected by treatment with
TLC showed the presence of another compound, which 0.5 M HCl in methanol at 50–60 °C to give the 5¢-O-
was not characterized, that ran around the base line on the methyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyri-
TLC in addition to the amino product (2). Nitrosation of 2 midine-5,7(4H,6H)-dione (9) in 75% yield. Similarly,
was accomplished with amyl nitrite, in the presence of a treatment of 4 with an appropriate alkyl halide (MeI, EtI,
catalytic amount of HCl in a mixture of ethanol and ethyl n-PrI, and BnBr) in the presence of 18-crown-6 did not
acetate, to give the 5-hydroxyimino-6-imino derivative 3 give the 5¢-O-alkyl nucleosides, but instead gave the usual
in an excellent yield of 89%. Direct conversion of 3 into 6-N-alkyl nucleosides only. Therefore, the presence of
4-(2¢,3¢-O-isopropylidene-b-D-ribofuranosyl)[1,2,5]thia-
both 18-crown-6 and DMC is essential for selective meth-
diazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione (4) was car- ylation on the primary alcohol. All new compounds ex-
ried out in good yield (73%) by reaction with hibited satisfactory elemental analyses and the IR, 1H and
Na2S2O3·5H2O in a 5% acetic acid solution at room tem- 13C NMR spectral data given in experimental part are con-
perature. Subsequent hydrolysis of 4 thus obtained, with sistent with the structures shown.
HCl in methanol afforded the desired 4-b-D-ribofurano-
It is clear that, in case of alkylating agents such as alkyl
halide, the alkylation preferentially occurred on the 6-N-
position of the pyrimidine ring, whereas with DMC in the
syl[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione
(5)12 in 88% yield.
When compound 4 was treated with an appropriate alkyl presence of 18-crown-6 and K2CO3, it took place
halide, in the presence of anhydrous K2CO3 in anhydrous chemoselectively on the 5¢-hydroxy position of the ribo-
DMF at room temperature, the alkylation proceeded to af- furanosyl moiety, without affecting the NH group of the
ford the corresponding 6N-alkyl-2¢,3¢-O-isopropylidene pyrimidine base. Furthermore, methylation with DMC, in
nucleosides (6a–f). Subsequent treatment of 6a–f with 0.5 the presence of 18-crown-6, gave much better yields for
M HCl in methanol at 50 °C gave the corresponding 6N- the reaction.
alkyl nucleosides (7a–f) in high yields after deprotection.
On the other hand, when compound 4 was treated with
dimethyl carbonate (DMC) in the presence of 18-crown-6
A plausible mechanism for selective alkylation on the pri-
mary alcohol can be outlined in the following way. DMC
is a versatile compound that enables phenolic mono-O-,
and anhydrous K2CO3, the alkylation proceeded on the
mono-S-, and mono-N-methylation reactions and can re-
hydroxy group at the 5¢-position to yield the 5¢-O-methyl-
act as a methylating agent in the presence of a nucleo-
4-(2¢,3¢-O-isopropylidene-b-D-ribofuranosyl) derivative 8
phile.14 18-Crown-6 is an organic compound that can
Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

PAPER
N- and O-Alkylation of Thiadiazolopyrimidine Nucleosides and Uridines
2691
coordinate some metal ions in its central cavity. Especial- cardiovascular and anti-inflammatory agents. In addition,
ly, 18-crown-6 displays a particular affinity for the potas- the combination of DMC with 18-crown-6 and potassium
sium cation.15 The above chemoselectivity can be carbonate made it possible to set up the chemoselective
explained on the basis of the principle of hard and soft ac- alkylation of 2¢,3¢-O-isopropylidene derivatives of 4-b-D-
ids and bases (HSAB principle).16 The chemoselective ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimidine 4, uri-
alkylation is due to the ambident character of DMC dine 10a and 5-bromouridine 10b. Under the investigated
which, in the presence of 18-crown-6 and K2CO3, acts as conditions in the presence of 18-crown-6, DMC is far su-
a hard electrophile. In contrast, the hydroxy group at the perior for chemoselective alkylation of such compounds
5¢-position of ribofuranosyl moiety of compound 4 can as 4, 10a, and 10b. The conditions lead to only primary al-
convert into an alkoxy ion, which is a harder nucleophile coholic O-methylation without affecting the NH group of
due to the increased basicity of K2CO3 in the presence of the pyrimidine base, whereas the alkylation of 4 with alkyl
18-crown-6. Consequently, the DMC, as a hard nucleo- halide gave only 6-N-alkylation without affecting the pri-
phile, reacts with the alkoxy ion, as a hard electrophile, mary hydroxy group of the ribofuranosyl moiety. Further
rather than the imino ion at the 3-position of the pyrimi- synthetic and mechanistic investigations as well as bio-
dine moiety, which behaves as a soft nucleophile. In 1987, logical evaluation of the [1,2,5]thiadiazolo[3,4-d]pyrimi-
Hovinen reported that the alkylation of 2¢,3¢-O-isopropy- dine nucleoside analogs are in progress, and will be
lideneuridine by methyl iodide, in the presence of excess reported in detail shortly.
sodium hydride in THF, afforded the 5¢-O-methyl deriva-
tive, exclusively.17 Later, Bessodes et al. also showed that
Melting points were determined using a Yanagimoto micro-melting
2¢,3¢-O-isopropylideneuridine can be preferentially meth-
ylated on the 5¢-hydroxy group by methyl iodide in THF,
in the presence of 18-crown-6 and potassium hydroxide at
room temperature, in 55% yield along with the N-alkylat-
ed product at the 3-position.18 It is worthwhile to report
here that DMC is a well known, non-toxic reagent19 and
our methodology of chemoselective O-alkylation for the
primary alcohol is widely applicable in nucleic acid chem-
istry and green chemistry.
point hot-stage apparatus and are uncorrected. IR spectra were re-
corded using a Jasco FT/IR-200 spectrophotometer as Nujol mulls.
Mass spectra were recorded at 70 eV ionizing voltage with FAB
ionization using VG-70SE spectrometer and glycerol as a matrix.
NMR spectra were obtained with a Varian VXR 300 MHz spec-
trometer. 1H NMR chemical shifts are expressed in parts per million
(ppm) based on internal TMS (d = 0.00 pm) in CDCl3 or DMSO-d6.
13C NMR chemical shifts are expressed in ppm based on solvent
signal of CDCl3. The coupling constants (J values) are given in Hz.
UV spectra were recorded in EtOH with a Beckman DU-600 spec-
trophotometer and absorption values in italics refer to wavelengths
at which shoulders or inflexions occur in the absorption. Specific
rotation was recorded in H2O or dioxane with a DIP-1000 digital
polarimeter. Elemental analyses were measured by a Yanako CHN
Corder MT-5 apparatus. All reagents were of commercial quality
from freshly opened containers and were used without further puri-
fication. Reaction progress was monitored by analytical thin layer
The method of this chemoselective alkylation was also ap-
plicable to uridine derivatives. Namely, the 2¢,3¢-O-iso-
propylidene derivatives of uridine (10a)20 and 5-
bromouridine (10b)21 were similarly methylated by treat-
ment with DMC, in the presence of 18-crown-6 and
K2CO3 in anhydrous DMF, to afford the corresponding 5¢-
O-methyl-2¢,3¢-O-isopropylideneuridine (11a)22 and its 5-
bromo derivative 11b21 with yields of 57% and 61%, re-
spectively (Scheme 2). Predominately, the methylation
occurred on the 5¢-hydroxy group of the ribofuranosyl
moiety.
chromatograph (TLC) on precoated glass plates (silica gel 60 F254
,
Merck) and products were visualized by UV light. Column chroma-
tography was accomplished on Daisogel IR-60 (63/210 mm, Daiso
Co.). The reaction temperatures are indicated as the temperature of
the oil bath. Anhydrous DMF was stored over activated 4 Å molec-
ular sieves and all other solvents were dried and freshly distilled pri-
or to use.
O
O
O
6-Amino-2¢,3¢-O-isopropylideneuridine (2)
X
X
X
HN
O
HN
O
A
mixture of 5¢,6-anhydro-6-hydroxy-2¢,3¢-O-isopropylidene-
HN
O
uridine13 (1; 5.0 g, 17.73 mmol), AcONH4 (0.96 g, 12.46 mmol) or
NH4Cl (0.66 g, 12.45 mmol) and liquid NH3 (~50 mL) in a sealed
steel tube was heated at 50 °C (20 kg/cm2) for 1.5 d. The ammonia
was removed and the residue was purified by column chromatogra-
phy on silica gel (EtOAc–EtOH, 10:1) to give the product 2.
O
N
O
N
O
N
ii
i
MeO
HO
MeO
a X = H
b X = Br
O
O
O
O
HO
OH
Yield: 2.1 g (40%); colorless powdery crystals; mp 229–231 °C
(EtOAc–EtOH) (Lit.12 229–230 °C); Rf = 0.43 (EtOAc–EtOH, 4:1).
10a,b
11a,b
12a,b
IR (Nujol): 3405 (OH), 3300, 3260, 3210 (NH), 1735, 1665 (C=O)
cm–1.
Scheme 2 Reagents and conditions: (i) Me2CO3, 18-crown-6,
K2CO3, anhyd DMF, 22–25 °C, 1 d; (ii) 0.5 M HCl, MeOH, 50 °C, 5–
7 h.
1H NMR (CDCl3): d = 1.34 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 3.76–
3.88 (m, 2 H, 5¢-H2), 4.08–4.13 (m, 1 H, 4¢-H), 4.87 (s, 1 H, 5-H),
4.94 (dd, J2¢,3¢ = 6.9 Hz, J3¢,4¢ = 4.2 Hz, 1 H, 3¢-H), 5.13 (dd,
J1¢,2¢ = 4.2 Hz, J2¢,3¢ = 6.9 Hz, 1 H, 2¢-H), 5.18 (dd, J = 4.2, 3.6 Hz,
1 H, 5¢-OH, D2O exch.), 6.32 (s, 2 H, NH2, D2O exch.), 6.52 (d,
J1¢,2¢ = 4.2 Hz, 1 H, 1¢-H), 9.57 (s, 1 H, NH, D2O exch.).
In conclusion, we have demonstrated the first general syn-
thesis of [1,2,5]thiadiazolo[3,4-d]pyrimidine nucleosides,
namely, 6-N- or 5¢-O-substituted 4-b-D-ribofurano-
syl[1,2,5]thiadiazolo[3,4-d]pyrimidines, as a new class of
UV (EtOH): lmax (log e) = 271 nm (4.52).
Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

2692
A. M. L. Hossion et al.
PAPER
5-Hydroxyimino-6-imino-2¢,3¢-O-isopropylidene-5,6-dihydro-
uridine (3)
1H NMR (DMSO-d6): d = 3.47 [ddd (dd after addition of D2O,
J4¢,5¢a = 6.0 Hz, Jgem = 11.7 Hz), J4¢,5¢a = 6.0 Hz, J5¢a,OH = 5.7 Hz,
Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.65 [ddd (dd after addition of D2O,
J4¢,5¢b = 4.2 Hz, Jgem = 11.7 Hz), J4¢,5¢b = 4.5 Hz, J5¢b,OH = 5.7 Hz,
Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.78 (ddd, J3¢,4¢ = 5.7 Hz, J4¢,5¢a = 6.0 Hz,
J4¢,5¢b = 4.5 Hz, 1 H, 4¢-H), 4.18 [q (dd after addition of D2O,
J2¢,3¢ = 5.7 Hz, J3¢,4¢ = 5.4 Hz), J = 5.7 Hz, 1 H, 3¢-H], 4.60 (t, J = 5.7
Hz, 1 H, 5¢-OH, D2O exch.), 4.67 [q (dd after addition of D2O,
J1¢,2¢ = 4.8 Hz, J2¢,3¢ = 5.7 Hz), J = 5.4 Hz, 1 H, 2¢-H], 5.03 (d,
J3¢,OH = 6.0 Hz, 1 H, 3¢-OH, D2O exch.), 5.17 (d, J2¢,OH = 5.1 Hz,
1 H, 2¢-OH, D2O exch.), 6.12 (d, J1¢,2¢ = 4.5 Hz, 1 H, 1¢-H), 12.03 (s,
1 H, NH, D2O exch.).
Compound 2 (0.5 g, 1.67 mmol) was dissolved in a mixture of EtOH
(10 mL) and EtOAc (10 mL) by warming. After cooling to r.t., amyl
nitrite (1.2 mL) was added to the solution dropwise with stirring
over 15 min. After one drop of concd HCl was added to the solution,
purple crystals deposited immediately. The mixture was stirred at
r.t. for 15 min more then kept in a refrigerator for several hours. The
solid deposit was filtered and washed with EtOAc to afford the
product 3.
Yield: 0.49 g (89%); purple powdery crystals; mp >300 °C
(EtOAc–EtOH) (Lit.12 >300 °C); Rf = 0.54 (EtOAc–AcOH, 4:1).
UV (EtOH): lmax (log e) = 249 (3.71), 315 nm (4.09).
IR (Nujol): 3335 (OH), 3200, 3150, 3090 (NH), 1740, 1700 (C=O)
cm–1.
Formation of 6-N-Alkylated [1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione Nucleosides 6a–f; General Procedure
To a cooled mixture of 4-(2¢,3¢-O-isopropylidene-b-D-ribofurano-
1H NMR (DMSO-d6): d = 1.28 (s, 3 H, CH3), 1.49 (s, 3 H, CH3),
3.51–3.60 (m, 2 H, 5¢-H2), 4.07 (m, 1 H, 4¢-H), 4.78 (dd, J2¢,3¢ = 6.3
Hz, J3¢,4¢ = 3.9 Hz, 1 H, 3¢-H), 5.16 (dd, J1¢,2¢ = 4.2 Hz, J2¢,3¢ = 6.3 Hz,
1 H, 2¢-H), 5.36 (br s, 1 H, 5¢-OH, D2O exch.), 6.16 (d, J1¢,2¢ = 4.2
Hz, 1 H, 1¢-H), 9.58 (br s, 1 H, =NOH, D2O exch.), 11.65 (s, 1 H, 3-
NH, D2O exch.), 13.84 (br s, 1 H, =NH, D2O exch.).
syl)[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7-(4H,6H)-dione
(4;
0.34g, 1.0 mmol) and anhyd K2CO3 (0.207 g, 1.5 mmol) in dried
DMF (4–5 mL) at 0 °C, was added an appropriate alkyl halide (1.5
mmol), and the mixture was stirred vigorously at 0 °C to r.t. for be-
tween 10 min and 4 h. The reaction mixture was poured into H2O
(10 mL) and the resulting solution was extracted with EtOAc (2 ꢀ 8
mL). The organic layer was dried over anhyd MgSO4 and evaporat-
ed in vacuo to yield either a colorless oil or a white solid. The crude
product was purified by column chromatography (EtOAc–n-hex-
ane) to afford the corresponding compounds 6a–f as colorless pow-
dery crystals.
UV (EtOH): lmax (log e) = 316 nm (4.55).
4-(2¢,3¢-O-Isopropylidene-b-D-ribofuranosyl)[1,2,5]thiadiazo-
lo[3,4-d]pyrimidine-5,7(4H,6H)-dione (4)
A mixture of 5-hydroxyimino-6-imino-2¢,3¢-O-isopropylidene-5,6-
dihydorouridine (3; 0.5 g, 1.52 mmol) and 5% AcOH (10 mL) was
stirred at r.t., and to the solution was added Na2S2O3·5H2O (0.70 g,
2.82 mmol) in portions. Stirring was continued until the color of the
solution changed completely from purple to colorless. When the re-
action was complete, the solution was evaporated to dryness in vac-
uo at low temperature. To the residue was added H2O (15 mL) and
the solution was extracted with EtOAc (3 ꢀ 10 mL). The combined
organic extracts were washed with brine (10 mL), dried over anhyd
MgSO4, and evaporated to dryness. After trituration of the residue
with n-hexane, the resulting precipitate was collected by filtration
and washed with n-hexane to isolate the product 4.
6-Methyl-4-(2¢,3¢-O-isopropylidene-b-D-ribofurano-
syl)[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione (6a)
Yield: 0.18 g (54%); [a]D20 –24.95 (c 1.00, dioxane); mp 72–74 °C;
Rf = 0.76 (EtOAc).
IR (Nujol): 1685, 1720 (C=O) cm–1.
1H NMR (CDCl3): d = 1.37 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 2.86
(dd, J5¢a,OH = 9.0 Hz, J5¢b,OH = 3.3 Hz, 1 H, 5¢-OH, D2O exch.), 3.49
(s, 3 H, NCH3), 3.82 [ddd (dd after addition of D2O, J4¢,5¢a = 3.6 Hz,
Jgem = 12.3 Hz), J4¢,5¢a = 3.6 Hz, J5¢a,OH = 9.0 Hz, Jgem = 12.3 Hz, 1 H,
5¢-Ha], 3.92 [ddd (dd after addition of D2O, J4¢,5¢b = 2.7 Hz,
Jgem = 12.3 Hz), J4¢,5¢b = 3.0 Hz, J5¢b,OH = 3.3 Hz, Jgem = 12.3 Hz,
1 H, 5¢-Hb], 4.33 (ddd, J3¢,4¢ = J4¢,5¢a = 3.6 Hz, J4¢,5¢b = 3.0 Hz, 1 H, 4¢-
H), 5.10 (dd, J2¢,3¢ = 6.6 Hz, J3¢,4¢ = 3.6 Hz, 1 H, 3¢-H), 5.31 (dd,
J1¢,2¢ = 3.6 Hz, J2¢,3¢ = 6.6 Hz, 1 H, 2¢-H), 6.61 (d, J1¢,2¢ = 3.6 Hz, 1 H,
1¢-H).
Yield: 0.38 g (73%); colorless powdery crystals; mp 126–127 °C
(EtOAc) (Lit.12 126–127 °C); Rf = 0.52 (EtOAc).
IR (Nujol): 3450 (OH), 3200 (NH), 1720 (C=O) cm–1.
1H NMR (CDCl3): d = 1.38 (s, 3 H, CH3), 1.63 (s, 3 H, CH3), 2.93
(br s, 1 H, 5¢-OH, D2O exch.), 3.82 [br d (dd after addition of D2O,
J4¢,5¢a = 3.9 Hz, Jgem = 12.3 Hz), 1 H, 5¢-Ha], 3.92 (ddd, J4¢,5¢b = 2.7
Hz, J5¢b,OH = 3.6 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Hb), 4.33 (ddd,
J3¢,4¢ = J4¢,5¢a = 3.9 Hz, J4¢,5¢b = 2.7 Hz, 1 H, 4¢-H), 5.07 (dd, J2¢,3¢ = 6.6
Hz, J3¢,4¢ = 3.9 Hz, 1 H, 3¢-H), 5.32 (dd, J1¢,2¢ = 3.6 Hz, J2¢,3¢ = 6.6 Hz,
1 H, 2¢-H), 6.54 (d, J1¢,2¢ = 3.6 Hz, 1 H, 1¢-H), 9.03 (br s, 1 H, NH,
D2O exch.).
13C NMR (CDCl3): d = 25.57 and 27.55 [C(CH3)2], 29.27 (NCH3),
63.03 (C5¢), 80.55 (C3¢), 82.36 (C2¢), 86.63 (C4¢), 92.09 (C1¢), 114.85
[C(CH3)2], 137.84 (C7a), 150.00 (C3a), 153.51 (C5), 154.29 (C7).
UV (EtOH): lmax (log e) = 250 (3.70), 312 nm (4.04).
UV (EtOH): lmax (log e) = 248 (3.73), 314 nm (4.13).
Anal. Calcd for C13H16N4O6S: C, 43.82; H, 4.53; N, 15.72. Found:
C, 43.97; H, 4.57; N, 15.59.
4-b-D-Ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimidine-
5,7(4H,6H)-dione (5)
6-Ethyl-4-(2¢,3¢-O-isopropylidene-b-D-ribofuranosyl)[1,2,5]thi-
adiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione (6b)
Yield: 0.25 g (68%); [a]D20 –26.19 (c 1.00, dioxane); mp 55–57 °C;
Rf = 0.77 (EtOAc).
A solution of 4 (0.5 g, 1.46 mmol) in a mixture of MeOH (50 mL)
and 0.5 M HCl (20 mL) was heated at 50 °C for 7 h. After cooling
to r.t., the solution was neutralized with Et3N and evaporated in vac-
uo. Finally, the solution was co-evaporated with EtOH to complete
dryness and the dry residue was treated with absolute EtOH. The in-
soluble material was filtered off, the filtrate was evaporated in vac-
uo and the residue was purified by column chromatography
(EtOAc) to give the product 5.
IR (Nujol): 1682, 1730 (C=O) cm–1.
1H NMR (CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3CH2), 1.38 (s,
3 H, CH3), 1.63 (s, 3 H, CH3), 2.87 (dd, J5¢a,OH = 9.0 Hz, J5¢b,OH = 3.3
Hz, 1 H, 5¢-OH, D2O exch.), 3.87 [ddd (dd after addition of D2O,
J4¢,5¢a = 3.6 Hz, Jgem = 12.3 Hz), J4¢,5¢a = 3.6 Hz, J5¢a,OH = 9.0 Hz,
Jgem = 12.3 Hz, 1 H, 5¢-Ha], 3.93 [ddd (dd after addition of D2O,
J4¢,5¢b = 2.7 Hz, Jgem = 12.3 Hz), J4¢,5¢b = 2.7 Hz, J5¢b,OH = 3.3 Hz,
Jgem = 12.3 Hz, 1 H, 5¢-Hb], 4.14 (q, J = 7.2 Hz, 2 H, CH3CH2), 4.34
(ddd, J3¢,4¢ = J4¢,5¢a = 3.6 Hz, J4¢,5¢b = 2.7 Hz, 1 H, 4¢-H), 5.09 (dd,
Yield: 0.39 g (88%); colorless powdery crystals; mp 115–116 °C
(amorphous, EtOAc) (Lit.12 115 °C); Rf = 0.27 (EtOAc).
IR (Nujol): 3385 (OH), 3190 (NH), 1720 (C=O).
Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

PAPER
N- and O-Alkylation of Thiadiazolopyrimidine Nucleosides and Uridines
2693
J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.6 Hz, 1 H, 3¢-H), 5.32 (dd, J1¢,2¢ = 3.3 Hz,
J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 6.61 (d, J1¢,2¢ = 3.3 Hz, 1 H, 1¢-H).
UV (EtOH): lmax (log e) = 248 (3.59), 312 nm (4.01).
Anal. Calcd for C16H20N4O8S: C, 44.86; H, 4.71; N, 13.08. Found:
C, 45.15; H, 4.69; N, 12.96.
UV (EtOH): lmax (log e) = 253 (3.59), 311 nm (4.01).
Anal. Calcd for C14H18N4O6S: C, 45.40; H, 4.90; N, 15.13. Found:
C, 45.59; H, 4.74; N, 15.21.
Ethyl 4-{4-(2¢,3¢-O-isopropylidene-b-D-ribofuranosyl)[1,2,5]thi-
adiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dion-6-yl}butanoate (6f)
Yield: 0.34 g (74%); [a]D20 –28.21 (c 1.00, dioxane); mp 52–54 °C;
Rf = 0.72 (EtOAc).
6-Propyl-4-(2¢,3¢-O-isopropylidene-b-D-ribofurano-
syl)[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione (6c)
Yield: 0.27 g (71%); [a]D20 –27.77 (c 1.00, dioxane); mp 60–62 °C;
Rf = 0.75 (EtOAc).
IR (Nujol): 1682, 1732 (C=O) cm–1.
1H NMR (CDCl3): d = 1.23 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.38 (s,
3 H, CH3), 1.62 (s, 3 H, CH3), 2.04 (quin, J = 7.2 Hz, 2 H,
OCCH2CH2CH2N), 2.41 (t, J = 7.2 Hz, 2 H, OCCH2CH2CH2N),
2.87 (dd, J5¢a,OH = 8.4 Hz, J5¢b,OH = 3.3 Hz, 1 H, 5¢-OH, D2O exch.),
3.81 [ddd (dd after addition of D2O, J4¢,5¢a = 3.9 Hz, Jgem = 12.3 Hz),
J4¢,5¢a = 3.6 Hz, J5¢a,OH = 8.4 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Ha], 3.91 [br
d (dd after addition of D2O, J4¢,5¢b = 2.7 Hz, Jgem = 12.3 Hz),
Jgem = 12.3 Hz, 1 H, 5¢-Hb], 4.09 (q, J = 7.2 Hz, 2 H, CH3CH2O),
4.14 (t, J = 6.9 Hz, 2 H, CH2N), 4.33 (ddd, J3¢,4¢ = J4¢,5¢a = 3.6 Hz,
J4¢,5¢b = 3.0 Hz, 1 H, 4¢-H), 5.08 (dd, J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.6 Hz,
1 H, 3¢-H), 5.31 (dd, J1¢,2¢ = 3.3 Hz, J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 6.60
(d, J1¢,2¢ = 3.3 Hz, 1 H, 1¢-H).
IR (Nujol): 1684, 1730 (C=O) cm–1.
1H NMR (CDCl3): d = 1.00 (t, J = 7.2 Hz, 3 H, CH3CH2CH2), 1.38
(s, 3 H, CH3), 1.63 (s, 3 H, CH3), 1.67–1.75 (m, 2 H, CH3CH2CH2),
2.86 (dd, J5¢a,OH = 9.0 Hz, J5¢b,OH = 3.3 Hz, 1 H, 5¢-OH, D2O exch.),
3.81 [ddd (dd after addition of D2O, J4¢,5¢a = 3.6 Hz, Jgem = 12.3 Hz),
J4¢,5¢a = 3.6 Hz, J5¢a,OH = 9.0 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Ha], 3.93
[ddd (dd after addition of D2O, J4¢,5¢b = 2.7 Hz, Jgem = 12.3 Hz),
J4¢,5¢b = 3.0 Hz, J5¢b,OH = 3.3 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Hb], 4.00–
4.05 (m, 2 H, CH3CH2CH2N), 4.34 (ddd, J3¢,4¢ = J4¢,5¢a = 3.6 Hz,
J4¢,5¢b = 3.0 Hz, 1 H, 4¢-H), 5.09 (dd, J2¢,3¢ = 6.6 Hz, J3¢,4¢ = 3.6 Hz,
1 H, 3¢-H), 5.32 (dd, J1¢,2¢ = 3.6 Hz, J2¢,3¢ = 6.6 Hz, 1 H, 2¢-H), 6.60
(d, J1¢,2¢ = 3.6 Hz, 1 H, 1¢-H).
UV (EtOH): lmax (log e) = 255 (3.66), 312 nm (4.03).
MS (FAB, glycerol matrix): m/z = 457 [MH+].
UV (EtOH): lmax (log e) = 253 (3.72), 313 nm (4.06).
Anal. Calcd for C15H20N4O6S: C, 46.87; H, 5.24; N, 14.57. Found:
C, 46.90; H, 5.64; N, 14.60.
Formation of 5¢-Methoxy Derivatives of Thiadiazolopyrimidine
and Uridine Nucleosides 8, 11a and 11b; General Procedure
A mixture of either 4, 10a or 10b (1.0 mmol), anhyd K2CO3 (2.5
mmol), 18-crown-6 (1 mmol) and anhyd DMF (6 mL) was cooled
at 22 °C. Me2CO3 (DMC; 1.5 mmol) was added to the mixture, and
the mixture was stirred at 22–25 °C for 1 d. After the reaction was
complete, the reaction mixture was poured into H2O (8 mL) and
neutralized with 10% HCl to yield a white solid. The resulting solid
was collected by filtration and purified by column chromatography
(EtOAc–n-hexane, 1:1) to afford the corresponding pure products 8,
11a and 11b as colorless powdery crystals.
6-Benzyl-4-(2¢,3¢-O-isopropylidene-b-D-ribofurano-
syl)[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dione (6d)
20
Yield: 0.32 g (74%); [a]D –25.20 (c 1.00, dioxane); mp 165–
167 °C; Rf = 0.78 (EtOAc).
IR (Nujol): 1680, 1726 (C=O) cm–1.
1H NMR (CDCl3): d = 1.36 (s, 3 H, CH3), 1.62 (s, 3 H, CH3), 2.77
(dd, J5¢a,OH = 9.0 Hz, J5¢b,OH = 3.3 Hz, 1 H, 5¢-OH, D2O exch.), 3.78
[ddd (dd after addition of D2O, J4¢,5¢a = 3.6 Hz, Jgem = 12.3 Hz),
J4¢,5¢a = 3.6 Hz, J5¢a,OH = 9.0 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Ha], 3.90
[ddd (dd after addition of D2O, J4¢,5¢b = 2.7 Hz, Jgem = 12.3 Hz),
J4¢,5¢b = 3.0 Hz, J5¢b,OH = 3.3 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Hb], 4.30
(ddd, J3¢,4¢ = J4¢,5¢a = 3.6 Hz, J4¢,5¢b = 3.0 Hz, 1 H, 4¢-H), 5.09 (dd,
J2¢,3¢ = 6.6 Hz, J3¢,4¢ = 3.6 Hz, 1 H, 3¢-H), 5.24 (s, 2 H, CH2Ph), 5.29
(dd, J1¢,2¢ = 3.6 Hz, J2¢,3¢ = 6.6 Hz, 1 H, 2¢-H), 6.59 (d, J1¢,2¢ = 3.6 Hz,
1 H, 1¢-H), 7.28–7.35 (m, 3 H, m,p-HPh), 7.50–7.53 (m, 2 H, o-
HPh).
5¢-O-Methyl-4-(2¢,3¢-O-isopropylidene-b-D-ribofurano-
syl)[1,2,5]thiadiazolo[3,4-d]pyrimidine-5,7(4H, 6H)-dione (8)
20
Yield: 0.27 g (75%); [a]D –29.84 (c 1.00, dioxane); mp 200–
202 °C; Rf = 0.82 (EtOAc).
IR (Nujol): 1724 (C=O) cm–1.
1H NMR (CDCl3): d = 1.37 (s, 3 H, CH3), 1.60 (s, 3 H, CH3), 3.72
(s, 3 H, 5¢-OCH3), 4.30–4.42 (m, 3 H, 5¢-H2 and 4¢-H), 5.00 (dd,
J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.6 Hz, 1 H, 3¢-H), 5.33 (dd, J1¢,2¢ = 1.5 Hz,
J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 6.61 (d, J1¢,2¢ = 1.5 Hz, 1 H, 1¢-H), 8.78 (s,
1 H, NH, D2O exch.).
UV (EtOH): lmax (log e) = 247 (3.61), 312 nm (4.05).
Anal. Calcd for C19H20N4O6S: C, 52.77; H, 4.66; N, 12.96. Found:
C, 52.96; H, 5.00; N, 13.00.
13C NMR (CDCl3): d = 25.38 and 27.26 [C(CH3)2], 55.02 (OCH3),
67.66 (C5¢), 81.66 (C3¢), 84.05 (C2¢), 85.78 (C4¢), 91.19 (C1¢), 114.57
[C(CH3)2], 138.64 (C7a), 149.39 (C3a), 154.17 (C5), 155.57 (C7).
Ethyl 2-{4-(2¢,3¢-O-isopropylidene-b-D-ribofuranosyl)[1,2,5]thi-
adiazolo[3,4-d]pyrimidine-5,7(4H,6H)-dion-6-yl}acetate (6e)
Yield: 0.24 g (56%); [a]D20 –21.04 (c 1.00, dioxane); mp 59–61 °C;
Rf = 0.74 (EtOAc).
UV (EtOH): lmax (log e) = 253 (3.54), 312 nm (3.99).
Anal. Calcd for C13H16N4O6S: C, 43.82; H, 4.53; N, 15.72. Found:
C, 43.91; H, 4.45; N, 15.58.
IR (Nujol): 1687, 1734 (C=O) cm–1.
1H NMR (CDCl3): d = 1.31 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.37 (s,
3 H, CH3), 1.62 (s, 3 H, CH3), 2.71 (dd, J5¢a,OH = 9.0 Hz, J5¢b,OH = 3.0
Hz, 1 H, 5¢-OH, D2O exch.), 3.78 [ddd (dd after addition of D2O,
J4¢,5¢a = 3.9 Hz, Jgem = 12.3 Hz), J4¢,5¢a = 3.9 Hz, J5¢a,OH = 9.0 Hz,
Jgem = 12.3 Hz, 1 H, 5¢-Ha], 3.91 [ddd (dd after addition of D2O,
J4¢,5¢b = 2.7 Hz, Jgem = 12.3 Hz), J4¢,5¢b = 3.0 Hz, J5¢b,OH = 3.0 Hz,
Jgem = 12.3 Hz, 1 H, 5¢-Hb], 4.25 (q, J = 7.2 Hz, 2 H, CH3CH2O),
4.31 (ddd, J3¢,4¢ = J4¢,5¢a = 3.9 Hz, J4¢,5¢b = 3.0 Hz, 1 H, 4¢-H), 4.79 (br
s, 2 H, CH2N), 5.07 (dd, J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.9 Hz, 1 H, 3¢-H),
5.30 (dd, J1¢,2¢ = 3.3 Hz, J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 6.60 (d, J1¢,2¢ = 3.3
Hz, 1 H, 1¢-H).
5¢-O-Methyl-2¢,3¢-O-isopropylideneuridine (11a)
Yield: 0.17 g (57%); [a]D20 –18.60 (c 1.00, dioxane); mp 64–66 °C
(Lit.20 foamy glass); Rf = 0.49 (EtOAc).
IR (Nujol): 1694, 1752 (C=O) cm–1.
1H NMR (CDCl3): d = 1.36 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 3.80
(s, 3 H, 5¢-OCH3), 4.33–4.43 (m, 3 H, 4¢-H and 5¢-H2), 4.84 (dd,
J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.3 Hz, 1 H, 3¢-H), 4.96 (dd, J1¢,2¢ = 2.1 Hz,
J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 5.72 (d, J5,6 = 8.1 Hz, 1 H, 5-H), 5.73 (d,
J1¢,2¢ = 2.1 Hz, 1 H, 1¢-H), 7.30 (d, J5,6 = 8.1 Hz, 1 H, 6-H), 8.81 (s,
1 H, NH, D2O exch.).
Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

2694
A. M. L. Hossion et al.
PAPER
UV (EtOH): lmax (log e) = 257 nm (3.26) (Lit.20 262 nm, MeOH).
J5¢a,OH = 5.4 Hz, J5¢b,OH = 5.1 Hz, 1 H, 5¢-OH, D2O exch.), 4.66 [q
(dd after addition of D2O, J1¢,2¢ = 4.5 Hz, J2¢,3¢ = 5.7 Hz), J = 5.1 Hz,
1 H, 2¢-H], 5.02 (d, J3¢,OH = 6.0 Hz, 1 H, 3¢-OH, D2O exch.), 5.15 (d,
J2¢,OH = 5.1 Hz, 1 H, 2¢-OH, D2O exch.), 6.19 (d, J1¢,2¢ = 4.5 Hz, 1 H,
1¢-H).
5-Bromo-5¢-O-methyl-2¢,3¢-O-isopropylideneuridine (11b)
Yield: 0.23 g (61%); [a]D20 –22.90 (c 1.00, dioxane); mp 88–90 °C
(Lit.21 foamy glass); Rf = 0.71 (EtOAc).
IR (Nujol): 1692, 1754 (C=O) cm–1.
UV (EtOH): lmax (log e) = 256 (3.50), 313 nm (3.90).
1H NMR (CDCl3): d = 1.36 (s, 3 H, CH3), 1.58 (s, 3 H, CH3), 3.82
(s, 3 H, 5¢-OCH3), 4.35 (dd, J4¢,5¢a = 5.4 Hz, Jgem = 12.3 Hz, 1 H, 5¢-
Ha), 4.43 (dd, J4¢,5¢b = 3.0 Hz, Jgem = 12.3 Hz, 1 H, 5¢-Hb), 4.45 (ddd,
J3¢,4¢ = 3.3 Hz, J4¢,5¢a = 5.4 Hz, J4¢,5¢b = 3.0 Hz, 1 H, 4¢-H), 4.83 (dd,
J2¢,3¢ = 6.3 Hz, J3¢,4¢ = 3.3 Hz, 1 H, 3¢-H), 4.92 (dd, J1¢,2¢ = 2.4 Hz,
J2¢,3¢ = 6.3 Hz, 1 H, 2¢-H), 5.83 (d, J1¢,2¢ = 2.4 Hz, 1 H, 1¢-H), 7.72 (s,
1 H, 6-H), 9.31 (s, 1 H, NH, D2O exch.).
Anal. Calcd for C11H14N4O6S·2/5H2O: C, 39.14; H, 4.42; N, 16.60.
Found: C, 39.43; H, 4.49; N, 16.78.
6-n-Propyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (7c)
20
Yield: 0.28 g (82%); [a]D –13.18 (c 1.00, H2O); mp 46–48 °C;
Rf = 0.31 (EtOAc).
13C NMR (CDCl3): d = 25.41 and 27.26 (2 ꢀ CH3), 55.46 (OCH3),
67.36 (C5¢), 80.89 (C3¢), 84.75 (C2¢), 90.03 (C4¢), 93.89 (C1¢), 97.42
(C5), 114.97 [C(CH3)2], 140.89 (C6), 149.60 (C2), 159.11 (C4).
IR (Nujol): 1680, 1725 (C=O) cm–1.
1H NMR (DMSO-d6): d = 0.91 (t, J = 7.2 Hz, 3 H, CH3CH2CH2),
1.60 (sext, J = 7.2 Hz, 2 H, CH3CH2CH2), 3.48 [ddd (dd after addi-
tion of D2O, J4¢,5¢a = 6.0 Hz, Jgem = 11.7 Hz), J4¢,5¢a = 6.3 Hz,
J5¢a,OH = 5.7 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.66 [ddd (dd after ad-
dition of D2O, J4¢,5¢b = 4.2 Hz, Jgem = 11.7 Hz), J4¢,5¢b = 4.8 Hz,
J5¢b,OH = 5.4 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.79 (ddd, J3¢,4¢ = 6.0
Hz, J4¢,5¢a = 6.3 Hz, J4¢,5¢b = 4.8 Hz, 1 H, 4¢-H), 3.86 (t, J = 7.2 Hz,
2 H, CH3CH2CH2N), 4.20 [q (dd after addition of D2O, J2¢,3¢ = 5.4
Hz, J3¢,4¢ = 6.0 Hz), J = 6.0 Hz, 1 H, 3¢-H], 4.61 (dd, J5¢a,OH = 5.7 Hz,
J5¢b,OH = 5.4 Hz, 1 H, 5¢-OH, D2O exch.), 4.66 [q (dd after addition
of D2O, J1¢,2¢ = 4.2 Hz, J2¢,3¢ = 5.4 Hz), J = 5.4 Hz, 1 H, 2¢-H], 5.04
(d, J3¢,OH = 6.3 Hz, 1 H, 3¢-OH, D2O exch.), 5.17 (d, J2¢,OH = 5.4 Hz,
1 H, 2¢-OH, D2O exch.), 6.18 (d, J1¢,2¢ = 4.2 Hz, 1 H, 1¢-H).
UV (EtOH): lmax (log e) = 274 nm (4.10).
Formation of Deprotected Thiadiazolopyrimidine and Uridine
Nucleosides 7a–f, 9, 12a and 12b; General Procedure
A solution of 6a–f, 8, 11a or 11b (1.0 mmol) in a mixture of MeOH
(25 mL) and 0.5 M HCl (10 mL) was heated at 50–60 °C for 3–5 h.
After cooling to r.t., the solution was neutralized with Et3N and
evaporated in vacuo. Finally, the solution was co-evaporated with
EtOH to complete dryness and the dry residue was treated with ab-
solute EtOH. The insoluble material was filtered off, the filtrate was
evaporated in vacuo and the residue was purified by column chro-
matography (EtOAc–n-hexane) to give the corresponding products
7a–f, 9, 12a, and 12b as colorless powdery crystals.
UV (EtOH): lmax (log e) = 255 (3.57), 314 nm (4.10).
Anal. Calcd for C12H16N4O6S·2/5H2: C, 41.00; H, 4.82; N, 15.94.
Found: C, 41.31; H, 4.91; N, 15.85.
6-Methyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (7a)
Yield: 0.24 g (75%); [a]D20 –20.09 (c 1.00, dioxane); mp 91–93 °C;
Rf = 0.32 (EtOAc).
IR (Nujol): 1678, 1725 (C=O) cm–1.
6-Benzyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (7d)
Yield: 0.31 g (80%); [a]D20 –20.20 (c 1.00, dioxane); mp 83–85 °C;
Rf = 0.35 (EtOAc).
1H NMR (DMSO-d6): d = 3.30 (s, 3 H, NCH3), 3.48 [ddd (dd after
addition of D2O, J4¢,5¢a = 6.3 Hz, Jgem = 11.7 Hz), J4¢,5¢a = 6.3 Hz,
J5¢a,OH = 5.7 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.66 [ddd (dd after ad-
dition of D2O, J4¢,5¢b = 4.2 Hz, Jgem = 11.7 Hz), J4¢,5¢b = 4.8 Hz,
J5¢b,OH = 5.4 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.79 (q, J = 6.0 Hz,
1 H, 4¢-H), 4.19 [q (t after addition of D2O, J = 5.7 Hz), J = 6.0 Hz,
1 H, 3¢-H], 4.59 (dd, J5¢a,OH = 5.7 Hz, J5¢b,OH = 5.4 Hz, 1 H, 5¢-OH,
D2O exch.), 4.66 [q (t after addition of D2O, J = 5.1 Hz), J = 5.4 Hz,
1 H, 2¢-H], 5.05 (d, J3¢,OH = 6.0 Hz, 1 H, 3¢-OH, D2O exch.), 5.17 (d,
J2¢,OH = 5.4 Hz, 1 H, 2¢-OH, D2O exch.), 6.19 (d, J1¢,2¢ = 4.5 Hz, 1 H,
1¢-H).
IR (Nujol): 1680, 1725 (C=O) cm–1.
1H NMR (DMSO-d6): d = 3.47 [ddd (dd after addition of D2O,
J4¢,5¢a = 6.3 Hz, Jgem = 11.7 Hz), J4¢,5¢a = 6.3 Hz, J5¢a,OH = 5.4 Hz,
Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.66 [ddd (dd after addition of D2O,
J4¢,5¢b = 4.2 Hz, Jgem = 11.7 Hz), J4¢,5¢b = 4.2 Hz, J5¢b,OH = 4.5 Hz,
Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.78 (ddd, J3¢,4¢ = 6.0 Hz, J4¢,5¢a = 6.3 Hz,
J4¢,5¢b = 4.2 Hz, 1 H, 4¢-H), 4.19 [ddd (t after addition of D2O, J = 5.7
Hz), J2¢,3¢ = 5.7 Hz, J3¢,4¢ = 6.0 Hz, J3¢,OH = 6.0 Hz, 1 H, 3¢-H], 4.58
(dd, J5¢a,OH = 5.4 Hz, J5¢b,OH = 4.5 Hz, 1 H, 5¢-OH, D2O exch.), 4.66
[t (t after addition of D2O, J = 5.7 Hz), J = 4.8 Hz, 1 H, 2¢-H], 5.05
(d, J3¢,OH = 6.0 Hz, 1 H, 3¢-OH, D2O exch.), 5.10 (s, 2 H, CH2-Ph),
5.15(d, J2¢,OH = 5.4 Hz, 1 H, 2¢-OH, D2O exch.), 6.19 (d, J1¢,2¢ = 4.2
Hz, 1 H, 1¢-H), 7.25–7.38 (m, 5 H, PhH).
UV (EtOH): lmax (log e) = 253 (3.75), 314 nm (4.06).
Anal. Calcd for C10H12N4O6S: C, 37.97; H, 3.82; N, 17.71. Found:
C, 38.02; H, 3.77; N, 17.49.
UV (EtOH): lmax (log e) = 255 (3.65), 314 nm (4.01).
Anal. Calcd for C16H16N4O6S: C, 48.97; H, 4.11; N, 14.28. Found:
C, 49.11; H, 4.06; N, 14.26.
6-Ethyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dione (7b)
Yield: 0.26 g (79%); [a]D –17.73 (c 1.00, H2O); mp 85–87 °C;
Rf = 0.33 (EtOAc).
IR (Nujol): 1680, 1724 (C=O) cm–1.
1H NMR (DMSO-d6): d = 1.18 (t, J = 7.2 Hz, 3 H, CH3CH2), 3.48
[ddd (dd after addition of D2O, J4¢,5¢a = 6.3 Hz, Jgem = 11.7 Hz),
J4¢,5¢a = 6.0 Hz, J5¢a,OH = 5.4 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.67
[ddd (dd after addition of D2O, J4¢,5¢b = 3.9 Hz, Jgem = 11.7 Hz),
J4¢,5¢b = 4.5 Hz, J5¢b,OH = 5.1 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.80
(ddd, J3¢,4¢ = 6.0 Hz, J4¢,5¢a = 6.0 Hz, J4¢,5¢b = 4.5 Hz, 1 H, 4¢-H), 3.96
(q, J = 7.2 Hz, 2 H, CH3CH2), 4.19 [q (dd after addition of D2O,
J2¢,3¢ = 5.7 Hz, J3¢,4¢ = 6.0 Hz), J = 5.7 Hz, 1 H, 3¢-H], 4.56 (dd,
20
Ethyl 2-{4-b-D-Ribofuranosyl[1,2,5]thiadiazolo[3,4-d]primi-
dine-5,7(4H,6H)-dion-6-yl}acetate (7e)
Yield: 0.30 g (77%); [a]D20 –17.53 (c 1.00, H2O); mp 112–114 °C;
Rf = 0.30 (EtOAc).
IR (Nujol): 1680, 1728 (C=O) cm–1.
1H NMR (DMSO-d6): d = 1.23 (t, J = 6.9 Hz, 3 H, CH3CH2O), 3.48
[ddd (dd after addition of D2O, J4¢,5¢a = 6.3 Hz, Jgem = 11.7 Hz),
J4¢,5¢a = 6.3 Hz, J5¢a,OH = 6.0 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha], 3.65
[ddd (dd after addition of D2O, J4¢,5¢b = 5.1 Hz, Jgem = 11.7 Hz),
J4¢,5¢b = 5.1 Hz, J5¢b,OH = 4.5 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Hb], 3.81
(ddd, J3¢,4¢ = 5.7 Hz, J4¢,5¢a = 6.3 Hz, J4¢,5¢b = 5.1 Hz, 1 H, 4¢-H), 4.14–
Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

PAPER
N- and O-Alkylation of Thiadiazolopyrimidine Nucleosides and Uridines
2695
4.21 (m, 1 H, 3¢-H), 4.17 (q, J = 6.9 Hz, 2 H, CH3CH2O), 4.62 (dd,
J5¢a,OH = 6.0 Hz, J5¢b,OH = 4.5 Hz, 1 H, 5¢-OH, D2O exch.), 4.66–4.75
(m, 1 H, 2¢-H), 4.68 (s, 1 H, NCHa), 4.69 (s, 1 H, NCHb), 5.06 (d,
J3¢,OH = 6.0 Hz, 1 H, 3¢-OH, D2O exch.), 5.24 (d, J2¢,OH = 5.7 Hz,
1 H, 2¢-OH, D2O exch.), 6.18 (d, J1¢,2¢ = 4.5 Hz, 1 H, 1¢-H).
D2O exch.), 5.48 (d, J2¢,OH = 5.4 Hz, 1 H, 2¢-OH, D2O exch.), 5.64
(d, J5,6 = 8.1 Hz, 1 H, 5-H), 5.75 (d, J1¢,2¢ = 5.1 Hz, 1 H, 1¢-H), 7.59
(d, J5,6 = 8.1 Hz, 1 H, 6-H), 11.36 (s, 1 H, NH, D2O exch.).
UV (EtOH): lmax (log e) = 260 nm (3.96).
UV (EtOH): lmax (log e) = 247 (3.75), 314 nm (4.09).
5-Bromo-5¢-O-methyluridine (12b)
20
Yield: 0.28 g (82%); [a]D –15.58 (c 1.00, dioxane); mp 190–
Anal. Calcd for C13H16N4O8S: C, 40.21; H, 4.15; N, 14.43. Found:
C, 40.02; H, 4.36; N, 14.50.
192 °C; Rf = 0.52 (EtOAc).
R (Nujol): 1680, 1751 (C=O) cm–1.
Ethyl 4-{4-b-D-Ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyrimi-
dine-5,7(4H,6H)-dion-6-yl}butanoate (7f)
Yield: 0.31 g (74%); [a]D –20.36 (c 1.00, H2O); mp 47–49 °C;
Rf = 0.29 (EtOAc).
IR (Nujol): 1680, 1730 (C=O) cm–1.
1H NMR (DMSO-d6): d = 1.18 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.86
(quin, J = 6.9 Hz, 2 H, CH2CH2CH2N), 2.38 (q, J = 7.2 Hz, 2 H,
CH2CH2CH2N), 3.48 [ddd (dd after addition of D2O, J4¢,5¢a = 6.3 Hz,
Jgem = 11.7 Hz), J4¢,5¢a = 6.3 Hz, J5¢a,OH = 6.0 Hz, Jgem = 11.7 Hz, 1 H,
5¢-Ha], 3.67 [ddd (dd after addition of D2O, J4¢,5¢b = 5.1 Hz,
Jgem = 11.7 Hz), J4¢,5¢b = 5.1 Hz, J5¢b,OH = 5.4 Hz, Jgem = 11.7 Hz,
1 H, 5¢-Hb], 3.79 (ddd, J3¢,4¢ = 6.0 Hz, J4¢,5¢a = 6.3 Hz, J4¢,5¢b = 5.1 Hz,
1 H, 4¢-H), 3.95 (t, J = 6.9 Hz, 2 H, CH2CH2CH2N), 4.04 (q, J = 7.2
Hz, 2 H, CH3CH2O), 4.19 [q (br s after addition of D2O), J = 6.0 Hz,
1 H, 3¢-H], 4.58 (dd, J5¢a,OH = 6.0 Hz, J5¢b,OH = 5.4 Hz, 1 H, 5¢-OH,
D2O exch.), 4.64 [q (br s after addition of D2O), J = 5.1 Hz, 2¢-H],
5.03 (d, J3¢,OH = 6.3 Hz, 1 H, 3¢-OH, D2O exch.), 5.15 (d, J2¢,OH = 5.1
Hz, 1 H, 2¢-OH, D2O exch.), 6.18 (d, J1¢,2¢ = 4.2 Hz, 1 H, 1¢-H).
1H NMR (DMSO-d6): d = 3.74 (s, 3 H, 5¢-OCH3), 3.94 [q (t after ad-
dition of D2O, J = 5.1 Hz), J = 5.1 Hz, 1 H, 2¢-H], 4.01 (ddd,
J3¢,4¢ = 5.4 Hz, J4¢,5a¢ = 4.8 Hz, J4¢,5b¢ = 3.3 Hz, 1 H, 4¢-H), 4.09 [ddd
(t after addition of D2O, J = 5.1 Hz), J2¢,3¢ = 5.1 Hz, J3¢,4¢ = 5.4 Hz,
J3¢,OH = 5.4 Hz, 1 H, 3¢-H], 4.27 (dd, J4¢,5a¢ = 4.8 Hz, Jgem = 12.0 Hz,
1 H, 5¢-Ha), 4.35 (dd, J4¢,5b¢ = 3.3 Hz, Jgem = 12.0 Hz, 1 H, 5¢-Hb),
5.26 (d, J3¢,OH = 5.4 Hz, 1 H, 3¢-OH, D2O exch.), 5.46 (d, J2¢,OH = 5.4
Hz, 1 H, 2¢-OH, D2O exch.), 5.72 (d, J1¢,2¢ = 5.1 Hz, 1 H, 1¢-H), 7.99
(s, 1 H, 6-H), 11.85 (s, 1 H, NH, D2O exch.).
20
UV (EtOH): lmax (log e) = 277 nm (3.96) [Lit.21 279 (pH 1), 277
(pH 10)].
Acknowledgment
We are grateful to the SC-NMR Laboratory of Okayama University
for 300 MHz 1H NMR and 13C NMR experiments.
References
UV (EtOH): lmax (log e) = 253 (3.70), 313 nm (4.02).
Anal. Calcd for C15H20N4O8S·2/5H2O: C, 42.53; H, 4.95; N, 13.23.
Found: C, 42.58; H, 5.00; N, 13.62.
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5¢-O-Methyl-4-b-D-ribofuranosyl[1,2,5]thiadiazolo[3,4-d]pyri-
midine-5,7(4H,6H)-dione (9)
20
Yield: 0.27 g (84%); [a]D –21.58 (c 1.00, H2O); mp 94–96 °C;
Rf = 0.20 (EtOAc).
IR (Nujol): 1715 (C=O) cm–1.
1H NMR (DMSO-d6): d = 3.68 (s, 3 H, 5¢-OCH3), 3.96 (ddd,
J3¢,4¢ = 5.7 Hz, J4¢,5¢a = 7.2 Hz, J4¢,5¢b = 3.3 Hz, 1 H, 4¢-H), 4.18 (dd,
J4¢,5¢a = 7.2 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha), 4.30 [q (t after addition
of D2O, J = 6.3 Hz), J = 6.3 Hz, 1 H, 3¢-H], 4.39 (dd, J4¢,5¢b = 3.3 Hz,
Jgem = 11.7 Hz, 1 H, 5¢-Hb), 4.60 [ddd (dd after addition of D2O,
J1¢,2¢ = 3.9 Hz, J2¢,3¢ = 6.3 Hz), J1¢,2¢ = 3.9 Hz, J2¢,3¢ = 5.7 Hz,
J2¢,OH = 5.1 Hz, 1 H, 2¢-H], 5.23 (d, J3¢,OH = 6.3 Hz, 1 H, 3¢-OH, D2O
exch.), 5.29 (d, J2¢,OH = 5.1 Hz, 1 H, 2¢-OH, D2O exch.), 6.14 (d,
J1¢,2¢ = 3.9 Hz, 1 H, 1¢-H), 12.03 (s, 1 H, NH, D2O exch.).
(6) Baird-Lambert, J.; Marwood, J. F.; Davies, L. P.; Taylor, K.
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(7) Davies, L. P.; Taylor, K. M.; Gregson, R. P.; Quinn, R. J.
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UV (EtOH): lmax (log e) = 243 (3.46), 313 nm (3.98).
Anal. Calcd for C10H12N4O6S: C, 37.97; H, 3.82; N, 17.71. Found:
C, 38.05; H, 3.78; N, 17.57.
(8) Davies, L. P.; Cook, A. F.; Poonian, M.; Taylor, K. M. Life
Sci. 1980, 26, 1089.
(9) Leonard, N. J.; Laursen, R. A. Biochemistry 1965, 4, 365.
(10) Hatfield, D.; Wyngaarden, J. B. J. Biol. Chem. 1964, 239,
2587.
5¢-O-Methyluridine (12a)
Yield: 0.22 g (85%); [a]D –13.04 (c 1.00, H2O); mp 153–155 °C
20
(Lit.17,22 134–135 °C); Rf = 0.09 (EtOAc).
IR (Nujol): 1696, 1742 (C=O) cm–1.
1H NMR (DMSO-d6): d = 3.72 (s, 3 H, 5¢-OCH3), 3.93 [ddd (t after
addition of D2O, J = 5.1 Hz), J1¢,2¢ = 5.1 Hz, J2¢,3¢ = 5.4 Hz,
J2¢,OH = 5.4 Hz, 1 H, 2¢-H], 3.99 (ddd, J3¢,4¢ = 5.1 Hz, J4¢,5a¢ = 5.7 Hz,
J4¢,5b¢ = 3.6 Hz, 1 H, 4¢-H), 4.07 [ddd (t after addition of D2O, J = 5.1
Hz), J2¢,3¢ = 5.4 Hz, J3¢,4¢ = 5.1 Hz, J3¢,OH = 5.4 Hz, 1 H, 3¢-H], 4.24
(dd, J4¢,5a¢ = 5.7 Hz, Jgem = 11.7 Hz, 1 H, 5¢-Ha), 4.33 (dd, J4¢,5b¢ = 3.6
Hz, Jgem = 11.7 Hz, 1 H, 5¢-Hb), 5.31 (d, J3¢,OH = 5.4 Hz, 1 H, 3¢-OH,
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573.
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Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York

2696
A. M. L. Hossion et al.
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Synthesis 2009, No. 16, 2689–2696 © Thieme Stuttgart · New York