Synthesis of novel pyrimidine nucleoside analogues owning multiple bases/sugars and their glycosidase inhibitory activity

Article abstract of DOI:10.1016/j.tet.2014.09.078

A series of novel nucleoside analogues having dual bases (pyrimidine and triazole) and sugars have been synthesized by CuAAC reaction of azido sugars with propynylated pyrimidines. These compounds were evaluated for their in vitro α-glucosidase inhibitory

Full text of DOI:10.1016/j.tet.2014.09.078

Tetrahedron 70 (2014) 8462e8473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel pyrimidine nucleoside analogues owning
multiple bases/sugars and their glycosidase inhibitory activity
a
,
y
b
,
y
a
c
Ravi Kumar Thakur , Akansha Mishra , K.K.G. Ramakrishna , Rohit Mahar ,
Sanjeev K. Shukla , A.K. Srivastava b , Rama P. Tripathi a
c
,
d
,
d
,d,
*
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow 226031, India
Academy of Scientific & Innovative Research (AcSIR), New Delhi 110001, India
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 August 2014
Received in revised form 24 September 2014
Accepted 24 September 2014
Available online 2 October 2014
A series of novel nucleoside analogues having dual bases (pyrimidine and triazole) and sugars have been
synthesized by CuAAC reaction of azido sugars with propynylated pyrimidines. These compounds were
evaluated for their in vitro
a
-glucosidase inhibitory activity. In this series, compounds 4b, 4d, 8a, 8b, 8c,
e, 8g, 8h, and 8i exhibited very good inhibition of -glucosidase enzyme. Nucleoside analogues 8a, 4b,
h, and 8c displayed 47.4%, 41.8%, 39.4%, and 34.6% inhibition, respectively, comparable to the standard
8
8
a
drug acarbose (53.4%).
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Pyrimidine nucleosides
Triazoles
Azido sugars
a
-Glucosidase
1. Introduction
particularly for triazoles the Copper-catalyzed AzideeAlkyne
Cycloaddition (CuAAC) has been widely used. CuAAC gives a sim-
9
Nucleosides and their analogues with modified bases and sugars
ple way to construct an assembly of complex molecules, having
are of great significance due to their chemotherapeutic potential
and diagnostic applications. Among such compounds those with
new and unknown structures with biological and physical prop-
1
10e12
erties
of great value. Monopropynylated pyrimidine nucleo-
heterocyclic rings such as isoxazoles, isoxazolines, or triazoles as
furanose ring substitute possess anticancer and antiviral activities.
Many other compounds with five-membered heterocyclic bases
bases serve as building blocks for the synthesis of biologically
relevant 1,2,3-triazoles, and they have been used as substrates for
2
13
1
a,14e20
the synthesis of triazole nucleoside derivatives,
oxiconazole
21
22
(
imidazoles and triazoles) have displayed interesting biological
analogues, nucleopeptides, and as inhibitors of different en-
3
4
23,24
properties, for example, brenedin and EICAR exhibited antiviral
activities against many RNA and DNA viruses and inhibit the tumor
cell proliferation (Fig. 1).
zymes.
Moreover, these propynylated nucleobases have also
2
5
been used in the synthesis of organogels, and as corrosion
5
26
inhibitors.
Triazolyl and dihydropyrimidine sugar hybrids28 (Fig. 1) are
known to inhibit glycosidases and therefore they are useful in de-
veloping new chemotherapeutic agents for several ailments in-
cluding antidiabetic, anticancer, and antimicrobial agents. In the
27
Compounds with triazolyl units (1,2,3- and 1,2,4-triazole) are
endowed with numerous biological activities such as antibacterial,
6
,7
antifungal, anti-tubercular, anti-HIV, and anticancer.
The
1,2,3-triazole unit, as surrogate of peptide bond offers many ad-
vantages toward the stability and biological activity in the bioactive
molecules. 1,3-Dipolar cycloaddition reaction is the most common
context of our ongoing research on the synthesis of base and sugar
8
29,30
modified nucleoside analogues,
as chemotherapeutic agents,
method to access five-membered heterocyclic rings, and
we were interested to access hybrid molecules consisting of py-
rimidine, triazole, and sugar moieties and evaluate their chemo-
therapeutic potential. In this communication we report the
synthesis of hitherto unprecedented nucleoside analogues with
two bases (pyrimidine and triazole) and sugars and their bio-
*
Corresponding author. Tel.: þ91 (0)522 2772450; fax: þ91 522 2623405/3938/
9
504; e-mail addresses: rp_tripathi@cdri.res.in, rpt.cdri@gmail.com (R.P. Tripathi).
y
These authors contributed equally to this work.
evaluation as a-glucosidase inhibitor.
http://dx.doi.org/10.1016/j.tet.2014.09.078
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
0

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8463
Fig. 1. Chemical structures of nucleoside analogues with significant chemotherapeutic potential.
2
2
. Results and discussion
spectroscopic data. These were identical in all respects to those
3
2e34
reported earlier.
2b, 3a, and 3b) and azido sugars (IeV) in our hand the CuAAC
reactions were performed in t-BuOH/H O (1:1) using equimolar
quantities of the reactants, CuSO $5H O (10 mol %) and sodium
Having the propynylated pyrimidines (2a,
.1. Chemistry
2
The preparation of starting propynylated pyrimidines com-
4
2
menced with the reaction of two pyrimidine bases, uracil (1a) and
thymine (1b) with 3-bromoprop-1-yne in DMF in the presence of
K CO at ambient temperature resulting into both mono and
2 3
di-N-propynylated derivatives 2a, 2b, 3a, and 3b, respectively,
in the ratio of 4:5 in good yields (Scheme 1). The mono and
di-N-propynylated products could be separated by column chro-
matography and structures were established on the basis of their
spectroscopic data.31
ascorbate (20 mol %) at ambient temperature. These conditions
were found to be optimum in terms of the solvent and the amount
of catalyst. The reactions were monitored (TLC) until the reaction
was complete.
1
Thus reaction of N -propynylated uracil (2a) with azido sugar (I)
led to the formation of cycloaddition product 4a in 93% yield
(Scheme 2, Table 1). The structural elucidation of the cycloadduct
was made on the basis of its spectroscopic data. The
The sugar azides IeV were prepared by the methods already
reported in literature and were characterized on the basis of their
1,4-regioselectivity during cycloaddition reaction was evidenced on
0
the basis of chemical shifts of triazolyl proton (H-5 ,
d 7.78) and
1
3
Scheme 1. Alkylation of pyrimidine bases at N - and N -position with 3-bromoprop-1-yne.
Scheme 2. Synthesis of mono-triazolo-pyrimidine nucleoside analogues.

8464
R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
Table 1
1
Preparation of nucleoside analogues (4ae4e) and (5ae5d) by CuAAC reactions of N -propynylated pyrimidines (2a, 2b) with azido sugars (IeV)
1
Entry
N -Propynylated pyrimidines
Sugar azides
Products
Yield (%)
1.
2a
93
2.
2a
87
3
4
.
.
2a
2a
92
89
5.
2a
86
6.
2b
91
7.
2b
87
8
9
.
.
2b
2b
92
9
1

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8465
0
0
carbons (C-4 ,
d
144.1; and C-5 ,
d
124.9 ppm), a characteristic fea-
evaluated for their inhibitory potential against the above
sidase enzyme at a concentration of 10
was calculated with respect to control. The
inhibitory data of screened compounds have been shown in Table 4.
As evident in Table 4, most of the triazolo-pyrimidine nucleoside
a
-gluco-
1
13
ture of the H and C NMR spectra of 1,4-regioisomers as reported
earlier in literature.35 Similarly cycloaddition reaction of propyny-
lated pyrimidines 2a and 2b with different glycosyl azides (IeV)
under the above mentioned reaction conditions led to the forma-
tion of respective cycloaddition products 4be4e and 5ae5d, re-
spectively, in good yields.
Further, to establish the regioselectivity and connectivity of dif-
ferent atoms in above cycloaddition reaction detailed NMR analysis
has been done. NMR analysis of one of the above prototypes was
m
M. Percentage inhibition
a
-glucosidase enzyme
analogues with deacetylated sugars showed better
enzyme inhibitory activity as compared to the acetylated sugar
analogues. Out of all the compounds screened for -glucosidase
enzyme, nine compounds (4b, 4d, 8a, 8b, 8c, 8e, 8g, 8h, and 8i)
exhibited promising -glucosidase enzyme inhibitory activities
a-glucosidase
a
a
0
0
0
carried out for compound 5a. HMBC correlation of CH
to C-5 strongly established the formation of 1,4-disubstituted
regioisomer. NOE correlations between CH
2
-6 and CH
2
-6
(Table 4). In this series, the deacetylated sugar triazolo-pyrimidine
nucleoside analogue 8a exhibited most promising inhibitory ac-
tivity with 47.4% inhibition against a-glucosidase enzyme. The
0
0
00
0
2
-6 and CH
2
-6 to H-5
showed the proximity of protons in the space and strongly supported
the formation of 1,4-disubstituted regioisomer (Fig. 2).
acetylated nucleoside analogue 4b (41.8%) and the deacetylated
nucleoside analogues 8c (34.6%) and 8h (39.4%) proved to be potent
Fig. 2. Important NOE and HMBC correlations of 5a.
1
3
The N ,N -dipropynylated pyrimidines 3a and 3b similarly on
CuAAC with 2 equiv of different sugar azides (IeV) separately under
the above optimized reaction conditions led to access of pyr-
imidinyl bis-triazolyl sugar hybrids 6ae6e, 7a and 7b, respectively,
in very good yields. All these compounds were characterized on the
basis of their spectroscopic data (Scheme 3, Table 2).
a-glucosidase enzyme inhibitors. Other deacetylated sugar
triazolo-pyrimidine nucleoside analogues 8i (29.8%) and 8e (26.5%)
exhibited moderate inhibition of the enzyme. Other compounds 8b,
8g, and 4d displayed enzyme inhibitory activity with 24.2%, 23.7%,
and 23.7% inhibition, respectively.
Scheme 3. Synthesis of bis-triazolo-pyrimidine nucleoside analogues.
The Zemplen deacetylation of the above peracetylated com-
pounds 4, 5, 6, and 7 with NaOMe/MeOH at room temperature led
to the formation of the deacetylated pyrimidine nucleoside ana-
logues 8ae8j, respectively, in good yields (Table 3).
3. Conclusions
In conclusion, we have developed a simple and economical
method for the 1,4-regioselective synthesis of hitherto un-
precedented pyrimidine nucleoside analogues involving CuAAc of
the propynylated pyrimidines with different sugar azides in am-
bient condition in very good yields. These compounds were eval-
2
.2. Biology
All the synthesized compounds were screened against the
-glucosidase enzyme. The compounds dissolved in DMSO were
uated for
a-glucosidase enzyme inhibitory activities with four
a
compounds 8a, 4b, 8h, and 8c exhibited 47.4%, 41.8%, 39.4%, and

8466
R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
Table 2
Preparation of nucleoside analogues (6ae6e) and (7a,7b) by CuAAC reactions of N -, N -bis-propynylated pyrimidines (3a,3b) with azido sugars (IeV)
1
3
1
3
Entry
N -,N -Bis-propynylated pyrimidines
Sugars azides
Product
Yield (%)
1.
3a
91
2.
3a
88
3
4
5
.
.
.
3a
3a
3a
88
92
87
91
6
7
.
.
3b
3b
9
3
3
4.6% inhibition of
a
-glucosidase enzyme as compared to acarbose
Merck Kieselgel 60 F254, with detection by UV light and/or spraying
with 5% H SO in EtOH, followed by heating. Column chromatog-
with 53.4% inhibition of the enzyme and thus hold potential to be
developed as antidiabetic agents.
2
4
raphy was performed on silica gel (60e120 mesh, E. Merck). IR
spectra were recorded as thin films or in chloroform solution with
ꢀ1
a PerkineElmer Spectrum RX-1 (4000e450 cm ) spectropho-
4
4
. Experimental
1
13
tometer. H and C NMR spectra were recorded on a Bruker
Avance-300 MHz and 400 MHz instruments, respectively, in CDCl
and DMSO-d . Chemical shift values are reported in parts per mil-
.1. General
3
6
lion (ppm) relative to TMS (tetramethylsilane) as the internal ref-
erence, unless otherwise stated; s (singlet), d (doublet), t (triplet),
m (multiplet), br s (broad singlet); J in hertz (Hz). MS were
Commercially available reagent grade chemicals were pur-
chased from SigmaeAldrich Chemical Co. or Spectrochem Pvt. Ltd
and were used as received. All reactions were followed by TLC on E.

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8467
performed using a Jeol SX-102 mass spectrometer ESIMS were
performed using a Quattro II (Micromass) instrument.
Table 3
Synthesized deacetylated compounds 8ae8j from acetylated products 4, 5, 6, and 7
Entry Acetylated
substrates
Deacetylated products
Yield (%)
4.2. General procedure for the synthesis of compounds 2 and 3
To stirring solution of pyrimidine base 1 (uracil or thymine,
1
1
mmol) in anhyd DMF (20 ml) and K
-yne (2 mmol) was added to the reaction mixture at room tem-
2 3
CO (1 mmol), 3-bromoprop-
1.
2.
3.
4.
4c
4d
4e
5c
95
perature. The reaction was completed in 24 h (TLC), the reaction
mixture was taken in ethyl acetate and washed with water. The
organic layer was separated and dried (anhyd Na SO ) and evap-
2 4
orated under reduced pressure to give the crude mass. The latter
was purified by column chromatography using 60e120 mesh silica
gel and ethyl acetate: hexane (1:1) as eluant to give the titled
compounds 2 and 3 detailed below.
96
92
93
31
4.2.1. 1-(Prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione (2a). Colorless
ꢁ
ꢁ
solid, yield (40%), mp 162e164 C, lit. mp 164e166 C.
4
.2.2. 5-Methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione
31
ꢁ
ꢁ
(2b). Colorless solid, yield (43%), mp 154e155 C, lit. mp 154e156 C.
4
.2.3. 1,3-Di(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione
31
ꢁ
ꢁ
(3a). Colorless solid, yield (50%), mp 103e104 C, lit. mp 105 C.
4
.2.4. 5-Methyl-1,3-di(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione
31
ꢁ ꢁ
(3b). Colorless solid, yield (54%), mp 102e103 C, lit. mp 101 C.
0
0
0
0
0
0
4
.3. 1-(6 -Azido-1 ,6 -dideoxy-2 ,3 ,4 -tri-O-acetyl-
b-
D-gluco-
0
pyranos-1 -yl)-propan-2-one (V)
To a stirring solution of
pyridine (25 ml) and Et
chloride (6.4 g, 34.1 mmol) was slowly added to the reaction mix-
ture portion-wise and stirring continued till the reaction was
complete (12 h, TLC). The reaction mixture was taken in ethyl ac-
etate and washed with water. The organic layer was separated and
b
-glycosylic ketone (5 g, 22.7 mmol) in
5
6
.
.
5d
6c
90
93
ꢁ
3
N (0.31 ml, 24.9 mmol) at 0 C, tosyl
2 4
dried (anhyd Na SO ) and evaporated under reduced pressure to
give the crude mass of the intermediate tosylated product.
To a stirring solution of the above crude tosylated product (8 g,
ꢁ
2
7
1.3 mmol) in pyridine (25 ml) at 0 C, acetic anhydride (6.7 ml,
ꢁ
0.2 mmol) was added drop wise maintaining 0 C temperature for
4
5 min. After the addition is complete, the reaction mixturewas stirred
at room temperature for 4 h till the reaction is complete (TLC). After
that the reaction mixture was extracted with ethyl acetate and water.
7
8
.
.
6d
6e
95
92
2 4
The organic layer was separated and dried with anhyd Na SO and
evaporated under reduced pressure to give the acetylated crude mass.
To the stirring solution of the above crude acetylated product
ꢁ
(
10 g, 20.0 mmol) in DMF (15 ml) at 80 C, NaN
3
(1.6 g, 24 mmol)
was slowly added and the reaction mixture was stirred for 8 h (TLC)
till the completion of reaction. The reaction mixture was parti-
tioned between ethyl acetate and water, the organic layer was dried
2 4
(anhyd Na SO ) and evaporated under reduced pressure to give
a crude mass. The latter was purified by column chromatography
(
50% ethyl acetate/hexane) to afford the desired sugar azide
ꢁ
V (5.2 g, 70%) as a colorless solid; mp 120e122 C; R
f
(50% ethyl
acetate/hexane) 0.8; nmax (KBr) 3023, 2101, 1747, 1380, 1221,
9
1
.
7a
7b
96
ꢀ
1
0
7
61 cm
;
d
H
(400 MHz, CDCl
3
): 5.16 (1H, t, J¼9.36 Hz, H-3 ), 4.95
0
0
(
1H, t, J¼9.47 Hz, H-4 ), 4.86 (1H, t, J¼9.58 Hz, H-2 ), 4.06e4.01 (1H,
0
0
m, H-1 ), 3.70e3.65 (1H, m, H-5 ), 3.23 (2H, d, J¼4.52 Hz, H-2), 2.70
0
(
1H, dd, J
1
¼16.57 Hz, J
2
¼8.80 Hz, H-6 ), 2.45 (1H, dd, J
1
¼16.57 Hz,
), 2.02 (3H, s,
4
): 204.6 (C-2),
0
J
2
¼3.07 Hz, H-6 ), 2.18 (3H, s, CH
3
), 2.02 (3H, s, CH
3
95
0.
CH
3
), 1.99 (3H, s, CH
3
);
d
C
(100 MHz, CDCl
3
þCCl
0
0
0
0
1
6
C
70.0, 169.7, 169.4, 77.0 (C-5 ), 73.8 (C-1 ), 73.8 (C-3 ), 71.4 (C-4 ),
0
0
9.5 (C-2 ), 50.9 (C-6 ), 45.2 (C-1), 31.1 (C-3), 20.5 (3C); M.F:
þ
15
H
21
N
3
O
8
; ESIMS: m/z 389 (Mþ18) .

8468
R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
Table 4
a
-Glucosidase inhibitory activity (10 mM) of the synthesized nucleoside analogues
S. no.
Synthesized compounds
%
a
-Glucosidase inhibition
5.19
41.8
S. no.
Synthesized compounds
% a-Glucosidase inhibition
1
2
3
4
5
6
7
8
9
1
1
1
1
.
.
.
.
.
.
.
.
4a
4b
4c
4d
4e
5a
5b
5c
5d
6a
6b
6c
6d
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
6e
7a
7b
8a
8b
8c
8d
8e
8f
22.1
11.0
20.2
47.4
24.2
34.6
19.6
26.5
21.9
23.7
39.4
29.8
15.9
53.4
20.9
23.7
19.2
21.3
17.9
14.5
17.1
.
0.
1.
2.
3.
3.28
8g
8h
8i
10.6
16.3
22.8
8j
27.
Acarbose
0
4
.4. General procedure for the synthesis of compounds 4 and 5
H-5 ), 7.74 (1H, d, J¼7.95 Hz, H-6), 5.87 (1H, d, J¼3.61 Hz, H-5),
00 00 0
5
.63e5.58 (2H, m, H-1 , H-3 ), 4.94 (2H, s, H-6 ), 4.62e4.58 (1H, m,
1
00 00 00
N -Propynylated pyrimidine 2 (1 mmol) and selected azido
H-2 ), 4.50e4.44 (2H, m, H-5 ), 4.41e4.37 (1H, m, H-4 ), 4.08e4.06
sugar (1 mmol) were suspended in a mixture of 1:1 tert-butanol/
water (20 ml) and kept for stirring at room temperature. To the
stirring reaction mixture freshly prepared solution of sodium
(1H, m, OH), 1.34 (3H, s, CH
3
),1.23 (3H, s, CH
3
);
d
C
(100 MHz, DMSO-
0
0
d
6
): 164.1 (C-4), 151.2 (C-2), 145.9 (C-4 ), 142.8 (C-6), 124.5 (C-5 ),
0
0
00
00
00
111.2, 104.9 (C-1 ), 101.7 (C-5), 85.4 (C-4 ), 79.5 (C-3 ), 74.0 (C-2 ),
00 0
þ
ascorbate (20 mol %) in 500
mL and freshly prepared solution of
49.4 (C-5 ), 42.8 (C-6 ), 27.1, 26.4; HRMS (ESI): MH , found
CuSO $5H O (10 mol %) in 200
4
2
mL water were sequentially added.
20
5 6
366.1406. C15H N O requires 366.1408.
The reaction mixture was stirred at ambient temperature for 3e4 h.
After completion of reaction (TLC), the reaction mixture was
extracted with EtOAc and water. The organic layer was dried
0
00 00 00 00
0
0
4.4.3. 1-[{1 -(2 ,3 ,4 ,6 -Tetra-O-acetyl-
b
-
D
-glucopyranosyl)-1 H-
0
0
0
1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-2,4(1H,3H)-dione (4c). It was
obtained by the reaction of 2a (0.1 g, 0.66 mmol), azido sugar III
(
2 4
anhyd Na SO ) and evaporated under reduced pressure to give
a crude mass. The latter was purified by silica gel (60e120 mesh)
column chromatography using chloroform/methanol (9:1) as elu-
ant to give the cycloaddition products detailed below.
4 2
(0.25 g, 0.66 mmol), CuSO $5H O (0.02 g, 0.06 mmol), and sodium
ascorbate (0.03 g, 0.13 mmol) in 1:1 tert-butanol/water (20 ml).
Purification by column chromatography using 60e120 mesh silica
gel (10% chloroform/methanol), gave the titled compound 4c
0
00
00 00 00 00
ꢁ
4
.4.1. 1-[{1 -(6 -Deoxy-1 ,2 :3 ,4 -di-O-isopropylidene-
a
-
D
-gal-
methyl]pyrimidine-
,4(1H,3H)-dione (4a). It was obtained by the reaction of 2a (0.1 g,
.66 mmol), azido sugar I (0.19 g, 0.66 mmol), CuSO $5H O (0.02 g,
.06 mmol), and sodium ascorbate (0.03 g, 0.13 mmol) in 1:1 tert-
(0.32 g, 92%) as a white solid; mp 198e200 C; R
methanol) 0.4; nmax (KBr) 3409, 3019, 1650, 1384, 758 cm
f
(10% chloroform/
0
0
0
0
0
0
0
ꢀ1
actopyranos-6 -yl)-1 H-1 ,2 ,3 -triazol-4 -yl}
; d
H
0
2
0
0
(400 MHz, CDCl
3
): 9.21 (1H, br s, NH), 7.96 (1H, s, H-5 ), 7.38 (1H, d,
0
0
4
2
J¼7.99 Hz, H-6), 5.80e5.78 (1H, m, H-1 ), 5.65 (1H, d, J¼7.85 Hz, H-
0
0
00
00
5), 5.36e5.34 (2H, m, H-2 , H-4 ), 5.23e5.18 (1H, m, H-3 ),
0
butanol/water (20 ml). Purification by column chromatography
using 60e120 mesh silica gel (10% chloroform/methanol), gave the
titled compound 4a (0.27 g, 93%) as a white solid; mp 177e179 C;
4.99e4.88 (2H, m, H-6 ), 4.21 (1H, dd, J
1
¼12.70 Hz, J
2
¼5.06 Hz,
0
0
00
H-6 ), 4.08 (1H, dd, J
1
¼12.70 Hz, J
2
¼1.98 Hz, H-6 ), 3.97e3.92 (1H,
ꢁ
00
m, H-5 ), 2.01 (3H, s, CH
3
), 1.99 (3H, s, CH
3
), 1.94 (3H, s, CH
3
), 1.76
R
f
(10% chloroform/methanol) 0.4; nmax (KBr) 3401, 3019, 1654,
(3H, s, CH
3
);
d
C
(100 MHz, CDCl
3
): 170.5, 169.9, 169.3, 168.8, 163.5
ꢀ
1
0
0
1385, 759 cm
;
d
H
(400 MHz, CDCl
3
): 8.72 (1H, br s, NH), 7.78 (1H,
(C-4), 150.9 (C-2), 144.0 (C-4 ), 142.5 (C-6), 122.7 (C-5 ), 102.8 (C-5),
0
00
00 00 00 00 00
s, H-5 ), 7.41 (1H, d, J¼7.9 Hz, H-6), 5.63e5.61 (1H, m, H-1 ), 5.42
85.8 (C-1 ), 75.2 (C-5 ), 72.4 (C-3 ), 70.5 (C-2 ), 67.6 (C-4 ), 61.5
0
00 0
þ
(
1H, d, J¼4.9 Hz, H-5), 4.97 (1H, d, J¼15.0 Hz, H-6 ), 4.83 (1H, d,
(C-6 ), 43.0 (C-6 ), 20.6, 20.5, 20.4, 20.0; HRMS (ESI): MH , found
0
0
00
J¼15.0 Hz, H-6 ), 4.58 (1H, dd, J
1
¼9.86 Hz, J
2
¼2.42 Hz, H-3 ), 4.52
26
5
524.1621. C21H N O11 requires 524.1623.
00
(
1H, dd, J
1
¼14.33 Hz, J
2
¼3.58 Hz, H-6 ), 4.35 (1H, dd, J
1
¼14.33 Hz,
0
0
00
0
00 00 00 00
0
J
2
¼8.77 Hz, H-6 ), 4.25 (1H, dd, J
1
¼4.74 Hz, J
2
¼2.42 Hz, H-2 ),
4.4.4. 1-[{1 -(2 ,3 ,4 ,6 -Tetra-O-acetyl-
b
-
D
-galactopyranosyl)-1 H-
(4d). It
was obtained by the reaction of 2a (0.1 g, 0.66 mmol), azido sugar
IV (0.25 g, 0.66 mmol), CuSO $5H O (0.02 g, 0.06 mmol), and so-
0
0
00
0 0 0 0
4
.14e4.07 (2H, m, H-4 , H-5 ), 1.41 (3H, s, CH
3
), 1.30 (3H, s, CH
3
),
1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-2,4(1H,3H)-dione
1.29 (3H, s, CH
3
), 1.21 (3H, s, CH
3
);
d
C
(100 MHz, CDCl
3
þCCl
4
): 163.6
0
0
00
(
C-4), 150.8 (C-2), 144.1 (C-4 ), 141.3 (C-6), 124.9 (C-5 ), 109.9 (C-8 ),
4
2
0
0
00
00
00
108.9 (C-7 ), 102.5 (C-5), 96.1 (C-1 ), 71.1 (C-4 ), 70.7 (C-3 ), 70.2
dium ascorbate (0.03 g, 0.13 mmol) in 1:1 tert-butanol/water
(20 ml). Purification by column chromatography using 60e120
mesh silica gel (10% chloroform/methanol), gave the titled com-
pound 4d (0.31 g, 89%) as a white solid; mp 145e147 C; R
chloroform/methanol) 0.4; nmax (KBr) 3404, 3021, 1633, 1525, 1388,
0
0
00
þ
00
0
(
C-2 ), 67.1 (C-5 ), 53.2 (C-6 ), 50.6 (C-6 ), 25.9, 25.8, 24.8, 24.4;
HRMS (ESI): MH , found 436.1827. C19
H
26
N
5
O
7
requires 436.1827.
ꢁ
f
(10%
0
0
00
00 00
00
4
.4.2. 1-[{1 -(5 -Deoxy-1 ,2 -O-isopropylidene-
a
-
D
-xylofuranos-5 -
0
0
0
0
ꢀ1
yl)-1 H-1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-2,4(1H,3H)-dione
4b). It was obtained by the reaction of 2a (0.08 g, 0.53 mmol),
azido sugar II (0.11 g, 0.53 mmol), CuSO $5H O (0.01 g, 0.05 mmol),
and sodium ascorbate (0.02 g, 0.1 mmol) in 1:1 tert-butanol/water
20 ml). Purification by column chromatography using 60e120
761 cm
;
d
H
(400 MHz, CDCl
3
): 9.30 (1H, br s, NH), 7.94 (1H, s,
0
00
(
H-5 ), 7.39 (1H, d, J¼7.9 Hz, H-6), 5.75 (1H, d, J¼9.1 Hz, H-1 ), 5.64
0
0
00
4
2
(1H, d, J¼7.7 Hz, H-5), 5.48e5.47 (1H, m, H-4 ), 5.39 (1H, m, H-2 ),
0
0
0
5.21e5.17 (1H, m, H-3 ), 5.01 (1H, d, J¼15.0 Hz, H-6 ), 4.84 (1H, d,
0
00
00
(
J¼15.0 Hz, H-6 ), 4.19e4.05 (3H, m, H-5 , H-6 ), 2.16 (3H, s, CH
1.97 (3H, s, CH ), 1.93 (3H, s, CH ), 1.79 (3H, s, CH ); (100 MHz,
): 170.3, 170.0, 169.8, 169.0, 163.6 (C-4), 150.8 (C-2), 144.1
3
),
mesh silica gel (10% chloroform/methanol), gave the titled com-
pound 4b (0.17 g, 87%) as a white solid; mp 148e150 C; R
chloroform/methanol) 0.3; nmax (KBr) 3400, 3019, 1654, 1385, 1215,
3
3
3
d
C
ꢁ
f
(10%
CDCl
3
0
0
00
00
(C-4 ), 142.4 (C-6), 122.5 (C-5 ), 102.7 (C-5), 86.4 (C-1 ), 74.1 (C-5 ),
ꢀ1
00 00 00 00 0
7
59 cm
;
d
H
(400 MHz, DMSO-d
6
): 11.29 (1H, br s, NH), 8.07 (1H, s,
70.5 (C-3 ), 68.1 (C-2 ), 66.8 (C-4 ), 61.2 (C-6 ), 42.8 (C-6 ), 20.6,

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8469
þ
00
00
00
0
2
0.6, 20.4, 20.1; HRMS (ESI): MH , found 524.1621. C21
26
H N
5
O
11
79.5 (C-3 ), 74.0 (C-2 ), 49.4 (C-5 ), 42.6 (C-6 ), 27.0, 26.4, 12.3 (CH
3
);
þ
reqiures 524.1623.
HRMS (ESI): MH , found 380.1561. C16
H N
22 5
O
6
requires 380.1565.
0
00 00
00 00 00
0 00 00 00 00 0
4.4.8. 1-[{1 -(2 ,3 ,4 ,6 -Tetra-O-acetyl-b-D-glucopyranosyl)-1 H-
1 ,2 ,3 -triazol-4 -yl}-methyl]-5-methyl pyrimidine-2,4(1H,3H)-dione
(5c). It was obtained by the reaction of 2b (0.12 g, 0.73 mmol), azido
4 2
sugar III (0.27 g, 0.73 mmol), CuSO $5H O (0.02 g, 0.07 mmol), and
4
.4.5. 1-[{{{1 -(1 ,6 -Dideoxy-2 ,3 ,4 -tri-O-acetyl-
b
-
D
0
-galactopyr-
0
0
000
00
0
0
0
0
0
0
00
0
anos-1 -yl)-propan-2 -one}-6 -yl}-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]
pyrimidine-2,4(1H,3H)-dione (4e). It was obtained by the reaction
of 2a (0.1 g, 0.66 mmol), azido sugar V (0.25 g, 0.66 mmol),
CuSO
4
$5H
2
O (0.02 g, 0.06 mmol), and sodium ascorbate (0.03 g,
sodium ascorbate (0.03 g, 0.15 mmol) in 1:1 tert-butanol/water
(20 ml). Purification by column chromatography using 60e120 mesh
0
.13 mmol) in 1:1 tert-butanol/water (20 ml). Purification by col-
umn chromatography using 60e120 mesh silica gel (10% chloro-
form/methanol), gave the titled compound 4e (0.30 g, 86%) as
silica gel (10% chloroform/methanol), gave the titled compound 5c
ꢁ
(0.36 g, 92%) as a white solid; mp 230e232 C; R
methanol) 0.4; nmax (KBr) 3399, 3019, 1637, 1384, 1215, 758 cm
f
(10% chloroform/
ꢁ
ꢀ1
a white solid; mp 214ee216 C; R
n
f
(10% chloroform/methanol) 0.4;
;
d
H
ꢀ1
0
max (KBr) 3407, 3021, 1633, 1590, 1389, 762 cm
;
d
H
(400 MHz,
): 8.86 (1H, br s, NH), 7.67 (1H, s, H-5 ), 7.43 (1H, d, J¼7.96 Hz,
¼7.92 Hz, J ¼2.11 Hz, H-5), 5.10 (1H, t,
(400 MHz, DMSO-d
6
): 11.34 (1H, br s, NH), 8.40 (1H, s, H-5 ), 7.56
0
00
CDCl
3
(1H, s, H-6), 6.32 (1H, d, J¼9.15 Hz, H-1 ), 5.62 (1H, t, J¼9.28 Hz,
0
0
00
00
H-6), 5.63 (1H, dd, J
1
2
H-4 ), 5.52 (1H, t, J¼9.51 Hz, H-2 ), 5.15 (1H, t, J¼9.64 Hz, H-3 ),
0
0
0
00
00
00
J¼9.37 Hz, H-3 ), 4.93e4.93 (2H, m, H-6 ), 4.81e4.71 (2H, m, H-2 ,
4.96e4.87 (2H, m, H-6 ), 4.38e4.34 (1H, m, H-5 ), 4.15e4.05 (2H, m,
0
0
00
00
H-4 ), 4.47 (1H, dd, J
1
¼14.60 Hz, J
2
¼2.03 Hz, H-6 ), 4.19 (1H, dd,
H-6 ), 2.03 (3H, s, CH
3 3 3
), 2.00 (3H, s, CH ),1.96 (3H, s, CH ),1.77 (3H, s,
0
0
00
J
(
(
1
¼14.60 Hz, J
2
¼8.41 Hz, H-6 ), 3.88e3.82 (1H, m, H-5 ), 3.79e3.74
CH
3
),1.76 (3H, s, CH
3
); (100 MHz, CDCl
d
C
3
þCCl
4
): 170.4,169.8, 169.2,
0
0
000
0
0
1H, m, H-1 ), 2.57 (1H, dd, J
1
¼17.20 Hz, J
2
¼9.22 Hz, H-1 ), 2.40
168.6, 163.9 (C-4), 150.9 (C-2), 142.7 (C-4 ), 139.8 (C-6), 122.6 (C-5 ),
111.3 (C-5), 85.8 (C-1 ), 75.2 (C-5 ), 72.4 (C-3 ), 70.5 (C-2 ), 67.6
(C-4 ), 61.4 (C-6 ), 42.7 (C-6 ), 20.6, 20.4 (2C), 20.0,12.2 (CH
(ESI): MH , found 538.1774. C22
000
00 00 00 00
1H, dd, J
1
¼17.20 Hz, J
2
¼2.68 Hz, H-1 ), 2.04 (3H, s, CH
3
), 2.03 (3H,
0
0
00
0
s, CH
3
), 1.95 (3H, s, CH
3
), 1.92 (3H, s, CH
3
);
d
C
(100 MHz, CDCl
3
):
3
); HRMS
0
þ
2
(
7
04.3, 170.0, 169.8, 169.7, 163.6 (C-4), 150.9 (C-2), 144.3 (C-4 ), 142.0
C-6), 124.8 (C-5 ), 102.7 (C-5), 76.1 (C-1 ), 73.6 (C-5 ), 73.5 (C-3 ),
28 5
H N O11 requires 538.1780.
0
00
00
00
0
0
00
00
0
þ
0
00 00 00 00
00
0
1.2 (C-2 ), 69.7 (C-4 ), 51.0 (C-6 ), 45.0 (C-6 ), 43.0 (-CH
2
), 30.5
), 20.6, 20.6, 20.5; HRMS (ESI): MH , found 522.1831.
10 requires 522.1831.
4.4.9. 1-[{1 -(2 ,3 ,4 ,6 -Tetra-O-acetyl-
b
-
D
-galactopyranosyl)-1 H-
0
0
0
(
CH
3
1 ,2 ,3 -triazol-4 -yl}-methyl]-5-methyl pyrimidine-2,4(1H,3H)-dione
C
H
22 28
N
5
O
(5d). It was obtained by the reaction of 2b (0.09 g, 0.55 mmol),
4 2
azido sugar IV (0.21 g, 0.55 mmol), CuSO $5H O (0.01 g,
0
00
00 00 00 00
4
.4.6. 1-[{1 -(6 -Deoxy-1 ,2 ;3 ,4 -di-O-isopropylidene-
a
-
D
-gal-
0.06 mmol), and sodium ascorbate (0.02 g, 0.11 mmol) in 1:1 tert-
butanol/water (20 ml). Purification by column chromatography
using 60e120 mesh silica gel (10% chloroform/methanol), gave the
0
0
0
0
0
0
0
actopyranos-6 -yl)-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]-5-methyl py-
rimidine-2,4(1H,3H)-dione (5a). It was obtained by the reaction of
b (0.08 g, 0.49 mmol), azido sugar I (0.18 g, 0.49 mmol),
CuSO $5H O (0.01 g, 0.05 mmol), and sodium ascorbate (0.02 g,
.1 mmol) in 1:1 tert-butanol/water (20 ml). Purification by column
chromatography using 60e120 mesh silica gel (10% chloroform/
methanol), gave the titled compound 5a (0.20 g, 91%) as a white
solid; mp 227e229 C; R
KBr) 3401, 3019, 1680, 1384, 759 cm
ꢁ
2
titled compound 5d (0.27 g, 91%) as a white solid; mp 195e197 C;
4
2
f
R (10% chloroform/methanol) 0.4; nmax (KBr) 3399, 3019, 1658,
ꢀ
1
0
1385, 1215, 758 cm
;
d
H
(400 MHz, CDCl
3
): 9.33 (1H, br s, NH), 7.99
0
00
(1H, s, H-5 ), 7.27 (1H, s, H-6), 5.80 (1H, d, J¼9.02 Hz, H-1 ),
0
0
00
5.50e5.50 (1H, m, H-4 ), 5.41 (1H, t, J¼9.40 Hz, H-2 ), 5.23 (1H, m,
ꢁ
00
0
f
(10% chloroform/methanol) 0.4; nmax
H-3 ), 5.04 (1H, d, J¼14.89 Hz, Hb-6 ), 4.86 (1H, d, J¼14.89 Hz,
ꢀ1
0
0
0
0
0
(
(
;
d
H
(300 MHz, CDCl
3
): 9.08
Ha-6 ), 4.26e4.18 (2H, m, H-6 ), 4.09 (1H, m, H-5 ), 2.23 (3H, s,
0
1H, br s, NH), 7.84 (1H, s, H-5 ), 7.32 (1H, s, H-6), 5.48 (1H, d,
CH
CH
3
), 2.03 (3H, s, CH
3 3 3
), 2.00 (3H, s, CH ),1.90 (3H, s, CH ),1.85 (3H, s,
0
0
0
J¼4.90 Hz, H-1 ), 5.01 (1H, d, J¼15.20 Hz, Hb-6 ), 4.87 (1H, d,
3
); (100 MHz, CDCl
d
C
3
þCCl
4
): 169.7, 169.6, 169.3, 168.5, 163.7
0
00
0
0
J¼15.20 Hz, Ha-6 ), 4.62 (1H, dd, J
1
¼7.72 Hz, J
2
¼2.55 Hz, H-3 ), 4.57
(C-4), 150.6 (C-2), 144.1 (C-4 ), 139.6 (C-6), 122.2 (C-5 ), 111.1 (C-5),
86.3 (C-1 ), 74.0 (C-5 ), 70.4 (C-3 ), 68.0 (C-2 ), 66.5 (C-4 ), 60.8
(C-6 ), 42.4 (C-6 ), 20.5, 20.4, 20.3, 20.0, 12.2 (CH
MH , found 538.1790. C22
00
00 00 00 00 00
(
1H, dd, J
1
¼14.38 Hz, J
2
¼3.50 Hz, Hb-6 ), 4.41 (1H, dd, J
1
¼14.38 Hz,
0
0
00
00
0
J
2
¼8.58 Hz, Ha-6 ), 4.31 (1H, dd, J
1
¼4.95 Hz, J
2
¼2.53 Hz, H-2 ),
3
); HRMS (ESI):
0
0
00
þ
4
.21e4.14 (2H, m, H-5 , H-4 ), 1.89 (3H, s, CH
3
), 1.48 (3H, s, CH
3
),
28
H N
5
O11 requires 538.1780.
1
CDCl
.37 (3H, s, CH
3
), 1.35 (3H, s, CH
3
), 1.28 (3H, s, CH
3
);
d
C
(75 MHz,
0
0
3
): 164.3 (C-4),151.0 (C-2),141.9 (C-4 ),140.3 (C-6),125.0 (C-5 ),
4.5. General procedure for the synthesis of compounds 6 and 7
00 00 00 00
111.2 (C-5), 110.1 (C-8 ), 109.2 (C-7 ), 96.4 (C-1 ), 71.3 (C-4 ), 70.9
0
0
00
00
00
0
00
þ
1
3
(
C-3 ), 70.5 (C-2 ), 67.3 (C-5 ), 50.8 (C-6 ), 42.9 (C-6 ), 26.1 (C-8 ),
N -,N -Bis-propynylated pyrimidine base 3 (1 mmol) and azido
sugar (2 mmol) were suspended in a mixture of 1:1 tert-butanol/
water (20 ml) and kept for stirring at room temperature. To the
stirring reaction mixture freshly prepared solution of sodium
0
0
00
00
2
6.0 (C-7 ), 25.0 (C-8 ), 24.6 (C-7 ), 12.4 (CH
3
); HRMS (ESI): MH ,
28 5 7
found 450.1982. C20H N O
requires 450.1983.
0
00
00 00
00
4
.4.7. 1-[{1 -(5 -Deoxy-1 ,2 -O-isopropylidene-
a
-
D
-xylofuranos-5 -
ascorbate (20 mol %) in 500
m
L and freshly prepared solution of
L water were sequentially added.
0
0
0
0
0
yl)-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]-5-methyl
pyrimidine-
CuSO $5H O (10 mol %) in 200 m
4
2
2
0
0
,4(1H,3H)-dione (5b). It was obtained by the reaction of 2b (0.1 g,
.61 mmol), azido sugar II (0.13 g, 0.61 mmol), CuSO $5H O (0.01 g,
.06 mmol), and sodium ascorbate (0.02 g, 0.12 mmol) in 1:1 tert-
The reaction mixture was stirred at ambient temperature for 6e8 h
and after the reaction is complete as observed on TLC. The reaction
mixture was extracted with EtOAc and water. The organic layer was
4
2
butanol/water (20 ml). Purification bycolumn chromatography using
2 4
dried over anhyd Na SO and evaporated under reduced pressure
6
0e120 mesh silica gel (10% chloroform/methanol), gave the titled
to give a white crude product. The latter was purified by silica gel
(60e120 mesh) column chromatography using 10% chloroform/
methanol as eluant to give the cycloaddition product 6 or 7,
depending upon the substrates taken.
ꢁ
compound 5b (0.20 g, 87%) as a white solid; mp 186e188 C; R
chloroform/methanol) 0.4; nmax (KBr) 3406, 3021, 1633, 1525, 1388,
f
(10%
ꢀ
1
7
5
61 cm
;
d
H
(400 MHz, DMSO-d
6
):11.28 (1H, brs, NH), 8.07 (1H, s, H-
0
00
), 7.62 (1H, s, H-6), 5.87e5.86 (1H, d, J¼3.61 Hz, H-1 ), 5.63e5.62
0
0
0
00
0 00 00 00 00 00
4.5.1. 1,3-Bis-[{1 -(6 -Deoxy-1 ,2 ;3 ,4 -di-O-isopropylidene-a-D-
(
1H, m, H-3 ), 4.90 (2H, s, H-6 ), 4.57 (1H, dd, J
1 2
¼13.87 Hz, J ¼3.61 Hz,
0
0
00
00
0
0
0
0
0
H-2 ), 4.49e4.44 (2H, m, H-5 ), 4.41e4.37 (1H, m, H-4 ), 4.08e4.06
galactopyranos-6 -yl)-1 H-1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-
(
(
1
1H, m, OH), 1.76 (3H, s, CH
3
), 1.34 (3H, s, CH
3
), 1.23 (3H, s, CH
3
);
d
C
2,4(1H,3H)-dione (6a). It was obtained by the reaction of 3a (0.1 g,
0
100 MHz, DMSO-d
6
): 164.7 (C-4),151.1 (C-2),142.9 (C-4 ),141.6 (C-6),
4 2
0.53 mmol), azido sugar I (0.30 g, 1.06 mmol), CuSO $5H O (0.01 g,
0
00
00
24.5 (C-5 ), 111.2 (eC(CH
3
)
2
), 109.3 (C-1 ), 104.9 (C-5), 85.4 (C-4 ),
0.05 mmol), and sodium ascorbate (0.02 g, 0.10 mmol) in 1:1 tert-

8470
R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
butanol/water (20 ml). Purification bycolumn chromatography using
4 2
sugar IV (0.39 g, 0.53 mmol), CuSO $5H O (0.01 g, 0.05 mmol), and
6
0e120 mesh silica gel (10% chloroform/methanol), gave the titled
sodium ascorbate (0.02 g, 0.106 mmol) in 1:1 tert-butanol/water
(20 ml). Purification by column chromatography using 60e120
ꢁ
compound 6a (0.37 g, 91%) as a white solid; mp 88e90 C; R
f
(10%
chloroform/methanol) 0.5; nmax (KBr) 3409, 3020, 1633, 1525, 1389,
mesh silica gel (10% chloroform/methanol), gave the titled com-
ꢀ1
0
0
ꢁ
761 cm
;
d
H
3
(400 MHz, CDCl ): 7.80 (1H, s, H-5 ), 7.70 (1H, s, H-5 ),
pound 6d (0.45 g, 92%) as a white solid; mp 114e116 C; R
f
(R
f
(10%
7
.36 (1H, d, J¼7.93 Hz, H-6), 5.64 (1H, d, J¼7.93 Hz, H-5), 5.43e5.42
chloroform/methanol) 0.4; nmax (KBr) 3411, 3019, 1665, 1385,
0
0
0
ꢀ1
0
0
(
2H, m, H-1 ), 5.18 (1H, d, J¼14.28 Hz, H-6 ), 5.07 (1H, d, J¼14.28 Hz,
758 cm
;
d
H
(400 MHz, CDCl
3
): 8.02 (1H, s, H-5 ), 7.88 (1H, s, H-5 ),
0
0
0
00
H-6 ), 4.97 (1H, d, J¼14.92 Hz, H-6 ), 4.84 (1H, d, J¼14.92 Hz, H-6 ),
7.41 (1H, d, J¼7.48 Hz, H-6), 5.86e5.80 (2H, m, H-1 ), 5.74 (1H, d,
0
0
00
00
00
00
4
.58e4.46 (4H, m, H-2 , H-3 ), 4.40e4.31 (2H, m, H-4 ), 4.26e4.23
J¼7.39 Hz, H-5), 5.53e5.50 (2H, m, H-4 ), 5.49e5.44 (2H, m, H-2 ),
0
0
00
0
00
(
2H, m, H-5 ), 4.12e4.07 (4H, m, H-6 ), 1.42 (3H, s, CH
3
), 1.41 (3H, s,
), 1.28 (3H, s,
5.30 (1H, d, J¼14.24 Hz, H-6 ), 5.26e5.21 (2H, m, H-3 ), 5.18e5.11
0
0
00
CH
CH
3
), 1.32 (3H, s, CH
3
), 1.30 (3H, s, CH
3
), 1.29 (3H, s, CH
3
(2H, m, H-6 ), 4.89 (1H, d, J¼14.8 Hz, H-6 ), 4.23e4.07 (6H, m, H-5 ,
0
0
3
), 1.21 (6H, s, 2ꢂCH
3
); (100 MHz, CDCl
d
C
3
þCCl
4
): 162.3 (C-4),
H-6 ), 2.25 (3H, s, CH
3
), 2.23 (3H, s, CH
), 2.01 (3H, s, CH ), 1.99 (3H, s, CH
); (100 MHz, CDCl ): 169.7 (2C),169.7 (2C),169.3 (2C),
þCCl
3
), 2.04 (3H, s, CH
3
), 2.03 (3H,
0
0
0
0
151.0 (C-2), 142.5 (C-4 ), 142.1 (C-4 ), 141.3 (C-6), 125.0 (C-5 ), 124.7
s, CH
s, CH
3
3
3
), 1.85 (3H, s, CH
3
), 1.84 (3H,
0
(
(
(
C-5 ), 109.8 (C(CH
3
)
2
), 109.7 (C(CH
3
)
2
), 108.9 (2C, C(CH
3
)
2
), 101.7
3
d
C
3
4
0
0
00
00
00
0
0
C-5), 96.1 (2ꢂC-1 ), 71.0 (2ꢂC-4 ), 70.6 (C-3 ), 70.6 (C-3 ), 70.2
168.5 (2C), 162.1 (C-4), 150.9 (C-2), 143.4 (C-4 ), 142.4 (C-4 ), 142.1
0
0
00
00
00
00
0
0 0 00 00
2ꢂC-2 ), 67.0 (C-5 ), 66.9 (C-5 ), 50.5 (C-6 ), 50.2 (C-6 ), 43.9 (C-6 ),
(C-6), 122.5 (C-5 ), 121.9 (C-5 ), 101.8 (C-5), 86.2 (C-1 ), 85.9 (C-1 ),
0
00 00 00 00 00
73.9 (C-5 ), 73.7 (C-5 ), 70.6 (C-3 ), 70.4 (C-3 ), 68.0 (C-2 ), 67.8
3
5.9 (C-6 ), 25.9 (2C), 25.8, 25.8, 24.8, 24.8, 24.3 (2C); HRMS (ESI):
þ
00
00
00
00
0
MH , found 759.3304. C34
47 8
H N O12 requires 759.3308.
(C-2 ), 66.7 (C-4 ), 66.6 (C-4 ), 60.8 (2ꢂC-6 ), 43.8 (C-6 ), 35.8
0
þ
(
C-6 ), 20.5 (2C), 20.4 (2C), 20.3 (2C), 20.0 (2C); HRMS (ESI): MH ,
0
0
00
0
00 00
0
4
.5.2. 1,3-Bis-[{1 -(5 -Deoxy-1 ,2 -O-isopropylidene-
a
-
D
-xylofur-
found 935.2907. C38
H
47
N
8
O20 requires 935.2901.
00
0
0
anos-5 -yl)-1 H-1 ,2 ,3 -triazol-4 -yl} methyl] pyrimidine-2,4(1H,3H)-
dione (6b). It was obtained by the reaction of 3a (0.1 g, 0.53 mmol),
0
00 00
00 00 00
4.5.5. 1,3-Bis-[{{{1 -(1 ,6 -dideoxy-2 ,3 ,4 -tri-O-acetyl-
b
-
D
-gal-
00
000
00
0
0
0
0
0
azido sugar II (0.23 g, 1.06 mmol), CuSO
and sodium ascorbate (0.02 g, 0.10 mmol) in 1:1 tert-butanol/water
20 ml). Purification by column chromatography using 60e120 mesh
4 2
$5H O (0.01 g, 0.05 mmol),
actopyranos-1 -yl)-propan-2 -one}-6 -yl}-1 H-1 ,2 ,3 -triazol-4 -yl}
methyl]-pyrimidine-2,4(1H,3H)-dione (6e). It was obtained by the
reaction of 3a (0.1 g, 0.53 mmol), azido sugar V (0.39 g, 1.06 mmol),
(
silica gel (10% chloroform/methanol), gave the titled compound 6b
4 2
CuSO $5H O (0.01 g, 0.05 mmol), and sodium ascorbate (0.02 g,
0.10 mmol) in 1:1 tert-butanol/water (20 ml). Purification by col-
umn chromatography using 60e120 mesh silica gel (10% chloro-
ꢁ
(
0.29 g, 88%) as a white solid; mp 92e94 C; R
f
(10% chloroform/
ꢀ
1
methanol) 0.35; nmax (KBr) 3401, 3019, 1654, 1384, 758 cm
; d
H
0
0
(400 MHz, DMSO-d
6
): 8.10 (1H, s, H-5 ), 7.92 (1H, s, H-5 ), 7.82 (1H, d,
form/methanol), gave the titled compound 6e (0.43 g, 87%) as
00
ꢁ
J¼7.96 Hz, H-6), 5.87e5.86 (2H, m, H-1 ), 5.76 (1H, d, J¼7.88 Hz, H-5),
a white solid; mp 170e172 C; R
f
(10% chloroform/methanol) 0.5;
00
0
0
ꢀ1
5
.61e5.59 (2H, m, H-3 ), 5.02e5.01 (4H, m, H-6 , H-6 ), 4.61e4.53 (2H,
n
max (KBr) 3415, 3019, 1661, 1403, 758 cm
H 3
; d (400 MHz, CDCl ):
0
0
00
00
0
0
m, H-2 ), 4.48e4.42(4H, m, H-5 ), 4.40e4.37 (2H, m, H-4 ), 4.07e4.04
7.76 (1H, s, H-5 ), 7.59 (1H, s, H-5 ), 7.45 (1H, d, J¼7.76 Hz, H-6), 5.71
0
0
00
(
2H, m, 2ꢂOH),1.33 (6H, s, C(CH
DMSO-d
C-6), 124.7 (C-5 ), 124.4 (C-5 ), 111.2 (2C, C(CH
3
)
2
),1.22 (s, 6H, C(CH
3
)
2
);
d
C
(100 MHz,
(1H, d, J¼7.76 Hz, H-5), 5.20e5.14 (4H, m, H-2 , H-4 ), 5.05e4.96
0
0
0
0
0
0
0
6
): 162.5 (C-4), 151.2 (C-2), 144.7 (C-4 ), 142.9 (C-4 ), 142.5
(2H, m, H-3 ), 4.86e4.77 (4H, m, H-6 ), 4.54e4.51 (2H, m, H-1 ),
0
0
00
00
00
(
1
3 2
) ), 104.9 (2ꢂC-1 ),
4.28e4.19 (2H, m, H-5 ), 3.94e3.82 (4H, m, H-6 ), 2.70e2.60 (2H,
m, CH ), 2.51e2.44 (2H, m, CH ), 2.09 (3H, s, CH ), 2.08 (3H, s, CH ),
2.07 (3H, s, CH ), 2.06 (3H, s, CH ), 2.02 (3H, s, CH ), 2.01 (3H, s,
CH ); (100 MHz, CDCl ): 204.4 (CO), 204.4
), 1.98 (6H, s, 2ꢂCH
CO), 170.0 (2C), 169.7 (2C), 169.7 (2C), 162.6 (C-4), 151.2 (C-2), 143.2
0
0
00
00
00
00.9 (C-5), 85.4 (2ꢂC-4 ), 79.5 (C-3 ), 79.5 (C-3 ), 74.0 (2ꢂC-2 ), 49.4
2
2
3
3
0
0
00
0
0
(C-5 ), 49.2 (C-5 ), 43.9 (C-6 ), 36.2 (C-6 ), 27.0 (2C), 26.4 (2C); HRMS
3
3
3
þ
(ESI): MH , found 619.2471. C26
35 8
H N O
10 requires 619.2471.
3
3
d
C
3
(
0
00 00 00 00
0
0
0
4
1
.5.3. 1,3-Bis-[{1 -(2 ,3 ,4 ,6 -tetra-O-acetyl-
b
-
D
-glucopyranosyl)-
(C-4 ), 142.5 (C-4 ), 142.2 (C-6), 124.9 (2ꢂC-5 ), 102.0 (C-5), 76.1
0
0
0
0
0
00
00
00
00
00
00
H-1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-2,4(1H,3H)-dione (6c). It
(C-1 ), 76.0 (C-1 ), 73.6 (2ꢂC-3 , 2ꢂC-5 ), 71.4 (C-2 ), 71.2 (C-2 ),
0
0
00
00
0
was obtained by the reaction of 3a (0.1 g, 0.53 mmol), azido sugar
III (0.39 g, 1.06 mmol), CuSO $5H O (0.01 g, 0.05 mmol), and so-
dium ascorbate (0.02 g, 0.10 mmol) in 1:1 tert-butanol/water
20 ml). Purification by column chromatography using 60e120
69.9 (C-4 ), 69.6 (C-4 ), 50.9 (2ꢂC-6 ), 46.2 (C-6 ), 45.3 (CH
2
), 45.1
0
4
2
(CH
2
), 44.1 (C-6 ), 30.6 (CH
3
), 30.5 (CH
3
), 20.6 (2C), 20.6 (2C), 20.5
þ
(2C); HRMS (ESI): MH , found 931.329. C40
931.3316.
51 8
H N O18 requires
(
mesh silica gel (10% chloroform/methanol), gave the titled com-
ꢁ
0
00 00 00 00
pound 6c (0.43 g, 88%) as a white solid; mp 108e110 C; R
f
(10%
4.5.6. 1,3-Bis-[{1 -(2 ,3 ,4 ,6 -tetra-O-acetyl-
b
-
D
-glucopyranosyl)-
pyrimidine-2,4(1H,3H)-
dione (7a). It was obtained by the reaction of 3b (0.12 g,
0.59 mmol), azido sugar III (0.44 g,1.18 mmol), CuSO $5H O (0.01 g,
0 0 0 0 0
chloroform/methanol) 0.5; nmax (KBr) 3409, 3019, 1665, 1384,
1 H-1 ,2 ,3 -triazol-4 -yl}methyl]-5-methyl
ꢀ
1
0
0
7
7
58 cm
; d (400 MHz, CDCl ): 8.02 (1H, s, H-5 ), 7.80 (1H, s, H-5 ),
H 3
00
.30 (1H, d, J¼7.92 Hz, H-6), 5.85e5.78 (2H, m, H-1 ), 5.67 (1H, d,
4
2
00
00
J¼7.92 Hz, H-5), 5.38e5.30 (4H, m, H-2 , H-4 ), 5.25e5.21 (2H, m,
0.06 mmol), and sodium ascorbate (0.02 g, 0.12 mmol) in 1:1 tert-
butanol/water (20 ml). Purification by column chromatography
using 60e120 mesh silica gel (10% chloroform/methanol), gave the
titled compound 7a (0.51 g, 91%) as a white solid; mp 115e117 C; R
(10% chloroform/methanol) 0.5; nmax (KBr) 3424, 3019, 1644, 1404,
0
0
0
0
H-3 ), 5.19e5.11 (2H, m, H-6 ), 5.01 (1H, d, J¼15.1 Hz, H-6 ), 4.88
0
00
(
1H, d, J¼15.1 Hz, H-6 ), 4.25e4.20 (2H, m, H-5 ), 4.12e4.05 (2H, m,
0
0
00
ꢁ
H-6 ), 3.97e3.93 (2H, m, H-6 ), 2.01 (3H, s, CH
.00 (3H, s, CH ), 1.99 (3H, s, CH ), 1.96 (3H, s, CH
.77 (3H, s, CH ), 1.76 (3H, s, CH
3
), 2.00 (3H, s, CH
3
),
),
f
2
1
(
1
(
7
4
3
3
3
), 1.95 (3H, s, CH
3
ꢀ
1
0
3
3
);
d
C
(100 MHz, CDCl
3
þCCl
4
): 170.4
758 cm
;
d
H
(400 MHz, DMSO-d
6
): 8.41 (1H, s, H-5 ), 8.24 (1H, s,
0
00
2C), 169.8 (2C), 169.3, 169.2, 168.8, 168.6, 162.3 (C-4), 151.2 (C-2),
43.6 (C-4 ), 142.8 (C-4 ), 142.3 (C-6), 122.6 (C-5 ), 121.8 (C-5 ), 102.1
C-5), 85.8 (C-1 ), 85.5 (C-1 ), 75.1 (C-5 ), 75.0 (C-5 ), 72.7 (C-3 ),
H-5 ), 7.67 (1H, s, H-6), 6.34e6.28 (2H, m, H-1 ), 5.67e5.60 (2H, m,
0
0
0
0
00 00 00
H-4 ), 5.56e5.49 (2H, m, H-2 ), 5.20e5.15 (2H, m, H-3 ), 5.13e4.95
0
0
00
00
00
00
0
00
00
(4H, m, H-6 ), 4.39e4.32 (2H, m, H-5 ), 4.17e4.05 (4H, m, H-6 ),
2.03 (3H, s, CH ), 2.03 (3H, s, CH ), 1.97 (3H, s,
), 1.96 (3H, s, CH ), 1.83 (3H, s, CH ), 1.76 (3H, s,
); (100 MHz, CDCl ): 170.2 (2C), 169.6 (2C), 169.1, 169.0,
þCCl
0
0
0
00
00
00
00
2.5 (C-3 ), 70.5 (C-2 ), 70.2 (C-2 ), 67.7 (2ꢂC-4 ), 61.4 (2ꢂC-6 ),
3
3
), 2.00 (6H, s, 2ꢂCH
3
0
4.2 (C-6 ), 35.9 (C-6 ), 20.6 (2C), 20.4 (4C), 20.0 (2C); HRMS (ESI):
CH
CH
3
3
3
), 1.76 (3H, s, CH
3
þ
MH , found 935.2897. C38
H
47
N
8
O
20 requires 935.2901.
3
d
C
3
4
0
0
1
68.6, 168.3, 162.9 (C-4), 151.2 (C-2), 143.7 (C-4 ), 143.0 (C-4 ), 138.2
0
00 00 00 00
0
0 0 00 00
4
1
.5.4. 1,3-Bis-[{1 -(2 ,3 ,4 ,6 -tetra-O-acetyl-
b
-D
-galactopyranosyl)-
(C-6), 122.4 (C-5 ), 121.5 (C-5 ), 110.3 (C-5), 85.7 (C-1 ), 85.4 (C-1 ),
0
0
0
0
00
00
00
00
00
0
H-1 ,2 ,3 -triazol-4 -yl}methyl]pyrimidine-2,4(1H,3H)-dione
75.0 (C-5 ), 74.9 (C-5 ), 72.6 (C-3 ), 72.4 (C-3 ), 70.5 (C-2 ), 70.1
(C-2 ), 67.6 (2ꢂC-4 ), 61.3 (2ꢂC-6 ), 43.9 (C-6 ), 36.0 (C-6 ), 20.5
0
0
00
00
0
(6d). It was obtained by the reaction of 3a (0.1 g, 0.53 mmol), azido

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8471
þ
0
0
(
2C), 20.4, 20.4, 20.3 (2C), 19.9 (2C), 12.8 (CH
3
); HRMS (ESI): MH ,
d
6
): 164.3 (C-4), 151.2 (C-2), 146.0 (C-4 ), 142.8 (C-6), 122.8 (C-5 ),
00 00 00 00
found 949.3063. C39
H
49
N
8
O
20 requires 949.3058.
101.7 (C-5), 88.5 (C-1 ), 78.8 (C-5 ), 74.0 (C-3 ), 69.7 (C-4 ), 68.9
0
0
00
0
þ
(
C-2 ), 60.8 (C-6 ), 42.8 (C-6 ); HRMS (ESI): MH , found 356.1203.
0
00 00 00 00
4
1
.5.7. 1,3-Bis-[{1 -(2 ,3 ,4 ,6 -tetra-O-acetyl-
b
-
D
-galactopyranosyl)-
pyrimidine-2,4(1H,3H)-
dione (7b). It was obtained by the reaction of 3b (0.12 g,
C H N O requires 356.1201.
13 18 5 7
0
0
0
0
0
H-1 ,2 ,3 -triazol-4 -yl}methyl]-5-methyl
0 00 00 00 000
4.6.3. 1-[{{{1 -(1 ,6 -Dideoxy-b-D-glucopyranos-1 -yl)-propan-2 -
one}-6 -yl}-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]pyrimidine-2,4(1H,3H)-
dione (8c). It was obtained by treating the acetylated compound 4e
(0.12 g, 0.23 mmol) with NaOMe in methanol, to give the fully
00
0
0
0
0
0
0
0
.59 mmol), azido sugar IV (0.44 g,1.18 mmol), CuSO
4
$5H
2
O (0.01 g,
.06 mmol), and sodium ascorbate (0.02 g, 0.12 mmol) in 1:1 tert-
butanol/water (20 ml). Purification by column chromatography
using 60e120 mesh silica gel (10% chloroform/methanol), gave the
deacetylated compound 8c (0.084 g, 92%) as a red solid; mp
ꢁ
ꢁ
titled compound 7b (0.52 g, 93%) as a white solid; mp 119e121 C;
138e140 C; R
3019, 1626, 1385, 758 cm
f
(20% chloroform/methanol) 0.35; nmax (KBr) 3434,
ꢀ1
R
1
f
(10% chloroform/methanol) 0.5; nmax (KBr) 3408, 3019, 1645,
; d (400 MHz, DMSO-d ): 11.29 (1H, br
H 6
ꢀ
1
0
0
385, 757 cm
;
d
H
(300 MHz, CDCl
3
): 8.05 (1H, s, H-5 ), 7.93 (1H, s,
s, NH), 7.82 (1H, s, H-5 ), 7.66 (1H, d, J¼8.02 Hz, H-6), 5.57 (1H, d,
0
00
0
00
H-5 ), 7.28 (1H, s, H-6), 5.86e5.80 (2H, m, H-1 ), 5.56e5.54 (2H, m,
J¼7.80 Hz, H-5), 4.90 (2H, s, H-6 ), 4.69e4.66 (1H, m, H-6 ),
0
0
00
0
00
00
H-4 ), 5.53e5.47 (2H, m, H-2 ), 5.34 (1H, d, J¼14.27 Hz, H-6 ),
4.31e4.25 (1H, m, H-6 ), 3.45e3.40 (4H, m, 3ꢂOH, H-1 ), 3.21e3.16
0
0
0
00 00 00
5
.27e5.21 (2H, m, H-3 ), 5.18 (1H, d, J¼14.27 Hz, H-6 ), 5.13 (1H, d,
(2H, m, H-3 , H-5 ), 3.01e2.96 (1H, m, H-2 ), 2.90e2.86 (1H, m, H-
0
0
00 000 000
4 ), 2.73e2.69 (1H, m, H-1 ), 2.35e2.29 (1H, m, H-1 ), 1.87 (3H, s,
J¼15.01 Hz, H-6 ), 4.84 (1H, d, J¼15.01 Hz, H-6 ), 4.23e4.10 (6H, m,
0
0
00
H-5 , H-6 ), 2.26 (3H, s, CH
.04 (3H, s, CH ), 2.02 (3H, s, CH
CH ), 1.87 (3H, s, CH ), 1.86 (3H, s, CH
2C), 170.1, 170.1, 169.8 (2C), 169.0, 169.0, 163.3 (C-4), 151.0 (C-2),
3
), 2.25 (3H, s, CH
), 2.01 (3H, s, CH
); (75 MHz, CDCl
3
), 2.05 (3H, s, CH
), 1.93 (3H, s,
): 170.3
3
),
CH
3
);
d
C
(100 MHz, DMSO-d
6
): 207.5 (CO), 164.3 (C-4), 151.2 (C-2),
0
0
00
2
3
3
3
145.8 (C-4 ), 142.5 (C-6), 124.7 (C-5 ), 101.7 (C-5), 78.4 (C-3 ), 77.8
00 00 00 00 00 000
3
3
3
d
C
3
(C-1 ), 76.5 (C-4 ), 73.9 (C-5 ), 72.0 (C-2 ), 51.6 (C-6 ), 46.5 (C-1 ),
0
þ
(
1
(
7
42.6 (C-6 ), 30.2; HRMS (ESI): MH , found 396.1511. C16
requires 396.1514.
22 5 7
H N O
0 0 0 0
43.6 (C-4 ), 142.6 (C-4 ), 138.3 (C-6), 122.6 (C-5 ), 122.2 (C-5 ), 110.3
00 00 00 00 00
C-5), 86.3 (C-1 ), 86.1 (C-1 ), 74.0 (C-5 ), 73.9 (C-5 ), 70.8 (C-3 ),
0
0
00
00
00
00
0 0 0 0 0 0
4.6.4. 1-[{1 -(b-D-Glucopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]-
5-methyl pyrimidine-2,4(1H,3H)-dione (8d). It was obtained by
treating the acetylated compound 5c (0.12 g, 0.22 mmol) with
0.5 (C-3 ), 68.0 (C-2 ), 67.7 (C-2 ), 66.8 (C-4 ), 66.6 (C-4 ), 61.1
C-6 ), 61.1 (C-6 ), 43.6 (C-6 ), 36.1 (C-6 ), 20.7 (2C), 20.6 (2C), 20.5
0
0
00
0
0
(
(
þ
2C), 20.3, 20.2, 12.9 (CH
3
); HRMS (ESI): MH , found 949.3044.
C
39
H
49
N
8
O
20 requires 949.3058.
NaOMe in methanol, to give the fully deacetylated compound 8d
ꢁ
(
0.076 g, 93%) as a red solid; mp 106e108 C; R
f
(20% chloroform/
ꢀ
1
4
.6. General procedure for the preparation of deacetylated
methanol) 0.4; nmax (KBr) 3400, 3019, 1650, 1384, 770 cm
(400 MHz, DMSO-d
; d
H
0
compounds 8ae8j
6
): 11.30 (1H, br s, NH), 8.25 (1H, s, H-5 ), 7.63
0
0
0
(
1H, s, H-6), 5.50 (1H, d, J¼9.23 Hz, H-1 ), 4.96e4.88 (2H, m, H-6 ),
The deacetylated sugar derivatives were prepared by treating
the corresponding acetylated compounds (4 or 5 or 6 or 7) in MeOH
with methanolic NaOMe at room temperature. Stirring of the re-
action mixture was continued till the reaction was complete
3.77e3.73 (2H, m, 2ꢂOH), 3.70e3.67 (2H, m, 2ꢂOH), 3.45e3.42
0
0
00
00
00
(3H, m, H-2 , H-3 , H-4 ), 3.39e3.35 (2H, m, H-6 ), 3.24e3.22 (1H,
0
0
m, H-5 ), 1.77 (3H, s, CH
151.2 (C-2),143.0 (C-4 ),141.7 (C-6),123.1 (C-5 ),109.5 (C-5), 87.9 (C-
3
);
d
C
(100 MHz, DMSO-d
6
): 164.8 (C-4),
0
0
00 00 00 00 00 00
(
30 min, TLC). After that the reaction mixture was neutralized by
1 ), 80.3 (C-5 ), 77.3 (C-3 ), 72.4 (C-4 ), 69.9 (C-2 ), 61.1 (C-6 ), 42.7
þ
0
þ
3 20 5 7
(C-6 ), 12.3 (CH ); HRMS (ESI): MH , found 370.1363. C14H N O
Amberlite IR-120-H ion-exchange resin, followed by filtration (the
resin is washed several times with methanol) and evaporation of
the filtrate to dryness, gives the titled pure compounds 8ae8j.
requires 370.1357.
0
0
0
0
0
0
4
.6.5. 1-[{1 -(
b
-
D
-Galactopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}-
0
0
0
0
0
0
4.6.1. 1-[{1 -(
b
-
D
-Glucopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]-
methyl]-5-methyl pyrimidine-2,4(1H,3H)-dione (8e). It was ob-
tained by treating the acetylated compound 5d (0.12 g, 0.22 mmol)
with NaOMe in methanol, to give the fully deacetylated compound
pyrimidine-2,4(1H,3H)-dione (8a). It was obtained by treating the
acetylated compound 4c (0.12 g, 0.22 mmol) with NaOMe in
methanol, to give the fully deacetylated compound 8a (0.074 g,
ꢁ
8e (0.074 g, 90%) as a red solid; mp 159e161 C; R
f
(20% chloroform/
ꢁ
ꢀ1
9
0
5%) as a red solid; mp 158e160 C; R
f
(20% chloroform/methanol)
methanol) 0.4; nmax (KBr) 3401, 3019, 1632, 1384, 758 cm
; d
H
ꢀ1
0
.4; nmax (KBr) 3432, 3019, 1655, 1385, 757 cm
): 11.32 (1H, br s, NH), 8.24 (1H, s, H-5 ), 7.72 (1H, d,
J¼7.91 Hz, H-6), 5.59 (1H, d, J¼7.81 Hz, H-5), 5.50 (1H, d, J¼9.19 Hz,
;
d
H
(400 MHz,
(400 MHz, DMSO-d
6
): 11.31 (1H, br s, NH), 8.19 (1H, s, H-5 ), 7.62 (s,
0
00
0
DMSO-d
6
1H, H-6), 5.45 (1H, d, J¼9.20 Hz, H-1 ), 4.95e4.87 (2H, m, H-6 ),
4.02e3.98 (1H, m, OH), 3.76e3.75 (2H, m, 2ꢂOH), 3.55e3.54 (2H,
0
0
0
00
00 00 00
m, H-2 , H-4 ), 3.53e3.51 (2H, m, H-3 , OH), 3.50e3.45 (3H, m,
H-1 ), 4.98e4.90 (2H, m, H-6 ), 3.76e3.72 (5H, m, 4ꢂOH, H-3 ),
00
00
00
00
00
3
.47e3.40 (3H, m, H-5 , H-6 ), 3.38e3.36 (1H, m, H-4 ), 3.25e3.21
H-5 , H-6 ), 1.76 (3H, s, CH
3
);
d
C
(100 MHz, DMSO-d
6
): 164.8 (C-4),
0
0
0
0
(
1H, m, H-2 );
d
C
(100 MHz, DMSO-d
6
): 164.3 (C-4), 151.2 (C-2),
151.2 (C-2), 143.0 (C-4 ), 141.7 (C-6), 122.8 (C-5 ), 109.4 (C-5), 88.5
0
0
00
00 00 00 00 00 00
146.0 (C-4 ), 142.8 (C-6), 123.1 (C-5 ), 101.7 (C-5), 87.9 (C-1 ), 80.3
(C-1 ), 78.8 (C-5 ), 74.0 (C-3 ), 69.7 (C-4 ), 68.9 (C-2 ), 60.8 (C-6 ),
0
0
00
00
00
00
0
0
þ
3
42.7 (C-6 ), 12.3 (CH ); HRMS (ESI): MH , found 370.1361.
(
C-5 ), 77.2 (C-3 ), 72.4 (C-4 ), 69.9 (C-2 ), 61.1 (C-6 ), 42.8 (C-6 );
þ
HRMS (ESI): MH , found 356.1218. C13
H
18
N
5
O
7
requires 356.1201.
C
14
H
20
N
5
O
7
requires 370.1357.
0
0
0
0
0
0
0
0
0
0
0
0
4
.6.2. 1-[{1 -(
b
-
D
-Galactopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}-
4.6.6. 1,3-Bis-[{1 -(
b
-
D
-glucopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}
methyl]-pyrimidine-2,4(1H,3H)-dione (8b). It was obtained by
treating the acetylated compound 4d (0.12 g, 0.22 mmol) with
methyl]pyrimidine-2,4(1H,3H)-dione (8f). It was obtained by treat-
ing the acetylated compound 6c (0.12 g, 0.12 mmol) with NaOMe in
NaOMe in methanol, to give the fully deacetylated compound 8b
methanol, to give the fully deacetylated compound 8f (0.072 g, 93%)
ꢁ
ꢁ
(
0.078 g, 96%) as a red solid; mp 120e122 C; R
f
(20% chloroform/
as a red solid; mp 107e109 C; R
f
(20% chloroform/methanol) 0.25;
ꢀ
1
ꢀ1
methanol) 0.4; nmax (KBr) 3408, 3019, 1634, 1384, 757 cm
;
d
H
n
max (KBr) 3409, 3019, 1601, 1384, 756 cm
): 8.28 (1H, s, H-5 ), 8.08 (1H, s, H-5 ), 7.82 (1H, d, J¼7.94 Hz, H-6),
H
; d (400 MHz, DMSO-
0
0
0
(
(
400 MHz, DMSO-d
6
): 11.33 (1H, br s, NH), 8.20 (1H, s, H-5 ), 7.74
d
6
00
1H, d, J¼8.08 Hz, H-6), 5.59 (1H, d, J¼7.86 Hz, H-5), 5.45 (1H, d,
5.79 (1H, d, J¼7.94 Hz, H-5), 5.53e5.47 (2H, m, H-1 ), 5.09e4.99
0
0
0
0
00
J¼9.19 Hz, H-1 ), 4.99e4.91 (2H, m, H-6 ), 4.02e3.97 (1H, m, OH),
(4H, m, H-6 ), 3.77e3.73 (7H, m, 7ꢂOH), 3.45 (3H, m, OH, H-5 ),
0
0
00
00 00 00 00
3
.76e3.75 (3H, m, 3ꢂOH), 3.55e3.54 (2H, m, H-3 , H-2 ), 3.53e3.51
3.43e3.41 (4H, m, H-6 ), 3.39e3.35 (3H, m, H-2 , H-4 , H-3 ),
0
0
00
00
00 00 00
C 6
3.26e3.20 (3H, m, H-2 , H-4 , H-3 ); d (100 MHz, DMSO-d ): 162.6
(
2H, m, H-5 , H-4 ), 3.50e3.48 (2H, m, H-6 );
d
C
(100 MHz, DMSO-

8472
R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
0
0
0
0 0
6
): 8.24 (1H, s, H-5 ), 8.04 (1H, s, H-5 ), 7.73 (1H,
(
1
(
(
5
C-4), 151.3 (C-2), 144.8 (C-4 ), 143.0 (C-4 ), 142.6 (C-6), 123.3 (C-5 ),
(400 MHz, DMSO-d
s, H-6), 5.48e5.42 (2H, m, H-1 ), 5.12e4.96 (4H, m, H-6 ), 4.03e3.96
0
00
00
00
00
0
22.9 (C-5 ), 101.1 (C-5), 87.9 (C-1 ), 87.8 (C-1 ), 80.3 (2ꢂC-5 ), 77.3
0
0
00
00
00
00
00
00
00
00
00
C-3 ), 77.2 (C-3 ), 72.4 (C-4 ), 72.4 (C-4 ), 69.9 (2ꢂ(C-2 )), 61.1
(8H, m, 8ꢂOH), 3.56e3.50 (12H, m, H-2 , H-3 , H-4 , H-5 , H-6 ),
0
0
0
0
þ
2ꢂC-6 ), 44.0 (C-6 ), 36.3 (C-6 ); HRMS (ESI): MH , found
1.84 (3H, s, CH
3
);
d
C
(100 MHz, DMSO-d
6
): 163.3 (C-4), 151.1 (C-2),
0
0
0
00
0
00
31
99.2059. C22H N
8
O
12 requires 599.2056.
143.2 (C-4 ), 142.8 (C-4 ), 140.6 (C-6), 123.0 (C-5 ), 122.6 (C-5 ), 108.7
0
0
00
(
C-5), 88.5 (C-1 ), 88.4 (C-1 ), 78.8 (2ꢂC-5 ), 74.0 (C-3 ), 74.0
0
0
0
0
0
0
00
00
00
00
0
4
.6.7. 1,3-Bis-[{1 -(
b
-
D
-galactopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}
methyl]pyrimidine-2,4(1H,3H)-dione (8g). It was obtained by
treating the acetylated compound 6d (0.12 g, 0.12 mmol) with
(C-3 ), 69.7 (2ꢂC-4 ), 68.8 (2ꢂC-2 ), 60.9 (2ꢂC-6 ), 43.8 (C-6 ),
0
þ
36.6 (C-6 ), 13.0 (CH
12 requires 613.2212.
3
); HRMS (ESI): MH , found 613.2184.
23 33 8
C H N O
NaOMe in methanol, to give the fully deacetylated compound 8g
ꢁ
(
0.073 g, 95%) as a red solid; mp 64e66 C; R
f
(20% chloroform/
Acknowledgements
ꢀ
1
methanol) 0.25; nmax (KBr) 3401, 3019, 1638, 1384, 758 cm
; d
H
0 0
6
): 8.25 (1H, s, H-5 ), 8.05 (1H, s, H-5 ), 7.83 (1H,
(
400 MHz, DMSO-d
R.K.T and A.M. are thankful to University Grants Commission
and Council of Scientific and Industrial Research, New Delhi re-
spectively for fellowships. Financial assistance from THUNDER
Project of Council of Scientific and Industrial Research is gratefully
acknowledged. We sincerely thank SAIF division, CSIR-CDRI for the
analytical facilities. This is CSIR-CDRI communication No: 8805.
d, J¼7.91 Hz, H-6), 5.79 (1H, d, J¼7.91 Hz, H-5), 5.48e5.42 (2H, m,
0
0
0
H-1 ), 5.09e4.99 (4H, m, H-6 ), 4.03e3.96 (2H, m, 2ꢂOH),
0
0
00
3
3
(
1
.75ee3.74 (6H, m, 6ꢂOH), 3.56e3.52 (6H, m, H-5 , H-6 ),
0
0
00
00
.50e3.48 (6H, m, H-2 , H-3 , H-4 );
d
C
(100 MHz, DMSO-d
C-4), 151.3 (C-2), 144.8 (C-4 ), 143.1 (C-4 ), 142.6 (C-6), 123.1 (C-5 ),
6
): 162.6
0
0
0
0
00
00
00
22.6 (C-5 ), 101.0 (C-5), 88.5 (C-1 ), 88.4 (C-1 ), 78.8 (2ꢂC-5 ), 74.0
0
0
00
00
00
0
(
2ꢂC-3 ), 69.7 (2ꢂC-4 ), 68.8 (2ꢂC-2 ), 60.9 (2ꢂC-6 ), 44.0 (C-6 ),
0
þ
Supplementary data
3
6.3 (C-6 ); HRMS (ESI): MH , found 599.2059. C22
H
31
N
8
O12 re-
quires 599.2056.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.09.078.
0
0
00 00
0
00
4
2
2
.6.8. 1,3-Bis-[{{{1 -(1 ,6 -dideoxy-
-one}-6 -yl}-1 H-1 ,2 ,3 -triazol-4 -yl}-methyl]pyrimidine-
,4(1H,3H)-dione (8h). It was obtained by treating the acetylated
b
-
D
-glucopyranos-1 -yl)-propan-
000
00
0
0
0
References and notes
compound 6e (0.12 g, 0.12 mmol) with NaOMe in methanol, to give
the fully deacetylated compound 8h (0.08 g, 92%) as a red solid; mp
1. (a) Trakossas, S.; Coutouli-Argyropoulou, E.; Hadjipavlou-Litina, D. J. Tetrahe-
dron Lett. 2011, 52, 1673 and references cited therein; (b) Xia, Y.; Liu, Y.; Rocchi,
P.; Wang, M.; Fan, Y.; Qu, F.; Iovanna, J. L.; Peng, L. Cancer Lett. 2012, 318, 145;
ꢁ
5
6e58 C; R
f
(20% chloroform/methanol) 0.3; nmax (KBr) 3401, 3019,
ꢀ1
0
1638, 1384, 768 cm
;
d
H
(400 MHz, DMSO-d
6
): 7.84 (1H, s, H-5 ),
(c) Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Nat. Rev. Drug Discov.
0
7
.75 (1H, d, J¼8.01 Hz, H-6), 7.66 (1H, s, H-5 ), 5.74 (1H, d, J¼8.01 Hz,
2013, 12, 447.
0
00
2. (a) Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron 1998, 54, 6587; (b) Lazrek,
H. B.; Taourirte, M.; Oulih, T.; Barascut, J. L.; Imbach, J. L.; Pannecouque, C.;
Witrouw, M.; de Clerck, E. Nucleosides Nucleotides Nucleic Acids 2001, 20, 1949;
(c) Merino, P. Curr. Med. Chem. 2006, 13, 539; (d) El Ashry, E. S. H.; Abdel-
Rahman, A.; Rashed, N.; Awad, L. F.; Rasheed, H. A. Nucleosides Nucleotides
Nucleic Acids 2006, 25, 299; (e) Cao, J.; Huang, X. J. Comb. Chem. 2008, 10, 526;
H-5), 5.01e4.98 (4H, m, H-6 ), 4.70e4.63 (2H, m, H-6 ), 4.30e4.21
0
0
00
00
00
(
3
3H, m, H-1 , H-6 ), 3.46e3.39 (8H, m, 6ꢂOH, H-5 , H-1 ),
00 00 00
.21e3.17 (3H, m, H-3 , H-5 ), 3.02e2.95 (2H, m, H-2 ), 2.90e2.86
0
0
000
000
(
1
2H, m, H-4 ), 2.73e2.69 (2H, m, H-1 ), 2.34e2.27 (2H, m, H-1 ),
.84 (3H, s, CH ), 1.83 (3H, s, CH ); (100 MHz, DMSO-d ): 207.6
3
3
d
C
6
(
f) N aꢀ jera, C.; Sansano, J. M. Org. Biomol. Chem. 2009, 7, 4567; (g) Chiacchio, U.;
0
0
(
6
2ꢂCO), 162.5 (C-4), 151.2 (C-2), 144.5 (C-4 ), 142.9 (C-4 ), 142.3 (C-
Padwa, A.; Romeo, G. Curr. Org. Chem. 2009, 13, 422.
3. Wender, P. A.; Touami, S. M.; Alayrac, C.; Philipp, U. C. J. Am. Chem. Soc. 1996, 118,
0 0 00 00
),124.9 (C-5 ),124.5 (C-5 ),101.0 (C-5), 78.4 (C-3 ), 78.4 (C-3 ), 77.8
6522.
0
0
00
00
00
00
(
C-1 ), 77.8 (C-1 ), 76.5 (C-4 ), 76.5 (C-4 ), 73.9 (2ꢂC-5 ), 72.0
4. Cozzi, P.; Mongelli, N. Curr. Pharm. Des. 1998, 4, 181.
0
0
00
00
00
000
000
(
C-2 ), 71.9 (C-2 ), 51.7 (C-6 ), 51.5 (C-6 ), 46.6 (C-1 ), 46.5 (C-1 ),
5. Perez-Castro, I.; Caamano, O.; Fernandez, F.; Garcıa, M. D.; Lopez, C.; Clercq, E.
D. Org. Biomol. Chem. 2007, 5, 3805.
0
0
þ
4
6
3.9 (C-6 ), 36.2 (C-6 ), 30.1 (2C); HRMS (ESI): MH , found
79.2675. C28
6
. Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696.
. Ganesh, A. Int. J. Chem. Sci. 2013, 11, 573.
. Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8, 1128.
9. Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1967, 100, 2494.
0. Amblard, F.; Cho, J. H.; Schinazi, R. F. Chem. Rev. 2009, 109, 4207.
1. Lallana, E.; Riguera, R.; Fernandez-Mejia, E. Angew. Chem., Int. Ed. 2011, 50, 8794.
H
39
N
8
O
12 requires 679.2682.
7
8
0
0
0
0
0
0
4
.6.9. 1,3-Bis-[{1 -(
b
-
D
-glucopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}
1
1
methyl]-5-methyl pyrimidine-2,4(1H,3H)-dione (8i). It was obtained
by treating the acetylated compound 7a (0.12 g, 0.12 mmol) with
12. Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399.
NaOMe in methanol, to give the fully deacetylated compound 8i
13. Efthymiou, T.; Gong, W.; Desaulniers, J. P. Molecules 2012, 17, 12665.
14. Chittepu, P.; Sirivolu, V. R.; Seela, F. Bioorg. Med. Chem. 2008, 16, 8427.
ꢁ
(
0.074 g, 96%) as a red solid; mp 70e72 C; R
f
(20% chloroform/
15. Lolk, L.; Pohlsgaard, J.; Jepsen, A. S.; Hansen, L. H.; Nielsen, H.; Steffansen, S. I.;
ꢀ1
methanol) 0.25; nmax (KBr) 3408, 3020, 1645, 1384, 769 cm
; d
H
Sparving, L.; Nielsen, A. B.; Vester, B.; Nielsen, P. J. Med. Chem. 2008, 51, 4957.
16. Ganesen, M.; Muraleedharan, K. M. Nucleoides Nucleotides Nucleic Acids 2010,
29, 91.
0 0
6
): 8.29 (1H, s, H-5 ), 8.09 (1H, s, H-5 ), 7.76 (1H,
(
400 MHz, DMSO-d
00
0
s, H-6), 5.53e5.47 (2H, m, H-1 ), 5.12e5.05 (2H, m, H-6 ), 5.04e4.97
17. Jorgensen, A. S.; Shaikh, K. I.; Enderlin, G.; Ivarsen, E.; Kumar, S.; Nielsen, P. Org.
0
00
(
6
2H, m, H-6 ), 3.78e3.72 (8H, m, 8ꢂOH), 3.70e3.66 (6H, m, H-5 , H-
Biomol. Chem. 2011, 9, 1381.
0
0
00
00
00
00
), 3.38e3.34 (3H, m, H-2 , H-3 , H-4 ), 3.25e3.20 (3H, m, H-2 ,
18. Parmenopoulou, V.; Chatzileontiadou, D. S. M.; Manta, S.; Bougiatioti, S.; Mar-
agozidis, P.; Gkaragkouni, D. N.; Kaffesaki, E.; Kantsadi, A. L.; Skamnaki, V. T.;
Zographos, S. E.; Zounpoulakis, P.; Balatsos, N. A. A.; Komiotis, D.; Leonidas, D.
D. Bioorg. Med. Chem. 2012, 20, 7184.
19. Krim, J.; Taourirte, M.; Grunewald, C.; Krstic, I.; Engels, J. W. Synthesis 2013, 45,
396.
20. Elayadi, H.; Smietana, M.; Pannecouque, C.; Leyssen, P.; Neyts, J.; Vasseur, J. J.;
Lazrek, H. B. Bioorg. Med. Chem. Lett. 2010, 20, 7365.
21. Soltani Rad, M. N.; Asrari, Z.; Behrouz, S.; Hakimelahi, G. H.; Khalafi-Nezhad, A.
Helv. Chim. Acta 2011, 94, 2194.
0
0
00
H-3 , H-4 ), 1.85 (3H, s, CH
1
3
);
d
C
(100 MHz, DMSO-d
6
): 163.3 (C-4),
0
0
0
51.1 (C-2), 143.1 (C-4 ), 142.7 (C-4 ), 140.6 (C-6), 123.2 (C-5 ), 122.9
0
00
00
00
(
(
6
C-5 ), 108.8 (C-5), 87.9 (C-1 ), 87.8 (C-1 ), 80.3(2ꢂC-5 ), 77.3
0
0
00
00
00
00
þ
C-3 ), 77.2 (C-3 ), 72.4 (C-4 ), 72.3 (C-4 ), 69.9(2ꢂC-2 ),
0
0
0
0
1.1(2ꢂC-6 ), 43.8 (C-6 ), 36.6 (C-6 ), 13.0 (CH
3
); HRMS (ESI): MH ,
found 613.2213. C23H N
33 8
O12 requires 613.2212.
0
0
0
0
0
0
22. Kramer, R. A.; Bleicher, K. H.; Wennemers, H. Helv. Chim. Acta 2012, 95, 2621.
4
.6.10. 1,3-Bis-[{1 -(
b
-
D
-galactopyranosyl)-1 H-1 ,2 ,3 -triazol-4 -yl}
2
2
3. Wang, P.; Leung, C. H.; Ma, D. L.; Lu, W.; Che, C. M. Chem. Asian J. 2010, 5, 2271.
4. Noel, O.; Xie, J. Synthesis 2013, 45, 134.
methyl]-5-methyl pyrimidine-2,4(1H,3H)-dione (8j). It was obtained
by treating the acetylated compound 7b (0.12 g, 0.12 mmol) with
NaOMe in methanol, to give the fully deacetylated compound 8j
0.073 g, 95%) as a red solid; mp 66e68 C; R
methanol) 0.25; nmax (KBr) 3401, 3019, 1650, 1384, 759 cm
25. Lu, J.; Hu, J.; Song, Y.; Ju, Y. Org. Lett. 2011, 13, 3372.
2
6. Negron-Silva, G. E.; Gonzalez-Olvera, R.; Angeles-Beltran, D.; Maldonado-Car-
mona, N.; Espinoza-Vazquez, A.; Plomar-Pardave, M. E.; Romero-Romo, M. A.;
Santillan, R. Molecules 2013, 18, 4613.
ꢁ
(
f
(20% chloroform/
ꢀ
1
;
d
H
27. Rossi, L. L.; Basu, A. Bioorg. Med. Chem. Lett. 2005, 15, 3596.

R.K. Thakur et al. / Tetrahedron 70 (2014) 8462e8473
8473
2
8. Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.; Srivastava, A. K.; Ahmad,
R.; Srivastava, R.; Srivastava, B. S. Bioorg. Med. Chem. 2003, 11, 2911.
9. Tripathi, S.; Maity, J. K.; Achari, B.; Mandal, S. B. Carbohydr. Res. 2005, 340, 1081.
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