Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via TBS-directed 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.jfluchem.2010.12.012

Herein described was a straightforward method for the highly regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldimethylsilyl (TBDMS) group as the directing group in the 1,3-dipol

Full text of DOI:10.1016/j.jfluchem.2010.12.012

Journal of Fluorine Chemistry 132 (2011) 166–174
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside
analogues via TBS-directed 1,3-dipolar cycloaddition reaction
Zhiru Xiong a, Xiao-Long Qiu b, Yangen Huang a, Feng-Ling Qing a,b,
*
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Herein described was
a straightforward method for the highly regioselective synthesis of 5-
Received 18 September 2010
Received in revised form 14 December 2010
Accepted 15 December 2010
Available online 23 December 2010
trifluoromethyl-1,2,3-triazole nucleoside analogues, which featured the utilization of tert-butyldi-
methylsilyl (TBDMS) group as the directing group in the 1,3-dipolar cycloaddition reactions. 4-tert-
Butyldimethylsilyl-5-trifluoromethyl-1,2,3-triazole nucleoside analogues were generated as the only
cycloaddition products in moderate yields (15–79%) via the treatment of glycosyl azides with 3,3,3-
trifluoro-1-tert-butyldimethylsilylpropyne 1 in toluene at 85 8C. Removal of TBS groups in these triazole
cycloadducts with tetrabutylammonium fluoride (TBAF) smoothly afforded the various 5-trifluor-
omethyl-1,5-disubstituted 1,2,3-triazole nucleoside analogues in good yields (40–88%).
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
Nucleoside analogues
Triazole
Trifluoromethyl group
1,3-Dipolar cycloaddition
Regioselective synthesis
1. Introduction
dipolar cycloaddition of glycosyl azides with alkynes [8]. This
classic thermal cycloaddition, however, usually suffers from the
Naturally occurring nucleosides and their synthetic analogues
have been the intensive research interest due to their highly
potential biological activity as antitumor and antiviral agents [1].
Among them nucleosides bearing a five-member ring nucleobase
are of great interest due the fact that they have exhibited unique
biological activities [2]. In the past years, many highly bioactive
triazole nucleosides have been synthesized and biologically
evaluated for virus and hepatitis therapies [3–6]. For example,
1,2,3-triazole TSAO analogue displayed very strong bioactivity for
inhibition of HIV-1 in CEM and MT-4 cells [4a] and 1,2,4-triazole
ribavirin derivative has been reported to be very potent for
treatment of drug-resistant pancreatic cancer [6a] (Fig. 1).
On the other hand, introduction of a trifluoromethyl group into
some nucleosides has drawn considerable attention in view of the
remarkable changes in the bioactivity and stability of the
corresponding compounds [7]. Thus, development of methodology
for synthesizing trifluoromethylated triazolo nucleoside analogues
has been of interest of organic chemists, medicinal chemists and
pharmacologists. So far, the most versatile method to access
triazole-based nucleoside analogues has been the Huisgen 1,3-
formation of regioisomeric mixture of products when azides were
treated with unsymmetrical acetylene [9]. Although the regiose-
lective synthesis of the 4-trifluoromethyl-substituted 1,2,3-tria-
zoles has been made by several groups [10], to the best of our
knowledge the regioselective incorporation of a CF3 group into 5-
position of 1,2,3-triazolo moiety of nucleosides has never been
explored [11]. Indeed, the strong electron-withdrawing property of
trifluoromethyl group makes it more accessible to 4-position of
triazole ring. Recently, Hlasta et al. [12] reported the use of
trimethylsilyl group as regiodirecting group to control the
regioselectivity in synthesizing 1,5-disubstituted 4-trimethylsilyl
1,2,3-triazoles via the cycloaddition reaction of 1-trimethylsilyla-
cetylenes and organoazides. Inspired by Hlasta’s work, we were
interested to investigate the viability of utilizing the trifluor-
omethylated acetylene as an efficient building block to regiose-
lective preparation of 5-trifluoromethylated 1,2,3-triazoles. Herein
described was our methodology of practically constructing 5-
trifluoromethyl 1,5-disubstituted 1,2,3-triazole nucleoside analo-
gues via tert-butyldimethylsilyl(TBS)-directed 1,3-dipolar cyclo-
addition reaction.
2. Results and discussion
* Corresponding author at: Shanghai Inst. of Organic Chemistry, Lab. of
Organofluorine Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
We first prepared the 3,3,3-trifluoro-1-tert-butyldimethylsilyl-
propyne
1 as the dipolarophile for cycloaddition reaction.
According to a modified procedure reported by Hanamoto and
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.12.012

Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
167
N
N
NH2
N
O
TBSO
H2N
C5H11
N
NHMe
O
O
OTBS
N
O
N
HO
O
S
O
O
HO
OH
TSAO analogue
EC50 = 80nM (HIV-1 in CEM)
EC50 = 160nM (HIV-1 in MT-4)
Ribavirin analogue
Potent activity for
pancreatic cancer
Fig. 1. Highly bioactive triazolo nucleoside analogues.
Scheme 1. Synthesis of 1 from 2-bromo-3,3,3-trifluoropropene.
Yamada [13], 1 could be provided by addition of commercially
available 2-bromo-3,3,3-trifluoropropene to a solution of in situ
generated lithium hexamethyldisilazide (LiHMDS) in THF using
hexamethylphosphoramide (HMPA) as additive, followed by
addition of tert-butyldimethylsilyl chloride(TBDMSCl). 19F NMR
spectroscopy of the reaction mixture illustrated that the reaction
proceeded smoothly. However, it was unexpectedly difficult to
isolate 1 from other components by fractional distillation due to
their close boiling points. 1H, 13C and 19F NMR showed that 1 was
contaminated by the hexamethyldisilazane (HMDS) and other
unknown compounds, which were also confirmed by the GC–MS
analysis (Scheme 1) [14].
Although the purification of the compound 1 was unsuccessful,
we believed that the cycloaddition between organic azides and the
crude compound 1 should be chemospecific, thus purification of 1
was not necessary [15]. To investigate the reactivity of 1 for 1,3-
dipolar cycloaddition, readily available benzyl azide 2 was chosen
as the model substrate. We were pleased to find that the
cycloaddition, when performed in toluene at 85 8C for 30 h,
Fig. 2. ORTEP drawing of the X-ray crystallographic structure of 7a.
in moderate yields (Table 1, entries 2–9), albeit lower yields
compared to 4 (Table 1, entry 1). Of all the O-protected glycosyl
azides, glycopyranosyl azides 6a and 6b (Table 1, entries 2 and 3)
were more reactive in the cycloaddition reaction than glycofur-
anosyl azides 6e and 6f (Table 1, entries 6–8), although higher
potential bioactivity should be expected from the latter ones. The
lower reactivity of 6e and 6f was ascribed to the larger steric
hindrance of furanose ring in the transition state of cycloaddition
than that of their pyranose counterparts. Additionally, it was found
that all the O-acyl glycosyl azides reacted smoothly to afford the
corresponding cycloadducts with retention of configuration at the
anomeric carbon (Table 1, entries 2 and 3 and entries 5–8). Lower
yield (37%) was resulted for O-benzyl glucosyl azide 6c (anomeric
provided the desired triazole cycloadduct
3 as the single
regioisomer product (Scheme 2). The regiochemistry assignment
of the compound 3 was determined by HMBC experiment [16].
Increasing reaction temperature from 85 8C to reflux temperature
or performing the reaction in THF provided the product in very low
yield along with some complicated byproducts.
The promising result obtained from the cycloaddition of benzyl
azide 2 with 1 stimulated us to extend the reaction to glycosyl
azide substrates. Thus, a series of O-protected glycosyl azides 6a–
6c [17], 6d [18], 6e–6g [19] and 6h [20] were prepared according to
the reported procedures and used for cycloaddition reaction. It
should be pointed out that for non-participating benzyl group
mixture 1:1) to afford the corresponding mixture 7c of two
a/b
anomers (Table 1, entry 4) which may due to more crowded steric
environment of azido group caused by benzyl group in 6c than that
caused by acetyl group in 6a or 6b [21]. It should be noted that
cycloaddition reaction also proceeded well for the azides 6d and
6h, where azido groups were not attached to anomeric carbon
(Table 1, entries 5 and 9), and the corresponding 1,2,3-triazole
nucleosides 7d and 7h were provided in 70% and 54% yield,
respectively. Most importantly, all the cycloaddition reactions
exhibited very excellent regioselectivity and exclusively delivered
the 5-trifluoromethyl-1,4,5-trisubstituted 1,2,3-triazoles. The ab-
solute structure of compound 7a was confirmed by X-ray
diffraction analysis (Fig. 2) [22]. The excellent regioselectivities
undoubtedly illustrated that the transition state of herein
described 1,3-dipolar cycloaddition was mainly directed by TBS
protected glycosyl azide 6c, anomeric mixture (a/b 1:1) was
obtained. O-Acyl glycosyl azide 6e was also contaminated by about
10% of 1,2-cis anomer [19b]. n-Octyl azide 4 was used as a control
and the results were summarized in Table 1. We were pleased to
find that all the glycosyl azides provided the desired cycloadducts
Scheme 2. Model cycloaddition reaction between 1 and benzyl azide 2.

168
Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
Table 1
Cycloaddition between glycosyl azides and 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne 1.a
N
N N
N
O
3
toluene
85 oC, 30 h
+
F3C
TBDMS
R
TBDMS
.
1
CF3
OP
P = protecting group,
R = glycosyl group
6
7
Entry
1
Glycosyl azides
Products
Entry
6
Glycosyl azides
Products
2
7
AcO
AcO
N
N
N
AcO
O
AcO
O
AcO
N3
AcO
TBDMS
OAc
OAc
6a
CF3
7a (65%)
3
4
8
9
O
N N
N
N3
O
p-ClBzO
p-ClBzO
TBDMS
p-ClBzO
CF3
7g (15%)e, f
6g
p-ClBzO
α:β 1:5
BnO
BnO
BnO
O
N3
OBn
6c
>
α:β 1:1
5
–
–
–
a
Isolated yield based on glycosyl azide, average of two runs.
ratio 1:1 determined by 1H NMR and 19F NMR.
isomer was observed based on 1H and 19F NMR analysis.
b a
/b
c
Less than 10% of
a
d
e
f
Product was contaminated by another regioisomer when at reflux temperature and/or extended time (48 h).
p-ClBz: p-ClC6H4CO.
Only
a
cycloadduct was isolated based on 1H NMR and 19F NMR analysis.
AcO
AcO
AcO
HO
group (rather than CF3 group) by means of a combination of steric
N
N
N
N
N
N
O
HO
O
MeONa/MeOH
95%
hindrance and electronical bias between
acetylene, as proposed elsewhere [12].
a and b position of
HO
OAc
OH
With the prepared 4-(tert-butyldimethylsilyl)-5-trifluoro-
methyl-1,2,3-triazoles in hand, removal of silyl groups in the
products was carried out via treatment with TBAF and the
corresponding 5-trifluoromethyl substituted 1,2,3-triazole nucle-
oside analogues were afforded in moderate to good yields (Table 2)
[23].
Finally, the global deprotection of the sugar moieties in the 5-
trifluoromethyl substituted 1,2,3-triazole nucleoside analogues
was examined briefly. Considering that global deprotection of
acetyl groups from the sugar moieties of all 1,2,3-triazole
nucleoside analogues would be achieved by standard conditions,
CF3
CF3
9a
10a
N N
N
N N
O
O
NH3/MeOH
80%
N
AcO
HO
CF3
CF3
AcO
OAc
HO
OH
9e
10e
Scheme 3. Deprotection of acetyl groups in compounds 9a and 9e.

Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
169
Table 2
Desilylation of 4-(tert-butyldimethylsilyl)-5-trifluoromethyl-1,2,3-triazoles.a
.
Entry Substrates
1
Products
Entry Substrates
6
Products
N
N
N
N
N
N
Bn
Bn
TBDMS
CF3
CF3
8 (88%)b
3
2
3
4
7
8
9
AcO
AcO
AcO
AcO
AcO
AcO
N
N
N
N
N
N
O
O
TBDMS
OAc
7a
OAc
CF3
CF3
9a (71%)
5
–
–
–
a
Isolated yield based on the glycosyl triazole.
b
Use aqueous HF as desilylating reagent.
c a
/
b
ratio 1:1.3 determined by 1H NMR and 19F NMR.
isomer was observed based on 1H and 19F NMR analysis.
d
Less than 5% of
a
e
p-ClBz: p-ClC6H4CO.
only glucopyranosyl 9a and glucofuranosyl 9e were chosen as our
model substrates to examine the final deprotection of acetyl
groups by Zemplen reagent [24a] and NH3/MeOH solution [24b],
respectively. Thus the desired 5-trifluoromethyl-1,2,3-triazoles
nucleoside analogues 10a and 10e were afforded in 95% and 85%
yield, respectively (Scheme 3).
Antivirus and cytotoxicity evaluation of the obtained 5-trifluor-
omethylated 1,2,3-triazole nucleoside analogues are currently in
progress and will be reported soon.
4. Experimental
4.1. General
3. Conclusion
Unless otherwise indicated, all reagents were obtained from
commercial available sources and were used without further
purification. THF was distilled from sodium/benzophenone ketyl
and toluene was distilled from sodium immediately before use. All
reactions were carried out in flame-dried glassware under a
nitrogen atmosphere. IR spectra of liquids were recorded as thin
film on KBr plates and IR spectra of solids were recorded as KBr
In summary, a straightforward method for highly regioselective
synthesis of trifluoromethylated 1,2,3-triazole nucleoside analo-
gues has been developed. This method afforded a practical and
efficient route to construct the 5-trifluoromethyl substituted 1,2,3-
triazole ring. Various 5-trifluoromethylated 1,2,3-triazole nucleo-
side analogues were prepared according to this methodology.

170
Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
pellets with a Nicolet 380 FT-IR spectrophotometer. 1H and 13C
NMR spectra were recorded on Bruker AM-400 spectrometer with
tetramethylsilane (TMS) as an internal standard. 19F NMR spectra
were recorded on Bruker AM-400 spectrometer with CFCl3 as an
external standard and low field is positive. Low-resolution mass
spectra (LRMS) and GC–MS were recorded on Shimadzu QP-2010.
High-resolution mass spectra (HRMS) were measured on FTMS-7.0
or Waters Micromass GCT, respectively. GC–HRMS were measured
on Waters Micromass GCT Premier. Elemental analyses were taken
on a Vario EL III elementary analysis instrument.
91.0 (100), 127.0 (13). 285.0 (28); anal. calcd for C16H22F3N3Si: C,
56.28; H, 6.49; N, 12.31. Found: C, 56.54; H, 6.55; N, 12.49.
4.3.2. 4-(tert-Butyldimethylsilyl)-1-octyl-5-(trifluoromethyl)-1H-
[1,2,3]-triazole (5)
IR (KBr, cmꢀ1
)
nmax 2931, 2861, 1464, 1258, 1174, 1133; 1H
4.46 (t, J = 7.2 Hz, 2H, octyl-CH2), 1.98–
NMR (400 MHz, CDCl3)
d
1.91 (m, 2H, octyl-CH2), 1.34–1.27 (m, 10H, 5 octyl-CH2), 0.94 (s,
9H, C(CH3)3), 0.88 (t, J = 6.8 Hz, 3H, octyl-CH3), 0.35 (s, 6H, 2 CH3);
13C NMR (100.6 MHz, CDCl3)
d 145.6 (triazole C-4), 132.5 (q,
J = 39.0 Hz, triazole C-5), 121.0 (q, J = 268.5 Hz, CF3), 50.1 (C-1),
31.7, 30.1, 29.0, 28.9, 26.5 (C-2,3,4,5,6), 26.4 (tert-butyl-CH3), 22.6
(C-7), 17.2 (tert-butyl-C), 14.0 (C-8), ꢀ5.2 (Si-CH3); 19F NMR
4.2. 3,3,3-Trifluoro-1-tert-butyldimethylsilylpropyne (1)
Hexamethyldisilazane (HMDS, 17.6 mL, 84.3 mmol) and hex-
amethylphosphoramide (HMPA, 0.9 mL, 5.17 mmol) were added
successively into THF (100 mL). Then, n-BuLi (1.6 M in hexane
solution, 52.8 mL, 84.48 mmol) was added dropwise at 0 8C. After
the mixture was stirred for 0.5 h at 0 8C, the whole solution was
cooled to ꢀ78 8C and 2-bromo-3,3,3-trifluoropropene (4 mL,
38.7 mmol) in THF (30 mL) was added slowly over 1 h via syringe
pump. After stirring for 30 min, tert-butylchlorodimethylsilane
(5.29 g, 35.1 mmol) in THF (30 mL) was added dropwise. The
reaction mixture was stirred for additional 30 min at ꢀ78 8C and
hexane (200 mL) was added successively to the resulting mixture
before it warmed to room temperature. The resulting solution was
washed carefully with saturated NH4Cl aqueous solution. The
organic layer was dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The resulting oil residue was purified by
Vigreux distillation (bp 94–101 8C/760 mmHg) to give crude 1 as a
cloudy oil (ca. 11 g, 31% determined by GC–MS analysis of final
fractional components) that can be used directly without further
purification. Characterization data of compound 1 in the crude
product were obtained by NMR and GC–MS analysis of final
(376.5 MHz, CDCl3)
d
ꢀ55.6 (s, 3F, CF3); MS (EI): m/z (%) 43.1 (23),
57.1 (26), 69.0 (95), 196.0 (52), 307.1 (100); anal. calcd for
17H32F3N3Si: C, 56.17; H, 8.87; N, 11.56. Found: C, 56.39; H, 9.18;
C
N, 11.65.
4.3.3. 1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-4-(tert-
butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7a)
IR (KBr, cmꢀ1
max 2956, 2860, 1755, 1238, 1169, 1141, 1096;
1H NMR (400 MHz, CDCl3)
6.00–5.95 (m, 1H, H-2), 5.84–5.82 (d,
)
n
d
J = 9.2 Hz, 1H, H-1), 5.44–5.39 (m, 1H, H-4), 5.29–5.24 (m, 1H, H-3),
4.27–4.22 (dd, J = 12.8, 4.8 Hz, 1H, H-6), 4.21–4.18 (dd, J = 12.8,
2.4 Hz, 1H, H-60), 3.98 (ddd, J = 10.4, 5.2, 2.4 Hz, 1H, H-5), 2.08 (s,
3H, acetyl-CH3), 2.07 (s, 3H, acetyl-CH3), 2.04 (s, 3H, acetyl-CH3),
1.86 (s, 3H, acetyl-CH3), 0.93 (s, 9H, C(CH3)3), 0.36 (s, 6H, 2 CH3);
13C NMR (100.6 MHz, CDCl3)
d 169.5 (acetyl-CO), 169.2 (acetyl-
CO), 168.2 (acetyl-CO), 167.2 (acetyl-CO), 146.1 (triazole C-4),
132.6 (q, J = 40.4 Hz, triazole C-5), 119.5 (q, J = 269.4 Hz, CF3), 83.8
(C-1), 74.1, 72.2, 68.8, 66.6 (C-2,3,4,5), 60.4 (C-6), 25.3 (tert-butyl-
CH3), 19.5 (2 acetyl-CH3), 19.2 (acetyl-CH3), 16.2 (tert-butyl-C),
ꢀ6.3 (Si-CH3); 19F NMR (376.5 MHz, CDCl3)
ꢀ55.2 (s, 3F, CF3); MS
d
fractional components: 1H NMR (400 MHz, CDCl3)
C(CH3)3), 0.22 (s, 6H, 2 CH3); 13C NMR (100.6 MHz, CDCl3)
d
1.00 (s, 9H,
115.4
(EI): m/z (%) 43.1 (88), 109.0 (54), 115.0 (9), 127.0 (19), 169 (100),
331.0 (6), 524.0 (10); anal. calcd for C23H34F3N3O9Si: C, 47.50; H,
5.89; N, 7.22. Found: C, 47.45; H, 6.26; N, 7.05.
d
(q, J = 257.6 Hz, CF3), 95.0 (q, J = 5.4 Hz, acetylene C-1), 93.1 (q,
J = 50.5 Hz, acetylene C-2), 28.1 (tert-butyl-CH3), 18.7 (tert-butyl-
C), ꢀ3.2 (Si-CH3); 19F NMR (376.5 MHz, CDCl3)
d
ꢀ50.8 (s, 3F, CF3);
4.3.4. 1-(2,3,4,6-Tetra-O-acetyl-
butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7b)
IR (KBr, cmꢀ1
max 2956, 2936, 2860, 1740, 1371, 1218, 1174,
1141, 1082; 1H NMR (400 MHz, CDCl3)
6.10–6.06 (m, 1H, H-2),
b-D-galactopyranosyl)-4-(tert-
GC–MS (ESI): m/z 208.1 [M]+; GC–HRMS-EI: m/z [M]+ calcd for
C9H15F3Si: 208.0895. Found: 208.0892.
) n
d
4.3. General procedure for 1,3-dipolar cycloaddition between organic
5.84 (d, J = 9.2 Hz, 1H, H-1), 5.54–5.53 (m, 1H, H-4), 5.25 (dd, J = 10,
3.6 Hz, 1H, H-3), 4.23–4.14 (m, 3H, H-5, H-6, H-60), 2.20 (s, 3H,
acetyl-CH3), 2.05 (s, 3H, acetyl-CH3), 2.02 (s, 3H, acetyl-CH3), 1.87
(s, 3H, acetyl-CH3), 0.94 (s, 9H, C(CH3)3), 0.37 (s, 6H, 2 CH3); 13C
azides and 3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne (1)
Into a 50 mL round-bottom flask equipped with a condenser
was added organic azide (1.0 equiv), 3,3,3-trifluoro-1-tert-butyl-
dimethylsilylpropyne 1 (1.0 equiv based on GC–MS analysis) and
toluene (10 mL, ca. 0.2 M). The mixture was stirred at 85 8C for 30 h
before cooled to room temperature. After removal of the solvent,
the residue was diluted with ethyl acetate, washed with brine and
dried over anhydrous Na2SO4. Filtration and removal of the solvent
gave a residue which was purified by flash column chromatogra-
phy on silica gel to give the 5-trifluoromethyl-substituted
cycloadduct.
NMR (100.6 MHz, CDCl3)
d 170.3 (acetyl-CO), 170.2 (acetyl-CO),
170.0 (acetyl-CO), 168.3 (acetyl-CO), 147.2 (triazole C-4), 133.3 (q,
J = 40.8 Hz, triazole C-5), 120.5 (q, J = 269.4 Hz, CF3), 85.9 (C-1),
74.1, 71.4, 67.3, 66.9 (C-2,3,4,5), 61.3 (C-6), 26.4 (tert-butyl-CH3),
20.6 (2 acetyl-CH3), 20.2 (acetyl-CH3), 17.2 (tert-butyl-C), ꢀ5.2 (Si-
CH3); 19F NMR (376.5 MHz, CDCl3)
(%) 43.1 (100), 109.0 (44), 115.0 (8), 127.0 (29), 169.0 (98), 229.0
(17), 331.0 (20), 524.0 (8); anal. calcd for C23H34F3N3O9Si: C, 47.50;
H, 5.89; N, 7.22. Found: C, 47.60; H, 5.96; N, 7.14.
d
ꢀ55.0 (s, 3F, CF3); MS (EI): m/z
4.3.1. 1-Benzyl-4-(tert-butyldimethylsilyl)-5-(trifluoromethyl)-1H-
4.3.5. 1-(2,3,4,6-Tetra-O-benzyl-
butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7c)
Mixture of
anomers. Major isomer: IR (KBr, cmꢀ1
3088, 3063, 3030, 2929, 2859, 1949, 1873, 1807, 1744, 1605,
1253, 1166, 1092, 734, 696; 1H NMR (400 MHz, CDCl3)
7.38–
6.94 (m, 20H, 4 OBn-H), 6.23 (d, J = 6 Hz, 1H, H-1), 5.05–4.89 (m,
3H, OBn-CH2, H-3), 4.78–4.44 (m, 6H, 3 OBn-CH2), 3.94–3.89 (m,
2H, H-2, H-5), 3.80–3.72 (m, 2H, H-4, H-6), 3.56 (dd, J = 11.2,
0.8 Hz, 1H, H-6), 0.99 (s, 9H, C(CH3)3), 0.44 (s, 3H, CH3, satellite
peak observed), 0.40 (s, 3H, CH3, satellite peak observed); 13C
D-glucopyranosyl)-4-(tert-
[1,2,3]-triazole (3)
IR (KBr, cmꢀ1
)
n
max 3093, 3068, 3036, 2957, 2859, 1637, 1524,
a
/
b
) nmax
1471, 1255, 1169, 1134, 725, 694; 1H NMR (400 MHz, CDCl3)
d
7.35–7.32 (m, 3H, phenyl-H), 7.26–7.24 (m, 2H, phenyl-H), 5.68 (s,
2H, benzyl-CH2), 0.94 (s, 9H, C(CH3)3), 0.35 (s, 6H, 2 CH3); 13C NMR
(100.6 MHz, CDCl3) d 145.2 (triazole C-4), 133.2 (phenyl-C), 131.6
d
(q, J = 39.2 Hz, triazole C-5), 127.8 (phenyl-C), 127.6 (phenyl-C),
126.6 (phenyl-C), 119.8 (q, J = 270.1 Hz, CF3), 52.4 (benzyl-CH2),
25.4 (tert-butyl-CH3), 16.1 (tert-butyl-C), ꢀ6.3 (Si-CH3); 19F NMR
(376.5 MHz, CDCl3)
d
ꢀ55.1 (s, 3F, CF3); MS (EI): m/z (%) 77.0 (9),
NMR (100.6 MHz, CDCl3) d 145.1 (triazole C-4), 138.5 (phenyl-C),

Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
171
138.2 (phenyl-C), 137.6 (phenyl-C), 137.4 (phenyl-C), 128.5 (2
phenyl-C), 128.4 (2 phenyl-C), 128.0 (phenyl-C), 127.9 (2
phenyl-C), 127.8 (phenyl-C), 127.7 (2 phenyl-C), 127.6 (phe-
nyl-C), 127.4 (phenyl-C), 120.7 (q, J = 269.1 Hz, CF3), 86.2 (C-1),
82.6, 80.0, 78.7, 77.3 (C-2,3,4,5), 75.8 (OBn-CH2), 75.3 (OBn-
CH2), 74.0 (OBn-CH2), 73.5 (OBn-CH2), 68.0 (C-6), 26.5 (tert-
butyl-CH3), 17.2 (tert-butyl-C), ꢀ5.1 (Si-CH3), one triazole
carbon not observed under the 13C NMR conditions; 19F NMR
butyl-C), ꢀ5.3 (Si-CH3), one triazole carbon and CF3 carbon not
observed under the 13C NMR conditions; 19F NMR (376.5 MHz,
CDCl3)
(100), 127.0 (16), 160.0 (5), 285.0 (31); anal. calcd for
35H36F3N3O7Si: C, 60.42; H, 5.22; N, 6.04. Found: C, 60.03; H,
d
ꢀ54.7 (s, 3F, CF3); MS (EI): m/z (%) 57.1 (5), 77.0 (11), 91.0
C
5.23; N, 5.81.
4.3.9. 1-(2-Deoxy-3,5-di-O-(4-chlorobenzoyl)-a-D-ribofuranosyl)-4-
(376.5 MHz, CDCl3)
(10), 91.0 (100), 127.0 (16), 160.0 (5), 285.0 (32); anal. calcd for
43H50F3N3O5Si: C, 66.73; H, 6.51; N, 5.43. Found: C, 66.29; H,
d
ꢀ54.7 (s, 3F, CF3); MS (EI): m/z (%) 77.0
(tert-butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7g)
IR (KBr, cmꢀ1
nmax 3100, 3070, 3041, 2956, 2931,2859, 1925,
1721, 1594, 1266, 1238, 1169, 1136, 758, 683; 1H NMR (400 MHz,
CDCl3) 7.99–7.93 (m, 4H, phenyl-H), 7.46–7.36 (m, 4H, phenyl-
)
C
6.36; N, 5.02.
d
H), 6.50 (dd, J = 6.8, 4 Hz, 1H, H-1), 5.98–5.94 (m, 1H, H-3), 4.68–
4.64 (m, 1H, H-4), 4.55 (dd, J = 4.8, 12 Hz, 1H, H-5), 4.44 (dd, J = 12,
6.4 Hz, 1H, H-50), 3.69 (ddd, J = 4, 7.2, 14.4 Hz, 1H, H-2), 2.83 (ddd,
J = 5.2, 7.2, 14.4 Hz, 1H, H-20), 0.95 (s, 9H, C(CH3)3), 0.36 (s, 6H, 2
4.3.6. 1-(6-Deoxy-1,2:3,4-di-O-isopropylidene-a-D-galactopyranos-
6-yl)-4-(tert-butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-
triazole (7d)
IR (KBr, cmꢀ1
)
n
max 2983, 2932, 2859, 1462, 1380, 1249, 1172,
CH3); 13C NMR (100.6 MHz, CDCl3)
d 167.5 (benzoyl-CO), 167.3
1127; 1H NMR (400 MHz, CDCl3)
d
5.47 (d, J = 5.6 Hz, 1H, H-1),
(benzoyl-CO), 149.1 (2 phenyl-C), 142.5 (phenyl-C), 142.0 (phenyl-
C), 135.4 (triazole C-4), 133.5 (2 phenyl-C), 131.3 (phenyl-C), 131.1
(phenyl-C), 130.1 (q, J = 39.5 Hz, triazole C-5), 123.0 (q,
J = 269.3 Hz, CF3), 89.8 (C-1), 85.9, 77.4, 66.3 (C-2,3,4), 39.9 (C-
5), 28.7 (tert-butyl-CH3), 19.5 (tert-butyl-C), ꢀ2.9 (Si-CH3); 19F
4.67–4.64 (m, 3H, H-3, H-6, H-60), 4.44–4.41 (m, 1H, H-5), 4.32 (dd,
J = 4.8, 2.4 Hz, 1H, H-2), 4.28 (dd, J = 8, 2 Hz, 1H, H-4), 1.50 (s, 3H,
isopropylidene-CH3), 1.44 (s, 3H, isopropylidene-CH3), 1.36 (s, 3H,
isopropylidene-CH3), 1.29 (s, 3H, isopropylidene-CH3), 0.92 (s, 9H,
C(CH3)3), 0.36 (s, 6H, 2 CH3); 13C NMR (100.6 MHz, CDCl3)
d
147.8
NMR (376.5 MHz, CDCl3)
53.1 (18), 81.0 (100), 111.0 (15), 139.0 (57), 235.9 (12); MS (ESI):
m/z 665.9 [M+Na]+; HRMS-ESI: m/z [M+Na]+ calcd for
d
ꢀ54.8 (s, 3F, CF3); GC–MS (EI): m/z (%)
(triazole C-4), 136.0 (q, J = 39.2 Hz, triazole C-5), 123.2 (q,
J = 269.2 Hz, CF3), 112.3 (isopropylidene-C), 111.4 (isopropyli-
dene-C), 98.5 (C-1), 73.4, 73.2, 72.8, 69.3 (C-2,3,4,5), 52.1 (C-6),
28.7 (isopropylidene-CH3), 28.3 (isopropylidene-CH3), 28.2 (iso-
propylidene-CH3), 27.3 (isopropylidene-CH3), 26.9 (tert-butyl-
CH3), 19.5 (tert-butyl-C), ꢀ2.9 (Si-CH3); 19F NMR (376.5 MHz,
C28H30Cl2F3N3O5SiNa: 666.1176. Found: 666.1180.
4.3.10. 1-(3-Deoxy-1,2:5,6-di-O-isopropylidene- -glucofuranos-
a
-D
3-yl)-4-(tert-butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-
CDCl3)
d
ꢀ55.0 (s, 3F, CF3); MS (MALDI): m/z 494.4 [M + H]+; HRMS-
triazole (7h)
MALDI: m/z [M + H]+ calcd for C21H35F3N3O5Si: 494.2293; found:
494.2300; anal. calcd for C21H34F3N3O5Si: C, 51.10; H, 6.94; N, 8.51.
Found: C, 51.00; H, 7.23; N, 8.49.
IR (KBr, cmꢀ1
)
n
max 2987, 2956, 2934, 2889, 2860, 1528, 1464,
1383, 1254, 1169, 1132, 1069; 1H NMR (400 MHz, CDCl3)
d
5.99 (d,
J = 4 Hz, 1H, H-1), 5.36 (dd, J = 8.8, 4 Hz, 1H, H-3 or H-2), 4.92 (dd,
J = 9.2, 5.6 Hz, 1H, H-4), 4.81–4.79 (m, 1H, H-5), 4.36–4.32 (m, 1H,
H-2 or H-3), 4.00 (dd, J = 8.8, 6.4 Hz, 1H, H-6), 3.5 (dd, J = 8.8, 6.4 Hz,
1H, H-60), 1.52 (s, 3H, isopropylidene-CH3), 1.28 (s, 3H, isopropy-
lidene-CH3), 1.25 (s, 3H, isopropylidene-CH3), 1.17 (s, 3H,
isopropylidene-CH3), 0.90 (s, 9H, C(CH3)3), 0.38 (s, 3H, CH3),
4.3.7. 1-(2,3,5-Tri-O-acetyl-
butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7e)
Major isomer: IR (KBr, cmꢀ1
nmax 2956, 2931, 2859, 1753,
1229, 1167, 1139; 1H NMR (400 MHz, CDCl3)
6.16 (d, J = 2 Hz, 1H,
b-D-ribofuranosyl)-4-(tert-
)
d
H-1), 6.13 (dd, J = 5.2, 2.4 Hz, 1H, H-3), 5.84 (dd, J = 6.4, 5.2 Hz, 1H,
H-2), 4.51–4.46 (m, 1H, H-4), 4.38 (dd, J = 12.4, 3.2 Hz, 1H, H-5),
4.15 (dd, J = 12.4, 4.4 Hz, 1H, H-50), 2.15 (s, 3H, acetyl-CH3), 2.12 (s,
3H, acetyl-CH3), 2.00 (s, 3H, acetyl-CH3), 0.95 (s, 9H, C(CH3)3), 0.35
0.33 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3)
d 145.4 (triazole C-
4), 133.2 (q, J = 39.5 Hz, triazole C-5), 121.0 (q, J = 268.8 Hz, CF3),
113.8 (isopropylidene-C), 109.8 (isopropylidene-C), 104.7 (C-1),
79.1, 75.4, 65.9 (C-2,3,4), 61.2 (C-5, C-6), 27.0 (isopropylidene-
CH3), 26.4 (isopropylidene-CH3), 26.3 (isopropylidene-CH3), 25.8
(isopropylidene-CH3), 25.0 (tert-butyl-CH3), 17.1 (tert-butyl-C),
(s, 6H, 2 CH3); 13C NMR (100.6 MHz, CDCl3)
d 170.5 (acetyl-CO),
169.3 (2 acetyl-CO), 147.0 (triazole C-4), 134.0 (triazole C-5, no
split observed), 121.9 (CF3, no split observed), 89.4 (C-1), 81.3, 74.6,
70.8 (C-2,3,4), 62.6 (C-5), 26.4 (tert-butyl-CH3), 20.6 (acetyl-CH3),
20.5 (acetyl-CH3), 17.2 (tert-butyl-C), ꢀ5.2 (Si-CH3); 19F NMR
ꢀ5.2 (Si-CH3); 19F NMR (376.5 MHz, CDCl3)
ꢀ55.6 (s, 3F, CF3); MS
d
(ESI): m/z 494.0 [M + H]+; HRMS-ESI: m/z [M + H]+ calcd for
C21H35F3N3O5Si: 494.2293. Found: 494.2308.
(376.5 MHz, CDCl3)
d
ꢀ54.8 (s, 3F); MS (EI): m/z (%) 43.1 (89), 69.1
(8), 97.0 (46), 117.0 (13),139.0 (100), 157.0 (38), 259.0 (14), 452.0
(16); anal. calcd for C20H30F3N3O7Si: C, 47.14; H, 5.93; N, 8.25.
Found: C, 47.30; H, 6.06; N, 8.18.
4.4. Preparation of 5-trifluoromethyl-1,5-disubstituted-1,2,3-
triazoles
4.4.1. 1-Benzyl-5-(trifluoromethyl)-1H-[1,2,3]-triazole (8)
4.3.8. 1-(2,3,5-Tri-O-benzoyl-
butyldimethylsilyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (7f)
IR (KBr, cmꢀ1
max 3091, 3068, 3036, 2956, 2931, 2888, 2859,
1635, 1523, 1254, 1169, 1135, 1058, 780, 725; 1H NMR (400 MHz,
CDCl3) 8.03–7.92 (m, 6H, phenyl-H), 7.61–7.33 (m, 9H, phenyl-H),
b
-
D
-ribofuranosyl)-4-(tert-
To a solution of 3 (103 mg, 0.3 mmol) in THF (3 mL) was added
hydrofluoric acid (0.13 mL, 40% aq., 3 mmol). After the starting
material had been consumed, the mixture was diluted with H2O.
The aqueous solution was extracted with ethyl acetate
(3 mL ꢁ 3 mL). The combined organic extracts were washed with
saturated NaHCO3 solution and brine, dried over anhydrous
Na2SO4. After removal of the solvent in vacuo, the crude product
was purified by flash chromatography on silica gel (ethyl acetate/
petroleum ether, 1:20, v/v) to afford 8 (60 mg, 88%) as a light
)
n
d
6.46 (dd, J = 5.2, 1.6 Hz, 1H, H-3), 6.43 (d, J = 1.6 Hz, 1H, H-1), 6.37
(dd, J = 4.8, 7.2 Hz, 1H, H-2), 4.95–4.91 (m, 1H, H-4), 4.71 (dd,
J = 12.4, 4 Hz, 1H, H-5), 4.57 (dd, J = 5.6, 12.4 Hz, 1H, H-50), 0.96 (s,
9H, C(CH3)3), 0.36 (s, 6H, 2 CH3); 13C NMR (100.6 MHz, CDCl3)
d
166.2 (benzoyl-CO), 165.0 (benzoyl-CO), 146.4 (triazole C-4), 133.9
(phenyl-C), 133.6 (phenyl-C), 133.2 (phenyl-C), 129.9 (2 phenyl-C),
129.8 (phenyl-C), 129.4 (phenyl-C), 128.7 (phenyl-C), 128.6 (2
phenyl-C), 128.5 (phenyl-C), 128.4 (phenyl-C), 89.7 (C-1), 81.2,
75.7, 71.7 (C-2,3,4), 63.5 (C-5), 26.4 (tert-butyl-CH3), 17.2 (tert-
yellow oil. IR (KBr, cmꢀ1
1562, 1248, 1172, 1139, 720, 694; 1H NMR (300 MHz, CDCl3)
)
nmax 3062, 3025, 2954, 2925, 2854, 1636,
d
8.00
(s, 1H, triazole C5-H), 7.37–7.34 (m, 3H, phenyl-H), 7.29–7.26 (m,
2H, phenyl-H), 5.66 (s, 2H, benzyl-CH2); 13C NMR (100.6 MHz,
CDCl3)
d 134.6 (triazole C-4), 133.6 (phenyl-C), 129.0 (phenyl-C),

172
Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
128.9 (phenyl-C), 127.8 (phenyl-C), 119.8 (q, J = 268.1 Hz, CF3),
53.6 (benzyl-CH2), one triazole carbon not observed under the 13
NMR conditions; 19F NMR (282 MHz, CDCl3)
MS (EI): m/z (%) 77.0 (9), 91.0 (100), 130.0 (72), 178.0 (23), 198.0
(22), 227.0 (9); anal. calcd for C10H8F3N3: C, 52.87; H, 3.55; N,
18.50. Found: C, 53.01; H, 3.73; N, 18.64.
(C-6); 19F NMR (376.5 MHz, CDCl3)
d
ꢀ58.2 (s, 3F, CF3); MS
C
(MALDI): m/z 682.2 [M+Na]+; HRMS-MALDI: m/z [M+Na]+ calcd for
d
ꢀ58.8 (s, 3F, CF3);
C37H36F3N3O5Na: 682.2499. Found: 682.2518.
4.4.2.4. 1-(6-Deoxy-1,2:3,4-di-O-isopropylidene-
a
-D
-galactopyra-
nos-6-yl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole
(9d). IR (KBr,
cmꢀ1
)
nmax 2989, 2937, 1635, 1562, 1458, 1257, 1214, 1164,
4.4.2. General procedure for the preparation of 5-trifluoromethyl-1,5-
disubstituted 1,2,3-triazoles nucleoside analogues (9)
1070; 1H NMR (400 MHz, CDCl3)
d
7.97 (s, 1H, triazole C5-H), 5.46
(d, J = 5.2 Hz, 1H, H-1), 4.68 (dd, J = 8, 2.4 Hz, 1H, H-3), 4.66–4.64
(m, 2H, H-6, H-60), 4.44–4.40 (m, 1H, H-5), 4.34 (dd, J = 5.6, 2.4 Hz,
1H, H-2), 4.29 (dd, J = 8, 2.4 Hz, 1H, H-4), 1.51 (s, 3H, isopropy-
lidene-CH3), 1.45 (s, 3H, isopropylidene-CH3), 1.37 (s, 3H,
isopropylidene-CH3), 1.28 (s, 3H, isopropylidene-CH3); 13C NMR
Tetrabutylammonium fluoride (TBAF, 1.9 equiv) was added to a
solution of 7 (1.0 equiv) in THF (3 mL, ca. 0.1 M). The mixture was
stirred at room temperature for 1 h, then washed with brine and
extracted with ethyl acetate. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the crude product was purified by
flash column chromatography on silica gel to give the desired 5-
trifluoromethyl-1,5-disubstituted 1,2,3-triazole nucleoside analo-
gues 9.
(100.6 MHz, CDCl3)
d 136.4 (triazole C-4), 131.0 (q, J = 41.2 Hz,
triazole C-5), 122.1 (q, J = 268.6 Hz, CF3), 112.4 (isopropylidene-C),
111.4 (isopropylidene-C), 98.5 (C-1), 73.3, 73.2, 72.6, 69.2 (C-
2,3,4,5), 52.2 (C-6), 28.2 (isopropylidene-CH3), 28.1 (isopropyli-
dene-CH3), 27.2 (isopropylidene-CH3), 26.9 (isopropylidene-CH3);
19F NMR (376.5 MHz, CDCl3)
d
ꢀ58.5 (s, 3F, CF3); MS (EI): m/z 379.1
4.4.2.1. 1-(2,3,4,6-Tetra-O-acetyl-
methyl)-1H-[1,2,3]-triazole (9a). IR (KBr, cmꢀ1
2852, 1749, 1571, 1224, 1153, 1039; 1H NMR (400 MHz, CDCl3)
b
-
D
-glucopyranosyl)-5-(trifluoro-
[M]+; HRMS-EI: m/z [M]+ calcd for C15H20F3N3O5: 379.1355. Found:
)
nmax 2964, 2927,
379.1350.
d
8.01 (s, 1H, triazole C5-H), 5.87–5.80 (m, 2H, H-1, H-2), 5.43 (m, 1H,
H-4), 5.26 (m, H-3), 4.23–4.22 (m, 2H, H-6, H-60), 4.00 (ddd, J = 10.0,
4.4, 3.2 Hz, 1H, H-5), 2.07 (s, 6H, acetyl-CH3), 2.04 (s, 3H, acetyl-
4.4.2.5. 1-(2,3,5-Tri-O-acetyl-
methyl)-1H-[1,2,3]-triazole (9e). Major isomer: IR (KBr, cmꢀ1
2956, 2850, 1743, 1588, 1371, 1236, 1147, 1112; 1H NMR
(400 MHz, CDCl3) 8.02 (s, 1H, triazole C5-H), 6.17 (dd, J = 5.2,
b-D-ribofuranosyl)-5-(trifluoro-
)
nmax
CH3), 1.88 (s, 3H, acetyl-CH3); 13C NMR (100.6 MHz, CDCl3)
d
170.5
d
(acetyl-CO), 170.1 (acetyl-CO), 169.2 (acetyl-CO), 168.5 (acetyl-
CO), 135.3 (triazole C-4), 128.7 (q, J = 42.2 Hz, triazole C-5), 119.5
(q, J = 268.8 Hz, CF3), 85.5 (C-1), 75.3, 72.8, 69.8, 67.5 (C-2,3,4,5),
61.4 (C-6), 20.6 (2 acetyl-CH3), 20.2 (2 acetyl-CH3); 19F NMR
2.8 Hz, 1H, H-2), 6.13 (d, J = 2.8 Hz, 1H, H-1), 5.79 (t, J = 5.8 Hz, 1H,
H-3), 4.54–4.50 (m, 1H, H-4), 4.39 (dd, J = 12.4, 3.2 Hz, 1H, H-5),
4.16 (dd, J = 12, 4 Hz, H-50) 2.15 (s, 3H, acetyl-CH3), 2.14 (s, 3H,
acetyl-CH3), 2.02 (s, 3H, acetyl-CH3); 13C NMR (100.6 MHz, CDCl3)
d
(376.5 MHz, CDCl3)
d
ꢀ58.2 (s, 3F, CF3); MS (EI): m/z (%) 43.0 (100),
170.5 (acetyl-CO), 169.5 (acetyl-CO), 169.2 (acetyl-CO), 134.6
(triazole C-4), 128.7 (q, J = 42.8 Hz, triazole C-5), 119.5 (q,
J = 269.9 Hz, CF3), 89.3 (C-1), 81.7, 74.1, 70.8 (C-2,3,4), 62.5 (C-
5), 20.6 (acetyl-CH3), 20.5 (acetyl-CH3), 20.4 (acetyl-CH3); 19F NMR
69.1 (5), 97.0 (20), 115.0 (11), 139.0 (41), 157.0 (11), 169.0 (8);
anal. calcd for C17H20F3N3O9: C, 43.69; H, 4.31; N, 8.99. Found: C,
43.79; H, 4.66; N, 8.87.
(376.5 MHz, CDCl3)
d
ꢀ58.3 (s, 3F, CF3); MS (EI): m/z (%) 43.1 (100),
4.4.2.2. 1-(2,3,4,6-Tetra-O-acetyl-
omethyl)-1H-[1,2,3]-triazole (9b). IR (KBr, cmꢀ1
1724, 1594, 1277, 1172, 1090; 1H NMR (400 MHz, CDCl3)
b
-
D
-galactopyranosyl)-5-(trifluor-
nmax 2976, 2930,
8.02 (s,
69.1 (5), 85.0 (22), 97.0 (11), 115.0 (19), 139.0 (15), 157.0 (9); anal.
calcd for C14H16F3N3O7: C, 42.54; H, 4.08; N, 10.63. Found: C, 42.92;
H, 4.08; N, 10.54.
)
d
1H, triazole C5-H), 5.93–5.86 (m, 2H, H-1, H-2), 5.55–5.54 (m, 1H,
H-4), 5.26 (dd, J = 8.8, 2.4 Hz, 1H, H-3), 4.25–4.15 (m, 3H, H-5, H-6,
H-60), 2.21 (s, 3H, acetyl-CH3), 2.05 (s, 3H, acetyl-CH3), 2.03 (s, 3H,
4.4.2.6. 1-(2,3,5-Tri-O-benzoyl-
methyl)-1H-[1,2,3]-triazole (9f). IR (KBr, cmꢀ1
3034, 2954, 1728, 1601, 1263, 1119, 1069, 1024, 709, 686; 1H NMR
(400 MHz, CDCl3) 8.02–7.94 (m, 7H, phenyl-H, triazole C5-H),
7.61–7.35 (m, 9H, phenyl-H), 6.53 (dd, J = 4.8, 1.6 Hz, 1H, H-2), 6.39
(d, J = 1.2 Hz, 1H, H-1), 6.30 (t, J = 6.4 Hz, 1H, H-3), 4.96–4.92 (m,
1H, H-4), 4.74 (dd, J = 4, 12 Hz, 1H, H-5), 4.56 (dd, J = 4.8, 12.8 Hz,
1H, H-50); 13C NMR (100.6 MHz, CDCl3)
d 166.1 (benzoyl-CO), 165.1
(benzoyl-CO), 165.0 (benzoyl-CO), 134.6 (2 phenyl-C), 134.0
(phenyl-C), 133.7 (phenyl-C), 133.3 (phenyl-C), 129.9 (phenyl-
C), 129.8 (phenyl-C), 129.3 (phenyl-C), 128.7 (phenyl-C), 128.6
(phenyl-C), 128.5 (phenyl-C), 128.4 (phenyl-C), 119.5 (q,
J = 272.0 Hz, CF3), 89.6 (C-1), 81.6, 75.2, 71.6 (C-2,3,4), 63.2 (C-
5), two triazole carbons not observed under the 13C NMR
b
-
D
-ribofuranosyl)-5-(trifluoro-
)
nmax 3147, 3063,
acetyl-CH3), 1.90 (s, 3H, acetyl-CH3); 13C NMR (100.6 MHz, CDCl3)
d
170.4 (acetyl-CO), 170.1 (acetyl-CO), 170.0 (acetyl-CO), 168.7
(acetyl-CO), 135.6 (triazole C-4), 128.6 (q, J = 42.4 Hz, triazole C-5),
119.5 (q, J = 268.4 Hz, CF3), 86.7 (C-1), 74.3, 70.9, 67.3, 66.7 (C-
2,3,4,5), 61.2 (C-6), 20.6 (2 acetyl-CH3), 20.5 (acetyl-CH3), 20.2
d
(acetyl-CH3); 19F NMR (376.5 MHz, CDCl3)
(EI): m/z (%) 43.1 (100), 69.1 (8), 97.0 (18), 115.0 (11), 139.0 (34),
157.0 (10), 169.0 (5); anal. calcd for C17H20F3N3O9: C, 43.69; H,
4.31; N, 8.99. Found: C, 43.86; H, 4.36; N, 8.64.
d
ꢀ58.0 (s, 3F, CF3); MS
4.4.2.3. 1-(2,3,4,6-Tetra-O-benzyl-
methyl)-1H-[1,2,3]-triazole (9c). Mixture of
isomer: IR (KBr, cmꢀ1
nmax 3145, 3031, 2917, 2868, 1955, 1877,
1812, 1741, 1562, 1247, 1142, 1096, 742, 700; 1H NMR (400 MHz,
CDCl3) 8.00 (s, 1H, triazole C5-H), 7.34–6.94 (m, 20H, 4 OBn-H),
D-glucopyranosyl)-5-(trifluoro-
a/b
anomers. Major
)
conditions; 19F NMR (376.5 MHz, CDCl3)
(EI): m/z (%) 57.1 (5), 77.0 (7), 91.0 (100), 113.0 (16), 181.0 (10),
252.0 (7); anal. calcd for C29H22F3N3O7: C, 59.90; H, 3.81; N, 7.23.
Found: C, 59.69; H, 3.84; N, 6.84.
d
ꢀ58.2 (s, 3F, CF3); MS
d
6.09 (d, J = 6 Hz, 1H, H-1), 4.99–4.84 (m, 3H, OBn-CH2, H-3), 4.74–
4.36 (m, 6H, 3 OBn-CH2), 3.88–3.84 (m, 2H, H-2, H-5), 3.78–3.69
(m, 2H, H-4, H-6), 3.51–3.48 (m, 1H, H-60); 13C NMR (100.6 MHz,
4.4.2.7. 1-(2-Deoxy-3,5-di-O-(4-chlorobenzoyl)-
5-(trifluoromethyl)-1H-[1,2,3]-triazole (9g). IR (KBr, cmꢀ1
3148, 3095, 3066, 2950, 2927, 2854, 1924, 1719, 1594, 1266,
1091, 758, 684; 1H NMR (400 MHz, CDCl3)
8.05 (s, 1H, triazole C5-
a-D-ribofuranosyl)-
CDCl3)
d
140.9 (phenyl-C), 140.5 (phenyl-C), 140.2 (phenyl-C),
) nmax
139.5 (phenyl-C), 136.9 (triazole C-4), 131.6 (q, J = 42.5 Hz, triazole
C-5), 131.0 (phenyl-C), 130.9 (2 phenyl-C), 130.8 (phenyl-C), 130.7
(phenyl-C), 130.6 (phenyl-C), 130.4 (phenyl-C), 130.3 (phenyl-C),
130.2 (2 phenyl-C), 130.1 (phenyl-C), 130.0 (phenyl-C), 122.0 (q,
J = 269.1 Hz, CF3), 88.3 (C-1), 84.8, 81.9, 80.4, 79.5 (C-2,3,4,5), 78.3
(OBn-CH2), 77.5 (OBn-CH2), 76.5 (OBn-CH2), 75.9 (OBn-CH2), 70.7
d
H), 7.93 (AA0BB0, J = 8.8 Hz, 4H, phenyl-H), 7.44–7.41 (m, 4H,
phenyl-H), 6.50–6.48 (m, 1H, H-1), 5.66–5.62 (m, 1H, H-3), 4.75
(dd, J = 8.4, 4 Hz, 1H, H-4), 4.67 (dd, J = 12, 3.6 Hz, 1H, H-5), 4.61
(dd, J = 12, 4.8 Hz, 1H, H-50), 3.50–3.45 (m, 1H, H-2), 3.14–3.06 (m,

Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
173
1H, H-20); 13C NMR (100.6 MHz, CDCl3)
d
165.2 (benzoyl-CO), 165.0
ESI: m/z [M+Na]+ calcd for C8H10F3N3O4Na: 292.0516. Found:
(benzoyl-CO), 140.3 (phenyl-C), 139.8 (phenyl-C), 135.0 (phenyl-
C), 134.9 (triazole C-4), 131.2 (phenyl-C), 129.0 (phenyl-C), 128.8
(phenyl-C), 128.7 (phenyl-C), 128.1 (q, J = 43.4 Hz, triazole C-5),
127.5 (phenyl-C), 119.7 (q, J = 268.0 Hz, CF3), 87.7 (C-1), 83.9, 74.9,
292.0529.
Acknowledgements
63.9 (C-2,3,4), 37.1 (C-5); 19F NMR (376.5 MHz, CDCl3)
d
ꢀ58.3 (s,
National Natural Science Foundation of China and Shanghai
Municipal Scientific Committee are gratefully acknowledged for
financial support.
3F, CF3); MS (ESI): m/z 551.9 [M+Na]+; HRMS-ESI: m/z [M+Na]+
calcd for C22H16Cl2F3N3O5Na: 552.0311. Found: 552.0314.
4.4.2.8. 1-(3-Deoxy-1,2:5,6-di-O-isopropylidene-
3-yl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole (9h). IR (KBr, cmꢀ1
nmax 2987, 2937, 1744, 1566, 1376, 1216, 1162, 1109; 1H NMR
(400 MHz, CDCl3) 8.05 (s, 1H, triazole C5-H), 6.05 (d, J = 4 Hz, 1H,
a-D-glucofuranos-
References
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[1] For reviews on the chemistry synthesis and biological activity of nucleoside
analogues see:
d
H-1), 5.44 (dd, J = 8.8, 4 Hz, 1H, H-3 or H-2), 4.97 (dd, J = 9.2, 5.6 Hz,
1H, H-4), 4.86–4.84 (m, 1H, H-5), 4.46–4.42 (m, 1H, H-2 or H-3),
4.06 (dd, J = 8.8, 6.4 Hz, 1H, H-6), 3.60 (dd, J = 8.8, 5.6 Hz, 1H, H-60),
1.57 (s, 3H, isopropylidene-CH3), 1.32 (s, 3H, isopropylidene-CH3),
1.31 (s, 3H, isopropylidene-CH3), 1.27 (s, 3H, isopropylidene-CH3);
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13C NMR (100.6 MHz, CDCl3)
d 134.2, 128.2 (q, J = 41.3 Hz, triazole
C-5), 119.9 (q, J = 268.3 Hz, CF3), 113.9 (isopropylidene-C), 110.0
(isopropylidene-C), 104.7 (C-1), 79.1, 75.2, 65.8, 61.2 (C-2,4,5,6),
27.0 (isopropylidene-CH3), 26.3 (isopropylidene-CH3), 25.7 (iso-
propylidene-CH3), 24.8 (isopropylidene-CH3), one glycosyl carbon
not observed under the 13C NMR conditions; 19F NMR (376.5 MHz,
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CDCl3)
d
ꢀ59.0 (s, 3F, CF3); MS (EI): m/z 379.1 [M]+; HRMS-EI: m/z
[M]+ calcd for C15H20F3N3O5: 379.1355. Found: 379.1358.
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4.5.1. 1-(b-D-Glucopyranosyl)-5-(trifluoromethyl)-1H-[1,2,3]-
triazole (10a)
To the peracetate protected compound 9a (63 mg, 0.14 mmol)
was added a solution of 0.005 M sodium methoxide (1.6 mg,
0.03 mmol) in dry methanol (6 mL). The pale yellow solution was
stirred at room temperature for 4 h and subsequently neutralized
by dropwise addition of AcOH (pH ꢂ 6). Filtration and evaporation
of solvent to dryness under reduced pressure afforded the desired
10a (38 mg, 95%) as a colorless syrup. IR (KBr, cmꢀ1
(br.), 2932, 2880, 1568, 1336, 1264, 1147, 1043; 1H NMR (400 MHz,
CD3OD) 8.15 (s, 1H, triazole C5-H), 5.46 (d, J = 8.8 Hz, 1H, H-1),
) nmax 3338
(b) Y. Liu, Y. Xia, Y. Fan, A. Maggiani, P. Rocchi, F. Qu, J.L. Iovanna, L. Peng, Bioorg.
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Peng, J. Med. Chem. 52 (2009) 1144–1155.
d
[7] For recent reviews, see:
4.21 (t, J = 8.8 Hz, 1H, H-2), 3.77 (dd, J = 12, 2.4 Hz, 1H, H-4), 3.60
(dd, J = 5.6, 12.8 Hz, 1H, H-6), 3.52–3.46 (m, 2H, H-5, H-60), 3.43–
(a) X.-L. Qiu, X.-H. Xu, F.-L. Qing, Tetrahedron 66 (2010) 789–843;
(b) W.-D. Meng, F.-L. Qing, in: I. Ojima (Ed.), Fluorine in Medicinal Chemistry and
Chemical Biology, Blackwell Publishing Ltd, New York, 200,9pp. 199–212, Chapter 8;
(c) K.W. Pankiewicz, Carbohydr. Res. 327 (2000) 87–105, and references cited
therein.
3.39 (m, 1H, H-3); 13C NMR (100.6 MHz, CD3OD)
d 134.0 (triazole
C4), 129.0 (q, J = 41.5 Hz, triazole C5), 119.7 (q, J = 268.0 Hz, CF3),
87.5 (C-1), 80.0, 77.1, 71.6, 69.5 (C-2,3,4,5), 60.9 (C-6). 19F NMR
[8] (a) R. Huisgen, in: A. Padwa (Ed.), 1,3-Diploar Cycloaddition Chemistry, Wiley,
New York, 1984, pp. 1–176;
(376.5 MHz, CD3OD)
d
ꢀ59.7 (s, 3F, CF3); MS (ESI): m/z 322.0
[M+Na]+; HRMS-ESI: m/z [M+Na]+ calcd for C9H12F3N3O5Na:
(b) A. Padwa, in: B.M. Trost (Ed.), Comprehensive Organic Synthesis, 4, Pergamon
Press, Oxford, 1991, pp. 1069–1109;
(c) W.-Q. Fan, A.R. Katritzky, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.),
Comprehensive Heterocyclic Chemistry II, 4, Pergamon Press, Oxford, 1996, pp.
101–126.
322.0621. Found: 322.0634.
4.5.2. 1-(b-D-Ribofuranosyl)-5-(trifluoromethyl)-1H-[1,2,3]-triazole
(10e)
[9] For selected examples, see:
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Org. Chem. 74 (2009) 4318–4323;
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E. Stiriba, J. Mol. Struct. 929 (2009) 6–9.
To the peracetate protected compound 9e (71 mg, 0.18 mmol)
was added a solution of 7 N NH3/MeOH (2 mL, 14 mmol). The
mixture was stirred at room temperature until TLC shows the
complete consumption of the starting material. After removal of
the solvent in vacuo, the crude product was purified by flash
column chromatography on silica gel (methanol/dichloromethane,
1:10, v/v) to give the desired 10e (38 mg, 80%) as a colorless syrup.
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analogues proceeded with no regioselectivity and both regioisomers were
obtained under the Huisgen condition (see Ref. 10b).
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[14] GC–MS analysis demonstrated that the fractional distillation product contained
3,3,3-trifluoro-1-tert-butyldimethylsilylpropyne (23%), hexamethyldisilazane
(44%) and some other unknown byproducts (33%).
Major isomer: IR (KBr, cmꢀ1
1145, 1042; 1H NMR (400 MHz, DMSO-d6)
)
nmax 3301, 2937, 1565, 1337, 1231,
8.46 (s, 1H, triazole
d
C5-H), 5.81 (d, J = 4 Hz, 1H, H-1), 5.32 (dd, J = 5.6, 9.6 Hz, 1H, H-2),
4.79–4.77 (m, 2H, H-3, H-4), 4.24–4.21 (m, 1H, H-5), 4.00–3.96 (m,
1H, H-50); 13C NMR (100.6 MHz, DMSO-d6)
d 135.1 (triazole C4),
[15] Azide group is extraordinary stable in cycloaddition reaction unless a good
dipolarophile such as acetylene is favorably presented. See:
V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, Angew. Chem. Int. Ed. 41
(2002) 2596–2599.
127.8 (q, J = 41.3 Hz, triazole C4), 119.8 (q, J = 268.2 Hz, CF3), 91.4
(C-1), 86.8, 74.0, 70.6 (C-2, 3, 4), 61.5 (C-5); 19F NMR (376.5 MHz,
DMSO-d6)
d
ꢀ57.3 (s, 3F, CF3); MS (ESI): m/z 292.0 [M+Na]+; HRMS-

174
Z. Xiong et al. / Journal of Fluorine Chemistry 132 (2011) 166–174
[16] HMBC experiment of the triazole 3 demonstrated that there existed a three-bond
proton-carbon correlation between proton of methyl in TBS group and C4 of
triazole, whereas no correlation was observed to the C5 with CF3 group attached.
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Centre and allocated the deposition number CCDC 787398.
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