Synthesis and reactivity of halogenated 1,2,4-triazole nucleoside analogues with high potential for chemical modifications

Article abstract of DOI:10.1055/s-2006-926281

1,2,4-Triazole nucleoside analogues bonded at N-1 of the base were synthesized by addition of N-halo-3,5-dibromo-1,2,4-triazoles to 1,2-unsaturated carbohydrate derivatives (glycals). Examples are given for 1,5-anhydro-3,4,6- tri-O-acetyl-2-deoxy-D-arabino-hex-1-enitol (tri-O-acetyl-D-glucal), and 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hex-1-enitol (tri-O-benzyl-D-glucal), respectively. The graduated reactivity of the three halogens [C-5 (triazole) > C-2 (sugar) > C-3 (triazole)] in the addition products allows subsequent regioselective replacement and deprotection reactions like hydrodehalogenations, nucleophilic substitutions (by methoxide, hydrazine, benzylamine, thiophenolate), deacetylations, and debenzylations, respectively. Thus, the paper opens a new synthetic approach to triazole nucleoside analogues of 2-deoxy-sugars. X-ray analyses support the structures of nine products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926281

496
PAPER
Synthesis and Reactivity of Halogenated 1,2,4-Triazole Nucleoside Analogues
with High Potential for Chemical Modifications
1
, 2,4-Triazole
t
Nucleo
e
side Analo
f
gues anie Libnow, Susanne Wille, Andrea Christiansen, Martin Hein, Helmut Reinke, Martin Köckerling,
Ralf Miethchen*
Universität Rostock, Institut für Chemie, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: ralf.miethchen@uni-rostock.de
Received 26 June 2005; revised 16 August 2005
In tribute to Prof. Dr. Hans Beyer (University of Greifswald) on the occasion of his 100th birthday
ty of 1,2,4-triazole nucleoside analogues has been widely
Abstract: 1,2,4-Triazole nucleoside analogues bonded at N-1 of
the base were synthesized by addition of N-halo-3,5-dibromo-1,2,4-
triazoles to 1,2-unsaturated carbohydrate derivatives (glycals). Ex-
amples are given for 1,5-anhydro-3,4,6-tri-O-acetyl-2-deoxy-D-ar-
demonstrated,16–19 thus our efforts were focused on pro-
viding a new synthetic strategy towards 2-deoxy-sugar
derivatives. The strategy presented in this paper allows
abino-hex-1-enitol (tri-O-acetyl-D-glucal), and 1,5-anhydro-3,4,6- the design of triazole nucleoside analogues with a variable
tri-O-benzyl-2-deoxy-D-arabino-hex-1-enitol (tri-O-benzyl-D-glu-
cal), respectively. The graduated reactivity of the three halogens [C-
5 (triazole) > C-2 (sugar) > C-3 (triazole)] in the addition products
1,2,4-triazoles to 1,2-unsaturated sugars (glycals) com-
allows subsequent regioselective replacement and deprotection re-
actions like hydrodehalogenations, nucleophilic substitutions (by
pattern of groups on the C-5 of the triazole ring. This was
achieved by regioselective additions of 1,3,5-trihalogeno-
bined with subsequent regioselective replacement of the
halogens by nucleophiles or by hydrogen. Indeed, the enol
ether unit of a glycal ensures, above all, the addition step
is highly regioselective but rarely diastereoselective.20–22
However, the loss of stereochemistry becomes less impor-
tant because the halogen atom, introduced into C-2 of the
sugar moiety, is finally removed by hydrodehalogenation.
methoxide, hydrazine, benzylamine, thiophenolate), deacetylations,
and debenzylations, respectively. Thus, the paper opens a new syn-
thetic approach to triazole nucleoside analogues of 2-deoxy-sugars.
X-ray analyses support the structures of nine products.
Key words: nucleoside analogues, 1,2,4-triazoles, additions to D-
glucals, nucleophilic substitutions, hydrodehalogenations
R
R
N
N
N N
OH
1,3,5-Tribromo-1,2,4-triazole (1), synthesized by a very
simple procedure in 1967,1 attracted interest as a bromina-
tion reagent shortly after publication.2 Addition products
of 1 to suitable unsaturated compounds offer valuable
synthetic potential due to the graduated reactivities of the
halogens in nucleophilic addition–elimination reactions.
Thus, investigations on 3,5-dibromo-1-methyl-1,2,4-tri-
azole have shown that the halogen atom located on C-5 is
significantly more reactive than that on C-3.3,4 This obser-
vation was convincingly confirmed by recent studies on
various 1-alkyl-3,5-dibromo-1,2,4-triazoles5 and on 1-
(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)-3(5)-bromo-5(3)-
carbamido-1,2,4-triazole6 as well as reactions with 1-phe-
nyl-5-bromo-1,2,4-triazole.7,8 It is assumed that the meso-
meric discrimination of intermediate A relative to B is the
reason for the difference in reactivity of the halogens
(Scheme 1).
Br
Br
Br
Br
R
N
N
OH
A
R
N
N
N N
Br
HO
Br
Br
Br
N
N
HO
B
Scheme 1
Additions of 1,3,5-tribromo-1,2,4-triazole (1) and 3,5-di-
bromo-1-iodo-1,2,4-triazole (2) to 3,4,6-tri-O-acetyl-1,5-
anhydro-2-deoxy-D-arabino-hex-1-enitol (3) and 1,5-an-
hydro-3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hex-1-eni-
tol (4), respectively, at room temperature in 1,4-dioxane
had been reported previously (Scheme 2).23 Three diaste-
reomeric triazole nucleoside analogues are formed, the
two a-configured major products with ‘D-manno’ and ‘D-
gluco’ configuration and the corresponding ‘b-D-gluco’
N-glycoside (minor product). The dominance of the a-
anomers in the product mixture is caused by the anomeric
effect. Components 5–7 (overall yield 83%) can be sepa-
rated by column chromatography. Figure 1 shows the re-
sult of X-ray structural analyses for these compounds.
Various methods for regiospecific and stereoselective
electrophilic addition reactions of azole and azine deriva-
tives to pyranoid and furanoid glycals were reported in the
literature as key steps in nucleoside syntheses.9–12
Herdewijn et al.13,14 and Eschenmoser et al.15 synthesized
pyranose nucleosides and investigated their incorporation
into oligonucleotides, respectively. The biological activi-
The overall yield of the three diastereomers hardly
changed if the acetyl protecting groups of the starting ma-
terial 3 were replaced by benzyl protecting groups (start-
ing material 4). However, the ratio of the three
diastereomers within the mixture changed after this re-
SYNTHESIS 2006, No. 3, pp 0496–0508
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926281; Art ID: T09305SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,2,4-Triazole Nucleoside Analogues
497
RO
RO
RO
RO
X
N
N
RO
RO
RO
RO
O
O
O
Br
Br
Br
Br
Br
N
+
1:X = Br
2:X = I
N
N
N
N
RO
N
N
N
N
N
i
X
X
X
RO
Br
Br
Br
"α-D-gluco"
"β-D-gluco"
"α-D-manno"
3:R = Ac
4:R = Bn
RO
RO
5: R = Ac; X = Br
8: R = Bn; X = Br
11: R = Ac; X = I
6: R = Ac; X = Br
9: R = Bn; X = Br
7: R = Ac; X = Br
10: R = Bn; X = Br
O
Scheme 2 Addition of 1,3,5-tribromo-1,2,4-triazole (1) and 3,5-dibromo-1-iodo-1,2,4-triazole (2), respectively, to the glycals 3 and 4: i) 1
(or 2), 1,4-dioxane, r.t., 5–6 h.
placement. The benzylated starting material 4 produced a achieved by heating the corresponding trihalogen deriva-
noticeably higher percentage of the a-D-gluco-configured tive with dimethyl phosphite dissolved in trimethyl phos-
diastereomer 9 at the expense of the a-D-manno diaste- phite. This is demonstrated with the precursors 5, 6, 7, 9,
reomer 8, than the acetylated starting material 3 yielding and 11 (Scheme 3). Regioselective hydrodebromination
6 and 5, respectively. The sum of the two a-diastereomers of iodo derivative 11 to 1-(3,4,6-tri-O-acetyl-2-deoxy-2-
remained nearly unchanged at 66–68% (Table 1).
iodo-a-D-mannopyranosyl)-3-bromo-1H-1,2,4-triazole
(17) demonstrated also that dimethyl phosphite did not at-
tack the iodo substituent linked to the sugar moiety
(Scheme 3). There was no evidence of an Arbuzov phos-
phorylation by trimethyl phosphite, even when trihalogen
derivative 5 was heated in pure trimethyl phosphite.
The N-glycosylated halotriazoles proved to be suitable
candidates for regioselective variation of the substituent
pattern. Separation of the two a-diastereomers is not re-
quired if the sugar linked halogen is hydrodehalogenated
in a final synthetic step. In this case, the ‘a-D-manno’ and
‘a-D-gluco’ precursors will give the same product. Thus, The high reactivity of the bromine linked to C-5 of the tri-
it is sufficient to separate the b-anomer from the diaste- azole ring allowed various regioselective nucleophilic
reomeric mixture of addition products.
substitutions in this position. Thus, methoxylation of the
benzylated precursors 9 and 10 by methanolic sodium
methoxide at room temperature yielded the corresponding
5-methoxy derivatives 19 and 20, in 92% and 88% yields,
respectively. In a further experiment, the crude mixture of
8, 9, and 10 obtained from the reaction of tribromotriazole
1 and glucal 4 was methoxylated under analogous condi-
tions to give 19, 20, and 26. After the b-anomeric 5-meth-
oxy-isomer 20 had been separated from the mixture by
column chromatography, the mixed fraction of the two a-
products 19 and 26 was deprotected as shown in
Scheme 5.
In order to explore the regioselectivity of subsequent reac-
tions, first of all hydrodebrominations were investigated.
It was found that hydrogen activated by Pd/C allows the
complete hydrodebromination of halogenated precursors
in one step. Thus, 1-(3,4,6-tri-O-acetyl-2-bromo-2-
deoxy-a-D-mannopyranosyl)-3,5-dibromo-1H-1,2,4-tri-
azole (5) gave at room temperature the bromine-free prod-
uct 12 in 90% yield (Scheme 3). The hydrodebromination
of the mixture of 5, 6, and 7 formed from 1 and 3
(Scheme 2) yielded a-nucleoside 12 (61%) and its b-iso-
mer 18 (12%) as shown in Scheme 3 (Table 1). Addition-
ally, small amounts of two by-products were identified, Moreover, 5-phenylthio derivative 23 was generated from
the glucal 3 and 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy- a-D-manno derivative 8 by treatment with thiophenolate
D-arabino-hexitol. The use of the H2/Pd/C/Et3N reagent at room temperature. The thiophenolate was generated in
system allows simultaneous hydrodebromination and de- situ from thiophenol and potassium carbonate. Further-
benzylation of the compounds in the case of benzylated more, the starting materials 8 and 9 were reacted with hy-
precursors of mixtures such as 8 and 9 or 19 and 26 drazine hydrate at room temperature to give the
(Scheme 5).
corresponding 5-hydrazino derivatives. Compound 24 ob-
tained from 8 was isolated as a syrupy substance, whereas
the crude 5-hydrazino derivative generated from 9 was
treated with acetone before isolation. The hydrazone 21
obtained in this manner at room temperature, is a crystal-
line compound (Scheme 4; Table 1).
It should be mentioned that the Bu3Sn/AIBN system was
less suitable as a selective reagent and led to mixtures of
products. A reagent combination of ethylmagnesium
chloride/[Fe(acac)3] in THF/NMP neither facilitated se-
lective hydrodebromination nor a cross-coupling reac-
tion.24 The detection of 1-(3,4,6-tri-O-acetyl-2-deoxy-a- At increased reaction temperatures, nucleophilic substitu-
D-mannopyranosyl)-3-bromo-1H-1,2,4-triazole
along tions can be accompanied by b-elimination of HBr. It is a
with dibromo compound 13 indicated that the bromine precondition for the elimination that the bromine atom on
atom linked to the heteroaromatic C-3 of starting material C-2 of the sugar moiety and the vicinal protons are in a
5 is the most stable.24
trans relationship. Such a situation exists with the C-3
proton of a-D-manno-configured halotriazole nucleosides
Selective hydrodebrominations of the most reactive bro-
mine atom on C-5 of the heteroaromatic ring was
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

498
S. Libnow et al.
PAPER
Table 1 Selected Analytical Data of Compounds 5–30
Product
5
Starting material Yield (%)
Mp (°C)
[a]D21 CHCl3 (c)
+26.7 (1.42)
+110.0 (0.80)
+24.0 (1.17)
+33.7 (0.70)
+60.9 (1.81)
+28.9 (0.85)
+22.9 (1.04)
+68.5 (1.27)
+26.2 (0.77)
n.d.f
Rf
1 + 3
38
30
15
28
38
19
63
90
95
61/12
94
94
95
86
92
88
76
93
82
91
76
10
72
89
60
59e
165–168 (cyclohexane–EtOAc)
190 (i-PrOH, dec)
142–143 (i-PrOH)
113–114 (cyclohexane–EtOAc)
Colorless syrup
0.40 (heptane–EtOAc, 1:2)
0.35 (heptane–EtOAc, 1:2)
0.32 (heptane–EtOAc, 1:2)
0.54 (heptane–EtOAc, 2:1)
0.51 (heptane–EtOAc, 2:1)
0.47 (heptane–EtOAc, 2:1)
0.29 (heptane–EtOAc, 2:1)
0.27 (EtOAc)
6
7
8
1 + 4
9
10
11
12
13
12/18
14
15
16
17
19
20
21
22
23
24
25
20
19/26
27
28
29
110–112 (i-PrOH)
166–168 (heptane–EtOAc, 10:1)
85–98 (dec.)
2 + 4
5
5
134–136 (i-PrOH)
85–98 (dec)/108–116 (dec)
145–158 (dec)
0.38 (heptane–EtOAc, 1:2)
0.27/0.26 (EtOAc)
a
6
+119.9 (0.94)
+40.5 (1.05)
+65.7 (0.82)
+34.7 (1.11)
+76.3 (1.06)
+21.2 (0.67)
+81.4 (1.25)
+4.2 (0.61)
+39.3 (1.28)
+29.5 (1.43)
+41.4 (1.14)
0.37 (heptane–EtOAc, 1:2)
0.35 (heptane–EtOAc, 1:2)
0.66 (heptane–EtOAc, 1:2)
0.53 (heptane–EtOAc, 1:2)
0.37 (heptane–EtOAc, 2:1)
0.38 (heptane–EtOAc, 2:1)
0.48 (heptane–EtOAc, 1:1)
0.46 (heptane–EtOAc, 2:1)
0.28 (heptane–EtOAc, 5:1)
0.56 (heptane–EtOAc, 1:2)
0.17 (heptane–EtOAc, 6:1)
0.38 (heptane–EtOAc, 2:1)
0.44 (heptane–EtOAc, 2:1)
0.47 (CHCl3–MeOH, 8:1)
0.15 (CHCl3–MeOH, 6:1)
7
114–115 (cyclohexane–EtOAc)
Colorless syrup
9
11
9
113–114 (i-PrOH)
Colorless syrup
10
9
137–138 (i-PrOH)
148–149 (i-PrOH)
98–100 (i-PrOH)
16
8
Colorless syrup
8
Colorless syrup
8
Colorless syrup
b
137–138 (i-PrOH)
b
n.d.
5
157–159 (cyclohexane–Et2O)
Colorless syrup
+36.0 (0.77)d
+52.5 (0.43)d
c
19/26
Colorless syrup
0.19 (toluene–EtOAc–EtOH,
3:1:1)
30
13
88
174–175 (cyclohexane–MeOH, 20:1) +30.1 (0.52)d
0.39 (CHCl3–MeOH, 8:1)
a From a mixture of 5, 6, and 7.
b From a mixture of 8, 9, and 10.
c From a mixture of 8 and 9.
d MeOH.
e There were also two incompletely deprotected by-products.
f Not determined.
and the C-1 proton of a-D-gluco-configured halotriazole temperature of about 100 °C. The reaction proceeded to
nucleosides. furnish the 2,3-unsaturated nucleoside analogue 25.
The introduction of a benzylamino function onto C-5 of 1- On refluxing a-D-gluco diastereomer 16 in methanolic so-
(3,4,6-tri-O-benzyl-2-bromo-2-deoxy-a-D-mannopyrano- dium methoxide, only HBr elimination was observed with
syl)-3,5-dibromo-1H-1,2,4-triazole (8) required a reaction no methoxylation of the heteroaromatic C-3. b-Elimina-
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

PAPER
1,2,4-Triazole Nucleoside Analogues
499
AcO
AcO
AcO
AcO
AcO
ii
95%
i
AcO
AcO
O
O
O
Br
90%
AcO
N
N
AcO
N
N
N
N
N
N
N
Br
Br
12
5
13
Br
Br
AcO
AcO
AcO
AcO
ii
O
6
O
ii
7
94%
AcO
N
N
94%
N
AcO
N
N
Br
Br
N
14
Br
15
Br
AcO
AcO
BnO
BnO
ii
O
ii
95%
O
11
9
86%
AcO
N
N
BnO
N
N
N
N
I
Br
17
Br
16
Br
AcO
AcO
AcO
i
mixture of
5/6/7
O
12
+
N
N
N
18
Scheme 3 Hydrodehalogenation of the halotriazole nucleoside analogues: i) H2, Pd/C, Et3N, EtOAc–MeOH, r.t., 12–15 h; ii) O=PH(OMe)2,
P(OMe)3, Et3N, r.t., 3 h.
tion of HBr is facile as H-1 and bromine are in a trans re- stereomeric mixture of the two methoxylated a-diaste-
lationship. The corresponding glycal derivative 22 was reomers 19 and 26, obtained from 8, 9, and 10
isolated in 93% yield.
(Scheme 4), was hydrogenated by H2/Pd/C/Et3N. The ex-
pected product, 1-(2-deoxy-a-D-glucopyranosyl)-5-meth-
oxy-1H-1,2,4-triazole (29), was isolated in 59% yield
(Scheme 5, Table 1) along with two by-products, incom-
pletely deprotected derivatives of the starting material. It
is important to mention that the hydrogenation of the start-
ing materials 19 and 26 was accompanied by cleavage of
the methoxy group unless triethylamine was added to the
reaction mixture.
Finally, selected deprotection reactions were investigated.
The glycosidic bond of triazole nucleoside analogues is
quite stable towards acids as long as the triazole ring con-
tains bromine. Cleavage of the glycosidic bond is effected
by acids, when the triazole ring does not contain electron
withdrawing substituents like halogens due to the in-
creased basicity of the triazole moiety. Thus, compounds
5 and 13 underwent selective deacetylation at room tem-
perature by 1% methanolic HCl yielding 27 and 30, re- The structures of the new products are supported by mi-
spectively, whereas the bromine-free nucleoside 12 was croanalyses, GC-MS analyses, and NMR data (correlation
attacked by the same reagent under the same reaction con- spectra and NOE measurements included). Crystals of
ditions. A diastereomeric mixture of methyl 2-deoxy-a/b- compounds 5–8, 11, 13, 14, 17, and 30 were suitable for
D-glucopyranosides25 (67%; a/b 10:1) resulted, along X-ray structural analyses. Thereby, it was confirmed that
with only 12% of the desired 1-(2-deoxy-a-D-glucopyra- the compounds with acetyl protecting groups adopt a
nosyl)-1H-1,2,4-triazole (28). The latter was therefore more or less distorted 4C1 chair conformation, whereas the
synthesized by simultaneous debenzylation and hydro- pyranose ring of the benzylated product 8 adopts a skew
debromination of benzyl-protected precursors. Thus, a conformation in the crystalline state. The puckering
mixture of a-anomeric tribromo derivatives 8 and 9 was parameters26 of the compounds are given in Table 2.
treated with H2/Pd/C/Et3N in EtOAc–MeOH at room tem- Moreover, the regioselective hydrodehalogenations on C-
perature. 1-(2-Deoxy-a-D-glucopyranosyl)-1H-1,2,4-tri- 5 could be confirmed for nucleosides 13, 14, and 17.
azole (28) was the only reaction product in this case, as C- Figures 1– 3 show the X-ray structures of compounds 5,
2 of the sugar moiety is no longer a chiral center as a result 6, 7, 8, 11, 17, 13, 14, and 30.27 The deprotected nucleo-
of the hydrodebromination (Scheme 5). In a second ex- side 30 crystallizes together with one mole of methanol
periment, which required only a few consecutive synthetic per mole of nucleoside.
steps relating to the preliminary addition reaction, the dia-
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

500
S. Libnow et al.
PAPER
BnO
BnO
BnO
BnO
Me
Me
1. ii
2. iii
O
OMe
N
N
i
O
HN
9
BnO
N
N
92%
76%
BnO
N
N
N
Br
Br
Br
19
Br
21
BnO
BnO
BnO
BnO
BnO
iv
O
O
i
OMe
N
16
10
93%
88%
BnO
N
N
N
N
N
Br
22
20
Br
Br
BnO
BnO
BnO
BnO
H2N
BnO
BnO
O
ii
91%
76%
O
SPh
N
v
NH
N
8
82%
N
N
N
N
vi
BnO
BnO
Br
Br
24
23
Br
Br
Bn
O
HN
BnO
N
N
N
25
Br
MeO
N
BnO
BnO
O
i
mixture of
8/9/10
N
19 + 20 +
N
Br
BnO
Br
26
Scheme 4 Deprotection and regioselective replacement reactions: i) NaOMe/MeOH, r.t., 12 h; ii) H2NNH2·H2O, 1,4-dioxane, r.t., 12 h;
iii) acetone, r.t., 15 min; iv) NaOMe/MeOH, reflux, 6 h; v) thiophenol, K2CO3, DMF, r.t., 6 h; vi) excess BnNH2, 100 °C, 6–8 h.
Table 2 Puckering Parameters26 of Compounds 5–8, 11, 13, 14, 17,
30
drodebrominated triazole rings of 12, 18, and 28 are char-
acterized by two singlets (7.98–8.01 and 8.29–8.64 ppm,
respectively). The methoxy groups of 19, 20, 26, and 29
Compound Puckering ampli- Q (°)
f (°)
appear at 4.12–4.16 ppm and 59.3 ppm in the 1H and 13
C
tude (Q)/Å
NMR spectra, respectively. The singlet corresponding to
the NH proton of compound 21 was monitored at 7.69
ppm. The chemical shift of the heteroaromatic carbon
atom bonded to the bromine changes significantly when
the bromine atom was replaced by another atom or group;
therefore it was possible to determine the reaction center
by monitoring both the 1H and 13C NMR spectra.
5
6
0.541 (4)
0.530 (3)
0.586 (3)
0.780 (2)
0.523 (4)
0.513 (2)
0.510 (3)
0.522 (1)
0.495 (2)
6.8 (4)
3.6 (3)
6.2 (4)
91.7 (1)
3.4 (4)
7.7 (2)
12.2 (2)
5.9 (1)
1.1 (2)
287 (3)
17.15 (5)
305 (3)
7
8
318.17 (17)
318.7 (7)
208.2 (18)
352.5 (14)
309.8 (15)
142 (13)
11
13
14
17
30
Interestingly, the synthesized a-D-manno-configured
products (5, 11, 13, 17, 23, 24, 27, and 30) exhibit differ-
ent conformations in solution. This is indicated by the
3
3
large variation in the proton couplings J1,2 and J4,5 for
3
these compounds. The values of the J1,2 coupling con-
stants range from 1.9 Hz in compound 24 up to 7.6 Hz in
3
compound 17. The corresponding values for J4,5 are 8.7
Hz for compound 24 and 4.7 Hz for 17. The coupling val-
ues for 17 do not match the expected C1-conformation,
found in the crystal structure (Figure 2).
4
1
The H NMR spectra of the mono-hydrodebrominated
heteroaromatic rings (compounds 13–17) show proton
signals between 8.00 and 8.29 ppm. The completely hy-
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

PAPER
1,2,4-Triazole Nucleoside Analogues
501
Figure 2 Molecular structures of 1-(3,4,6-tri-O-benzyl-2-bromo-2-
deoxy-a-D-mannopyranosyl)-3,5-dibromo-1H-1,2,4-triazole (8), 1-
(3,4,6-tri-O-acetyl-2-iodo-2-deoxy-a-D-mannopyranosyl)-3,5-dibro-
mo-1H-1,2,4-triazole (11), and 1-(3,4,6-tri-O-acetyl-2-iodo-2-deoxy-
a-D-mannopyranosyl)-3-bromo-1H-1,2,4-triazole (17) with 30% pro-
bability of the thermal ellipsoids.
Figure 1 Molecular structures of 1-(3,4,6-tri-O-acetyl-2-bromo-2-
deoxy-a-D-mannopyranosyl)-3,5-dibromo-1H-1,2,4-triazole (5), 1-
(3,4,6-tri-O-acetyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-3,5-di-
bromo-1H-1,2,4-triazole (6) and 1-(3,4,6-tri-O-acetyl-2-bromo-2-de-
oxy-b-D-glucopyranosyl)-3,5-dibromo-1H-1,2,4-triazole (7) with
30% probability of the thermal ellipsoids
The favored attack of the heteroaromatic position 5 by nu-
cleophiles can be explained by the formation of a more
stabilized intermediate in an addition–elimination SN-
mechanism (see Scheme 1).
In summary, trihalogenated triazole nucleoside analogues
were accessible from simple precursors, i.e., 1,3,5-tribro-
mo-1,2,4-triazole and 1,2-unsaturated carbohydrates. The
three bromine atoms linked to C-2 (pyranose) and C-3, C-
5 (triazole) of the target molecules showed graduated re-
activities C-5 > C-2 > C-3. This sequence allowed re-
gioselective variations of the substituent pattern,
culminating in nucleoside analogues of halogen free 2-
deoxy-sugars. The most reactive bromine on C-5 could be
regioselectively replaced by nucleophiles or by hydrogen.
Dimethylphosphite was found to be a highly selective hy-
drodehalogenation reagent for the most reactive bromine
at the heteroaromatic C-5. The complete removal of resid-
ual halogens was achieved by treatment with H2, Pd/C,
Et3N. This procedure can be carried out at any point in the
synthesis. Simultaneous debenzylation was achieved by
H2, Pd/C, Et3N, so that completely deprotected and dehy-
drobrominated 1,2,4-triazole nucleosides were accessible
by this procedure from benzyl-protected precursors. Prod-
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502
S. Libnow et al.
PAPER
can be replaced by nucleophiles. That means, additional
potential exists for consecutive reactions with the com-
pounds reported in this paper.
Mps were obtained using a Leitz polarizing microscope (Laborlux
12 Pol) equipped with a hot stage (Mettler FP 90) and are uncorrect-
ed. Microanalyses were carried out with a CHNS-analyser Thermo-
1
quest Flash EA 1112. H and 13C NMR spectra were recorded on
Bruker instruments: AC 250 and ARX 300, with TMS as the inter-
1
nal standard for H and 13C NMR spectra. Optical rotations were
measured on a polar LmP (IBZ Meßtechnik) instrument. Column
chromatography was carried out with Merck Silica Gel 60 (63–200
mm) and TLC on Merck Silica Gel 60 F254 sheets.
All crystal structure investigations were done on a Bruker X8 Apex
diffractometer with CCD area detector, Mo-Ka radiation and graph-
ite monochromator at 100–243 K. The structures were solved by di-
rect methods and refined by the full matrix least squares method
with the Bruker SHELXTL software package. Due to the higher
values of the absorption coefficient semiempirical absorption cor-
rection calculations were done on the basis of the intensities of
equivalent reflections; for selected crystal data of compounds 5–8,
11, 13, 14, 17, and 30, see Table 3.
Addition of 1,3,5-Trihalogeno-1,2,4-triazoles to Glycals; Typi-
cal Procedure
To a stirred solution of glucal 3 (1.5 g, 5.5 mmol) in anhyd 1,4-di-
oxane (25 mL), tribromotriazole 11 (2.0 g, 6.6 mmol) was added at
r.t. under an argon atmosphere. The suspension was stirred until the
glucal could no longer be detected by TLC (ca. 1 h). After filtration,
the solution was concentrated under reduced pressure, and the resi-
due was separated by column chromatography (heptane–EtOAc,
10:1→7:1) to give 1.2 g (38%) of a-manno derivative 5, 954 mg
(30%) of a-gluco derivative 6, and 477 mg (15%) of b-gluco deriv-
ative 7.
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-a-D-mannopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (5)
1H NMR (250 MHz, CDCl3): d = 6.14 (d, 1 H, 3J1,2 = 5.3 Hz, H-1),
3
3
5.68 (dd, 1 H, J2,3 = 3.8, J3,4 = 6.2 Hz, H-3), 5.24 (dd, 1 H,
3J3,4 = 6.2, 3J4,5 = 7.0 Hz, H-4), 5.00 (dd, 1 H, 3J1,2 = 5.3, 3J2,3 = 3.8
3
2
Hz, H-2), 4.43 (q, 1 H, J5,6a = 6.1 Hz, J6a,6b = 12.2, H-6a), 4.21
(ddd, 1 H, 3J4,5 = 7.0, J5,6a = 6.1, J5,6b = 3.0 Hz, H-5), 4.11 (dd, 1
3
3
3
2
H, J5,6b = 3.0, J6a,6b = 12.2 Hz, H-6b), 2.19, 2.14, 2.09 (3 s, 9 H,
3 × CH3).
13C NMR (63 MHz, CDCl3): d = 170.6, 169.4, 169.4 (3 × C=O),
141.7, 131.4 (C-3 triazole, C-5 triazole), 83.9 (C-1), 73.3 (C-5),
69.9 (C-3), 66.9 (C-4), 61.2 (C-6), 45.7 (C-2), 20.9, 20.9, 20.8
(3 × CH3).
Anal. Calcd for C14H16Br3N3O7 (578.01): C, 29.09; H, 2.79; N, 7.27.
Found: C, 29.18; H, 2.77; N, 7.32.
Figure 3 Molecular structures of 1-(3,4,6-tri-O-acetyl-2-bromo-2-
deoxy-a-D-mannopyranosyl)-3-bromo-1H-1,2,4-triazole (13), 1-
(3,4,6-tri-O-acetyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-3-bromo-
1H-1,2,4-triazole (14), and 1-(2-deoxy-a-D-mannopyranosyl)-3-bro-
mo-1H-1,2,4-triazole (30).
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (6)
3
1H NMR (250 MHz, CDCl3): d = 6.19 (dd, 1 H, J2,3 = 10.8,
3J3,4 = 9.3 Hz, H-3), 6.18 (d, 1 H, 3J1,2 = 5.8 Hz, H-1), 5.20 (dd, 1 H,
3
3
3J3,4 = 9.3, J4,5 = 10.3 Hz, H-4), 4.54 (ddd, 1 H, J5,6a = 2.1,
uct mixtures of ‘a-gluco’ and ‘a-manno’-configured 2-
bromo-2-deoxy derivatives (together up to 70%) gave the
same triazole nucleoside analogues on hydrodehalogena-
tion of the sugar moiety. This possibility reduces the dis-
advantages considerably, which results from the poor
stereoselectivity of the initial addition step.
3J5,6b = 3.8, 3J4,5 = 10.3, H-5), 4.41 (dd, 1 H, 3J1,2 = 5.8, 3J2,3 = 10.8
Hz, H-2), 4.31 (dd, 1 H, J5,6b = 3.8, J6a,6b = 12.6 Hz, H-6b), 4.00
(dd, 1 H, J5,6a = 2.1, J6a,6b = 12.6 Hz, H-6a), 2.09, 2.08 (3 s, 9 H,
3 × CH3).
3
2
3
2
13C NMR (63 MHz, CDCl3): d = 170.6, 169.8, 169.6 (3 s, 3 × C=O),
141.7, 132.5 (C-3 triazole, C-5 triazole), 82.9 (C-1), 71.8 (C-5),
71.3 (C-3), 68.8 (C-4), 61.3 (C-6), 44.9 (C-2), 20.8, 20.7, 20.6
(3 × CH3).
Zumbrunn5 recently showed that the less reactive bromine
atom at C-3 of 1-alkyl-3-bromo-1,2,4-triazoles likewise
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

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1,2,4-Triazole Nucleoside Analogues
503
HO
HO
HO
HO
HO
ii
mixture of
O
O
i
Br
8/9
5
60%
89%
N
N
HO
N
N
N
N
28
Br
27
Br
HO
HO
HO
HO
HO
i
ii
O
O
mixture of
OMe
N
13
19/26
88%
59%
HO
N
N
N
N
Br
N
29
Br
30
Scheme 5 Deprotection of halotriazole nucleoside analogues: i) 1% methanolic HCl, r.t., 10–12 h; ii: H2, Pd/C, Et3N, EtOAc–MeOH, r.t., 12–15 h.
Anal. Calcd for C14H16Br3N3O7 (578.01): C, 29.09; H, 2.79; N, 7.27.
Found: C, 29.27; H, 2.78; N, 6.99.
Anal. Calcd for C14H16Br3N3O7 (578.01): C, 29.09; H, 2.79; N, 7.27.
Found: C, 29.09; H, 2.82; N, 7.03.
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-b-D-glucopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (7)
Addition of Tribromotriazole 1 to Glycal 4
Glucal 4 (3.0 g, 7.21 mmol) and tribromotriazole 11 (2.6 g, 8.58
mmol) were reacted as described for glucal 3. Column chromatog-
raphy (heptane–EtOAc, 20:1→15:1) gave 1.46 g (28%) of 8, 1.98 g
(38%) of 9, and 0.99 g (19%) of 10.
1H NMR (250 MHz, CDCl3): d = 5.66 (d, 1 H, 3J1,2 = 9.8 Hz, H-1),
3
3
5.47 (dd, 1 H, J2,3 = 10.6, J3,4 = 9.3 Hz, H-3), 5.11 (dd, 1 H,
3J3,4 = 9.3, J4,5 = 10.1 Hz, H-4), 4.61 (dd, 1 H, J1,2 = 9.8,
3
3
3J2,3 = 10.6 Hz, H-2), 4.27 (dd, 1 H, 3J5,6a = 4.9, 2J6a,6b = 12.6 Hz, H-
3
2
6a), 4.12 (dd, 1 H, J5,6b = 2.2, J6a,6b = 12.6 Hz, H-6b), 4.05–3.97
(m, 1 H, J4,5 = 10.1, J5,6a = 4.9, J5,6b = 2.2 Hz, H-5), 2.09, 2.05,
2.02 (3 s, 9 H, 3 × CH3).
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-mannopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (8)
3
3
3
1H NMR (250 MHz, CDCl3): d = 7.46–7.09 (m, 15 H, Ph), 6.15 (d,
1 H, 3J1,2 = 5.3 Hz, H-1), 4.87 (dd, 1 H, 3J1,2 = 5.3, 3J2,3 = 3.4 Hz, H-
2), 4.76, 4.68 (2 d, 2 H, 2JHa,Hb = 11.7 Hz, CH2Ph), 4.62, 4.40 (2 d,
2 H, 2JHa,Hb = 11.2 Hz, CH2Ph), 4.60, 4.45 (2 d, 2 H, 2JHa,Hb = 12.1
13C NMR (63 MHz, CDCl3): d = 170.6, 169.7, 169.3 (3 × C=O),
142.1, 131.7 (C-3 triazole, C-5 triazole), 85.8 (C-1), 75.3 (C-5),
74.4 (C-3), 68.6 (C-4), 61.6 (C-6), 46.7 (C-2), 20.8, 20.6, 20.6
(3 × CH3).
3
3
Hz, CH2Ph), 4.32 (dd, 1 H, J2,3 = 3.4, J3,4 = 5.0 Hz, H-3), 4.02–
3.90 (m, 2 H, 3J3,4 = 5.0, J5,6a = 4.2 Hz, H-4, H-5), 3.73 (dd, 1 H,
3
Table 3 Crystal Data of 5–8, 11, 13, 14, 17, 30
Product
Formula
Space group Unit cell dimensions
Parameters/
Independent
reflections
R1(observed)/
R1(all)
5
6
C14H16Br3N3O7
C14H16Br3N3O7
C14H16Br3N3O7
C29H28Br3N3O4
C14H16Br2IN3O7
C14H17Br2N3O7
C14H17Br2N3O7
C14H17BrIN3O7
C9H15Br2N3O5
P212121
P21
a = 8.9674(7) Å, b = 10.7922(8) Å, c = 21.1264(16) Å,
247/2666
247/5767
247/3519
352/9316
0.0215/0.0233
0.0274/0.0318
0.0296/0.0304
0.0322/0.0496
0.0387/0.0432
0.0236/0.0244
0.0522/0.0846
0.0306/0.0570
0.0345/0.0636
a = b = g = 90°, V = 2044.6(3) Å3
a = 10.738(5) Å, b = 8.9274(4) Å, c = 11.7147(6) Å,
a = g = 90°, b = 115.462(2)°, V = 1013.96(8) Å3
7
P21
a = 8.1810(16) Å, b = 8.4251(17) Å, c = 15.196(3) Å,
a = g = 90°, b = 98.40(3)°, V = 1063.1(4) Å3
8
P21
a = 4.9548(1) Å, b = 14.8212(4) Å, c = 19.5384(5) Å,
a = g = 90°, b = 96.678(2)°, V = 1425.09(6) Å3
11
13
14
17
30
P212121
P21
a = 10.2246(7) Å, b = 11.2241(9) Å, c = 18.2309(15) Å, 248/6241
a = b = g = 90°, V = 2092.2(3) Å3
a = 10.1049(2) Å, b = 8.2230(2) Å, c = 11.5463(3) Å,
a = g = 90°, b = 91.230(1)°, V = 959.19(4) Å3
238/4397
P212121
P212121
P212121
a = 9.4075(7) Å, b = 13.1334(11) Å, c = 15.1824(13) Å, 235/9588
a = b = g = 90°, V = 1875.8(3) Å3
a = 10.5920(4) Å, b = 11.2945(4) Å, c = 16.8889(6) Å,
a = b = g = 90°, V = 2020.44(13) Å3
238/12388
a = 7.7126(3) Å, b = 8.7008(4) Å, c = 21.0408(9) Å,
a = b = g = 90°, V = 1411.96(10) Å3
174/9291
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504
S. Libnow et al.
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2
3
3J5,6a = 4.2, J6a,6b = 11.0Hz, H-6a), 3.62 (dd, 1 H, J5,6b = 2.6,
70.1 (C-3), 67.1 (C-4), 61.0 (C-6), 22.9 (C-2), 20.8, 20.7, 20.6
(3 × CH3).
2J6a,6b = 10.9 Hz, H-6b).
13C NMR (63 MHz, CDCl3): d = 141.0 (C-3 triazole), 137.9, 137.6,
137.3 (3 × CquatPh), 131.1 (C-5 triazole), 128.7, 128.5, 128.4, 128.2,
127.9 (Ph), 85.1 (C-1), 77.2, 75.2, 74.4 (C-3, C-4, C-5), 73.8, 73.6,
73.0 (3 × CH2Ph), 68.2 (C-6), 48.6 (C-2).
Anal. Calcd for C14H16Br2IN3O7 (625.01): C, 26.90; H, 2.58; N,
6.72. Found: C, 27.41; H, 2.59; N, 6.58.
Hydrodehalogenations with Hydrogen in the Presence of Pd/C;
Typical Procedure
Anal. Calcd for C29H28Br3N3O4 (722.0): C, 48.22; H, 3.91; N, 5.82.
Found: C, 48.18; H, 3.97; N, 5.84.
To a stirred solution of 5 (500 mg, 0.87 mmol) in EtOAc (10 mL)
and Et3N (1.0 mL), 10% Pd/C (100 mg, 0.09 mmol) was added un-
der an argon atmosphere. Argon was then replaced by hydrogen (1
atm) and stirring was continued at r.t. for about 15 h (TLC). After
filtration, the residue was washed with EtOAc, and the combined
solution was concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (heptane–EtOAc, 1:2)
to give 288 mg (97%) of desired 12 (Rf 0.09) along with 5 mg (2%)
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (9)
1H NMR (250 MHz, CDCl3): d = 7.47–7.13 (m, 15 H, Ph), 6.15 (d,
3
2
1 H, J1,2 = 5.8 Hz, H-1), 5.01, 4.91 (2 d, 2 H, JHa,Hb = 10.5 Hz,
2
OCH2), 4.87, 4.58 (2 d, 2 H, JHa,Hb = 10.7 Hz, OCH2), 4.79 (dd, 1
3
3
H, J2,3 = 10.6, J3,4 = 8.9 Hz, H-3), 4.61, 4.47 (2 d, 2 H,
of
3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hexitol
2JHa,Hb = 12.0 Hz, OCH2), 4.38 (dd, 1 H, 3J1,2 = 5.8, 3J2,3 = 10.6 Hz,
(Rf 0.44).
3
H-2), 4.35–4.28 (m, 1 H, J4,5 = 10.2 Hz, H-5), 3.88 (dd, 1 H,
3J3,4 = 9.0, J4,5 = 10.2 Hz, H-4), 3.78 (dd, 1 H, J5,6a = 3.0,
2J6a,6b = 11.0 Hz, H-6a), 3.60 (dd, 1 H, 3J5,6b = 1.9, 2J6a,6b = 11.0 Hz,
H-6b).
3
3
1-(3,4,6-Tri-O-acetyl-2-deoxy-a-D-glucopyranosyl)-1H-1,2,4-
triazole (12)
1H NMR (250 MHz, CDCl3): d = 8.29, 8.00 (2 s, 2 H, H-3 triazole,
H-5 triazole), 6.05 (dd, 1 H, 3J1,2a = 1.8, 3J1,2b = 5.7 Hz, H-1), 5.77
(ddd, 1 H, 3J2a,3 = 5.5, 3J2b,3 = 10.7, 3J3,4 = 8.9 Hz, H-3), 5.10 (dd, 1
13C NMR (63 MHz, CDCl3): d = 140.9 (C-3 triazole), 137.9, 137.7,
137.6 (3 × CquatPh), 132.3 (C-5 triazole), 128.7, 128.6, 128.3, 128.2,
128.1, 128.0 (15 C, Ph), 83.9 (C-1), 80.7, 79.0, 74.8 (C-3, C-4, C-
5), 76.2, 75.7, 73.8 (3 s, 3 × CH2Ph), 67.9 (C-6), 48.4 (C-2).
3
3
3
H, J3,4 = 8.9, J4,5 = 9.5 Hz, H-4), 4.30 (dd, 1 H, J5,6a = 4.9,
2J6a,6b = 12.5 Hz, H-6a), 3.96 (dd, 1 H, 3J5,6b = 2.4, 2J6a,6b = 12.5 Hz,
H-6b), 3.82 (ddd, 1 H, 3J4,5 = 9.5, 3J5,6a = 4.9, 3J5,6b = 2.4 Hz, H-5),
2.82 (ddd, 1 H, 3J1,2a = 1.8, 3J2a,2b = 13.8, 3J2a,3 = 5.5 Hz, H-2a), 2.26
Anal. Calcd for C29H28Br3N3O4 (722.0): C, 48.22; H, 3.91; N, 5.82.
Found: C, 48.64; H, 4.04; N, 5.65.
3
3
3
(m, 1 H, J1,2b = 5.7, J2a,2b = 13.8, J2b,3 = 10.7 Hz, H-2b), 2.05,
2.04, 2.03 (3 s, 9 H, 3 × CH3).
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-b-D-glucopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (10)
13C NMR (75 MHz, CDCl3): d = 170.7, 170.1, 169.9 (3 × C=O),
152.1, 143.7 (C-3 triazole, C-5 triazole), 81.0 (C-1), 71.2 (C-5),
69.9 (C-3), 68.5 (C-4), 61.7 (C-6), 32.3 (C-2), 21.0, 20.8, 20.8
(3 × CH3).
1H NMR (250 MHz, CDCl3): d = 7.43–7.12 (m, 15 H, Ph), 5.56 (d,
3
2
1 H, J1,2 = 9.8 Hz, H-1), 5.01, 4.89 (2 d, 2 H, JHa,Hb = 10.6 Hz,
OCH2), 4.83, 4.59 (2 d, 2 H, 2JHa,Hb = 10.7 Hz, OCH2), 4.62 (t, 1 H,
3J2,3 = 9.9 Hz, H-2), 4.56, 4.49 (2 d, 2 H, 2JHa,Hb = 12.1 Hz, OCH2),
3.94–3.83 (m, 1 H, 3J3,4 = 8.0, 3J2,3 = 9.8 Hz, H-3), 3.77–3.69 (m, 4
H, H-4, H-5, H-6a, H-6b).
Anal. Calcd for C14H19N3O7 (341.32): C, 49.27; H, 5.61; N, 12.31.
Found: C, 49.39; H, 5.84; N, 12.06.
13C NMR (63 MHz, CDCl3): d = 148.3 (C-3 triazole), 137.7, 137.7,
137.6 (3 × CquatPh), 131.4 (C-5 triazole), 128.7, 128.6, 128.2, 128.1,
128.0 (15 C, Ph), 86.4 (C-1), 85.5, 78.6, 78.3 (C-3, C-4, C-5), 76.2,
75.4, 73.8 (3 s, 3 × OCH2), 68.2 (C-6), 50.2 (C-2).
Hydrodehalogenation of a Mixture of Diastereomers
A mixture of diastereomers 5, 6, and 7 (1.5 g, 2.61 mmol) obtained
by addition of tribromotriazole 1 to glucal 3 was hydrodebrominat-
ed by hydrogen in the presence of Pd/C as described for compound
12. Column chromatography gave 544 mg (61%) of a-anomer 12
and 107 mg (12%) of the crystalline b-anomer 18.
Anal. Calcd for C29H28Br3N3O4 (722.0): C, 48.22; H, 3.91; N, 5.82.
Found: C, 48.19; H, 3.89; N, 5.89.
1-(3,4,6-Tri-O-acetyl-2-deoxy-b-D-glucopyranosyl)-1H-1,2,4-
triazole (18)
1-(3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-a-D-mannopyranosyl)-
3,5-dibromo-1H-1,2,4-triazole (11)
1H NMR (250 MHz, CDCl3): d = 8.31, 7.98 (2 s, 2 H, H-3 triazole,
H-5 triazole), 5.65 (dd, 1 H, 3J1,2a = 2.3, 3J1,2b = 11.2 Hz, H-1), 5.23–
5.09 (m, 2 H, 3J2a,3 = 4.6, 3J2b,3 = 5.8, 3J4,5 = 9.8, J = 5.8, J = 5.0 Hz,
H-3, H-4), 4.30 (dd, 1 H, 3J5,6a = 4.9, 2J6a,6b = 12.5 Hz, H-6a), 4.14
A suspension of 3,5-dibromo-1,2,4-triazole1 (1.0 g, 4.4 mmol) and
t-BuOK (0.5 g, 4.4 mmol) in anhyd 1,4-dioxane (50 mL) was quick-
ly warmed to about 50 °C and then stirred at r.t. ICl (0.73 g, 4.5
mmol) was added after 1 h and glucal 3 (0.75 g, 2.75 mmol) was
added after a further 60 min. Stirring of the mixture was continued
at r.t. until the glucal could no longer be detected by TLC. Subse-
quently, the suspension was filtered through celite, the filtrate was
concentrated under reduced pressure, and the residue was purified
by column chromatography (heptane–EtOAc, 5:1) to give 1.08 g
(63%) of 11.
3
2
(dd, 1 H, J5,6b = 2.3, J6a,6b = 12.5 Hz, H-6b), 3.87 (ddd, 1 H,
3
3
3J4,5 = 9.8, J5,6a = 4.9, J5,6b = 2.3 Hz, H-5), 2.69 (ddd, 1 H,
3J1,2a = 2.3, J2a,2b = 12.7, J2a,3 = 4.6 Hz, H-2a), (m,
1 H,
3
3
3J1,2b = 11.2, 3J2a,2b = 12.7, 3J2b,3 = 5.8 Hz, H-2b), 2.07, 2.05 (3 s, 9
H, 3 × CH3).
13C NMR (63 MHz, CDCl3): d = 170.8, 170.3, 169.7 (3 × C=O),
152.1, 142.6 (C-3 triazole, C-5 triazole), 83.4 (C-1), 75.0 (C-5),
70.5 (C-3), 68.2 (C-4), 62.1 (C-6), 35.3 (C-2), 21.0, 20.9, 20.8
(3 × CH3).
1H NMR (250 MHz, CDCl3): d = 6.16 (d, 1 H, 3J1,2 = 6.1 Hz, H-1),
3
3
5.31 (dd, 1 H, J2,3 = 3.8, J3,4 = 5.5 Hz, H-3), 5.15 (dd, 1 H,
3J3,4 = 5.6, 3J4,5 = 6.9 Hz, H-4), 5.11 (dd, 1 H, 3J2,3 = 3.8, 3J1,2 = 6.1
Hz, H-2), 4.42 (dd, 1 H, 3J5,6a = 6.3, 2J6a,6b = 12.2 Hz, H-6a), 4.29–
3
3
Monohydrodehalogenations with Dimethylphosphite; Typical
Procedure
4.20 (m, 1 H, J4,5 = 6.7, J5,6b = 3.2 Hz, H-5), 3.95 (dd, 1 H,
3J5,6b = 3.2, J6a,6b = 12.2 Hz, H-6b), 2.20, 2.14, 2.08 (3 s, 9 H,
2
To a stirred solution of 5 (300 mg, 0.52 mmol) in P(OCH3)3 (5 mL),
O=PH(OCH3)2 (60 mg, 0.54 mmol) and Et3N (0.2 mL) were added
under an argon atmosphere. Stirring was continued for 3 h at r.t.
(TLC). The mixture was concentrated under reduced pressure and
the residue was co-distilled with EtOAc several times until the res-
3 × CH3).
13C NMR (63 MHz, CDCl3): d = 170.3, 169.6, 169.1 (3 × C=O),
140.4, 130.1 (C-3 triazole, C-5 triazole), 84.7 (C-1), 73.1 (C-5),
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

PAPER
1,2,4-Triazole Nucleoside Analogues
505
idue was free of the pungent smell. Column chromatography (hep-
phy (heptane–EtOAc, 3:1) gave 611 mg (95%) of the syrupy prod-
tane–EtOAc, 3:1) gave 246 mg (95%) of the crystalline compound
uct 16.
13.
1H NMR (250 MHz, CDCl3): d = 8.10 (s, 1 H, H-5 triazole), 7.45–
7.17 (m, 15 H, Ph), 5.92 (d, 1 H, 3J1,2 = 5.6 Hz, H-1), 5.00, 4.91 (2
d, 2 H, 2JHa,Hb = 10.5 Hz, CH2Ph), 4.87, 4.59 (2 d, 2 H, 2JHa,Hb = 10.7
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-a-D-mannopyranosyl)-
3-bromo-1H-1,2,4-triazole (13)
2
Hz, CH2Ph), 4.57, 4.47 (2 d, 2 H, JHa,Hb = 12.1 Hz, CH2Ph), 4.80
1H NMR (250 MHz, CDCl3): d = 8.20 (s, 1 H, H-5 triazole), 6.14 (d,
1 H, 3J1,2 = 6.9 Hz, H-1), 5.57 (dd, 1 H, 3J2,3 = 3.5, 3J3,4 = 5.4 Hz, H-
3
3
(dd, 1 H, J2,3 = 10.7, J3,4 = 8.8 Hz, H-3), 4.42–4.31 (m, 2 H,
3J1,2 = 5.6, 3J2,3 = 10.7, 3J4,5 = 10.1, 3J5,6a = 3.3, 3J5,6b = 1.9 Hz, H-2,
H-5), 3.87 (dd, 1 H, 3J3,4 = 8.8, 3J4,5 = 10.1 Hz, H-4), 3.75 (dd, 1 H,
3
3
3), 5.09 (dd, 1 H, J3,4 = 5.4, J4,5 = 5.2 Hz, H-4), 5.03 (dd, 1 H,
3J1,2 = 6.9, J2,3 = 3.5 Hz, H-2), 4.80 (dd, 1 H, J5,6a = 8.1,
3
3
2
3
3J5,6a = 3.3, J6a,6b = 11.0 Hz, H-6a), 3.58 (dd, 1 H, J5,6b = 1.9,
2J6a,6b = 12.5 Hz, H-6a), 4.24 (m, 1 H, J4,5 = 5.2, J5,6a = 8.1,
3J5,6b = 2.9 Hz, H-5), 3.95 (dd, 1 H, 3J5,6b = 2.9, 2J6a,6b = 12.5 Hz, H-
6b), 2.19, 2.15, 2.07 (3 s, 9 H, 3 × CH3).
3
3
2J6a,6b = 11.0 Hz, H-6b).
13C NMR (63 MHz, CDCl3): d = 147.0 (C-5 triazole), 141.0 (C-3
triazole), 138.0, 137.7, 137.6 (3 s, 3 × CquatPh), 128.7, 128.6, 128.3,
128.2, 128.1, 128.0 (15 C, Ph), 84.7 (C-1), 81.1, 79.1, 76.1 (C-3, C-
4, C-5), 75.6, 75.1, 73.7 (3 s, 3 × CH2Ph), 68.0 (C-6), 48.7 (C-2).
13C NMR (300 MHz, CDCl3): d = 171.1, 169.5, 169.0 (3 × C=O),
146.1 (C-5 triazole), 141.5 (C-3 triazole), 82.8 (C-1), 75.1 (C-5),
69.7 (C-3), 67.0 (C-4), 60.3 (C-6), 45.4 (C-2), 20.9, 20.8, 20.8
(3 × CH3).
Anal. Calcd for C29H29Br2N3O4 (643.39): C, 54.14; H, 4.54; N, 6.53.
Found: C, 54.61; H, 4.63; N, 6.29.
Anal. Calcd for C14H17Br2N3O7 (499.11): C, 33.69; H, 3.43; N, 8.42.
Found: C, 33.97; H, 3.47; N, 8.26.
1-(3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-a-D-mannopyranosyl)-3-
bromo-1H-1,2,4-triazole (17)
Compound 11 (300 mg, 0.47 mmol) was hydrodebrominated by
O=PH(OCH3)2 as described for compound 5. Column chromatogra-
phy (heptane–EtOAc, 3:1) gave 221 mg (86%) of the crystalline
product 17.
1H NMR (250 MHz, CDCl3): d = 8.19 (s, 1 H, H-5 triazole), 6.18 (d,
1 H, 3J1,2 = 7.6 Hz, H-1), 5.30 (dd, 1 H, 3J2,3 = 3.4, 3J3,4 = 4.7 Hz, H-
3), 5.16 (dd, 1 H, 3J1,2 = 7.6, 3J2,3 = 3.4 Hz, H-2), 5.00 (t, 1 H, 3J3,4/
4,5 = 4.7 Hz, H-4), 4.83 (dd, 1 H, 3J5,6a = 8.4, 2J6a,6b = 12.6 Hz, H-6a),
4.33–4.24 (m, 1 H, 3J4,5 = 4.7, 3J5,6a = 8.4, 3J5,6b = 3.0 Hz, H-5), 3.94
(dd, 1 H, 3J5,6b = 3.0, 2J6a,6b = 12.6 Hz, H-6b), 2.21, 2.16, 2.01 (3 s,
9 H, 3 × CH3).
13C NMR (75 MHz, CDCl3): d = 171.2, 169.5, 168.9 (3 × C=O),
146.1 (C-5 triazole), 141.5 (C-3 triazole), 83.6 (C-1), 75.3 (C-5),
70.7 (C-3), 67.0 (C-4), 60.2 (C-6), 23.6 (C-2), 21.0, 21.0, 20.9 (3 s,
3 × CH3).
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-3-
bromo-1H-1,2,4-triazole (14)
Compound 6 (130 mg, 0.22 mmol) was hydrodebrominated by
O=PH(OCH3)2 as described for compound 13. Column chromatog-
raphy (heptane–EtOAc, 3:1→1:1) gave 105 mg (94%) of 14.
1H NMR (250 MHz, CDCl3): d = 8.16 (s, 1 H, H-5 triazole), 6.20
3
3
3
(dd, 1 H, J2,3 = 10.9, J3,4 = 9.2 Hz, H-3), 5.98 (d, 1 H, J1,2 = 5.7
Hz, H-1), 5.19 (dd, 1 H, 3J3,4 = 9.2, 3J4,5 = 10.4 Hz, H-4), 4.57 (ddd,
3
3
3
1 H, J4,5 = 10.4, J5,6a = 4.0, J5,6b = 2.1 Hz, H-5), 4.40 (dd, 1 H,
3J1,2 = 5.7, J2,3 = 10.9 Hz, H-2), 4.27 (dd, 1 H, J5,6a = 4.0,
2J6a,6b = 12.7, H-6a), 4.03 (dd, 1 H, 3J5,6b = 2.1, 2J6a,6b = 12.7 Hz, H-
6b), 2.09, 2.08, 2.07 (3 s, 9 H, 3 × CH3).
3
3
13C NMR (63 MHz, CDCl3): d = 170.6, 169.8, 169.6 (3 × C=O),
147.1 (C-5 triazole), 141.7 (C-3 triazole), 83.7 (C-1), 72.2 (C-5),
71.6 (C-3), 68.8 (C-4), 61.4 (C-6), 45.2 (C-2), 20.8, 20.8, 20.8 (3 s,
3 × CH3).
Anal. Calcd for C14H17BrIN3O7 (546.11): C, 30.79; H, 3.14; N, 7.69.
Found: C, 30.69; H, 3.10; N, 7.53.
Anal. Calcd for C14H17Br2N3O7 (499.11): C, 33.69; H, 3.43; N, 8.42.
Found: C, 34.04; H, 3.47; N, 8.27.
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-
3-bromo-5-methoxy-1H-1,2,4-triazole (19)
1-(3,4,6-Tri-O-acetyl-2-bromo-2-deoxy-b-D-glucopyranosyl)-3-
bromo-1H-1,2,4-triazole (15)
Compound 7 (110 mg, 0.19 mmol) was hydrodebrominated by
O=PH(OCH3)2 as described for compound 13. Column chromatog-
raphy (heptane–EtOAc, 3:1) gave 90 mg (94%) of 15.
A solution of 9 (500 mg, 0.69 mmol) in methanolic NaOMe (1%;
30 mL) was stirred for 10–12 h at r.t. under an argon atmosphere.
After neutralization by an acidic ion exchange resin, the solution
was concentrated under reduced pressure, and the residue was puri-
fied by column chromatography (heptane–EtOAc, 5:1) to give 427
mg (92%) of 19.
1H NMR (250 MHz, CDCl3): d = 8.20 (s, 1 H, H-5 triazole), 5.55 (d,
1 H, 3J1,2 = 9.9 Hz, H-1), 5.45 (dd, 1 H, 3J2,3 = 10.6, 3J3,4 = 9.3 Hz,
H-3), 5.14 (dd, 1 H, 3J3,4 = 9.3, 3J4,5 = 10.1 Hz, H-4), 4.59 (dd, 1 H,
1H NMR (250 MHz, CDCl3): d = 7.46–7.16 (m, 15 H, Ph), 5.91 (d,
3
3
3J1,2 = 9.9, J2,3 = 10.6 Hz, H-2), 4.28 (dd, 1 H, J5,6a = 5.2,
2J6a,6b = 12.6 Hz, H-6a), 4.14 (dd, 1 H, 3J5,6b = 2.2, 2J6a,6b = 12.6 Hz,
H-6b), 3.98 (ddd, 1 H, 3J4,5 = 10.1, 3J5,6a = 5.2, 3J5,6b = 2.2 Hz, H-5),
2.11, 2.07, 2.05 (3 s, 9 H, 3 × CH3).
3
2
1 H, J1,2 = 5.8 Hz, H-1), 5.02, 4.91 (2 d, 2 H, JHa,Hb = 10.6 Hz,
2
CH2Ph), 4.85 (t, 2 H, JHa,Hb = 10.7 Hz, CH2Ph), 4.80 (dd, 1 H,
3J2,3 = 10.7, 3J3,4 = 8.8 Hz, H-3), 4.60, 4.48 (2 d, 2 H, 2JHa,Hb = 12.1
Hz, CH2Ph), 4.33 (dd, 1 H, 3J1,2 = 5.8, 3J2,3 = 10.7 Hz, H-2), 4.39–
4.31 (m, 1 H, 3J5,6b = 2.0 Hz, H-5), 4.15 (s, 3 H, OCH3), 3.84 (dd, 1
13C NMR (75 MHz, CDCl3): d = 170.6, 169.7, 169.4 (3 × C=O),
145.8 (C-5 triazole), 141.9 (C-3 triazole), 87.1 (C-1), 75.3 (C-5),
74.3 (C-3), 68.6 (C-4), 61.7 (C-6), 47.1 (C-2), 20.8, 20.6, 20.6
(3 × CH3).
3
3
3
H, J3,4 = 8.8, J4,5 = 10.1 Hz, H-4), 3.76 (dd, 1 H, J5,6a = 3.3,
2J6a,6b = 11.0 Hz, H-6a), 3.60 (dd, 1 H, 3J5,6b = 2.0, 2J6a,6b = 11.0 Hz,
H-6b).
Anal. Calcd for C14H17Br2N3O7 (499.11): C, 33.69; H, 3.43; N, 8.42.
Found: C, 34.04; H, 3.47; N, 8.27.
13C NMR (63 MHz, CDCl3): d = 160.5 (C-5 triazole), 136.8 (C-3
triazole), 138.1, 137.9, 137.7 (3 × CquatPh), 128.6, 128.5, 128.2,
128.1, 128.0, 127.9 (15 C, Ph), 81.1 (C-1), 80.5, 79.3, 74.4 (C-3, C-
4, C-5), 76.0, 75.5, 73.7 (3 × CH2Ph), 68.1 (C-6), 59.3 (s, OCH3),
49.1 (C-2).
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-
3-bromo-1H-1,2,4-triazole (16)
Compound 9 (725 mg, 1.0 mmol) was hydrodebrominated by
O=PH(OCH3)2 as described for compound 5. Column chromatogra-
Anal. Calcd for C30H31Br2N3O5 (673.4): C, 53.51; H, 4.64; N, 6.24.
Found: C, 53.31; H, 4.62; N, 6.13.
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

506
S. Libnow et al.
PAPER
3
3
3
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-b-D-glucopyranosyl)-3-
bromo-5-methoxy-1H-1,2,4-triazole (20)
Compound 10 (500 mg, 0.69 mmol) was methoxylated as described
for compound 19. The crude product was purified by column chro-
matography (heptane–EtOAc, 5:1) to give 408 mg (88%) of 20.
(m, 1 H, J4,5 = 7.0 Hz, J5,6a = 5.6 Hz, J5,6b = 3.1 Hz, H-5), 4.32
(‘t’, 1 H, 3J = 4.1 Hz, H-3), 3.95 (dd, 1 H, 3J3,4 = 5.1, 3J4,5 = 7.0 Hz,
H-4), 3.90 (dd, 1 H, 3J5,6a = 5.6, 2J6a,6b = 11.1 Hz, H-6a), 3.78 (dd, 1
H, 3J5,6b = 3.1, 2J6a,6b = 11.1 Hz, H-6b).
13C NMR (63 MHz, CDCl3): d = 143.6 (C-1), 142.5 (C-5 triazole),
141.7 (C-3 triazole), 137.8, 137.7, 137.7 (3 × CquatPh), 128.6, 128.2,
128.1, 127.9 (15 C, Ph), 86.4 (C-2), 79.1, 73.7, 73.7 (C-3, C-4, C-
5), 73.6, 73.5, 70.7 (3 × CH2Ph), 67.7 (C-6).
1H NMR (250 MHz, CDCl3): d = 7.44–7.11 (m, 15 H, Ph), 5.35 (d,
3
2
1 H, J1,2 = 10.0 Hz, H-1), 5.00, 4.88 (2 d, 2 H, JHa,Hb = 10.4 Hz,
2
CH2Ph), 4.82, 4.53 (2 d, 2 H, JHa,Hb = 10.8 Hz, CH2Ph), 4.56 (t, 1
3
2
H, J2,3 = 10.0 Hz, H-2), 4.56, 4.49 (2 d, 2 H, JHa,Hb = 12.2 Hz,
CH2Ph), 4.16 (s, 3 H, OCH3), 3.87–3.78 (m, 1 H, 3J2,3 = 10.0 Hz, H-
3), 3.74–3.67 (m, 4 H, H-4, H-5, H-6a, H-6b).
Anal. Calcd for C29H28BrN3O4 (562.45): C, 61.93; H, 5.02; N, 7.47.
Found: C, 61.75; H, 5.04; N, 7.06.
13C NMR (63 MHz, CDCl3): d = 159.9 (C-5 triazole), 148.2 (C-3
triazole), 137.7, 137.5, 137.4 (3 × CquatPh), 128.6, 128.5, 128.2,
128.1, 128.0, 127.9 (15 C, Ph), 85.7 (C-1), 84.1, 78.5, 78.1 (C-3, C-
4, C-5), 76.1, 75.4, 73.7 (3 × OCH2), 68.4 (C-6), 59.3 (OCH3), 50.2
(C-2).
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-mannopyranosyl)-
3-bromo-5-phenylthio-1H-1,2,4-triazole (23)
A solution of 8 (200 mg, 0.3 mmol), thiophenol (0.3 mL, 0.3 mmol),
and K2CO3 (0.08 g, 0.6 mmol) in anhyd DMF (15 mL) was stirred
for 6 h at r.t. After addition of H2O (50 mL), the aqueous phase was
extracted with EtOAc (3 × 20 mL), the combined organic layers
were washed with H2O (2 × 50 mL), dried (Na2SO4), and concen-
trated under reduced pressure. Column chromatography of the resi-
due (heptane–EtOAc, 5:1; Rf 0.2) gave 0.17 g (82%) of the syrupy
compound 23.
Anal. Calcd for C30H31Br2N3O5 (673.40): C, 53.51; H, 4.64; N, 6.24.
Found: C, 53.30; H, 4.63; N, 6.17.
Methoxylation of a Mixture of Diastereomers
A mixture of 8, 9, and 10 (1.3 g, 1.8 mmol) was methoxylated by
methanolic NaOMe (1%; 50 mL) as described for compound 19.
The diastereomer 20 (125 mg, 10%) was separated by column chro-
matography (heptane–EtOAc, 5:1); the mixed fraction 19/26 (870
mg, 72%) was treated with hydrogen in the presence of Pd/C as de-
scribed below. The two components were characterized by NMR.
1H NMR (300 MHz, CDCl3): d = 7.56–7.12 (m, 20 H, Ph), 6.29 (d,
1 H, 3J1,2 = 4.5 Hz, H-1), 4.92 (dd, 1 H, 3J1,2 = 4.4, 3J2,3 = 3.5 Hz, H-
2), 4.76, 4.68 (2 d, 2 H, 2JHa,Hb = 11.6 Hz, OCH2), 4.69, 4.46 (2 d, 2
H, 2JHa,Hb = 11.1 Hz, OCH2), 4.62, 4.46 (2 d, 2 H, 2JHa,Hb = 12.1 Hz,
OCH2), 4.35 (dd, 1 H, 3J2,3 = 3.75, 3J3,4 = 6.3 Hz, H-3), 3.99 (dd, 1
3
3
3
H, J3,4 = 6.4, J4,5 = 8.0 Hz, H-4), 3.94–3.85 (m, 1 H, J5,6b = 2.9,
3J5,6a = 4.4 Hz, H-5), 3.73 (dd, 1 H, 3J5,6a = 4.5, 2J6a,6b = 11.1 Hz, H-
6a), 3.56 (dd, 1 H, 3J5,6b = 2.9, 2J6a,6b = 11.1 Hz, H-6b).
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-glucopyranosyl)-
3-bromo-5-[1-(methylethylidene)hydrazino]-1H-1,2,4-triazole
(21)
To a stirred solution of 9 (800 mg, 1.12 mmol) in 1,4-dioxane (50
mL), H2NNH2·H2O (3 mmol) was added at r.t. and stirring was con-
tinued for 6 h (TLC). Acetone (1–2 mL) was added and stirring was
continued for 15 min, the mixture was concentrated under reduced
pressure, and the residue was purified by column chromatography
(heptane–EtOAc, 3:1; Rf 0.13) to give 0.6 g (76%) of 21.
13C NMR (63 MHz, CDCl3): d = 154.0 (C-5 triazole), 140.2 (C-3
triazole), 138.0, 137.7, 137.3 (3 s, 3 × CquatPh), 132.9, 129.7, 129.3,
128.6, 128.5, 128.2, 128.0, 127.8 (20 C, Ph), 84.3 (C-1), 77.2, 75.2,
74.2 (C-3, C-4, C-5), 74.1, 73.5, 72.7 (3 s, 3 × OCH2), 68.2 (C-6),
49.0 (C-2).
Anal. Calcd for C35H33Br2N3O4S (751.53): C, 55.94; H, 4.43; N,
5.59. Found: C, 55.73; H, 4.49; N, 5.37.
1H NMR (500 MHz, CDCl3): d = 7.69 (s, 1 H, NH), 7.52–7.19 (m,
3
15 H, Ph), 6.87 (d, 1 H, J1,2 = 5.8 Hz, H-1), 5.07, 4.42 (2 d, 2 H,
1-(3,4,6-Tri-O-benzyl-2-bromo-2-deoxy-a-D-mannopyranosyl)-
3-bromo-5-hydrazino-1H-1,2,4-triazole (24)
2JHa,Hb = 10.8 Hz, CH2Ph), 4.91 (dd, 1 H, 3J3,4 = 8.8, 3J2,3 = 10.4 Hz,
H-3), 4.89, 4.65 (2 d, 2 H, 2JHa,Hb = 11.1 Hz, CH2Ph), 4.58, 4.50 (2
To a stirred solution of 8 (300 mg, 4.6 mmol) in 1,4-dioxane (15
mL), H2NNH2·H2O (0.6 g, 12 mmol) was added at r.t., and stirring
was continued for 4–5 h (TLC). Then the mixture was concentrated
under reduced pressure and the residue was purified by column
chromatography (heptane–EtOAc, 2:1; Rf 0.13) to give 0.25 g
(91%) of 24.
2
3
d, 2 H, JHa,Hb = 12.1 Hz, CH2Ph), 4.40 (ddd, 1 H, J5,6b = 2.0,
3J5,6a = 3.6, J4,5 = 10.1 Hz, H-5), 4.36 (dd, 1 H, J1,2 = 5.9,
3
3
3J2,3 = 10.4 Hz, H-2), 3.82 (dd, 1 H, J3,4 = 8.8, 3J4,5 = 10.0 Hz, H-
3
4), 3.77 (dd, 1 H, 3J5,6a = 3.6, 2J6a,6b = 11.1 Hz, H-6a), 3.66 (dd, 1 H,
3J5,6b = 2.0, J6a,6b = 11.1 Hz, H-6b), 2.08, 1.89 [2 s, 6 H,
2
N=C(CH3)2].
1H NMR (250 MHz, CDCl3): d = 7.46–7.09 (m, 15 H, Ph), 5.77 (d,
13C NMR (63 MHz, CDCl3): d = 155.0 (C-5-triazole), 151.7 [s,
N=C(CH3) 2], 138.3, 138.0, 137.8, 137.3 (C-3-triazole, 3 × CquatPh),
128.6, 128.3, 128.1, 128.0, 127.9 (15 C, Ph), 82.6 (C-1), 81.6 (C-3),
79.5 (C-4), 76.0, 75.4, 73.7 (3 s, 3 × CH2Ph), 74.3 (C-5), 68.2 (C-
6), 49.6 (C-2), 25.3, 16.0 [2 s, N=C(CH3)2].
1 H, 3J1,2 = 1.9 Hz, H-1), 5.23 (dd, 1 H, 3J1,2 = 1.9, 3J2,3 = 3.6 Hz, H-
2
2), 4.84 (d, 1 H, JHa,Hb = 10.9 Hz, OCH2), 4.78, 4.61 (2 d, 2 H,
2JHa,Hb = 11.6 Hz, OCH2), 4.56–4.41 (m, 3 H, OCH2), 4.02 (dd, 1 H,
3J2,3 = 3.7, 3J3,4 = 8.5 Hz, H-3), 3.83–3.53 (m, 4 H, 3J3,4 = 8.5 Hz, H-
4, H-5, H-6a, H-6b).
Anal. Calcd for C32H35Br2N5O4 (713.47): C, 53.87; H, 4.94; N, 9.82.
Found: C, 53.84; H, 4.90; N, 9.70.
13C NMR (63 MHz, CDCl3): d = 159.4 (C-5 triazole), 137.5 (C-3
triazole), 137.7, 137.6, 137.1 (3 × CquatPh), 128.8, 128.7, 128.6,
128.3, 128.2, 128.1 (15 C, Ph), 86.0 (C-1), 76.5 (C-3), 74.3 (C-5),
74.0 (C-4), 75.2, 73.7, 71.6 (3 × OCH2), 68.8 (C-6), 48.6 (C-2).
1,5-Anhydro-3,4,6-tri-O-benzyl-1-C-(3-bromo-1H-1,2,4-tri-
azol-1-yl)-2-deoxy-D-arabino-hex-1-enitol (22)
A solution of 16 (200 mg, 0.31 mmol) in methanolic NaOMe (1%;
15 mL) was refluxed for 6 h. After neutralization by an acidic ion
exchange resin, the solution was concentrated under reduced pres-
sure, and the residue was purified by column chromatography (hep-
tane–EtOAc, 3:1) to give 162 mg (93%) of 22.
Anal. Calcd for C29H31Br2N5O4 (573.40): C, 51.73; H, 4.64; N,
10.40. Found: C, 52.21; H, 4.82; N, 10.15.
1-(3,4,6-Tri-O-benzyl-2-deoxy-a-D-erythro-hex-2-enopyrano-
syl)-5-benzylamino-3-bromo-1H-1,2,4-triazole (25)
A solution of 8 (100 mg, 0.14 mmol) in benzylamine (8 mL) was
stirred for 8 h at 100 °C, then stirring was continued for 4–5 h at r.t.
(TLC). The solution was concentrated under reduced pressure and
1H NMR (250 MHz, CDCl3): d = 8.30 (s, 1 H, H-5 triazole), 7.40–
7.23 (m, 15 H, Ph), 5.66 (d, 1 H, 3J2,3 = 3.6 Hz, H-2), 4.80, 4.65 (2
d, 2 H, 2JHa,Hb = 11.5 Hz, CH2Ph), 4.69, 4.53 (2 d, 2 H, 2JHa,Hb = 11.6
2
Hz, CH2Ph), 4.55 (‘t’, 2 H, JHa,Hb = 12.6 Hz, CH2Ph), 4.50–4.44
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

PAPER
1,2,4-Triazole Nucleoside Analogues
507
the residue was purified by column chromatography (heptane–
EtOAc, 6:1; Rf 0.17) to give 71 mg (76%) of 25.
1-(2-Deoxy-a-D-glucopyranosyl)-5-methoxy-1H-1,2,4-triazole
(29)
A mixture of diastereomers 19 and 26 (870 mg, 1.29 mmol) in
EtOAc–MeOH (1:1, 30 mL) was treated with Pd/C in a hydrogen
atmosphere as described for compound 28. Column chromatogra-
phy (toluene–EtOAc–EtOH, 3:1:1; Rf 0.19) gave 198 mg (59%) of
29 along with two incompletely deprotected by-products [Rf 0.25
(20 mg) and Rf 0.32 (70 mg)].
1H NMR (500 MHz, CDCl3): d = 7.60–7.13 (m, 20 H, Ph), 6.10 (d,
1 H, 3J1,2 = 3.1 Hz, H-1), 5.97 (t, 1 H, 3JNH,CH2 = 5.8 Hz, NH), 5.02
(d, 1 H, 3J1,2 = 3.2 Hz, H-2), 4.92, 4.83 (2 d, 2 H, 2JHa,Hb = 11.4 Hz,
OCH2), 4.67, 4.49 (2 d, 2 H, 2JHa,Hb = 11.5 Hz, OCH2), 4.46 (d, 1 H,
3
2JHa,Hb = 12.1 Hz, OCH2), 4.43–4.38 (m, 3 H, JNH,CH2 = 5.8 Hz,
OCH2, NCH2), 4.25–4.19 (m, 1 H, 3J5,6b = 4.4, 3J4,5 = 5.7 Hz, H-5),
3
3
4.07 (d, 1 H, J4,5 = 5.7 Hz, H-4), 3.60 (dd, 1 H, J5,6a = 5.8,
2J6a,6b = 10.3 Hz, H-6a), 3.54 (dd, 1 H, 3J5,6b = 4.5, 2J6a,6b = 10.3 Hz,
H-6b).
1H NMR (250 MHz, CD3OD): d = 7.56 (s, 1 H, triazole-H), 5.91 (d,
3
3
3
1 H, J1,2 = 6.1 Hz, H-1), 4.56 (ddd, 1 H, J2a,3 = 5.5, J3,4 = 8.5,
3J2b,3 = 11.1 Hz, H-3), 4.09 (s, 3 H, OCH3), 3.74 (dd, 1 H,
3J5,6a = 2.5, J6a,6b = 11.9 Hz, H-6a), 3.64 (dd, 1 H, J5,6b = 4.8,
2
3
13C NMR (63 MHz, CDCl3): d = 156.7, 156.5 (C-5 triazole, C-3),
138.9, 137.8, 137.2, 136.1 (4 s, 4 × CquatPh), 131.9 (C-3 triazole),
131.1, 129.0, 128.8, 128.7, 128.6, 128.3, 128.2, 128.0, 127.9, 127.7
(20 C, Ph), 93.8 (C-2), 81.7 (C-1), 74.0 (C-5), 73.8, 73.7, 70.2 (3 s,
3 × OCH2), 71.4 (C-4), 68.6 (C-6), 47.6 (NHCH2).
2J6a,6b = 11.9 Hz, H-6b), 3.46 (ddd, 1 H, J5,6a = 2.5, J5,6b = 4.6,
3
3
3J4,5 = 9.6 Hz, H-5), 3.41–3.33 (m, 1 H, H-4), 2.40 (ddd, 1 H,
3J1,2a = 1.0, J2a,3 = 5.6, J2a,2b = 13.7 Hz, H-2a), 2.02 (ddd, 1 H,
3
2
3J1,2b = 6.2, 3J2b,3 = 11.1, 2J2a,2b = 13.7 Hz, H-2b).
13C NMR (63 MHz, CD3OD): d = 161.1 (C-5 triazole), 148.1 (C-3
triazole), 80.0 (C-1), 76.6, 72.9, 70.0 (C-3, C-4, C-5), 62.6 (C-6),
59.1 (OCH3), 36.4 (C-2).
Anal. Calcd for C36H35BrN4O4 (667.60): C, 64.77; H, 5.28; N, 8.39.
Found: C, 64.48; H, 5.55; N, 7.96.
1-(2-Bromo-2-deoxy-a-D-mannopyranosyl)-3,5-dibromo-1H-
1,2,4-triazole (27)
1-(2-Bromo-2-deoxy-a-D-mannopyranosyl)-3-bromo-1H-1,2,4-
triazole (30)
Compound 13 (200 mg, 0.4 mmol) was deacetylated by methanolic
HCl as described for 27.
A solution of 5 (240 mg, 0.415 mmol) in methanolic HCl [1%; pre-
pared from AcCl (0.4 mL) and anhyd MeOH (16 mL)] was stirred
for 10 h at r.t. under an argon atmosphere. When the reaction was
complete (TLC) the solution was neutralized by the addition of
NaHCO3, filtered through a thin layer of basic alumina, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (CHCl3–MeOH, 15:1) to give 168 mg (89%) of the
crystalline compound 27; Rf 0.06 (heptane–EtOAc, 1:2).
1H NMR (250 MHz, CD3OD): d = 8.62 (s, 1 H, H-5 triazole), 6.26
(d, 1 H, 3J1,2 = 4.3 Hz, H-1), 4.97 (dd, 1 H, 3J1,2 = 4.3, 3J2,3 = 3.6 Hz,
H-2), 4.20 (dd, 1 H, 3J2,3 = 3.6, 3J3,4 = 6.9 Hz, H-3), 3.81 (dd, 1 H,
3
3J3,4 = 6.9, J4,5 = 7.7 Hz, H-4), 3.80–3.64 (m, 3 H, H-5, H-6a, H-
6b).
1H NMR (250 MHz, CD3OD): d = 6.22 (d, 1 H, 3J1,2 = 5.2 Hz, H-1),
4.95 (dd, 1 H, J1,2 = 5.2, J2,3 = 3.4 Hz, H-2), 4.36 (dd, 1 H,
3J2,3 = 3.4, 3J3,4 = 5.9 Hz, H-3), 3.84 (dd, 1 H, 3J3,4 = 5.9, 3J4,5 = 7.2
Hz, H-4), 3.80–3.70 (m, 3 H, H-6a, H-6b, H-5).
13C NMR (63 MHz, CD3OD): d = 141.4, 133.0 (C-3 triazole, C-5
triazole), 86.3 (C-1), 80.0 (C-5), 72.2 (C-3), 70.0 (C-4), 62.1 (C-6),
52.5 (C-2).
13C NMR (63 MHz, CD3OD): d = 147.9 (C-5 triazole), 140.7 (C-3
triazole), 86.8 (C-1), 80.2, 71.6, 69.6 (C-3, C-4, C-5), 62.2 (C-6),
53.0 (C-2).
3
3
Anal. Calcd for C8H11Br2N3O4·CH3OH (405.04): C, 26.69; H, 3.73;
N, 10.37. Found: C, 26.64; H, 3.64; N, 9.69.
Acknowledgment
Anal. Calcd for C8H10Br3N3O4 (451.89): C, 21.26; H, 2.23; N, 9.30.
Found: C, 21.44; H, 2.47; N, 8.99.
We are grateful to Doz. Dr. Arno Balszuweit for helpful discussions
on the phosphite reagent.
1-(2-Deoxy-a-D-glucopyranosyl)-1H-1,2,4-triazole (28)
To a stirred solution of the diastereomers 8 and 9 (400 mg, 0.55
mmol) in EtOAc–MeOH (1:1, 20 mL), Pd/C (100 mg, 0.09 mmol)
was added under an argon atmosphere. Subsequently, argon was re-
placed by hydrogen (1 atm) and stirring was continued at r.t. for
about 15 h (TLC). The solution was filtered, the residue was washed
with EtOAc–MeOH (1:1) and the combined solutions were concen-
trated under reduced pressure. The crude product was purified by
column chromatography (toluene–EtOAc–EtOH, 15:1:1) to give 71
mg (60%) of 28 as a colorless syrup.
References
(1) Kröger, C.-F.; Miethchen, R. Chem. Ber. 1967, 100, 2250.
(2) Becker, H. G. O.; Eisenschmidt, V.; Bubig, M.; Jähnisch, K.;
Klein, N.; Kowalski, W.; Misselwitz, R.; Müller, R.;
Reimann, P.; Roth, C.; Sauter, W.-D.; Schößler, W.;
Thorein, B. Z. Chem. 1969, 9, 325.
(3) Unlike 3,5-dibromo-1,2,4-triazole itself, which is
deprotonated and so deactivated by sodium hydroxide, the
corresponding N-alkyl derivative reacts with this reagent via
3-bromo-5-hydroxy-1-methyl-1,2,4-triazole to the
tautomeric 3-bromo-1-methyl-1,2,4-triazolone-(5). The
reaction stops at this stage, because the 3-bromo-1-methyl-
1,2,4-triazolone-(5) is now likewise deactivated by
deprotonation: Miethchen, R.; Kröger, C.-F. unpublished
results.
1H NMR (250 MHz, CD3OD): d = 8.64, 8.01 (2 s, 2 H, H-3 triazole,
H-5 triazole), 6.13 (br d, 1 H, 3J1,2a = 5.4 Hz, H-1), 4.20 (ddd, 1 H,
3
3
3J2a,3 = 5.3, J2b,3 = 11.3, J3,4 = 8.1 Hz, H-3), 3.80 (dd, 1 H,
2
3
3J5,6a = 2.2, J6a,6b = 12.2 Hz, H-6a), 3.68 (dd, 1 H, J5,6b = 5.2,
2J6a,6b = 12.3 Hz, H-6b), 3.44–3.33 (m, 2 H, 3J3,4 = 8.1, 3J4,5 = 10.1,
3J5,6a = 2.3 Hz, H-4, H-5), 2.72 (ddd, 1 H, 3J1,2a = 1.2, 2J2a,2b = 14.0,
3J2a,3 = 5.2 Hz, H-2a), 2.07 (ddd, 1 H, J1,2b = 5.4, J2a,2b = 14.0,
3
2
3J2b,3 = 11.3 Hz, H-2b).
(4) The data reported for nucleophilic substitutions on 3,5-
dibromo-1,2,4-triazole with alkali hydroxides and alkoxides
in following patent are not correct: Becker, H. G. O.;
Eisenschmidt, V.; Wehner, K. Ger. Pat. DD 19670415,
1967; Chem. Abstr. 1969, 70, 28922.
13C NMR (63 MHz, CD3OD): d = 151.7, 145.3 (C-3 triazole, C-5
triazole), 83.9 (C-1), 77.2 (C-5), 72.5 (C-3), 69.7 (C-4), 62.5 (C-6),
35.9 (C-2).
MS (CI, i-C4H10): m/z (%) = 215.7 [M+].
(5) Zumbrunn, A. Synthesis 1998, 1357.
(6) Wu, Q.; Qu, F.; Wan, J.; Zhu, X.; Xia, Y.; Peng, L. Helv.
Chim. Acta 2004, 87, 811.
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York

508
S. Libnow et al.
PAPER
(7) Kovalew, E. G.; Postowskii, I. Ja. Khim. Geterotsikl. Soedin.
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(23) The use of solvents like CHCl3 and NMP gave only low
yields of the desired compounds. THF proved to be
unsuitable, because it was attacked by 1,3,5-tribromo-1,2,4-
triazole (1) resulting in ring-opening and insertion of the 1-
oxy-tetramethylene chain between the glycosidic position
and N-1 of the triazole ring. The diastereomeric O-glyco-
sides (54%) were formed along with about 26% of the
desired products: Christiansen, A.; Miethchen, R.
unpublished results.
(24) Tribromo derivative 5, EtMgCl/[Fe(acac)3] in THF/NMP
gave 1-(3,4,6-tri-O-acetyl-2-deoxy-a-D-mannopyranosyl)-
3-bromo-1H-1,2,4-triazole along with dibromo compound
13.
(12) Winterfeld, G. A.; Das, J.; Schmidt, R. R. Eur. J. Org. Chem.
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(27) Crystallographic data for the structures in this paper have
been deposited at the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 265777
(11), 265778 (17), 276274 (5), 276275 (6), 276276 (7),
276277 (8), 276278 (13), 276279 (14), and 276280 (30).
Copies of these data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44(1223)336033 or e-mail:
(18) Hanna, N. B.; Dimitrijevich, S. D.; Larson, S. B.; Robins, R.
K.; Revankar, G. R. J. Heterocycl. Chem. 1988, 25, 1857.
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references therein.
(21) Collins, P.; Ferrier, R. Monosaccharides, their Chemistry
and their Roles in Natural Products; J. Wiley & Sons:
Chichester, 1995.
deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/conts/
retrieving.html.
Synthesis 2006, No. 3, 496–508 © Thieme Stuttgart · New York