Synthesis of novel NH-1,2,3-triazolo-nucleosides by the Banert cascade reaction

Article abstract of DOI:10.1016/j.tet.2013.01.042

Nucleoside analogs with the 4,5-dimethyl-NH-1,2,3-triazolo-linker between thymine and a carbohydrate, or a hydroxyalkoxyl, or phosphonomethoxyl residue, were obtained by the Bannert cascade reaction from 1-(4-azidobut-2-yn-1-yl) thymine and the carbohydrate or acyclic alcohol. The reaction conditions were developed on the basis of a thermal analysis of the starting azide and by the optimization of the reaction components ratio. The best results were obtained when the reaction cascade employed the azide/nucleophile molar ratio of 1/14, at 55 °C, with no solvent addition. The reaction showed good discrimination between the pentofuranose hydroxyls, yielding triazoles linked at the carbohydrate 5′-oxygen atom.

Full text of DOI:10.1016/j.tet.2013.01.042

Tetrahedron 69 (2013) 2619e2627
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel NH-1,2,3-triazolo-nucleosides by the Banert
cascade reaction
*
ꢀ
Mariola Koszytkowska-Stawinska , Wojciech Sas
Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Nucleoside analogs with the 4,5-dimethyl-NH-1,2,3-triazolo-linker between thymine and a carbohydrate,
or a hydroxyalkoxyl, or phosphonomethoxyl residue, were obtained by the Bannert cascade reaction
from 1-(4-azidobut-2-yn-1-yl)thymine and the carbohydrate or acyclic alcohol. The reaction conditions
were developed on the basis of a thermal analysis of the starting azide and by the optimization of the
reaction components ratio. The best results were obtained when the reaction cascade employed the
azide/nucleophile molar ratio of 1/14, at 55 ꢀC, with no solvent addition. The reaction showed good
discrimination between the pentofuranose hydroxyls, yielding triazoles linked at the carbohydrate 50-
oxygen atom.
Received 8 October 2012
Accepted 15 January 2013
Available online 31 January 2013
Keywords:
Nucleoside analogs
Fleximers
NH-1,2,3-Triazoles
Propargyl azides
Banert cascade reaction
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
series, nucleosides 4, were formally derived from insertion of the 4-
methyl-1H-1,2,3-triazole linker between a sugar and a nucleobase.8
The identification of tenofovir and cidofovir (Fig. 1a) as antiviral
agents active against a broad spectrum of DNA and RNA viruses1
has stimulated research on nucleoside analogs featuring a high
degree of structural flexibility.2 Modifications of the sugar-
enucleobase linkage resulted in the development of a unique class
of nucleoside analogs termed ‘shape-modified nucleosides’ or
‘fleximers’ (Fig. 1b and c). The first group of fleximers (Fig. 1b)
contains an aglycone derived from 5-(pyrimidin-6-yl)-1H-imidaz-
ole (compounds 13), 4-(pyrimidin-5-yl)-1H-imidazole (compounds
24) or 4-(pyrimidin-5-yl)-1H-1,2,3-triazole (compounds 35). For-
mally, structures of the compounds 1 and 2 were derived from
purine nucleosides (adenosine, guanosine, inosine or isoguanosine)
by splitting of their purine systems into imidazole and pyrimidine
components and then reconnecting of the resulting heterocycles
with the C(5)eC(60) bond (compounds 1) or with the C(4)eC(50)
bond (compounds 2). Derivatives 3 are analogs of nucleosides 2,
resulting from replacement of the 1H-imidazole ring with the 1H-
1,2,3-triazole one. Among analogs 1e3, the guanosine-derived an-
Their analogs 5 originated from translocation of the nucleobase-
bearing 1,2,3-triazole residue from the C-10 to the exo-cyclic car-
bon of the sugar moiety.9 In contrast to analogs 5, compound 6
possess the 4-methyl-2H-1,2,3-triazole linker between the nucle-
obase and the sugar residue.9a This compound was recently syn-
thesized in our laboratory. To the best of our knowledge, it is the
only example of a 1,2,3-triazole fleximer with a modified sub-
stitution pattern of the 1,2,3-triazole core. Among compounds 4e6,
some of fleximers 4 and 5 were reported to show antitumor8a or
anti-HBV9b,c activity.
Herein, we describe the synthesis of 4,5-disubstituted-NH-1,2,3-
triazoles 7, 8 and their O- or N-substituted-derivatives, NH-1,2,3-
triazolo-nucleosides 9 and 10 (Fig. 2). Derivatives 10 represent
a novel series of fleximers bearing the 4,5-dimethyl-NH-1,2,3-
triazole linker between the sugar and the nucleobase.
It is worth noting that although the pharmacological signifi-
cance of the 4,5-disubstituted-NH-1,2,3-triazole system is well
documented,10 nucleoside analogs bearing this functionality have
not been extensively explored.11 Biochemical properties of the
compounds were not reported.
alog 1a was identified as inhibitor of S-adenosyl-L-homocysteine
hydrolase.6 The activity of nucleoside 1a was suggested to be
a consequence of its high conformational adaptability to the target
enzyme active site, resulting from a rotation of the pyrimidine ring
about the C(5)eC(60) bond.6,7 The second series of fleximers com-
prises compounds 4e6 (Fig. 1c). The parent compounds of the
2. Results and discussion
2.1. Synthesis
A
literature survey of the synthetic approaches to 4,5-
* Corresponding author. Tel.: þ48 22 234 5442; fax: þ48 22 628 2741; e-mail
disubstituted-NH-1,2,3-triazoles12 revealed that one of the most
ꢀ
address: mkoszyt@ch.pw.edu.pl (M. Koszytkowska-Stawinska).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.042

ꢀ
2620
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
(a)
(b)
(c)
Fig. 1. (a) Structures of tenofovir and cidofovir; (b) nucleoside fleximers bearing an aglycone derived from 5-(pyrimidin-6-yl)-1H-imidazole, 4-(pyrimidin-5-yl)-1H-imidazole or
4-(pyrimidin-5-yl)-1H-1,2,3-triazole; (c) nucleoside fleximers bearing 4-methyl-1H- or 4-methyl-2H-1,2,3-triazole linker between a sugar and a nucleobase.
Fig. 2. Target 4,5-disubstituted-NH-1,2,3-triazoles 7, 8 and their O- or N-substituted-derivatives, NH-1,2,3-triazolo-nucleosides 9 and 10.
common methods used, i.e., the 1,3-dipolar cycloaddition of trime-
thylsilyl azide (or its equivalent, such as benzyl azide) to internal
alkynes, required harsh reaction conditions (e.g., 105 ꢀC/48 h for
trimethylsilyl azide,11a or 70 ꢀC/3 days for benzyl azide11b). Moreover,
the cycloaddition of benzyl azide yielded a mixture of two regioi-
someric N-benzyl-1,2,3-triazoles. Their de-benzylation needed an
additional reaction step. Owing to these inconveniences, we pre-
sumed that the Banert cascade reaction13 would be useful to syn-
thesize the target compounds 7e10. The number of publications on
the synthetic applications of the Banert cascade reaction is lim-
ited.10,13,14 The reaction involves a thermal rearrangement of
a propargyl azide into the corresponding triazafulvene, which is
trapped in situ by a nucleophilic reagent to give a 4,5-disubstituted-
NH-1,2,3-triazole. A survey of the reported examples revealed that,
the reaction has not been applied in the nucleoside or carbohydrate
chemistry. Moreover, in contrast to the azides used, the reported
nucleophilic reagents were limited to low-molecular weight, mostly
monofunctional alcohols, amines, thiols, or electron-rich aromatics
(including heteroaromatics). From a preparative point of view, two
variants of the Banert cascade reaction have been reported. One-step
variant15 involved the preparation of a propargyl azide from the
corresponding halide (or sulfonate) and sodium azide, followed by
its in situ-treatment with a nucleophilic reagent at an elevated
temperature.13a,15 In the two-step variant, the propargyl azide was
isolated prior to its subsequent treatment with the nucleophilic
reagent.10aeh
In order to revise an applicability of these two preparative
protocols to the synthesis of the target compounds 7e10, mesylate
13, and azide 14 were prepared and then their reactivity was ex-
amined (Scheme 1). Our experiment with mesylate 13 was based
on the report from Sharpless and Loren14 and involved treatment of
13 with 1 equiv of sodium azide in a 1,4-dioxaneewater mixture
at 75 ꢀC. The target hydroxymethyl-triazole 7 was obtained in
40% yield.
The reaction involving azide 14 and water was performed at
55 ꢀC. The reaction temperature was chosen on the basis of the DSC

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2621
Scheme 1. Reagents and conditions: (i) BSA, acetonitrile, 20 ꢀC, 5 days; (ii) NaN3, NH4Cl, DMF, 20 ꢀC, 1 h; (iii) 1,4-dioxane, 75 ꢀC, 4.5 h; (iv) 55 ꢀC, overnight.
and TGA analyses of azide 14 (Section 2.2). This reaction gave
product 7 in 76% yield. Under the same conditions, the reaction with
ammonium hydroxide gave aminomethyl-triazole 8 in 81% yield. On
the basis of these findings, azide 14 was chosen as the substrate in
the synthesis of nucleosides 9 and 10 (Schemes 2 and 3).
best yield of triazole 16a (64%) was obtained from run (iv)
employing the 14/15a molar ratio of 1/14, with no solvent addition.
The Pd-catalyzed hydrogenolysis of compound 16a under the
hydrogen-transfer conditions gave the target nucleoside 9a in 95%
yield.
Scheme 2. Reagents and conditions: (i) or (ii) 1,4-dioxane, 55 ꢀC, overnight; (iii) or (iv) 55 ꢀC, overnight; (v) Pd/C, cyclohexene, EtOH, 50 ꢀC, 2 days; (vi) trifluoroacetic acid, MeOH,
20 ꢀC, 2 days; (vii) NH4OH, MeOH, 70 ꢀC, 4 days.
The optimization of the ratio of azide (14)/nucleophile/1,4-
dioxane, with 2-(benzyloxy)ethanol (15a) as the nucleophile, is
shown in Scheme 2a. The triazole 16a and ditriazoles 17 were ob-
tained from all the performed runs. The products were readily
isolated from the reaction mixtures by column chromatography.16
Ditriazoles 17, obtained as an inseparable mixture of two isomers,
were derived from the subsequent reaction between triazole 16a
and the triazafulvene intermediate formed from azide 14.17 The
The same two-step methodology was used for the preparation of
nucleosides 9bed (Scheme 2b). The reactions involving azide 14 and
alcohols 15bed, employing the previously established azide (14)/
alcohol (15) molar ratio of 1/14 under the solvent-free conditions,
gave the corresponding triazoles 16bed in the yields ranging from
39% to 54%. The final de-alkylation of the side chains in compounds
16bed were performed by: (a) trifluoroacetic acid-mediated de-
acetalization (for 16b); (b) ammonia-promoted de-alkylation

ꢀ
2622
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
Scheme 3. Reagents and conditions: (i) 55 ꢀC, overnight; (ii) H2 (21 atm), Pd/C, EtOH, 25 ꢀC, 6 days.
(for 16c), or (c) hydrogenolysis under the Pd-catalyzed hydrogen-
transfer conditions (for 16d). The corresponding nucleosides 9bed
were afforded in yields ranging from 65% to 82%.
product 10c or 10d with the triazole moiety located at the carbo-
hydrate 50-oxygen atom. Nucleoside 10e was obtained from de-
rivative 19 by the Pd-catalyzed hydrogenolysis in 79% yield.
The results from experiments performed with alcohols 15 were
subsequently used in the synthesis of nucleosides 10aee from
carbohydrates 18aee18 (Scheme 3). The reaction products were
obtained in the yields ranging from 43% to 85%. The reactions
2.2. Thermal analysis
The DSC analysis of azide 14 revealed two secondary transi-
tions at 43.4 ꢀC and at 49.6 ꢀC, as well as an exothermic transition
above 80 ꢀC (Fig. 3). The TGA analysis showed no mass loss
employing 2,3-O-cyclohexylidene-
b-D-ribofuranose (18c) or 1,2-O-
isopropylidene- -xylofuranose (18d) yielded the corresponding
a-D
Fig. 3. DSC and TGA thermographs of azide 14: DSC sample mass, 2.42 mg; TGA sample mass, 10 mg.

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2623
between 28 ꢀC and 100 ꢀC (Fig. 3). Therefore, taking into account
4. Experimental
the cascade course of the rearrangement of propargyl azides,13a
we assumed that the transitions observed in the DSC thermo-
gram might be correlated with: [3,3]-sigmatropic rearrangement
of 14, cyclization of the resulting allenyl azide to the corre-
sponding triazafulvene, and polymerization of the triazafulvene
in the absence of an external nucleophile.13a,14 Following this
assumption, temperature of 55 ꢀC was anticipated as sufficient
for the formation of the triazafulvene precursor of the target
compounds.
4.1. Materials and methods
Pre-coated Merck silica gel 60 F254 plates were used for thin-
layer chromatography (TLC, 0.2 mm); spots were detected under
UV light (254 nm). Silica gel (200e400 mesh, Merck) was used for
column chromatography. Optical rotations were measured with
a PolAAr32 polarimeter. High Resolution Mass Spectra (Electro-
spray Ionization, ESI) were recorded on a MarinerÒ spectrometer.
The NMR spectra were measured on a Varian Gemini-200BB
spectrometer (1H NMR at 200 MHz, 13C NMR at 50 MHz) or a Var-
ian VNMRS spectrometer (1H NMR at 500 MHz, 13C NMR at
2.3. Structure elucidation
125 MHz) at 25 ꢀC. 1H and 13C chemical shifts (
d) are reported in
The structures of the new compounds were determined using
NMR spectroscopy. The 13C resonances of the triazole carbon
atoms of triazoles 7e10, 16, and 19 (from 134.82 to 145.12 ppm)
were broadened, most probably due to a dynamic equilibrium
between the tautomeric forms of the compounds and the in-
fluence of the adjacent quadrupolar nitrogen nuclei. In order to
determine the location of these 13C resonances, the 13C NMR
spectra of compounds 16a, 9a, 9b, and 9d were recorded in
a DMSO-d6/trifluoroacetic acid (TFA) mixture. The 13C resonances
for the triazole carbon atoms of compound 16d were not de-
termined. The 1H and 13C chemical shifts for nucleosides 10c, 10d,
and 19 were assigned by 1He13C HMBC NMR experiments (see
Experimental). The numbering of atoms in these compounds, as
well as the 1He13C HMBC correlations crucial for the confirmation
of their substitution pattern within the carbohydrate unit, are
shown in Fig. 4.
parts per million (ppm) relative to the solvent signals: CDCl3, dH
(residual CHCl3) 7.26 ppm, dC 77.16 ppm; DMSO-d6, dH (residual
DMSO-d5) 2.50 ppm, dC 39.52 ppm; signals are quoted as ‘s’ (sin-
glet), ‘d’ (doublet), ‘t’ (triplet), ‘m’ (multiplet), ‘br’ (broad), and
‘t-like m’ (triplet-like multiplet). Coupling constants (J) are reported
in Hertz. The 1He13C HMBC (Heteronuclear Multiple Bond Corre-
lation) spectra were measured on a Varian VNMRS spectrometer.
The IR spectrum of azide 14 was recorded on a Specord M80 (Carl-
Zeiss Jena) spectrometer. DSC measurement was performed on
a DSC Q200 V24.2 Build 107 instrument: 5.0 K/min, open Al pan,
flow rate of nitrogen 25.0 mL/min, flow rate of helium 25.0 mL/min.
TGA analysis was performed on a NETZSCH STA 449 C instrument:
5.0 K/min, Al2O3 pan, flow rate of argon 60 mL/min. Anhydrous
MgSO4 was employed as a drying agent. Volatiles were distilled off
under reduced pressure on a rotating evaporator.
Fig. 4. Numbering of atoms and the selected 1He13C HMBC correlations in nucleosides 10c, 10d, and 19.
3. Conclusion
The concentration of ammonium hydroxide used was 25 wt %.
1,4-Dioxane, acetonitrile, and N,N-dimethylformamide were dried
in accordance with known methods. N,O-Bis(trimethylsilyl)acet-
amide, thymine (11) 2-(benzyloxy)ethanol (15a), 2,2-dimethyl-4-
(hydroxymethyl)-1,3-dioxolane (15b), diethyl (hydroxymethyl)
phosphonate (15c) or 1,3-bis(benzyloxy)propan-2-ol (15d) were
used as purchased (SigmaeAldrich).
The Banert cascade reaction involving the nucleobase-bearing
propargyl azide 14 and a variety of functionalized nucleophiles,
including carbohydrate derivatives, was shown to serve as a con-
venient tool for the synthesis of 4,5-disubstituted-NH-1,2,3-
triazolo-nucleosides. The applied solvent-free procedure was ad-
vantageous from both the preparative and ecological point of view.
Although an appreciated molar excess of the organic nucleophilic
reagent (the alcohol or the carbohydrate derivative) was used in the
presented transformations, the target triazoles were routinely
isolated by column chromatography, owing to a significant differ-
ence in polarity of the nucleophile and the corresponding triazole.
The organic nucleophilic reagents recovered from the reaction
mixtures did not need an additional purification prior to reuse in
a subsequent reaction. We hope that the reported study will be of
interest for research groups involved in the synthesis of both 1,2,3-
triazolo-nucleosides and carbohydrate 1,2,3-triazolo-conjugates. A
study on the improvement and extension of the presented meth-
odology is now in progress. This study, including a SAR analysis of
the obtained compounds, will be a subject of a forthcoming
publication.
4.2. 1-(4-Mesyloxybut-2-yn-1-yl)-5-methylpyrimidine-
2,4(1H,3H)-dione (13)
A
mixture of thymine (11, 1.0 g, 7.9 mmol) and N,O-
bis(trimethylsilyl)acetamide (BSA, 3.21 g, 15.8 mmol) in dry ace-
tonitrile (80 mL) was stirred at 20 ꢀC for 1 h under an argon
atmosphere. Then, 1,4-bis(mesyloxy)but-2-yne19 (12, 5.74 g,
23.7 mmol) was added. The reaction mixture was kept at room
temperature for 5 days and then ethyl acetate (250 mL) and a sat-
urated aqueous solution of sodium bicarbonate (10 mL) were
added. The mixture was stirred for 1 h and filtered through a Celite
pad. The organic phase was separated from the filtrate, washed
with brine (50 mL), and dried. Volatiles were distilled off. Column
chromatography of the residue (CHCl3/MeOH, from 99/1 to 95/5,

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2624
v/v) gave 13 (1.04 g, 48%) as a white solid (mp 154e155 ꢀC). dH
(200 MHz, DMSO-d6) 1.76 (br s, 3H), 3.24 (s, 3H), 4.60 (s, 2H), 5.00
(s, 2H), 7.58 (br d, JHH 1.2, 1H), 11.40 (br s, 1H, NH). dC (125 MHz,
DMSO-d6) 11.91, 35.69, 37.65, 57.96, 77.29, 83.99, 109.43, 140.15.
150.40, 164.13. HRMS m/z calcd for C10H12N2O5SNa (MþNa)þ
295.0365, found 295.0366.
azide 14, 2-(benzyloxy)ethanol (15a) and 1,4-dioxane was prepared
in accordance with the 14/15a/1,4-dioxane ratios given in Scheme
2a and stirred at 55 ꢀC overnight. The reaction mixture was
cooled to 20 ꢀC and volatiles were distilled off. Column chroma-
tography of the residue (CHCl3/MeOH, from 99/1 to 95/5, v/v) gave
16a (76 mg, 44% from run (i); or 88 mg, 52% from run (ii)) as a white
solid (mp 129e131 ꢀC) and ditriazoles 17 (76 mg, 53% from run (i);
or 36 mg, 25% from run (ii)) as a colorless oil. 16a: dH (200 MHz,
DMSO-d6) 1.72 (d, 4JHH 1.0, 3H), 3.42e3.71 (m, 4H), 4.46 (br s, 2H),
4.61 (s, 2H), 4.93 (s, 2H), 7.15e7.32 (m, 5H), 7.50 (br d, 4JHH 1.0, 1H).
dC (50 MHz, DMSO-d6/TFA) 12.00, 41.02, 62.34, 69.05, 69.21, 72.16,
108.84, 127.46, 127.59, 128.28, 138.44, 140.04, 140.36, 141.15, 150.86,
164.34. HRMS m/z calcd for C18H21N5O4Na (MþNa)þ 394.1491,
found 394.1482. Ditriazoles (17), a mixture in a molar ratio of 4/6: dH
(500 MHz, DMSO-d6) 1.65 (br s, 1.2H), 1.72 (br s, 1.8H), 1.73 (br s,
1.8H), 1.75 (br s, 1.2H), 3.53e3.59 (m, 4H), 4.42e4.48 (m, 2H), 4.57
(s, 0.8H), 4.76 (s, 1.2H), 4.90 (s, 1.2H), 4.92 (s, 1.2H), 4.98 (s, 0.8H),
5.09 (s, 0.8H), 5.77 (s, 1.2H), 5.86 (s, 0.8H), 7.25e7.42 (m, 5H), 7.41
4
4.3. 1-(4-Azidobut-2-yn-1-yl)-5-methylpyrimidine-
2,4(1H,3H)-dione (14)
A mixture of 13 (724 mg, 2.66 mmol), sodium azide (207 mg,
3.19 mmol), ammonium chloride (40 mg), and dry N,N-dime-
thylformamide (32 mL) was stirred at 20 ꢀC for 1 h. Then, the sol-
vent was distilled off under vacuum (water bath, 25e30 ꢀC,
0.4 mmHg). The residue was sonicated with cold water (20 mL) for
3 min and filtered. The white solid was dried in a vacuum dessicator
over phosphorus pentoxide to give 14 (564 mg, 97%). dH (500 MHz,
DMSO-d6) 1.76 (d, 4JHH 1.0, 3H), 4.19 (s, 2H), 4.58 (s, 2H), 7.58 (br d,
4JHH 1.0, 1H), 11.34 (br s, 1H, NH). dC (50 MHz, DMSO-d6) 11.94,
36.50, 39.35, 77.50, 81.59, 109.45, 140.15, 150.38, 164.15. nmax (eN3)/
4
4
4
(br d, JHH 1.0, 0.4H), 7.46 (br d, JHH 1.0, 0.6H), 7.53 (br d, JHH 1.0,
4
0.4H), 7.55 (br d, JHH 1.0, 0.6H), 11.27 (br s, 1.2H, NH), 11.31 (br s,
0.8H, NH). HRMS m/z calcd for C27H30N10O6Na (MþNa)þ 613.2247,
KBr 2101 cmꢁ1
242.0654, found 242.0649.
.
HRMS m/z calcd for C9H9N5O2Na (MþNa)þ
found 613.2235.
4.6.1.2. From runs (iii) and (iv), Scheme 2a. The runs (iii) and (iv)
were performed from 200 mg (0.92 mmol) of azide 14. A mixture of
azide 14 and 2-(benzyloxy)ethanol (15a) was prepared in accor-
dance with a 14/15a/1,4-dioxane ratios given in Scheme 2a and
stirred at 55 ꢀC overnight. The reaction mixture was cooled to 20 ꢀC.
Column chromatography of the mixture (CHCl3/MeOH, from 99/1
to 95/5, v/v) gave 16a (157 mg, 46% from run (iii); or 218, mg 64%
from run (iv)) and 17 (71 mg, 25% from run (iii); or 20 mg, 7% from
run (iv)). The spectroscopic data of 16a and 17 were in accordance
with those reported in Section 4.6.1.1.
4.4. 1-((5-(Hydroxymethyl)-NH-1,2,3-triazol-4-yl)methyl)-5-
methylpyrimidine-2,4(1H,3H)-dione (7)
4.4.1. From mesylate (13). A mixture of 13 (140 mg, 0.51 mmol),
sodium azide (33 mg, 0.51 mmol), ammonium chloride (107 mg,
1.02 mmol), 1,4-dioxane (2.5 mL), and water (0.8 mL) was stirred at
75 ꢀC for 4.5 h. The reaction mixture was cooled to 20 ꢀC and vol-
atiles were distilled off. Column chromatography of the residue
(CHCl3/MeOH, 9/1, v/v) gave 7 (49 mg, 40%) as a white solid (mp
187e198 ꢀC dec). dH (200 MHz, DMSO-d6) 1.74 (s, 3H), 4.58 (s, 2H),
4.94 (s, 2H), 7.55 (s, 1H), 11.28 (br s, 1H, NH), 14.62 (br s, 1H, NH). dC
(50 MHz, DMSO-d6) 12.07, 41.33, 54.13, 108.88, 140.86, 141.37,
145.12, 150.95, 164.42. HRMS m/z calcd for C9H11N5O3Na (MþNa)þ
260.0760, found 260.0760.
4.6.2. 1-((5-((2-Hydroxyethoxy)methyl)-NH-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9a). A mixture of
16a (211 mg, 0.57 mmol), methanol (8 mL), cyclohexene (8 mL), and
palladium (10% on charcoal, 20 mg) was stirred at 50 ꢀC for 2 days
under an argon atmosphere. The reaction mixture was cooled to
20 ꢀC and filtered through a Celite pad. Volatiles were distilled off
from the filtrate. Column chromatography of the residue (CHCl3/
MeOH, 7/3, v/v) gave 9a (152 mg, 95%) as a white solid (mp
4.4.2. From azide (14). A mixture of 14 (100 mg, 0.46 mmol) and
water (2 mL) was stirred at 55 ꢀC overnight. The reaction mixture
was cooled to 20 ꢀC and volatiles were distilled off. Column chro-
matography of the residue (CHCl3/MeOH, 9/1, v/v) gave 7 (84 mg,
76%). The spectroscopic data of 7 were in accordance with those
reported in Section 4.4.1.
4
144e146 ꢀC). dH (200 MHz, DMSO-d6) 1.74 (d, JHH 1.0, 3H),
3.43e3.45 (AA0BB0-t, 2H), 3.50e3.52 (AA0BB0-t, 2H), 4.59 (s, 2H),
4.95 (s, 2H), 7.53 (br s, 1H), 11.34 (br s, 1H, NH). dC (125 MHz, DMSO-
d6/TFA) 12.15, 41.29, 60.36, 62.46, 72.04, 109.14, 140.18, 140.43,
141.42, 151.10, 164.55. HRMS m/z calcd for C11H15N5O4Na (MþNa)þ
304.1022, found 304.1029.
4.5. 1-((5-(Aminomethyl)-NH-1,2,3-triazol-4-yl)methyl)-5-
methylpyrimidine-2,4(1H,3H)-dione (8)
A mixture of azide 14 (100 mg, 0.46 mmol) and ammonium
hydroxide (2 mL) was stirred at 55 ꢀC overnight (sealed tube). The
reaction mixture was cooled to 20 ꢀC and volatiles were distilled off.
Column chromatography of the residue (CHCl3/MeOH, 9/1, v/v)
gave 8 (88 mg, 81%) as a white solid (mp >179 ꢀC dec). dH (200 MHz,
DMSO-d6) 1.74 (br s, 3H), 3.88 (s, 2H), 4.92 (s, 2H), 7.46 (br s, 3H,
4.7. 1-((5-((2,3-Dihydroxypropoxy)methyl)-NH-1,2,3-triazol-
4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9b)
4.7.1. 1-((5-(((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)-NH-
1,2,3-triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(16b). According to the procedure described in Section 4.6.1.2,
compound 16b was obtained from azide 14 (100 mg, 0.46 mmol)
and 2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (15b, 845 mg,
6.4 mmol). Column chromatography (CHCl3/MeOH, from 99/1 to
95/5, v/v) gave 16b (86 mg, 54%) as a colorless oil. dH (500 MHz,
CDCl3) 1.32 (s, 3H), 1.38 (br s, 3H), 1.84 (s, 3H), 3.56 (d, 3JHH 5.0, 2H),
3.67 (dA) and 4.02 (dB) (AB part of ABX system, 2JAB 7.0, 3JAx 7.5, 3JBx
7.5, 2H), 4.23e4.31 (X part of ABX system, 1H), 4.76 (s, 2H), 5.02 (AB
4
NH), 7.59 (br d, JHH 0.8, 1H). dC (125 MHz, DMSO-d6) 11.98, 34.80,
41.03, 108.32, 138.18, 141.26, 141.51, 150.92, 164.30. HRMS m/z calcd
for C9H13N6O2 (MþH)þ 237.1100, found 237.1096.
4.6. 1-((5-((2-Hydroxyethoxy)methyl)-NH-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9a)
4.6.1. 1-((5-((2-(Benzyloxy)ethoxy)methyl)-NH-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (16a) and ditriazoles (17)
2
quartet, JAB 17.0, 2H), 7.38 (s, 1H), 10.19 (br s, 1H, NH), 13.79 (br s,
4.6.1.1. From runs (i) and (ii), Scheme 2a. The runs (i) and (ii)
were performed from 100 mg (0.46 mmol) of azide 14. A mixture of
1H, NH). dC (125 MHz, DMSO-d6) 12.00, 25.35, 26.67, 40.98, 62.57,
66.02, 70.98, 74.16, 108.56, 108.92, 139.92, 140.37, 141.10, 150.86,

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2625
164.33. HRMS m/z calcd for C15H22N5O5 (MþH)þ 352.1616, found
99/1, v/v) gave 9d (32 mg, 65%) as a white solid (mp 151e153 ꢀC). dH
(200 MHz, DMSO-d6) 1.74 (br s, 3H), 3.38e3.52 (m, 7H), 4.72 (s, 2H),
4.95 (s, 2H), 7.57 (br s, 1H), 11.27 (br s, 1H, NH). dC (125 MHz, DMSO-
d6/TFA) 12.08, 41.18, 60.96, 61.59, 81.44,109.14,140.21,140.49,141.42,
151.16,164.57. HRMS m/z calcd for C12H17N5O5Na (MþNa)þ 334.1127,
found 334.1127.
352.1615.
4.7.2. 1-((5-((2,3-Dihydroxypropoxy)methyl)-NH-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9b). A mixture of
16b (78 mg, 0.22 mmol), methanol (1 mL), water (0.5 mL), and TFA
(0.1 mL) was kept at 20 ꢀC for 2 days. Volatiles were distilled off
to give 9b (62 mg, 82%) as a white solid (mp 133e135 ꢀC). dH
(200 MHz, DMSO-d6) 1.74 (br s, 3H), 3.27e3.47 (m, 4H), 3.53e3.61
(m, 1H), 4.58 (s, 2H), 4.94 (s, 2H), 7.55 (br s, 1H), 11.30 (br s, 1H, NH).
dC (125 MHz, DMSO-d6) 12.00, 41.04, 62.55, 63.03, 70.46, 72.10,
108.83, 139.91, 140.20, 141.25, 150.84, 164.32. HRMS m/z calcd for
C12H17N5O5Na (MþNa)þ 334.1127, found 334.1138.
4.10. 5-Methyl-1-((5-((((3aR,5R,5aS,8aS,8bR)-2,2,7,7-
tetramethyltetrahydro-3aH-bis([1,3]dioxolo)[4,5-b:40,50-d]py-
ran-5-yl)methoxy)methyl)-NH-1,2,3-triazol-4-yl)methyl)py-
rimidine-2,4(1H,3H)-dione (10a)
According to the procedure described in Section 4.6.1.2, com-
pound 10a was obtained from azide 14 (50 mg, 0.23 mmol) and
1,2:3,4-di-O-isopropylidene-a-D
-galactopyranose18a (18a, 830 mg,
4.8. 1-((5-((Ethoxyhydroxyphosphorylmethoxy)methyl)-NH-
1,2,3-triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-di-
one (9c)
3.2 mmol). Column chromatography (CHCl3/MeOH, 99/1, v/v) gave
10a (64 mg, 58%) as a colorless syrup. dH (500 MHz, CDCl3) 1.26 (s,
3H), 1.27 (s, 3H), 1.37 (s, 3H), 1.45 (s, 3H), 1.82 (br s, 3H), 3.58e3.74
(m, 2H), 3.96e4.06 (m, 1H), 4.20 (dA) and 4.57 (dB) (AB part of ABX
4.8.1. 1-((5-((Diethoxyphosphorylmethoxy)methyl)-NH-1,2,3-triazol-
4 - yl ) m e t h yl ) - 5 - m e t hyl p y r i m i d i n e - 2 , 4 ( 1 H , 3 H ) - d i o n e
(16c). According to the procedure described in Section 4.6.1.2,
compound 16c was obtained from azide 14 (100 mg, 0.46 mmol)
and diethyl (hydroxymethyl)phosphonate (15c, 1.2 g, 6.4 mmol).
Column chromatography (CHCl3/MeOH, 99/1, v/v) gave 16c (84 mg,
47%) as a colorless oil. dH (500 MHz, CDCl3) 1.19e1.22 (t-like m, 6H),
2
3
3
system, JAB 8.0, JAx 0.0, JBx 2.0, 2H), 4.28e4.29 (m, 1H), 4.72 and
4.76 (AB system, 2JAB 12.0, 2H), 4.97 and 5.07 (AB system, 2JAB 14.5,
2H), 5.51 (d, JHH 5.0, 1H), 7.45 (br s, 1H), 10.18 (br s, 1H, NH). dC
3
(125 MHz, DMSO-d6) 11.93, 24.18, 24.78, 25.81, 25.87, 41.18, 62.93,
66.35, 68.96, 69.73, 70.51, 70.51, 95.66, 107.75, 108.32, 108.78, 141.10,
141.51, 141.73, 150.76, 164.23. ½a D27
ꢁ36.7 (c 2.30, MeOH). HRMS m/z
ꢂ
4
3
calcd for C21H30N5O8 (MþH)þ 480.2089, found 480.2092.
1.74 (d, JHH 1.0, 3H), 3.82 (d, JHP 8.5, 2H), 4.00e4.05 (quintet-like
4
m, 4H), 4.70 (s, 2H), 4.95 (s, 2H), 7.54 (br d, JHH 1.0, 1H). dC
(125 MHz, CDCl3) 12.00, 16.32 (d, 4JCP 5.9), 40.91, 61.89 (d, 3JCP 6.8),
2
3
4.11. 1-((5-((((3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(10b)
63.26 (d, JCP 162.4), 64.11 (d, JCP 13.6), 108.96, 139.46, 140.35,
141.15, 150.88, 164.34. HRMS m/z calcd for C14H22N5O6PNa
(MþNa)þ 410.1205, found 410.1191.
4.8.2. 1-((5-((Ethoxyhydroxyphosphorylmethoxy)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9c). A
mixture of 16c (96 mg, 0.25 mmol), ammonium hydroxide (4 mL),
and methanol (1 mL) was kept at 70 ꢀC for 4 days (sealed tube).
Volatiles were distilled off to give 9c (70 mg, 81%) as a slightly
yellow oil. dH (200 MHz, DMSO-d6) 1.05e1.12 (t-like m, 3H), 1.74 (br
s, 3H), 3.43 (d, 3JHP 8.2, 2H), 3.68e3.82 (quintet-like m, 2H), 4.65 (s,
2H), 4.92 (s, 2H), 7.65 (br s, 1H), 9.63 (br s, 1H, NH). dC (50 MHz,
DMSO-d6) 11.89,16.90 (d, 4JCP 5.7), 33.94, 59.18 (d, 3JCP 5.7), 63.49 (d,
3JCP 10.3), 66.80 (d, 2JCP 154.0), 108.71, 138.87, 139.39, 141.40, 150.82,
164.31. HRMS m/z calcd for C12H19N5O6P (MþH)þ 360.1068, found
360.1085.
According to the procedure described in Section 4.6.1.2, com-
pound 10b was obtained from azide 14 (100 mg, 0.46 mmol) and 1-
O-methyl-2,3-O-isopropylidene-b-D
-ribofuranose18b (18b, 1.3 g,
6.4 mmol). Column chromatography (CHCl3/MeOH, 99/1, v/v) gave
10b (84 mg, 43%) as a colorless syrup. dH (500 MHz, CDCl3) 1.28 (s,
3H), 1.45 (s, 3H), 1.85 (br s, 3H), 3.03 (s, 3H), 3.55 (dA) and 3.61 (dB
)
(AB part of ABX system, 2JAB 10.0, 3JAx 6.5, 3JBx 6.5, 2H), 4.32e4.35 (X
part of ABX system, 1H), 4.57 (d, 3JHH 6.5, 1H), 4.65 (d, 3JHH 6.5, 1H),
2
4.73 and 4.79 (AB system, JAB 12.5, 2H), 4.97 (s, 1H), 5.01 (s, 2H),
7.37 (br s, 1H), 9.93 (br s, 1H, NH). dC (125 MHz, DMSO-d6) 11.94,
24.63, 26.23, 41.05, 54.10, 62.79, 70.81, 81.55, 84.20, 84.43, 108.46,
108.86, 111.48, 141.04, 141.60, 141.67, 150.83, 164.26. ½a D26
ꢁ31.6
ꢂ
(c 1.36, MeOH). HRMS m/z calcd for C18H26N5O7 (MþH)þ 424.1827,
4.9. 1-((5-((1,3-Dihydroxypropan-2-oxy)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9d)
found 424.1829.
4.9.1. 1-((5-((1,3-Bis(benzyloxy)propan-2-oxy)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(16d). According to the procedure described in Section 4.6.1.2,
compound 16d was obtained from azide 14 (100 mg, 0.46 mmol)
and 1,3-bis(benzyloxy)propan-2-ol (15d, 1.7 g, 6.4 mmol). Column
chromatography (CHCl3/MeOH, 99/1, v/v) gave 16d (89 mg, 39%) as
a colorless oil. dH (200 MHz, CDCl3) 1.80 (br s, 3H), 3.52e3.71 (m,
4H), 3.80e3.91 (m, 1H), 4.54 (br s, 4H), 4.89 (s, 2H), 4.92 (s, 2H),
7.28e7.34 (m, 11H), 9.18 (br s, 1H, NH). dC (50 MHz, CDCl3) 12.34,
41.45, 62.99, 70.11, 73.71, 78.37, 111.07, 127.98, 128.07, 128.61, 137.63,
140.72, 151.27, 164.42. The 13C resonances for the triazole carbon
atoms of the compound were not determined. HRMS m/z calcd for
C26H29N5O5Na (MþNa)þ 514.2067, found 514.2067.
4.12. 1-((5-((((3a0R,40R,60R,6a0R)-40-Hydroxytetrahydrospiro
[cyclohexane-1,20-furo[3,4-d][1,3]dioxol]-60-yl)methoxy)
methyl)-NH-1,2,3-triazol-4-yl)methyl)-5-methylpyrimidine-
2,4(1H,3H)-dione (10c)
According to the procedure described in Section 4.6.1.2, com-
pound 10c was obtained from azide 14 (50 mg, 0.23 mmol) and 2,3-
O-cyclohexylidene-b-D
-ribofuranose18c (18c, 740 mg, 3.2 mmol).
Column chromatography (CHCl3/MeOH, 95/5, v/v) gave 10c (69 mg,
67%) as a white foam. dH (200 MHz, DMSO-d6) 1.30e1.54 (m, 10H,
H-20b), 1.74 (br s, 3H, H-500a), 3.45e3.75 (m, 2H, H-50), 3.98e4.19 (t-
like m, 1H, H-40), 4.43e4.52 (m, 2H, H-20, H-30), 4.62 (s, 2H, H-5a),
4.95 (s, 2H, H-4a), 5.20 (s,1H, H-10), 7.52 (br s,1H, H-600a),11.30 (br s,
1H, NH). dC (50 MHz, DMSO-d6) 12.00 (C-500a), 23.44 (C-20b), 23.69
(C-20b), 24.65 (C-20b), 33.94 (C-20b), 35.89 (C-20b), 40.98 (C-4a),
62.52 (C-5a), 71.57 (C-50), 81.77 (C-30), 84.00 (C-40), 85.29 (C-20),
102.10 (C-10), 108.89 (C-500), 111.94 (C-20a), 139.98 (C-4 or C-5),
140.24 (C-5 or C-4), 141.11 (C-600), 150.87 (C-200), 164.29 (C-400).
4.9.2. 1-((5-((1,3-Dihydroxypropan-2-oxy)methyl)-NH-1,2,3-triazol-
4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (9d). According
to the procedure described in Section 4.6.2, compounds 9d was ob-
tained from 80 mg of 16d. Column chromatography (CHCl3/MeOH,

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2626
½
a 2D3
ꢂ
ꢁ10.9 (c 1.24, MeOH). HRMS m/z calcd for C20H28N5O7 (MþH)þ
85.20, 104.28, 108.88, 110.42, 139.28, 140.53, 141.32, 150.94, 164.37.
450.1983, found 450.1990.
HRMS m/z calcd for C17H25N6O6 (MþH)þ 409.1836, found 409.1830.
An optical rotation of the compound was not determined due to its
low solubility in water or common organic solvents.
4.13. 1-((5-((((3aR,5R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl)methoxy)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(10d)
Acknowledgements
This work was financed by Warsaw University of Technology
and by the European Union within the European Regional De-
velopment Fund; Project No. POIG.01.01.02-14-102/09. The authors
thank Dr. Aldona Zalewska, Warsaw University of Technology,
for recording and interpretation of the DSC thermogram, and
According to the procedure described in Section 4.6.1.2, com-
pound 10d was obtained from azide 14 (50 mg, 0.23 mmol) and 1,2-
O-isopropylidene-a-D
-xylofuranose18d (18d, 610 mg, 3.2 mmol).
Column chromatography (CHCl3/MeOH, 99/1, v/v) gave 10d (63 mg,
67%) as a colorless syrup. dH (500 MHz, DMSO-d6) 1.23 (s, H-10b,
ꢀ
Dr. Wioletta Rarog-Pilecka, Warsaw University of Technology, for
4
3H), 1.37 (s, H-10b, 3H), 1.76 (d, JHH 1.0, 3H, H-500a), 3.54 (dA) and
recording and interpretation of the TGA thermogram.
3
3
3.68 (dB) (AB part of ABX system, 2JAB 10.5, JAx 7.0, JBx 4.5, 2H, H-
50), 3.99 (br s, 1H, H-30), 4.10e4.13 (X part of ABX system, 1H, H-40),
4.39 (d, 3JHH 3.5, 1H, H-20), 4.62 (s, 2H, H-5a), 4.96 (s, 2H, H-4a), 5.82
(d, 3JHH 4.0, 1H, H-10), 7.48 (br d, 4JHH 1.0, 1H, H-600a), 11.14 (br s, 1H,
NH). dC (50 MHz, DMSO-d6) 12.02 (C-500a), 26.11 (C-10b), 26.64
(C-10b), 41.69 (C-4a), 63.27 (C-5a), 68.41 (C-50), 73.85 (C-30), 79.36
(C-40), 84.95 (C-20), 104.46 (C-10), 108.88 (C-500), 110.48 (C-10a),
140.28 (C-4 or C-5), 141.12 (C-600), 142.18 (C-5 or C-4), 150.86 (C-200),
References and notes
1. De Clercq, E. Clin. Microbiol. Rev. 2003, 16, 569.
2. (a) Antiviral Nucleosides: Chiral Synthesis and Chemotherapy, 1st ed.; Chu, C. K.,
Ed.; Elsevier Science: 2003; (b) Modified Nucleosides: In Biochemistry, Bio-
technology and Medicine; Herdewijn, P., Ed.; WILEY-VCH GmbH
& KGaA:
Weinheim, 2008.
3. (a) Seley, K. L.; Zhang, L.; Hagos, A. Org. Lett. 2001, 3, 3209; (b) Seley, K. L.;
Zhang, L.; Hagos, A.; Quirk, S. J. Org. Chem. 2002, 67, 3365.
4. (a) Seley, K. L.; Salim, S.; Zhang, L.; O’Daniel, P. I. J. Org. Chem. 2005, 70, 1612; (b)
Seley, K. L.; Salim, S.; Zhang, L. Org. Lett. 2005, 7, 63.
164.29 (C-400). ½a D23
ꢁ13.8 (c 1.38, MeOH) HRMS m/z calcd for
ꢂ
C17H24N5O7 (MþH)þ 410.1670, found 410.1677.
5. St Amant, A. H.; Bean Leslie, A.; Guthrie, J. P.; Hudson, R. H. E. Org. Biomol. Chem.
2012, 10, 6521.
6. Seley, K. L.; Quirk, S.; Salim, S.; Zhang, L.; Hagos, A. Bioorg. Med. Chem. Lett.
2003, 13, 1985.
7. (a) Polak, M.; Seley, K. L.; Plavec, J. J. Am. Chem. Soc. 2004, 126, 8159; (b) Bardon,
4.14. 1-((5-(((((3aR,5R,6S,6aR)-6-Hydroxy-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)methyl)amino)methyl)-NH-
1,2,3-triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-di-
one (10e)
A. B.; Wetmore, S. D. J. Phys. Chem. A 2005, 109, 262.
8. (a) Yu, L.; Wua, Q.-P.; Zhang, Q.-S.; Liu, Y.-H.; Li, Y.-Z.; Zhou, Z.-M. Bioorg. Med.
Chem. Lett. 2010, 20, 240; (b) Chittepu, P.; Sirivolu, R. V.; Seela, F. Bioorg. Med.
Chem. 2008, 16, 8427.
4.14.1. 1-((5-((Benzyl(((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl)amino)methyl)-NH-
1,2,3-triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(19). According to the procedure described in Section 4.6.1.2, com-
pound 19 was obtained from azide 14 (132 mg, 0.6 mmol) and 5-
ꢀ
9. (a) Koszytkowska-Stawinska, M.; Mironiuk-Puchalska, E.; Rowicki, T. Tetrahe-
dron 2012, 68, 214; (b) Ahmed, A.-G.; Abdel-Rahman, A. A.-H.; Zeid, I. F.; Salem,
E. E.-D.; Ranouf, A. A. Mansoura J. Chem. 2006, 33, 87; (c) Ahmed, A.-G.;
Abdel-Rahman, A. A.-H.; Zeid, I. F.; Salem, E. E.-D.; Ranouf, A. A. Mansoura J. Chem.
2006, 33, 105; (d) Luoa, L.; Heb, X.-P.; Shend, Q.; Lid, J.-Y.; Shic, X.-X.; Xie, J.; Li, J.;
Chen, G.-R. Chem. Biodiversity 2011, 8, 2035.
(benzylamino)-5-deoxy-1,2-O-isopropylidene-a-D
-xylofuranose18e
(18e, 2.33 g, 8.3 mmol). Column chromatography (CHCl3/MeOH,
from 99/1 to 95/5, v/v) gave 19 (255 mg, 85%) as a pale yellow oil. dH
(500 MHz, DMSO-d6) 1.21 (s, 3H, H-10b), 1.34 (s, 3H, H-10b), 1.73
(d, 4JHH 1.0, 3H, H-500a), 2.63 (dA) and 2.75 (dA) (AB part of ABX system,
2JAB 14.0, 3JAx 7.0, 3JBx 4.0, 2H, H-50), 3.62 and 3.64 (AB system, 2JAB
10. For selected examples, see: (a) Weide, T.; Saldanha, S. A.; Minond, D.; Spicer, T.
ꢁ
P.; Fotsing, J. R.; Spaargaren, M.; Frere, J.-M.; Bebrone, C.; Sharpless, K. B.;
Hodder, P. S.; Fokin, V. V. ACS Med. Chem. Lett. 2010, 1, 150; (b) Minond, D.;
Saldanha, S. A.; Subramaniam, P.; Spaargaren, M.; Spicer, T.; Fotsing, J. R.;
Weide, T.; Fokin, V. V.; Sharpless, K. B.; Galleni, M.; Bebrone, C.; Lassaux, P.;
Hodder, P. Bioorg. Med. Chem. 2009, 17, 5027; (c) Baker, R.; Elliott, J.;
Stevenson, G. I.; Swain, C. J. WO Patent 9701553A1; Chem. Abstr. 1997, 126, 171
610; (d) Baker, R.; Elliott, J.; Stevenson, G. I.; Swain, C. J. WO Patent 9701554A1;
Chem. Abstr. 1997, 126, 171 611; (e) Moseley, J. D.; Swain, C. J.; Williams, B. J. GB
Patent 2 302 689A; Chem. Abstr. 1997, 126, 277 501; (f) Owens, A. P. WO Patent
9629317A1; Chem. Abstr. 1996, 126, 8122; (g) Seward, E. M.; Carlson, E.;
Harrison, T.; Haworth, K. E.; Herbert, R.; Kelleher, F. J.; Kurtz, M. M.; Moseley, J.;
Owen, S. N.; Owens, A. P.; Sadowski, S. J.; Swain, C. J.; Williams, B. J. Bioorg. Med.
Chem. Lett. 2002, 12, 2515; (h) Harrison, T.; Owens, A. P.; Williams, B. J.; Swain,
C. J.; Williams, A.; Carlson, E. J.; Rycroft, W.; Tattersall, F. D.; Cascieri, M. A.;
Chicchi, G. G.; Sadowski, S.; Rupniak, N. M. J.; Hargreaves, R. J. J. Med. Chem.
2001, 44, 4296; (i) Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Lewis, R.; Russell,
M. G. N.; Smith, A.; Wafford, K.; McKernan, R. M.; Street, L. J.; Castro, J. L. Bioorg.
Med. Chem. Lett. 2005, 15, 4998.
3
14.5, 2H, CH2-Ph), 3.79 (s, 2H, H-5a), 3.88 (d, JHH 2.5, 1H, H-30),
4.16e4.18 (m,1H, H-40), 4.34 (d, 3JHH 4.0,1H, H-20), 4.89 and 4.94 (AB
system, 2JAB 15.5, 2H, H-4a), 5.79 (d, 3JHH 4.0,1H, H-10), 7.18e7.21 (m,
2H, Ph), 7.29e7.31 (m, 3H, Ph), 7.48 (d, 4JHH 1.0,1H, H-600),11.23 (br s,
1H, NH). dC (125 MHz, DMSO-d6) 12.06 (C-500a), 26.21 (C-10b), 26.71
(C-10b), 41.20 (C-4a), 47.97 (C-5a), 52.05 (C-50), 58.23 (CH2-Ph), 74.62
(C-30), 78.57 (C-40), 84.95 (C-20), 104.39 (C-10), 108.91 (C-500), 110.47
(C-10a), 127.01 (Ph), 128.25 (Ph), 128.88 (Ph), 137.80 (C-4 or C-5),
138.79 (Ph), 140.38 (C-5 or C-4), 141.41 (C-600), 150.92 (C-200), 164.43
(C-400). ½a 2D6
ꢁ25.5 (c 1.96, MeOH). HRMS m/z calcd for C24H31N6O6
ꢂ
11. (a) De Las Heras, F. G.; Tam, S. Y.-K.; Klein, R. S.; Fox, J. J. J. Org. Chem. 1976, 41, 84;
(b) Youcef, R. A.; Dos Santos, M.; Roussel, S.; Baltaze, J.-P.; Lubin-Germain, N.;
(MþH)þ 499.2300, found 499.2298.
€
Uziel, J. J. Org. Chem. 2009, 74, 4318; (c) Tong, W.; Wu, J.-C.; Sandstrom, A.;
Chattopadhyaya, J. Tetrahedron 1990, 46, 3037.
12. (a) Rachwal, S.; Katritzky, A. R. Comprehensive Heterocyclic Chemistry III;
4.14.2. 1-((5-(((((3aR,5R,6S,6aR)-6-Hydroxy-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl)methyl)amino)methyl)-NH-1,2,3-
triazol-4-yl)methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (10e). A
mixture of 19 (150 mg, 0.3 mmol), palladium (10% on charcoal,
30 mg), and ethanol (5 mL) was hydrogenated (21 atm) at 25 ꢀC for
6 days. The volatiles were distilled off from the reaction mixture.
Column chromatography of the residue (CHCl3/MeOH, from 9/1 to
8/2, v/v) gave 10e (97 mg, 79%) as a colorless syrup. dH (500 MHz,
DMSO-d6) 1.20 (s, 3H), 1.34 (s, 3H), 1.74 (br s, 3H), 2.70 (dA) and 2.77
Elsevier: 2008, Chapter 5.01, pp 1e158; (b) Kripovalov, V. P.; Shkurko, O. P. Russ.
ꢀ
Chem. Rev. 2005, 74, 339; (c) Tome, A. C. Science of Synthesis; Thieme: New York,
NY, 2004; Vol. 13, pp 415e601.
13. (a) Banert, K. Liebigs Ann. Recl. 1997, 2005; (b) Banert, K. In Organic Azides:
€
Syntheses and Applications; Brase, S., Banert, K., Eds.; John Wiley & Sons Ltd.:
2010; pp 147e154.
14. Loren, J. C.; Sharpless, K. B. Synthesis 2005, 9, 1514.
15. This variant is recommended for low-molecular weight propargyl azides owing
to their susceptibility to explosion (see, Ref. 13).
16. TLC analysis of the crude reaction mixtures showed additional, highly-polar by-
products. However, the by-products were not isolated from the column chro-
matography. Mass balance from the chromatography, calculated relative to
azide 14, might indicate on an oligomeric/polymeric structure of the by-
products. The mass balance deficiency of 15a recovered from runs (iii) and
(iv), calculated relative to products 16a and 17, was less than 10%.
(
dB) (AB part of ABX system, 2JAB 12.0, 3JAx 6.3, 3JBx 5.3, 2H), 3.84 (s,
2H), 3.95 (d, 3JHH 2.5, 1H), 4.02e4.05 (m, 1H), 4.37 (d, 3JHH 3.5, 1H),
4.93 (s, 2H), 5.79 (d, 3JHH 4.0, 1H), 7.58 (d, 4JHH 1.0, 1H). dC (125 MHz,
DMSO-d6) 12.01, 26.16, 26.69, 41.04, 42.44, 46.93, 74.16, 79.45,

ꢀ
M. Koszytkowska-Stawinska, W. Sas / Tetrahedron 69 (2013) 2619e2627
2627
17. The reaction between an initially formed triazole and
a
triazafulvene in-
Lima, E. S.; Kaiser, C. R.; Silva, F. P., Jr.; Ferreira, V. F. J. Med. Chem. 2010, 53, 2364;
(c) Liu, D.; Caparelli, C. A. Synthesis 1991, 933; (d) White, J. D.; Jeffrey, S. C. J. Org.
Chem. 1996, 61, 2600; (e) Cho, B. T.; Kim, N. J. Chem. Soc., Perkin Trans. 1 1996,
2901.
termediate formed from a propargyl azide was suggested in Ref. 14. However to
the best of our knowledge, products resulting from the reaction were for the
first time identified in our study.
€
€
€€
18. (a) Roslund, M. U.; Klika, K. D.; Lehtila, R. L.; Tahtinen, P.; Sillanpaa, R.; Leino, R.
19. Alcaide, B.; Almendros, P.; Rodríguez-Acebes, R. J. Org. Chem. 2002, 67,
1925.
J. Org. Chem. 2004, 69, 18; (b) Ferreira, S. B.; Sodero, A. C. R.; Cardoso, M. F. C.;