Synthesis of 1,2,3-triazolo-nucleosides via the post-triazole N-alkylation

Article abstract of DOI:10.1016/j.tet.2011.10.067

2-Substituted-2H-1,2,3-triazolo-nucleosides with 3-phosphonopropyl, 2-hydroxyethyl, 2-cyanoethyl, carbamoylmethyl, or 1-deoxy-2,5-anhydro-d- mannitol-1-yl on the triazole N-2 nitrogen atom were obtained via the DBU-promoted N-alkylation of 3-(pivaloyloxym

Full text of DOI:10.1016/j.tet.2011.10.067

Tetrahedron 68 (2012) 214e225
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Tetrahedron
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Synthesis of 1,2,3-triazolo-nucleosides via the post-triazole N-alkylation
*
ꢀ
Mariola Koszytkowska-Stawinska , Ewa Mironiuk-Puchalska, Tomasz Rowicki
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:
Received 18 July 2011
Received in revised form 5 October 2011
Accepted 17 October 2011
Available online 24 October 2011
2-Substituted-2H-1,2,3-triazolo-nucleosides with 3-phosphonopropyl, 2-hydroxyethyl, 2-cyanoethyl,
carbamoylmethyl, or 1-deoxy-2,5-anhydro-D-mannitol-1-yl on the triazole N-2 nitrogen atom were
obtained via the DBU-promoted N-alkylation of 3-(pivaloyloxymethyl)-1-[(NH-1,2,3-triazol-4-yl)methyl]
thymine with diethyl 3-bromopropylphoshonate, 2-bromoethanol, acrylonitrile, methyl bromoacetate,
or 3,4,6-tris(O-benzoyl)-2,5-anhydro-D-mannitol 1-tosylate. The N-2/N-1 regioselectivity of the alkyl-
ation varied from 57/43 (methyl bromoacetate) to 97/3 (diethyl 3-bromopropylphoshonate). The 1-
substituted-1H-1,2,3-triazoles, when formed in the appreciated amount in the alkylation reaction,
were converted into the corresponding 1-substituted-1H-1,2,3-triazolo-nucleosides. The substitution
pattern of 2-substituted-2H-1,2,3-triazolo-nucleosides was confirmed by 1He15N HMBC NMR spectra;
the triazole nitrogen atoms were identified through their correlations with the triazole exo-cyclic
protons.
Keywords:
1,2,3-Triazoles
2H-1,2,3-Triazole
N-Unsubstituted-1,2,3-triazole
Nucleosides
Click chemistry
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
best of our knowledge, compound 18 represents the only example of
the N-unsubstituted-1,2,3-triazolo-nucleoside. Among analogues
The discovery of azidothymidine (Fig. 1, AZT) and ribavirine
(Fig. 1) as antiviral drugs provided an inspiration for the synthesis
and biological evaluation of their 1,2,3-triazolo-analogues. Gener-
ally, the 1,2,3-triazole framework offers the 1H-, 2H- or 4H-sub-
stitution pattern, depending on the position of the substituents in
the ring.1 However, the majority of the 1,2,3-triazolo-nucleosides
described to date bear the 1H-1,2,3-triazole residue in their struc-
ture. Taking into account the 1H-1,2,3-triazole-substitution pattern,
these analogues can be classified as 1,4-disubstited-,2,3 1,5-
disubstited-,4 or 1,4,5-trisubstituted-1H-1,2,3-triazoles.5 The two
former subclasses of analogues have attracted considerable interest
since the copper-6 or ruthenium-mediated4d,7 azideealkyne cyclo-
additionwasdeveloped for theregioselectivesynthesisof 1,4- or1,5-
disubstited-1H-1,2,3-triazoles, respectively. The role of the triazole
residue in the structure of the aforementioned nucleoside analogues
is schematically shown in Fig. 1: (i) a substituent in a sugar2,4aef or
a nucleobase2a,c,4g moiety of the parent nucleoside (structures A or
B), (ii) a nucleobase surrogate (structures C2aec,4hen,5), or (iii)
a spacer between the nucleobase and the sugar or a sugar mimic
(structures D2a,b,3). Nucleoside analogues bearing an N-unsub-
stituted-1,2,3-triazole residue or a 2-substituted-2H-1,2,3-triazole
framework are much less explored (Fig. 1, compounds 1e3). To the
bearing the 2-substituted-2H-1,2,3-triazole framework, the only
derivatives 29 with the triazole in the role of the nucleobase surro-
gate were described to date. Literature data on 2-substituted-2H-
1,2,3-triazoles bearing a nucleobase residue are also limited. Only
a few 2-(purin-8-yl)-2H-1,2,3-triazoles 310 were reported. Among
them, the butyl derivative 3a (ST 1535) has received great attention
because of its pronounced antiparkinsonian activity.11 A small
number of the N-unsubstituted- or 2-substituted-2H-1,2,3-triazolo-
nucleoside analogues might be considered as one of the factors
restricting systematic structureeactivity relationship (SAR) studies
of 1,2,3-triazolo-nucleosides. In the field of non-nucleoside 1,2,3-
triazoles, the SAR studies taking into account 2-substituted-2H-
1,2,3-triazoles led to the identification of several 2-substituted-2H-
1,2,3-triazole-derived local anaesthetics,12aec Kv 1.5 channel block-
ers,12d antitubercular agents,12e or anti-inflammatory agents.12f Re-
cently,
a
novel 2-substituted-2H-1,2,3-triazole-based drug
candidate (Merck & Co., MK-4305) has been approved for phase III
clinical trials for the treatment of primary insomnia.13 In the field of
1,2,3-triazolo-nucleosides, the reported SAR studies have been fo-
cused mostly on isomeric 1,4-/1,5-disubstituted-1H-1,2,3-triazolo-
nucleosides.4a,b,i,l,m Since nucleoside analogues bearing the 2-
substituted-2H-1,2,3-triazol-2-yl residue represent
a relatively
narrowclass of compounds, an effect of the triazole N-2 substitution
pattern onbiological properties of1,2,3-triazolo-nucleosides has not
been fully explored. A SAR study, comparing compound 2a (Fig. 1)
and its triazole N-1 isomer (Fig. 1, compound C, n¼1, R¼4-C(O)NH2,
* Corresponding author. Tel.: þ48 22 234 5442; fax: þ48 22 628 2741; e-mail
ꢀ
S¼
b-D-2-deoxyribofuranosyl) in terms of their base-pairing
address: mkoszyt@ch.pw.edu.pl (M. Koszytkowska-Stawinska).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.067

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
215
Fig. 1. Schematic representations of 1,4- or 1,5-disubstituted-1H-1,2,3-triazolo-nucleosides (structures AeD) as well as the reported 1,2,3-triazolo-nucleosides with the N-un-
substituted- or 2-substituted-2H-1,2,3-triazole framework.
properties during Taq polymerase-catalyzed biosynthesis of DNA,
was reported.9a In this study, 2a showed more favourable base-
pairing properties than its triazole N-1 isomer. As suggested in the
original paper, the advantageous base-pairing properties of 2a
might be determined by the specific electronic distribution within
its triazole residue. In the light of the above-mentioned biological
activities of 2-substituted-2H-1,2,3-triazoles, the synthesis of novel
2-substituted-2H-1,2,3-triazolo-nucleosides is of interest because of
their potential bioactivity.14
Among the aforementioned 1,2,3-triazolo-nucleosides AeD
(Fig. 1), analogues D3 have recently attracted considerable atten-
tion because of their pronounced physicochemical features3d or
biological2a,b activity (such as antiviral,3b antitumour,3a anti-
microbial3g) or enzyme-binding3j properties. However, their 2-
substituted-2H-1,2,3-triazole congeners have not yet been de-
scribed. Herein we report a series of 1,2,3-triazolo-analogues of
AZT, compounds 4, 5 and 6 (Fig. 2). Compounds 5 and 6 are isomeric
derivatives of NH-1,2,3-triazole 4, bearing a substituent on the tri-
azole N-2 or N-1 nitrogen atom, respectively. The different sub-
stitution pattern of compounds 4, 5 and 6 within the triazole ring
would be expected to have an effect on their biochemical
properties.
applicability of this method for the preparation of 5 might be
limited. Therefore in the presented study, we focused on de-
veloping an efficient protocol for alkylation of 4 under milder re-
action conditions than those used for the preparation of 2. We
chose to evaluate our methodology with biologically important17
functionalities, such as sugar, hydroxyalkyl, phosphonoalkyl, or
carbamoyl. Based on the literature on the alkylation reactions of
non-nucleoside NH-1,2,3-triazoles,1 we expected that some of the
alkylations performed in this study would give the target triazole
N-2-alkylated products accompanied by the corresponding triazole
N-1 isomers. Therefore, the scope and limitations concerning the
applicability of the triazole N-alkylation method for the efficient
preparation of isomeric derivatives 5 and 6 were investigated.
2.1. Synthesis
NH-1,2,3-Triazoles are commonly synthesized by the cycload-
dition of alkynes and hydrazoic acid18 (or its equivalents, such as
sodium azide,19 trimethylsilyl azide20 or the selected organic
azides21). In our study, 4 was obtained from 1-propargylthymine22
(7) with two methods (Scheme 1). In the first of them, the cyclo-
addition of 7 with trimethylsilyl azide (TMSeN3, 8a) at 120 ꢀC,
Fig. 2. The target analogues of AZT.
2. Results and discussion
followed by the treatment of a crude reaction mixture with
methanol at 20e22 ꢀC, gave 4 in 78% yield. In the second method,
the CuI/diisopropylethyl amine (DIPEA)-catalyzed coupling of 7
with pivaloyloxymethyl azide21c (8b) in tetrahydrofuran (THF) at
70 ꢀC gave the pivaloyloxymethyl derivative 6a in 80% yield. Then,
the treatment of 6a with a methanolic NH4OH at 20e22 ꢀC afforded
4 in 88% yield. The combined yield of 4 from this two-step synthesis
(70%) was lower than that obtained with the use of 8a. However,
this disadvantage was compensated by a lower cost of the reagents
used, including reagents needed for the preparation of piv-
aloyloxymethyl azide (8b), and the possibility of carrying out the
coupling reaction under milder, non-anhydrous conditions. The
effective de-pivaloyloxymethylation of 6a with NH4OH instead of
A literature survey of synthetic routes to 2-substituted-2H-1,2,3-
triazoles1,12,15 led us to an assumption that a methodology in-
volving a triazole N-alkylation of NH-1,2,3-triazole 4 (or its
pyrimidine-protected form) would be a convenient approach to the
target compounds 5. Although the N-alkylation of NH-1,2,3-
triazoles can be considered as one of the most commonly used
methods for the synthesis of structurally diverse 2-substituted-2H-
1,2,3-triazoles,16 its application in the chemistry of nucleoside an-
alogues has been limited to the synthesis of compounds 2
(Fig.1).9eei However, owing to the harsh reaction conditions used (a
protonic acid and a prolonged heating at above 120 ꢀC), the

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
216
aqueous sodium hydroxide, as recommended in the original
work21c on 1-(pivaloyloxymethyl)-1H-1,2,3-triazoles, let us to avoid
the subsequent acidification of the reaction mixture. In a conse-
quence, the isolation of the reaction product was simplified.
derivative 11 (21% yield). In order to prevent the concomitant al-
kylation of 4 on the pyrimidine N-3 nitrogen atom, the pyrimidine-
protected derivative 13 was prepared and then its reactions with 9a
in the presence of various bases were examined (Scheme 2b). Thus,
the reaction of 7 with chloromethyl pivalate (PivO-CH2Cl) in the
presence of K2CO3 gave 12 in 93% yield. Then, the treatment of 12
with TMSeN3 (8a), under the same conditions as those used for 4,
afforded 13 in 79% yield. Next, treatment of 13 with 9a in the
presence of NEt3, under the same conditions as that used for 4,
afforded the 2-(2-cyanoethyl) derivative 14a in 51% yield and the 1-
(2-cyanoethyl) derivative 15a in 38% yield. The same reaction car-
ried out in the presence of DIPEA yielded a 14a/15a mixture in
a ratio of 55/45. Analogously, the reaction carried out in the pres-
ence of pyridine (Py) gave the 14a/15a mixture in a ratio of 58/42.
Additionally, compared to the reactions conducted in the presence
of NEt3 or DIPEA, the conversion of the starting 13 was very low
(49% by 1H NMR spectroscopic analysis). The highest 14a/15a ratio
was achieved with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the
additive; 14a was obtained in 81% yield. The minor product 15a
(16% yield) was readily separated by column chromatography.
Next, derivative 13 was reacted with bromides 9bed or tosylate
9e in the presence of DBU (Scheme 3a). While a commercially
available methyl bromoacetate (9b), 2-bromoethanol (9c) or
diethyl 3-bromopropylphosphonate (9d) were used as purchased,
the sugar-derived tosylate 9e was obtained from 1-O-benzoyl-2,5-
Scheme 1. Reagents and conditions: (i) 1. toluene, 120 ꢀC, 1 day; 2. MeOH, 20e22 ꢀC,
30 min; (ii) CuI, DIPEA, THF, 70 ꢀC, overnight.
The preliminary alkylation of 4 with acrylonitrile (9a) is shown
in Scheme 2a. The alkylation of NH-1,2,3-triazoles has been com-
monly reported under basic conditions, mainly in the presence of
K2CO3 or Na2CO3.12,16 However under these conditions, we ex-
pected of a simultaneous alkylation of 4 on the pyrimidine N-3
nitrogen atom. This expectation was based on our experience on
the preparation of 7 from thymine and propargyl bromide in the
presence of K2CO3,3i where 1,3-dipropargylthymine was formed in
ca. 40% yield. Therefore, in the preliminary reaction of 4 with 9a we
employed triethylamine (NEt3) as a base. Literature data on the
preparation of 1-(2-cyanoethyl)thymine23 revealed that thymine
did not undergo alkylation on the N-3 nitrogen atom with acrylo-
nitrile in the presence of NEt3. Additionally, tertiary amines16f (in-
cluding NEt3) have been reported to promote the N-2 alkylation of
NH-1,2,3-triazoles in good regioselectivity. As seen in Scheme 2a,
the reaction of 4 with 9a gave four products. Column chromatog-
raphy of the reaction mixture afforded a 5a/10 mixture in a molar
ratio of 80/20 (by 1H NMR spectroscopic analysis), 1-(2-
cyanoethyl)-derivative 6b (17% yield) and 2,30-bis(2-cyanoethyl)-
anhydro-
-mannitol24 (16) via the monobenzoyl tosylate 17
D
(Scheme 3b). The 14/15 combined yields obtained from the alkyl-
ations of 13 with 9bed varied from 87% for 9b to 69% for 9e. The N-
2-substituted products 14bed were readily separated from the
corresponding N-1 isomers 15bed by column chromatography. The
sugar derivative 15e was the only exception; column chromatog-
raphy of the reaction mixture afforded 14e in 57% yield and a 14e/
15e mixture in a ratio of 70/30 ratio (by 1H NMR spectroscopic
analysis) in 12% combined yield. Taking into account the isolated
yields of the products obtained from the reactions performed with
bromides 9bed, the preference to alkylation of 13 at the triazole N-
2 nitrogen atom increased in the series of 9b<9c<9d. An expla-
nation of this finding is rather difficult at the present stage of our
study. Steric effects or a specific nature of the R-substituent on the
electrophilic carbon site of 9bed might be considered as a factor
influencing the course of the alkylation reaction.25
(a)
(b)
Scheme 2. Reagents and conditions: (i) NEt3, DMF, 20e22 ꢀC, 1 d; (ii) PivO-CH2Cl, K2CO3, DMF, 20e22 ꢀC, 2 days; (iii) 1. toluene, 120 ꢀC, overnight; 2. MeOH, 20e22 ꢀC, 1 h; (iv) Base
(NEt3, DIPEA, Py or DBU), DMF, 20e22 ꢀC, 1 day.

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
217
Preparation of 1-substituted-1H-1,2,3-triazoles 6bei is depicted
in Schemes 5 and 6. Formation of 15aec in relatively high yields
(Schemes 2 and 3) inspired us to transform them into their
pyrimidine-deprotected forms (Scheme 5). Interestingly, 15a (or 6b
as its pyrimidine-deprotected form) proved to be much more sen-
sitive to NH3 than 5a. While 5a was stable in a methanolic NH3 for 2
months, the treatment of 15a with a methanolic NH4OH at 20e22 ꢀC
resulted in the formation of a complex mixture. The expected 6bwas
accompanied by 4, a product of a retro-Michael de-cyanoethylation,
and amide 6c. The column chromatography of the mixture afforded
a 4/6b mixture in a ratio of 40/60 (by 1H NMR spectroscopic analysis)
and a 6b/6c mixture in a ratio of 30/70 (by 1H NMR spectroscopic
analysis). On the other hand, treatment of 15b or 15c with a meth-
anolic NH3, or a methanolic NH4OH at 20e22 ꢀC afforded 6d (82%
yield) or 6e (77% yield), respectively. Compound 6e was also ob-
tained in 78% yield by the CuI/DIPEA-catalyzed ‘click’ coupling of 7
with 2-azidoethanol26 (8c) in tetrahydrofuran (THF) at 70 ꢀC
(Scheme 6a). Finally, the azideealkyne ‘click’ coupling method was
applied to complete a series of the target of 1,2,3-triazolo-nucleo-
sides (Scheme 6a). Under the previously used conditions, the cou-
pling of 7 with diethyl 3-azidopropylphosphonate27 (8d) or the
sugar-derived azide 8e (the synthesis of which is shown in Scheme
6b) gave 6f (76% yield) or 6g (70% yield), respectively. In the next
step, derivatives 6f and 6g were converted into the final compounds
6h and 6i, respectively. The de-alkylation of 6f with TMSBr, under
the same conditions as those described for de-alkylation of de-
rivative 5d, gave 1-(3-phosphonopropyl)-1H-1,2,3-triazole de-
rivative 6h in 85%yield. The de-benzoylation of 6g with a methanolic
NH3, under the same conditions as those described for deprotection
of derivative 14e, gave 6i in 86% yield.
(a)
(b)
Scheme 3. Reagents and conditions: (i) DBU, DMF, 20e22 ꢀC, 1 day; (ii) BzCl, Py,
20e22 ꢀC, 1 day; (iii) TsCl, Py, 20e22 ꢀC, 1 day.
2.2. Structure elucidation
The 1H and 13C chemical shifts for the triazole N-2 substituted
compounds 5 (a, c, f), 11 and 14a as well as for the triazole N-1
substituted compounds 6 (a, b, e, i) were fully assigned by 1He13C
HMBC NMR experiments (Tables 1 and 2). In the 1He13C HMBC
NMR spectra of compounds 6 (a, b, e, i), the 1He13C HMBC corre-
lation of H-1a4C-5 was observed. In the 1H NMR spectra, the
signal due to the triazole H-5 proton of the N-2 substituted triazoles
5 (a, c, f) occurred at higher field (7.67e7.78 ppm) compared to the
signal of the corresponding N-1 substituted isomers 6 (b, e, i)
(8.00e8.14 ppm). In the 13C NMR spectra, the signal due to the
triazole C-5 carbon atom of compounds 5 (a, c, f), occurred at lower
Conversion of 14aee into the target 2,4-disubstituted-2H-1,2,3-
triazoles 5aef is shown in Scheme 4. Derivatives 14a, 14b, 14c and
14e were converted into 5a, 5b, 5c or 5f, respectively, under the
treatment with a methanolic NH4OH, or a methanolic NH3, at
20e22 ꢀC; the yields of products varied from 74% to 86%. Phos-
phonate 14d was transformed into the final 5e in two steps: (1) de-
pivaloyloxymethylation of 14d with a methanolic NH4OH at
20e22 ꢀC, and (2) de-alkylation of the resulting 5d with trime-
thylsilyl bromide (TMSBr) at 20e22 ꢀC, followed by treatment of
the crude reaction mixture with methanol at 20e22 ꢀC. The total
yield of 5e from 14d was 71%.
Scheme 4. Reagents and conditions: (i) NH4OH, MeOH, 20e22 ꢀC, overnight; (ii) NH3/MeOH, 20e22 ꢀC: (a) 3 days, or (b) overnight; (iii) 1. TMSBr, acetonitrile, 20e22 ꢀC, overnight;
2. MeOH, 20e22 ꢀC, 1 h.

Scheme 5. Reagents and conditions: (i) NH4OH, MeOH, 20e22 ꢀC, overnight; (ii) NH3/MeOH, 20e22 ꢀC, 3 days.
(a)
(b)
Scheme 6. Reagents and conditions: (i) CuI, DIPEA, THF, 70 ꢀC, overnight; (ii) 1. TMSBr, acetonitrile, 20e22 ꢀC, overnight; 2. MeOH, 20e22 ꢀC, 1 h; (iii) NH3/MeOH, 20e22 ꢀC, 3 days;
(iv) NaN3, Bu4NHSO4, DMF, 50 ꢀC, 3 days.
Table 1
Numbering and 1H chemical shift assignments in selected 2-substituted-2H-1,2,3-triazoles and 1-substituted-1H-1,2,3-triazoles
1a
1b
2a
2b
5
Other signals
5aa
5ca
5fb
4.69
4.39
4.59, 4.63
3.13
7.78 4a (4.93), 30 (11.38), 50a (1.75), 60 (7.59)
3.79e3.86 7.68 (4a, OH) (4.89), 30 (11.32), 50a (1.75), 60 (7.59)
7.67 4a (4.97), 50a (1.86), 60 (7.50), 100 (4.27e4.30), 200 (3.98), 300 (4.02), 400 (3.79e3.82), 500 (3.58, 3.65), Ph (7.41e7.88)
8.19 4a (4.90), 30 (11.29), 50a (1.73), 60 (7.60), t-Bu (1.09)
6aa
6ba
6ea
6ib
6.27
4.64
4.37
4.62, 4.65
3.17
3.76
8.14 4a (4.91), 30 (11.31), 50a (1.75), 60 (7.61)
8.01 4a (4.89), 30 (11.28), 50a (1.75), 60 (7.61), OH (5.01)
8.00 4a (4.97), 50a (1.84), 60 (7.48), 100 (4.16e4.19), 200 (3.85), 300 (4.11), 400 (4.02e4.05), 500 (4.40, 4.47), Ph (7.47e8.04)
11a
14aa
4.66
4.67
3.13
3.13
7.79 4a (5.01), 30a (4.07), 30b (2.83), 50a (1.82), 60 (7.71)
7.80 4a (5.01), 30a (5.78), 50a (1.82), 60 (7.75), t-Bu (1.09)
a
In DMSO-d6.
In CD3OD.
b

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
219
Table 2
13C chemical shift assignments in selected 2-substituted-2H-1,2,3-triazoles and 1-substituted-1H-1,2,3-triazoles
1a
1b
2a
2b
5
Other signals
5aa
5ca
5fb
49.75
57.05
57.74
17.91
59.56
133.87
133.09
134.63
4 (144.24), 4a (42.02), 20 (150.81), 40 (164.34), 50 (109.11), 50a (12.00), 60 (141.06), CN (118.19)
4 (143.39), 4a (42.08), 20 (150.81), 40 (164.34), 50 (109.05), 50a (12.00), 6’ (141.14)
4 (144.95), 4a (43.58), 20 (152.76), 40 (166.79), 50 (111.59), 50a (12.24), 60 (142.62), 100 (83.43), 200 (79.95),
300 (78.52), 400 (85.83), 500 (63.03), Ph (128.62, 129.51, 132.92, 134.94), PheC(O)e (172.37)
4 (143.00), 4a (42.07), 20 (150.73), 40 (164.27), 50 (108.92), 50a (11.94), 60 (141.15),
t-Bu (26.47, 38.23), t-Bu-C(O)e (176.45)
6aa
70.08
124.78
6ba
6ea
6ib
45.00
52.28
52.93
18.38
59.81
123.78
124.01
126.27
4 (142.79), 4a (42.20), 20 (150.70), 40 (164.25), 50 (108.87), 50a (11.93), 60 (141.12), CN (118.10)
4 (142.27), 4a (42.21), 20 (150.77), 40 (164.34), 50 (108.89), 50a (12.00), 60 (141.22)
4 (143.90), 4a (43.65), 20 (152.66), 40 (166.73), 50 (111.55), 50a (12.22), 60 (142.55), 100 (82.91), 200 (79.25),
300 (78.64), 400 (82.75), 500 (65.48), Ph (129.65, 130.63, 131.22, 134.38), PheC(O)e (167.81)
4 (143.92), 4a (43.27), 20 (150.58), 30a (36.21), 30b (15.47) 40 (162.77), 50 (108.25), 50a (12.49),
60 (140.16), CN (118.14, 118.41)
11a
49.67
49.70
17.82
17.83
133.84
133.90
14aa
4 (143.76), 4a (43.23), 20 (150.29), 30a (64.94), 40 (162.39), 50 (108.26), 50a (12.39), 60 (140.94), CN (118.08),
t-Bu (26.62, 38.24), t-Bu-C(O)e (176.60)
a
In DMSO-d6.
In CD3OD.
b
field (133.09e134.63 ppm) compared to the signal of the corre-
sponding N-1 substituted isomers 6 (b, e, i) (123.78e126.27 ppm).
The triazole N-2-substitution pattern of compounds 5 was con-
firmed by the 1He15N HMBC NMR spectra of 14a and 5c. As shown
in the spectrum of 14a (Fig. 3), the interactions between the H-2a
protons and the triazole nitrogen atoms (i.e., H-2a4N-2 and N-
14H-2a4N-3) were observed in these spectra. The N-2 resonance
(ꢁ129.2 ppm for 14a, or ꢁ127.4 ppm for 5c) was distinguished of
from those corresponding to the N-1 or N-3 nitrogen atom by the
correlation of H-2b4N-2. The N-1 resonance (ꢁ49.6 ppm for 14a,
or ꢁ49.2 ppm for 5c) and the N-3 resonance (ꢁ54.8 ppm for 14a, or
ꢁ54.6 ppm for 5c) were differentiated by the correlations of H-
54N-14H-2a as well as H-4a4N-34H-2a. Moreover, the spectra
featured the interaction of both the H-4a protons and the H-60
protons with the pyrimidine N-10 nitrogen atom (ꢁ250.4 ppm for
14a, or ꢁ249.1 ppm for 5c).
of potential alkylating reagents (e.g., Michael acceptors or alkyl
halides) or their precursors (e.g., alcohols), our approach to
compounds 5 offers an opportunity to synthesize (2-substituted-
2H-1,2,3-triazol-4-ylmethyl)nucleosides with a variety of bi-
ologically important functionalities. As shown on the example
of compound 14b, derivatives with an alkoxycarbonyl function
might be further modified, for instance by an amidation
reaction. The 1-substituted-1H-1,2,3-triazoles, when formed in
the appreciated amount in the alkylation reaction, were con-
verted into the corresponding 1-substituted-1H-1,2,3-triazolo-
nucleosides 6. The 1He15N HMBC NMR spectra of compounds
14a and 5c were particularly informative and useful for verifi-
cation of the N-2 substitution pattern of the target compounds
5, since all signals due to the triazole nitrogen atoms were
observed and assigned through their correlations with the
triazole exo-cyclic protons. A study on the improvement and
Fig. 3. 1He15N HMBC NMR spectrum of 14a (DMSO-d6).
3. Conclusion
extension of the presented methodology for the synthesis
of highly functionalized 2-substituted-2H-1,2,3-triazolo-nucleo-
sides is now in progress. This study, including a SAR analysis of
the obtained compounds, will be a subject of a forthcoming
publication.
The post-triazole N-alkylation process was successfully ap-
plied to the synthesis of 2-substituted-2H-1,2,3-triazolo-nucle-
osides 5. Taking into account the broad commercial availability

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
220
4. Experimental
ammonium hydroxide (10 mL) and methanol (5 mL) was stirred at
20e22 ꢀC overnight. Volatiles were distilled off. The residue was
triturated with a cooled methanol and 4 as a white solid was fil-
tered off and dried on air (129 mg, 88%). The NMR spectra were
consistent with those described in Section 4.2.
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). Column chromatography was performed using silica gel
(200e400 mesh, Merck). Optical rotations were measured with
a PolAAr32 polarimeter. High Resolution Mass Spectra (Electrospray
Ionisation, ESI) were performed on a MarinerÒ spectrometer unless
otherwise indicated. The NMR spectra were measured on a Varian
Gemini-200BB spectrometer (1H NMR at 200 MHz, 13C NMR at
4.4. Reaction of 4 with acrylonitrile (9a)
Triethylamine (122 mg, 1.2 mmol, 170 mL) was added to a solu-
tion of 4 (225 mg, 1.1 mmol) in anhydrous DMF (5 mL). The mixture
was stirred at 20e22 ꢀC for 30 min and then acrylonitrile (9a)
(62 mg, 1.5 mmol, 80 mL) was added in one portion. The mixture
50 MHz) or a Varian VNMRS spectrometer (1H NMR at 500 MHz, 13
NMR at 125 MHz).1H and 13C chemical shifts (
) are reported in parts
C
was stirred at 20e22 ꢀC for 1 day and then ethyl acetate (25 mL)
was added. The solution was washed with water (5 mL) and brine
(5 mL) and dried. Volatiles were distilled off. Column chromatog-
raphy (CHCl3/MeOH, 99/1, v/v) of the residue gave a 5a/10 mixture
of 80/20 molar ratio (80 mg), 6b (45 mg, 17%, a white solid, mp
>224 ꢀC dec) and 11 (65 mg, 21%, colourless oil). The 5a/10 molar
ratio was based on relative intensities of the triazole H-5 proton
signals: 5a, 7.78 ppm; 10, 8.16 ppm. 1-[(2-(2-Cyanoethyl)-2H-1,2,3-
triazol-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (5a) and
3-(2-cyanoethyl)-1-[(1-(2-cyanoethyl)-1H-1,2,3-triazol-4-yl)
d
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; or CD3OD (residual CH3OH) 3.31 ppm, dC
49.00 ppm; signals are quoted as ‘s’ (singlet), ‘d’ (doublet), ‘t’ (trip-
let), ‘m’ (multiplet), ‘br s’ (broad singlet), and ‘dd’ (doublet of dou-
blets). Coupling constants J are reported in Hertz. The 1He13C or
1He15N HMBC (Heteronuclear Multiple Bond Correlation) spectra
were measured on a Varian VNMRS spectrometer. 15N chemical
shifts in 5c or 14a are reported in parts per million (ppm) relative to
the signal of CH3NO2 as an external standard. Anhydrous MgSO4 was
employed as a drying agent. Volatiles were distilled off under re-
duced pressure on a rotating evaporator. The concentration of am-
monium hydroxide used was 25 wt %. The concentration of
a methanolic solution of NH3 used was 7 N (SigmaeAldrich).
methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (10). dH (200 MHz,
DMSO-d6) 1.74 (s, 2.4H),1.82 (s, 0.6H), 2.82 (t, 0.4H, 3JH,H 6.5), 3.13 (t,
3
2H, 3JH,H 6.5), 4.06 (t, 0.4H, 3JH,H 6.5), 4.67 (t, 2H, JH,H 6.5), 4.92 (s,
1.6H), 5.00 (s, 0.4H), 7.58 (s, 0.8H), 7.74 (s, 0.2H), 7.78 (s, 0.8H), 8.16
(s, 0.2H), 11.32 (br s, 1H). LRMS m/z calcd for: (a) C11H12N6O2Na
[MþNa]þ 283.09; found 283.1 (5a), and (b) C14H15N7O2Na [MþNa]þ
336.1; found 336.1 (10). HRMS m/z calcd for C14H15N7O2Na
[MþNa]þ 336.1185; found 336.1169 (10). For spectral data of 5a, see:
Section 4.9.5.1. 1-[(1-(2-Cyanoethyl)-1H-1,2,3-triazol-4-yl)methyl]-
5-methylpyrimidine-2,4(1H,3H)-dione (6b). dH (500 MHz, DMSO-d6)
1.75 (d, 3H, 4JH,H 1.0), 3.17 (t, 2H, 3JH,H 6.5), 4.64 (t, 2H, 3JH,H 6.5), 4.91
(s, 2H), 7.61 (q, 1H, 4JH,H 1.0), 8.14 (s, 1H), 11.31 (s, 1H). dC (125 MHz,
DMSO-d6) 11.93, 18.38, 42.20, 45.00, 108.87, 118.10, 123.78, 141.12,
142.88, 150.70, 164.25. HRMS m/z calcd for C11H12N6O2Na [MþNa]þ
283.0919; found 283.0914. 3-(2-Cyanoethyl)-1-[(2-(2-cyanoethyl)-
2H-1,2,3-triazol-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione
(11). dH (500 MHz, DMSO-d6) 1.82 (d, 3H, 4JH,H 1.0), 2.83 (t, 2H, 3JH,H
6.5), 3.13 (t, 2H, 3JH,H 6.5), 4.07 (t, 2H, 3JH,H 6.5), 4.66 (t, 2H, 3JH,H 6.5),
5.01 (s, 2H), 7.71 (q, 1H, 4JH,H 1.0), 7.79 (s, 1H). dC (125 MHz, DMSO-
d6) 12.49, 15.47, 17.82, 36.21, 43.27, 49.67, 108.25, 118.14, 118.41,
133.84, 140.16, 143.92, 150.58, 162.77. HRMS m/z calcd for
C14H15N7O2Na [MþNa]þ 336.1185; found 336.1183.
4.2. 5-Methyl-1-[NH-1,2,3-triazol-4-ylmethyl]pyrimidine-
2,4(1H,3H)-dione (4) from 7 and 8a
Trimethylsilyl azide (8a, 576 mg, 5.0 mmol, 0.6 mL) was added to
a solution of 1-propargylthymine (7) (200 mg, 1.0 mmol) in anhy-
drous toluene (2 mL). The mixture was heated in an oil bath (120 ꢀC)
for 1 day under argon and volatiles were distilled off. The residue
was dissolved in methanol (10 mL). The solution was kept at
20e22 ꢀC for 1 h and then volatiles were distilled off. The residue
was treated with cold methanol and 4 was filtered off as awhite solid
and dried on air (162 mg, 78%, mp >230 ꢀC dec). dH (200 MHz,
DMSO-d6) 1.75 (d, 3H, JH,H 1.2), 4.92 (s, 2H), 7.60 (q, 1H, JH,H 1.2),
7.81 (s, 1H), 11.31 (br s, 1H, NH). dC (50 MHz, DMSO-d6, CF3CO2H)
12.03, 42.03,109.06,128.84 (br),141.27,142.06,150.89,164.42. HRMS
m/z calcd for C8H9N5O2Na [MþNa]þ 230.0654; found 230.0659.
4
4
4.3. 5-Methyl-1-[NH-1,2,3-triazol-4-ylmethyl]pyrimidine-
2,4(1H,3H)-dione (4) from 7 and 8b
4.5. 3-(Pivaloyloxymethyl)-1-propargylthymine (12)
Anhydrous K2CO3 (5.53 g, 40.0 mmol) was added to a solution of
7 (1.32 g, 8.0 mmol) in anhydrous DMF (25 mL). The mixture was
stirred at 20e22 ꢀC for 30 min and then chloromethyl pivalate
(2.41 g, 16.0 mmol, 2.3 mL) was added in one portion. The mixture
was stirred at 20e22 ꢀC for 2 days and filtered through a CeliteÒ
pad. The pad was washed with DMF (10 mL). Filtrates were col-
lected and volatiles were distilled off. Column chromatography of
the residue (CHCl3) gave 12 (2.07 g, 93%) as a white solid (mp
93e96 ꢀC). dH (500 MHz, CDCl3) 1.17 (s, 9H), 1.96 (s, 3H), 2.48 (t, 1H,
4.3.1. 5-Methyl-1-[(1-(pivaloyloxymethyl)-1H-1,2,3-triazol-4-yl)
methyl]pyrimidine-2,4(1H,3H)-dione (6a). Diisopropylethylamine
(190 mg, 1.4 mmol, 250
mL) was added to a mixture of 1-
propargylthymine (7) (267 mg, 1.6 mmol), pivaloyloxymethyl azide
(8b) (240 mg, 1.5 mmol), copper(I) iodide (30 mg, 0.16 mmol) and
THF (15 mL). The mixture was heated at 70 ꢀC (an oil bath) overnight
and filtered through a CeliteÒ pad. The pad was washed with THF
(10 mL). The filtrates were collected and evaporated to dryness un-
der reduced pressure. Column chromatography of the residue
(CHCl3/MeOH, 99/1, v/v) gave 6a (423 mg, 80%) as a white solid (mp
166e168 ꢀC). dH (500 MHz, DMSO-d6) 1.09 (s, 9H), 1.73 (d, 3H, 4JH,H
1.0), 4.90 (s, 2H), 6.27 (s, 2H), 7.60 (q, 1H, 4JH,H 1.0), 8.19 (s, 1H), 11.29
(br s, 1H). dC (125 MHz, DMSO-d6) 11.94, 26.47, 38.23, 42.07, 70.08,
108.92,124.78,141.15,143.00,150.73,164.27,176.45. HRMS m/z calcd
for C14H19N5O4Na [MþNa]þ 344.1329; found 344.1325.
3
4JH,H 2.5), 4.56 (d, 2H, JH,H 2.5), 5.95 (s, 2H), 7.28 (s, 1H). dC
(125 MHz, CDCl3) 13.12, 27.12, 37.65, 38.92, 65.33, 75.48, 76.34,
110.84, 137.46, 150.56, 162.70, 177.60. HRMS (EI, 70 eV) m/z calcd for
C14H18N2O4 Mþ 278.1267; found 278.1277.
4.6. 5-Methyl-3-(pivaloyloxymethyl)-1-[(NH-1,2,3-triazol-4-
yl)methyl]pyrimidine-2,4(1H,3H)-dione (13)
4.3.2. 5-Methyl-1-[NH-1,2,3-triazol-4-ylmethyl]pyrimidine-
Treatment of 12 (1.32 g, 4.7 mmol) with trimethylsilyl azide (8a)
2,4(1H,3H)-dione (4). A mixture of 6a (228 mg, 0.7 mmol),
(2.77 g, 24 mmol, 3.2 mL) under the conditions described in Section

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
221
4.2 gave 13 (1.20 g, 79%) as colourless oil, after column chroma-
tography (CHCl3/MeOH, 95/5, v/v). dH (500 MHz, CDCl3) 1.15 (s, 9H),
1.92 (s, 3H), 5.04 (s, 2H), 5.98 (s, 2H), 7.31 (s, 1H), 7.80 (s, 1H), 13.25
(br s, 1H, NH). dC (50 MHz, CDCl3) 13.09, 27.10, 38.98, 43.61, 65.19,
110.81, 130.26 (br), 139.23, 141.74 (br), 151.06, 163.01, 177.90. HRMS
m/z calcd for C14H19N5O4Na [MþNa]þ 344.1329; found 344.1318.
110.34, 134.88, 138.83, 143.57, 150.72, 162.63, 166.93, 177.37. HRMS
m/z calcd for C17H23N5O6Na [MþNa]þ 416.1541; found 416.1550.
Compound 15b, dH (200 MHz, CDCl3) 1.09 (s, 9H), 1.84 (d, 3H, 4JH,H
0.8), 3.62 (s, 3H), 4.93 (s, 2H), 5.12 (s, 2H), 5.85 (s, 2H), 7.33 (q, 1H,
4JH,H 0.8), 7.80 (s, 1H). dC (50 MHz, CDCl3) 12.83, 26.91, 38.73, 43.68,
53.04, 54.62, 64.96, 110.26, 125.16, 139.30, 142.27, 150.77, 162.72,
166.56, 177.47. HRMS m/z calcd for C17H23N5O6Na [MþNa]þ
416,1541; found 416.1553.
4.7. Reaction of 13 with acrylonitrile (9a) in the presence of
NEt3
4.9.2. 1-[(2-(2-Hydroxyethyl)-2H-1,2,3-triazol-4-yl)methyl]-5-
methyl-3-(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-dione (14c) and
1-[(1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl]-5-methyl-3-
(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-dione (15c). According
to the procedure described in Section 4.4, compounds 14b and 15b
were synthesized from 13 (320 mg, 1.0 mmol) and 2-bromoethanol
(9c). Column chromatography of the residue (CHCl3/MeOH, 95/5, v/
v) gave 14c (223 mg, 61%) and 15c (78 mg, 21%) as colourless oils.
According to the procedure described in Section 4.4, the reaction
was performed from 280 mg (0.9 mmol) of 13. Column chroma-
tography (CHCl3/MeOH, 99/1, v/v) of the residue gave 14a (172 mg,
51%, colourless oil) and 15a (128 mg, 38%, colourless oil). 1-[(2-(2-
Cyanoethyl)-2H-1,2,3-triazol-4-yl)methyl]-5-methyl-3-(pivaloylox-
ymethyl)pyrimidine-2,4(1H,3H)-dione (14a). dH (500 MHz, CDCl3)
4
1.16 (s, 9H), 1.92 (d, 3H, JH,H 1.0), 3.03 (t, 2H, 3JH,H 7.0), 4.67 (t, 2H,
3JH,H 7.0), 4.95 (s, 2H), 5.95 (s, 2H), 7.16 (q, 1H, 4JH,H 1.0), 7.66 (s, 1H).
Compound 14c, dH (200 MHz, CDCl3) 1.09 (s, 9H), 1.84 (d, 3H, JH,H
4
4
3
dH (500 MHz, DMSO-d6) 1.09 (s, 9H), 1.82 (d, 3H, JH,H 1.0), 3.13 (t,
0.8), 3.22 (br s, 1H, OH), 3.99e4.02 (m, 2H), 4.43e4.48 (t, 2H, JH,H
4
2H, 3JH,H 6.0), 4.67 (t, 2H, 3JH,H 6.0), 5.01 (s, 2H), 5.78 (s, 2H), 7.75 (q,
5.0), 4.89 (s, 2H), 5.88 (s, 2H), 7.17 (q, 1H, JH,H 0.8), 7.56 (s, 1H). dC
4
1H, JH,H 1.0), 7.80 (s, 1H). dC (50 MHz, CDCl3) 12.93, 18.38, 26.96,
(50 MHz, CDCl3) 12.87, 26.93, 38.75, 43.46, 56.98, 60.64, 65.04,
110.40, 133.87, 139.04, 142.60, 150.77, 162.75, 177.54. HRMS m/z
calcd for C16H23N5O5Na [MþNa]þ 388.1597; found 388.1584.
38.88, 43.24, 49.91, 65.06, 110.70, 116.15, 134.85, 138.59, 143.49,
150.78, 162.64, 177.46. dC (125 MHz, DMSO-d6) 12.39, 17.83, 26.62,
38.24, 43.23, 49.70, 64.94, 108.26, 118.08, 133.90, 140.94, 143.76,
150.29, 162.39, 176.60. HRMS m/z calcd for C17H22N6O4Na [MþNa]þ
397.1595; found 397.1588. 1-[(1-(2-Cyanoethyl)-1H-1,2,3-triazol-4-
yl)methyl]-5-methyl-3-(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-
dione (15a). dH (200 MHz, CDCl3) 1.18 (s, 9H), 1.94 (d, 3H, 4JH,H 1.2),
3.04 (t, 2H, 3JH,H 6.6), 4.64 (t, 2H, 3JH,H 6.6), 4.98 (s, 2H), 5.94 (s, 2H),
4
Compound 15c, dH (200 MHz, CDCl3) 1.13 (s, 9H), 1.86 (d, 3H, JH,H
1.2), 3.33 (br s, 1H, OH), 3.96e4.01 (t-like m, 2H), 4.42e4.47 (t-like
m, 2H), 4.91 (s, 2H), 5.87 (s, 2H), 7.34 (q, 1H, 4JH,H 1.2), 7.81 (s, 1H). dC
(50 MHz, CDCl3) 12.90, 26.99, 38.84, 43.85, 52.81, 60.86, 65.02,
110.40, 124.74, 139.46, 141.83, 150.87, 162.85, 177.71. HRMS m/z
calcd for C16H23N5O5Na [MþNa]þ 388.1597; found 388.1603.
4
7.35 (q, 1H, JH,H 1.2), 7.84 (s, 1H). dC (50 MHz, CDCl3) 13.08, 19.44,
27.15, 38.96, 43.98, 45.87, 65.17, 110.73, 116.14, 124.43, 139.22,
142.73, 150.98, 162.84, 177.67. HRMS m/z calcd for C17H22N6O4Na
[MþNa]þ 397.1595; found 397.1588.
4.9.3. 1-[(2-(3-(Diethoxyphosphoryl)propyl)-2H-1,2,3-triazol-4-yl)
methyl]-5-methyl-3-(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-di-
one (14d) and 1-[(1-(3-(diethoxyphosphoryl)propyl)-1H-1,2,3-
triazol-4-yl)methyl]-5-methyl-3-(pivaloyloxymethyl)pyrimidine-
2,4(1H,3H)-dione (15d). According to the procedure described in
Section 4.4, compounds 14d and 15d were synthesized from 13
(321 mg, 1.0 mmol) and diethyl 3-bromopropylphosphonate (9d).
Column chromatography of the residue (CHCl3/MeOH, 99/1, v/v)
gave 14d (334 mg, 67%) and 15d (27 mg, 5%) as colourless oils.
4.8. Reactions of 13 with acrylonitrile (9a) in the presence of
DIPEA, Py or DBU
The reactions were conducted in accordance with the procedure
described in Section 4.4, using 13 (100 mg, 0.3 mmol) and DIPEA, Py
or DBU (0.36 mmol) instead of NEt3. After the usual work-up, a 1H
NMR spectrum of the crude reaction mixture was recorded
(200 MHz, CDCl3). Conversion of 13 was calculated as a ratio be-
tween the intensity of the signal corresponding to the triazole H-5
proton of 13 (7.80 ppm) and combined intensities of the signals
corresponding to the triazole H-5 proton of 14a (7.66 ppm) and 15a
(7.84 ppm). The 14a/15a ratio was determined from the intensities of
signals corresponding to the triazole H-5 proton of 14a and 15a. The
reaction carried out in the presence of DBU, when repeated from
480 mg (1.5 mmol) of 13, gave 14a (454 mg, 81%) and 15a (90 mg,
16%), after column chromatography (CHCl3/MeOH, 99/1, v/v).
3
Compound 14d, dH (200 MHz, CDCl3) 1.18 (s, 9H), 1.31 (t, 6H, JH,H
4
7.0), 1.68e1.82 (m, 2H), 1.94 (d, 3H, JH,H 1.2), 2.14e2.36 (m, 2H),
4.01e4.18 (quintet-like m, 4H), 4.50e4.58 (t-like m, 2H), 4.94 (s,
4
2H), 5.97 (s, 2H), 7.16 (q, 1H, JH,H 1.2), 7.61 (s, 1H). dC (50 MHz,
CDCl3) 12.75,16.26 (d, JC,P 5.7), 22.62 (d, JC,P 142.6), 22.82 (d, JC,P 4.6),
26.79, 38.58, 43.23, 54.68 (d, JC,P 17.1), 61.51 (d, JC,P 6.9), 64.88,
110.18, 133.68, 138.83, 142.42, 150.60, 162.53, 177.23. HRMS m/z
calcd for C21H34N5O7NaP [MþNa]þ 522.2094; found 522.2101.
3
Compound 15d, dH (200 MHz, CDCl3) 1.12 (s, 9H), 1.27 (t, 6H, JH,H
4
7.0), 1.59e1.77 (m, 2H), 1.88 (d, 3H, JH,H 1.2), 2.06e2.28 (m, 2H),
3
3.97e4.12 (quintet-like m, 4H), 4.54 (t, 2H, JH,H 6.8), 4.92 (s, 2H),
5.89 (s, 2H), 7.32 (q, 1H, 4JH,H 1.2), 7.67 (s, 1H). dC (125 MHz, CDCl3)
12.88, 16.44 (d, JC,P 5.9), 22.63 (d, JC,P 143.0), 23.62 (d, JC,P 3.9), 26.98,
38.78, 43.79, 50.16 (d, JC,P 15.5), 61.83 (d, JC,P 5.9), 65.05, 110.37,
123.81, 139.24, 142.08, 150.83, 162.73, 177.45. HRMS m/z calcd for
C21H34N5O7NaP [MþNa]þ 522.2094; found 522.2103.
4.9. Reaction of 13 with alkylating agents 9bee in the
presence of DBU
4.9.1. 1-[(2-(Methoxycarbonylmethyl)-2H-1,2,3-triazol-4-yl)methyl]-
5-methyl-3-(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-dione (14b)
and 1-[(1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl)methyl]-5-
methyl-3-(pivaloyloxymethyl)pyrimidine-2,4(1H,3H)-dione
(15b). According to the procedure described in Section 4.4, com-
pounds 14b and 15b were synthesized from 13 (321 mg, 1.0 mmol)
and methyl bromoacetate (9b). Column chromatography of the
residue (CHCl3/MeOH, 99/1, v/v) gave 14b (197 mg, 50%) and 15b
(143 mg, 37%) as colourless oils. Compound 14b, dH (200 MHz,
4.9.4. 1-((2-(((2R,3R,4R,5R)-3,4-Dibenzoyloxy-5-(benzoyloxymethyl)
tetrahydrofuran-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)-3-(piv-
aloyloxymethyl)-5-methylpyrimidine-2,4(1H,3H)-dione (14e) and 1-
((1-(((2R,3R,4R,5R)-3,4-dibenzoyloxy-5-(benzoyloxymethyl)tetrahy-
drofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-3-(pivaloylox-
y m e t h y l ) - 5 - m e t h y l p y r i m i d i n e - 2 , 4 ( 1 H , 3 H ) - d i o n e
(15e). 4.9.4.1. ((2R,3S,4S,5R)-3,4-Dihydroxy-5-(tosyloxymethyl)tet-
rahydrofuran-2-yl)methyl benzoate (17). A mixture of 1-O-benzoyl-
2,5-anydromannitol (16) (1.2 g, 4.4 mmol) and Py (8 mL) was cooled
on an ice bath and tosyl chloride (930 mg, 4.9 mmol) was added in
4
CDCl3) 1.09 (s, 9H), 1.84 (d, 3H, JH,H 0.8), 3.70 (s, 3H), 4.91 (s, 2H),
4
5.14 (s, 2H), 5.88 (s, 2H), 7.15 (q, 1H, JH,H 0.8), 7.62 (s, 1H). dC
(50 MHz, CDCl3) 12.83, 26.88, 38.69, 43.26, 52.81, 55.23, 64.99,

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
222
four portions within 30 min. The mixture was stirred at 20e22 ꢀC
for 1 day and volatiles were distilled off. Column chromatography
of the residue (CHCl3/acetone, 85/15, v/v) gave 17 (970 mg, 53%) as
3H), 3.13 (t, 2H, 3JH,H 6.2), 4.69 (t, 2H, 3JH,H 6.2), 4.93 (s, 2H), 7.59 (br
s, 1H), 7.78 (s, 1H), 11.38 (br s, 1H, NH). dC (50 MHz, DMSO-d6) 12.00,
17.91, 42.02, 49.75, 109.11, 118.19, 133.87, 141.06, 144.24, 150.81,
164.34. HRMS m/z calcd for C11H12N6O2Na [MþNa]þ 283.0914;
found 283.0921. The treatment of 14a (158 mg, 0.4 mmol) with
a methanolic solution of NH3 (20 mL) at 20e22 ꢀC overnight gave
5a (90 mg, 86%).
colourless oil. ½a D27
þ19.2 (c 0.130, MeOH). dH (200 MHz, CDCl3) 2.38
ꢂ
(s, 3H), 4.06e4.25 (m, 8H), 4.10e4.35 (m, 2H), 7.25e7.29 (m, 2H),
7.36e7.43 (m, 2H), 7.50e7.54 (m, 1H), 7.73e7.77 (m, 2H), 7.98e8.02
(m, 2H). dC (50 MHz, CDCl3) 21.71, 64.56, 69.41, 77.69, 77.73, 80.01,
80.76, 128.06, 128.53, 129.62, 129.84, 130.02, 132.26, 133.39, 145.31,
166.99. HRMS m/z calcd for C20H22O8N8SNa [MþNa]þ 445.0933;
found 445.0945.
4.9.5.2. 1-[(2-(Carbamoylmethyl)-2H-1,2,3-triazol-4-yl)methyl]-
5-methylpyrimidine-2,4(1H,3H)-dione (5b). A mixture of 14b
(158 mg, 0.4 mmol) and a methanolic solution of NH3 (25 mL) was
stirred at 20e22 ꢀC for 3 days. Volatiles were distilled off. Column
chromatography of the residue (CHCl3/MeOH, 9/1, v/v and then
MeOH) gave 5b (89 mg, 83%) as a white solid (mp 168 ꢀC dec). dH
(200 MHz, DMSO-d6) 1.75 (s, 3H), 4.90 (s, 2H), 5.05 (s, 2H), 7.34 (br
s, 1H, NH2), 7.60 (br s, 1H), 7.68 (br s, 1H, NH2), 7.71 (s, 1H). dC
(50 MHz, CDCl3) 12.04, 42.06, 56.47, 109.05, 133.68, 141.19, 143.91,
150.89, 164.47, 167.37. HRMS m/z calcd for C10H12N6O3Na [MþNa]þ
287.0867; found 287.0870.
4.9.4.2. (2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(tosyloxymethyl)
tetrahydrofuran-3,4-diyl dibenzoate (9e). A mixture of 17 (166 mg,
0.4 mmol) and Py (3 mL) was cooled on an ice bath and benzoyl
chloride (274 mg, 2.0 mmol, 230 mL) was added in one portion. The
mixture was stirred at 20e22 ꢀC overnight and evaporated to
dryness under reduced pressure. The residue was dissolved in
dichloromethane (20 mL), washed with water, hydrochloric acid
(5%, 3 mL), water (3 mL) and dried. The solvent was distilled off.
Column chromatography of the residue (CH2Cl2) gave 9e (196 mg,
80%) as colourless oil. ½a D27
ꢂ
ꢁ11.7 (c 0.426, CHCl3). dH (500 MHz,
4.9.5.3. 1-[(2-(2-Hydroxyethyl)-2H-1,2,3-triazol-4-yl)methyl]-5-
methylpyrimidine-2,4(1H,3H)-dione (5c). According to the pro-
cedure described in Section 4.3.2, 5c was synthesized from 14c
(170 mg, 0.5 mmol). Column chromatography of the residue (CHCl3/
MeOH, 95/5, v/v) gave 5c (103 mg, 88%) as a white solid (mp
CDCl3) 2.37 (s, 3H), 4.41 and 4.43 (AB part of the ABX system, 2H,
3
2
3JAX 3.0, JBX 3.5, JAB 10.7), 4.47e4.49 (m, 1H), 4.50e4.53 (m, 4H),
4.59 and 4.65 (AB part of the ABX system, 2H, 3JAX 4.0, 3JBX 6.0, 2JAB
11.8), 5.56e5.58 (m, 1H), 5.69e5.71 (m, 1H), 7.34e7.55 (m, 7H),
7.57e7.90 (m, 3H), 7.80e7.82 (m, 2H), 7.98e7.80 (m, 2H), 8.04e8.08
(m, 2H), 8.15e8.18 (m, 4H). dC (50 MHz, CDCl3) 21.66, 64.51, 69.38,
79.48, 79.53, 81.64, 81.76, 128.21, 128.52, 128.63, 128.75, 128.92,
129.41, 129.67, 129.88, 129.92, 129.96, 130.14, 133.44, 133.34, 133.89,
133.94, 145.31, 165.57, 165.59, 166.27. HRMS m/z calcd for
C34H30O10S Na [MþNa]þ 653.1449; found 653.1465.
4
151e153 ꢀC). dH (200 MHz, DMSO-d6) 1.75 (d, 3H, JH,H 1.0),
3
3.79e3.86 (m, 2H), 4.39 (t, 2H, JH,H 5.4), 4.89 (s, 2H), 7.59 (q, 1H,
4JH,H 1.0), 7.68 (s, 1H), 11.32 (br s, 1H, NH). dC (50 MHz, DMSO-d6)
12.00, 42.08, 57.05, 59.56, 109.05, 133.09, 141.14, 143.39, 150.81,
164.34. HRMS m/z calcd for C10H13N5O3Na [MþNa]þ 274.0916;
found 274.0910.
4.9.4.3. 1-((2-(((2R,3R,4R,5R)-3,4-Dibenzoyloxy-5-(benzoylox-
ymethyl)tetrahydrofuran-2-yl)methyl)-2H-1,2,3-triazol-4-yl)
methyl)-3-(pivaloyloxymethyl)-5-methylpyrimidine-2,4(1H,3H)-di-
one (14e) and 1-((1-(((2R,3R,4R,5R)-3,4-dibenzoyloxy-5-(benzoylox-
ymethyl)tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)
methyl)-3-(pivaloyloxymethyl)-5-methylpyrimidine-2,4(1H,3H)-di-
one (15e). Treatment of 13 (114 mg, 0.4 mmol) with tosylate 9e
according to the procedure described in Section 4.4, followed by
column chromatography of the residue (CHCl3), gave 14e (155 mg,
57%) and a 14e/15e mixture (32 mg). The 14e/15e ratio of 80/20 was
determined from the relative intensities of the triazole H-5 proton
signals (500 MHz, CDCl3; 14e, dH 5.94 ppm; 15e, dH 5.91 ppm).
4.9.5.4. 1-[(2-(3-(Diethoxyphosphoryl)propyl)-2H-1,2,3-triazol-
4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (5d). According
to the procedure described in Section 4.3.2, 5d was synthesized
from 12d (287 mg, 0.6 mmol). Column chromatography of the
residue (CHCl3/MeOH, 95/5, v/v) gave 5d (213 mg, 97%) as colour-
less oil. dH (200 MHz, CDCl3) 1.15 (t, 6H, 3JH,H 7.0), 1.52e1.69 (m, 2H),
1.73 (d, 3H, 4JH,H 1.2), 1.95e2.19 (m, 2H), 3.87e4.02 (quintet-like m,
4H), 4.35 (t, 2H, 3JH,H 6.8), 4.81 (s, 2H), 7.10 (q, 1H, 4JH,H 1.2), 7.51 (s,
1H), 10.47 (br s, 1H, NH). dC (50 MHz, CDCl3) 12.10, 16.19 (d, JC,P 6.1),
22.46 (d, JC,P 142.3), 22.76 (d, JC,P 4.6), 42.12, 54.59 (d, JC,P 17.5), 61.62
(d, JC,P 6.1), 110.96, 133.75, 139.79, 142.66, 151.06, 164.61. HRMS m/z
calcd for C15H24N5O5NaP [MþNa]þ 408.1413; found 408.1419.
Compound 14e, ½a D27
ꢂ
þ5.2 (c 0.192, MeOH). dH (500 MHz, C6D6) 1.11
4
(s, 9H), 1.59 (d, 3H, JH,H 1.0), 4.34 (s, 2H), 4.41e4.44 (m, 1H),
4.52e4.66 (m, 4H), 4.79e4.83 (m, 1H), 5.66e5.67 (t-like m, 1H),
4.9.5.5. 5-Methyl-1-[(2-(3-phosphonopropyl)-2H-1,2,3-triazol-4-
yl)methyl]pyrimidine-2,4(1H,3H)-dione (5e). A mixture of 5d
(180 mg, 0.5 mmol) and anhydrous acetonitrile (10 mL) was cooled
on an ice bath and trimethylsilyl bromide (770 mg, 5.0 mmol,
4
5.73e5.74 (t-like m, 1H), 6.10 (s, 2H), 6.27 (q, 1H, JH,H 1.0),
6.99e7.03 (m, 5H), 7.07 (m, 4H), 7.34 (s, 1H), 8.93e8.94 (m, 2H),
8.06e8.07 (m, 2H), 8.14e8.16 (m, 2H). dC (50 MHz, C6D6) 12.89,
27.13, 38.91, 43.19, 55.77, 63.84, 65.85, 79.77, 79.82, 82.53, 82.63,
110.03, 128.59, 128.75, 128.80, 129.39, 129.61, 130.10, 130.13, 130.17,
130.42, 133.94, 133.58, 133.69, 134.77, 138.46, 143.91, 150.92, 162.48,
165.40, 165.46, 166.09, 177.19. HRMS m/z calcd for C41H41N5O11Na
[MþNa]þ 802.2700; found 802.2684. The 14e/15e mixture, dH
(500 MHz, CDCl3) 1.15 (s, 1.8H), 1.16 (s, 7.2H), 4.60e4.92 (m, 8H),
5.53e5.56 (m, 0.4H), 5.67e5.70 (m, 1.6H), 5.91(s, 0.4H), 5.94 (s,
1.6H), 7.12 (s, 0.8H), 7.29 (s, 0.2H), 7.34e7.62 (m, 9H), 7.63 (s, 0.8H),
7.87 (s, 0.2H), 7.96e8.07 (m, 6H).
660 m
L) was added dropwise. The mixture was left at 20e22 ꢀC
overnight and volatiles were distilled off. The residue was dissolved
in methanol (10 mL). The mixture was stirred at 20e22 ꢀC for 1 h
and concentrated to dryness under reduced pressure. The residue
was dissolved in water (50 mL) and extracted with dichloro-
methane (3ꢃ20 mL). The aqueous phase was evaporated to dryness
under reduced pressure. Lyophilization of the residue gave 5e
(110 mg, 73%) as a yellowish oil. dH (200 MHz, DMSO-d6) 1.42e1.59
(m, 2H), 1.73 (s, 3H), 1.94e2.10 (m, 2H), 4.10e4.44 (m, 4H), 4.88 (s,
2H), 7.56 (s, 1H), 7.68 (s, 1H), 10.30 (br s, 1H, NH). dC (50 MHz, CDCl3)
12.23, 24.69 (d, JC,P 137.7), 23.71 (d, JC,P 3.7), 42.43, 54.80 (d, JC,P
18.1), 109.47, 133.41, 141.47, 143.81, 151.09, 164.75. HRMS m/z calcd
for C11H15N5O5P [M]ꢁ 328.0811; found 328.0805.
4.9.5. Preparation of 5aef from 14aee. 4.9.5.1. 1-[(2-(2-
Cyanoethyl)-2H-1,2,3-triazol-4-yl)methyl]-5-methylpyrimidine-
2,4(1H,3H)-dione (5a). According to the procedure described in
Section 4.3.2, 5a was obtained from 14a (247 mg, 0.6 mmol).
Crystallisation of the residue (methanol) gave 5a (138 mg, 84%) as
a white solid (mp >155 ꢀC dec). dH (200 MHz, DMSO-d6) 1.75 (br s,
4.9.5.6. 1-((2-(((2R,3S,4R,5R)-3-Benzoyloxy-4-hydroxy-5-(hy-
droxymethyl)tetrahydrofuran-2-yl)methyl)-2H-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (5f). According to

ꢀ
M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
223
the procedure described in Section 4.9.5.2, 5f synthesized from 14e
(48 mg, 0.55 mmol). Column chromatography of the residue
(110 mg, 0.14 mmol). Column chromatography of the residue
(CHCl3/MeOH, 95/5, v/v) gave 6e (105 mg, 78%).
(CHCl3/MeOH, 95/5, v/v) gave 5f (47 mg, 74%) as colourless oil. ½a D27
ꢂ
þ30.6 (c 0.638, MeOH). dH (500 MHz, CD3OD) 1.86 (d, 3H, 4JH,H 1.0),
4.10.4. 1-[(1-(3-(Diethoxyphosphoryl)-1H-1,2,3-triazol-4-yl))
methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (6f). According to
the procedure described in Section 4.3.1, 6f was obtained from 7 and
diethyl 3-azidopropylphosphonate (8d) (184 mg, 0.8 mmol). Col-
umn chromatography of the residue (CHCl3/acetone, 95/5, v/v) gave
6f (242 mg, 76%) as awhite solid (mp 77e79 ꢀC). dH (200 MHz, CDCl3)
1.31 (t, 6H, 3JH,H 7.0),1.64e1.73 (m,1H),1.77e1.81 (m,1H),1.90 (d, 3H,
4JH,H 1.2), 2.10e2.22 (m, 2H), 4.01e4.17 (quintet-like m, 4H),
4.41e4.48 (t, 2H, 3JH,H 7.0), 4.95 (s, 2H), 7.33 (q, 1H, 4JH,H 1.2), 7.75 (s,
1H), 9.05 (br s, 1H, NH). dC (50 MHz, CDCl3) 12.44, 16.59 (d, JC,P 6.1),
22.78 (d, JC,P 142.7), 23.75 (d, JC,P 5.0), 43.07, 50.33 (d, JC,P 15.6), 62.00
(d, JC,P 6.5), 111.41, 124.04, 140.28, 142.28, 151.08, 164.24. HRMS m/z
calcd for C15H24N5O5NaP [MþNa]þ 408.1413; found 408.1402.
3.58 and 3.65 (AB part of an ABX system, 2H, 2JAB 11.5, 3JAX 4.0, 3JBX
3
3
5.0), 3.79e3.82 (m, 1H), 3.98 (dd, 1H, JH,H 5.0, JH,H 5.0), 4.02 (dd,
1H, 3JH,H 5.0, 3JH,H 5.5), 4.27e4.30 (m, 1H), 4.59 and 4.63 (AB part of
2
3
3
an ABX system, 2H, JAB 14.0, JAX 4.5, JBX 3.0), 4.97 (s, 2H),
7.41e7.47 (m, 2H), 7.50 (q, 1H, 4JH,H 1.0), 7.52e7.55 (m, 1H), 7.67 (s,
1H), 7.86e7.88 (m, 2H). dH (125 MHz, CD3OD) 12.24, 43.58, 57.74,
63.03, 78.52, 79.95, 83.43, 85.83, 111.59, 128.62, 129.51, 132.92,
134.63, 134.94, 142.62, 144.95, 152.76, 166.79, 172.37. HRMS m/z
calcd for C21H23N5O7Na [MþNa]þ 480.1495; found 480.1492.
4.10. Preparation of 6bei
4.10.1. 1-[(1-(2-Cyanoethyl)-1H-1,2,3-triazol-4-yl)methyl]-5-
methylpyrimidine-2,4(1H,3H)-dione (6b), 1-[(1-(2-carbamoylethyl)-
1H-1,2,3-triazol-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione
4.10.5. 1-((1-(((2R,3S,4S,5R)-3,4-Dihydroxy-5-(benzoyloxymethyl)
tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-5-
methylpyrimidine-2,4(1H,3H)-dione (6g). 4.10.5.1. ((2R,3S,4S,5R)-
3,4-Dihydroxy-5-(azidomethyl)tetrahydrofuran-2-yl)methyl benzoate
(8e). Sodium azide (200 mg, 3.1 mmol) was added to a mixture of
16 (260 mg, 0.6 mmol), anhydrous DMF (12 mL) and tetrabuty-
lammonium hydrogen sulfate (25 mg, 0.9 mmol). The mixture was
stirred at 50 ꢀC for 3 days and filtered through a CeliteÒ pad. The
pad was washed with DMF (10 mL). The filtrates were collected and
evaporated to dryness under reduced pressure. Column chroma-
tography of the residue (CHCl3/MeOH, 95/5, v/v) gave 8e (167 mg,
(6c)
and
5-methyl-1-[NH-1,2,3-triazol-4-ylmethyl]pyrimidine-
2,4(1H,3H)-dione (4). According to the procedure described in
Section 4.3.2, the treatment of 15a (89 mg, 0.2 mmol) with
a methanolic solution of NH4OH gave 27 mg of a 4/6b mixture (40/
60 ratio) and 29 mg of a 6b/6c mixture (30/70 ratio). The compo-
nent ratio in the mixtures was established from 1H NMR spectro-
scopic analysis (200 MHz, DMSO-d6), based on the relative intensity
of the triazole H-5 proton: 2, 7.81 ppm; 6b, 8.15 ppm; or 6c,
7.99 ppm. The 4/6b mixture, dH (200 MHz, DMSO-d6) 1.75 (s, 3H
from 4þ3H from 6b), 3.17 (t, 3JH,H 7.0, 2H from 6b), 4.64 (t, 3JH,H 7.0,
2H from 6b), 4.92 (s, 2H from 4þ2H from 6b), 7.60 (s, 1H from 4),
7.62 (s, 1H from 6b), 7.81 (s, 1H from 4), 8.15 (s, 1H from 6b). The 6b/
6c mixture, dH (200 MHz, DMSO-d6) 1.74 (s, 3H from 6bþ3H from
6c), 2.68 (t, 3JH,H 6.6, 2H from 6c), 3.17 (t, 3JH,H 7.0, 2H from 6b), 4.51
93%) as colourless oil. ½a D27
ꢂ
þ53.7 (c 0.354, MeOH). dH (500 MHz,
3 3
CDCl3) 3.36 and 3.54 (AB part of an ABX system, 2H, JAX 4.0, JBX
4.0, 2JAB 13.0), 4.01e4.03 (m, 1H), 4.14e4.17 (m, 4H), 4.19e4.24 (m,
1H), 4.46e4.49 (m, 2H), 7.38e7.41 (m, 2H), 7.52e7.54 (m, 1H),
8.00e8.03 (m, 2H). dC (125 MHz, CDCl3) 52.01, 64.71, 77.85, 77.90,
80.52, 81.20, 128.58, 129.39, 129.82, 133.59, 167.40. HRMS m/z calcd
for C13H15N3O5Na [MþNa]þ 316.0909; found 316.0911.
3
3
(t, JH,H 6.6, 2H from 6c), 4.63 (t, JH,H 7.0, 2H from 6b), 4.87 (s, 2H
from 6c), 4.91 (s, 2H from 6b), 6.94 (1H from 6c, NH2), 7.45 (1H from
6c, NH2), 7.59 (s, 1H from 6c), 7.63 (s, 1H from 6b), 7.99 (s, 1H from
6c), 8.15 (s, 1H from 6b). HRMS m/z calcd for C11H14N6O3Na
[MþNa]þ 301.1025; found 301.1029. For spectral data of 4 or 6b, see
procedure in Sections 4.2 or 4.4, respectively.
4.10.5.2. 1-((1-(((2R,3S,4S,5R)-3,4-Dihydroxy-5-(benzoylox-
ymethyl)tetrahydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)
methyl)-5-methylpyrimidine-2,4(1H,3H)-dione (6g). According to
the procedure described in Section 4.3.1, 6g was synthesized from 7
and 8e (180 mg, 0.6 mmol). Column chromatography of the residue
(CHCl3/MeOH, 9/1, v/v) gave 6g (196 mg, 70%) as a white solid (mp
4.10.2. 1-[(1-(Carbamoylmethyl)-1H-1,2,3-triazol-4-yl)methyl]-5-
methylpyrimidine-2,4(1H,3H)-dione (6d). According to the pro-
cedure described in Section 4.9.5.2, 6d was synthesized from 15b
(70 mg, 0.2 mmol). Column chromatography of the residue (CHCl3/
MeOH, 9/1, v/v and then MeOH) gave 6d (39 mg, 82%) as a white
solid (mp >180 ꢀC dec). dH (200 MHz, DMSO-d6) 1.75 (s, 3H), 4.90 (s,
2H), 5.04 (s, 2H), 7.38 (br s, 1H, NH2), 7.63 (br s, 1H), 7.73 (br s, 1H,
NH2), 8.01 (s, 1H). dC (50 MHz, CDCl3) 11.98, 42.17, 51.42, 108.85,
125.15, 141.20, 142.18, 150.76, 164.31, 167.26. HRMS m/z calcd for
C10H12N6O3Na [MþNa]þ 287.0867; found 287.0872.
89e90 ꢀC). ½a 2D7
ꢂ
þ25.2 (c 0.218, MeOH). dH (500 MHz, CD3OD) 1.84
4
3 3
(s, d, 3H, JH,H 1.0), 3.85 (dd, 1H, JH,H 6.5, JH,H 5.5), 4.02e4.05 (m,
3
3
1H), 4.11 (dd, 1H, JH,H 6.0, JH,H 5.5), 4.16e4.19 (m, 1H), 4.40 and
4.47 (AB part of the ABX system, 2H, 3JAX 3.5, 3JBX 5.0, 2JAB 12.0), 4.62
and 4.65 (AB part of the ABX system, 2H, 3JAX 3.5, 3JBX 6.0, 2JAB 14.0),
4.97 (s, 1H), 7.47e7.52 (m, 2H), 7.48 (s, 1H), 7.60e7.63 (m, 1H), 8.00
(s, 1H), 8.02e8.04 (m, 2H). dC (125 MHz, CD3OD) 12.22, 43.65, 52.93,
65.48, 78.64, 79.25, 82.75, 82.91, 111.55, 126.27, 129.65, 130.63,
131.22, 134.38, 142.55, 143.90, 152.66, 166.73, 167.81. HRMS m/z
calcd for C21H23N5O7Na [MþNa]þ 480.1495; found 480.1490.
4.10.3. 1-[(1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl]-5-
methylpyrimidine-2,4(1H,3H)-dione
(6e). 4.10.3.1. Method
4.10.6. 5-Methyl-1-[(1-(3-phosphonopropyl)-1H-1,2,3-triazol-4-yl)
methyl]pyrimidine-2,4(1H,3H)-dione (6h). According to the pro-
cedure described in Section 4.9.5.5, 6h was obtained from 6f
(85 mg, 0.2 mmol). Lyophilization of the residue gave 6h (62 mg,
85%) as a yellowish oil. dH (200 MHz, DMSO-d6) 1.15e1.47 (m, 2H),
1.74 (br s, 3H), 1.85e2.16 (m, 2H), 4.30e4.42 (t-like m, 2H), 4.88 (s,
2H), 7.63 (br s,1H), 8.09 (s, 1H). dC (125 MHz, DMSO-d6) 11.93, 25.13,
25.83 (d, JC,P 136.1), 42.17, 50.14 (d, JC,P 14.6), 108.84, 123.55, 141.18,
142.28, 150.73, 164.28. HRMS m/z calcd for C11H15N5O5P [M]ꢁ
328.0811; found 328.0805.
A. According to the procedure described in Section 4.3.2, 6e was
synthesized from 15c (132 mg, 0.4 mmol). Column chromatography
of the residue (CHCl3/MeOH, 95/5, v/v) gave 6e (80 mg, 77%) as
a white solid (mp 186e187 ꢀC). dH (500 MHz, DMSO-d6) 1.75 (s, 3H),
3.76 (m, 2H), 4.37 (t, 2H, 3JH,H 5.5), 4.89 (s, 2H), 5.01 (br s, 1H, OH),
7.61 (s, 1H), 8.01 (s, 1H), 11.28 (br s, 1H, NH). dC (50 MHz, DMSO-d6)
12.00, 42.21, 52.28, 59.81, 108.89, 124.01, 141.22, 142.27, 150.77,
164.34. HRMS m/z calcd for C10H13N5O3Na [MþNa]þ 274.0916;
found 274.0907.
4.10.3.2. Method B. According to the procedure described in
Section 4.3.1, 6e was obtained from 7 and 2-azidoethanol (8c)
4.10.7. 1-((1-(((2R,3S,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetra-
hydrofuran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)-5-

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M. Koszytkowska-Stawinska et al. / Tetrahedron 68 (2012) 214e225
224
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methylpyrimidine-2,4(1H,3H)-dione (6i). According to the pro-
cedure described in Section 4.9.5.2, 6i was synthesized from 6g
(160 mg, 0.4 mmol). Column chromatography of the residue
(CHCl3/MeOH, 9/1, v/v) gave 6i (109 mg, 86%) as a white solid (mp
63e64 ꢀC). ½a 2D7
þ42.9 (c 0.466, MeOH). dH (200 MHz, CD3OD) 1.86
ꢂ
(s, 3H), 3e54-3.66 (m, 2H), 3.72e3.83 (m, 2H), 3.97e4.03 (m, 1H),
4.08e4.16 (m, 1H), 4.52e4.70 (m, 2H), 4.90 (s, 2H), 7.55 (s, 1H), 8.03
(s, 1H). dC (50 MHz, CD3OD) 12.24, 43.64, 53.13, 62.98, 78.02, 79.37,
82.76, 85.39, 111.55, 126.31, 142.63, 143.85, 152.70, 166.81. HRMS m/
z calcd for C14H19N5O6Na [MþNa]þ 376.1233; found 376.1219.
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 Professor Adam Gryff-Keller and M.Sc. Sergey Molchanov,
Warsaw University of Technology, for their invaluable help with the
designing of 2D NMR experiments.
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from the relative magnitude of the HOMO coefficients at the nitrogen atoms of
the neutral 2H- and 1H-1,2,3-triazole. The HOMO control was postulated to
have a more pronounced effect on directing bulky ethyl bromide or methyl
bromoacetate than the sterically unhindered methyl iodide. On the other hand,
the reported study on alkylation of 4-nitro-NH-1,2,3-triazole with phenyl
bromoacetate or ethyl bromoacetate demonstrated that a specific character of
the substituent on the electrophilic carbon site of the alkylating agent could
play a role in the alkylation selectivity (Vereshchagin, L. I.; Kuznetsova, N. I.;
Kirillova, L. P.; Shcherbakov, V. V.; Sukhanov, G. T.; Gareev, G. A. Chem. Heter-
ocycl. Compd. 1986, 22, p 745). On the other hand, on varying from phenyl
bromoacetate to ethyl bromoacetate the inversion of N-2/N-1 selectivity of the
alkylation (i.e., from 67/33 to 33/67, respectively) was reported. However,
plausible reasons for these observations (including an effect of the nitro group
on the course of the reaction) were not discussed in the original paper.
26. Lu, X.; Bittman, R. J. Org. Chem. 2005, 70, 4746.
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nation of a relation between a structure of a tetragonal alkylating agent and an
alkylation regioselectivity of NH-1,2,3-triazoles (the term of ‘systematic in-
vestigation’ means here a series of reactions between a specific NH-1,2,3-
triazole derivative and different alkylating agents with the same leaving
group, conducted under identical conditions). For instance, in the reported
alkylations of NH-1,2,3-triazole an increase in N-2 selectivity was observed in
the series: methyl iodide<ethyl bromide<methyl bromoacetate (Wang, X.-j.;
Zhang, L.; Krishnamurthy, D.; Senanayake, C. H.; Wipf, P. Org. Lett. 2010, 12, p
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