5-Triazolyluracils and their N1-sulfonyl derivatives: Intriguing reactivity differences in the sulfonation of triazole N1′-substituted and N1′-unsubstituted uracil molecules

Article abstract of DOI:10.1002/ejoc.201501088

We describe the synthesis of novel C5-triazolyl derived N¹-sulfonylpyrimidines through Cu^I-catalyzed alkyne-azide cycloaddition followed by sulfonylation of the formed C5-triazolyl derivatives with various sulfonyl chlorides under basic conditions. In the latter step, an intriguing difference in the reactivity of the pyrimidine N¹ was observed that depended on the nature of the substituent at a distant triazole N^1′ site. The N^1′-unsubstituted compounds gave very small amounts of sulfonylation products, whereas N^1′-substituted systems produced high yields of the respective N¹-sulfonyl-5-(1,2,3-triazol-4-yl)uracils. Computational analysis revealed a close correlation between the strength of the employed base catalysts and their abilities to increase the nucleophilicity of the uracil N¹ atom through subsequent deprotonation, leading to more products. Following this step, the phosphazene tBu-P4 superbase was applied in the sulfonylation, resulting in exclusive formation of the triazole N^1′-unsubstituted N¹-sulfonylpyrimidines. The synthesis of C5-triazolyl-substituted pyrimidines and C5-triazolyl derived N¹-sulfonylpyrimidines is described. Computational studies of the sulfonation step shed light on the differences in reactivity and revealed a connection between the strength of the employed base and its tendency to increase the nucleophilicity of the reacting uracil N¹ atom by deprotonation.

Full text of DOI:10.1002/ejoc.201501088

FULL PAPER
DOI: 10.1002/ejoc.201501088
5-Triazolyluracils and Their N1-Sulfonyl Derivatives: Intriguing Reactivity
Differences in the Sulfonation of Triazole N1Ј-Substituted and
N1Ј-Unsubstituted Uracil Molecules
[a]
[b]
[a]
ˇ
Dijana Saftic´, Robert Vianello,* and Biserka Zinic´*
Keywords: Nucleobases / Sulfonylation / Substituent effects / Regioselectivity / Density functional calculations
We describe the synthesis of novel C5-triazolyl derived
N1-sulfonylpyrimidines through CuI-catalyzed alkyne–azide
cycloaddition followed by sulfonylation of the formed C5-tri-
azolyl derivatives with various sulfonyl chlorides under basic
conditions. In the latter step, an intriguing difference in the
reactivity of the pyrimidine N1 was observed that depended
on the nature of the substituent at a distant triazole N1Ј site.
The N1Ј-unsubstituted compounds gave very small amounts
of sulfonylation products, whereas N1Ј-substituted systems
produced high yields of the respective N1-sulfonyl-5-(1,2,3-
triazol-4-yl)uracils. Computational analysis revealed a close
correlation between the strength of the employed base cata-
lysts and their abilities to increase the nucleophilicity of the
uracil N1 atom through subsequent deprotonation, leading to
more products. Following this step, the phosphazene tBu–P4
superbase was applied in the sulfonylation, resulting in ex-
clusive formation of the triazole N1Ј-unsubstituted N1-sulfon-
ylpyrimidines.
Introduction
In our earlier synthetic studies focused on novel candi-
dates for antitumor agents,[1,2] we have shown that pyrimid-
ine derivatives containing sulfonamide pharmacophores at
the N1 position of the pyrimidine ring exhibit promising
anticancer activity both under in vitro[3,4] and in vivo[5] con-
ditions. The N1-sulfonylpyrimidines (Figure 1, A) showed
potent growth inhibitory effects against human tumour cell
lines, whereas the effects on normal human fibroblasts were
much smaller.[3a] Pyrimidine nucleobase derivatives of this
type were found to inhibit the activities of specific enzymes
involved in DNA/RNA synthesis and they showed the abil-
ity to induce apoptosis in human tumour cells.[3a,6] In vivo
experiments have shown that some N1-sulfonylcytosine de-
rivatives have strong antitumor activity against mouse
mammary carcinoma.[5a]
Figure 1. Structures of N1-sulfonylpyrimidines (A), 5-(1,2,3-triazol-
4-yl)uracil derivatives (B), and N1-sulfonyl-5-(1,2,3-triazol-4-yl)-
uracil derivatives (C).
(CuAAC) giving 1,4-disubstituted 1,2,3-triazole ring[7]
emerges as the method of choice for further synthetic modi-
fication of N1-sulfonylpyrimidines (Figure 1, B–C).
In the quest to develop novel biologically active com-
pounds for the treatment of cancer, the widely used CuI-
catalyzed Huisgen alkyne–azide 1,3-dipolar cycloaddition
Previous research efforts in drug design showed that in-
troduction of the 1,2,3-triazole fragment in nucleic acid-
based agents increased the bioavailability of the compound
by increasing the lipophilicity, which, in turn, also enabled
better diffusion through the cell membrane.[8] In addition,
oligonucleotides containing a triazole moiety at the pyrim-
idine C5 position are capable of forming duplexes of higher
stability because of enhanced π–π stacking interactions.[9] It
was also reported that the DNA/RNA duplex formed by
oligonucleotides containing a few consecutive triazole-
modified nucleotides exhibited increased thermal stability
because of the additional stabilisation by the stacking inter-
actions among triazoles located in the major groove.[10]
In this work, we report the development of a synthetic
strategy towards the C5–1,2,3-triazolyl derived N1-sulfonyl-
[a] Laboratory of Supramolecular and Nucleoside Chemistry,
Division of Organic Chemistry and Biochemistry, Rueer
Bosˇkovic´ Institute,
Bijenicˇka cesta 54, 10000 Zagreb, Croatia
E-mail: biserka.zinic@irb.hr
http://www.irb.hr/eng/People/Biserka-Zinic
[b] Computational Organic Chemistry and Biochemistry Group,
Division of Organic Chemistry and Biochemistry, Rueer Bosˇ-
kovic´ Institute,
Bijenicˇka cesta 54, 10000 Zagreb, Croatia
E-mail: robert.vianello@irb.hr
http://www.irb.hr/eng/People/Robert-Vianello
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501088.
Eur. J. Org. Chem. 2015, 7695–7704
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Saftic´, R. Vianello, B. Zinic´
FULL PAPER
pyrimidine derivatives C (Figure 1) that contain three well- to be easily varied through the use of a range of alkyl hal-
known pharmacophores: a nucleobase, a 1,2,3-triazole,[11] ides. Compounds 2, 3, 5 and 6 were obtained in 81–100%
and a sulfonyl fragment, which might jointly promote their yields. NMR spectroscopic analysis of the isolated products
biological activity. The approach is based on the readily ac- clearly indicate that no 1,5-disubstituted regioisomers were
cessible 5-ethynyluracil, which undergoes the CuI-catalysed present, as was the case with some purines reported pre-
cycloaddition reaction with azides generated in situ to give viously.[17] Derivative 4 was obtained in 60% yield by the
a new class of C5–1,2,3-triazolyl nucleobase analogues (B) reduction of 3 with sodium borohydride in 1,2-dimethoxy-
that are sulfonated at the N1 position using the methodol- ethane (DME). Compound 2 was treated with ammonia to
ogy previously developed for other pyrimidine deriva- give 7, lacking an N1Ј substituent, in quantitative yield.[10]
tives.[1–3,12] However, the outcome of the latter condensa-
First we examined the condensation of 7, having the un-
tion unexpectedly depends on the nature of the substituent substituted triazole ring, with selected sulfonyl chlorides as
at a very distant N1Ј position of the 1,2,3-triazole ring, re- the most direct access to N1-sulfonyluracil derivatives. It is
sulting in either low yields or no products for R1 = H (Fig- known that monosubstituted triazoles can exist as a mix-
ure 1), while enabling the preparation of the respective N1- ture of three different tautomers, with the 2H-4-Ph tauto-
sulfonylpyrimidine derivatives C in high yields with R1 ϶ mer b being the most stable in both the crystal and gas
H. This enables the construction of libraries of compounds phase,[18] whereas 1H-4-Ph (a) and 1H-5-Ph (c) possess 3.9
of type C in a highly efficient way in amounts necessary for and 4.8 kcalmol–1 higher total Gibbs free-energy, respec-
biological testing. The observed reactivity differences were tively, than b in the gas phase (Scheme 2, R = phenyl). On
interpreted by computations as principally being a conse- the other hand, in aqueous solution, 1H (a) and 2H (b)
quence of different basicity strengths of the employed base tautomers have practically identical energies and both are
catalysts, which produce different protonation forms of pyr- present.[18] Hence, under basic conditions and depending on
imidines entering the condensation.
the strength of the base, in the reaction involving 7 with
sulfonyl chlorides, sulfonylation at both the N1 pyrimidine
and the triazole N1Ј position may be expected.
Results and Discussion
Synthesis
Starting from the commercially available uracil, 5-iodou-
racil was easily obtained by using iodine in 1,4-dioxane and
nitric acid, as described earlier.[13,14] Sonogashira coupling
of 5-iodouracil and trimethylsilylacetylene (TMSA),[15] fol-
lowed by removal of the TMS group with 1 m NaOH, gave
5-ethynyluracil 1 in 94% yield (Scheme 1).[16]
Scheme 2. Possible tautomeric forms of monosubstituted 1,2,3-tri-
azoles.
Base/solvent systems that have been frequently used in
similar condensation reactions were examined, including:
(1) pyridine, (2) bis(trimethylsilyl)acetamide (BSA) in aceto-
nitrile, (3) 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
N,N-dimethylformamide (DMF), and (4) K2CO3 in
DMF.[1] Method (1) failed to give any N1-sulfonylated
uracil derivative, whereas methods (3) and (4) using tosyl
chloride gave only 9 and 11% of 9, respectively. With
method (2) using BSA/acetonitrile, the sufonylated products
8 and 9 were obtained in poor yields (6 and 8%, respec-
tively) using commercially available 5-bromothiophene-2-
sulfonyl chloride or tosyl chloride (Scheme 3). The results
of these synthetic studies show that, although formed in
low yields, only N1-sulfonyl pyrimidine products could be
identified, indicating that sulfonylation occurred at the pyr-
imidine N1 atom preferentially.
Scheme 1. Copper-catalyzed 1,3-dipolar cycloaddition of 5-ethyn-
yluracil 1 with azides prepared in situ. Reagents and conditions:
(a) i. R1-X, EtOH/H2O, DMEDA, NaN3, CuI, Na-ascorbate,
100 °C, 1 h; ii. alkyne 1, DMEDA, CuI, Na-ascorbate, 100 °C,
0.5 h; (b) DME, NaBH4, MeOH, reflux, 60%; (c) 2 in dioxane,
NH3 (aq.), room temp., 1.5 h, 100%.
The 1,2,3-triazole ring was synthesised directly from un-
In an attempt to improve the yields, the use of much
protected 1 by using sodium azide, alkyl halides, and an stronger NaH base was examined. In three parallel experi-
in situ azidation/cycloaddition protocol (Scheme 1).[10] This ments, derivative 7 (1 equiv.) was dissolved in anhydrous
reaction allows the N1Ј substituent of the 1,2,3-triazole ring DMF, and NaH (1, 2, or 3 equiv.) was added followed by
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5-Triazolyluracils and Their N1-Sulfonyl Derivatives
Scheme 3. Synthesis of monosubstituted 1,2,3-triazolo N1-sulfonyluracil derivatives 8 and 9.
the addition of tosyl chloride. The products were isolated Table 1. Condensation reactions of 7 with tosyl chloride and tBu–
P4 superbase.
by preparative TLC. In the reaction involving equimolar
quantities of 7, NaH, and tosyl chloride, the formation of
9 could not be observed by TLC, and the starting material
7 was completely recovered. In the reactions with 2 and
3 equiv. NaH, the formation of N1-sulfonylated 9 as a sole
product was observed; 9 was isolated in 5.5 and 11% yield,
respectively. In both reactions, 80% of the starting material
was recovered.
Entry
7
TsCl
tBu-P4 Yield of 9 [%]
Recovery
of 7 [%]
[equiv.] [equiv.] [equiv.]
1
2
3
4
5
1
1
1
1
1
1
1
1
2
2
1
2
3
1
3
not observed[a]
trace[a]
80
60
31
100
–
trace[a]
not observed[a]
100[a] / 21–58[b]
[a] Monitored by TLC. [b] Isolated yield.
It was found that the yield was not improved either upon
extremely prolonged reaction time (2 weeks) with 20% ex-
cess of tosyl chloride or by increasing the reaction tempera- tates condensation. Notably, isolation of product 9 (21, 47,
ture (microwave assisted synthesis at 150 °C). However, and 58% yields were obtained, depending on the method
these results clearly indicated that an increase in the amount of isolation) was difficult because of both the large excess
of employed base promoted the reaction, suggesting that of tBu–P4 base and the instability of the formed N1–S bond
subsequent deprotonation of the initial formed 7 enhanced during isolation. Considerable degradation of 9 occured
its reactivity. Unfortunately, the increase in the reaction after each additional chromatographic purification.
yield was not significant, which could be attributed to
We then turned our attention to the condensation of N1Ј-
known difficulties and side-reactions occurring with the ap- substituted triazoles 2–6 and various sulfonyl chlorides
plication of strongly nucleophilic NaH as a base catalyst in (Table 2). The reaction of 2 with BSA/acetonitrile gave 10
DMF.[19]
in only 15% yield. However, by using DBU in DMF, 10
In the same vein, and according to the computational was obtained in 70% yield. Employing the latter reaction
results presented herein (see below), it was reasonable to conditions with 3–6 and sulfonyl chlorides, the respective
assume that the application of the phosphazene tBu–P4 N1-sufonylated products were obtained in good to excellent
base, as one of the strongest nonionic superbases with low yields (Table 2). Product 13, having a 5-bromothiophene-2-
nucleophilicity (pKBH+ ≈ 42.7 in MeCN),[20] would produce sulfonyl group at the N1 position, was efficiently trans-
higher yields of the condensation reactions of derivative 7 formed into 14 (92% yield) by removing the bromine under
with tosyl chloride. To test this hypothesis, we performed catalytic hydrogenolysis. In addition, the preparation of 8,
additional experiments, the results of which are presented containing the N1Ј-unsubstituted triazole ring, was exam-
in Scheme 3 and Table 1.
ined by using ammonium hydroxide/dioxane mixture and
Derivative 7 (1 equiv.) was dissolved in anhydrous DMF, N1Ј-pivaloyloxymethyl derivative 10.[10] However, a product
cooled to –78 °C and tBu–P4 was added. The reaction mix- mixture consisting of 2, 7, and 5-bromothiophene-2-
tures were stirred for 30 min at –78 °C, removed to an ice sulfonic acid was obtained as a result of cleavage of the N1-
bath and tosyl chloride was added. The progress of the re- sulfonylbromothiofene and N1Ј-pivaloyloxy-methyl groups.
action was monitored by TLC. Initial experiments resulted Similarly, the catalytic hydrogenolysis of the N-benzyl
in the recovery of 7 (Table 1, entries 1–4), whereas per- group from 14 with ammonium formate in MeOH gave un-
forming the reactions under the conditions shown in entry desired product 5-(1-benzyl-1H-1,2,3-triazol-4-yl)uracil (5)
5 resulted in complete conversion of derivative 7 into the instead of the N1Ј-unsubstituted triazole derivative, demon-
desired product 9 within 1 h. The latter result strongly sup- strating the instability of the N1–S bond under these condi-
ports our hypothesis that triple-deprotonation of 7 facili- tions.
Eur. J. Org. Chem. 2015, 7695–7704
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FULL PAPER
Table 2. Condensation reaction of 1,4-disubstituted triazoles 2–6 0.1 kcalmol–1 lower in energy than 7b, thus mimicking the
with tosyl chloride or 5-bromothiophene-2-sulfonyl chloride.[a]
situation reported for the system in aqueous solution.[18] In
the gas phase, the situation is reversed, meaning that 7b is
the global minimum, being 1.6 kcalmol–1 more stable than
7a, which is in line with previous reports.[18] First deproton-
ation of both 7 and 5 corresponds to removing the uracil
N1 proton with pKa values of 12.0 and 14.0, respectively. In
7, deprotonation at N1Ј and N3 sites gives 0.9 and
4.8 kcalmol–1 less stable conjugate bases, whereas in 5, N3
deprotonation is 5.2 kcalmol–1 less favourable. This sug-
gests that monoanionic 7– is the predominant form of this
molecule in DMF, whereas 5 is roughly in 5Ǟ5– equilib-
rium, because the autoprotolysis constant for DMF is
around 27–29.[21] Molecule 7 could undergo a second de-
protonation by removing the triazole N1Ј proton (pKa
=
17.5), whereas N3 deprotonation is 13.1 kcalmol–1 less feas-
ible. The N3–H group on uracil is more acidic in 5 (pKa =
29.9) than in 7 (pKa = 32.7), which could be attributed to
a positive influence of the attached benzyl moiety in sta-
bilising the 52– dianion. To put these data into perspective,
we also calculated the pKa values in DMF of the basic cata-
lysts we employed in condensation reactions and obtained
pKa (DBUH+ ǞDBU) = 15.0; pKa (HCO3– ǞCO32–) =
–
20.5, and pKa (H2CO3 ǞHCO3 ) = 11.3.
Pyridine is a very weak base, with a pKa of 3.57 mea-
sured in DMF.[22] This mismatch with the uracil acidity is
also evidenced in, for example, water, in which the pKa val-
ues of pyridine and uracil assume 5.3 and 9.5, respec-
tively.[23] Therefore, in pyridine, both 7 and 5 will remain
unionised. All attempts to model either the transition state
structure or the product of the nucleophilic attack of the
unionised uracil N1 atom in 7 and 5 with tosyl chloride
(Me-Ph-SO2Cl), selected here as a model reactant, failed
because the complex decomposed to reactants, suggesting
that unionised N1 is not sufficiently nucleophilic for the re-
[a] Reaction conditions for the conversion of 13 into 14: H2
(42 psi), Pd/C (10%), CH2Cl2/MeOH (1:1), r.t., 48 h.
+
action. Even with a very electrophilic MePh-SO2 cation, 7
forms a very weak nonbonding complex, with a N1–S dis-
tance of 2.168 Å and interaction free energy of only ΔGINT
= –1.5 kcalmol–1. This we rationalise with the atomic
charge on the N1 atom of –0.64 |e| in 7, which was the least
negative for this reaction centre amongst all protonation
Computational Mechanistic Studies
To rationalize the observed reactivity trends, we exam-
ined the conformations of 7 and 5, and their deprotonated
forms, in DMF solution (Figure 2). 1H-4-Derivative 7a is
the most stable form of 7 (Scheme 2), but this was only
Figure 2. Acid-base equlibria of systems 7 and 5 together with the calculated pKa values in DMF corresponding to the most favourable
deprotonation reactions.
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5-Triazolyluracils and Their N1-Sulfonyl Derivatives
forms of the system 7. Together, these results explain why (νIMAG = 189i cm–1), with an increase of 2.3 kcalmol–1 rela-
the investigated condensation of 7 and 5 was unsuccessful tive to 5–, suggesting that this reaction proceeds around 50
when performed in pyridine solution.
times slower for 7–. This fact, together with the reduced
With a pKa of 15.0, DBU can efficiently deprotonate exergonicty (ΔrG = –7.2 kcalmol–1), and the longer N1–S
both systems to their monoanionic forms 7– and 5–. The bond of 1.756 Å in the product 7–SO2R, provides an expla-
latter reacts with Me-Ph-SO2Cl by forming a reactive com- nation for why the condensation of 7 with DBU/DMF re-
plex that is 3.6 kcalmol–1 higher in energy than that of the sulted either in poor yields or even with no expected prod-
separated reactants (Table 3). From there, it takes ucts at all (Table 2).
9.7 kcalmol–1 to arrive at the transition state for the forma-
tion of the N1–S chemical bond (νIMAG = 182i cm–1), thus DBU in DMF by more than five orders of magnitude. With
leading to
total activation free energy ΔG‡ of its pKa value of 20.5, it is capable of deprotonating 7 to its
Potassium carbonate (K2CO3) is a stronger base than
a
13.3 kcalmol–1. Following that, the desired product is dianion 72–, by removing both the uracil N1 and triazole
formed with a chloride anion, Cl–, departing as the leaving N1Ј protons (Figure 2). The reaction of 72– with Me-Ph-
group. In the product, the N1–S bond length is 1.748 Å, SO2Cl is very favourable (ΔrG = –16.9 kcalmol–1), with fur-
being reduced from 3.524 and 2.366 Å in the respective re- ther reduction in the product N1–S bond to 1.742 Å,
actants and transition state. The overall reaction is favour- whereas the calculated barrier (ΔG# = 13.5 kcalmol–1) is
able and fairly exergonic with ΔrG = –11.8 kcalmol–1, mak- lower than that for 7– by 1.7 kcalmol–1. This explains why
ing this process thermodynamically spontaneous. The ki- 7, when used with K2CO3, gives more product than with
netic and thermodynamic parameters of this reaction, to- DBU. Nevertheless, the increase in the reaction yield is not
gether with the obtained yield of 75% (Table 2, compound spectacular because the calculated reaction barrier is
16), will serve as a reference point for other reaction path- 0.2 kcalmol–1 higher than for 5–. It turns out that this sub-
ways. In contrast to 5–, bringing 7– close to Me-Ph-SO2Cl tle difference in the reaction kinetics is enough that, under
is favourable and the energy is lowered by –0.4 kcalmol–1. these conditions, the reaction yield for 72– is reduced almost
Nevertheless, the reaction barrier raises to 15.6 kcalmol–1 seven times relative to 5–, being only 11%. Nevertheless,
utilising K2CO3 as a base represents a clear advancement
in comparison with DBU/DMF, for which the reaction in-
volving 7 was unsuccessful, because, in the latter case, it
Table 3. Free-energy profiles for different protonation states of starts with monoanionic 7–, which also appears to be insuf-
systems 5 and 7 with Me-Ph-SO2Cl in DMF solution obtained by
ficiently nucleophilic for successful condensation. Interest-
the (SMD)/MP2/6-311++G(2df,2pd)//(SMD)/M06–2X/631+G(d)
ingly, deprotonation of the triazole amino group increases
model. Bond lengths d1 and d2 correspond to the separation be-
the negative charge on the reacting uracil N1 atom from
tween N1(uracil)···S and S···Cl–, respectively.
–0.68 |e| (7–) to –0.71 |e| (72–) through the resonance effect,
providing one of the factors for the enhanced reactivity of
the dianion.
Along this line, it is interesting to investigate the reactiv-
ity of the trianion 73–, for which the NBO charge analysis
predicts further negative charge build-up on the N1 atom to
as much as –0.80 |e|. This is, indeed, reflected in the reaction
profile, because the activation free energy drops signifi-
cantly to ΔG‡ = 9.0 kcalmol–1, and the overall transforma-
tion becomes largely exergonic, with ΔrG = –37.4 kcalmol–1
(Table 3), which is closely followed by the shortest N1–S dis-
tance of 1.708 Å in all of the investigated products. These
results suggest that a base with the appropriate basicity
(pKa value above 30 in DMF) would make the complete
reaction more feasible, which would proceed around 1500
times faster than for 5–, with the latter exhibiting the second
lowest activation free energy studied here. This was exactly
the case in a reaction involving 7 with three equivalents of
tBu–P4 superbase, which exhibited measured pKa values of
42.7 and 30.3 in acetonitrile and dimethyl sulfoxide
(DMSO),[20] respectively, which is clearly a base that is
strong enough to both generate a trianion 73– and enable
its complete transformation (Table 1). This fact underlines
the decisive impact of the increased nucleophilicity of the
reacting uracil N1 atom on the feasibility of forming con-
densation products, which is a result of the subsequent de-
protonation of the reactants.
Relative energy [kcalmol–1
System Reactants Transition state Products
]
Geometry [Å]
(M)
5–
(R)
3.6
(TS)
13.3
(P)
d1
d2
2.113 (R)
–11.8
3.524 (R)
2.366 (TS) 2.310 (TS)
1.748 (P)
7–
–0.4
3.0
15.2
13.5
9.0
–7.2
3.953 (R)
2.101 (R)
2.329 (TS) 2.327 (TS)
1.756 (P)
72–
–16.9
–37.4
3.997 (R)
2.104 (R)
2.426 (TS) 2.284 (TS)
1.742 (P)
73–
6.4
3.296 (R)
2.138 (R)
2.544 (TS) 2.311 (TS)
1.708 (P)
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tikfolien Kieselgel 60 F254 and preparative thick-layer (2 mm)
chromatography was done on Merck 60 F254. Melting points were
determined with a Kofler hot-stage apparatus and are uncorrected.
UV spectra were recorded with a Philips PU8700 UV/Vis spectro-
Conclusions
In this work we showed that novel C5–1,2,3-triazolyl-de-
rived pyrimidines 2–6 can be prepared by the CuI-catalysed
Huisgen alkyne–azide 1,3-dipolar cycloaddition (CuAAC)
photometer. IR spectra were obtained as KBr pellets with a Per-
1
reactions from easily accessible 5-ethynyluracil 1, sodium kin–Elmer 297 spectrophotometer. H and 13C NMR spectra were
recorded in [D6]DMSO with a Varian Gemini 300 (300/75 MHz)
spectrometer using [D6]DMSO as the internal standard. High-reso-
lution mass spectra (HRMS) were obtained with a Micromass Q-
Tof2 hybrid quadrupole time-of-flight mass spectrometer.
azide, and alkyl halides by using an in situ azidation/cyclo-
addition protocol. This approach allows the N1Ј substituent
of the 1,2,3-triazole ring to be easily varied through the use
of a range of alkyl halides. Compounds 2, 3, 5 and 6 were
obtained in 81–100% yields. Derivative 4 was obtained by
the reduction of 3 with sodium borohydride/DME in 60%
yield. Compound 2 was treated with ammonia to give 7,
lacking an N1Ј triazole substituent, in quantitative yield.
We also showed that C5–1,2,3-triazolyl-derived N1-sulf-
onylpyrimidine derivatives 10–13, 15 and 16, bearing vari-
ous substituents at the N1Ј triazole nitrogen, could be pre-
pared in 35–90% yields by the condensation reaction of
pyrimidine derivatives 2–6 and various sulfonyl chlorides
under basic conditions (DBU) in DMF. In contrast, under
the same reaction conditions or by using other bases such
as pyridine, K2CO3 in DMF, and BSA in acetonitrile, deriv-
ative 7, lacking the N1Ј triazole substituent, gave either trace
amounts or no respective N1-sufonylated products at all.
General One-Pot Procedure for 1,3-Dipolar Cycloadditions
(CuAAC): Sodium azide (2 mmol), CuI (0.2 mmol), sodium ascorb-
ate (0.1 mmol) and N,NЈ-dimethylethylenediamine (DMEDA)
(0.3 mmol) were added to a solution of the alkyl halide (2 mmol)
in EtOH/H2O (7:3, 5 mL). The mixture was heated at 100 °C for
1 h, then 5-ethynyluracil
1
(0.8 mmol), sodium ascorbate
(0.1 mmol), CuI (0.2 mmol) and DMEDA (0.3 mmol) were added.
The mixture was heated at 100 °C for 30 min and concentrated un-
der reduced pressure.
5-(1-Pivaloyloxymethyl-1H-1,2,3-triazol-4-yl)uracil (2): According
to the general CuAAC procedure, chloromethyl pivalate (297 μL,
2 mmol, 97%) was used to give the product 2. The crude material
was recrystallised immediately from methanol, yield 190 mg (81%);
white solid, m.p. 245–248 °C; Rf = 0.4 (CH2Cl2/MeOH, 9:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 228 (4.3), 290 (4.2) nm. IR
The observed reactivity differences between the N1Ј-unsub- (KBr): νmax = 3165, 3076, 1755, 1710, 1672, 1553, 1445, 1433, 1238,
˜
1117, 1030 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 11.25–
11.45 (br. s, 2 H, NH-1, NH-3), 8.45 (s, 1 H, H-6), 8.08 (s, 1 H, H-
5Ј), 6.34 (s, 2 H, CH2), 1.12 (s, 9 H, 3ϫCH3) ppm. 13C NMR
(75 MHz, APT, [D6]DMSO): δ = 176.5 (s, C=O), 162.0 (s, C-4),
150.5 (s, C-2), 139.4 (s, C-4Ј), 138.0 (d, C-6), 122.8 (d, C-5Ј), 103.2
(s, C-5), 70.0 (t, CH2), 38.2 [s, (CH3)3C-], 26.4 (q, CH3) ppm.
HRMS (ESI-TOF): m/z calcd. for C12H16N5O4 [M + H]+ 294.1202;
found 294.1185.
stituted triazole 7, and 2–6, bearing various N1Ј substitu-
ents, appears intriguing considering the remote position of
substituents to the preferred pyrimidine N1 sulfonylation
site.
The results of the computational analysis aided in the
interpretation of the observed reactivities and revealed a
tight connection between the strength of the employed base
catalyst and its ability to increase the nucleophilicity of the
reacting uracil N1 atom through subsequent deprotonation,
which is evident in the negative charge buildup on this site
from –0.64 and –0.68 to –0.71 and –0.80 |e| in 7, 7–, 72–
and 73–, respectively. In addition, the calculated free-energy
profiles are found to be fully consistent with the observed
reaction yields. Following computational results, the appli-
cation of the nonionic superbase catalyst with low nucleo-
philicity, tBu–P4, in the condensation of 7 with tosyl chlor-
ide gave complete conversion into the desired product 9
(TLC monitoring), which was, however, isolated in 21–58%
yields due to cleavage of the unstable N1–S bond.
Therefore, we can conclude that the experimental find-
ings and computational results presented herein are consis-
tent in suggesting that the present synthetic strategy offers
a promising route towards new families of biologically
active N1-sulfonyl-5-(1,2,3-triazol-4-yl)uracil derivatives.
We would also like to emphasise that the calculated pKa
values for all three acidic N-H sites in 7 [pKa(N1) = 12.0;
pKa(N1Ј) = 17.5; pKa(N3) = 32.7] could be of interest in
designing further organic synthesis and for the construction
of various novel conjugates of C5–1,2,3-trazolyl uracils.
Ethyl 2-[4-(Uracil-5-yl)-1H-1,2,3-triazol-1-yl]acetate (3): According
to the general CuAAC procedure, ethyl bromoacetate (223 μL,
2 mmol) was used to give the product 3. The crude material was
recrystallised immediately from methanol, yield 212 mg (quant.);
white solid; m.p. 255–258 °C; Rf = 0.4 (CH2Cl2/MeOH, 9:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 232 (4.1), 290 (3.9) nm. IR
(KBr): νmax = 3157, 3142, 3074, 1754, 1713, 1682, 1639, 1452, 1398,
˜
1
1229, 1207 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 11.39 (s, 1
H, NH-3), 11.18 (br. s, 1 H, NH-1), 8.38 (s, 1 H, H-6), 8.06 (s, 1
H, H-5Ј), 5.41 (s, 2 H, CH2), 4.18 (dd, J = 7.1, 14.2 Hz, 2 H, CH2),
1.22 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, APT,
[D6]DMSO): δ = 167.2 (s, C=O), 162.1 (s, C-4), 150.5 (s, C-2),
139.00 (s, C-4Ј), 137.6 (d, C-6), 123.4 (d, C-5Ј), 103.7 (s, C-5), 61.4
(t, CH2), 50.3 (t, CH2), 13.9 (q, CH3) ppm. HRMS (ESI-TOF): m/z
calcd. for C10H12N5O4 [M + H]+ 266.0889; found 266.0885.
Deprotection of 3: 5-[1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl]uracil
(4): To
a suspension of 5-triazolyl derivative 3 (100 mg,
0.377 mmol) in DME (4 mL), sodium borohydride (74.3 mg,
1.885 mmol) was added. The white suspension was heated to reflux
for 20 min and then a mixture of DME (2 mL) and methanol
(337 μL, 8.29 mmol) was added dropwise. The resulting cloudy
mixture was heated to reflux overnight and the solvent was evapo-
rated under reduced pressure. The residue was purified by prepara-
tive chromatography (CH2Cl2/MeOH, 3:1) to give the product 4,
yield 50 mg (60%); white solid; m.p. 267–269 °C; Rf = 0.2 (CH2Cl2/
MeOH, 6:1). UV (MeOH): λmax (logε, dm3 mol–1 cm–1) = 232
Experimental Section
General Information: Solvents were distilled from appropriate dry-
ing agents shortly before use. TLC was carried out on DC-plas-
(4.12), 291 (3.97) nm. IR (KBr): ν
= 3240, 3173, 3107, 3066,
˜
max
1716, 1670, 1553, 1443, 1370, 1217 cm–1. 1H NMR (300 MHz, [D6]-
7700
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7695–7704

5-Triazolyluracils and Their N1-Sulfonyl Derivatives
DMSO): δ = 11.40 (s, 1 H, NH-3), 11.19 (br. s, 1 H, NH-1), 8.29
(s, 1 H, H-6), 8.02 (s, 1 H, H-5Ј), 5.02 (t, J = 5.2 Hz, 1 H, OH),
quenched with a small amount of methanol. The resulting solid
(unreacted 7) was filtered off. The filtrate was evaporated and the
4.42 (t, J = 5.3 Hz, 2 H, CH2OH), 3.77 (dd, J = 5.1, 10.4 Hz, 2 H, residue was purified by preparative chromatography (CH2Cl2/
CH2CH2OH) ppm. 13C NMR (75 MHz, APT, [D6]DMSO): δ =
162.2 (s, C-4), 150.6 (s, C-2), 138.8 (s, C-4Ј), 137.3 (d, C-6), 122.4
MeOH, 9:1) to give the product 8, yield 15 mg (6%); white solid;
m.p. 173–175 °C; Rf = 0.4 (CH2Cl2/MeOH, 9:1). UV (MeOH): λmax
(d, C-5Ј), 104.0 (s, C-5), 59.9 (t, CH2), 52.1 (t, CH2) ppm. HRMS (logε, dm3 mol–1 cm–1) = 234 (4.11), 289 (4.21) nm. IR (KBr): ν
˜
max
(ESI-TOF): m/z calcd. for C8H10N5O3 [M + H]+ 224.0784; found
= 3456, 3096, 1720, 1701, 1686, 1541, 1437, 1393, 1256, 1178,
224.0773.
1022 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 15.30 (br. s, 1 H,
NH-1Ј), 12.18 (br. s, 1 H, NH-3), 8.62 (s, 1 H, H-5Ј), 8.45 (s, 1 H,
H-6), 7.96 (d, J = 4.2 Hz, 1 H, H-3ЈЈ or H-4ЈЈ), 7.50 (dd, J = 4.2 Hz,
1 H, H-3ЈЈ or H-4ЈЈ) ppm. 13C NMR (75 MHz, APT, [D6]DMSO):
δ = 159.8 (s, C-4), 149.8 (s, C-2), 146.7 (s, C-4Ј), 138.6 (d, C-5Ј),
138.5 (d, C-6), 138.4 (s, C-2ЈЈ), 135.1 (d, C-3ЈЈ), 131.6 (d, C-4ЈЈ),
124.8 (s, C-5ЈЈ), 100.9 (s, C-5) ppm. HRMS (ESI-TOF): m/z calcd.
for C10H7BrN5O4S2 [M + H]+ 403.9123; found 403.9112.
5-(1-Benzyl-1H-1,2,3-triazol-4-yl)uracil (5): According to the gene-
ral CuAAC procedure, benzyl bromide (243 μL, 2 mmol) was used
to give the product 5. The crude material was recrystallised imme-
diately from the methanol/dichloromethane, yield 190 mg (81%);
white solid; m.p. 270–272 °C; Rf = 0.5 (CH2Cl2/MeOH, 9:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 231 (4.1), 291 (4.0) nm. IR
(KBr): νmax = 3221, 3151, 3065, 3032, 1728, 1682, 1551, 1456, 1425,
˜
1227, 1045 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 11.40 (s, 1
1
1-(p-Tolylsulfonyl)-5-(1H-1,2,3-triazol-4-yl)uracil (9)
H, NH-3), 11.19 (br. s, 1 H, NH-1), 8.37 (s, 1 H, H-6), 8.02 (s, 1
H, H-5Ј), 7.30–7.40 (m, 5 H, Ph), 5.63 (s, 2 H, CH2) ppm. 13C
NMR (75 MHz, APT, [D6]DMSO): δ = 162.2 (s, C-4), 150.6 (s, C-
2), 139.3 (s, Ph), 137.6 (d, C-6), 136.2 (s, C-4Ј), 128.8 (d, Ph), 128.1
(d, Ph), 127.9 (d, Ph), 122.0 (d, C-5Ј), 103.8 (s, C-5), 52.7 (t,
CH2) ppm. HRMS (ESI-TOF): m/z calcd. for C13H12N5O2 [M +
H]+ 270.0991; found 270.0971.
BSA/CH3CN Procedure: To a suspension of 5-triazolyl derivative 7
(100 mg, 0.56 mmol) in anhydrous acetonitrile (2 mL), BSA
(431 μL, 1.67 mmol, 95%) was added dropwise and the reaction
mixture was heated to reflux for 30 min. The colourless solution
was then cooled to 0 °C and p-toluenesulfonyl chloride (tosyl chlor-
ide, TsCl) (106.4 mg, 0.56 mmol) was added. The reaction mixture
was stirred for an additional 1 h under reflux and quenched with
a small amount of methanol. The resulting solid (unreacted 7) was
filtered off. The filtrate was evaporated and the residue was purified
by preparative TLC (CH2Cl2/MeOH, 9:1) to give product 9 (15 mg,
8%) as a white powder.
Benzyl 2-[4-(Uracil-5-yl)-1H-1,2,3-triazol-1-yl]acetate (6): Accord-
ing to the general CuAAC procedure, benzyl 2-bromoacetate
(330 μL, 2 mmol, 96%) was used to give the product 6. The crude
material was recrystallised immediately from methanol, yield
260 mg (quant.); white solid; m.p. 292–295 °C; Rf = 0.4 (CH2Cl2/
MeOH, 9:1). UV (MeOH): λmax (logε, dm3 mol–1 cm–1) = 231 (4.1),
DBU/DMF Procedure: To a solution of 5-triazolyl derivative 7
(100 mg, 0.56 mmol) in anhydrous DMF (3 mL) under an argon
atmosphere, DBU (86 μL, 0.56 mmol, 97%) was added dropwise.
The colourless solution was stirred at room temperature for 30 min,
then cooled to 0 °C and tosyl chloride (106.4 mg, 0.56 mmol) was
added. The resulting clear yellow mixture was stirred at room tem-
perature for an additional 3 h. The solvent was evaporated under
reduced pressure and the residue was purified by preparative TLC
(CH2Cl2/MeOH, 9:1) to give product 9 (17 mg, 9%) as a white
powder.
291 (4.0) nm. IR (KBr): νmax = 3215, 3160, 3065, 3034, 1744, 1724,
˜
1682, 1553, 1493, 1223, 1203 cm–1. 1H NMR (300 MHz, [D6]-
DMSO): δ = 11.43 (s, 1 H, NH-3), 11.22 (br. s, 1 H, NH-1), 8.42
(s, 1 H, H-6), 8.06 (s, 1 H, H-5Ј), 7.38 (m, 5 H, Ph), 5.51 (s, 2 H,
OCH2Ph), 5.21 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, APT, [D6]-
DMSO): δ = 167.3 (s, C=O), 162.2 (s, C-4), 150.6 (s, C-2), 139.0 (s,
Ph), 137.6 (d, C-6), 135.4 (s, C-4Ј), 128.5 (d, Ph), 128.3 (d, Ph),
128.1 (d, Ph), 123.5 (d, C-5Ј), 103.7 (s, C-5), 66.7 (t, OCH2Ph), 50.3
(t, NCH2CO) ppm. HRMS (ESI-TOF): m/z calcd. for C15H14N5O4
[M + H]+ 328.1046; found 328.1025.
K2CO3/DMF Procedure: To a suspension of 5-triazolyl derivative 7
(100 mg, 0.56 mmol) and K2CO3 (77.2 mg, 0.56 mmol) in anhy-
drous DMF (3 mL) cooled to 0 °C under an argon atmosphere,
tosyl chloride (106.4 mg, 0.56 mmol) was added and the reaction
mixture was stirred at room temperature for 3 h. The solvent was
evaporated under reduced pressure and the residue was purified by
preparative TLC (CH2Cl2/MeOH, 9:1) to give the product 9
(20.5 mg, 11%) as a white powder.
Deprotection of 2: 5-(1H-1,2,3-Triazol-4-yl)uracil (7): A solution of
5-triazolyl derivative 2 (100 mg, 0.341 mmol) in a mixture of diox-
ane and concentrated aqueous ammonia (1:3 v/v,74 mL) was stirred
at room temperature for 1.5 h. The clear colourless solution was
concentrated under reduced pressure, and the residue was crystal-
lised from water to obtain product 7, yield 61 mg (quant.); white
solid; m.p. Ͼ 300 °C; Rf = 0.6 (CH2Cl2/MeOH, 3:1). UV (MeOH):
λmax (logε, dm3 mol–1 cm–1) = 231 (4.23), 290 (4.12) nm. IR (KBr):
General tBu-P4/DMF Procedure: Derivative 7 (1 mmol) was dis-
solved in anhydrous DMF (4.2 mL), cooled to –78 °C in a dry ice/
acetone cooling bath under an argon atmosphere, and tBu–P4
(3 mmol, 0.8 m in hexane) was added. The solution was stirred for
30 min at –78 °C, then placed into an ice bath and warmed to 0 °C.
After addition of tosyl chloride (2 mmol) at 0 °C, the reaction solu-
tion was warmed slowly to room temperature and vigorous stirring
was continued for 1.5 h.
ν
= 3140, 3084, 3032, 1761, 1720, 1683, 1549, 1429, 1389,
˜
max
1234 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 14.87 (br. s, 1 H,
NH-1Ј), 11.39 (br. s, 2 H, NH-1, NH-3), 8.12 (s, 1 H, H-5Ј), 7.97
(s, 1 H, H-6) ppm. 13C NMR (75 MHz, APT, [D6]DMSO): δ =
162.2 (s, C-4), 150.6 (s, C-2), 138.4 (d, C-6), 128.7 (s, C-4Ј), 119.8
(d, C-5Ј), 103.4 (s, C-5) ppm. HRMS (ESI-TOF): m/z calcd. for
C6H6N5O2 [M + H]+ 180.0521; found 180.0513.
1-(5-Bromothiophene-2-sulfonyl)-5-(1H-1,2,3-triazol-4-yl)uracil (8)
Method A: According to the general tBu–P4/DMF procedure, de-
rivative 7 (42.5 mg, 0.237 mmol), tBu–P4 (890 μL, 0.712 mmol,
0.8 m in hexane), and tosyl chloride (90.46 mg, 0.474 mmol) were
used. The reaction was quenched with 1 m HCl (712 μL,
0.712 mmol), the solvent was removed under reduced pressure, and
the oil residue was purified by preparative chromatography to ob-
tain the product 9. The plates were developed two times in a mix-
ture of CH2Cl2/EtOAc (3:1) and additionally in a mixture CH2Cl2/
BSA/CH3CN Procedure: To a suspension of 5-triazolyl derivative
7 (121.3 mg, 0.677 mmol) in anhydrous acetonitrile (2 mL), BSA
(523 μL, 2.03 mmol, 95%) was added dropwise and the reaction
mixture was heated to reflux for 30 min. The colourless solution
was then cooled to 0 °C and the 5-bromothiophene-2-sulfonyl
chloride (157.4 mg, 0.677 mmol, 97%) was added. The reaction
mixture was stirred for an additional 3 h under reflux and
Eur. J. Org. Chem. 2015, 7695–7704
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7701

ˇ
D. Saftic´, R. Vianello, B. Zinic´
FULL PAPER
MeOH (9:1) to give the product 9 (16.6 mg, 21%) as a white
solid.
0.558 mmol) were used to give the product 11., yield 210 mg (90%);
white solid; m.p. 240–242 °C; Rf = 0.6 (CH2Cl2/MeOH, 20:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 230 (4.35), 287 (4.08) nm.
Method B: According to the general tBu–P4/DMF procedure, de-
rivative 7 (15 mg, 0.084 mmol), tBu–P4 (314 μL, 0.251 mmol, 0.8 m
in hexane) and tosyl chloride (31.93 mg, 0.167 mmol) were used.
The solvent was removed under reduced pressure and the oil resi-
due was purified by preparative chromatography to obtain the
product 9. The plates were developed two times in a mixture of
CH2Cl2/EtOAc (3:1) and additionally in a mixture of CH2Cl2/
MeOH (9:1) to give the product 9 (13 mg, 47%) as a white solid.
IR (KBr): ν
= 3169, 3104, 3055, 1738, 1680, 1594, 1466, 1436,
˜
max
1383, 1261, 1231, 1192, 1176, 1084, 1045, 1013 cm–1 1H NMR
.
(300 MHz, [D6]DMSO): δ = 12.07 (br. s, 1 H, NH-3), 8.76 (s, 1 H,
H-6), 8.50 (s, 1 H, H-5Ј), 8.01 (d, J = 8.5 Hz, 2 H, Ph), 7.50 (d, J
= 8.2 Hz, 2 H, Ph), 5.46 (s, 2 H, CH2), 4.19 (dd, J = 7.1, 14.2 Hz,
2 H, CH2), 2.43 [s, 3 H, CH3(Ph)], 1.23 (t, J = 7.1 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, APT, [D6]DMSO): δ = 167.2 (s,
C=O), 161.1 (s, C-4), 146.6 (s, C-2), 146.5 (s, Ph), 137.7 (s, C-4Ј),
132.9 (s, Ph), 132.4 (d, C-6), 129.9 (d, Ph), 129.3 (d, Ph), 124.8 (d,
C-5Ј), 106.9 (s, C-5), 61.5 (t, CH2), 50.4 (t, CH2), 21.2 [q, CH3(Ph)],
14.0 (q, CH3 ) ppm. HRMS (ESI-TOF): m/z calcd. for
C17H18N5O6S [M + H]+ 420.0978; found 420.0974.
Method C: According to the general tBu–P4/DMF procedure, de-
rivative 7 (30 mg, 0.167 mmol), tBu–P4 (628 μL, 0.502 mmol, 0.8 m
in hexane) and tosyl chloride (63.86 mg, 0.335 mmol) were used.
The solution was diluted with hexane, the hexane phase was re-
moved, and the DMF layer was evaporated under reduced pressure.
The oil residue was purified by preparative chromatography
(CH2Cl2/EtOAc, 3:1) to give the product 9, yield 55.82 mg (58%);
white solid; m.p. 238–240 °C; Rf = 0.4 (CH2Cl2/MeOH, 9:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 229 (4.26), 264 (4.06), 296
1-(p-Tolylsulfonyl)-5-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]uracil
(12): According to DBU/DMF general procedure, 5-triazolyl deriv-
ative 4 (30 mg, 0.134 mmol) and tosyl chloride (25.6 mg,
0.134 mmol) were used to give product 12, yield 30 mg (59%);
white solid; m.p. 236–238 °C; Rf = 0.5 (CH2Cl2/MeOH, 9:1). UV
(MeOH): λmax (logε, dm3 mol–1 cm–1) = 231 (4.20), 286 (3.39) nm.
(4.17) nm. IR (KBr): ν
= 3447, 3069, 1713, 1678, 1637, 1593,
˜
max
1445, 1394, 1198, 1161 cm–1. H NMR (300 MHz, [D6]DMSO): δ
= 15.05 (br. s, 1 H, NH-1Ј), 11.49 (br. s, 1 H, NH-3), 8.44 (s, 1 H,
H-5Ј), 8.04 (s, 1 H, H-6), 7.90 (d, J = 8.4 Hz, 2 H, Ph), 7.49 (d, J
= 8.0 Hz, 2 H, Ph), 2.40 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
APT, [D6]DMSO): δ = 162.0 (s, C-4), 150.5 (s, C-2), 147.1 (s, C-
4Ј), 145.8 (s, Ph), 141.8 (d, C-5Ј), 138.1 (d, C-6), 132.0 (s, Ph), 130.6
(d, Ph), 128.1 (d, Ph), 101.0 (s, C-5), 21.4 (q, CH3) ppm. HRMS
(ESI-TOF): m/z calcd. for C13H12N5O4S [M + H]+ 334.0605; found
334.0592.
1
IR (KBr): ν
= 3418, 3160, 3107, 1710, 1686, 1649, 1630, 1594,
˜
max
1448, 1431, 1259, 1188, 1176, 1159, 1084, 1070, 1040, 1022 cm–1.
1H NMR (300 MHz, [D6]DMSO): δ = 12.06 (s, 1 H, NH-3), 8.73
(s, 1 H, H-6), 8.40 (s, 1 H, H-5Ј), 8.00 (d, J = 8.5 Hz, 2 H, Ph),
7.50 (d, J = 8.1 Hz, 2 H, Ph), 4.47 (t, J = 5.4 Hz, 2 H, CH2OH),
3.9–4.3 (br. s, 1 H, CH2OH), 3.79 (t, J = 5.3 Hz, 2 H, CH2CH2OH),
2.43 [s, 3 H, CH3(Ph)] ppm. 13C NMR (75 MHz, APT, [D6]-
DMSO): δ = 161.1 (s, C-4), 146.6 (s, C-2), 146.5 (s, Ph), 137.5 (s,
C-4Ј), 132.9 (s, Ph), 132.1 (d, C-6), 129.9 (d, Ph), 129.2 (d, Ph),
123.8 (d, C-5Ј), 107.1 (s, C-5), 59.9 (t, CH2), 52.3 (t, CH2), 21.2 [q,
CH3(Ph)] ppm. HRMS (ESI-TOF): m/z calcd. for C15H16N5O5S
[M + H]+ 378.0872; found 378.0852.
General Procedure for Condensation of 1,4-Disubstituted Triazoles
2–6 with Sulfonyl Chlorides
DBU/DMF Procedure: To a solution of appropriate 5-triazolyl
derivative (0.341 mmol) in anhydrous DMF (2 mL), DBU
(0.341 mmol, 97%) was added dropwise. The clear, colourless solu-
tion was stirred at room temperature for 30 min. The solution was
then cooled to 0 °C and the appropriate sulfonyl chloride
(0.341 mmol) was added. The resulting clear yellow mixture was
stirred at room temperature for an additional 3 h. The solvent was
evaporated under reduced pressure and the residue was purified by
crystallisation from methanol to afford the product.
1-(5-Bromothiophene-2-sulfonyl)-5-(1-benzyl-1H-1,2,3-triazol-4-
yl)uracil (13): According to the DBU/DMF general procedure, 5-
triazolyl derivative 5 (250 mg, 0.928 mmol) and 5-bromothiophene-
2-sulfonyl chloride (209.4 mg, 0.928 mmol, 97%) were used to give
the product 13, yield 150 mg (35%); white solid; m.p. 204–207 °C;
Rf = 0.8 (CH2Cl2/MeOH, 9:1). UV (MeOH): λmax (log ε,
dm3 mol–1 cm–1) = 235 (4.3), 290 (4.3) nm. IR (KBr): ν
= 3062,
˜
max
1751, 1742, 1698, 1678, 1541, 1460, 139, 1259, 1182 cm–1. 1H NMR
(300 MHz, [D6]DMSO): δ = 12.21 (br. s, 1 H, NH-3), 8.60 (s, 1 H,
H-6), 8.50 (s, 1 H, H-5Ј), 7.97 (d, J = 4.2 Hz, 1 H, H-3ЈЈ or H-4ЈЈ),
7.50 (d, J = 4.2 Hz, 1 H, H-3ЈЈ or H-4ЈЈ), 7.32–7.38 (m, 5 H, Ph),
5.67 (s, 2 H, CH2) ppm. 13C NMR (75 MHz, APT, [D6]DMSO): δ
= 161.2 (s, C-4), 146.9 (s, C-2), 138.6 (d, C-6), 138.0 (s, Ph), 136.0
(s, C-4Ј), 135.2 (s, C-2ЈЈ), 131.8 (d, C-3ЈЈ or C-4ЈЈ), 131.6 (d, C-3ЈЈ
or C-4ЈЈ), 128.8 (d, Ph), 128.2 (d, Ph), 127.9 (d, Ph), 124.8 (s, C-
5ЈЈ), 123.5 (d, C-5Ј), 107.4 (s, C-5), 52.8 (t, CH2) ppm. HRMS (ESI-
TOF): m/z calcd. for C17H13BrN5O4S2 [M + H]+ 493.9592; found
493.9591.
1-(5-Bromothiophene-2-sulfonyl)-5-(1-pivaloyloxymethyl-1H-1,2,3-
triazol-4-yl)uracil (10): According to DBU/DMF general pro-
cedure, 5-triazolyl derivative 2 (100 mg, 0.341 mmol) and 5-bromo-
thiophene-2-sulfonyl chloride (79.3 mg, 0.341 mmol, 97 %) were
used to give the product 10, yield 124 mg (70%); white solid; m.p.
233–235 °C; Rf = 0.7 (CH2Cl2/MeOH, 9:1). UV (MeOH): λmax
(logε, dm3 mol–1 cm–1) = 237 (4.2), 290 (4.3) nm. IR (KBr): ν
=
˜
max
3217, 3150, 3096, 1730, 1720, 1693, 1537, 1448, 1429, 1389, 1257,
1188, 1140, 1022 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 12.25
(br. s, 1 H, NH-3), 8.64 (s, 1 H, H-6), 8.56 (s, 1 H, H-5Ј), 7.97 (d,
J = 4.3 Hz, 1 H, H-3ЈЈ or H-4ЈЈ), 7.50 (d, J = 4.2 Hz, 1 H, H-3ЈЈ
or H-4ЈЈ), 6.38 (s, 2 H, CH2), 1.12 (s, 9 H, 3ϫCH3) ppm. 13C NMR
(75 MHz, APT, [D6]DMSO): δ = 176.5 (s, C=O), 161.0 (s, C-4),
153.7 (s, C-2), 146.8 (s, C-4Ј), 138.7 (d, C-6), 138.0 (s, C-2ЈЈ), 135.1
(d C-3ЈЈ), 132.4 (d, C-4ЈЈ or C-5Ј), 131.7 (d, C-4ЈЈ or C-5Ј), 124.9
(s, C-5ЈЈ), 106.9 (s, C-5), 70.1 (t, CH2), 38.2 [s, (CH3)3C-], 26.5 (q,
CH3) ppm. HRMS (ESI-TOF): m/z calcd. for C16H17BrN5O6S2 [M
+ H]+ 517.9804; found 517.9796.
Hydrogenolysis of 13: 1-(Thiophene-2-sulfonyl)-5-(1-benzyl-1H-
1,2,3-triazol-4-yl)uracil (14): 5-Triazolyl derivative 13 (100 mg,
0.202 mmol) was dissolved in a 1:1 mixture of CH2Cl2/MeOH
(120 mL) and 10% Pd/C (20 mg) was added. The reaction mixture
was treated with hydrogen gas (42 psi) in a Parr hydrogenation ap-
paratus for 48 h. The mixture was filtered through a Celite pad and
washed with boiling methanol (20 mL). The combined methanol
filtrates were concentrated under reduced pressure and the crude
Ethyl 2-{4-[(1-p-Tolylsulfonyl)uracil-5-yl]-1H-1,2,3-triazol-1-yl}- material was purified using crystallisation with a CH2Cl2/MeOH
acetate (11): According to DBU/DMF general procedure, 5-triazo-
lyl derivative 3 (148 mg, 0.558 mmol) and tosyl chloride (106.4 mg,
mixture to obtain the product 14, yield 77 mg (92%); white solid;
m.p. 240–243 °C; Rf = 0.6 (CH2Cl2/MeOH, 20:1). UV (MeOH):
7702
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7695–7704

5-Triazolyluracils and Their N1-Sulfonyl Derivatives
λmax (logε, dm3 mol–1 cm–1) = 231 (4.3), 287 (4.1) nm. IR (KBr): (2df,2pd)//(SMD)/M06-2X/6-31+G(d) models employed here,
ν
= 3215, 1734, 1697, 1541, 1448, 1257, 1182 cm–1. 1H NMR
which turned out to be very accurate in estimating both pKa and
reaction thermodynamic values in solution.[25] All of the transition
state structures were verified to have the appropriate imaginary fre-
quency, from which the corresponding reactants and products were
˜
max
(300 MHz, [D6]DMSO): δ = 12.12 (br. s, 1 H, NH-3), 8.66 (s, 1 H,
H-6), 8.48 (s, 1 H, H-5Ј), 8.28 (dd, J = 5.0, 1.4 Hz, 1 H, H-3ЈЈ or
H-4ЈЈ or H-5ЈЈ), 8.11 (dd, J = 4.0, 1.5 Hz, 1 H, H-3ЈЈ or H-4ЈЈ or
H-5ЈЈ), 7.30–7.39 (m, 6 H, Ph, H-3ЈЈ or H-4ЈЈ or H-5ЈЈ), 5.67 (s, 2 determined using the Intrinsic Reaction Coordinate (IRC) pro-
H, CH2) ppm. 13C NMR (75 MHz, APT, [D6]DMSO): δ = 160.9 cedure.[26] pKa values were calculated in a relative fashion using
(s, C-4), 146.5 (s, C-2), 138.5 (d, C-6), 137.9 (d, C-3ЈЈ or C-4ЈЈ or AH + BREF– ǞA– + BREFH equation, and employing the following
C-5ЈЈ), 137.9 (s, Ph or C-2ЈЈ), 135.9 (s, C-4Ј), 134.6 (s, Ph or C-2ЈЈ),
reference bases (BREFH): Ph2NH (pKa = 25.50)[27] for the N–H
131.9 (d, C-3ЈЈ or C-4ЈЈ or C-5ЈЈ), 128.7 (d, Ph), 128.1 (d, C-3ЈЈ or deprotonation in 5 and 7, N,N,NЈ,NЈ-tetramethylguanidine (pKa =
C-4ЈЈ or C-5ЈЈ), 128.0 (d, Ph), 127.9 (d, Ph), 123.4 (d, C-5Ј), 107.2
13.65)[27] for DBUH+ and pyridineH+, H3PO4 (pKa = 8.48)[28] and
(s, C-5), 52.8 (t, CH2) ppm. HRMS (ESI-TOF): m/z calcd. for H2PO4 (pKa = 10.58)[28] for the first and second deprotonation
–
C17H14N5O4S2 [M + H]+ 416.0487; found 416.0468.
of H2CO3, respectively. Atomic charges were obtained through the
Natural Bond Orbital (NBO)[29] analysis at the (SMD)/M06-2X/6-
31+G(d) level. All of the calculations were performed using the
Gaussian 09 software.[30]
Benzyl 2-{4-[(1-p-Tolylsulfonyl)uracil-5-yl]-1H-1,2,3-triazol-1-yl}-
acetate (15): According to the DBU/DMF general procedure, 5-
triazolyl derivative 6 (100 mg, 0.306 mmol) and tosyl chloride
(58.3 mg, 0.306 mmol) were used to give the product 15, yield
126 mg (86%); white solid; m.p. 215–217 °C; Rf = 0.7 (CH2Cl2/
MeOH, 20:1). UV (MeOH): λmax (log ε, dm3 mol–1 cm–1) = 231
Acknowledgments
Financial support from the Croatian Science Foundation (grant
number HRZZ-1477) is gratefully acknowledged. R. V. gratefully
acknowledges the European Commission for an individual FP7
Marie Curie Career Integration Grant (contract number PCIG12-
GA-2012-334493).
(4.37), 285 (4.11) nm. IR (KBr): ν
= 3313, 3139, 1736, 1682,
˜
max
1543, 1448, 1385, 1254, 1191, 1175, 1020 cm–1 1H NMR
.
(300 MHz, [D6]DMSO): δ = 12.07 (br. s, 1 H, NH-3), 8.76 (s, 1 H,
H-6), 8.53 (s, 1 H, H-5Ј), 8.01 (d, J = 8.4 Hz, 2 H, Ph), 7.50 (d, J
= 8.2 Hz, 2 H, Ph), 7.37–7.41 (m, 5 H, Ph), 5.56 (s, 2 H, OCH2Ph),
5.22 (s, 2 H, CH2), 2.43 [s, 3 H, CH3(Ph)] ppm. 13C NMR
(75 MHz, APT, [D6]DMSO): δ = 167.2 (s, C=O), 161.1 (s, C-4),
146.6 (s, C-2), 146.5 (s, Ph), 137.8 (s, Ph), 135.4 (s, C-4Ј), 132.9 (s,
Ph), 132.4 (d, C-6), 129.9 (d, Ph), 129.3 (d, Ph), 128.5 (d, Ph),
128.3 (d, Ph), 128.1 (d, Ph), 124.9 (d, C-5Ј), 106.8 (s, C-5), 66.8 (t,
OCH2Ph), 50.4 (t, NCH2CO), 21.2 [q, CH3(Ph)] ppm. HRMS
(ESI-TOF): m/z calcd. for C22H20N5O6S [M + H]+ 482.1134; found
482.1120.
ˇ
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1-(p-Tolylsulfonyl)-5-(1-benzyl-1H-1,2,3-triazol-4-yl)uracil (16): Ac-
cording to the DBU/DMF general procedure, 5-triazolyl derivative
5 (50 mg, 0.186 mmol) and tosyl chloride (35.4 mg, 0.186 mmol)
were used to give the product 16, yield 59 mg (75%); white solid;
m.p. 204–206 °C; Rf = 0.7 (CH2Cl2/MeOH, 20:1). UV (MeOH):
λmax (logε, dm3 mol–1 cm–1) = 230 (4.33), 286 (4.01) nm. IR (KBr):
ˇ
ˇ
ˇ
ˇ
ˇ
[4] F. Supek, M. Kralj, M. Marjanovic´, L. Suman, T. Smuc, I.
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ˇ
ν
= 3057, 1747, 1594, 1560, 1492, 1458, 1330, 1085 cm–1. 1H
˜
max
ˇ
ˇ
NMR (300 MHz, [D6]DMSO): δ = 12.04 (br. s, 1 H, NH-3), 8.73
(s, 1 H, H-6), 8.49 (s, 1 H, H-5Ј), 7.99 (d, J = 8.4 Hz, 2 H, Ph),
7.49 (d, J = 8.3 Hz, 2 H, Ph), 7.33–7.38 (m, 5 H, Ph), 5.67 (s, 2 H,
CH2Ph), 2.42 [s, 3 H, CH3(Ph)] ppm. 13C NMR (75 MHz, APT,
[D6]DMSO): δ = 161.2 (s, C-4), 146.6 (s, C-2), 146.4 (s, Ph), 138.0
(s, Ph), 136.0 (s, C-4Ј), 132.9 (s, Ph), 132.3 (d, C-6), 129.8 (d, Ph),
129.2 (d, Ph), 128.7 (d, Ph), 128.1 (d, Ph), 127.9 (d, Ph), 123.4 (d,
C-5Ј), 106.9 (s, C-5), 52.8 (t, CH2Ph), 21.2 [q, CH3(Ph)] ppm.
HRMS (ESI-TOF): m/z calcd. for C20H18N5O4S [M + H]+
424.1079; found 424.1090.
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and computational feasibility, all molecular geometries were op-
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7703

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Received: August 21, 2015
Published Online: November 10, 2015
7704
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7695–7704