New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase

Article abstract of DOI:10.1016/j.ejmech.2014.02.041

O-Perbenzoylated 5-(β-D-glucopyranosyl)tetrazole was reacted with N-benzyl carboximidoyl chlorides to give the corresponding 4-benzyl-3-(β-D- glucopyranosyl)-5-substituted-1,2,4-triazoles. Removal of the O-benzoyl and N-benzyl protecting groups by base catalysed transesterification and catalytic hydrogenation, respectively, furnished a series of 3-(β-D-glucopyranosyl)- 5-substituted-1,2,4-triazoles with aliphatic, mono- and bicyclic aromatic, and heterocyclic substituents in the 5-position. Enzyme kinetic studies revealed these compounds to inhibit rabbit muscle glycogen phosphorylase b: best inhibitors were the 5-(4-aminophenyl)- (K_i 0.67 μM) and the 5-(2-naphthyl)-substituted (K_i 0.41 μM) derivatives. This study uncovered the C-glucopyranosyl-1,2,4-triazoles as a novel skeleton for nanomolar inhibition of glycogen phosphorylase.

Full text of DOI:10.1016/j.ejmech.2014.02.041

European Journal of Medicinal Chemistry 76 (2014) 567e579
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
New synthesis of 3-(
b-D-glucopyranosyl)-5-substituted-1,2,4-
triazoles, nanomolar inhibitors of glycogen phosphorylase
a
a
a
a
a
a
}
Sándor Kun , Éva Bokor , Gergely Varga , Béla Szocs , András Páhi , Katalin Czifrák ,
Marietta Tóth a, László Juhász a, Tibor Docsa b, Pál Gergely b, László Somsák a
,
*
a Department of Organic Chemistry, University of Debrecen, POB 20, H-4010 Debrecen, Hungary
b Department of Medical Chemistry, Medical and Health Science Centre, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
O-Perbenzoylated 5-(
to give the corresponding 4-benzyl-3-(
b
-D-glucopyranosyl)tetrazole was reacted with N-benzyl carboximidoyl chlorides
-D-glucopyranosyl)-5-substituted-1,2,4-triazoles. Removal of the
O-benzoyl and N-benzyl protecting groups by base catalysed transesterification and catalytic hydroge-
nation, respectively, furnished a series of 3-( -D-glucopyranosyl)-5-substituted-1,2,4-triazoles with
Received 1 October 2013
Received in revised form
11 February 2014
Accepted 14 February 2014
Available online 15 February 2014
b
b
aliphatic, mono- and bicyclic aromatic, and heterocyclic substituents in the 5-position. Enzyme kinetic
studies revealed these compounds to inhibit rabbit muscle glycogen phosphorylase b: best inhibitors
were the 5-(4-aminophenyl)- (Ki 0.67 mM) and the 5-(2-naphthyl)-substituted (Ki 0.41 mM) derivatives.
This study uncovered the C-glucopyranosyl-1,2,4-triazoles as a novel skeleton for nanomolar inhibition
of glycogen phosphorylase.
Keywords:
1,2,4-Triazole
C-glucopyranosyl derivative
Bioisoster
Ó 2014 Elsevier Masson SAS. All rights reserved.
Glycogen phosphorylase
Inhibitor
1. Introduction
diseases caused by abnormalities in glycogen metabolism, first of
all T2DM [5e7], but also myocardial [8,9] and cerebral [10,11] is-
Type 2 diabetes mellitus (T2DM) is a severe disease with large
economic consequences, which is significantly under-diagnosed
and incompletely treated in the general population [1,2]. Control
of blood glucose levels is a key objective in treating diabetic pa-
tients, who are most often prescribed modification of diet and ex-
ercise, one or more oral hypoglycaemic agents, as well as insulin. In
spite of the availability of different classes of hypoglycaemic drugs,
current treatments are often unable to achieve an intensive degree
of blood glucose control to reduce effectively the incidence and
severity of diabetic complications [3].
Hepatic glucose output is elevated in type 2 diabetic patients
and current evidence indicates that glycogenolysis (release of
monomeric glucose from the glycogen polymer storage form) is an
important contributor to the abnormally high production of
glucose by the liver. Glycogen phosphorylase (GP) is the enzyme
responsible for glycogen breakdown to produce glucose and related
metabolites for energy supply [4]. Due to its key role in the mod-
ulation of glycogen metabolism, pharmacological inhibition of GP
has been regarded as an effective therapeutic approach to treating
chaemias and tumours [12e15]. Therefore, the study of glycogen
phosphorylase inhibitors [16] (GPIs) is a continuing challenge for
synthetic and medicinal chemistry [17,18], computational chemis-
try [19], protein crystallography [5,20], and physiology [21]. The
biochemical and pharmacological background of this research has
been thoroughly summarized in several reviews of the past decade,
therefore, the reader is kindly referred to those papers [4,22,23].
Several structural classes of GP inhibitors have been reported
[5,17,18,24] whose binding sites identified in GP include the cata-
lytic site, the purine inhibitory site, the allosteric site, the glycogen
storage site, the new allosteric inhibitor site and the lately discov-
ered benzimidazole-binding site. The most widely studied group of
molecules is that of glucose derivatives [7,25e35] which bind pri-
marily to the active site of GP [36]. The best glucose analogue GPIs
are glucopyranosylidene-spiro-heterocycles (Ki 0.16e0.63
N-acyl-N0-
-D-glucopyranosyl ureas (Ki 0.35e0.7 M) exhibiting
submicromolar inhibition [26] of rabbit muscle GPb, the prototype
of GPs [20]. Glucopyranosylidene-spiro-thiohydantoin (Ki 29.8
against rat liver GP) was shown to exert considerable in vivo blood
sugar diminishing activity [37], and an N-acyl-N0-
-D-glucopyr-
mM) and
b
m
mM
b
anosyl urea derivative improved glucose tolerance and had
remarkable effects in rearranging hepatic metabolism in diabetic
mice [38].
* Corresponding author.
E-mail address: somsak@tigris.unideb.hu (L. Somsák).
http://dx.doi.org/10.1016/j.ejmech.2014.02.041
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

568
S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
N-Acyl-
b
-D-glucopyranosylamines (compounds I in Chart 1)
crystallographic studies on several RMGPb-I complexes showed the
presence of a H-bond between the amide NH and the main chain
C]O of His377 (outline X in Chart 1), and the strong binding was
attributed to a large extent to this interaction.
were among the first synthetic glucose analogue inhibitors of GP
[39] and several derivatives modified in the acyl groups were
investigated [40e44]. In this series N-(2-naphthoyl)-b-D-gluco-
pyranosylamine (IC) was the best inhibitor [41], which also served
as a lead structure for bioisosteric replacements [45e48]. X-Ray
Inserting a 1,2,3-triazole ring in place of the NHCO moiety as in II
revealed that I and II were equipotent inhibitors [49] and the
Chart 1. Glycogen phosphorylase inhibitors (GPIs, Ki [mM] against rabbit muscle GPb, IeVIII); synthetic targets of this study (IX); outline of binding of glucose analogues at the
active site of GP highlighting important H-bonds to His377 and interactions in the so-called b-channel for N-acyl-b-D-glucopyranosylamine type inhibitors (X) and 2-b-D-glu-
copyranosyl benzimidazole (XI) as observed by X-ray crystallography.

S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
569
Scheme 1. Retrosynthetic analysis of the target compounds IX based on 1,3-dipolar cycloadditions (Glc ¼ O-protected -D-glucopyranosyl residue, PG ¼ protecting group).
b
structural features of the binding determined by X-ray crystallog-
raphy were also very similar [42]. Oxadiazoles IIIeV, prepared in
each possible variant [50,51,55], showed that the constitution of
the heterocycle had a strong bearing on the inhibition: the
most efficient inhibitor among these compounds was 5-(b-D-
glucopyranosyl)-3-(2-naphthyl)-1,2,4-oxadiazole (IVC) which had
a similar efficiency to that of IC. Other studies with C-glucopyra-
nosyl heterocycles showed that benzothiazole VI was much less
Table 1
Synthesis of 3-(b-D-glucopyranosyl)-5-substituted-1,2,4-triazoles.
R
Yield (%)
3 (Solvent)
4
5
6
a
b
c
CH3
e
e
See Ref. [62]
See Ref. [62]
e
73 (from 5a)
98 (from 5b)
93 (from 5t)
85 (from 4d)
62 (from 5d)
90 (from 4e)
79 (from 4f)
77 (from 4g)
67 (from 5u)
95 (from 4i)
75 (from 5j)
94 (from 6j)
86 (from 5l)
98 (from 4m)
72 (from 5n)
72 (from 6n)
92 (from 4p)
90 (from 4q)
81 (from 5q)
40 (from 5r)
e
C(CH3)3
CH2OH
C6H5
e
e
e
e
d
69 (toluene)
73
See Ref. [62]
e
f
g
h
i
j
k
l
m
n
o
p
q
C6H4-4-CH3
C6H4-4-C(CH3)3
C6H4-4-CF3
C6H4-4-OH
C6H4-4-OCH3
C6H4-4-NO2
49 (m-xylene)
61 (m-xylene)
88 (toluene)
e
94
98
61
e
e
e
e
e
62 (m-xylene)
38 (toluene)
e
68
91
e
e
See Ref. [62]
e
C6H4-4-NH2
C6H4-4-COOH
C6H3-3,5-(CH3)2
C6H3-3,5-(NO2)2
C6H3-3,5-(NH2)2
C6H2-3,4,5-(OCH3)3
e
e
75 (from 3s)
e
66 (m-xylene)
e
62
e
See Ref. [62]
e
e
e
65 (m-xylene)
52 (toluene)
91
85
e
C10H7 (2-naphthyl)
See Ref. [62]
r
s
t
C5H4N (2-pyridyl)
C6H4-4-COOBn
CH2OCOCH3
e
e
e
e
e
See Ref. [62]
e
69 (m-xylene)
e
See Ref. [62]
See Ref. [62]
e
u
C6H4-4-OCOCH3
e
e

570
S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
Table 2
efficient than benzimidazoles VII and VIII [33,52]. An X-ray crys-
tallographic study of the RMGPbeVII complex revealed the pres-
ence of a specific H-bond between NH of the heterocycle and the
main chain C]O of His377 [53] (outline XI in Chart 1), and the
stronger binding of VII was explained by this interaction which
cannot exist in the case of VI.
Inhibition of rabbit muscle glycogen phosphorylase b by 3-(
substituted-1,2,4-triazoles (6).
b-D-glucopyranosyl)-5-
Based on these structureeactivity relationships it was antici-
pated that C-glucopyranosyl 1,2,4-triazoles of type IX, non-classical
bioisosteres of compounds IeV, could be more efficient GPIs. Very
recently we have demonstrated in a preliminary communication
R
Ki [
mM]
R
Ki [mM]
that IX (R ¼ 2-naphthyl, Ki 0.41
mM) indeed fulfils these expecta-
tions [54]. In this paper we disclose a new synthesis and structuree
activity relationships of IX with a wide range of substituents R.
In the literature C-glycopyranosyl-1,2,4-triazoles are represented
by some 1,3,5-trisubstituted derivatives obtained from glycosyl cy-
anides with 1-aza-2-azoniaallene salts [56] or with hydrazonoyl
chlorides in the presence of Yb(OTf)3 [57]. 3-Glycopyranosyl-5-
substituted-1,2,4-triazoles IX have been unknown until our very
recent preliminary communication describing the synthesis of these
a eCH3
499
j
33.5
0.67
NO2
NH2
b eC(CH3)3
no inh. at k
625
mM
compounds by acylation of N1-tosyl-C-(2,3,4,6-tetra-O-benzoyl-
b-
D-glucopyranosyl)formamidrazone followed by N- and/or O-
deprotection [54]. However, this synthetic sequence was rather long
(5e6 steps from the corresponding glucosyl cyanide) and compli-
cated by the removal of the N-tosyl moiety from the heterocycle.
c
eCH2OH
105
l
no inh. at
COOH 625
m
M
Therefore,
a more straightforward synthesis of the target
compounds has been sought for and accomplished by the ring
transformation of 5-(2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl)
tetrazole.
CH3
d
7
m
39.7
2. Results and discussion
CH3
2.1. Syntheses
NO2
To select a suitable synthetic pathway towards compounds IX a
retrosynthetic analysis for the construction of the 1,2,4-triazole ring
was carried out taking into account 1,3-dipolar cycloadditions
(Scheme 1). It was envisaged that synthetic methods [58] for 1,3,5-
trisubstituted-1,2,4-triazoles [59,60] with a protecting group as the
1-substituent could be applied. Given the tautomeric nature of this
heterocycle three N-protected isomers may exist whose discon-
nections A and B refer to cycloadditions between nitrilimines and
nitriles. Following route A the known glucosyl cyanide and 2,5-
disubstituted-tetrazoles or N-protected hydrazones or their ha-
lides would have been the necessary starting compounds, however,
this possibility was ruled out due to the costly reagents and cata-
lysts. For the analogous route B precursors of the intermediate C-
glucosyl-nitrilimine would have been required which are unknown
in the literature. Therefore, our attention turned to disconnection C,
actually a variant of B, which needed the relatively easily available
C-glucosyl-tetrazole and imidoyl-halides. The analogous discon-
nection C0 (not shown in details) was also discarded because of the
necessity to prepare a series of tetrazoles and lack of the glucose
based precursor of the imidoyl-halide.
e
1.7
n
no inh. at
625
m
M
CH3
NO2
NH2
f
778
o
14
C(CH3)3
NH2
OCH3
OCH3
g
111
2.9
1.9
p
q
r
518a
0.41
707
CF3
OCH3
Syntheses of the target compounds were started by the prepa-
ration of O-protected C-glucopyranosyl-tetrazole 1 (Table 1) from
2,3,4,6-tetra-O-benzoyl-b-D-glucopyranosyl cyanide [61] accord-
h
OH
ing to our recent procedure [27]. N-Benzyl arenecarboxamides 2,
obtained from the corresponding acid chloride and benzylamine,
were converted to imidoyl chlorides by SOCl2 which were then
reacted without purification with tetrazole 1 in a one-pot fashion to
give 4-benzyl-1,2,4-triazole derivatives 3. The O-benzoyl protecting
groups were removed by the Zemplén method to give 4.
Subsequent catalytic hydrogenation gave fully deprotected C-
glucopyranosyl-1,2,4-triazoles 6deg,i,m,p,q. Several O-perben-
N
i
OCH3
a
Calculated from the IC50 value by using a web-based tool [64].
zoylated 3-glucopyranosyl-5-substituted derivatives
5
were

S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
571
obtained in an alternative synthetic pathway published recently
3. Conclusion
[62], and these compounds were also converted to the corre-
sponding unprotected 6aed,h,j,l,n,q,r by the Zemplén protocol.
Amino compounds 6k and 6o were obtained from the corre-
sponding nitro derivatives 6j and 6n, respectively, by catalytic
hydrogenation.
A new synthetic sequence has been elaborated for the prepa-
ration of 3-( -D-glucopyranosyl)-5-substituted-1,2,4-triazoles by
converting 5-(2,3,4,6-tetra-O-benzoyl- -D-glucopyranosyl)tetra-
zole with N-benzyl carboximidoyl chlorides into O-perbenzoylated
4-benzyl-3-( -D-glucopyranosyl)-5-substituted-1,2,4-triazoles and
b
b
b
2.2. Enzyme kinetic studies
subsequent O- and N-deprotection. These triazole derivatives with
aliphatic, phenyl, substituted phenyl, 2-naphthyl, and 2-pyridyl
substituents in the 5-position were evaluated as inhibitors of rab-
bit muscle glycogen phosphorylase b. Compounds with aliphatic
groups exhibited weak inhibition, while several phenyl derivatives
were low micromolar inhibitors. Nanomolar inhibition was
observed for the 5-(4-aminophenyl)- and the 5-(2-naphthyl)-
substituted compounds of the series rendering these derivatives to
be among the best glucose derived GPIs with similar efficiency as
The new compounds were assayed against rabbit muscle
glycogen phosphorylase b as described in earlier publications
[40,63], and the results are collected in Table 2.
Compounds 6aec with aliphatic substituents proved weak in-
hibitors and were much less efficient than the corresponding
“parent” amides I (shown in Chart 1; for R ¼ CH3: Ki 32
m
M [39];
R ¼ C(CH3)3: IC50 7.5 mM [41]; R ¼ CH2OH: Ki 18 [42] or 20 [49]
mM),
however, the trend in the strength of inhibition remained the same
(t-butyl derivatives were the less efficient followed by the methyl
and hydroxymethyl compounds in both series).
those of glucopyranosylidene-spiro-heterocycles and N-acyl-N0-
b-
D-glucopyranosyl ureas.
Appending a phenyl substituent to the heterocycle as in 6d
resulted in a significantly better inhibitor. A comparison to the
corresponding amide I (R ¼ C6H5: Ki 81 [39] or 144 [40]) indicated
more than an order of magnitude stronger inhibition by the tri-
azole, and this strengthening was higher than those observed with
the aliphatic amide-triazole pairs. Introduction of substituents in
the 4-position of the phenyl ring brought about large changes in the
inhibition. The 4-tolyl derivative 6e was w4 times better than 6d,
and comparing it to the relevant amide I (R ¼ 4-CH3-C6H4: IC50
4.5 mM [41]) revealed a very large increase of the binding strength
in favour of the triazole. The bulky 4-t-butyl substituent in 6f
4. Experimental
4.1. General methods
Melting points were measured on a Kofler hot-stage and are
uncorrected. Optical rotations were determined with a Perkine
Elmer 241 polarimeter at rt. NMR spectra were recorded with
Bruker 360 (360/90 MHz for 1H/13C) spectrometer. Chemical shifts
are referenced to Me4Si (1H), or to the residual solvent signals (13C).
Mass spectra were recorded on a Bruker Micro TOF-Q mass spec-
trometer. Microanalyses were performed on an Elementar Vario
Micro Cube. TLC was performed on DC-Alurolle Kieselgel 60 F254
(Merck), and the plates were visualised under UV light and by
gentle heating. For column chromatography Kieselgel 60 (Merck,
particle size 0.063e0.200 mm) was used. 5-(20,30,40,60-Tetra-O-
caused
a significant weakening of the inhibition. The 4-
trifluoromethyl derivative 6g proved also a weak inhibitor, and
this was surprising especially in the light of the similar size of CH3
(6e) and CF3 (6g). The presence of a phenolic hydroxyl group in
position 4 (6h) made again a good inhibitor, and the 4-methoxy
compound 6i proved slightly better and comparable to 6e. Intro-
duction of the 4-nitro substituent weakened the binding in com-
parison to 6d, however, the 4-amino derivative 6k was inhibiting in
the submicromolar range. This may reveal the significance of a
basic group in making contacts to the relevant parts of the enzyme.
A carboxylic acid function in the 4-position (6l) was fully detri-
mental for the binding and this may be at least in part due to the
size of this group (compare with the slightly acidic 6h).
benzoyl-
b
-D-glucopyranosyl)tetrazole [27] (1) and 5-substituted-
-D-glucopyranosyl)-1,2,4-triazoles
3-(20,30,40,60-tetra-O-benzoyl-
b
[62] 5a,b,d,j,n,q,r,t,u were prepared according to published
procedures.
4.2. General procedure I for the synthesis of N-benzyl-arene-
carboxamides (2)
Multiple substitutions in the phenyl ring (6mep) resulted in
generally weaker inhibitors, although the importance of the basic
substituents was corroborated by the diamino derivative 6o
showing the highest efficiency within this group of inhibitors.
The 2-naphthyl compound 6q proved the best inhibitor of the
whole series, and its nanomolar inhibition constant rendered this
derivative among the most efficient glucose analogue inhibitors of
GP. Comparing 6q to the corresponding amide I (R ¼ 2-naphthyl: Ki
10 [41] or 13 [42]) indicates a w25e30-fold stronger binding for the
triazole.
In a flame dried three necked bottle, equipped with a CaCl2 tube,
benzylamine (1 mL, 9.16 mmol) and TEA (1.53 mL, 11 mmol,
1.2 equiv.) was dissolved in the appropriate anhydrous solvent
(5 mL, CH2Cl2, THF or toluene, depending on the solubility of acid
chloride). To this stirred mixture a solution (in 5 mL anhydrous
CH2Cl2, THF or toluene) of an acid chloride (9.16 mmol,1 equiv.) was
added dropwise at 0 ꢀC. The mixture was slowly allowed to reach rt,
stirred for 2 h, then diluted, and extracted with water. The organic
phase was dried over MgSO4, the solvent was evaporated, and the
crude product was crystallised from EtOH.
The 2-pyridyl moiety of 6r was disadvantageous for the inhi-
bition (a similar tendency was observed in the N-acyl-N0-
b
-D-glu-
Yields of the synthesized derivatives: N-benzyl-benzamide [65]
(2d, 64%), N-benzyl-4-methylbenzamide [66] (2e, 81%), N-benzyl-
copyranosyl urea series [24]).
A comparison of the inhibitory potency of these triazole de-
rivatives clearly shows them to be superior to the corresponding
oxadiazoles (IIIeV in Chart 1), as well. For the directly comparable
pairs of 1,2,4-triazoles 6 and the best 1,2,4-oxadiazoles IV the in-
crease of the efficiency is in the 9e29-fold range for the phenyl and
2-naphthyl substituted derivatives, respectively.
Further studies to understand the binding peculiarities of this
series of GPIs by molecular dockings and X-ray crystallography are
in progress and will be disclosed in due course.
4-tert-butylbenzamide
trifluoromethylbenzamide
[67]
[68]
(2f,
(2g,
97%),
76%),
N-benzyl-4-
N-benzyl-4-
methoxybenzamide [66] (2i, 67%), N-benzyl-4-nitrobenzamide
[69] (2j, 77%), N-benzyl-3,5-dimethylbenzamide [67] (2m, 81%),
N-benzyl-3,4,5-trimethoxybenzamide [70] (2p, 98%), N-benzyl-
naphthalene-2-carboxamide [71] (2q, 74%), N-benzyl-(4-
benzyloxycarbonyl)-benzamide (2s, 56%, mp: 127e129 ꢀC). Phys-
ical as well as NMR data of the title compounds are in agreement
with those reported in the cited literature.

572
S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
4.3. General procedure II for the synthesis of 4-benzyl-3-(20,30,40,60-
foam. Rf: 0.20 (1:1 EtOAc-hexane); [
NMR (CDCl3) d (ppm): 7.97e6.98 (29H, m, aromatics), 6.04, 5.98,
a
]
¼ ꢁ4 (c 0.50, CHCl3); 1H
D
tetra-O-benzoyl-
(3)
b
-D-glucopyranosyl)-5-substituted-1,2,4-triazoles
5.68 (3 ꢂ 1H, 3 pseudo t, J ¼ 9.5, 9.5 Hz in each, H-20, H-30, H-40),
5.50 (1H, d, J ¼ 16.5 Hz, PhCH2), 5.31 (1H, d, J ¼ 16.5 Hz, PhCH2), 5.13
(1H, d, J ¼ 9.5 Hz, H-10), 4.48 (1H, dd, J ¼ 12.4, 2.6 Hz, H-60a), 4.34
(1H, dd, J ¼ 12.4, 5.4 Hz, H-60b), 4.20 (1H, ddd, J ¼ 9.8, 5.4, 2.6 Hz, H-
An N-benzyl-arenecarboxamide (2, 4.63 mmol, 3 equiv.) was
dissolved in thionyl chloride (20 mL), and refluxed for 2 h. After
distilling off the excess of thionyl chloride under diminished
pressure, 20 mL of anhydrous toluene was evaporated from the
50), 2.33 (3H, s, CH3); 13C NMR (CDCl3)
d (ppm): 165.8, 165.7, 165.0,
164.6 (CO), 156.7, 149.7 (triazole C-3, C-5), 140.2, 135.4, 133.4e123.6
(aromatics), 76.6, 73.8, 73.0, 69.9, 69.0 (C-10 e C-50), 62.8 (C-60), 47.9
(PhCH2), 21.3 (CH3). Anal: Calcd for C50H41N3O9 (827.88): C, 72.54;
H, 4.99; N, 5.08. Found: C, 72.65; H, 4.88; N, 5.20.
residue. 5-(20,30,40,60-Tetra-O-benzoyl-
b-D-glucopyranosyl)tetra-
zole [27,52] (1, 1.54 mmol, 1 equiv.) and anhydrous toluene or
xylene (20 mL) were added, the mixture was heated to reflux
temperature, and the reaction was monitored by TLC (1:1 EtOAc-
hexane). After total consumption of the tetrazole the solvent was
removed and the residue was purified by column chromatography.
4.8. 4-Benzyl-5-(4-tert-butylphenyl)-3-(20,30,40,60-tetra-O-benzoyl-
b-D-glucopyranosyl)-1,2,4-triazole (3f)
4.4. General procedure III for removal of O-acyl protecting groups
From tetrazole 1 (0.70 g, 1.08 mmol) and N-benzyl-4-tert-
by the Zemplén protocol
butylbenzamide (2f, 0.93 g, 3.23 mmol) in m-xylene according to
General procedure II. Reaction time: 3 h. Purified by column
chromatography (1:1 EtOAc-hexane) to yield 0.57 g (61%) yellow
An O-acylated compound was dissolved in dry MeOH (5 mL/
100 mg, a few drops of CHCl3 were added in case of incomplete
dissolution) and a catalytic amount of a NaOMe solution (1 M in
MeOH) was added. The mixture was kept at rt and monitored by
TLC (7:3 CHCl3eMeOH). When the starting material was consumed
the mixture was neutralised with a cation exchange resin Amber-
lyst 15 (Hþ form) (or with acetic acid), then the resin was filtered off
and the solvent removed. The residue was purified by column
chromatography.
solid. Mp: 231e233 ꢀC; Rf: 0.28 (1:1 EtOAc-hexane); [
a
]
¼ ꢁ43 (c
D
0.37, CHCl3);1H NMR (CDCl3)
d (ppm): 7.97e7.00 (29H, m, aro-
matics), 6.00, 5.97, 5.65 (3 ꢂ 1H, 3 pseudo t, J ¼ 9.6, 9.6 Hz in each,
H-20, H-30, H-40), 5.51 (1H, d, J ¼ 16.5 Hz, PhCH2), 5.33 (1H, d,
J ¼ 16.5 Hz, PhCH2), 5.11 (1H, d, J ¼ 9.6 Hz, H-10), 4.49 (1H, dd,
J ¼ 12.2,1.9 Hz, H-60a), 4.32 (1H, dd, J ¼ 12.2, 5.3 Hz, H-60b), 4.17 (1H,
ddd, J ¼ 9.6, 5.2, 1.9 H-50), 1.29 (9H, s, C(CH3)3); 13C NMR (CDCl3)
d
(ppm): 165.9, 165.7, 165.1, 164.7 (CO), 156.7, 153.4 (triazole C-3, C-
5), 149.7, 135.5, 133.5e123.7 (aromatics), 76.7, 73.9, 73.1, 69.9, 69.1
(C-10 e C-50), 62.9 (C-60), 48.0 (PhCH2), 34.2 (C(CH3)3), 31.1
(C(CH3)3). Anal: Calcd for C53H47N3O9 (869.95): C, 73.17; H, 5.45; N,
4.83. Found: C, 73.11; H, 5.36; N, 4.91.
4.5. General procedure IV for the removal of benzyl protecting
groups
A benzylated compound (0.5 mmol) was dissolved in anhydrous
MeOH (25 mL), 10% Pd(C) (20 mg) was added, and H2 gas was
bubbled through the reaction mixture at 50 ꢀC. After disappearance
of the starting material (monitored by TLC, 7:3 CHCl3eMeOH) the
reaction mixture was filtered through a pad of celite, the solvent
was evaporated, and the residue was purified by column
chromatography.
4.9. 4-Benzyl-5-(4-trifluoromethylphenyl)-3-(20,30,40,60-tetra-O-
benzoyl-
b
-D-glucopyranosyl)-1,2,4-triazole (3g)
From tetrazole
1
(0.60 g, 0.93 mmol) and N-benzyl-4-
trifluoromethylbenzamide (2g, 0.78 g, 2.78 mmol) in toluene ac-
cording to General procedure II. Reaction time: 16 h. Purified by
column chromatography (1:4 / 1:1 EtOAc-hexane) to yield 0.72 g
4.6. 4-Benzyl-5-phenyl-3-(20,30,40,60-tetra-O-benzoyl-
glucopyranosyl)-1,2,4-triazole (3d)
b-D-
(88%) white solid. Mp: 213e215 ꢀC; [
NMR (CDCl3)
a
]
¼ ꢁ26 (c 0.54, CHCl3); 1H
D
d
(ppm): 7.94e6.95 (29H, m, aromatics), 6.06e5.98
(2 ꢂ 1H, m, H-20 and/or H-30 and/or H-40), 5.70 (1H, pseudo t,
J ¼ 9.2, 9.2 Hz, H-20 or H-30 or H-40), 5.60 (1H, d, J ¼ 16.4 Hz, PhCH2),
5.29 (1H, d, J ¼ 16.4 Hz, PhCH2), 5.21 (1H, d, J ¼ 8.8 Hz, H-10), 4.50
(1H, dd, J ¼ 12.3, <1 Hz, H-60a), 4.34 (1H, dd, J ¼ 12.3, 4.8 Hz, H-60b),
From tetrazole 1 (2.00 g, 3.08 mmol) and N-benzyl-benzamide
(2d, 1.95 g, 9.25 mmol) in toluene according to General procedure
II. Reaction time: 16 h. Purified by column chromatography (1:1
EtOAc-hexane) to yield 1.73 g (69%) colourless syrup. Rf: 0.15 (1:1
4.23 (1H, ddd, J ¼ 9.2, 4.8, <1 Hz, H-50); 13C NMR (CDCl3)
d (ppm):
EtOAc-hexane); [
a]
¼ ꢁ25 (c 0.50, CHCl3); 1H NMR (CDCl3)
165.8,165.7,165.1, 164.8 (CO), 155.4,150.3 (triazole C-3, C-5), 134.9e
D
2
d
(ppm): 7.95e6.97 (30H, m aromatics), 5.99e5.96 (2 ꢂ 1H, m, H-20
125.0 (aromatics), 132.0 (q, J(C, F) ¼ 34.6 Hz, CeCF3), 123.5 (q, 1J(C,
and/or H-30 and/or H-40), 5.67 (1H, pseudo t, J ¼ 10.6, 9.3 Hz, H-20 or
H-30 or H-40), 5.63 (1H, d, J ¼ 15.9 Hz, PhCH2), 5.53 (1H, d,
J ¼ 15.9 Hz, PhCH2), 5.16 (1H, d, J ¼ 9.3 Hz, H-10), 4.49 (1H, dd,
J ¼ 12.2, 2.4 Hz, H-60a), 4.33 (1H, dd, J ¼ 12.2, 5.4 Hz, H-60b), 4.19
¼ 271.3 Hz, CF3), 76.8, 73.7, 73.2, 69.9, 68.9 (C-10 e C-50), 62.7 (C-
F)
60), 48.2 (PhCH2). Anal: Calcd for C50H38F3N3O9 (881.85): C, 68.10; H,
4.34; N, 4.77. Found: C, 68.23; H, 4.41; N, 4.63.
(1H, ddd, J ¼ 9.6, 5.4, 2.4 Hz, H-50); 13C NMR (CDCl3)
d
(ppm): 165.9,
4.10. 4-Benzyl-5-(4-methoxyphenyl)-3-(20,30,40,60-tetra-O-benzoyl-
165.7, 165.1, 164.8 (CO), 156.7, 149.8 (triazole C-3, C-5), 135.4e126.2
(aromatics), 76.8, 73.8, 73.2, 70.0, 69.1 (C-10 e C-50), 62.9 (C-60), 48.1
(PhCH2). Anal: Calcd for C49H39N3O9 (813.85): C, 72.31; H, 4.83; N,
5.16. Found: C, 72.47; H, 4.88; N, 5.03.
b-D-glucopyranosyl)-1,2,4-triazole (3i)
From tetrazole (1.0 g, 1.54 mmol) and N-benzyl-4-
1
methoxybenzamide (2i, 1.12 g, 4.64 mmol) in m-xylene according
to General procedure II. Purified by column chromatography
(1:1 / 2:1 EtOAc-hexane) to yield 0.81 g (62%) white amorphous
4.7. 4-Benzyl-5-(4-methylphenyl)-3-(20,30,40,60-tetra-O-benzoyl-
D-glucopyranosyl)-1,2,4-triazole (3e)
b-
solid. Rf: 0.45 (2:1 EtOAc-hexane); [
NMR (CDCl3)
a
]
¼ ꢁ19 (c 0.55, CHCl3); 1H
D
d
(ppm): 7.98e6.98 (27H, m, aromatics); 6.87 (2H, d,
From tetrazole
1
(0.50 g, 0.77 mmol) and N-benzyl-4-
J ¼ 8.8 Hz, aromatics), 6.06e5.91 (2 ꢂ 1H, m, H-20 and/or H-30 and/
or H-40), 5.65 (1H, pseudo t, J ¼ 9.6, 9.6 Hz, H-20 or H-30 or H-40),
5.50 (1H, d, J ¼ 16.6 Hz, PhCH2), 5.29 (1H, d, J ¼ 16.6 Hz, PhCH2), 5.18
(1H, d, J ¼ 9.6, H-10), 4.48 (1H, dd, J ¼ 12.3, 2.6 Hz, H-60a), 4.32 (1H,
methylbenzamide (2e, 0.52 g, 2.31 mmol) in m-xylene according
to General procedure II. Reaction time: 3 h. Purified by column
chromatography (1:1 EtOAc-hexane) to yield 0.32 g (49%) brownish

S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
573
dd, J ¼ 12.3 and 5.4 Hz, H-60b), 4.19 (1H, ddd, J ¼ 9.6, 5.4, 2.6 Hz, H-
C-50), 62.8 (C-60), 60.8 (OMe), 55.8 (2 ꢂ OMe), 48.1 (PhCH2). Anal:
Calcd for C52H45N3O12 (903.93): C, 69.09; H, 5.02; N, 4.65. Found: C,
69.19; H, 4.96; N, 4.51.
50), 3.79 (3H, s, OMe); 13C NMR (CDCl3)
d (ppm): 166.0, 165.8, 165.2,
164.8 (CO), 161.1 (MeOPh C-4), 156.7, 149.7 (triazole C-3, C-5),
135.5e126.1, 118.8, 114.2 (2) (aromatics), 76.7, 73.9, 73.2, 70.0, 69.1
(C-10 e C-50), 63.0 (C-60), 55.3 (OMe), 48.1 (PhCH2). Anal: Calcd for
4.14. 4-Benzyl-5-(2-naphthyl)-3-(20,30,40,60-tetra-O-benzoyl-
glucopyranosyl)-1,2,4-triazole (3q)
b-D-
C
50H41N3O10 (843.87): C, 71.16; H, 4.90; N, 4.98. Found: C, 71.08; H,
5.01; N, 4.91.
From tetrazole 1 (0.60 g, 0.93 mmol) and N-benzyl-naphtha-
lene-2-carboxamide (2q, 0.73 g, 2.78 mmol) in toluene according to
General procedure II. Reaction time: 3 h. Purified by column
chromatography (1:1 / 3:2 EtOAc-hexane) to yield 0.41 g (52%)
pale yellow amorphous solid. Rf: 0.25 (1:1 EtOAc-hexane);
4.11. 4-Benzyl-5-(4-nitrophenyl)-3-(20,30,40,60-tetra-O-benzoyl-
D-glucopyranosyl)-1,2,4-triazole (3j)
b-
From tetrazole
1 (0.50 g, 0.77 mmol) and N-benzyl-4-
nitrobenzamide (2j, 0.59 g, 2.31 mmol) in toluene according to
General procedure II. Reaction time: 16 h. Purified by column
chromatography (1:1 EtOAc-hexane) to yield 0.25 g (38%) yellow
[a
]
D
¼ ꢁ33 (c 0.50, CHCl3); 1H NMR (CDCl3)
d (ppm): 7.96e7.01
(32H, m, aromatics), 6.08, 6.02, 5.70 (3 ꢂ 1H, 3 pseudo t, J ¼ 9.3,
9.3 Hz in each, H-20, H-30, H-40), 5.58 (1H, d, J ¼ 15.9 Hz, PhCH2),
5.38 (1H, d, J ¼ 15.9 Hz, PhCH2), 5.19 (1H, d, J ¼ 9.3 Hz, H-10), 4.49
(1H, dd, J ¼ 11.9, 2.6 Hz, H-60a), 4.35 (1H, dd, J ¼ 11.9, 5.3 Hz, H-60b),
syrup. Rf: 0.28 (1:1 EtOAc-hexane); [
NMR (CDCl3)
a
]
¼ ꢁ41 (c 0.50, CHCl3); 1H
D
d
(ppm): 8.18 (2H, d, J ¼ 8.5 Hz, aromatics), 7.92e7.19
(25H, m, aromatics), 6.95 (2H, d, J ¼ 6.9 Hz, aromatics), 6.05, 6.00,
5.72 (3 ꢂ 1H, 3 pseudo t, J ¼ 9.5, 9.5 Hz in each, H-20, H-30, H-40),
5.66 (1H, d, J ¼ 16.5 Hz, PhCH2), 5.31 (1H, d, J ¼ 16.5 Hz, PhCH2),
5.26 (1H, d, J ¼ 9.4 Hz, H-10), 4.51 (1H, dd, J ¼ 12.1, <1 Hz, H-60a),
4.35 (1H, dd, J ¼ 12.1, 5.1 Hz, H-60b), 4.27 (1H, ddd, J ¼ 9.5, 5.1,
4.23 (1H, ddd, J ¼ 9.3, 5.3, 2.6 Hz, H-50); 13C NMR (CDCl3)
d (ppm):
165.8, 165.7, 165.0, 164.7 (CO), 156.6, 149.9 (triazole C-3, C-5),
135.4e123.9 (aromatics), 76.7, 73.8, 73.0, 69.9, 69.0 (C-10 e C-50),
62.8 (C-60), 48.2 (PhCH2). Anal: Calcd for C53H41N3O9 (863.91): C,
73.68; H, 4.78; N, 4.86. Found: C, 73.80; H, 4.69; N, 4.97.
2.2 Hz, H-50); 13C NMR (CDCl3)
d (ppm): 165.8, 165.6, 165.1, 164.9
(CO), 154.6,150.7 (triazole C-3, C-5),148.6,134.6e123.7 (aromatics),
76.8, 73.6, 73.2, 70.1, 68.9 (C-10 e C-50), 62.7 (C-60), 48.4 (PhCH2).
Anal: Calcd for C49H38N4O11 (858.85): C, 68.52; H, 4.46; N, 6.52.
Found: C, 68.64; H, 4.52; N, 6.43.
4.15. 4-Benzyl-5-(4-benzyloxycarbonylphenyl)-3-(20,30,40,60-tetra-
O-benzoyl-
b
-D-glucopyranosyl)-1,2,4-triazole (3s)
From tetrazole
1
(0.30 g, 0.46 mmol) and N-benzyl-(4-
benzyloxycarbonyl)-benzamide (2s, 0.48 g, 1.39 mmol) in m-
xylene according to General procedure II. Reaction time: 3 h. Pu-
rified by column chromatography (1:4 / 1:1 EtOAc-hexane) to
yield 0.30 g (69%) brownish foam. Rf: 0.23 (1:1 EtOAc-hexane);
4.12. 4-Benzyl-5-(3,5-dimethylphenyl)-3-(20,30,40,60-tetra-O-
benzoyl-
b-D-glucopyranosyl)-1,2,4-triazole (3m)
From tetrazole
1
(1.0 g, 1.54 mmol) and N-benzyl-3,5-
[a
]
D
¼ ꢁ26 (c 0.54, CHCl3); 1H NMR (CDCl3)
d (ppm): 8.07e6.94
dimethylbenzamide (2m, 1.11 g, 4.64 mmol) in m-xylene accord-
ing to General procedure II. Reaction time: 3 h. Purified by column
chromatography (1:1 / 2:1 EtOAc-hexane) to yield 0.85 g (66%)
white solid. Mp: 225e227 ꢀC; Rf: 0.28 (1:1 EtOAc-hexane);
(34H, m, aromatics), 6.01e5.99 (2 ꢂ 1H, m, H-20 and/or H-30 and/or
H-40), 5.68 (1H, pseudo t, J ¼ 9.4, 8.6 Hz, H-20 or H-30 or H-40), 5.57
(1H, d, J ¼ 16.5 Hz, PhCH2), 5.35 (2H, s, PhCH2), 5.29 (1H, d,
J ¼ 16.5 Hz, PhCH2), 5.18 (1H, d, J ¼ 9.2 Hz, H-10), 4.49 (1H, dd,
J ¼ 12.3, 2.0 Hz, H-60a), 4.33 (1H, dd, J ¼ 12.3, 5.3 Hz, H-60b), 4.20
[
a
]
¼ ꢁ19 (c 0.37, CHCl3); 1H NMR (CDCl3)
d (ppm): 7.98e7.00
D
(28H, m, aromatics), 6.12, 6.05, 5.75 (3 ꢂ 1H, 3 pseudo t, J ¼ 9.5,
9.3 Hz in each, H-20, H-30, H-40), 5.50 (1H, d, J ¼ 16.4 Hz, PhCH2),
5.32 (1H, d, J ¼ 16.4 Hz, PhCH2), 5.22 (1H, d, J ¼ 9.6 Hz, H-10), 4.52
(1H, dd, J ¼ 12.5, 2.6 Hz, H-60a), 4.39 (1H, dd, J ¼ 12.6, 5.2 Hz, H-60b),
4.26 (1H, ddd, J ¼ 9.5, 5.2, 2.6 Hz, H-50), 2.19 (6H, s, 2 ꢂ CH3); 13C
(1H, ddd, J ¼ 9.5, 5.3, 2.0 Hz, H-50); 13C NMR (CDCl3)
d (ppm): 165.8,
165.7,165.5,165.0,164.8 (CO),155.8,150.3 (triazole C-3, C-5),135.6e
126.0 (aromatics), 76.8, 73.7, 73.2, 70.0, 68.9 (C-10 e C-50), 67.0
(COOCH2Ph), 62.8 (C-60), 48.2 (PhCH2). Anal: Calcd for C57H45N3O11
(947.98): C, 72.22; H, 4.78; N, 4.43. Found: C, 72.28; H, 4.91; N, 4.34.
NMR (CDCl3)
d (ppm): 165.6, 165.5, 164.9, 164.5 (CO), 156.7, 149.6
(triazole C-3, C-5), 138.0 (2), 135.3e126.0 (aromatics), 76.4, 73.8,
72.6, 69.8, 68.8 (C-10 e C-50), 62.6 (C-60), 47.9 (PhCH2), 20.9
(2 ꢂ CH3). Anal: Calcd for C51H43N3O9 (841.90): C, 72.76; H, 5.15; N,
4.99. Found: C, 72.69; H, 5.07; N, 4.86.
4.16. 4-Benzyl-3-(b-D-glucopyranosyl)-5-phenyl-1,2,4-triazole
(4d)
From triazole 3d (0.82 g, 1.00 mmol) according to General pro-
cedure III. Reaction time: 4 days. Purified by column chromatog-
raphy (9:1 / 4:1 CHCl3eMeOH) to yield 0.29 g (73%) pale yellow
4.13. 4-Benzyl-5-(3,4,5-trimethoxyphenyl)-3-(20,30,40,60-tetra-O-
benzoyl-
b-D-glucopyranosyl)-1,2,4-triazole (3p)
syrup. Rf: 0.55 (7:3 CHCl3eMeOH); [
a
]
¼ ꢁ15 (c 0.60, MeOH); 1H
D
NMR (D2O)
d
(ppm): 7.50e6.94 (10H, m, aromatics), 5.31 (2H, s,
From tetrazole 1 (0.50 g, 0.77 mmol) and N-benzyl-3,4,5-
trimethoxybenzamide (2p, 0.7 g, 2.31 mmol) in m-xylene accord-
ing to General procedure II. Reaction time: 8 h. Purified by column
chromatography (3:2 EtOAc-hexane) to yield 0.45 g (65%) pale
PhCH2), 4.48 (1H, d, J ¼ 10.6 Hz, H-10), 3.98 (1H, pseudo t, J ¼ 9.3,
9.3 Hz, H-20 or H-30 or H-40), 3.67e3.47 (4 ꢂ 1H, m, H-60a, H-60b, H-
20 and/or H-30 and/or H-40), 3.34 (1H, m, H-50); 13C NMR (D2O)
d
(ppm): 156.9, 153.2 (triazole C-3, C-5), 135.2, 131.2, 129.3 (2), 129.1
yellow syrup. Rf: 0.15 (3:2 EtOAc-hexane); [
a
]
¼ ꢁ33 (c 0.60,
(2), 129.0 (2), 128.3, 126.4 (2), 125.4 (aromatics), 80.3, 77.2, 72.1,
D
CHCl3); 1H NMR (CDCl3)
d
(ppm): 7.96e7.00 (25H, m, aromatics),
71.8, 69.4 (C-10 e C-50), 60.8 (C-60), 47.6 (PhCH2). Anal: Calcd for
6.62 (2H, s, aromatics), 6.10e5.99 (2 ꢂ 1H, m, H-20 and/or H-30 and/
or H-40), 5.70 (1H, pseudo t, J ¼ 9.3, 9.3 Hz, H-20 or H-30 or H-40),
5.55 (1H, d, J ¼ 16.8 Hz, PhCH2), 5.31 (1H, d, J ¼ 16.8 Hz, PhCH2), 5.22
(1H, d, J ¼ 9.3 Hz, H-10), 4.45 (1H, dd, J ¼ 10.8, <1 Hz, H-60a), 4.32e
4.24 (2 ꢂ 1H, m, H-60b, H-50), 3.83 (3H, s, OMe), 3.59 (6H, s,
C21H23N3O5 (397.42): C, 63.46; H, 5.83; N, 10.57. Found: C, 63.32; H,
5.75; N, 10.68.
4.17. 4-Benzyl-3-(b-D-glucopyranosyl)-5-(4-methylphenyl)-1,2,4-
triazole (4e)
2 ꢂ OMe); 13C NMR (CDCl3)
d (ppm): 165.8, 165.7, 165.0, 164.7 (CO),
156.5, 153.2, 150.0 (triazole C-3, C-5, 3,4,5-(MeO)3Ph C-3, C-5),
From triazole 3e (0.52 g, 0.63 mmol) according to General pro-
cedure III. Reaction time: days. Purified by column
135.7e121.5, 106.1 (2) (aromatics), 76.7, 73.8, 73.1, 70.0, 68.9 (C-10 e
2

574
S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
chromatography (9:1 / 4:1 CHCl3eMeOH) to yield 0.25 g (94%)
colourless syrup. Rf: 0.35 (4:1 CHCl3eMeOH); [
¼ ꢁ4 (c 0.50,
MeOH); 1H NMR (CD3OD)
(ppm): 7.34e7.23 (7H, m, aromatics),
m, H-20 and/or H-30 and/or H-40, H-50); 13C NMR (CD3OD)
d (ppm):
a]
163.0 (4-MeOPh C-4), 157.2, 154.9 (triazole C-3, C-5), 136.9, 131.6
(2), 130.1 (2), 129.1, 127.5 (2), 119.5, 115.5 (2) (aromatics), 82.4, 79.3,
74.2, 73.6, 71.1 (C-10 e C-50), 62.6 (C-60) 55.9 (OMe), 48.6 (PhCH2).
Anal: Calcd for C22H25N3O6 (427.45): C, 61.82; H, 5.90; N, 9.83.
Found: C, 61.87; H, 6.02; N, 9.75.
D
d
7.00 (2H, d, J ¼ 6.6 Hz, aromatics), 5.41 (1H, d, J ¼ 16.9 Hz, PhCH2),
5.34 (1H, d, J ¼ 16.9 Hz, PhCH2), 4.34 (1H, d, J ¼ 9.7 Hz, H-10), 3.92
(1H, pseudo t, J ¼ 9.1, 8.9 Hz, H-20 or H-30 or H-40), 3.75 (1H, dd,
J ¼ 12.0, <1 Hz, H-60a), 3.63e3.54 (2H, m, H-60b, H-20 or H-30 or H-
40) 3.43e3.72 (2H, m, H-20 or H-30 or H-40, H-50), 2.34 (3H, s, CH3);
4.21. 4-Benzyl-3-(b-D-glucopyranosyl)-5-(4-nitrophenyl)-1,2,4-
triazole (4j)
13C NMR (CD3OD)
d
(ppm): 157.4, 155.0 (triazole C-3, C-5), 142.4,
136.9, 130.7 (2), 130.1 (2), 130.0 (2), 129.2, 127.5 (2), 124.7 (aro-
matics), 82.5, 79.3, 74.2, 73.6, 71.1 (C-10 e C-50), 62.7 (C-60), 47.7
(PhCH2), 21.5 (CH3). Anal: Calcd for C22H25N3O5 (411.45): C, 64.22;
H, 6.12; N, 10.21. Found: C, 64.37; H, 6.19; N, 10.10.
From triazole 3j (0.23 g, 0.27 mmol) according to General pro-
cedure III. Reaction time: 6 h. The product precipitated from the
reaction mixture and was used after filtration without further pu-
rification. Yield: 0.11 g (91%), pale yellow needles. Mp: 153e155 ꢀC;
4.18. 4-Benzyl-3-(
b
-D-glucopyranosyl)-5-(4-tert-butylphenyl)-
[a]
¼ ꢁ20 (c 0.50, MeOH); 1H NMR (CD3OD)
d (ppm): 8.29 (2H, d,
D
1,2,4-triazole (4f)
J ¼ 8.6 Hz, aromatics), 7.75 (2H, d, J ¼ 8.6 Hz, aromatics), 7.28 (3H,
m, aromatics), 7.05 (2H, d, J ¼ 6.3 Hz, aromatics), 5.54 (1H, d,
J ¼ 16.8 Hz, PhCH2), 5.48 (1H, d, J ¼ 16.8 Hz, PhCH2), 4.48 (1H, d,
J ¼ 9.7 Hz, H-10), 3.98 (1H, pseudo t, J ¼ 8.9, 8.9 Hz, H-20 or H-30 or
H-40), 3.82 (1H, dd, J ¼ 11.9, <1 Hz, H-60a), 3.65 (1H, dd, J ¼ 12.0,
5.4 Hz, H-60b), 3.50e3.43 (2 ꢂ 1H, m, H-20 and/or H-30 and/or H-40),
From triazole 3f (0.49 g, 0.56 mmol) according to General pro-
cedure III. Reaction time: 1 day. Purified by column chromatog-
raphy (4:1 CHCl3eMeOH) to yield 0.25 g (98%) yellow syrup. Rf:
0.31 (4:1 CHCl3eMeOH); [
(CD3OD)
a
]
¼ ꢁ3 (c 0.31, MeOH); 1H NMR
D
d
(ppm): 7.45 (2H, d, J ¼ 8.3 Hz, aromatics), 7.35 (2H, d,
3.72 (1H, m, H-50); 13C NMR (CD3OD)
d (ppm): 155.9, 155.5 (triazole
J ¼ 8.3 Hz, aromatics), 7.23 (3H, m, aromatics), 6.99 (2H, d,
J ¼ 6.4 Hz, aromatics), 5.40 (1H, d, J ¼ 16.8 Hz, PhCH2), 5.33 (1H, d,
J ¼ 16.8 Hz, PhCH2), 4.31 (1H, d, J ¼ 9.7 Hz, H-10), 3.89 (1H, pseudo t,
J ¼ 9.4, 9.0 Hz, H-20 or H-30 or H-40), 3.74 (1H, dd, J ¼ 12.1, 2.6 Hz, H-
60a), 3.56 (1H, dd, J ¼ 12.1, 5.3 Hz, H-60b), 3.41e3.34 (2H, m, H-20
and/or H-30 and/or H-40), 3.25 (1H, ddd, J ¼ 9.8, <1 Hz, H-50), 1.27
C-3, C-5), 150.4, 136.5, 133.9, 131.4 (2), 130.2 (2), 129.3, 127.7 (2),
125.0 (2) (aromatics), 82.6, 79.4, 74.2, 73.7, 71.2 (C-10 e C-50), 62.7
(C-60), 49.0 (PhCH2). Anal: Calcd for C21H22N4O7 (442.42): C, 57.01;
H, 5.01; N, 12.66. Found: C, 56.87; H, 5.11; N, 12.54.
4.22. 4-Benzyl-5-(3,5-dimethylphenyl)-3-(b-D-glucopyranosyl)-
1,2,4-triazole (4m)
(9H, s, C(CH3)3), 13C NMR (CD3OD)
d
(ppm): 157.3, 155.4, 155.1
(triazole C-3, C-5, 4-tBuPh C-4), 136.9e124.7 (aromatics), 82.5, 79.3,
74.2, 73.6, 71.1 (C-10 e C-50), 62.7 (C-60), 48.7 (PhCH2), 35.8
(C(CH3)3), 31.6 (C(CH3)3). Anal: Calcd for C25H31N3O5 (453.53): C,
66.21; H, 6.89; N, 9.27. Found: C, 66.27; H, 6.78; N, 9.39.
From triazole 3m (0.64 g, 0.76 mmol) according to General
procedure III. Reaction time: 3 h. Purified by column chromatog-
raphy (4:1 CHCl3eMeOH) to yield 0.20 g (62%) of yellow syrup. Rf:
0.66 (7:3 CHCl3eMeOH); [
a]
¼ ꢁ8 (c 0.69, MeOH); 1H NMR
D
4.19. 4-Benzyl-3-(b-D-glucopyranosyl)-5-(4-trifluoromethyl-
(CD3OD) d (ppm): 7.25e6.95 (8H, m, aromatics), 5.36 (1H, d,
phenyl)-1,2,4-triazole (4g)
J ¼ 16.8 Hz, PhCH2), 5.29 (1H, d, J ¼ 16.8 Hz, PhCH2), 4.38 (1H, d,
J ¼ 9.7 Hz, H-10), 3.96 (1H, pseudo t, J ¼ 9.3, 8.9 Hz, H-20 or H-30 or
H-40), 3.76 (1H, dd, J ¼ 12.2, 1.4 Hz, H-60a), 3.60 (1H, dd, J ¼ 12.2,
5.4 Hz, H-60b), 3.48e3.40 (2H, m, H-20 and/or H-30 and/or H-40),
3.33e3.28 (1H, m, H-50), 2.18 (6H, s, 2 ꢂ CH3); 13C NMR (CD3OD)
From triazole 3g (0.50 g, 0.57 mmol) according to General pro-
cedure III. Reaction time: 4 h. Purified by column chromatography
(4:1 CHCl3eMeOH) to yield 0.16 g (61%) white crystals. Mp: 208e
210 ꢀC; [
a]
¼ ꢁ18 (c 0.48, MeOH); 1H NMR (CD3OD)
d
(ppm): 7.77e
d (ppm): 157.7, 155.2 (triazole C-3, C-5), 140.2 (2), 137.2, 133.4, 130.3
D
7.05 (9H, m, aromatics), 5.51 (1H, d, J ¼ 16.9 Hz, PhCH2), 5.45 (1H, d,
J ¼ 16.9 Hz, PhCH2), 4.48 (1H, d, J ¼ 9.3 Hz, H-10), 3.99 (1H, m, H-20
or H-30 or H-40), 3.82 (1H, dd, J ¼ 11.7, <1 Hz, H-60a), 3.65 (1H, dd,
J ¼ 11.7, <1 Hz, H-60b), 3.47e3.37 (3 ꢂ 1H, m, H-20 and/or H-30 and/
(2), 129.4, 128.0 (2), 127.9 (2), 127.6 (aromatics), 82.7, 79.5, 74.4,
73.8, 71.3 (C-10 e C-50), 62.9 (C-60), 49.1 (PhCH2), 21.6 (2 ꢂ CH3).
Anal: Calcd for C23H27N3O5 (425.48): C, 64.93; H, 6.40; N, 9.88.
Found: C, 65.02; H, 6.47; N, 9.74.
or H-40, H-50); 13C NMR (CD3OD)
d (ppm): 156.0, 155.6 (triazole C-3,
2
C-5), 136.6 (aromatics), 133.4 (q, J(C, F) ¼ 31.7 Hz, CeCF3), 131.7e
127.0 (aromatics), 125.2 (q, 1J(C, F) ¼ 271.3 Hz, CF3), 82.5, 79.3, 74.2,
73.6, 71.1 (C-10 e C-50), 62.7 (C-60), 48.9 (PhCH2). Anal: Calcd for
4.23. 4-Benzyl-3-(b-D-glucopyranosyl)-5-(3,4,5-trimethoxy-
phenyl)-1,2,4-triazole (4p)
C
22H22F3N3O5 (465.42): C, 56.77; H, 4.76; N, 9.03. Found: C, 56.69;
From triazole 3p (0.42 g, 0.46 mmol) according to General
procedure III. Reaction time: 6 h. Purified by column chromatog-
raphy (9:1 / 4:1 CHCl3eMeOH) to yield 0.20 g (91%) colourless
H, 4.71; N, 9.14.
4.20. 4-Benzyl-3-(
1,2,4-triazole (4i)
b
-D-glucopyranosyl)-5-(4-methoxyphenyl)-
syrup. Rf: 0.42 (4:1 CHCl3eMeOH); [
a]
¼ ꢁ17 (c 0.53, MeOH); 1H
D
NMR (CD3OD) d (ppm): 7.38e7.28 (3H, m, aromatics), 7.12 (2H, d,
J ¼ 7.3 Hz, aromatics), 6.69 (2H, s, aromatics), 5.50 (1H, d,
J ¼ 17.1 Hz, PhCH2), 5.42 (1H, d, J ¼ 17.1 Hz, PhCH2), 4.45 (1H, d,
J ¼ 9.6 Hz, H-10), 4.00 (1H, pseudo t, J ¼ 8.6, 9.6 Hz, H-20 or H-30 or
H-40), 3.80 (1H, dd, J ¼ 12.0, <1 Hz, H-60a), 3.77 (4H, m, H-60b,
1 ꢂ OMe), 3.63 (7H, m, H-60b, 2 ꢂ OMe), 3.50e3.43 (2 ꢂ 1H, m, H-20
and/or H-30 and/or H-40), 3.63 (1H, m, H-50); 13C NMR (CD3OD)
From triazole 3i (0.80 g, 0.95 mmol) according to General pro-
cedure III. Reaction time: 3 h. Purified by column chromatography
(4:1 CHCl3eMeOH) to yield 0.23 g (68%) yellow syrup. Rf: 0.33 (4:1
CHCl3eMeOH). [
a]
D
¼ ꢁ14 (c 0.35, MeOH); 1H NMR (CD3OD)
d
(ppm): 7.37 (2H, d, J ¼ 8.8 Hz, aromatics), 7.32e7.20 (3H, m, ar-
omatics), 7.05e6.99 (2H, m, aromatics), 6.96 (2H, d, J ¼ 8.8 Hz, ar-
omatics), 5.42 (1H, d, J ¼ 16.8 Hz, PhCH2), 5.35 (1H, d, J ¼ 16.8 Hz,
PhCH2), 4.35 (1H, d, J ¼ 9.6 Hz, H-10), 3.84 (1H, pseudo t, J ¼ 10.8 Hz,
9.6 Hz, H-20 or H-30 or H-40), 3.78 (3H, s, OMe), 3.77 (1H, dd, J ¼ 12.4,
2.3 Hz, H-60a), 3.61 (1H, dd, J ¼ 12.4, 5.3 Hz, H-60b), 3.41e3.29 (3H,
d (ppm): 157.2, 155.2 (triazole C-3, C-5), 154.9 (2), 141.0, 137.4, 130.2
(2),129.1,127.4 (2),122.8,107.5 (2) (aromatics), 82.5, 79.3, 74.2, 73.6,
71.1 (C-10 e C-50), 62.8 (C-60), 61.1 (OMe), 56.6 (2 ꢂ OMe), 48.8
(PhCH2). Anal: Calcd for C24H29N3O8 (487.50): C, 59.13; H, 6.00; N,
8.62. Found: C, 59.22; H, 6.09; N, 8.49.

S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
575
4.24. 4-Benzyl-3-(
b
-D-glucopyranosyl)-5-(2-naphthyl)-1,2,4-
4.28. 3-(b-D-Glucopyranosyl)-5-hydroxymethyl-1,2,4-triazole [54]
triazole (4q)
(6c)
From triazole 3q (0.50 g, 0.58 mmol) according to General
procedure III. Reaction time: 3 h. Purified by column chromatog-
raphy (9:1 CHCl3eMeOH) to yield 0.22 g (85%) white crystals. Mp:
From triazole 5t [62] (0.18 g, 0.25 mmol) according to General
procedure III. Reaction time: 5 days. (The mixture was neutralised
with acetic acid.) Purified by column chromatography (3:2 CHCl3e
MeOH) to yield 0.06 g (93%) colourless syrup. Rf: 0.38 (1:1 CHCl3e
243e245 ꢀC; [
a
]
D
¼ ꢁ19 (c 0.51, MeOH); 1H NMR (DMSO-d6)
d
(ppm): 8.03e7.02 (12H, m, aromatics), 5.48 (1H, d, J ¼ 16.9 Hz,
MeOH); [
a
]
¼ ꢁ3 (c 0.42, MeOH); 1H NMR (CD3OD)
d (ppm): 4.67
D
PhCH2), 5.42 (1H, d, J ¼ 16.9 Hz, PhCH2), 4.35 (1H, d, J ¼ 9.3 Hz, H-
10), 3.86 (1H, pseudo t, J ¼ 9.3, 9.3 Hz, H-20 or H-30 or H-40), 3.62 (1H,
dd, J ¼ 11.9, <1 Hz, H-60a), 3.42 (1H, dd, J ¼ 11.9, 5.3 Hz, H-60b),
3.31e3.17 (3 ꢂ 1H, m, H-20 and/or H-30 and/or H-40, H-50); 13C NMR
(2H, s, CH2), 4.35 (1H, d, J ¼ 9.2 Hz, H-10), 3.83 (1H, dd, J ¼ 12.3,
<1 Hz, H-60a), 3.68e3.59 (2H, m, H-20 or H-30 or H-40, H-60b), 3.49e
3.40 (3H, m, H-20 and/or H-30 and/or H-40, H-50); 13C NMR (CD3OD)
d
(ppm): 160.5, 160.4 (triazole C-3, C-5), 82.2, 79.2, 76.3, 74.4, 71.2
(DMSO-d6)
d
(ppm): 154.3, 153.3 (triazole C-3, C-5), 136.1e124.6
(C-10 e C-50), 62.8 (C-60), 57.4 (CH2). Anal: Calcd for C9H15N3O6
(261.23): C, 41.38; H, 5.79; N, 16.09. Found: C, 41.31; H, 5.91; N,
16.23.
(aromatics), 81.2, 78.0, 72.3, 71.4, 69.8 (C-10 e C-50), 61.0 (C-60), 46.8
(PhCH2). Anal: Calcd for C25H25N3O5 (447.48): C, 67.10; H, 5.63; N,
9.39. Found: C, 67.02; H, 5.74; N, 9.27.
4.29. 3-(b-D-Glucopyranosyl)-5-phenyl-1,2,4-triazole [54] (6d)
4.25. 5-(4-Carboxyphenyl)-3-(20,30,40,60-tetra-O-benzoyl-
glucopyranosyl)-1,2,4-triazole (5l)
b-D-
A) From triazole 4d (0.20 g, 0.50 mmol) according to General
procedure IV. Reaction time: 4 h. Purified by column chromatog-
raphy (4:1 CHCl3eMeOH) to yield 0.13 g (85%) colourless syrup.
B) From triazole 5d [62] (0.25 g, 0.35 mmol) according to Gen-
eral procedure III. Reaction time: 3 days. Purified by column
chromatography (4:1 CHCl3eMeOH) to yield 0.07 g (62%) colourless
Triazole 3s (0.56 g, 0.59 mmol) was dissolved in anhydrous
EtOAc (35 mL), 10% Pd(C) (55 mg) was added and H2 was bubbled
through the reaction mixture at 50 ꢀC. After disappearance of the
starting material (6 h, monitored by TLC, 1:1 EtOAc-hexane) the
reaction was filtered through a pad of celite, the solvent was
evaporated, and the residue was purified by column chromatog-
raphy (EtOAc) to yield 0.34 g (75%) colourless syrup. Rf: 0.58 (1:3
syrup. Rf: 0.48 (7:3 CHCl3eMeOH); [
a
]
¼ þ31 (c 0.20, H2O); 1H
D
NMR (D2O)
d
(ppm): 7.66 (2H, d, J ¼ 7.9 Hz, aromatics), 7.38e7.36
(3H, m, aromatics), 4.45 (1H, d, J ¼ 9.2 Hz, H-10), 3.87 (1H, dd,
J ¼ 11.9, <1 Hz, H-60a), 3.77e3.69 (2H, m, H-20 or H-30 or H-40, H-
60b), 3.64e3.54 (3H, m, H-20 and/or H-30 and/or H-40, H-50); 13C
AcOH-toluene); [
a
]
¼ ꢁ33 (c 0.48, MeOH); 1H NMR (CD3OD)
D
d
(ppm): 8.02e7.12 (24H, m, aromatics), 6.24 (1H, pseudo t, J ¼ 9.5,
9.5 Hz, H-30), 6.08 (1H, pseudo t, J ¼ 9.6, 9.5 Hz, H-20), 5.95 (1H,
pseudo t, J ¼ 9.5, 9.5 Hz, H-40), 5.38 (1H, d, J ¼ 9.9 Hz, H-10), 4.66e
NMR (D2O) d (ppm): 159.1, 157.8 (triazole C-3, C-5), 130.9, 129.3 (2),
126.9, 126.5 (2) (aromatics), 80.2, 77.2, 74.7, 72.8, 69.5 (C-10 e C-50),
61.0 (C-60). Anal: Calcd for C14H17N3O5 (307.30): C, 54.72; H, 5.58; N,
13.67. Found: C, 54.85; H, 5.45; N, 13.54.
4.58 (3H, m, H-60a, H-60b, H-50); 13C NMR (CD3OD)
d (ppm): 169.2
(COOH), 167.6,167.2,166.7, 166.4 (CO),134.7e127.4 (aromatics), 77.7
(C-50), 75.7 (C-30), 74.8 (C-10), 73.1 (C-20), 71.1 (C-40), 64.6 (C-60).
Anal: Calcd for C43H33N3O11 (767.74): C, 67.27; H, 4.33; N, 5.47.
Found: C, 67.14; H, 4.47; N, 5.39.
4.30. 3-(b-D-Glucopyranosyl)-5-(4-methylphenyl)-1,2,4-triazole
(6e)
4.26. 3-(
b
-D-Glucopyranosyl)-5-methyl-1,2,4-triazole [54] (6a)
From triazole 4e (0.20 g, 0.49 mmol) according to General pro-
cedure IV. Reaction time: 3 h. Purified by column chromatography
(4:1 CHCl3eMeOH) to yield 0.14 g (90%) white foam. Rf: 0.51 (7:3
From triazole 5a [62] (0.25 g, 0.38 mmol) according to General
procedure III. Reaction time: 3 days. Purified by column chroma-
tography (7:3 CHCl3eMeOH) to yield 0.07 g (73%) colourless syrup.
CHCl3eMeOH); [
a]
¼ þ6 (c 0.45, MeOH); 1H NMR (D2O)
d (ppm):
D
7.31 (2H, d, J ¼ 7.9 Hz, aromatics), 6.93 (2H, d, J ¼ 7.9 Hz, aromatics),
4.36 (1H, d, J ¼ 9.5 Hz, H-10), 3.83 (1H, dd, J ¼ 11.9, <1 Hz, H-60a),
3.72 (1H, dd, J ¼ 11.9, 3.1 Hz, H-60b), 3.66 (1H, pseudo t, J ¼ 9.2,
8.9 Hz, H-20 or H-30 or H-40), 3.59e3.50 (3H, m, H-20 and/or H-30
Rf: 0.55 (1:1 CHCl3eMeOH); [
a
]
D
¼ þ21 (c 0.36, MeOH); 1H NMR
(D2O)
d
(ppm): 4.36 (1H, d, J ¼ 9.2 Hz, H-10), 3.82 (1H, dd, J ¼ 11.9,
<1 Hz, H-60a), 3.68e3.63 (2H, m, H-20 or H-30 or H-40, H-60b), 3.56e
3.43 (3H, m, H-20 and/or H-30 and/or H-40, H-50), 2.36 (3H, s, CH3);
and/or H-40, H-50), 2.06 (3H, s, CH3); 13C NMR (D2O)
d (ppm): 159.5,
13C NMR (D2O)
d
(ppm): 159.6, 156.2 (triazole C-3, C-5), 80.8, 77.7,
157.5 (triazole C-3, C-5),141.9,130.0 (2),126.6 (2),123.8 (aromatics),
80.5, 77.6, 75.2, 73.3, 69.9 (C-10 e C-50), 61.4 (C-60), 21.1 (CH3). Anal:
Calcd for C15H19N3O5 (321.33): C, 56.07; H, 5.96; N, 13.08. Found: C,
55.98; H, 5.85; N, 12.96.
75.3, 73.1, 70.1 (C-10 e C-50), 61.5 (C-60), 11.4 (CH3). Anal: Calcd for
C9H15N3O5 (245.23): C, 44.08; H, 6.17; N, 17.13. Found: C, 44.19; H,
6.23; N, 17.01.
4.27. 5-(tert-Butyl)-3-(
b-D-glucopyranosyl)-1,2,4-triazole (6b)
4.31. 5-(4-tert-Butylphenyl)-3-(b-D-glucopyranosyl)-1,2,4-triazole
[54] (6f)
From triazole 5b [62] (0.25 g, 0.36 mmol) according to General
procedure III. Reaction time: 2 days. (The mixture was neutralised
with acetic acid.) Purified by column chromatography (4:1 CHCl3e
MeOH) to yield 0.10 g (98%) colourless syrup. Rf: 0.51 (7:3 CHCl3e
From triazole 4f (0.20 g, 0.44 mmol) according to General pro-
cedure IV. Reaction time: 3 h. Purified by column chromatography
(4:1 CHCl3eMeOH) to yield 0.13 g (79%) colourless syrup. Rf: 0.22
MeOH); [
a
]
¼ ꢁ6 (c 0.25, MeOH); 1H NMR (CD3OD)
d
(ppm): 4.33
(4:1 CHCl3eMeOH); [
a]
¼ þ8 (c 0.55, DMSO); 1H NMR (CD3OD)
D
D
(1H, d, J ¼ 8.6 Hz, H-10), 3.82 (1H, dd, J ¼ 11.9, 2.5 Hz, H-60a), 3.69e
3.64 (2H, m, H-20 or H-30 or H-40, H-60b), 3.50e3.40 (3H, m, H-20
and/or H-30 and/or H-40, H-50), 1.34 (9H, s, C(CH3)3); 13C NMR
d
(ppm): 7.90 (2H, d, J ¼ 8.0, aromatics), 7.51 (2H, d, J ¼ 8.0, aro-
matics), 4.48 (1H, d, J ¼ 9.5 Hz, H-10), 3.90 (1H, dd, J ¼ 11.5, <1 Hz,
H-60a), 3.77e3.73 (2H, m, H-20 or H-30 or H-40, H-60b), 3.59e3.51
(3H, m, H-20 and/or H-30 and/or H-40, H-50), 1.33 (9H, s, C(CH3)3); 13C
(CD3OD)
d (ppm): 166.6, 162.1 (triazole C-3, C-5), 82.2, 79.3, 76.9,
74.2, 71.2 (C-10 e C-50), 62.8 (C-60), 33.3 (C(CH3)3) 29.6 (C(CH3)3).
Anal: Calcd for C12H21N3O5 (287.31): C, 50.16; H, 7.37; N, 14.63.
Found: C, 50.09; H, 7.52; N, 14.57.
NMR (CD3OD) d (ppm): 161.6, 158.1 (triazole C-3, C-5), 154.7, 127.4
(2), 126.9 (2) (aromatics), 82.0, 79.1, 76.3, 74.3, 71.1 (C-10 e C-50),
62.6 (C-60), 35.7 (C(CH3)3), 31.6 (C(CH3)3). Anal: Calcd for

576
S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
C18H25N3O5 (363.41): C, 59.49; H, 6.93; N, 11.56. Found: C, 59.60; H,
(352.30): C, 47.73; H, 4.58; N, 15.90. Found: C, 47.81; H, 4.62; N,
6.84; N, 11.47. MS-ESI (m/z): 386.169 [M þ Na]þ
15.78. MS-ESI (m/z): 375.093 [M þ Na]þ.
4.32. 3-(
b-D-Glucopyranosyl)-5-(4-trifluoromethylphenyl)-1,2,4-
4.36. 5-(4-Aminophenyl)-3-(b-D-glucopyranosyl)-1,2,4-triazole
triazole (6g)
(6k)
From triazole 4g (85 mg, 0.18 mmol) according to General pro-
cedure IV. Reaction time: 1.5 h. Purified by column chromatography
(9:1 CHCl3eMeOH) to yield 52 mg (77%) white amorphous solid. Rf:
Triazole 6j (0.10 g, 0.28 mmol) was dissolved in dry MeOH
(3 mL), and 0.01g PdeC (10%) was added. The reaction mixture was
stirred at rt under hydrogen atmosphere for 1 h. After completion
of the transformation monitored by TLC (1:1 CHCl3eMeOH) PdeC
was filtrated through a pad of celite, the solvent was evaporated in
vacuo and the residue was purified by column chromatography (4:1
CHCl3eMeOH) to yield 0.09 g (94%) amorphous yellow product. Rf:
0.20 (4:1 CHCl3eMeOH); [
(CD3OD)
a
]
¼ þ13 (c 0.52, MeOH); 1H NMR
D
d
(ppm): 8.09 (2H, br s, aromatics), 7.66 (2H, br s, aro-
matics), 4.40 (1H, d, J ¼ 7.2 Hz, H-10), 3.80 (1H, dd, J ¼ 10.7, <1 Hz, H-
60a), 3.66e3.20 (5H, m, H-20, H-30, H-40, H-50, H-60b); 13C NMR
(CD3OD)
d
(ppm): 160.2,159.1 (triazole C-3, C-5),134.9,132.3 (q, 2J(C,
0.59 (1:1 CHCl3eMeOH); [
(DMSO-d6)
a
]
¼ þ9 (c 1.46, DMSO); 1H NMR
D
¼ 34.6 Hz, CeCF3), 127.9 (2), 126.8 (2) (aromatics), 125.6 (q, 1J(C,
d
(ppm): 7.64 (2H, d, J ¼ 8.0 Hz, aromatics), 6.60 (2H, d,
F)
¼ 271.3 Hz, CF3), 82.3, 79.2, 75.9, 74.6, 71.2 (C-10 e C-50), 62.7 (C-
J ¼ 8.0 Hz, aromatics), 5.51 (2H, br s, NH2), 4.98, 4.79, 4.53 (4H, 3 br
s, OH), 4.13 (1H, d, J ¼ 9.2 Hz, H-10), 3.70e3.64 (2H, m, H-20 or H-30
or H-40, H-60a), 3.42e3.16 (4H, m, H-20 and/or H-30 and/or H-40, H-
F)
60). Anal: Calcd for C15H16F3N3O5 (375.30): C, 48.00; H, 4.30; N,
11.20. Found: C, 48.12; H, 4.35; N, 11.07.
50, H-60b); 13C NMR (DMSO-d6)
d (ppm): 161.3, 155.0 (triazole C-3,
4.33. 3-(
(6h)
b
-D-Glucopyranosyl)-5-(4-hydroxyphenyl)-1,2,4-triazole
C-5), 150.3, 127.1 (2), 114.7, 113.6 (2) (aromatics), 81.4, 78.3, 75.7,
72.4, 70.2 (C-10 e C-50), 61.3 (C-60). Anal: Calcd for C14H18N4O5
(322.32): C, 52.17; H, 5.63; N, 17.38. Found: C, 52.21; H, 5.55; N,
17.26. MS-ESI (m/z): 345.118 [M þ Na]þ.
From triazole 5u [62] (0.57 g, 0.73 mmol) according to General
procedure III. Purified by column chromatography (4:1 CHCl3e
MeOH) to yield 0.16 g (67%) white solid. Mp: 172e174 ꢀC;
4.37. 5-(4-Carboxyphenyl)-3-(b-D-glucopyranosyl)-1,2,4-triazole
(6l)
[
a
]
¼ þ14 (c 0.35, DMSO); 1H NMR (CD3OD)
d
(ppm): 7.69 (2H, d,
D
J ¼ 8.2 Hz, aromatics), 6.79 (2H, d, J ¼ 8.5 Hz, aromatics), 4.38 (1H, d,
J ¼ 9.6 Hz, H-10) 3.82 (1H, d, J ¼ 11.0, <1 Hz, H-60a), 3.68e3.64 (2H,
m, H-20 or H-30 or H-40, H-60b), 3.53e3.41 (3H, m, H-20 and/or H-30
From triazole 5l (0.24 g, 0.32 mmol) according to General pro-
cedure III. Reaction time: 5 days. Purified by column chromatog-
raphy (1:1 CHCl3eMeOH) to yield 0.10 g (86%) yellowish syrup. Rf:
and/or H-40, H-50); 13C NMR (CD3OD)
d (ppm): 162.1, 160.6, 157.6
(triazole C-3, C-5, 4-HOPh C-4), 129.2 (2), 126.9, 116.8 (2) (aro-
matics), 82.0, 79.2, 76.5, 74.4, 71.2 (C-10 e C-50), 62.7 (C-60). Anal:
Calcd for C14H17N3O6 (323.30): C, 52.01; H, 5.30; N, 13.00. Found: C,
51.93; H, 5.41; N, 13.12.
0.55 (1:1:1 toluene-AcOH-MeOH); [
NMR (DMSO-d6)
a
]
¼ þ6 (c 0.54, MeOH); 1H
D
d
(ppm): 8.10e8.04 (4H, m, aromatics), 4.33 (1H, d,
J ¼ 9.7 Hz, H-10), 3.74e3.65 (2H, m, H-20 and/or H-30 and/or H-40, H-
60a), 3.47 (1H, ddd, J ¼ 8.9, 5.3, <1 Hz, H-50), 3.37e3.25 (2H, m, H-20
and/or H-30 and/or H-40, H-60b), 3.20 (1H, pseudo t, J ¼ 9.0, 8.9 Hz,
4.34. 3-(
b-D-Glucopyranosyl)-5-(4-methoxyphenyl)-1,2,4-triazole
H-20 or H-30 or H-40); 13C NMR (DMSO-d6)
d (ppm): 168.7 (COOH),
(6i)
158.4, 157.8 (triazole C-3, C-5), 134.1, 133.1, 129.9 (2), 125.7 (2) (ar-
omatics), 81.6, 78.1, 74.5, 72.6, 70.2 (C-10 e C-50), 61.3 (C-60). Anal:
Calcd for C15H17N3O7 (351.31): C, 51.28; H, 4.88; N, 11.96. Found: C,
51.15; H, 4.96; N, 11.89.
From triazole 4i (0.24 g, 0.55 mmol) according to General pro-
cedure IV. Purified by column chromatography (7:3 CHCl3eMeOH)
to yield 0.18 g (95%) colourless syrup. Rf: 0.52 (7:3 CHCl3eMeOH);
[
a]
D
¼ þ12 (c 0.41, MeOH); 1H NMR (CD3OD)
d
(ppm): 7.82 (2H, d,
4.38. 5-(3,5-Dimethylphenyl)-3-(b-D-glucopyranosyl)-1,2,4-
triazole (6m)
J ¼ 8.3 Hz, aromatics), 6.92 (2H, d, J ¼ 8.3 Hz, aromatics), 4.46 (1H, d,
J ¼ 9.5 Hz, H-10), 3.86 (1H, dd, J ¼ 12.1, <1 Hz, H-60), 3.75 (5H, m, H-
20 and/or H-30 and/or H-40, H-60b, OMe), 3.60e3.50 (3H, m, H-20
From triazole 4m (0.14 g, 0.34 mmol) according to General
procedure IV. Reaction time: 3 h. Purified by column chromatog-
raphy (4:1 CHCl3eMeOH) to yield 0.11 g (98%) colourless syrup. Rf:
and/or H-30 and/or H-40, H-50); 13C NMR (CD3OD)
d (ppm): 162.6 (4-
MeOPh C-4),160.1,159.1 (triazole C-3, C-5),129.0 (2),121.5,115.3 (2)
(aromatics), 82.0, 79.1, 76.3, 74.3, 71.1 (C-10 e C-50), 62.7 (C-60), 55.9
(OMe). Anal: Calcd for C15H19N3O6 (337.33): C, 53.41; H, 5.68; N,
12.46. Found: C, 53.55; H, 5.63; N, 12.56.
0.54 (3:1 CHCl3eMeOH); [
(CD3OD)
a
]
¼ þ12 (c 0.57, MeOH); 1H NMR
D
d
(ppm): 7.48 (2H, s, aromatics), 6.99 (1H, s, aromatic), 4.43
(1H, d, J ¼ 9.6 Hz, H-10), 3.85 (1H, dd, J ¼ 12.0, 1.3 Hz, H-60a), 3.73e
3.68 (2H, m, H-20 or H-30 or H-40, H-60b), 3.56e3.40 (3H, m, H-20
and/or H-30 and/or H-40, H-50), 2.25 (6H, s, 2 ꢂ CH3); 13C NMR
4.35. 3-(b-D-Glucopyranosyl)-5-(4-nitrophenyl)-1,2,4-triazole (6j)
(CD3OD)
d (ppm): 162.2, 157.6 (triazole C-3, C-5), 139.7 (2), 132.7,
From triazole 5j [62] (0.65 g, 0.85 mmol) according to General
procedure III. Reaction time: 1 day. Purified by column chroma-
tography (4:1 CHCl3eMeOH) to yield 0.22 g (75%) pale yellow solid.
128.0, 125.2 (2) (aromatics), 82.0, 79.1, 76.2, 74.3, 71.1 (C-10 e C-50),
62.7 (C-60), 21.3 (2 ꢂ CH3). Anal: Calcd for C16H21N3O5 (335.36): C,
57.30; H, 6.31; N, 12.53. Found: C, 57.41; H, 6.24; N, 12.41.
Mp: 166e169 ꢀC; [
a]
D
¼ þ20 (c 1.3, DMSO); 1H NMR (DMSO-d6)
d
(ppm): 8.34 (2H, d, J ¼ 8.2 Hz, aromatics), 8.26 (2H, d, J ¼ 7.8 Hz,
4.39. 5-(3,5-Dinitrophenyl)-3-(b-D-glucopyranosyl)-1,2,4-triazole
(6n)
aromatics), 5.15, 5.10, 4.57 (4H, 3 br s, OH), 4.34 (1H, d, J ¼ 9.7 Hz, H-
10), 3.71 (1H, dd, J ¼ 11.7, 5.4 Hz, H-60a), 3.63 (1H, pseudo t, J ¼ 9.2,
9.0 Hz, H-20 or H-30 or H-40), 3.46e3.28 (3H, m, H-20 and/or H-30
and/or H-40, H-50, H-60b), 3.18 (1H, pseudo t, J ¼ 9.0, 8.9 Hz, H-20 or
From triazole 5n [62] (0.52 g, 0.63 mmol) according to General
procedure III. Reaction time: 3 day. Purified by column chroma-
tography (7:3 CHCl3eMeOH) to yield 0.18 g (72%) white solid. Mp:
H-30 or H-40); 13C NMR (DMSO-d6)
d (ppm): 158.2, 157.0 (triazole C-
3, C-5), 147.5, 136.7, 126.8 (2), 124.2 (2) (aromatics), 81.6, 77.9, 74.0,
203e205 ꢀC; [
a]
¼ ꢁ21 (c 0.11, DMSO); 1H NMR (DMSO-d6-D2O)
D
72.5, 70.0 (C-10 e C-50), 61.2 (C-60). Anal: Calcd for C14H16N4O7
d (ppm): 9.02 (2H, s, aromatics), 8.83 (1H, s, aromatic), 4.37 (1H, d,

S. Kun et al. / European Journal of Medicinal Chemistry 76 (2014) 567e579
577
J ¼ 9.8 Hz, H-10), 3.69 (1H, dd, J ¼ 11.9, <1 Hz, H-60a), 3.58 (1H,
pseudo t, J ¼ 9.1, 9.1 Hz, H-20 or H-30 or H-40), 3.47 (1H, dd, J ¼ 11.9,
5.6 Hz, H-60b), 3.35e3.30 (2H, m, H-20 or H-30 or H-40, H-50), 3.22
(1H, pseudo t, J ¼ 9.1, 9.1 Hz, H-20 or H-30 or H-40); 13C NMR (DMSO-
7.41e7.38 (1H, m, Py), 4.57 (1H, d, J ¼ 9.2 Hz, H-10), 3.94 (1H, dd,
J ¼ 11.9, <1 Hz, H-60a), 3.83e3.76 (2H, m, H-20 or H-30 or H-40, H-
60b), 3.70e3.57 (3H, m, H-20 and/or H-30 and/or H-40, H-50); 13C
NMR (D2O)
d (ppm): 158.5, 156.8 (triazole C-3, C-5), 149.4, 145.3,
d6)
d
(ppm): 162.2, 157.3 (triazole C-3, C-5), 148.5 (2), 137.7, 124.1
138.3, 125.5, 122.0 (Py), 80.0, 76.8, 74.3, 72.5, 69.3 (C-10 e C-50), 60.7
(C-60). Anal: Calcd for C13H16N4O5 (308.29): C, 50.65; H, 5.23; N,
18.17. Found: C, 50.77; H, 5.10; N, 18.29. MS-ESI (m/z): 331.100
[M þ Na]þ, 639.217 [2M þ Na]þ, 309.118 [M þ H]þ.
(2), 115.5 (aromatics), 80.8, 77.9, 75.8, 73.2, 70.5 (C-10 e C-50), 61.3
(C-60). Anal: Calcd for C14H15N5O9 (397.30): C, 42.32; H, 3.81; N,
17.63. Found: C, 42.39; H, 3.93; N, 17.56.
4.40. 5-(3,5-Diaminophenyl)-3-(b-D-glucopyranosyl)-1,2,4-
Acknowledgement
triazole (6o)
This work was supported by the Hungarian Scientific Research
Fund (OTKA CK77712, CNK80709, PD105808), TÁMOP-4.2.2.-08/1/
2008-0014, TÁMOP 4.2.1./B-09/1/KONV-2010-0007, and TÁMOP-
4.2.2./B-10/1-2010-0024 projects implemented through the New
Hungary Development Plan, co-financed by the European Social
Fund, and Bolyai János Research Fellowship, and Magyary Zoltán
Scholarship (TÁMOP-4.2.4.A/2-11/1-2012-0001) to MT.
Triazole 6n (0.07 g, 0.18 mmol) was dissolved in dry MeOH
(10 mL), and 0.015 g PdeC (10%) was added. The reaction mixture
was stirred at rt under hydrogen atmosphere for 1 h. After
completion of the transformation monitored by TLC (1:1 CHCl3e
MeOH) PdeC was filtrated through a pad of celite, the solvent was
evaporated in vacuo and the residue was purified by column
chromatography (1:1 CHCl3eMeOH) to yield 0.04 g (72%) amor-
phous brownish product. Rf: 0.33 (1:1 CHCl3eMeOH); 1H NMR
Appendix A. Supplementary data
(DMSO-d6-D2O)
d
(ppm): 6.49 (2H, d, J ¼ 2.0 Hz, aromatics), 5.84
(1H, t, J ¼ 2.0, aromatic), 4.16 (1H, d, J ¼ 9.9 Hz, H-10), 3.65 (1H, dd,
J ¼ 12.6, <1 Hz, H-60a), 3.57 (1H, pseudo t, J ¼ 9.9, 9.2 Hz, H-20 or H-
30 or H-40), 3.42 (1H, dd, J ¼ 12.6, 4.9 Hz, H-60b), 3.32e3.17 (3H, m,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.02.041.
H-20 and/or H-30 and/or H-40, H-50); 13C NMR (DMSO-d6)
d (ppm):
References
159.7, 158.8 (triazole C-3, C-5), 149.6 (2), 130.6, 102.3 (2), 102.1
(aromatics), 81.2, 78.2, 75.4, 73.1, 70.3 (C-10 e C-50), 61.5 (C-60).
Anal: Calcd for C14H19N5O5 (337.33): C, 49.85; H, 5.68; N, 20.76.
Found: C, 49.99; H, 5.75; N, 20.64.
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4.41. 3-(b-D-Glucopyranosyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-
triazole (6p)
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From triazole 4p (0.18 g, 0.37 mmol) according to General pro-
cedure IV. Reaction time: 3 h. Purified by column chromatography
(9:1 CHCl3eMeOH) to yield 0.14 g (92%) colourless syrup. Rf: 0.37
(4:1 CHCl3eMeOH); [
a
]
¼ þ5 (c 0.44, MeOH); 1H NMR (D2O)
D
d
(ppm): 6.64 (2H, s, aromatics), 4.57 (1H, d, J ¼ 9.3 Hz, H-10), 4.05
(1H, dd, J ¼ 11.9, <1 Hz, H-60a), 3.92 (1H, dd, J ¼ 11.9, <1 Hz, H-60b),
3.88e3.72 (4H, m, H-20, H-30, H-40, H-50), 3.65e3.64 (9H, m,
3 ꢂ OMe); 13C NMR (D2O)
d (ppm): 159.8, 157.4 (triazole C-3, C-5),
152.6 (2), 138.3, 122.7, 103.2 (2) (aromatics), 80.5, 77.5, 75.0, 73.4,
70.0 (C-10 e C-50), 61.5 (C-60), 61.2 (OMe), 56.1 (2 ꢂ OMe). Anal:
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(6q)
A) From triazole 4q (0.10 g, 0.23 mmol) according to General
procedure IV. Reaction time: 3 h. Purified by column chromatog-
raphy (4:1 CHCl3eMeOH) to yield 0.07 g (90%) colourless syrup.
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Rf: 0.36 (1:1 CHCl3eMeOH); [
a
]
¼ þ30 (c 0.22, H2O); 1H NMR
D
(D2O)
d
(ppm): 8.49 (1H, d, J ¼ 4.0 Hz, Py), 7.85e7.78 (2H, m, Py),

578
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