A new synthetic access to 2-N-(glycosyl)thiosemicarbazides from 3-N-(glycosyl)oxadiazolinethiones and the regioselectivity of the glycosylation of their oxadiazolinethione precursors

Article abstract of DOI:10.3762/bjoc.9.16

Glycosylations of 5-(1H-indol-2-yl)-1,3,4-oxadiazoline-2(3H)-thione delivered various degrees of S- and/or N-glycosides depending on the reaction conditions. S-Glycosides were obtained regiospecifically by grinding oxadiazolinethiones with acylated a-D-glycosyl halides in basic alumina, whereas 3-N-(glycosyl)oxadiazolinethiones were selectively obtained by reaction with HgCl₂ followed by heating the resultant chloromercuric salt with α-D-glycosyl halides in toluene under reflux. On using Et₃N or K₂CO₃ as a base, mixtures of S- (major degree) and N-glycosides (minor degree) were obtained. Pure 3-N-(glycosyl) oxadiazolinethiones can also be selectively obtained from glycosylsulfanyloxadiazoles by the thermal S→N migration of the glycosyl moiety, which is proposed to occur by a tight-ion-pair mechanism. Thermal S→N migration of the glycosyl moiety can be used for purification of mixtures of S- or N-glycosides to obtain the pure N-glycosides. The aminolysis of the respective S- or N-glycosides with ammonia in aqueous methanol served as further confirmation of their structures. While in S-glycosides the glycosyl moiety was cleaved off again, 3-N-(glycosyl)oxadiazolinethiones showed a ring opening of the oxadiazoline ring (without affecting the glycosyl moiety) to give N-(glycosyl)thiosemicarbazides. Herewith, a new synthetic access to one of the four classes of glycosylthiosemicarbazides was found. The ultimate confirmation of new structures was achieved by X-ray crystallography. Finally, action of ammonia on benzylated 3-N-(galactosyl)oxadiazolinethione unexpectedly yielded 3-N-(galactosyl)triazolinethione. This represents a new path to the conversion of glycosyloxadiazolinethiones to new glycosyltriazolinethione nucleosides, which was until now unknown.

Full text of DOI:10.3762/bjoc.9.16

A new synthetic access to 2-N-(glycosyl)thiosemi-
carbazides from 3-N-(glycosyl)oxadiazolinethiones
and the regioselectivity of the glycosylation of
their oxadiazolinethione precursors
El Sayed H. El Ashry*1,2,§, El Sayed H. El Tamany3,
Mohy El Din Abdel Fattah3, Mohamed R. E. Aly4, Ahmed T. A. Boraei1,3
and Axel Duerkop5
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 135–146.
1HEJ Research Institute of Chemistry, International Center for
Chemical and Biological Sciences, Karachi University, Karachi,
Pakistan, 2Chemistry Department, Faculty of Science, Alexandria
University, Alexandria, Egypt, 3Chemistry Department, Faculty of
Science, Suez Canal University, Ismailia, Egypt, 4Chemistry
Department, Faculty of Applied Science, Port Said University, Port
Said, Egypt and 5Institute of Analytical Chemistry, Chemo and
Biosensors, Universitätsstrasse 31, 93053 Regensburg, Germany
doi:10.3762/bjoc.9.16
Received: 11 October 2012
Accepted: 18 December 2012
Published: 21 January 2013
Associate Editor: S. Flitsch
© 2013 El Ashry et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
El Sayed H. El Ashry* - eelashry60@hotmail.com
* Corresponding author
§ Tel: +203-4246601; fax: +203-4271360
Keywords:
glycosyloxadiazolinethiones; glycosylsulfanyloxadiazoles;
glycosylthiosemicarbazides; thermal rearrangement; X-ray
crystallography
Abstract
Glycosylations of 5-(1H-indol-2-yl)-1,3,4-oxadiazoline-2(3H)-thione delivered various degrees of S- and/or N-glycosides
depending on the reaction conditions. S-Glycosides were obtained regiospecifically by grinding oxadiazolinethiones with acylated
α-D-glycosyl halides in basic alumina, whereas 3-N-(glycosyl)oxadiazolinethiones were selectively obtained by reaction with
HgCl2 followed by heating the resultant chloromercuric salt with α-D-glycosyl halides in toluene under reflux. On using Et3N or
K2CO3 as a base, mixtures of S- (major degree) and N-glycosides (minor degree) were obtained. Pure 3-N-(glycosyl)oxadiazo-
linethiones can also be selectively obtained from glycosylsulfanyloxadiazoles by the thermal S→N migration of the glycosyl
moiety, which is proposed to occur by a tight-ion-pair mechanism. Thermal S→N migration of the glycosyl moiety can be used for
purification of mixtures of S- or N-glycosides to obtain the pure N-glycosides. The aminolysis of the respective S- or N-glycosides
with ammonia in aqueous methanol served as further confirmation of their structures. While in S-glycosides the glycosyl moiety
135

Beilstein J. Org. Chem. 2013, 9, 135–146.
was cleaved off again, 3-N-(glycosyl)oxadiazolinethiones showed a ring opening of the oxadiazoline ring (without affecting the
glycosyl moiety) to give N-(glycosyl)thiosemicarbazides. Herewith, a new synthetic access to one of the four classes of glycosyl-
thiosemicarbazides was found. The ultimate confirmation of new structures was achieved by X-ray crystallography. Finally, action
of ammonia on benzylated 3-N-(galactosyl)oxadiazolinethione unexpectedly yielded 3-N-(galactosyl)triazolinethione. This repre-
sents a new path to the conversion of glycosyloxadiazolinethiones to new glycosyltriazolinethione nucleosides, which was until
now unknown.
Introduction
Modified nucleosides are versatile motifs for studying the rela- semicarbazides stimulated the development of direct regioselec-
tionship between the structure and functions of nucleic acids tive formations of the corresponding 3-N-(glycosyl)oxadiazo-
and problems of metabolism, besides their main potential in linethiones, which are shown in this work. Earlier literature
curing viral infections and cancer diseases [1]. The 1,3,4-oxadi- showed that 3-N-(glycosyl)oxadiazolinethiones could be
azolines and 1,2,4-triazolines are potential inhibitors of physio- obtained from the chloromercuric salts of 1,3,4-oxadiazo-
logically relevant isoforms of the zinc enzyme carbonic anhy- lethiones by heating at high temperatures in dry nitromethane
drase (CA, EC 4.2.2.1), i.e., cytosolic CA I and CA II, the under reflux using dry calcium sulfate [34] or toluene [35-37].
tumor-associated transmembrane isoenzyme CA IX with inhibi- In continuation of our previous work [33] in which the syn-
tion constants in the low micromolar range [2]. Coupling of thesis of compounds 5 to 13 and 20 were published in a prelimi-
aglycones with relevant glycosyl donors is the common ap- nary manner without the experimental details, this paper intro-
proach involved in the synthesis of most nucleosides. Another duces more examples for the thermal rearrangement of S-glyco-
strategy for the synthesis of nucleoside analogues is the use of sides to the corresponding N-glycosides, which deliver excel-
glycosylamines and related N-bonded glycosides [3-7], such as lent yields without solvent or a catalyst in a short reaction time.
glycosylisothiocyanates, which afford glycosylthiosemicar- Moreover, the thiosemicarbazide II precursors can also be
bazides [8] or glycosyl 3-thioureidothiourea derivatives [9]. selectively obtained from 3-N-(glycosyl)oxadiazolinethiones.
These 4-N-(glycosyl)thiosemicarbazides [8] were used for the
synthesis of Schiff-like bases [10] and 4-N-glycosyl(thiosemi-
carbazido)phosphorothionates as precursors for the synthesis of
the herbicidal and fungicidal agents thiazolidine-4-ones [11].
Thiosemicarbazide (TSC) and related amines were used to
prepare modified amylase and amylopectin for biological
studies [12]. Moreover, glycosylthiosemicarbazides are formed
in vivo to modify cell-surface sialic acid. This is known as a
metabolic cell-surface-engineering technique for cell-surface
interactions and consequently shows the potential of these com-
Scheme 1: Structures of the different glycosylthiosemicarbazides.
pounds for the development of anticancer agents [13-16]. Anti-
tuberculosis effects of glycosylthiosemicarbazides were also
reviewed [17]. Glycosylamines are used also as enzyme inhibi- In addition to our previous work [33], we investigated the
tors and vaccine precursors [18-21], and in glycopeptide syn- potential of the benzylated N-glycosides as precursors for the
thesis [22,23] and in glycodendrimers and glycoclusters [24,25]. respective thiosemicarbazides. Surprisingly, the formation of
the galactosyl-1,2,4-triazoline-3-thione from the galactosyl-
There are four structural isomers of glycosyl-thiosemicar- 1,3,4-oxadiazole-2(3H)-thione was discovered for the first time.
bazides according to the location of the glycosyl residue This is a new method for the conversion of an 1,3,4-oxadiazole-
on the thiosemicarbazide; the 1-N-, 2-N-, S- and 4-N- 2(3H)-thione ring into a 1,2,4-triazoline-3-thione, because
(glycosyl)thiosemicarbazides (Scheme 1). To the best of our formerly, only conversions of 1,3,4-oxadiazolethione (by reac-
knowledge, examples of 1-N-(I)-type [26] and 4-N-(III)-type tion of hydrazine hydrate) to 4-amino-1,2,4-triazolinethiones
glycosylthiosemicarbazides [27-31] are known. While we had were reported [38-40]. The products of the new reactions are
focused on simple alkylations and glycosylations of 1,3,4- verified by the X-ray single-crystal analysis of the galactosyl-
oxadiazolethione [32,33] and on 2-N-(glycosyl)thiosemicar- 1,2,4-triazoline-3-thione, and a representative glucopyranosyl-
bazides II obtained from the aminolysis of 3-N-(glycosyl)oxadi- sulfanyl-1,3,4-oxadiazole and glucopyranosylthiosemicar-
azolinethione precursors, the growing interest in glycosylthio- bazide, each.
136

Beilstein J. Org. Chem. 2013, 9, 135–146.
Results and Discussion
Thermal rearrangement of the S-glycosides 5–7 under solvent-
The regiospecificity of glycosylations of 1,3,4-oxadiazo- free and atmospheric conditions afforded the corresponding
linethiones was tested by reacting 5-(1H-indol-2-yl)-1,3,4- 3-N-glycosides 8–10. The conversion was achieved in a few
oxadiazoline-2(3H)-thione (1) with a set of α-D-glycosyl minutes with good to excellent yields (60–90%). Therefore, the
halides 2–4 under different conditions. Glycosylations in the thermal rearrangement from S- to N-glycosides may also serve
presence of either Et3N or K2CO3 yielded a mixture of both the as a rapid and economic (free of solvents) purification step for
S- (5–7) and N-linked (8–10) glycosides in varying yields of crude mixtures of S- and 3-N-glycosides obtained from
42–71% and 12–35%, respectively (Scheme 2). Generally, both glycosylations mediated by either Et3N or K2CO3. Additional
bases could be considered more regioselective towards S-glyco- experiments on crude mixtures of S- and 3-N-glycosides
sides than towards the N-glycosyl analogues. Grinding the reac- successfully afforded pure N-glycosides.
tants with basic alumina afforded regiospecifically S-linked
glycosides 5–7 in 52–63% yields. However, if glycosylations The mechanism of this rearrangement is presumably proceeding
were carried out on the chloromercuric salt of 1 in toluene by an ionization–recombination pathway in which a thermally
under reflux, 3-N-linked glycosides 8–10 were regiospecifi- induced heterolysis of the thioglycosidic bond results in a tight
cally obtained in 48–60% yields.
ion pair generated upon ionization of this bond. An intramolec-
ular reaction of the tight ion pair results in migration of the
Anomeric β-configurations of the S-linked 5–7 and N-linked glycosyl moiety from sulfur to nitrogen, which proceeds with
8–10 glycosides were deduced from the 1H NMR spectra, complete retention of configuration. As a result, a tight-ion-pair
which revealed large J1,2 values of 10.3–10.6 and 9.2–9.5 Hz, mechanism in which the migrating group retains chirality is
respectively, for the anomeric protons. The chemical shifts of suggested (Scheme 2).
the anomeric protons of S-glycosides were at lower values (δ
5.45–5.56 ppm) than those of N-glycosides (δ 5.92–6.10 ppm). Aminolysis of the N-glycosides 8–10 (Scheme 3) mediated with
The differentiation between S- and N-glycosides was supported ammonia in aqueous methanolic solution led to de-O-acetyla-
by the presence or absence of the signal of the carbon atom of tion of the glycan moieties along with aminolysis of the oxadia-
the C=S moiety in the 13C NMR spectra. In other words, the zole ring affording 2-N-(glycosyl)thiosemicarbazides 11–13
13C NMR spectra of the N-glycosides 8–10 revealed signals at instead of the corresponding nucleosides 14–16. The oxadia-
δc 176.10–177.40 ppm. Anomeric carbons in both types were zole ring cleavage combined with de-O-acetylation of 8–10 is
observed at δ 83.20–84.00 ppm.
proven by three facts. First, the molecular weights derived from
Scheme 2: Glycosylations of oxadiazolinethione.
137

Beilstein J. Org. Chem. 2013, 9, 135–146.
Scheme 3: Synthesis of glycosylthiosemicarbazides by solvolysis.
the mass spectra of the products 11–13 are higher by seventeen 8.5–9.0 Hz indicated the stability of the pyranose ring and its
atomic mass units than would be those of the deacetylated prod- β-anomeric configuration under these conditions.
ucts 14–16. Second, the IR spectra of 11–13 show new amide
absorption bands that do not appear in the IR spectra of their Aminolysis of the S-glycosides 5–7 (Scheme 4) under the same
precursors. Finally, the 13C NMR spectra of 11–13 show signals conditions (ammonia in aqueous methanolic solution) generally
for NC=O groups at δC 159.40–162.90 ppm in addition to the led to splitting of the thioglycosyl moiety as a result of hydro-
NC=S groups at δC 183.10–184.50 ppm. Deacetylation of 10 is lysis of the bond between the oxadiazole (C2) and the glyco-
only confined to the O-acetyl groups, but the N-acetyl group sidic sulfur atom. Hence, the indolyloxadiazolone 20 was
survived under these conditions. This was confirmed by an formed [33] whereas the expected deacetylated glycosides
extra 13C NMR signal at δC 172.50 ppm for the NHCOCH3 17–19 were not obtained. Structure elucidation of 20 yielded a
group of 13. The presence of 1H NMR signals at δH melting point of 271–273 °C [33], while literature reports give a
6.46–6.55 ppm as doublets with coupling constants of J1,2 = value of 102 °C [41] or 285 °C [42]. Therefore, compound 20
Scheme 4: Solvolysis of glycosylsulfanyloxadiazoles.
138

Beilstein J. Org. Chem. 2013, 9, 135–146.
was prepared in another reaction sequence [33] to prove its Aminolysis of the benzylated N-glycosides 26 and 27 was done
structure and the correctness of the physical and structural data with ammonia in aqueous methanolic solution to obtain add-
obtained. Hence, the indol-2-carbohydrazide (21) was reacted itional new thiosemicarbazide derivatives. Although, the reac-
with methyl chloroformate followed by cyclization of the tion conditions remained unchanged compared to the cleavage
resulting ester 22. As a result, 20 was obtained in high yield, of 8–10, derivatives 26 and 27 (Scheme 6) yielded different
and its structural analytical data were identical with those of the products under these conditions. Oxadiazole ring cleavage
aminolysis product (Scheme 4).
combined with de-O-acetylation converted 26 into the corres-
ponding 2-N-(glycosyl)thiosemicarbazide 29 while the galac-
For ultimate confirmation of the structures of S- and N-glyco- tonucleoside 27 was converted into the galactosyltriazole 30.
sides 5–10, the benzylation of the indole was chosen, because We propose that it is formed by a cyclization with the elimina-
these derivatives can serve to prove the glycosyl rearrangement tion of water from a thiosemicarbazide as intermediate. The
and glycosyl TSC formation. Moreover, crystalline glycosides structure of 30 (and other key compounds) could be confirmed
are obtained that are suitable for X-ray analysis. In the presence by X-ray crystallography. The large values of the coupling
of K2CO3, the S- and N-glycosides 23–28 (Scheme 5) were constants (J1,2) of the anomeric protons of the N-glycosides 29,
obtained. Disappearance of the NH-signal of the indole in the 30 indicate that β-configuration is still retained here.
1H NMR spectra of all products and appearance of the benzyl
methylene protons at δH 5.76–5.97 ppm and the methylene X-ray analysis
carbon at δC 48.4–48.8 ppm in the 13C NMR spectra support a Single-crystal X-ray diffraction experiments yielded unam-
successful benzylation. Additional NMR signals of the phenyl biguous confirmations of the structural assignments of the
protons and carbon atoms of the phenyl ring were another S-glycoside 23, the 2-N-(glycosyl)thiosemicarbazide 29, and the
strong evidence for the N-benzylation of the indole units. The galactosyltriazole 30. Single crystals were slowly grown in
different (yet large) values of the coupling constants (J1,2) of EtOH. 23 crystallized in the monoclinic space group C2 with
the anomeric protons of S-glycosides 23–25 (10–10.4 Hz) and the following unit cell parameters: a = 25.7078 Å, α = 90º, b =
of the N-glycosides 26–28 (9.5–9.6 Hz), respectively, indicate 7.1500 Å, β = 105.2576º, c = 17.8411 Å, γ = 90º and V =
that all benzylated glycosides still have the β-configuration. 3163.81 Å3. The crystallographic data of 23 are shown in
Successful thermal S→N glycosyl migration (and the concomi- Table 1. The whole molecule is nonplanar; the phenyl group is
tant change of structural analytical data of the products) served located perpendicular to the plane of the indole ring by making
as a final proof that N-glycosylated products were obtained a torsion angle of C(8)N(1)C(1)C(2) = 95.9º while the oxadia-
from their former pure S-analogues.
zole ring is located in the plane of the indole ring by making
Scheme 5: Benzylation of the S- and N-glycosides 5–10.
139

Beilstein J. Org. Chem. 2013, 9, 135–146.
Scheme 6: Aminolysis of benzylated indolyl-3-N-(glucosyl)- and (galactosyl)oxadiazolinethiones.
Table 1: Crystal data, instrumental and refinement data for 23.
Table 1: Crystal data, instrumental and refinement data for 23.
(continued)
Crystal data
Monochromator
Graphite
Empirical formula
Formula weight
Crystal size
C31H31N3O10S
Theta range for data
collection
3.56 to 73.15°
637.66
Index ranges
−31<=h<=31, −8<=k<=7,
−22<=l<=22
0.2241 × 0.0456 × 0.0328 mm
Crystal description
Crystal color
Stick
Reflections
collected/unique
11616/4707 [R(int) = 0.0199]
Colorless
Monoclinic
C2
Crystal system
Space group
Reflections greater
I>2\s(I);4572
Analytical
Absorption correction
Unit-cell dimensions
a = 25.7078 Å; α = 90°
b = 7.15002 Å; β = 105.2576°
c = 17.8411 Å; γ = 90°
Max. and min. transmission 0.960 and 0.833
Refinement
Volume
3163.81(8) Å3
4
Z
Refinement method
Full-matrix least-squares on F2
Calculated density
Absorption coefficient
F(000)
1.339 Mg/m3
1.433 mm−1
1336
Hydrogen treatment;
Data/restraints/parameters 4707/1/406
Goodness-of-fit on F2
1.040
Final R indices
[I>2sigma(I)]
R1 = 0.0305, wR2 = 0.0817
Data collection
R indices (all data)
R1 = 0.0314, wR2 = 0.0827
0.024(14)
Measurement device type
SuperNova, single source at
offset, Atlas
Absolute structure
parameter
Measurement method
Temperature
w Scans
123 K
Largest diff. peak and hole 0.286 and −0.282 e·Å−3
Wavelength
1.54184 Å
140

Beilstein J. Org. Chem. 2013, 9, 135–146.
torsion angles of N(1)C(15)C(16)O(1) = −171.48°,
C(14)C(15)C(16)O(1) = 10.6º and N(1)C(15)C(16)N(2) = 9.2°,
respectively. The crystallographic analysis revealed that the
sugar molecule has the glucopyranose form and has 4C1 con-
formation. The anomeric β-configuration is derived from the
bond lengths of O(2)–C(18) and O(2)–C(19), which are 1.416
and 1.442 Å, and all substituents have equatorial orientation.
Moreover, the crystal data revealed that the S(1)–C(17) bond
length is 1.743 Å suggesting a certain degree of conjugation
with the oxadiazole ring, whereas the S(1)–C(18) bond length is
1.816 Å, which is typical for single bonds of this kind [43]. The
crystal structure and molecular conformation is stabilized by
three intramolecular C–H···N hydrogen bonds, three intramolec-
ular C–H···O hydrogen bonds, and five intermolecular C–H···O
hydrogen bonds in the crystal network (Figure 1, Figure 2 and
Table 1).
Figure 1: ORTEP representation of 23.
Figure 2: Packing diagram of 23.
141

Beilstein J. Org. Chem. 2013, 9, 135–146.
Compound 29 (Figure 3, Figure 4 and Table 2) crystallized as a
cyclic dimer and contains two independent molecules in the unit
cell. The dimer is stabilized by an intermolecular hydrogen
bond N(8)–H(8M)···S(1). Moreover, S(1)–C(17) and
S(2)–C(40) displayed bond lengths of 1.699 and 1.660 Å, res-
pectively, reflecting the double-bond character of the thiocar-
bonyl unit of the TSC group. This also supports the cleavage of
the oxadiazole ring in the reaction of 26 to 29. The bond lengths
O(6)–C(18) and O(6)–C(22) are 1.414 and 1.433 Å (similar to
those found in 23), respectively, which shows that the sugar
moiety still has the glucopyranose form with 4C1 anomeric
β-configuration. In addition, the crystal structure of 29 shows
that the whole molecule is nonplanar. The phenyl group makes
a dihedral angle of C(1)N(1)C(9)C(10) = −100.3°, which means
that it is perpendicular to the indole ring.
Table 2: Crystal data, instrumental and refinement data for 29.
Crystal data
Empirical formula
Formula weight
Crystal size
C23H26N4O6S
486.55
0.3575 × 0.0513 × 0.0329 mm
Crystal description
Crystal color
Needle
Colorless
Monoclinic
P21
Crystal system
Space group
Unit-cell dimensions
a = 6.25643 Å; α = 90°
b = 41.019 Å; β= 96.092°
c = 9.1898 Å; γ = 90°
Volume
2345.06 Å3
4
Z
Calculated density
Absorption coefficient
F(000)
1.378 Mg/m3
1.632 mm−1
1024
Data collection
Measurement device type
SuperNova, single source at
offset, Atlas
Measurement method
Temperature
w Scans
293 K
Wavelength
1.54184 Å
Graphite
4.31 to 73.83°
Monochromator
Theta range for data
collection
Index ranges
−4<=h<=7, −50<=k<=50,
−11<=l<=10
Reflections
8866/7227 [R(int) = 0.0371]
collected/unique
Figure 3: ORTEP representation of 29.
Figure 4: Packing diagram of 29.
142

Beilstein J. Org. Chem. 2013, 9, 135–146.
Table 2: Crystal data, instrumental and refinement data for 29.
Table 3: Crystal data, instrumental and refinement data for 30.
(continued)
Crystal data
Reflections greater
I>2\s(I) 6676
Analytical
Empirical formula
Formula weight
Crystal size
C23H24N4O5S·H2O
Absorption correction
486.55
Max. and min. transmission 0.953 and 0.749
0.5666 × 0.0262 × 0.0131 mm
Refinement
Crystal description
Crystal color
Needle
Colorless
Monoclinic
P21
Refinement method
Full-matrix least-squares on F2
Crystal system
Space group
Hydrogen treatment;
Data/restraints/parameters 7227/1/633
Unit cell dimensions
a = 9.7950 Å; α = 90°
b = 4.93845 Å; β = 90.813°
c = 22.3598 Å; γ = 90°
Goodness-of-fit on F2
1.009
Final R indices
[I>2sigma(I)]
R1 = 0.0431, wR2 = 0.1113
Volume
1081.48 Å3
2
R indices (all data)
R1 = 0.0463, wR2 = 0.1132
0.054(15)
Z
Absolute structure
parameter
Calculated density
Absorption coefficient
F(000)
1.491 Mg/m3
1.770 mm−1
510
Largest diff. peak and hole 0.798 and −0.275 e·Å−3
Data collection
Single-crystal diffraction analysis of 30 (Figure 5, Figure 6 and
Table 3) showed that the S(1)–C(17) bond length of 1.694 Å
reflects double-bond character (similar to the bond lengths of
S(1)–C(17) and S(2)–C(40) with 1.699(3) and 1.660(3) Å, res-
pectively, of 29) and suggests the thione form. O(5)–C(18) and
O(5)–C(22) bond lengths are 1.411 and 1.439 Å, respectively
(again similar to those found in 23 and 29), which shows that,
first, the compound still has the cyclic galactopyranose struc-
ture, and second, the sugar moiety is stable, even if the oxadia-
zole moiety has opened and the TSC formed has cyclized to
form a triazole. The whole structure is nonplanar and the phenyl
group still oriented perpendicular to the indole ring making
Measurement device type
SuperNova, single source at
offset, Atlas
Measurement method
Temperature
w Scans
123 K
Wavelength
1.54184 Å
Graphite
3.95 to 72.89°
Monochromator
Theta range for data
collection
Index ranges
−11<=h<=11, −5<=k<=3,
−25<=l<=27
Reflections
collected/unique
3935/3005 [R(int) = 0.0286]
Reflections greater
I>2\s(I) 2785
Analytical
Absorption correction
Max. and min. transmission 1.00000 and 0.86469
Refinement
Refinement method
Hydrogen treatment;
Full-matrix least-squares on
F2
Data/restraints/parameters 3005/1/327
Goodness-of-fit on F2
1.027
Final R indices
[I>2sigma(I)]
R1 = 0.0378, wR2 = 0.0933
R indices (all data)
R1 = 0.0422, wR2 = 0.0959
0.00(2)
Absolute structure
parameter
Largest diff. peak and hole 0.372 and −0.231 e·Å−3
torsion angles of C(8)–N(1)–C(7)–C(1) = 85.2° and
C(15)–N(1)–C(7)–C(1) = −88.4°. On the other hand, the tria-
zole ring is located in the plane of the indole ring making only
small torsion angles of C(14)–C(15)–C(16)–N(4) = 3.6(4)° and
N(1)–C(15)–C(16)–N(2) = 2.2(4)°. The molecular con-
formation is stabilized by an intramolecular hydrogen bond
Figure 5: ORTEP representation of 30.
143

Beilstein J. Org. Chem. 2013, 9, 135–146.
Figure 6: Packing diagram of 30.
O(4)–H(4)···O(3) and a water molecule links two molecules in (glycosyl)oxadiazolinethiones may be prepared by a mild
the crystal lattice through an intermolecular hydrogen bond solvent-free thermal S→N migration of the glycosyl moiety in
O(6)–H(6P)···S(1).
glycosylsulfanyloxadiazoles. (Benzylindolyl)glycosylsulfanyl-
1,3,4-oxadiazoles could be thermally rearranged into the corres-
ponding N-glycosides. These may either be converted into the
Conclusion
In conclusion, 2-N-(glycosyl)thiosemicarbazides of type II corresponding (benzylindolyl)-2-N-(glycosyl)thiosemicar-
(from the four glycosylthiosemicarbazide structural isomers bazides (of type II) or into the galactosyl triazolinethione from
I–IV shown in Scheme 1) were synthesized from 3-N- the galactosyl oxadiazolinethione, as confirmed by X-ray
(glycosyl)oxadiazolinethiones, which were accessed by single-crystal analysis and from further common structural
new regioselective glycosylations. Additionally, 3-N- analytical data.
144

Beilstein J. Org. Chem. 2013, 9, 135–146.
6. Fernandez-Bolanos, J. G.; Lopez, O. Synthesis of Heterocycles from
Glycosylamines and Glycosyl Azides. In Heterocycles from
Carbohydrate Precursors; El Ashry, E. S. H., Ed.; Topics in
Heterocyclic Chemistry, Vol. 7; Springer: Berlin, 2007; pp 31–66.
7. Fuentes, J.; Angulo, M.; Pradera, M. A. J. Org. Chem. 2002, 67,
2577–2587. doi:10.1021/jo0110303
Supporting Information
Complete crystallographic data of the structural analysis of
compounds 23, 29 and 30 have been deposited with the
Cambridge Crystallographic Data Centre, CCDC
867245–867247. Copies of this information may be
obtained free of charge from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, UK. (fax: +44-1223-336033, e-mail:
deposit@ccdc.cam.ac.uk or via
8. Ogura, H.; Takahashi, H.; Sakaguchi, M. Nucleic Acids Res. 1978, 1
(Suppl. 2), s251–s256. doi:10.1093/nar/1.suppl_2.s251
9. Sun, W.; Yao, J.; Bai, L.; Wang, X. Acta Crystallogr., Sect. E 2009, 65,
o242. doi:10.1107/S1600536808043833
10.Wieniawski, W.; Gmernicka-haftek, C. Diss. Pharm. Pharmacol. 1968,
20, 411–417.
11.Li, Y. X.; Wang, H. A.; Yang, X. P.; Cheng, H. Y.; Wang, Z. H.;
Li, Y. M.; Wang, S. H.; Yan, D. W. Carbohydr. Res. 2009, 344,
1248–1253. doi:10.1016/j.carres.2009.03.027
http://www.ccdc.cam.ac.uk).
Supporting Information File 1
Complete experimental section with full characterization
data of all compounds.
12.El Khadem, H. S.; Fatiadi, A. J. Adv. Carbohydr. Chem. Biochem.
2004, 59, 135–173. doi:10.1016/S0065-2318(04)59004-2
13.Marcaurelle, L. A.; Bertozzi, C. R. Glycobiology 2002, 12, 69R–77R.
doi:10.1093/glycob/12.6.69R
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-16-S1.pdf]
14.Davis, B. G. Chem. Rev. 2002, 102, 579–602. doi:10.1021/cr0004310
15.Langenhan, J. M.; Thorson, J. S. Curr. Org. Synth. 2005, 2, 59–81.
doi:10.2174/1570179052996937
Supporting Information File 2
Chemical information files (cif) of compounds 23, 29 and
30.
16.Alviano, C. S.; Farbiarz, S. R.; De Souza, W.; Angluster, J.;
Travassos, L. R. J. Gen. Microbiol. 1991, 137, 837–841.
doi:10.1099/00221287-137-4-837
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-16-S2.rar]
17.Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K. Med. Res. Rev.
2005, 25, 93–131. doi:10.1002/med.20017
18.Fernández-Bolaños, J. G.; Zafra, E.; López, O.; Robina, I.; Fuentes, J.
Tetrahedron: Asymmetry 1999, 10, 3011–3023.
doi:10.1016/S0957-4166(99)00314-6
Acknowledgements
19.Fuentes, J. J.; Molina, J. L.; Pradera, M. A. Tetrahedron: Asymmetry
1998, 9, 2517–2532. doi:10.1016/S0957-4166(98)00243-2
20.Fujita, Y.; Abdel-Aal, A.-B. M.; Wimmer, N.; Batzloff, M. R.;
Good, M. F.; Toth, I. Bioorg. Med. Chem. 2008, 16, 8907–8913.
doi:10.1016/j.bmc.2008.08.064
The authors thank Prof. Atta-Ur-Rahman and Prof. M. I.
Choudhary for making available the facilities for research at
ICCBS. We would like also to thank Dr. Manfred Zabel from
the University of Regensburg for performing the X-ray
analyses, and Dr. Gasser M. Khairy and Prof. Dr. Hassan A.
Azab from Suez Canal University for their help with the X-ray
measurements. The support from the Higher Education
Commission (HEC) Pakistan (Project No. 20-697/R&D/06/38)
is highly appreciated.
21.El Ashry, E. S. H.; Rashed, N.; Shobier, H. S. Pharmazie 2000, 55,
251–262.
22.Taylor, C. M. Tetrahedron 1998, 54, 11317–11362.
doi:10.1016/S0040-4020(98)00477-3
23.Günther, W.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1990, 29,
1050–1051. doi:10.1002/anie.199010501
24.Dubber, M.; Lindhorst, T. K. Org. Lett. 2001, 3, 4019–4022.
doi:10.1021/ol016717o
References
1. García Fernández, J. M.; Ortiz Mellet, C.
25.Lindhorst, T. K.; Kieburg, C. Angew. Chem., Int. Ed. Engl. 1996, 35,
1953–1956. doi:10.1002/anie.199619531
Adv. Carbohydr. Chem. Biochem. 2000, 55, 35–135.
doi:10.1016/S0065-2318(00)55004-5
26.Belkadi, M.; Othman, A. A. Trends Appl. Sci. Res. 2011, 6, 19–33.
doi:10.3923/tasr.2011.19.33
2. Almajan, G. L.; Barbuceanu, S.-F.; Innocenti, A.; Scozzafava, A.;
Supuran, C. T. J. Enzyme Inhib. Med. Chem. 2008, 23, 101–107.
doi:10.1080/14756360701342417
27.Ghosh, S.; Misra, A. K.; Bhatia, G.; Khan, M. M.; Khanna, A. K.
Bioorg. Med. Chem. Lett. 2009, 19, 386–389.
doi:10.1016/j.bmcl.2008.11.070
3. Schmidt, R. R.; Guilliard, W.; Heermann, D.; Hoffmann, M.
J. Heterocycl. Chem. 1983, 20, 1447–1451.
28.Alexacou, K.-M.; Tenchiu, A.-C.; Chrysina, E. D.; Charavgi, M.-D.;
Kostas, I. D.; Zographos, S. E.; Oikonomakos, N. G.; Leonidas, D. D.
Bioorg. Med. Chem. 2010, 18, 7911–7922.
4. El Ashry, E. S. H.; El Kilany, Y.; Nahas, N. M. Manipulation of
Carbohydrate Carbon Atoms for the Synthesis of Heterocycles. In
Heterocycles from Carbohydrate Precursors; El Ashry, E. S. H., Ed.;
Topics in Heterocyclic Chemistry, Vol. 7; Springer: Berlin, 2007;
pp 1–30.
doi:10.1016/j.bmc.2010.09.039
29.Tao, J.; Wang, D.-Z.; Cao, L.-H. J. Chin. Chem. Soc. 2007, 54,
1287–1292.
30.Thanh, N. D.; Giang, N. T. K.; Hoai, L. T. E-J. Chem. 2010, 7, 899–907.
31.Tao, J.; Wang, D.-Z.; Cao, L.-H. J. Chin. Chem. Soc. 2010, 57,
1077–1080.
5. Pleuss, N.; Kunz, H. Synthesis 2005, 122–130.
doi:10.1055/s-2004-834911
145

Beilstein J. Org. Chem. 2013, 9, 135–146.
32.El Ashry, E. S. H.; El Tamany, E. S. H.; Abd El Fattah, M. E. D.;
Aly, M. R. E.; Boraei, A. T. A. Lett. Org. Chem. 2009, 6, 462–469.
doi:10.2174/157017809789124902
33.El Ashry, E. S. H.; El Tamany, E. H.; Aly, M. R. E.; Boraei, A. T. A.
Synlett 2010, 2247–2250. doi:10.1055/s-0030-1258024
34.Ahmad, R.; Iqbal, R.; Akhtar, H.; Zia-ul-Haq; Duddeck, H.;
Stefaniak, L.; Sitkowski, J. Nucleosides, Nucleotides Nucleic Acids
2001, 20, 1671–1682. doi:10.1081/NCN-100105903
35.Wagner, G.; Dietzsch, B.; Krake, U. Pharmazie 1975, 30, 694–698.
36.Abdel-Megeid, F. M. E.; Elkaschef, M. A.-F.; Abdel-Bary, H. M. A.
Carbohydr. Res. 1977, 59, 95–102.
doi:10.1016/S0008-6215(00)83296-6
37.Wagner, G.; Dietzsch, B. Pharmazie 1976, 31, 153–154.
38.Khanum, S. A.; Shashikanth, S.; Umesha, S.; Kavitha, R.
Eur. J. Med. Chem. 2005, 40, 1156–1162.
doi:10.1016/j.ejmech.2005.04.005
39.Farghaly, A.-R.; El-Kashef, H. ARKIVOC 2006, xi, 76–90.
40.Mekuskiene, G.; Burbuliene, M. M.; Jakubkiene, V.; Udrenaite, E.;
Gaidelis, P.; Vainilavicius, P. Chem. Heterocycl. Compd. 2003, 39,
1364–1368. doi:10.1023/B:COHC.0000010654.66587.4a
41.Hirmath, S. P.; Hirmath, D. M.; Purohit, M. G. Indian J. Chem. 1983,
22B, 571–576.
42.Robba, M.; Maume, D.; Lancelot, J. C. Bull. Soc. Chim. Fr. 1977, 3–4,
333–336.
43.El Ashry, E. S. H.; Aly, A. A.; Amer, M. R.; Shah, M. R.; Ng, S. W.
Carbohydr. Res. 2011, 346, 169–176.
doi:10.1016/j.carres.2010.11.005
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.16
146