Synthesis of 5-aryl-3-C-glycosyl- and unsymmetrical 3,5-diaryl-1,2,4-triazoles from alkylidene-amidrazones

Article abstract of DOI:10.1039/c5ra05702g

Among 1,2,4-triazole derivatives with versatile biological activities 3-C-glucopyranosyl-5-substituted-1,2,4-triazoles belong to the most efficient inhibitors of glycogen phosphorylase, and are thus potential antidiabetic agents. In seeking new synthetic methods for this class of compounds oxidative ring closures of N¹-alkylidene carboxamidrazones were studied. O-Peracylated N¹-(β-d-glycopyranosylmethylidene)-arenecarboxamidrazones were prepared from the corresponding glycosyl cyanides and amidrazones by Raney-Ni reduction in the presence of NaH₂PO₂. Bromination of the so obtained compounds by NBS gave hydrazonoyl bromide type derivatives which were ring closed to 3-C-glycosyl-5-substituted-1,2,4-triazoles in pyridine or by NH₄OAc in AcOH. Under the same conditions O-perbenzoylated N¹-arylidene-C-(β-d-glucopyranosyl)-formamidrazones gave the expected 1,2,4-triazoles as minor products only. N¹-Arylidene-arenecarboxamidrazones were also transformed into 3,5-diaryl-1,2,4-triazoles with NBS/NH₄OAc in AcOH indicating high functional group tolerance and general applicability of the method.

Full text of DOI:10.1039/c5ra05702g

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Page 1 of 28
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Synthesis of 5-aryl-3-C-glycosyl- and unsymmetrical 3,5-diaryl-1,2,4-triazoles from
alkylidene-amidrazones
Béla Szőcs, Éva Bokor, Katalin E. Szabó, Attila KissꢀSzikszai, Marietta Tóth, and László
Somsák
A general synthetic method was elaborated for 3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles with different
groups in positions 3 and 5.

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Synthesis of 5ꢀArylꢀ3ꢀCꢀGlycosylꢀ and Unsymmetrical 3,5ꢀDiarylꢀ
1,2,4ꢀTriazoles from AlkylideneꢀAmidrazones
Béla Szőcs, Éva Bokor, Katalin E. Szabó, Attila KissꢀSzikszai, Marietta Tóth,* and László
Somsák*
Department of Organic Chemistry, University of Debrecen,
POB 20, H-4010 Debrecen, Hungary
Abstract
Among 1,2,4ꢀtriazole derivatives with versatile biological activities 3ꢀCꢀglucopyranosylꢀ5ꢀ
substitutedꢀ1,2,4ꢀtriazoles belong to the most efficient inhibitors of glycogen phosphorylase,
and are thus potential antidiabetic agents. In seeking new synthetic methods for this class of
compounds oxidative ring closures of N1ꢀalkylidene carboxamidrazones were studied. Oꢀ
Peracylated N1ꢀ(βꢀ
Dꢀglycopyranosylmethylidene)ꢀarenecarboxamidrazones were prepared
from the corresponding glycosyl cyanides and amidrazones by RaneyꢀNi reduction in the
presence of NaH2PO2. Bromination of the so obtained compounds by NBS gave hydrazonoyl
bromide type derivatives which were ring closed to 3ꢀCꢀglycosylꢀ5ꢀarylꢀ1,2,4ꢀtriazoles in
pyridine or by NH4OAc in AcOH. Under the same conditions Oꢀperbenzoylated N1ꢀarylideneꢀ
Cꢀ(βꢀDꢀglucopyranosyl)ꢀformamidrazones gave the expected 1,2,4ꢀtriazoles as minor products
only. N1ꢀArylideneꢀarenecarboxamidrazones were also transformed into 3,5ꢀdiarylꢀ1,2,4ꢀ
triazoles with NBS/NH4OAc in AcOH indicating high functional group tolerance and general
applicability of the method.
* Corresponding authors ꢀ Tel: +3652512900 ext 22471 (MT) or 22348 (LS), Fax: +3652512744, Eꢀmail:
toth.marietta@science.unideb.hu, somsak.laszlo@science.unideb.hu.
1

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Keywords: Carbohydrates; Heterocycles; CꢀβꢀDꢀGlycopyranosyl derivatives; 1,2,4ꢀTriazoles
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Introduction
In the past few decades 1,2,4ꢀtriazole derivatives received great attention due to their broad
applicability as medicinal agents. Among others, 1,2,4ꢀtriazoles have shown enormous
potential as antifungal, anticancer, antibacterial, antitubercular, antiviral, antiꢀinflammatory,
analgesic, anticonvulsant, antiparasitic, antidiabetic, antiobesitic, antihistaminic, antiꢀ
neuropathic, and antihypertensive medications in clinical use.1ꢀ3 Notably, topiroxostat, a drug
approved in 2013 for the treatment of hyperuricemia and gout, has a 3,5ꢀdipyridylꢀ1,2,4ꢀ
triazole scaffold.4
The importance of this heterocyclic moiety resulted in the development of many practical
synthetic routes to 1,2,4ꢀtriazole derivatives. The majority of the methods relies on the
intramolecular cyclization of acylamidrazone intermediates obtained from the reaction of
amides, thioamides, imidates, nitriles, and acid chlorides with acylhydrazines or
amidrazones.3, 5, 6 Another versatile method for the syntheses of 1,2,4ꢀtriazoles is the 1,3ꢀ
dipolar cycloaddition of cyanides with nitrilimines generated in situ from hydrazonoyl
chlorides or substituted tetrazoles.3, 5
We have recently shown that Cꢀglucopyranosyl 1,2,4ꢀtriazoles represent one of the most
efficient type of glucose analogue inhibitors of glycogen phosphorylase (e. g. compound J in
Scheme 1 with Gly = βꢀDꢀglucopyranosyl and R = 2ꢀnaphthyl has an inhibitor constant Ki of
0.41 µM against rabbit muscle glycogen phosphorylase b) and thus have potential in
developing new pharmacological treatments of diseases wherein the regulation of glycogen
metabolism plays significant roles, e. g. in type 2 diabetes, cerebral and cardiac ischemias,
and tumor growth.7, 8
3

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The synthesis of compounds J by applying Cꢀglycosyl acylamidrazone intermediates was not
straightforward due to unexpected bifurcation of these reactions leading to either 1,3,4ꢀ
oxadiazoles or the desired 1,2,4ꢀtriazoles.9 The first efficient preparation of Oꢀperbenzoylated
3ꢀβꢀDꢀglucopyranosylꢀ5ꢀsubstitutedꢀ1,2,4ꢀtriazoles J (Scheme 1) was effected by the
acylation of tosylamidrazones D obtained from the readily available glucopyranosyl cyanide
A via intermediates B and C in altogether 4 synthetic steps.7, 9 A shorter, 3 steps route to J
was elaborated by the Nꢀimidoylation of tetrazole H and subsequent ring closure of the
intermediary CꢀglycosylꢀNꢀimidoyl nitrilimine followed by removal of the Nꢀbenzyl
protecting group of I.8
Route
Synthetic steps
4
Overall yields (%)
38-47
Ref.
7, 9
A→B→C→D→J
8
A→H→I→J
3
49
A→F→J
2
5
20-27
this work
this work
A→B→C→E→G→J
6-9 (G→J by PIDA)
Scheme 1. Synthetic routes towards 3ꢀglycosylꢀ5ꢀsubstitutedꢀ1,2,4ꢀtriazoles.
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Given the importance of this compound class we envisaged that an even shorter sequence
could lead from A to J via the oxidative ring closure of Nꢀglycosylmethylideneꢀamidrazones
F. The preparation of F was foreseen through the adaptation of our method to get various Cꢀ
glycosylꢀimine derivatives by Raney Ni reduction of A in the presence of e. g. hydrazine
derivatives.10ꢀ12
Construction of five membered aromatic heterocycles with three heteroatoms in the 1,2,4ꢀ(or
1,3,4ꢀ)positions is frequently based on oxidative ring closing reactions of Nꢀacylꢀhydrazones
and analogous compounds (Scheme 2): thus, Nꢀacylꢀ and Nꢀthioacylꢀhydrazones K give the
corresponding 1,3,4ꢀoxaꢀ and ꢀthiadiazoles L, respectively. The analogous formation of 1,2,4ꢀ
triazoles is also known, however, this method is almost exclusively used for the synthesis of
various condensed 1,2,4ꢀtriazoloꢀheterocycles R from cyclic amidrazones Q13, 14 (some
literature examples using various oxidants: Br2,15 Pb(OAc)4,16, 17 NBS,18 air (O2),19 and
hypervalent iodine reagents20ꢀ23). Formation of 3,4,5ꢀtrisubstitutedꢀ1,2,4ꢀtriazoles from
aldehyde tosylhydrazones and Schiffꢀbases under oxidative conditions (PhIO and NBS) was
also reported.24
5

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Z
N N
oxidation
R
N
R
R'
Z
N
R'
H
K
Z = O, S widely applied
L
M
Z = NH scarcely known
(see text)
N
chain-ring
tautomerisation
of M
oxidation
to N
HN NH
HN N
tautomerisation
R
R
R
R'
R'
N
N
H
P
O
N N
H
N
oxidation
R
N
N
N
Q
R
widely applied
Scheme 2. Oxidative ring closures of Nꢀacylꢀhydrazone type compounds
Very few examples are known for the oxidative closure of alkylidene amidrazones M to give
the corresponding 1,2,4ꢀtriazoles N: to the best of our knowledge oxidations by HgO25, 26 or
Ag2O25 to give 3,4,5ꢀtrisubstitutedꢀ1,2,4ꢀtriazoles as well as dehydrogenations at elevated
temperature by Pd(C)27, 28 to 3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles were reported only. In some
cases the formation of triazoline O (actually a ring tautomer of M) from amidrazones and
carbonyl compounds was postulated29 whose oxidation (also from other tautomers, e. g. P)
gave the triazole N.30
Based on these preliminaries we have undertaken the synthesis of Nꢀglycosylmethylideneꢀ
amidrazones F and studying their oxidative reactions. Although it represents a longer route
towards 1,2,4ꢀtriazoles J, preparation of some NꢀarylideneꢀCꢀglycosylꢀamidrazones G and
their oxidation has also been carried out to reveal any possible effect of the different
substitution pattern of the amidrazone moiety. In addition, the extension of these studies to
aromatic derivatives to investigate a broader functional group tolerance is also reported.
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Results and Discussion
Syntheses of sugar derived alkylidene amidrazones were accomplished by adapting literature
protocols. Thus, glycosyl cyanides 1,31 2,32 or ꢀ333, 34 were reacted with aminoguanidine (4)
and aromatic carboxamidrazones 5ꢀ7 (preparation described in our earlier paper9) under
reductive conditions10ꢀ12 to give the corresponding glycosylmethylidene amidrazones 8ꢀ13 in
medium yields (Scheme 3).
Scheme 3. Synthesis of N1ꢀglycosylmethylideneꢀamidrazones
OꢀPerbenzoylated NꢀarylideneꢀCꢀglucopyranosyl formamidrazones 18ꢀ20 were obtained in
reactions of amidrazone 149 and the corresponding aldehydes 15ꢀ17 (Scheme 4).
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Scheme 4. Synthesis of N1ꢀarylideneꢀCꢀglycosyl formamidrazones
Alkylidene amidrazones 8ꢀ13 and 18ꢀ20 exist in the ‘open’ tautomeric forms (cf. Scheme 2)
as depicted in Schemes 3 and 4, respectively, that is indicated by two C=N resonances35 in
their 13C NMR spectra in the range of 150ꢀ160 ppm. No special efforts were made to
determine the tautomeric equilibria with regard to the position of the NH protons, however,
this seems different in these compounds based on the chemical shift of exchangable proton
signals (see Supporting information). Therefore, both tautomers a and b may be present and
are shown in the respective Schemes.
Oxidation of the above amidrazones was tried under a variety of conditions (e. g. Pb(OAc)4 in
CH3CN, K3[Fe(CN)6] in EtOH or CH3CN, MnO2 in CH2Cl2, KMnO4 in CH3COOH at r. t. to
reflux temperatures for 9, HgO in mꢀxylene, DDQ in THF at r. t. to reflux temperatures for
18), however, these reactions gave complex product mixtures not worth for tracking down
their components. On the other hand, reactions with PIDA or NBS gave cleaner
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transformations whose product mixtures could be either separated by column chromatography
or analysed by LCꢀMS methods.
Reactions of alkylidene amidrazones (Table 1, compound type IV) with PIDA resulted in
product mixtures each of which contained the expected 1,2,4ꢀtriazoles of type V either
detected (entries 1ꢀ4) or isolated (entries 2, 3) albeit in very low yields. In addition to triazoles
V other compounds, such as nitriles VI, acetates VII, and alkylated triazoles VIII were also
identified in the mixtures wherein VI and VII proved to be the main products which could be
isolated in good yields in most cases (entries 2ꢀ4).
Table 1. Reactions of sugar derived N1ꢀalkylideneꢀamidrazones with PIDAa
Detectedb or isolatedc compounds
Entry Starting
compound
R1
R2
Ph
V
VI
VII
VIII
(type IV)
b
b
b
1.
2.
+
+
not
detectedd
+
+
9
b
b
b
Ph
+
not
+
18
detectedd
not
21c (16)
1c (67)
not
isolated
isolated
b
b
b
b
3.
4.
4ꢀMeOꢀPh
Pyrenꢀ1ꢀyl
+
+
+
+
19
20
22c (13)
1c (75)
not
not
isolated
isolated
b
b
b
b
+
+
+
+
not
1c (85)
23c (69)
not
isolated
isolated
aRoman numbers denote compound types and are identical with those in mechanistic Scheme 6.
bDetected by LCMS (for details see Supporting information).
cIsolated yield (%) after column chromatography.
dThe compound can be present in the mixture, but was not detected due to its low molecular weight.
9

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Based on the analysis of the product mixtures and the generally accepted reactivity pattern of
diacyloxyꢀiodobenzene reagents13 a mechanistic proposal has been set up to explain the
outcome of these reactions (Scheme 6). For the sake of simplicity only tautomers b are shown
for alkylidene amidrazones IV. Thus, nucleophilic attack by the N1 nitrogen of IV onto PIDA
(route A) may give ion pair I which by loss of AcOH and intramolecular addition of N3 to the
carbeniumion next to R1 results in II. Reductive elimination of PhI and concomitant
deprotonation of II end in the formation of 3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles V. Attack of
PIDA by N2 of amidrazone IV (route B) may give intermediate III which, upon loss of PhI
and AcOH and subsequent tautomerisation, results in V. PIDA may also be attacked by the N3
nitrogen of IV (route C) to give IX from which the reductive elimination–deprotonation
sequence results in a fragmention to nitrile VI and diazo compound X. The latter may alkylate
the AcOH present in the mixture to give acetate VII. Alkylation of any tautomer of the
triazole V by X may lead to isomeric Nꢀalkyl triazoles VIII. Route C may be less probable if
the R2–C–N3 moiety of amidrazone IV is part of a ring, therefore, high yielding formation of
triazole V can be observed in such cases as reported many times in the literature to give fusedꢀ
triazole derivatives (cf. introduction).
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Scheme 6. Proposed mechanism for the reaction of N1ꢀalkylideneꢀamidrazones with PIDA
Next, oxidations by NBS were tried with N1ꢀglycosylmethylideneꢀamidrazones 8ꢀ13 (Table
2). Each amidrazone gave the corresponding bromo derivative 24ꢀ29 with NBS in CH2Cl2 at
r. t. in good yield in most cases. These bromides proved surprisingly stable and could be
purified by column chromatography. The position of the bromine was identified on the basis
of changes in the 1H NMR spectra: while for the starting compounds 8ꢀ11 a double doublet
was to be observed in the range of 4.48ꢀ4.66 ppm for Hꢀ1, this proton showed a doublet
around 4.76ꢀ4.78 ppm for 24ꢀ27. The Hꢀ1 signals appeared at 4.22 (dd) and 4.36 (d) for 13
and 29, respectively. The resonances for Hꢀ1 in the brominated derivatives 24ꢀ29
characteristically shifted downfield by 0.1ꢀ0.3 ppm in comparison to those in the parent
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compounds 8ꢀ13. In the 13C spectra the bromination caused a downfield shift of a sugar
carbon to ~82 ppm. On the other hand, the resonance of the glycosylmethylidene carbon
(CH=N around 151 ppm in 9ꢀ13) shifted upfield by ~20 ppm in the brominated compounds
(CBr=N around 130ꢀ132 ppm in 25ꢀ29) due to the heavy atom effect.36
Table 2. Transformation of N1ꢀglycosylmethylideneꢀamidrazones to Cꢀglycosylꢀ1,2,4ꢀtriazoles by bromination
and subsequent ring closure
Isolated yield (%)
Bromination
Triazole formation
Starting
compound
8
Gly
R
Conditions A
Conditions B
NH2
24 (30)
complex reaction
mixture
complex reaction
mixture
Ph
25 (74)
26 (64)
27 (70)
28 (not
isolated)
29 (66)
21 (56)
30 (32)
31 (55)
32 (32)*
21 (58)
30 (53)
ꢀ
ꢀ
9
2ꢀPyridyl
2ꢀNaphthyl
Ph
10
11
12
Ph
33 (64)
ꢀ
13
*obtained from crude 28, yield for the two steps
Ring closure of the bromides was attempted in two ways: by heating in AcOH in the presence
of NH4OAc (conditions A in Table 2) or by boiling in dry pyridine (conditions B).
Transformation of 24 resulted in complex reaction mixtures under both conditions. With other
bromides 25ꢀ29 formation of 1,2,4ꢀtriazoles 21, 30ꢀ33, respectively, could be effected in
acceptable to good yields whereby none of the applied methods proved superior to the other
one.
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Under similar conditions the reaction of N1ꢀbenzylideneꢀCꢀglucopyranosyl amidrazone 18
with NBS gave a complex mixture from which no discrete products could be isolated by
column chromatography. An LCꢀMS analysis of this reaction mixture and that of 9 is
presented in Table 3 showing that the same types of compounds were formed in both
reactions. Thus, the presence of the primary hydrazonoyl bromide type products XIII could
be justified (see Supporting information), and also the expected triazoles V were to be
observed. Besides these derivatives additional products of type XI derived from two
molecules of IV as well as nitriles VI could also be detected (see mechanistic discussion
below). The formation of triazoles V under the bromination conditions prompted experiments
to increase the ratio of this product in these circumstances. Therefore, reactions of 9 and 19
with NBS were carried out in the presence or absence of NH4OAc in CH2Cl2, AcOH, or 1,4ꢀ
dioxane at r. t. or with boiling. However, the isolated yield of the corresponding triazoles 21
and 22, respectively, did not exceed 25ꢀ35 %, therefore, the two steps procedure remained
more advantageous.
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Table 3. LCꢀMS analysis of reaction mixtures of sugar derived N1ꢀalkylideneꢀamidrazones with NBSa
Detectedb or isolatedc compounds
Entry
1.
Starting
compound
(type IV)
9
R1
R2
Ph
V
VI
XI
XIII
b
b
b,e
+
+
not
+
+
detectedd
not isolated
25 (74)c
b
b
b
b,e
2.
Ph
+
+
+
18
aRoman numbers denote compound types and are identical with those in mechanistic Scheme 8.
bDetected by LCMS (for details see Supporting information).
cIsolated yield (%) after column chromatography.
dThe compound can be present in the mixture, but was not detected due to its low molecular weight.
eDetectable form: Br→OH
In order to study the broader applicability and functional group tolerance of the above NBSꢀ
mediated ring closing reactions, they were extended to several aromatic derivatives. To start
these studies, a variety of N1ꢀarylideneꢀarenecarboxamidrazones 35 were synthesized by the
reaction of ethyl benzimidate (34) with aldehydeꢀhydrazones in dry EtOH at reflux
temperature (conditions A in Scheme 7) in moderate to good yields (Table 4). Better yields
were achieved when alkylideneꢀamidrazones 35 and 36 were obtained in a condensation
reaction of benzamidrazone (5) or pyridineꢀ2ꢀcarboxamidrazone (6), respectively, with
aromatic aldehydes in dry EtOH at reflux temperature (conditions B in Scheme 7, Table 4).
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Scheme 7. Syntheses of N1ꢀarylideneꢀarenecarboxamidrazones and their transformation into
3,5ꢀdiarylꢀ1,2,4ꢀtriazoles.
In the reactions of 35 and 36 with NBS no attempts were made to isolate the putative
intermediate carbohydrazonoyl bromides 37 and 38 which, as crude products, were
transformed to the desired triazoles 39 and 40, respectively (conditions C in Scheme 7). In
these reactions 5ꢀarylꢀ4ꢀarylidenaminoꢀ3ꢀphenylꢀ1,2,4ꢀtriazoles37 41 were also isolated
(41a,d) or detected (41b,c,e) as byꢀproducts. By changing the order of addition of the reagents
(conditions D in Scheme 7) formation of triazoles 41 could be avoided, and the desired
products 39aꢀj were obtained in better yields (Table 4). The pyridine derivatives 40 were
prepared only in this way. Amidrazones 35k and 36k with a free OH group resulted in
complex reaction mixtures in both conditions C and D, while 36e containing a methylsulfanyl
group (MeS) was converted to the corresponding sulfoxide 40e.
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Table 4. Syntheses (yield, %) of N1ꢀarylideneꢀarenecarboxamidrazones (35, 36) and 3,5ꢀdiarylꢀ1,2,4ꢀtriazoles (39ꢀ41)
Ar1
Amidrazone
Triazole
Triazole
Amidrazone
Triazole
35
39
41
36
40
Conditions in Scheme 7
Ar2
A
B
C
D
C
B
D
86
93
22
68
14
75
59
a
b
c
ꢀ
39
ꢀ
81
85
82
34
22
17
64
60
50
not isolated
not isolated
38
61
85
74
45
40
58
d
ꢀ
80
30
61
not isolated
82
e
56
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47
59
84
90
94
78
ꢀ
ꢀ
ꢀ
60
34
35
ꢀ
ꢀ
ꢀ
79
87
81
58
ꢀ
f
g
h
40
74
82
ꢀ
56
ꢀ
95
61
i
ꢀ
ꢀ
77
93
ꢀ
ꢀ
40
ꢀ
ꢀ
ꢀ
81
79
30
ꢀ
j
k
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To understand the formation of the isolated and observed products in the NBSꢀmediated
reactions a mechanistic rationale is proposed in Scheme 8. N1ꢀAlkylidene amidrazones IV are
brominated to give the hydrazonoyl bromide type compounds XIII from which the R1 = Gly
derivatives (24ꢀ29) proved sufficiently stable and could also be isolated. Intramolecular ring
closure of XIII may directly give triazoles V and this may be facilitated by the removal of
HBr in the presence of a basic solvent (cf. reactions in pyridine) or an added base (reactions in
the presence of NH4OAc). In reactions with NH4OAc the ammonium salt may act as a source
of NH3 and this may lead to the formation of XII (N1ꢀcarboximidoꢀamidrazones) which can
ring close to triazoles V that was demonstrated with isolated compounds XII earlier.9
Hydrazonoyl bromides XIII may be prone to loss of bromide ion to form carbocation XIV as
it was made likely in kinetic studies of several hydrazonoyl halides.38ꢀ40 Cation XIV may form
the triazole V directly or via XII depending on the reaction conditions. The presence of this
cation in the reaction mixtures may also account for the formation of the observed/isolated
byꢀproducts. 4ꢀAlkylideneaminoꢀ3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles XI are analogues of known
symmetric 4ꢀarylideneaminoꢀ3,5ꢀdiarylꢀ1,2,4ꢀtriazoles obtained by chlorination of Nꢀ
alkylidene hydrazides.37 Formation of XI can be envisaged by an attack of unreacted
alkylideneꢀamidrazone IV on cation XIV to give intermediate XV which upon ring closure
accompanied by loss of NH3 may yield tetrazepine XVI. Subsequent extrusion of nitrile VI
with concomitant formation of the 1,2,4ꢀtriazole ring give compounds XI which were isolated
in the aromatic series (41a,d) and identified by mass spectrometry in the reactions of the
sugar derived amidrazones 9 and 18.
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Scheme 8. Mechanistic proposal for the reaction of N1ꢀalkylideneꢀamidrazones with NBS.
Conclusion
Oxidative ring closing conditions were studied for the preparation of unsymmetrical 3,5ꢀ
disubstitutedꢀ1,2,4ꢀtriazoles from acyclic N1ꢀalkylideneꢀcarboxamidrazones. Although among
others also PIDA proved unsuitable for this transformation, based on detailed analyses of the
reaction mixtures, a mechanistic proposal was set up to rationalize the success of this reagent
in obtaining fused 1,2,4ꢀtriazoles. NBS and Oꢀperacylated N1ꢀ(glycopyranosylmethylidene)ꢀ
arenecarboxamidrazones gave stable and isolable hydrazonoyl bromide type compounds
which were ring closed to the corresponding Cꢀglycosylꢀ1,2,4ꢀtriazoles under basic
conditions. Extension of the method to aromatic substrates revealed that NBS in AcOH in the
presence of NH4OAc was a generally applicable reagent combination to get the target
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compounds. A mechanistic rationale was proposed to account for the formation of byꢀ
products in these transformations. With this study we have demonstrated that N1ꢀalkylideneꢀ
amidrazones can be transformed into 3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles with different groups
attached to the carbon atoms of the heterocycle. The method constitutes the shortest synthetic
route to 3ꢀ(βꢀDꢀglycopyranosyl)ꢀ5ꢀsubstitutedꢀ1,2,4ꢀtriazoles, among which the glucose
derivatives belong to the most efficient inhibitors of glycogen phosphorylase, and are thereby
potential antidiabetic agents.
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Experimental
General methods
Melting points were measured in open capillary tubes or on a Kofler hotꢀstage and are
uncorrected. Optical rotations were determined with a Perkin–Elmer 241 polarimeter at room
temperature. NMR spectra were recorded with Bruker 360 (360/90 MHz for 1H/13C) or
Bruker 400 (400/100 MHz for 1H/13C) spectrometers. Chemical shifts are referenced to TMS
as the internal reference (1H), or to the residual solvent signals (13C). Microanalyses were
performed on an Elementar vario Micro cube. LCꢀMS was performed on a Hypersil Gold (50
× 2.1mm, 1.9 µm, with precolumn filter, Thermo Electron Corp., San Jose, CA, USA)
column, using an Accela HPLC system (Thermo Electron Corp., San Jose, CA, USA) coupled
with a Thermo LTQ XL mass spectrometer (Thermo Electron Corp., San Jose, CA, USA)
operated in a full scan positive ion ESI mode or with a Bruker micrOTOFꢀQ instrument. TLC
was performed on DCꢀAlurolle Kieselgel 60 F254 (Merck). TLC plates were visualized under
UV light, and by gentle heating. For column chromatography Kieselgel 60 (Merck, particle
size (0.063ꢀ0.200mm) was applied. Organic solutions were dried over anhydrous MgSO4, and
concentrated under diminished pressure at 40ꢀ50 °C (water bath).
General procedure I for the synthesis of Oꢀperacylated Nꢀ[Cꢀ(βꢀDꢀglycopyranosyl)meꢀ
thylideneamino]guanidine (8) and N1ꢀ[Cꢀ(βꢀ
Dꢀglycopyranosyl)methylidene]areneꢀ
carboxamidrazones (9ꢀ13)
Aminoguanidine × H2CO3 (4, 0.50 mmol) or an arenecarboxamidrazone (5ꢀ7, 0.50 mmol) was
dissolved in a mixture of pyridine (1.5 mL) and H2O (0.9 mL), and stirred for 20 min at rt.
Then AcOH (0.9 mL), RaneyꢀNi (0.38 g, from an aqueous suspension, Merck), NaH2PO2
(0.20 g, 2.27 mmol), and the corresponding Oꢀperacylated βꢀDꢀglycopyranosyl cyanide (1ꢀ3,
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0.25 mmol) were added to the mixture. The reaction mixture was vigorously stirred and
heated at 40 °C. When the reaction was complete (TLC, EtOAc/hexane = 1:2) the insoluble
materials were filtered off with suction, and washed with CH2Cl2 (10 mL). The organic layer
of the filtrate was separated, washed with H2O (2 x 6 mL), dried (MgSO4), and evaporated in
vacuo, traces of pyridine were removed by repeated coꢀevaporations with toluene. The residue
was purified by column chromatography.
General procedure II for the synthesis of N1ꢀarylideneꢀCꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀ
Dꢀ
glucopyranosyl)formamidrazones (18ꢀ20)
Cꢀ(2,3,4,6ꢀTetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl)formamidrazone9 (14, 1.0 g, 1.57 mmol) and
the corresponding aromatic aldehyde (15ꢀ17, 1.1 equiv.) was heated in dry EtOH (20 mL) at
reflux temperature, and the reaction was monitored by TLC (EtOAc/hexane = 1:1). After total
consumption of the starting formamidrazone the product was separated either by filtration or
by column chromatography.
General procedure III for the transformation of N1ꢀarylideneꢀCꢀ(2,3,4,6ꢀtetraꢀOꢀ
benzoylꢀβꢀDꢀglucopyranosyl)formamidrazones (18ꢀ20) by PIDA
To a solution of the corresponding arylidene amidrazone (18ꢀ20, 0.10 g) in dry CH2Cl2 (3
mL) PIDA (2 equiv.) was added and the reaction mixture was stirred at rt. After
disappearance of the starting material monitored by TLC (EtOAc/hexane = 1:1) the mixture
was diluted with CH2Cl2 (15 mL), extracted with water (10 mL), satd aq NaHCO3 solution
(10 mL), and then with water (10 mL). The organic phase was dried over MgSO4, filtered the
solvent was evaporated under reduced pressure. The resulting products were separated by
column chromatography.
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General procedure IV for the synthesis of Oꢀperacylated NꢀarenecarboximidoylꢀCꢀ(βꢀ
Dꢀ
glycopyranosyl)carbohydrazonoyl bromides (24ꢀ29)
An alkylidene amidrazone (8ꢀ13, 0.28 mmol) was dissolved in CH2Cl2 (4 mL), then Nꢀ
bromosuccinimide (0.05 g, 0.28 mmol) was added. The mixture was stirred at rt. When the
reaction was complete (TLC, EtOAc/hexane = 1:2) the solvent was evaporated, and the
residue was purified by column chromatography.
General procedure V for the synthesis of Oꢀperacylated 3ꢀsubstitutedꢀ5ꢀ(βꢀDꢀ
glycopyranosyl)ꢀ1,2,4ꢀtriazoles (21, 30ꢀ33)
A carbohydrazonoyl bromide (24ꢀ29, 0.14 mmol) was dissolved in glacial AcOH (3 mL), then
NH4OAc (0.012 g, 0.15 mmol) was added. The mixture was stirred and heated at 110 °C.
When the reaction was complete (TLC, EtOAc/toluene = 2:7) the mixture was diluted with
H2O (6 mL), and washed with CH2Cl2 (3 x 7 mL). The organic layer was separated and
washed with cold, saturated NaHCO3 solution (8 mL), and H2O (8 mL), dried (MgSO4), and
evaporated under reduced pressure. The residue was purified by column chromatography.
General procedure VI for the synthesis of Oꢀperacylated 3ꢀsubstitutedꢀ5ꢀ(βꢀDꢀ
glycopyranosyl)ꢀ1,2,4ꢀtriazoles (21, 30)
A carbohydrazonoyl bromide (24ꢀ26, 0.10 mmol) was dissolved in anhydrous pyridine (6
mL). The mixture was stirred and heated at 110 °C. The reaction was monitored by TLC
(EtOAc/toluene = 1:3). When the reaction was complete the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography.
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General procedure VII for the synthesis of N1ꢀarylideneꢀbenzamidrazones (35)
Ethylbenzimidate (34, 1.01 mmol) was dissolved in dry EtOH (10mL), and the corresponding
aryl hydrazone (1.01 mmol) was added. The reaction mixture was stirred and heated at reflux
temperature overnight. The reaction was monitored by TLC (EtOAc/hexane = 1:3). When the
reaction was complete the solvent was evaporated under reduced pressure, and the residue
was crystallized from ethanolꢀhexane mixture.
General procedure VIII for the synthesis of N1ꢀarylideneꢀarenecarboxamidrazones (35,
36)
An arenecarboxamidrazone (59 or 641, 1.1 mmol) was dissolved in dry EtOH (8 mL), and the
corresponding aromatic aldehyde (1.21 mmol) was added. The reaction mixture was stirred
and heated at reflux temperature. The reaction was monitored by TLC (EtOAc/hexane = 1:2).
When the reaction was complete the solvent was evaporated under reduced pressure, and the
residue was crystallized from ethanolꢀhexane mixture.
General procedure IX for the synthesis of unsymmetrical 3,5ꢀdisubstitutedꢀ1,2,4ꢀ
triazoles (39, 40)
An arylidene amidazone (35 or 36, 0.331 mmol) was dissolved in CH2Cl2 (10 mL), and NBS
(0.059 g, 0.331 mmol) was added. The reaction mixture was stirred at room temperature.
When the reaction was complete (TLC, EtOAc/hexane = 1:3) the solvent was evaporated
under reduced pressure.The crude product was dissolved in glacial acetic acid (8 mL), then
ammonium acetate (0.028 g, 0.364 mmol) was added. The reaction mixture was stirred and
heated at 110 °C overnight. When the reaction was complete (TLC, EtOAc/toluene = 1:3) the
mixture was diluted with H2O (30 mL), and washed with EtOAc (4 x 15 mL). The organic
layer was separated, and washed with water (15 mL), dried (MgSO4), and evaporated under
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reduced pressure. The residue was purified by column chromatography (EtOAc/hexane =
1:2).
General procedure X for the synthesis of unsymmetrical 3,5ꢀdisubstitutedꢀ1,2,4ꢀtriazoles
(39, 40)
An arylidene amidazone (35 or 36, 0.83 mmol) and ammonium acetate (0.13 g, 0.1.66 mmol)
was dissolved in glacial AcOH (16 mL), then NBS (0.148 g, 0.83 mmol) was added. The
mixture was stirred and heated at 110 °C overnight. When the reaction was complete (TLC,
EtOAc/toluene = 1:3) the mixture was diluted with H2O (30 mL), and washed with EtOAc (4
x 15 mL). The organic layer was separated, and washed with water (15 mL), dried (MgSO4),
and evaporated under reduced pressure. The residue was purified by column chromatography
(EtOAc/hexane = 1:2).
Acknowledgement
This work was supported by the Hungarian Scientific Research Fund (OTKA 77712 and
PD105808), the BAROSS REG_EA_09ꢀ1ꢀ2009ꢀ0028 (LCMS_TAN) project as well as by
TÁMOPꢀ4.2.4.A/ 2ꢀ11/1ꢀ2012ꢀ0001 'National Excellence Program' to MT supported by the
European Union and the State of Hungary, coꢀfinanced by the European Social Fund.
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