Synthesis of new pharmacologically oriented heterocyclic ensembles, [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans

Article abstract of DOI:10.1016/j.mencom.2019.05.015

The effective synthesis of pharmacologically oriented heterocyclic ensembles, [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans, comprising furoxan moiety as NO-donor and pharmacophoric pyrazolylthiazole fragment is based on the condensation of (2-hydrazinylthiaz

Full text of DOI:10.1016/j.mencom.2019.05.015

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 288–291
Synthesis of new pharmacologically oriented heterocyclic
ensembles, [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans
Margarita A. Epishina,a Alexander S. Kulikov,a Leonid L. Fershtat,a
Ivan V. Ananyevb,c and Nina N. Makhova*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: mnn@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
119991 Moscow, Russian Federation
c G. V. Plekhanov Russian University of Economics, 117997 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2019.05.015
R2
R2
The effective synthesis of pharmacologically oriented hetero-
cyclic ensembles, [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans,
comprising furoxan moiety as NO-donor and pharmacophoric
pyrazolylthiazole fragment is based on the condensation of
(2-hydrazinylthiazol-4-yl)furoxan hydrobromides with linear
1,3-diketones. The reaction proceeds through hydroxy-
pyrazoline intermediate.
NHNH2·HBr
N
S
N
N
O
S
O
N
R1
R2
R2
R1
N
AcOH, 80°C, H+
N
N
O
O
N
R1 = Me, Ph
O
O
R
2 = Me, CF3, Ph
67–94%
Nitrogen-containing heterocycles are among the most significant
structural components of multitude pharmaceuticals.1 Furoxans
(1,2,5-oxadiazole 2-oxides) have attracted attention in recent
decades owing to their ability to release NO under physiological
conditions.2 Our latest studies in the furoxan chemistry3 were
directed towards the construction of potential drug candidates,
new hybrid structures containing furoxan motif as NO-donor
linked to various pharmacophoric nitrogen-containing hetero-
cycles.4 Recently, the cytotoxic activity against five human cancer
cell lines was revealed for a series of the synthesized hybrid
structures.5 One of the prospective heterocyclic frameworks for
new furoxan-containing hybrid structures seems to be pyrazolyl-
thiazole whose representatives are effective in treatment of cardio-
vascular diseases as selective inhibitors of fibrinogen-mediated
platelet aggregation,6 they display antinociceptive7 and antibacterial
activities against gram-positive and gram-negative bacteria,8 and
are toxic against Candida elegans.9
was accomplished by heating in AcOH (see Scheme 1). Com-
pound 1b was characterized as the hydrazone with 4-nitro-
benzaldehyde (see Online Supplementary Materials).
O
O
Br
R
Me
R
i
ii
N
N
N
N
O
O
O
O
NHNH2·HBr
S
O
N
self-cyclization
R
R
NH·HBr
NHNH2
for 2a
S
or iii for 2b
N
N
N
N
O
O
O
O
2a R = Me
2b R = Ph, 89%
1a R = Me, 84%
1b R = Ph, 90%
Scheme 1 Reagents and conditions: i, Br2 (1 equiv.), AcOH, 47% HBr,
50°C, 1.5 h; ii, H2NC(=S)NHNH2 (1 equiv.), MeCN, 20°C, 4–12 h;
iii, AcOH, 80°C, 7 h.
Recently,10 we have synthesized promising 4-(2-hydrazinyl-
thiazol-4-yl)-3-methylfuroxan hydrobromide 1a and some its
analogues by the reaction of the corresponding bromoacetyl-
furoxans with thiosemicarbazide under mild conditions (Scheme 1).
Obviously, hydrazine moiety can be regarded as a backbone for
the construction of pyrazole cycle, and compounds of type 1a
can be converted into conjugates comprising valuable furoxan,
thiazole and pyrazole cores. The specific goal of this work was
the synthesis of new hybrids bearing the NO-donor furoxan
and the pyrazolylthiazole moieties.
Pyrazolylthiazoles are regularly obtained by the condensation
of 2-hydrazinylthiazoles with 1,3-dicarbonyl compounds in polar
solvents (EtOH, MeOH,AcOH) under acid catalysis. The outcome
of this reaction is substrate- and acid-dependent, for instance,
heating of 2-hydrazinyl-4-phenylthiazole with acetylacetone or
dibenzoylmethane in the presence of AcOH gives fused bicyclic
thiazolo[2,3-c][1,2,4]triazepine derivatives.11,12 However, target
pyrazolylthiazole is smoothly formed from 2-hydrazinyl-4-phenyl-
thiazole and acetylacetone upon refluxing in MeOH with TsOH
as the catalyst.13 Pyrazolylthiazoles are formed as single products
in the reaction of hydrazinylbenzothiazoles with acetylacetone and
HCl as the catalyst.14 A higher temperature is required for the
reaction of aryl(hydrazinyl)thiazoles bearing electron-withdrawing
substituents in the aromatic ring.15 In this work, the search for
optimal conditions for the formation of pyrazolylthiazole system
from hydrazines of type 1 was performed with compound 1a and
acetylacetone 3a as the model substrates (Scheme 2, Table 1).
To extend a set of initial compounds, we prepared 4-(2-hydrazinyl
-
thiazol-4-yl)-3-phenylfuroxan hydrobromide 1b on the basis of
4-acetyl-3-phenylfuroxan as the starting material. Since this ketone
was described many years ago16 without experimental details
and spectral characteristics, herein we renewed and improved its
synthesis (Scheme S1, see Online Supplementary Materials).
Its acetyl group was brominated, and the bromoacetyl derivative
obtained was condensed with thiosemicarbazide, however, instead
of expected compound 1b its acyclic precursor 2b was obtained.
The cyclization of the latter into required thiazolylfuroxan 1b
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 288 –

Mendeleev Commun., 2019, 29, 288–291
NHNH2·HBr
Me
Me
N
NHNH2·HBr
N
N
N
S
S
N
R1
N
R2
R2
i
Me
Me
+
Me
+
S
Me
O
O
N
O
O
3a R2 = Me
3b R2 = Ph
3c R2 = CF3
O
N
N
O
O
O
1a R1 = Me
1b R1 = Ph
N
N
O
O
1a
3a
Scheme 2
4a
R2
R2
F3C
CF3
HO
N
S
N
Table 1 Optimization of the reaction conditions for the synthesis of
compound 4a.a
N
N
N
N
+
R1
N
S
Me
Yield
of 4a (%)
Entry
Solvent
Catalyst
T/°C
t/h
N
N
N
O
O
1
2
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
EtOH
EtOH
EtOH
EtOH
–
20
20
20
20
80
80
80
80
80
20
80
80
80
72
72
24
24
10
2
11
70
71
71
35
43
64
83
93
7
O
O
HCl (0.25 equiv.)
HCl (1 equiv.)
HCl (2 equiv.)
–
4'c (in case of 1a + 3c)
4a–f
3
4d R1 = Ph, R2 = Me (65%)
4e R1 = R2 = Ph (84%)
4a R1 = R2 = Me (93% optimized)
4b R1 = Me, R2 = Ph (82%)
4c R1 = Me, R2 = CF3
4
5
4f R1 = Ph, R2 = CF3 (94%)
6
HCl (0.25 equiv.)
HCl (0.25 equiv.)
HCl (0.25 equiv.)
H2SO4 (0.35 equiv.)
–
iii
i
ii
iv
7
4
4c
(86%)
4c
4c + 4'c
1a + 3c
4'c
(65%)
8
10
6
(81%)
9
v
4e
(82%)
2b + 3b
10
11
12
13
72
10
6
–
0
Scheme 3 Reagents and conditions: i, AcOH, 0.35 equiv. H2SO4, 80°C, 6 h;
ii, EtOH, 0.35 equiv. H2SO4, 80°C, 5 h; iii, AcOH, 0.35 equiv. H2SO4,
80°C, 11 h; iv, AcOH, 1.0 equiv. H2SO4, 80°C, 5 h; v, AcOH, 0.35 equiv.
H2SO4, 80°C, 6 h. Molar ratios: 1:3a,c = 1:2, 1:3b = 1:1.4.
HCl (0.25 equiv.)
H2SO4 (0.35 equiv.)
71
87
10
a Molar ratio 1a/3a of 1:2, solvent 4 ml per 1 mmol of 1a.
Since the initial compound 1a contained latent HBr acid,
the first attempts to obtain the target compound 4a were made
without additional catalyst in AcOH or EtOH at 20°C for 72 h or
at 80°C for 10 h. The yields in these cases in AcOH were 35 and
11%, respectively (see Table 1, entries 1 and 5). Compound 4a
was practically not formed in EtOH without catalyst additives
(entries 10 and 11). Using HCl as the catalyst (0.25 equiv.) enabled
to obtain good results in both solvents and at both temperatures
(entries 2–4, 6–8, 12). The maximum yields were achieved with
H2SO4 (0.35 equiv.) (entries 9 and 13).
The optimal conditions for the preparation of compound 4a
were extended for the reaction of hydrazine derivatives 1a,b
with three 1,3-dicarbonyl compounds 3a–c (Scheme 3).† The
expected [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans 4a–e were
obtained in all cases, however, the target structure 4c was formed
in the mixture with non-dehydrated intermediate product 4'c. The
whole dehydration of compound 4'c into 4c was reached upon
prolonged heating (11 h) of the reactants 1a and 3c under the
same conditions. The non-dehydrated intermediate 4'c can be
independently prepared by refluxing reactants 1a and 3a in EtOH
with 0.35 equiv. of H2SO4 as a catalyst for 5 h (see Scheme 3).
Its dehydration into pyrazole 4c was performed by heating in
AcOH at 80°C for 5 h in the presence of 1 equiv. of H2SO4.
It is interesting to note that similar hydroxypyrazoline was not
fixed in the reaction of thiazolylfuroxan 1b with hexafluoro-
acetylacetone 3c.
Since the conditions for the cyclization of thiosemicarbazide
2b into hydrazinylthiazole 1d are similar to those for the prepara-
tion of pyrazolylthiazoles of type 4, it seemed reasonable to test
acyclic precursor 2b in the straightforward synthesis of such
pyrazolylthiazoles 4. To our delight, heating of reactant 2b with
dibenzoylmethane 3b under the optimal conditions really afforded
the final compound 4e in very good yield (see Scheme 3).
Unfortunately, attempts to react some other furoxan thiazole
hydrazine hydrobromides (reported in ref. 10) bearing (2-hydrazinyl-
thiazol-4-yl) substituent at C(3) of the furoxan ring with 1,3-diketones
were generally unsuccessful. Exceptionally, reaction between
4-amino-3-(2-hydrazinylthiazol-4-yl)furoxan and dibenzoylmethane
3b under optimal conditions gave pyrazole 5 in yield of 70%
(Scheme 4).
Ph
Ph
†
General procedure for reaction of (2-hydrazinylthiazol-4-yl)furoxan
NHNH2·HBr
hydrobromides 1 with 1,3-diketones 3. The suspension of compound 1
(1 mmol) in AcOH (4 ml) was stirred with 1,3-diketone 3a–e (2 mmol of
3a,c, or 1.4 mmol of 3b, or 1 mmol of 3d,e) in the presence of conc. H2SO4
(0.35 mmol) at 80°C for 6 h. The mixture was cooled to room temperature,
poured into water (10 ml), the formed precipitate was filtered, washed
with water and PriOH and dried in air. When the precipitate was not
formed, AcOH was evaporated and the residue was treated similarly.
4-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)thiazol-4-yl]-3-methylfuroxan
4a. Cream solid, yield 0.26 g (93%), mp 197–198°C, Rf 0.42 (CHCl3).
IR (KBr, n/cm–1): 3140, 1602, 1573, 1530, 1473, 1377, 1360, 1040, 968,
823, 775, 633. 1H NMR (300 MHz, CDCl3) d: 2.30 (s, 3H), 2.49 (s, 3H),
2.67 (s, 3H), 6.05 (s, 1H), 7.75 (s, 1H); 13C NMR (75.5 MHz, CDCl3) d:
10.4, 14.6, 14.8, 111.4, 113.3, 117.1, 140.8, 142.5, 153.1, 153.5, 164.5.
HRMS (ESI) m/z: [M+H]+ 278.0720 (calc. for C11H12N5O2S, m/z:
278.07130).
N
S
N
N
N
S
H2N
Ph
Ph
H2N
i
+
O
O
N
N
N
N
O
O
3b
O
O
5 (70%)
Scheme 4 Reagents and conditions: i, AcOH, 0.35 equiv. H2SO4, 80°C, 6 h.
For further evaluation of reactivity of (thiazol-4-yl)furoxan
hydrobromides 1a,b, we have studied their condensation with
cyclic 1,3-diketones such as dimedone 3d and indanedione 3e
(1:1 molar ratio) under optimal conditions. As could be expected,
the condensation proceeded only at one carbonyl group to form
– 289 –

Mendeleev Commun., 2019, 29, 288–291
OH
C(10)
R
N
Me
Me
C(9)
H
O
N
F(3)
C(15)
N
O
C(8) F(2)
N
C(11)
C(6)
i
N
+
1a,b
1a,b
Me
Me
S
O(1)
N(1)
O(2)
C(7)
C(12)
O
O
F(1)
N(3)
C(13)
C(14)
3d
6a R = Me (75%)
6b R = Ph (74%)
C(1)
C(2)
F(5)
F(6)
N(4)
C(5)
S(1)
C(3)
C(16)
F(4)
R
N(5)
N(2)
O
H
N
N
N
C(4)
i
+
N
O
O
N
S
O
O
Figure 1 ORTEP view of the molecular structure of 4f with thermal
ellipsoids drawn at the 50% probability level.
6c R = Me (75%)
6d R = Ph (70%)
3e
Scheme 5 Reagents and conditions: i, AcOH, 0.35 equiv. H2SO4, 80°C, 6 h.
exemplified on hexafluoro derivative 4'c. The condensation of
(hydrazinylthiazol-4-yl)furoxans hydrobromides 1a,d with cyclic
1,3-dicarbonyl compounds 3d,e resulted in the monohydrazone
derivatives 6a–d.
hydrazones 6a–d in high yields (Scheme 5). It is interesting to
note that the second carbonyl group in the cyclohexane ring of
compounds 6a,b exists as the enol form both in solid state and in
solution (an absence of C=O group absorption band in IR spectrum
and a signal of C=O group in 13C NMR spectra as well as an
appearance of OH group signal in 1H NMR spectra).
I. V. Ananyev is grateful to the Russian Foundation for Basic
Research (project no. 18-33-20075).
All synthesized compounds were characterized by spectral
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.05.015.
1
(IR and H, 13C NMR spectroscopy and HRMS) and analytical
methods. The absorption bands of carbonyl group were present
in IR spectra of hydrazones 6c,d. In addition, resonance signals
for NH groups (d 11–12 ppm) in H NMR spectra and for
1
References
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stabilization. The details of theoretical analysis and crystal
structure determination are given in the Online Supplementary
Materials.
In summary, effective synthesis of pharmacologically oriented
hybrid structures [2-(1H-pyrazol-1-yl)thiazol-4-yl]furoxans 4a–f
and 5 comprising the furoxan moiety as NO-donor and pharmaco-
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pyrazoline intermediate which would dehydrate into pyrazole as
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– 290 –

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Received: 12th December 2018; Com. 18/5772
– 291 –