Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles

Article abstract of DOI:10.3762/bjoc.14.256

A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-1H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl diselenides. The reactions were conducted in MeCN as solvent at reflux temperature under air. The methodology presents a large functional group tolerance to electron-deficient, electron-rich, and bulky substituents and gave the expected products in good to excellent yields. The synthesized 1,3-diphenyl-4-(phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound confirmed by X-ray analysis.

Full text of DOI:10.3762/bjoc.14.256

Molecular iodine-catalyzed one-pot multicomponent
synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles
Camila S. Pires1, Daniela H. de Oliveira1, Maria R. B. Pontel1, Jean C. Kazmierczak2,
Roberta Cargnelutti2, Diego Alves1, Raquel G. Jacob1 and Ricardo F. Schumacher*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2789–2798.
1LASOL - CCQFA - Universidade Federal de Pelotas - UFPel - P.O.
doi:10.3762/bjoc.14.256
Box 354 - 96010-900, Pelotas, RS, Brazil and 2Departamento de
Química, Universidade Federal de Santa Maria – UFSM, 97105-900,
Santa Maria, RS, Brazil
Received: 06 July 2018
Accepted: 25 October 2018
Published: 06 November 2018
Email:
Ricardo F. Schumacher* - ricardo.schumacher@ufsm.br
Associate Editor: T. J. J. Müller
*
Corresponding author
© 2018 Pires et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
diaryl diselenide; diazo compound; 1H-pyrazole; molecular iodine;
multicomponent reaction
Abstract
A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-
1
H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl diselenides. The reactions were conducted in
MeCN as solvent at reflux temperature under air. The methodology presents a large functional group tolerance to electron-deficient,
electron-rich, and bulky substituents and gave the expected products in good to excellent yields. The synthesized 1,3-diphenyl-4-
(
phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound con-
firmed by X-ray analysis.
Introduction
Selenium-containing compounds are of great importance in bio- alkynyl halides or pseudo-halides [3], an updated protocol that
active compounds, pharmaceuticals, and as chemical intermedi- describe reduced waste generation and atom-economy is
ates for organic and inorganic synthesis [1,2]. As a conse- desired. In this context, the multicomponent cyclization/direct
quence, the development of efficient and practical methods for selanylation is a practical and economical way to incorporate
C–Se bond formation is still a promising field of research in organylselanyl moieties in aryl and heteroaryl compounds
organic chemistry. Despite the several number of methodolo- avoiding the necessity of pre-functionalization, multistep syn-
gies describing the transition metal-catalyzed cross-coupling thesis and tedious work-up [4,5]. In this context, the prepara-
reaction of diorganyl diselenides with (hetero)aryl, alkenyl, and tion of diverse selanylated indoles and imidazopyridines, for ex-
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ample, is widely found in literature [6,7]. However, the prepara- special, 5-amino-1H-pyrazoles are valuable compounds that
tion of 4-arylselanyl-1H-pyrazoles is quite scarce. Tiecco and present several biological and pharmaceutical activities includ-
co-workers described the preparation of phenylseleno substi- ing antiviral, anticancer, antituberculosis, anti-inflammatory,
tuted pyrazolidines by reacting allylhydrazines with phenylsela- antifungal and antidepressive activity [14-17]. Moreover, they
nenyl sulfate generated in situ (Scheme 1) [8]. Attanasi and have been extensively used as synthons to prepare a wide
co-workers described the synthesis of 4-(phenylseleno)pyrazol- variety of fused N-heterocycles of synthetic and pharmacologi-
3
-ones through α-(phenylseleno)hydrazone reagents under basic cal importance [18-20]. Thus, an effective strategy for the
conditions [9]. In 2015, Yu and co-workers described one ex- design and the preparation of new pharmacologically promis-
ample for the condensation reaction of α-oxo ketene dithio- ing drugs that combine at least two bioactive moieties in one
acetal with hydrazine hydrate to produce the 3-methyl-5- molecule avoiding residual metal in transition-metal catalysis in
methylsulfanyl-4-phenylselanyl-1H-pyrazole [10]. Our research environmental benign conditions is desired. Recently, Sun and
group described the multicomponent synthesis of 3,5-dimethyl- co-workers described their interesting results on the I2-cata-
4
-arylselanyl-1H-pyrazoles catalyzed by copper iodide using lyzed efficient synthesis of 5-amino-4-sulfanylpyrazoles using
DMSO as solvent [4]. More recently, Zora and co-workers re- diverse β-ketonitriles, arylhydrazines and aryl sulfonyl
ported the one-pot preparation of 4-phenylselanyl-1H-pyra- hydrazides as sulfur source [21]. The chemistry of iodine-cata-
zoles through reaction of α,β-alkynic hydrazones with phenylse- lyzed transformations has emerged as a greener, efficient and
lenyl chloride [11].
economical alternative to transition metals in organic synthesis
22-24]. However, the synthesis of selenium-containing
[
In this context, pyrazoles are one of the most important 5-aminopyrazoles under iodine-catalyzed three-component
N-heterocycles found in natural products including formycin, reaction was not described so far.
pyrazofurin and withasomnine, for example. Still, pyrazole
unities are present in several commercially available drugs such In view of this, we present a direct and selective multicompo-
as celecoxib, lonazolac, rimonabant and sildenafil [12,13]. In nent strategy to synthesize 5-amino-4-(arylselanyl)-1H-pyra-
Scheme 1: Synthesis of selanyl-pyrazoles and their derivatives previously described.
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Beilstein J. Org. Chem. 2018, 14, 2789–2798.
zoles 4 by reacting benzoylacetonitrile derivatives 1, arylhydra- 0.5 mmol) were solubilized in MeCN (3 mL) and molecular
zines 2 and diorganyl diselenides 3 (Scheme 2). The reaction is iodine (50 mol %) was added. The mixture was stirred at reflux
catalysed by molecular iodine in MeCN as solvent.
temperature and after 48 h under these conditions, the expected
product 4a was obtained in 71% yield (Table 1, entry 1). With
these result, we attempted to investigate the parameters
Results and Discussion
Initially, to optimize the reaction conditions experiments were regarding quantities (Table 1, entries 2 and 3). Based on it,
performed using benzoylacetonitrile (1a), phenylhydrazine (2a) we observed that the use of a minimum amount of diphenyl
and diphenyl diselenide (3a) as standard substrates to define the diselenide (3a) caused a decrease in the reaction yield,
best reaction conditions. During the experiments different pa- giving the product 4a in 54% (Table 1, entry 2). However,
rameters were evaluated such as temperature, reaction time, sol- when the reaction was performed using a slight excess of 2a
vent, reagent amount and heating method (conventional heating (0.7 mmol) and 3a (0.5 mmol) the reaction yield increased
or ultrasound, Table 1).
significantly to 96% (Table 1, entry 3). The treatment of
a, 2a and 3a in the presence of 25, 50 and 75 mol % of
1
In a first experiment, benzoylacetonitrile (1a, 0.5 mmol), molecular iodine afforded the expected product 4a in 68,
phenylhydrazine (2a, 0.5 mmol) and diphenyl diselenide (3a, 96 and 75% yield, respectively (Table 1, entries 3–5). In
Scheme 2: Multicomponent reaction proposed in this work.
Table 1: Optimization of the reaction conditions.a
entry
2a (mmol)
3a (mmol)
I2 (mol %)
solvent
temp. (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
0.5
0.5
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
50
50
50
25
75
50
50
50
50
50
50
MeCN
MeCN
reflux
reflux
reflux
reflux
reflux
80
48
48
48
48
48
48
48
48
48
36
2
71
54
96
68
75
–
MeCN
MeCN
MeCN
toluene
DMF
80
16
55
12
68
47
1,4-dioxane
MeCN
80
60
10
MeCN
reflux
)))
11c
MeCN
aReaction was performed using 1a (0.5 mmol), 2a and 3a in 3 mL of solvent followed by the addition of molecular iodine. The consumption of starting
materials was followed by TLC. bYields are given for isolated products. cThe reaction was carried under ultrasound conditions operating at amplitude
of 60% and a frequency of 20 kHz.
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Beilstein J. Org. Chem. 2018, 14, 2789–2798.
this sense, better results were obtained when using 50 mol % due to the high-energy transference in the reaction during the
of I2.
cavitation process. Unfortunately, under this condition a low
reaction yield of 42% was obtained even after 2 h of reaction
In the next step, the reaction was performed in different sol- (Table 1, entry 11).
vents such as toluene, 1,4-dioxane and dimethylformamide, but
a considerable decrease in the yield of 4a was observed With the establishment of the best reaction conditions for the
(
Table 1, entries 6–8). Similarly, when the reaction was con- synthesis of 4a described in Table 1, entry 3, we envisaged
ducted at a lower temperature (Table 1, entry 9) or in a shorter extending this methodology to diverse benzoylacetonitriles
reaction time (Table 1, entry 10), the product 4a was isolated in 1a–f, arylhydrazines 2a–f and differently substituted diaryl
a poorer yield. The use of ultrasonic irradiation was also tested diselenides 3a–f. In general, as shown in Table 2, most of the
Table 2: Substrate scope for the synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles 4.a
entry
ketonitrile 1
aryl hydrazine 2
diaryl diselenide 3
product 4 (yield)b
1
2a
1a
3a
4a (96%)
2
2a
1b
3a
4b (73%)
3
2a
3a
1c
4c (35%)
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Table 2: Substrate scope for the synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles 4.a (continued)
4
2a
1d
3a
4d (78%)
5
2a
1e
3a
4e (81%)
6
2a
1f
3a
4f (62%)c
7
2b
1a
3a
4g (63%)
8
1a
3a
2c
4h (52%)
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Table 2: Substrate scope for the synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles 4.a (continued)
9
1a
2d
3a
4i (80%)
10
1a
2e
3a
4j (76%)
11
1a
3a
2f
4k (–)d
12
2a
1a
3b
4l (54%)
13
2a
1a
3c
4m (63%)
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Beilstein J. Org. Chem. 2018, 14, 2789–2798.
Table 2: Substrate scope for the synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles 4.a (continued)
14
15
16
2a
2c
2c
1a
1a
1a
3
d
4
n (80%)
3e
4o (24%)
3
f
4p (–)d
aReactions were performed by using 1 (0.5 mmol), 2 (0.7 mmol), 3 (0.5 mmol) and I2 (50 mol %) in MeCN (3 mL) at reflux temperature for 48 h in air.
bYield is given for isolated products. cYield is given for a mixture of 5-amino-4-(phenylselanyl)pyrazole and 5-aminopyrazole (1:2) determined by
1H NMR. dProduct not obtained.
reactions proceeded smoothly and provided the desired prod- corresponding product 4f was isolated as a non-separable mix-
ucts in moderate to excellent yields (see Supporting Informa- ture with the non-selenylated 5-aminopyrazole (Table 2,
tion File 1 for full experimental data).
entry 6).
The substrate scope of this reaction was investigated under the Next we evaluated the reactivity of different functionalized
optimized reaction conditions. Initially, to achieve this goal, we arylhydrazines 2a–f using benzoylacetonitrile 1a and diphenyl
carried out a reaction of phenylhydrazine (2a) and diphenyl diselenide 3a as standard reagents (Table 2, entries 7–11).
diselenide (3a) with benzoylacetonitrile 1b containing an elec- Substituted arylhydrazines were sensitive to the electronic
tron-donating group on the aromatic ring, that provided the cor- effect of the groups directly bonded to aromatic ring. In this
responding product 4b gently in 73% yield. When we per- sense, arylhydrazines 2b and 2c containing EDG at the aromat-
formed the reaction by using the benzoylacetonitrile derivative ic ring gave lower yields than arylhydrazines 2d and 2e contain-
1
c substituted with a methoxy group, a lower isolated yield was ing EWG (Table 2, entries 7 and 8 vs 9 and 10). On the other
observed (Table 2, entry 3). This may be associated with the hand, when 2,4-dinitrophenylhydrazine was used, the expected
high reactivity of 1c which produced many byproducts as ob- pyrazole 4k was not detected by GC–MS analysis. (Table 2,
served by TLC and GC–MS analysis. Benzoylacetonitriles 1d,e entry 11).
substituted with electron-withdrawing groups such as Br and Cl
were also tested and afforded the corresponding products 4d In addition, different diaryl diselenides 3b–e were studied to
and 4e in good yields (Table 2, entries 4 and 5). However, when produce valuable 5-amino-4-(arylselanyl)-1H-pyrazoles 4l–o
we used an ortho-chloro substituted benzoylacetonitrile 1f, the (Table 2, entries 12–15). In this case, it is possible to see that all
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Beilstein J. Org. Chem. 2018, 14, 2789–2798.
diaryl diselenides were efficiently coupled to 5-amino-1H-pyra- undergoes a cyclization reaction followed by an oxidative arom-
zole to produce the corresponding products in yields ranging atization to yield 1H-pyrazol-5-amine 5. At the same time, the
from 24% to 80%. However, when the bulkier 1,2-dimesityl diaryl diselenide 3 reacts with the molecular iodine to generate
diselenide 3f was employed, no product was obtained (Table 2, an electrophilic selenium species B. The following step is the
entry 16).
nucleophilic attack of the electron-rich pyrazole 5 to species B
to afford product 4 after releases a proton and produce HI. The
To gain insight into the mechanistic profile we also evaluated presence of oxygen into the reaction system is expected to
whether 5-amino-1H-pyrazole 5a could produce 5-amino-4- regenerate the iodine to continue the catalytic cycle.
(
phenylselanyl)-1H-pyrazole 4a via direct C–H bond selanyla-
tion reaction catalyzed by iodine. Thus, when 5a reacted with To verify the synthetic application of 5-amino-4-(arylselanyl)-
diphenyl diselenide (3a) in the presence of 50 mol % of I2 in 1H-pirazoles 4, we selected compound 4a to prepare a new
acetonitrile as solvent and under reflux, the desired product 4a diazopyrazole derivative 6 based on the methodology described
could be obtained in 90% yield as depicted in Scheme 3.
by Jiang and co-workers [26]. In this context, by reacting the
-(phenylselanyl)pyrazol-5-amine 4a with CuI (5 mol %), 1,10-
4
On the basis of previous reports [21,25] a mechanism can be phenantroline (15 mol %) and tert-butyl hydroperoxide in
proposed for this reaction as depicted in Scheme 4. Initially, we dichloromethane at room temperature for 2 h, the respective
believe that arylhydrazine 2 reacts with benzoylacetonitrile 1 by diazo aromatic compound 6 could be obtained in 50% yield
a 1,2-addition reaction in the presence of iodine as Lewis acid (Scheme 5). As can be seen, the reaction proceeded smoothly
to generate the hydrazone intermediate A. Then, hydrazone A allowing formation of the new N=N bond without cleavage of
Scheme 3: Direct selanylation reaction of 5-amino-pyrazole 5a with diphenyl diselenide (3a) under the optimized conditions.
Scheme 4: Proposed reaction mechanism.
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Beilstein J. Org. Chem. 2018, 14, 2789–2798.
Scheme 5: Synthesis of diazo pyrazole derivative 6.
the C–Se bond under the oxidant media and the presence of
copper salt.
Supporting Information
The Supporting Information features full experimental data
To confirm the structure of 6, its molecular structure was also
analyzed by single-crystal X-ray diffraction (CCDC: 1853770).
The molecular structure is demonstrated in Figure 1.
and copies of 1H and 13C NMR spectra of pyrazoles 4 and
6
.
Supporting Information File 1
Experimental part.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-256-S1.pdf]
Acknowledgements
The authors thank FAPERGS (ARD 16/2551-0000358-0 and
PRONEM 16/2551-0000240-1), CNPq, CAPES and FINEP for
the financial support. CNPq is also acknowledged for the
fellowship for R.G.J. and D.A.
ORCID® iDs
Ricardo F. Schumacher - https://orcid.org/0000-0003-4723-1925
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A variety of 4-(arylselanyl)-1H-pyrazol-5-amines was prepared
in a one-pot multicomponent procedure starting from easily
available benzoylacetonitriles, arylhydrazines and diaryl
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