Synthesis of 4-Organoselanyl-1H-pyrazoles: Oxone -Mediated Electrophilic Cyclization of α,β-Alkynyl Hydrazones by Using Diorganyl Diselenides

Article abstract of DOI:10.1055/s-0037-1611747

A simple and efficient method for the synthesis of 4organoselanyl-1 H -pyrazoles has been developed, taking place under metal- and halogen-free conditions. Electrophilic species of selenium were easily generated in situ by the reaction of diorganyl diselenides with Oxone in ethanol as solvent in an open-flask at 70 °C. These electrophilic selenium species were employed in the selenylation/cyclization of α,β-alkynyl hydrazones, giving the title compounds in moderate to excellent yields. The final species of selenium obtained from the reaction of diphenyl diselenide with Oxone were characterized by ⁷⁷ Se NMR spectroscopy and high-resolution mass spectrometry (HRMS).

Full text of DOI:10.1055/s-0037-1611747

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
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G. Perin et al.
Paper
Synthesis
Synthesis of 4-Organoselanyl-1H-pyrazoles: Oxone®-Mediated
Electrophilic Cyclization of ,-Alkynyl Hydrazones by Using
Diorganyl Diselenides
Gelson Perin*a
Patrick C. Nobrea
Daniela H. Mailahna
Márcio S. Silvaa
Thiago Barcellosb
Raquel G. Jacoba
0
0
0
0-0
0
0
3-0
3
5
9-
0
8
1
1
R3
N
SeR
R1
HN
Oxone®
R2
RSeSeR
+
R1
N
ethanol, 70 °C
open flask
N
R3
2a–g
R2
1a–k
3a–q
mild reaction condition
good yield, 17 examples
easy to scale-up
Eder J. Lenardãoa
Claudio Santic
0
0
0
0-0
0
0
1-7
9
2
0-3
2
8
9
77Se NMR and HRMS studies
metal- and halogen-free
Juliano A. Roehrsd
a Laboratório de Síntese Orgânica Limpa – LASOL, CCQFA, Universidade
Federal de Pelotas – UFPel, P. O. Box 354, 96010-900, Pelotas, RS, Brazil
gelson_perin@ufpel.edu.br
b Laboratório de Biotecnologia de Produtos Naturais e Sintéticos, Univer-
sidade de Caxias do Sul – UCS, Caxias do Sul, RS, Brazil
c Department of Pharmaceutical Sciences, University of Perugia, Via del
Liceo 1, Perugia, Italy
d Instituto Federal de Educação Ciência e Tecnologia Sul-rio-grandense,
IFSul, 96015360, Pelotas, RS, Brazil
Received: 17.12.2018
Accepted after revision: 05.02.2019
Published online: 14.03.2019
As a consequence, a large number of synthetic method-
ologies have been developed to access the pyrazole core.17
Broadly speaking, substituted pyrazoles are conventionally
obtained through the condensation of 1,3-dicarbonyl com-
pounds with hydrazines,18 by 1,3-dipolar cycloaddition re-
actions,19 by the reaction of hydrazines with ,-unsaturat-
ed carbonyl compounds,20 by the intramolecular cyclization
reaction of N-propargyl hydrazones or ,-unsaturated
hydrazones,21 and by other methods.22
In parallel, selenium-containing compounds have re-
ceived increased attention in the last years, due to their
promising applications as catalysts23 and synthetic inter-
mediates,24 mainly as versatile reagents in selective reac-
tions.25 Also, their biological and pharmacological activities
are an important feature of these compounds,26 and espe-
cially those which incorporate a heterocycle scaffold have
been extensively synthesized,27 in the course of looking at
improving their biological activities.28 However, synthetic
procedures leading to 4-(organoselanyl)pyrazoles are still
scarcely reported.29 For instance, Zhang, Zhong, and co-
worker described the direct selenylation of arylpyrazoles
with diaryl diselenides by using the FeBr3/I2 complex as the
catalyst in MeCN at 80 °C (Scheme 1a).29a Recently, Zora and
co-workers described the condensation reaction of ,-
alkynyl aldehydes with hydrazines, leading to ,-alkynyl
hydrazones, which were transformed in situ into 4-(phe-
nylselanyl)pyrazoles upon treatment with phenylselanyl
chloride (Scheme 1b).29b Both methods have limitations
concerning the use of halogenated species, especially for
the electrophilic phenylselanyl chloride, which demands
DOI: 10.1055/s-0037-1611747; Art ID: ss-2018-m0849-op
Abstract A simple and efficient method for the synthesis of 4-orga-
noselanyl-1H-pyrazoles has been developed, taking place under metal-
and halogen-free conditions. Electrophilic species of selenium were eas-
ily generated in situ by the reaction of diorganyl diselenides with Ox-
one® in ethanol as solvent in an open-flask at 70 °C. These electrophilic
selenium species were employed in the selenylation/cyclization of ,-
alkynyl hydrazones, giving the title compounds in moderate to excellent
yields. The final species of selenium obtained from the reaction of di-
phenyl diselenide with Oxone® were characterized by 77Se NMR spec-
troscopy and high-resolution mass spectrometry (HRMS).
Key words selenium, Oxone®, 1H-pyrazoles, cyclizations, alkynes,
hydrazones
N-Heterocyclic compounds are of particular interest in
medicinal chemistry owing to their biological properties,
playing a key role in drug discovery and development.1
Among the myriad of N-heterocycle systems, the pyrazole
ring possesses a notable presence in biologically active mol-
ecules.2–16 Pyrazole derivatives exhibit a variety of pharma-
cological activities, including antimicrobial,3 antifungal,4
analgesic,5 anti-inflammatory,6 antiviral,7 antibacterial,8
and anticancer ones.9 Additionally, the pyrazole core is
present in the structure of important commercial drugs
(e.g., celecoxib,10 tepoxalin,2c lonazolac,11 and sidenafil12)
and agrochemicals (e.g., fipronil,13 tebufenpyrad,14 penthio-
pyrad,15 and fluazolate16).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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G. Perin et al.
Paper
Synthesis
caution and attention with regard to safe handling. Another
limitation is that only phenyl- or benzylselanyl derivatives
have been used. Seeking to overcome these drawbacks, our
group reported a one-pot multicomponent approach to 4-
(organoselanyl)pyrazoles, using hydrazines, 1,3-diketones,
and diorganyl diselenides in the presence of catalytic cop-
per bromide and bipyridine (Scheme 1c). Unfortunately,
this methodology proved to be inefficient in the formation
of 1,3,5-triaryl-4-(organoselanyl)-1H-pyrazole.29c
at room temperature.34a More recently, Marini and co-
workers reported the use of Oxone® in the oxidation of vi-
nyl selenides to the corresponding selenones using water as
the solvent at 60 °C.34b Recently, some of us have showed
that Oxone® is an efficient reagent for the in situ generation
of electrophilic selenium species, which were used in the
selenomethoxylation and selenohydroxylation of nonacti-
vated alkenes, affording selectively -methoxy- and -hy-
droxy selenides, respectively.34c This strategy was extended
to the synthesis of 2-organoselanylnaphthalenes by the car-
bocyclization of alkynols in aqueous medium,34d in the di-
rect arylselenylation of imidazo[2,1-b]thiazoles, imid-
azo[1,2-a]pyridines, and 1H-pyrazoles,34e and in the syn-
thesis of diorganyl selenides by the reaction of diorganyl
diselenides with arylboronic acids using ethanol as the sol-
vent at 60 °C.34f
(a) Zhang & Zhong: Synthesis of 4-(arylselanyl)pyrazole by iron catalysis
SeAr1
NC
NC
FeBr3/I2
Ar1SeSeAr1
+
N
N
NH2
MeCN, 80 °C
32–78%
NH2
N
N
Ar
Ar
(b) Zora: Synthesis of 4-(phenylselanyl)pyrazoles from phenylselanyl chloride
SePh
Despite the recent advances in the synthesis of seleni-
um-containing pyrazoles, the current methods are not gen-
eral or green enough to allow the full exploration of the
chemistry and pharmacological behavior of this class of
compounds. As part of our ongoing interest in the develop-
ment of green protocols to access organoselenium com-
pounds,27e,28d,34,35 we herein report the first use of Oxone®
as an oxidant in the synthesis of 4-(organoselanyl)-1H-pyr-
azoles 3. This new approach is based on the selenocycliza-
tion of ,-alkynyl hydrazones 1 using electrophilic seleni-
um species generated in situ, through the reaction of di-
organyl diselenides 2 with Oxone® in ethanol (Scheme 1d).
We initiated our investigation by searching for the best
reaction conditions for the preparation of 1,3,5-triphenyl-
4-(phenylselanyl)-1H-pyrazole (3a) by using ,-alkynyl
hydrazone36 1a as nucleophilic partner and diphenyl disele-
nide (2a) as the source of the electrophile, which was gen-
erated in situ by Oxone® (Table 1). When the reaction of 1a
(0.250 mmol), 2a (0.125 mmol), and Oxone® (0.250 mmol)
was carried out in ethanol (2.0 mL) at room temperature, in
an open-air flask for 24 hours, product 3a was obtained in
only 45% yield (entry 1). To evaluate the influence of the re-
action temperature, reactions were carried out in ethanol at
50 °C, 70 °C, and under reflux (entries 2–4). Satisfactorily,
the product 3a was obtained in 88% yield after stirring at
70 °C for 4 h. Around the same yield (90%) was obtained un-
der reflux, but in both cases 1a was not completely con-
sumed. Aiming to improve the performance of the reaction,
other solvents were also evaluated, including DMSO, DMF,
PEG-400, glycerol, and water. None of them, however,
proved to be better than ethanol (entries 5–9 vs entry 3).
After fixing ethanol as the solvent and 70 °C as the reac-
tion temperature, the influence of the diphenyl diselenide
(2a) and Oxone® amounts was checked (Table 1, entries 10–
13). We started by increasing the amounts both of disele-
nide 2a (1.2 equiv) and of Oxone® (2.0 equiv) relative to 1a
and a good outcome was observed, with the title compound
3a being isolated in 95% yield after 3 hours (entry 10). Aim-
O
H
1) 80 °C, neat, 1 h
N
Ar1
N
+
Ar1
Ar
NH2
2) PhSeCl, NaHCO3
DCM or DCE, r.t.
25–95%
N
Ar
(c) Jacob & Alves: Synthesis of 4-(organoselanyl)pyrazoles by copper catalysis
R1
H
SeR
R2
CuBr (10 mol%)
bpy (10 mol%)
N
O
O
Ar
NH2
+
N
R1
R2
DMSO, 100 °C
air
42–98%
N
RSeSeR
Ar
(d) This work: Electrophilic cyclization of α,β-alkynyl hydrazones
R3
R2
SeR
HN
Oxone®
N
N
+
RSeSeR
R1
EtOH, 70 °C
open flask
40–97%
R1
N
R2
R3
1
2
3
Scheme 1 Previously reported methods for the synthesis of 4-(orga-
noselanyl)pyrazoles and our general reaction scheme
In the last years, Oxone® has been increasingly described
as a versatile, green reagent in organic synthesis.30–34 Such
versatility has been demonstrated in various transforma-
tions, such as the tandem conversion of 2-aminobenzyl-
amines into 2-substituted benzimidazoles,30a the one-pot
cascade synthesis of 2-aminobenzimidazoles and 2-amino-
benzoxazoles,30b the one-pot synthesis of -bromo ketones
and -azido ketones,30c the one-pot synthesis of diaryliodo-
nium salts,30d and the halogenation of pyrazoles,30e among
other transformations.31 Oxone® is a commercially available
triple salt (2KHSO5·KHSO4·K2SO4) containing about 50 mol%
of the active oxidant, potassium peroxymonosulfate salt
(HOOSO3K). It has advantages over other oxidants, especial-
ly regarding its stability under several conditions, simplici-
ty in handling, low toxicity, and, consequently, environ-
mental safety.32 Although Oxone® has been successfully
employed in the preparation of organosulfur compounds,33
only a few protocols on its use with selenium derivatives
have been reported so far.34 In 1995, Ceccherelli and co-
workers described the oxidation of diorganyl selenides to
the corresponding selenones by using Oxone® in methanol
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G. Perin et al.
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Synthesis
Table 1 Optimization of the Reaction Parameters for the Synthesis of
4-(Phenylselanyl)-1H-pyrazole 3a Promoted by Oxone® a
good outcomes. Diaryl diselenides containing electron-re-
leasing groups 4-Me (2b) and 4-MeO (2c) afforded the ex-
pected 4-(arylselanyl)pyrazoles 3b and 3c in 85 and 90%
yields after 5 h and 3 h of reaction, respectively (Scheme 2).
Similarly, electron-poor 4-fluoro (2d) and 4-chloro-substi-
tuted (2e) diaryl diselenides afforded the respective prod-
ucts 3d and 3e in 92 and 93% yields after 6 h and 4.5 h, re-
spectively.
When the sterically hindered dimesityl diselenide 2f
was used, the corresponding product 3f was obtained in
95% yield after 24 hours of reaction (Scheme 2). The same
time of 24 hours was required when using dibutyl disele-
nide 2g as the substrate, with the desired product 3g being
isolated in 95% yield.
The scope of the ,-alkynyl hydrazones 1b–k was next
investigated in the reaction with diphenyl diselenide (2a)
(Scheme 2). 4-Methyl-substituted ,-alkynyl hydrazone
1b (R1 = 4-MeC6H4) reacted with 2a under our conditions to
afford the expected selenylated pyrazole 3h in 92% yield af-
ter 4 hours. The presence of an electron-withdrawing sub-
stituent (R1 = 4-ClC6H4, 1c) negatively affects the reaction,
and 8 hours were necessary to afford 3i in 95% yield. The
alkyl-substituted ,-alkynyl hydrazone 1d (R1 = Bu) was
cyclized to the expected product 3j in 84% yield after 3
hours. In this case, the corresponding pyrazole without the
phenylselanyl group was obtained in 12% yield.
Ph
SePh
HN
Ph
solvent, Oxone®
N
Ph
PhSeSePh
+
Ph
N
temperature
open flask
N
2a
Ph
Ph
1a
3a
Entry
2a (mmol) Solvent
Oxone®
(mmol)
Temp
(°C)
Time
(h)
Yieldb
(%)
1
2
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.125
0.150
0.150
0.150
0.150
EtOH
EtOH
EtOH
EtOH
DMSO
DMF
0.250
0.250
0.250
0.250
0.250
0.250
0.250
0.250
0.250
0.300
0.150
0.075
0.150
25
50
70
24
8
45
76
88
90
32
38
65
47
NR
95
93
46
91c
3
4
4
reflux
4
5
70
70
70
70
70
70
70
70
70
24
24
24
24
24
3
6
7
PEG-400
glycerol
H2O
8
9
10
11
12
13
EtOH
EtOH
EtOH
EtOH
4
24
19
a Reaction conditions: 1a (0.250 mmol), 2a, Oxone®, solvent (2.0 mL),
open flask.
We also examined the influence of the R2 substituent on
,-alkynyl hydrazones 1 in the reaction (Scheme 2). Elec-
tron-rich hydrazone 1e (R2 = 4-MeOC6H4) reacted with 2a
in the presence of Oxone® to form pyrazole 3k in 85% after
4 hours. With R2 = 4-ClC6H4 (1f), the reactivity was dimin-
ished, and a longer time (8 h) was necessary to afford the
desired pyrazole 3l, which was obtained in 91% yield. Simi-
larly, when the reaction was performed with aliphatic ,-
alkynyl hydrazone 1g (R2 = Bu), the title compound 3m was
obtained in 86% yield after 5 hours. As observed in the syn-
thesis of 3j (R1 = Bu), in this case a small amount (10%) of
the non-selenylated pyrazole was obtained.
b Yield of isolated product; NR = no reaction.
c Performed under inert atmosphere of argon.
ing to increase the atom efficiency of the reaction, the
amount of Oxone® was reduced to 1.2 equiv (0.150 mmol)
and, fortunately, 1a was completely consumed after 4
hours, delivering the product 3a in 93% yield (entry 11).
Further reducing the amount of the oxidant, however,
caused a drastic drop in the yield of 3a, even after a pro-
longed reaction time (entry 12). The use of an inert atmo-
sphere of argon was also examined, but a remarkable in-
crease in the reaction time was necessary, indicating that
the oxygen in the air positively impacts the reaction (entry 13).
With the optimized reaction conditions in hands (Table
1, entry 11), we proceeded to explore the generality of this
approach for the synthesis of various substituted 4-(orga-
noselanyl)-1H-pyrazoles 3 (Scheme 2). The reactivity of a
variety of ,-alkynyl hydrazones 1a–k toward a range of
selenium electrophilic species, generated in situ from dior-
ganyl diselenides 2a–g and Oxone®, was examined. In gen-
eral, our method proved to be efficient and robust, afford-
ing the corresponding 4-(organoselanyl)-1H-pyrazoles 3a–
q in moderate to excellent yields (40–97%). First, the reac-
tion scope of ,-alkynyl hydrazone 1a with different diaryl
diselenides 2b–f was evaluated. From the recorded yields, it
can be noted that the reaction is not sensitive to electronic
effects in the aromatic ring of the diselenide 2, with elec-
tron-rich and electron-poor diselenides affording equally
Finally, the scope of the R3 substituent in the ,-alkynyl
hydrazone 1 was evaluated (Scheme 2). In this case, our re-
sults revealed that the presence of substituents on the phe-
nyl ring of R3 causes an increase in the required reaction
time. Additionally, the reaction is sensitive to the nature of
the attached substituents. For example, ,-alkynyl hydra-
zone 1k (R3 = 2,4-F2C6H3) afforded the corresponding 4-
(phenylselanyl)-1H-pyrazole 3q in only 40% yield after 24
hours. This outcome contrasts with those observed when
electron-rich ,-alkynyl hydrazones 1h–j (R3 = 3-MeC6H4,
4-MeOC6H4 and 2,4-Me2C6H3) were used as substrates,
which gave the respective 4-(phenylselanyl)-1H-pyrazoles
3n–p in 97, 86, and 97% yields, after 8–12 hours of reaction
(Scheme 2).
The gram-scale synthesis of 1,3,5-triphenyl-4-(phe-
nylselanyl)-1H-pyrazole 3a demonstrated the robustness of
the method (Scheme 3). A mixture of ,-alkynyl hydra-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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G. Perin et al.
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Synthesis
zone 1a (5.0 mmol, 1.48 g), diphenyl diselenide (2a; 3.0
mmol, 0.942 g), and Oxone® (3.0 mmol, 0.921 g) was stirred
in ethanol (40.0 mL) at 70 °C for 4 hours. Product 3a was
isolated in 84% yield (4.2 mmol, 1.89 g). The method proved
to be efficient in obtaining the product of interest 3a, with a
small decrease in yield on a 20-fold scale-up.
R3
HN
SeR
R1
Oxone®
N
R2
RSeSeR
+
R1
N
ethanol, 70 °C
open flask
N
R3
R2
1a–k
2a–g
3a–q
O
Se
N
Se
Se
N
N
N
N
N
3a, 4 h (93%)
3b, 5 h (85%)
3c, 3 h (90%)
Cl
F
Se
Se
Se
N
N
N
N
N
N
3d, 6 h (92%)
3e, 4.5 h (87%)
3f, 24 h (95%)
Cl
Se
Se
Se
N
N
N
N
N
N
3g, 24 h (95%)
3h, 4 h (92%)
3i, 8 h (95%)
Se
Se
Se
N
O
Cl
N
N
N
N
N
3j, 3 h (84%)
3k, 4 h (85%)
3l, 8 h (91%)
Se
Se
Se
N
N
N
N
N
N
3m, 5 h (86%)
3n, 11 h (97%)
3o, 12 h (86%)
O
Se
Se
N
N
N
N
F
3p, 8 h (97%)
3q, 24 h (40%)
F
Scheme 2 Substrate scope for the synthesis of 4-(organoselanyl)-1H-pyrazoles 3a–q promoted by Oxone®. Reagents and conditions: 1 (0.250 mmol), 2
(0.150 mmol), Oxone® (0.150 mmol), EtOH (2.0 mL), open flask, 70 °C; yields are of isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

E
G. Perin et al.
Paper
Synthesis
ture of diphenyl diselenide (2a) (1.0 equiv) and Oxone® (1.0
equiv) was stirred at 70 °C in methanol-d4, and the 77Se
NMR experiment was immediately performed. The spec-
trum contained a signal at  = 1218 (Figure 1, spectrum A),
and a signal at  = 463 (diphenyl diselenide; 2a; not shown).
According to the literature, this new signal at  = 1218 can
be attributed to methyl benzeneseleninate (5) (Lit.37  =
1216). To confirm this hypothesis, further 77Se NMR spectra
(DMSO-d6) were recorded (Figure 1, spectra B and C). The
Ph
N
SePh
N
HN
Ph
Oxone® (3.0 mmol)
Ph
Ph
+
PhSeSePh
2a
N
EtOH, 70 °C
open flask
Ph
Ph
1a
3a
5.0 mmol
3.0 mmol
84% isolated yield
Scheme 3 Gram-scale synthesis of 1,3,5-triphenyl-4-(phenylselanyl)-
1H-pyrazole (3a) under the optimized conditions
To gain some understanding of the reaction mechanism,
some control experiments were conducted, including 77Se
NMR and HRMS analyses to identify the intermediate(s) in-
volved in the reaction. Initially, we examined the role of Ox-
one® in the reaction. When a mixture of ,-alkynyl hydra-
zone 1a and diphenyl diselenide (2a) was stirred in ethanol
at 70 °C in the absence of Oxone®, no product 3a was
formed. To verify which of the three ingredients of Oxone®
is acting in the formation of the electrophilic selenium spe-
cies, two experiments using potassium bisulfate (KHSO4)
and potassium sulfate (K2SO4) instead of Oxone® were per-
formed. In both experiments, the title product 3a was not
detected, indicating that potassium peroxymonosulfate salt
(HOOSO3K) is crucial in this reaction. Next, radical scaven-
gers 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and ben-
zo-1,4-quinone (BQ) were added to the reaction mixture
under the standard conditions; the expected product 3a
was obtained in 71 and 65% yield, respectively (Scheme 4a).
These outcomes suggest that most of the reaction pathway
does not involve free-radical intermediates. Moreover,
when the reaction was performed in the absence of diphe-
nyl diselenide (2a), only trace amounts of the expected
1,3,5-triphenyl-1H-pyrazole 4 was detected (Scheme 4b).
This find reveals that the C–Se bond formation does not oc-
cur after the ring closure step, and that 4 is not an interme-
diate in this reaction.
PhSeSePh and Oxone® in methanol-d4
(A)
O
Se
5
Ph
OMe
(B)
Benzeseleninic acid in DMSO-d6
O
Se
6
Ph
OH
Benzeseleninic acid after addition of
(C)
MeOH in DMSO-d6
O
Se
5
Ph
OMe
Ph
SePh
HN
Oxone®
Ph
N
+
PhSeSePh
Ph
(a)
Ph
EtOH, 70°C
open flask
radical scavenger
(3 equiv)
N
N
Ph
Ph
1a
2a
3a
(D)
PhSeSePh and Oxone® after addition
of H2O in methanol-d4
radical scavenger: I) TEMPO: 71%
II) BQ: 65%
Ph
N
O
O
Ph
HN
Se
5
Se
6
Ph
Oxone®
(b)
Ph
OMe
Ph
OH
N
N
Ph
EtOH, 70 °C
open flask
Ph
4
Ph
1a
traces
(recovery of 1a, 96%)
Scheme 4 Control experiments: (a) reaction of ,-alkynyl hydrazone
1a with diphenyl diselenide (2a); (b) reaction of ,-alkynyl hydrazone
1a with Oxone®
Figure 1 77Se NMR experiments of oxidized forms of diphenyl disele-
nide (2a): blue spectrum (A): diphenyl diselenide (2a) and Oxone® in
methanol-d4; green spectrum (B): benzeneseleninic acid in DMSO-d6;
purple spectrum (C): benzeneseleninic acid after MeOH addition in
DMSO-d6; orange spectrum (D): diphenyl diselenide (2a) and Oxone®
after addition of H2O in methanol-d4.
Our next endeavor was the determination of the identi-
ty of the electrophilic species formed by the reaction of di-
organyl diselenide 2 with Oxone®. To this purpose, a mix-
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77Se NMR spectrum of benzeneseleninic acid (PhSeO2H)
presented a signal at  = 1160, which is in agreement with
the literature.23b Subsequently, methanol was added to the
tube, and a new signal was observed at  = 1210, corre-
sponding to methyl benzeneseleninate (5). The selenoester
5 was originally proposed by Henriksen and Stuhr-Hansen
to be the product of the reaction of benzeneseleninic acid
(6) with methanol.37 Therefore, when the analysis was car-
ried out in DMSO-d6, benzeneseleninic acid (6) is the main
species in the solution, while the addition of methanol re-
sults in the replacement of the hydroxy for a methoxy
group. The variation in the 77Se chemical shifts observed for
methyl benzeneseleninate (5) and benzeneseleninic acid
(6), formed by the reaction with Oxone®, is probably due to
the acidic medium produced by the Oxone® reagent and the
solvent effect (Figure 1, spectrum A vs C).
Aiming to confirm the role of the solvent in the electro-
philic selenium identity, water was added to the metahnol-
d4 solution of (PhSe)2/Oxone®. As a result, a second signal at
 = 1172 appeared in the 77Se NMR spectrum (Figure 1,
spectrum D). This outcome corroborates that a chemical
equilibrium between the oxidized forms of the electrophilic
selenium species is developing. In addition, not all of the di-
phenyl diselenide (2a) was consumed by Oxone®, indicating
its participation in the chemical equilibrium. To speculate
about the influence of the acidic medium in the formation
of methyl benzeneseleninate (5), an excess of KHSO4 was
added. However, no change in the 77Se chemical shift was
observed (Supporting Information, Figure 59S:  = 1214).
When p-toluenesulfonic acid was added in excess, the 77Se
chemical shift moved to a higher field (Supporting Informa-
tion, Figure 60S:  = 1201).
We also investigated the nature of the intermediates
through high-resolution mass spectrometry (HRMS) analy-
sis. Initially, an aliquot of a pre-stirred (for 10 min) mixture
of diphenyl diselenide (2a) and Oxone® in ethanol was solu-
bilized in acetonitrile and immediately injected in an AP-
CI(+) source. A cationized ion with m/z = 190.9610 was de-
tected along with diphenyl diselenide (2a) ion at m/z =
313.9126. The accurate mass and isotopic pattern of the ion
with m/z = 190.9611 suggest the formula C6H7O2Se, which
corresponds to the benzeneseleninic acid (6) [M + H]+ ion.
Along with the benzeneseleninic acid peak, the ethyl selen-
inate intermediate is also observed, showing a peak with
m/z = 218.9921 [M + H]+. Interestingly, when the aliquot
was solubilized in methanol, the most intense ion showed
in the spectrum has an m/z of 204.9769 [M + H]+, which cor-
responds to the methyl benzeneseleninate intermediate 5.
These results are in agreement with those revealed by
the 77Se NMR spectroscopy, in which the solvent has an im-
portant participation in the chemical equilibrium of the ox-
idized forms of the electrophilic selenium species.
and Oxone® in ethanol. Aliquots were taken and directly in-
jected in the APCI source. However, only the ion attributed
to the product 3a was detected.
As observed from the 77Se NMR and HRMS experiments,
benzeneseleninic acid 6 is formed in the reaction between
(PhSe)2 (2a) and Oxone®. In the presence of ethanol, 6 is
converted into ethyl benzeneseleninate.
Finally, to give support to the active electrophilic spe-
cies, benzeneseleninic acid (6) was directly used as the elec-
trophilic selenium partner in the reaction with ,-alkynyl
hydrazone 1a in EtOH at 70 °C. In spite of the longer reac-
tion time (26 h), the expected product 3a was obtained in
92% yield (Scheme 5a). In an attempt to collect additional
evidence on the pathway to obtain the selenide 3a from
PhSeSePh/Oxone® and ,-alkynyl hydrazone 1a, the sele-
noxide 7, a possible intermediate in the reaction described
above,38 was prepared39 and used as starting material in the
reaction with Oxone® (1.0 equiv) or KHSO4 (1.0 equiv) un-
der our standard conditions for 4 hours (Scheme 5b and c).
In both experiments, selenoxide 7 remained intact, thus
eliminating the possibility of it being an intermediate in the
reaction.
Ph
SePh
HN
O
Ph
N
EtOH, 70 °C
Ph
Se
+
Ph
OH
Ph
N
26 h
N
(a)
(b)
(c)
Ph
open flask
Ph
1a
6
3a, 92%
O
SePh
SePh
N
Ph
Oxone®
Ph
Ph
Ph
N
N
EtOH, 70 °C
open flask
N
Ph
3a
Ph
7
KHSO4
3a
7
as above
Scheme 5 Control experiments: (a) reaction of benzeneseleninic acid
(6) with 1a; (b) reaction of selenoxide 7 with Oxone®; (c) reaction of 7
with KHSO4
On the basis of the control experiments and the collect-
ed data in the 77Se NMR and HRMS analyses, we suggest the
following mechanism for the reaction of 1a with 2a
(Scheme 6). Firstly, a SET from diphenyl diselenide (2a) to
–
HSO5 , followed by the Se–Se bond cleavage, affords the
–
strong electrophilic selenium species PhSeOSO3 (I) and
PhSeOH (II). These are most probably the active electro-
philes in the reaction with hydrazone 1. These reactive spe-
cies are similar to those proposed by Tieco, in the oxidation
of diselenides with ammonium persulfate.40 The electro-
philes I and II, in the presence of methanol and Oxone® (an
oxidizing environment) can be transformed into benzene-
seleninic acid (6) and methyl benzeneseleninate (5 when R
= Me), which were detected in the NMR and HRMS experi-
ments. Once formed, both electrophiles can react with ,-
In an attempt to detect the possible intermediates in-
volved in the selenylation step, ,-alkynyl hydrazone 1a
was added to the initial mixture of diphenyl diselenide (2a)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

G
G. Perin et al.
Paper
Synthesis
–
alkynyl hydrazone 1 to give, after elimination of HSO4
creased understanding of the reactivity and can help to
broaden the use of this environmentally friendly oxidant to
generate electrophilic selenium species in organic synthesis.
(from the reaction with I) or water (from the reaction with
the protonated species III). In the cyclization step, the R3
substituent of ,-alkynyl hydrazone 1 has a strong influ-
ence on the reaction; the electron-poor ,-alkynyl hydra-
zone 1k (R3 = 2,4-F2C6H3) showed to be less reactive, giving
only 40% yield of the expected product 3q after 24 hours of
reaction (Scheme 2). Even if this proposal does not clarify
what happens in the control reaction showed in Scheme 5a,
using benzeneseleninic acid (6) as starting material, we be-
lieve that it is a plausible mechanism, which presents new
insights into this unprecedented reaction.
The reactions were monitored by TLC carried out on Merck silica gel
(60 F254) by using UV light as visualizing agent and 5% vanillin in 10%
H2SO4 and heat as developing agents. Baker silica gel (particle size
0.040–0.063 mm) was used for flash chromatography. 1H NMR spec-
tra were obtained on Bruker Ascend 400 and Bruker Fourier 300 spec-
trometers at 400 MHz and 300 MHz, respectively. Spectra were re-
corded of samples in CDCl3 solutions. Chemical shifts are referenced
to tetramethylsilane (TMS) as the external reference. 13C NMR spectra
were obtained on Bruker Ascend 400 and Bruker Fourier 300 spec-
trometers at 100 MHz and 75 MHz, respectively. Chemical shifts are
referenced to the solvent peak of CDCl3. 77Se NMR spectra were ob-
tained on a Bruker Avance III HD 400 MHz instrument by employing a
direct broadband probe. Chemical shifts are referenced to diphenyl
diselenide ( = 463). The pulse sequence used was gated decoupling.
The acquisition parameters for the 77Se NMR experiments were 32 K
of complex points, spectral window between  = 300–1300 ppm, re-
laxation delay of 1 s, and around 1024 scans. Low-resolution mass
spectra (MS) were obtained with a Shimadzu GC-MS-QP2010 mass
spectrometer. The high-resolution electrospray ionization mass spec-
trometry (QTOF) analyses were performed on a Bruker Daltonics mi-
crOTOF-Q II instrument operating in positive mode. The samples
were solubilized in HPLC-grade acetonitrile and injected into the APCI
source by means of a syringe pump at a flow rate of 5.0 L·min–1. The
following instrument parameters were applied: capillary and cone
voltages were set to +3500 V and –500 V, respectively, with a desolva-
tion temperature of 180 °C. For data acquisition, processing and iso-
tope simulations, Compass 1.3 for micrOTOF-Q II software (Bruker
daltonics, USA) was used. Melting point values were measured in a
Marte PFD III instrument with a 0.1 °C precision. Oxone® was pur-
chased from Sigma Aldrich.
Generation of the electrophile:
–
PhSe
OSO3
OH
+
PhSe
2a
from Oxone®
+
–
PhSe
PhSe
PhSe OSO3
–2
OH SO4
+
+
–
PhSeOSO3
+ PhSeOH
PhSe
–
OH
I
II
Oxone®
ROH
–
PhSeOSO3
PhSeOR
O
O
O
H2O
I
Se
Se
Ph
OR
+
Ph
OH
Oxone®
6
5: R = Me
ROH
Se
PhSeOH
6: R = Et
Ph
OH
II
6
detected by 77Se NMR: (R = Me; δ ≈ 1218 ppm)
(R = Me; m/z = 204.9763 [M+H]+)
detected by HRMS:
(R = Et; m/z = 218.9920 [M+H]+)
Cyclization:
–
–
Ph
PhSe OSO3
– HSO4
I
SePh
N
77Se NMR Experiments; General Procedure
Ph
H
N
To a 10 mL round-bottomed glass vial, 2a (0.1 mmol) and Oxone® (0.2
mmol) were added in the appropriate deuterated solvent (1.0 mL).
The resulting mixture was stirred for 10 min at 70 °C. After that, a
sample of 0.5 mL was transferred to the NMR tube for the 77Se NMR
experiments.
Ph
Ph
N
Ph
H+
N
1a
Ph
3a
+
OH2
– H2O
PhSe
OH
PhSe
III
II
Scheme 6 Proposed mechanism for the synthesis of 4-(organose-
lanyl)-1H-pyrazole 3a promoted by Oxone®
Mechanistic Studies: Monitoring Short-Live Intermediates by
HRMS
For mechanistic investigation, the short-lived intermediates were as-
sessed by HRMS analysis through aliquots which were taken directly
from the reaction experiments and immediately solubilized with
MeCN or MeOH and injected into the APCI source at a constant flow
rate of 3.0 L/min. The presence of a selenium atom in the intermedi-
ates was confirmed by the characteristic isotopic pattern of selenium
showing six stable and abundant isotopes. The peaks attributed to the
intermediates were better detected using the APCI source.
In conclusion, a simple and general metal-free and halo-
gen-free approach to prepare 4-organoselanyl-1H-pyra-
zoles via electrophilic cyclization of ,-alkynyl hydrazones
was developed. The electrophilic selenium species were
generated in situ by the reaction of diorganyl diselenides
with Oxone® in ethanol as the solvent, at 70 °C in an open
flask. Eco-friendly conditions, broad substrate scope, and
excellent atom-efficiency make this protocol synthetically
useful to obtain 4-organoselanyl-1H-pyrazoles. The final
products of the reaction of PhSeSePh with Oxone® were
identified by 77Se NMR spectroscopy and HRMS, and an
equilibrium between the oxidized forms of selenium was
observed. The outcomes described here contribute to an in-
4-Organoselanyl-1H-pyrazoles 3; General Procedure
To a 10 mL round-bottomed glass vial the appropriate ,-alkynyl hy-
drazone36 1a–k (0.25 mmol), diorganyl diselenide 2a–g (0.15 mmol),
EtOH (2.0 mL), and Oxone® (0.046 g; 0.15 mmol) were added. The re-
sulting mixture was stirred for the time indicated in Scheme 2 at
70 °C in an open flask. The reactions were monitored by TLC until to-
tal disappearance of the starting materials. After that, the reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

H
G. Perin et al.
Paper
Synthesis
mixture was added to H2O (50.0 mL), extracted with EtOAc (3 × 15.0
mL), dried over MgSO4, and concentrated under vacuum. The residue
was purified by column chromatography [silica gel 60A (0.060–0.200
mm, Across), hexane–EtOAc, 97:3].
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C27H19FN2OSe: 471.0776;
found: 471.0773.
4-[(4-Chlorophenyl)selanyl]-1,3,5-triphenyl-1H-pyrazole (3e)
Yield: 0.106 g (87%); yellowish solid; mp 164–168 °C.
1H NMR (400 MHz, CDCl3):  = 7.89–7.87 (m, 2 H), 7.32–7.17 (m, 11
H), 7.10–7.08 (m, 2 H), 7.04–6.99 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 154.8, 148.4, 139.7, 132.6, 132.2,
131.9, 130.3, 129.9, 129.8, 129.2, 128.9, 128.8, 128.4, 128.3, 128.24,
128.2, 127.5, 124.9, 101.4.
MS: m/z (%) = 486 (57.6) [M+], 406 (100.0), 267 (21.7), 180 (61.9), 77
(84.5), 51 (20.2).
1,3,5-Triphenyl-4-(phenylselanyl)-1H-pyrazole (3a)
Yield: 0.105 g (93%); yellowish solid; mp 127–129 °C.
1H NMR (400 MHz, CDCl3):  = 7.99–7.97 (m, 2 H), 7.39–7.10 (m, 18
H).
13C NMR (100 MHz, CDCl3):  = 154.9, 148.4, 139.9, 134.1, 132.7,
130.3, 129.9, 129.1, 128.8, 128.76, 128.6, 128.4, 128.2, 128.15, 128.1,
127.4, 125.8, 124.9, 101.7.
77Se NMR (76 MHz, CDCl3):  = 233.5.
MS: m/z (%) = 452 (24.3) [M+], 372 (50.0), 268 (10.2), 180 (35.3), 165
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C27H19ClN2OSe: 487.0480;
found: 487.0483.
(15.4), 77 (100.0), 51 (35.5).
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C27H20N2Se: 453.0870;
4-(Mesitylselanyl)-1,3,5-triphenyl-1H-pyrazole (3f)
found: 453.0870.
Yield: 0.118 g (95%); white solid; mp 138–141 °C.
1H NMR (400 MHz, CDCl3):  = 7.82–7.81 (m, 2 H), 7.38–7.37 (m, 3 H),
7.23–7.18 (m, 8 H), 7.00–6.97 (m, 2 H), 6.59 (s, 2 H), 2.12 (s, 3 H), 1.96
(s, 6 H).
1,3,5-Triphenyl-4-(4-tolylselanyl)-1H-pyrazole (3b)
Yield: 0.099 g (85%); white solid; mp 158–160 °C.
1H NMR (400 MHz, CDCl3):  = 8.00–7.98 (m, 2 H), 7.39–7.19 (m, 13
H), 7.07 (d, J = 8.0 Hz, 2 H), 6.96 (d, J = 8.0 Hz, 2 H), 2.24 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 154.9, 148.3, 139.9, 135.6, 132.8,
130.4, 130.2, 130.0, 129.9, 128.8, 128.7, 128.4, 128.2, 128.13, 128.1,
127.4, 124.9, 102.0, 20.9.
13C NMR (100 MHz, CDCl3):  = 154.5, 146.2, 141.5, 139.9, 137.2,
133.3, 130.5, 130.3, 128.4, 128.7, 128.6, 128.4, 128.3, 127.93, 127.9,
127.1, 124.6, 104.8, 23.7, 20.7.
MS: m/z (%) = 494 (73.3) [M+], 296 (100.0), 198 (81.8), 91 (16.7), 77
(62.9), 51 (11.8).
77Se NMR (76 MHz, CDCl3):  = 226.0.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C30H26N2Se: 495.1339;
found: 495.1341.
MS: m/z (%) = 466 (52.4) [M+], 386 (100.0), 267 (9.2), 193 (10.3), 180
(26.4), 91 (4.8), 77 (28.0), 51 (4.6).
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2Se: 467.1026;
found: 467.1017.
4-(Butylselanyl)-1,3,5-triphenyl-1H-pyrazole (3g)
Yield: 0.103 g (95%); white solid; mp 125–126 °C.
1H NMR (400 MHz, CDCl3):  = 8.12–8.01 (m, 2 H), 7.46–7.43 (m, 2 H),
7.39–7.20 (m, 11 H), 2.37 (t, J = 7.4 Hz, 2 H), 1.28 (quin, J = 7.4 Hz, 2 H),
1.08 (sext, J = 7.4 Hz, 2 H), 0.65 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 154.1, 147.1, 139.9, 133.3, 130.6,
130.4, 128.7, 128.6, 128.4, 128.13, 128.1, 128.0, 127.1, 124.8, 102.5,
31.5, 29.0, 22.3, 13.3.
MS: m/z (%) = 432 (54.2) [M+], 376 (20.0), 296 (100.0), 193 (39.1), 180
(44.6), 77 (63.5), 57 (3.4), 51 (14.0).
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C25H24N2Se: 433.1183;
found: 433.1187.
4-[(4-Methoxyphenyl)selanyl]-1,3,5-triphenyl-1H-pyrazole (3c)
Yield: 0.108 g (90%); white solid; mp 143–147 °C.
1H NMR (400 MHz, CDCl3):  = 7.93–7.91 (m, 2 H), 7.33–7.11 (m, 13
H), 6.99 (d, J = 8.8 Hz, 2 H), 6.60 (d, J = 8.8 Hz, 2 H), 3.62 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 158.4, 154.7, 148.0, 139.9, 132.9,
131.3, 130.5, 130.1, 128.74, 128.73, 128.5, 128.2, 128.13, 128.1, 127.3,
124.9, 123.6, 114.8, 103.1, 55.2.
77Se NMR (76 MHz, CDCl3):  = 218.9.
MS: m/z (%) = 482 (39.8) [M+], 402 (100.0), 201 (3.7), 77 (7.6), 51 (6.2).
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2OSe: 483.0976;
found: 483.0976.
1,3-Diphenyl-4-(phenylselanyl)-5-(4-tolyl)-1H-pyrazole (3h)
Yield: 0.107 g (92%); white solid; mp 133–134 °C.
1H NMR (400 MHz, CDCl3):  = 7.79 (d, J = 8.2 Hz, 2 H), 7.26–7.02 (m,
17 H), 2.26 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 155.0, 148.4, 139.9, 138.0, 134.3,
130.3, 130.0, 129.9, 129.1, 128.9, 128.7, 128.5, 128.2, 128.1, 127.4,
125.7, 124.9, 101.5, 21.3.
77Se NMR (76 MHz, CDCl3):  = 233.9.
MS: m/z (%) = 466 (51.7) [M+], 386 (100.0), 193 (14.2), 180 (41.8), 165
(10.4), 91 (3.9), 77 (36.4), 51 (6.6).
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2Se: 467.1026;
4-[(4-Fluorophenyl)selanyl]-1,3,5-triphenyl-1H-pyrazole (3d)
Yield: 0.108 g (92%); yellowish solid; mp 129–130 °C.
1H NMR (400 MHz, CDCl3):  = 7.98–7.95 (m, 2 H), 7.39–7.26 (m, 11
H), 7.23–7.17 (m, 2 H), 7.13–7.08 (m, 2 H), 6.84 (t, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 161.6 (d, J = 243.7 Hz), 154.7, 148.1,
139.7, 132.6, 130.9 (d, J = 7.6 Hz), 130.3, 129.8, 128.9, 128.8, 128.4,
128.3, 128.2, 128.17, 128.0 (d, J = 3.1 Hz), 127.5, 124.8, 116.2 (d, J =
21.5 Hz), 102.3.
77Se NMR (76 MHz, CDCl3):  = 229.8.
MS: m/z (%) = 470 (62.2) [M+], 390 (100.0), 285 (8.2), 180 (42.0), 77
found: 467.1022.
(41.5), 51 (8.3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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G. Perin et al.
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Synthesis
5-(4-Chlorophenyl)-1,3-diphenyl-4-(phenylselanyl)-1H-pyrazole
3-Butyl-1,5-diphenyl-4-(phenylselanyl)-1H-pyrazole (3m)
(3i)
Yield: 0.093 g (86%); yellowish solid; mp 63–66 °C.
Yield: 0.115 g (95%); white solid; mp 142–141 °C.
1H NMR (400 MHz, CDCl3):  = 7.87 (d, J = 8.6 Hz, 2 H), 7.26–7.01 (m,
17 H).
1H NMR (400 MHz, CDCl3):  = 7.85 (d, J = 7.1 Hz, 2 H), 7.45–7.02 (m,
13 H), 2.73 (t, J = 7.6 Hz, 2 H), 1.29 (quin, J = 7.6 Hz, 2 H), 1.08 (sext, J =
7.6 Hz, 2 H), 0.63 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 153.6, 148.6, 139.7, 134.2, 133.7,
131.3, 130.3, 129.7, 129.6, 129.2, 128.9, 128.8, 128.5, 128.3, 128.2,
127.6, 125.9, 124.9, 101.6.
13C NMR (100 MHz, CDCl3):  = 154.3, 150.0, 140.0, 133.9, 132.9,
129.2, 129.1, 128.4, 128.13, 128.1, 128.0, 125.7, 99.7, 31.2, 25.5, 22.3,
13.4.
77Se NMR (76 MHz, CDCl3):  = 233.1.
MS: m/z (%) = 432 (74.4) [M+], 351 (26.4), 310 (33.6), 275 (26.4), 233
(100.0), 160 (33.9), 130 (21.2), 91 (44.7), 77 (46.8), 51.7.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C25H24N2Se: 433.1183;
MS: m/z (%) = 486 (63.0) [M+], 406 (100.0), 180 (26.3), 165 (13.0), 77
(46.2), 51 (10.7).
found: 433.1178.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C27H19ClN2Se: 487.0480;
found: 487.0476.
3,5-Diphenyl-4-(phenylselanyl)-1-(3-tolyl)-1H-pyrazole (3n)
Yield: 0.113 g (97%); white solid; mp 116–117 °C.
5-Butyl-1,3-diphenyl-4-(phenylselanyl)-1H-pyrazole (3j)
Yield: 0.091 g (84%); white solid; mp 62–63 °C.
1H NMR (400 MHz, CDCl3):  = 7.98–7.96 (m, 2 H), 7.39–7.10 (m, 15
H), 7.06 (d, J = 7.6 Hz, 1 H), 6.99 (d, J = 7.6 Hz, 1 H), 2.30 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 154.9, 148.4, 139.8, 138.9, 134.1,
132.8, 130.3, 130.0, 129.1, 128.7, 128.5, 128.4, 128.23, 128.2, 128.1,
125.8, 125.6, 122.0, 101.5, 21.3.
77Se NMR (76 MHz, CDCl3):  = 233.3.
MS: m/z (%) = 466 (65.6) [M+], 386 (100.0), 194 (42.0), 91 (33.4), 77
1H NMR (400 MHz, CDCl3):  = 7.29–7.12 (m, 15 H), 2.76 (t, J = 7.3 Hz,
2 H), 1.69 (quin, J = 7.3 Hz, 2 H), 1.39 (sext, J = 7.3 Hz, 2 H), 0.88 (t, J =
7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.8, 146.9, 140.0, 133.7, 130.2,
130.1, 129.0, 128.7, 128.6, 128.56, 128.1, 127.1, 125.7, 124.8, 102.9,
31.5, 27.4, 22.7, 13.8.
77Se NMR (76 MHz, CDCl3):  = 210.3.
(8.2), 51 (4.2).
MS: m/z (%) = 432 (74.1) [M+], 390 (96.8), 351 (21.7), 309 (28.0), 193
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2Se: 467.1026;
(47.5), 180 (83.1), 91 (43.7), 77 (100.0), 51 (17.5).
found: 467.1023.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C22H24N2Se: 433.1183;
found: 433.1178.
1-(4-Methoxyphenyl)-3,5-diphenyl-4-(phenylselanyl)-1H-pyra-
zole (3o)
Yield: 0.104 g (86%); yellowish solid; mp 116–120 °C.
3-(4-Methoxyphenyl)-1,5-diphenyl-4-(phenylselanyl)-1H-pyra-
1H NMR (400 MHz, CDCl3):  = 7.96 (d, J = 6.8 Hz, 2 H), 7.38–7.08 (m,
15 H), 6.80 (d, J = 8.9 Hz, 2 H), 3.76 (s, 3 H).
zole (3k)
Yield: 0.102 g (85%); yellowish oil.
1H NMR (400 MHz, CDCl3):  = 7.98 (d, J = 7.2 Hz, 2 H), 7.35–7.09 (m,
15 H), 6.75 (d, J = 8.6 Hz, 2 H), 3.69 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 159.8, 154.8, 148.3, 139.9, 134.2,
132.8, 131.5, 129.1, 128.7, 128.3, 128.26, 128.1, 128.0, 127.3, 125.7,
124.8, 121.9, 113.6, 101.3, 55.0.
13C NMR (100 MHz, CDCl3):  = 158.7, 154.6, 148.3, 134.2, 133.1,
132.8, 130.3, 129.9, 129.1, 128.7, 128.5, 128.4, 128.2, 128.1, 126.3,
125.7, 113.9, 101.0, 55.4.
77Se NMR (76 MHz, CDCl3):  = 233. 6.
MS: m/z (%) = 482 (53.8) [M+], 402 (100.0), 210 (23.3), 77 (23.2), 51
77Se NMR (76 MHz, CDCl3):  = 233.9
(4.0).
MS: m/z (%) = 482 (49.7) [M+], 402 (100.0), 325 (3.3), 210 (27.7), 77
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2OSe: 483.0976;
(31.0), 51 (8.3).
found: 483.0970.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C28H22N2OSe: 483.0976;
found: 483.0972.
1-(2,4-Dimethylphenyl)-3,5-diphenyl-4-(phenylselanyl)-1H-pyra-
zole (3p)
Yield: 0.116 g (97%); yellowish solid; mp 59–61 °C.
3-(4-Chlorophenyl)-1,5-diphenyl-4-(phenylselanyl)-1H-pyrazole
1H NMR (400 MHz, CDCl3):  = 7.98–7.96 (m, 2 H), 7.36–7.09 (m, 14
(3l)
Yield: 0.111 g (91%); yellowish solid; mp 136–137 °C.
H), 6.98–6.95 (m, 2 H), 2.28 (s, 3 H), 2.02 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.90–7.87 (m, 2 H), 7.31–7.15 (m, 10
H), 7.09–7.02 (m, 7 H).
13C NMR (100 MHz, CDCl3):  = 155.1, 147.1, 139.6, 135.0, 133.8,
132.6, 131.6, 129.2, 128.9, 128.5, 128.3, 128.2, 127.7, 125.9, 124.9,
101.9.
13C NMR (100 MHz, CDCl3):  = 154.6, 149.8, 138.9, 136.6, 134.9,
134.5, 132.9, 131.5, 130.0, 129.5, 129.2, 128.6, 128.3, 128.1, 128.05,
127.8, 127.0, 125.6, 99.3, 21.1, 17.6.
77Se NMR (76 MHz, CDCl3):  = 234.7.
MS: m/z (%) = 480 (100.0) [M+], 399 (83.4), 385 (32.2), 323 (21.0), 208
77Se NMR (76 MHz, CDCl3):  = 233.4.
(39.5), 105 (12.1), 91 (4.9), 77 (28.6), 51 (5.4).
MS: m/z (%) = 486 (71.4) [M+], 406 (100.0), 214 (46.9), 77 (64.2), 51
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C29H24N2Se: 481.1183;
(13.9).
found: 481.1173.
HRMS (APCI-QTOF): m/z [M + H]+ calcd for C27H19ClN2Se: 487.0480;
found: 487.0476.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

J
G. Perin et al.
Paper
Synthesis
1-(2,4-Difluorophenyl)-3,5-diphenyl-4-(phenylselanyl)-1H-pyra-
zole (3q)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611747.
Yield: 0.049 g (40%); yellowish solid; mp 100–101 °C.
1H NMR (400 MHz, CDCl3):  = 7.94–7.92 (m, 2 H), 7.55–7.49 (m, 1 H),
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7.39–7.10 (m, 13 H), 6.95–6.90 (m, 1 H), 6.82–6.77 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 162.7 (dd, J = 250.3, 10.7 Hz), 156 (dd,
J = 254.1, 12.5 Hz), 155.7, 150.7, 133.9, 132.5, 130.0 (d, J = 10.2 Hz),
129.7, 129.2, 129.1, 129.0, 128.5, 128.42, 128.4, 128.2, 128.1, 125.9,
124.6 (dd, J = 12.3, 4.2 Hz), 111.8 (dd, J = 22.5, 4.0 Hz), 104.9 (dd, J =
26.2, 23.4 Hz), 100.9.
References
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Selenoxide 739
To a 10 mL round-bottomed flask containing a solution of pyrazole 3a
(0.25 mmol) in DCM (2.0 mL) at 0 °C under stirring, a solution of m-
CPBA (0.55 mmol, 2.2 equiv) in DCM (2 mL) was added. After stirring
for 1.5 h, the mixture was quenched with a saturated aq Na2SO3 solu-
tion (10 mL) and diluted with DCM. The organic layer was separated,
washed with a saturated aq NaHCO3 solution (10 mL), dried over Mg-
SO4, and filtered, and the solvent was evaporated under vacuum. After
that, the crude reaction mixture was purified by chromatography [sil-
ica gel 60A (0.060–0.200 mm, Acros), hexane–EtOAc, 50:50].
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1,3,5-Triphenyl-4-(phenylseleninyl)-1H-pyrazole
Yield: 0.897 g (78%); white solid; mp 188–190 °C.
1H NMR (400 MHz, CDCl3):  = 7.86 (dd, J = 7.8, 1.4 Hz, 2 H), 7.37–7.24
(m, 15 H), 7.14–7.10 (m, 3 H).
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Funding Information
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The authors are grateful to Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa
do Estado do Rio Grande do Sul (FAPERGS) for financial support
(Grant number: 17/2551-0000987-8). This study was financed in part
by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
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Acknowledgment
The work described in this manuscript is part of the scientific activity
of the international multidisciplinary ‘SeS Redox and Catalysis’ net-
work.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

K
G. Perin et al.
Paper
Synthesis
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