Arylseleninic acid as a green, bench-stable selenylating agent: Synthesis of selanylanilines and 3-selanylindoles

Article abstract of DOI:10.1039/d0ob01073a

Arylseleninic acids were used as an electrophilic selenium source in aromatic substitution reactions, using N,N-substituted anilines and indoles as nucleophiles at 70 °C for 6-15 h. A total of fourteen 4-selanylanilines and five 3-selanylindoles were selectively obtained in good to excellent yields. The starting benzeneseleninic acids are easily prepared from the respective diselenides, are bench stable and easy to handle, affording water as the only waste at the end of the reaction. This journal is

Full text of DOI:10.1039/d0ob01073a

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Chem., 2020, DOI: 10.1039/D0OB01073A.
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DOI: 10.1039/D0OB01073A
ARTICLE
Arylseleninic Acid as a Green, Bench-Stable Selenylating Agent:
Synthesis of Selanylanilines and 3-Selanylindoles
Received 00th January 20xx,
Accepted 00th January 20xx
Laura Abenante,a Nathalia B. Padilha,a João M. Anghinoni,a Filipe Penteado,a Ornelio Rosati,b
Claudio Santi,b Marcio S. Silva,a,* and Eder J. Lenardãoa,*
DOI: 10.1039/x0xx00000x
Arylseleninic acids were used as electrophilic selenium source in aromatic substitution reactions, using N,N-substituted
anilines and indoles as nucleophiles at 70 oC for 6-15 h. A total of fourteen 4-selanylanilines and five 3-selanylindoles were
selectively obtained in good to excellent yields. The starting benzeneseleninic acids are easily prepared from the
respective diselenides, are bench stable and easy to handle, affording water as the only waste at the end of the reaction.
Introduction
Anticancer agents
Antidepressant-like
O
O
Selenium-containing compounds are recognized for decades
for their useful and unique chemical properties, being
extensively employed as catalysts, as well as synthetic building
blocks and intermediates in organic synthesis.1 Besides that,
the discovery of the essential role of selenium in mammalian
biological systems leaded to clarify its essential role as a
component of some selenoenzymes like glutathione
peroxidase (GPx), thioredoxin reductase (TrxR) and
deiodinases (ID). These selenoenzymes are connected to
protect tissue and cells against damage from reactive species
Se
Cl
Se
O
O
O
O
O
O
N
Se
Se
O
A
N
C
N
Ph
N
B
N
H
D
Anti-inflammatory
AChE inhibitor
O
HN
Se
F
NH
N
SePh
O
E
Figure 1. Examples of Se-containing bioactive compounds.
Among the plethora of methods to prepare organoselenium
derivatives, one of the most useful approach is the reaction of
electrophilic selenium species to electron-rich systems.6 In
these reactions, the electrophile is generally prepared in situ
by oxidation of the Se-Se bond on diorganyl diselenides, which
can be oxidized by several reagents, including iodine,7
persulfate/peroxides,8 and transition metal (TM)-based
reagents and catalysts.9 PhSeCl and PhSeBr, obtained from the
reaction of diphenyl diselenide with SO2Cl2 (or Cl2) and Br2
respectively, are commercially available and largely used as
selenylating agents.6 However, they suffer of low stability due
of
activation/deactivation of the T3/T4 hormones in thyroid, and
there has been object of constant search for the
identification of new small organoselenium molecules that can
mimic the functions of these enzymes.1a In view of the
connection of a number of diseases with the oxidative stress,
many Se-containing antioxidants have been prepared, several
of them being very effective against important disorders,
including cancer,2 inflammatory processes3 and depression.4
oxygen
(ROS)
or
are
responsible
of
the
a
For instance, the Se-functionalized indole
A and the
imidazopyridine B presented antidepressant-like activity in to a moisture sensibility, and the high nucleophilicity of
mice,4b,e while the 3-arylselanyl indole C and the selenoxide D
are as active against cancer cells as combretastatin A-4.2e
Besides heterocycles, selenoaniline derivatives have also
shown pharmacological activities, like compound E, which
chloride or bromide counterions that can lead to undesirable
side reactions, by other less nucleophilic counter ions which
are stabilized by resonance, through the exchange reaction
with the corresponding silver salts (Scheme 1).10
The synthesis of most of the useful electrophilic selenium
species involves sometimes harsh reaction conditions and
dangerous reagents, affording large amounts of waste and
leading to low selectivity in the formation of the new C-Se
bond. In this context, the search for alternative, bench-stable
and easy to prepare and to handle electrophilic selenylating
agents has attracted the interest of synthetic organic chemists.
For instance, dihydroxy arylselenonium p-toluenesulfonate,
presents
acetylcholinesterase
diarylselenide F, a potent anti-inflammatory agent in vitro.3d
a
potential anti-Alzheimer activity, inhibiting
(AchE)5
and
the
symmetrical
a. LASOL - CCQFA, Universidade Federal de Pelotas - UFPel, P.O. Box 354, 96010-900
Pelotas, RS, Brazil. * E-mail: silva.ms@ufpel.edu.br (MSS) and
lenardao@ufpel.edu.br (EJL).
+
ArSe(OH)2 TsO-, prepared from equivalent amounts of the
b. Group of Catalysis, Synthesis and Organic Green Chemistry, Department of
Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123 Perugia,
PG, Italy.
corresponding seleninic acid and p-TsOH,11 was used by
Henriksen and coworkers to prepare unsymmetrical diaryl
selenides from electron-rich arenes.11d
†
Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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"In situ" formation of Se-electrophilic species
View Article Online
Herein, we disclose our results onDOtIh: e10.1a0p39p/lDic0aOtBio0n1073oAf
arylseleninic acid 1 as a selenylating agent in the electrophilic
selenylation of N,N-substituted anilines 2 and indoles 4. This
protocol does not involve transition metal catalysis nor the use
of strong acids or reducing agents.
Nu-
oxidant
PhSe+
PhSe-SePh
PhSe-Nu
"in situ"
waste
by-products
Unstable halide-based Se-electrophilic species
Results and Discussion
halogen
source
Nu-
PhSe-Nu
PhSe-SePh
PhSeX
Initially, we selected benzeneseleninic acid 1a as source of
electrophilic reagent and N,N-dimethylaniline 2a as substrate,
in order to study the effect of several parameters, including
solvent, temperature and reaction time, to afford the desired
N,N-dimethyl-4-(phenylselanyl)aniline 3a (Table 1). When an
equimolar mixture of 1a and 2a in DMF was stirred at room
temperature for 24 h the reaction failed and no traces of the
target compound was observed either using a 20% excess of
aniline (Table 1, entries 1-2). The temperature was then
X
= Cl, Br
X Nu)
(+
-
unstable
under air
Stable Se-based reagent (this work)
O
Nu-
H2O2
Se
PhSe-SePh
PhSe-Nu
Ph
OH
 storable  bench-stable
 easy to handle  highly reactive
Scheme 1. Se-electrophilic species in reactions with nucleophiles.
o
increased to 70 C, and satisfactorily, the desired product was
isolated in 42% yield after 24 h (Table 1, entry 3). In order to
More recently, Yi and coworkers12 described the use of sodium
selenite, NaO2SeR, in combination with dimethylphosphite (2
equiv) as a reducing agent and CuCl as a catalyst to prepare 3-
selanylindoles. The electrophilic species of selenium, according
to the authors, is generated in situ by action of (MeO)2P(O)H,
Cu(I) salt and DMSO. An advocated advantage of both
improve the reaction yield, a 20% excess of aniline 2a was
o
used at 70 C. Under this condition, the expected product 3a
was obtained in 91% yield after 24 h. However, increasing the
temperature to 100 oC, the yield dropped to 80%, and diphenyl
procedures is the use of stable and inodorous seleninic acid as diselenide was observed as a side product (Table 1, entries 4
selenium source. However, the use of equivalent amounts of
strong acid or reducing agent under heating for several hours
and the inherent low atom-efficiency are important drawbacks
of both procedures.
The use of benzeneseleninic acid as a catalyst in oxygen-
transfer and other oxidation reactions is well established.1a,13
However, its behavior as a Se-based electrophile has received
little attention, despite the electrophilic nature of the
selenium atom in this compound.14 Hevesi and coworkers have
used methyl- and benzeneseleninic acids in the presence of
H3PO2 to prepare β-hydroxyselenides from olefins.14a In their
studies on the oxidation of amines with benzeneseleninic
anhydride (BSA) and benzeneseleninic acid, Milliet and
and 5). Interestingly, when the stoichiometric ratio was
changed by using a 20% excess of benzeneseleninic acid 1a,
the reaction at 70 °C afforded, again, compound 3a in a yield
of 91% (Table 1, entry 6). Considering that 2a and 3a have a
similar Rf, the use of an excess of reactant 1a resulted to be
preferable in order to facilitate the purification of the target
compound. The effect of different solvents (protic and aprotic
polar ones) was also investigated under the same reaction
conditions. As it can be seen in Table 1 (entries 7-10), none of
the tested solvents resulted to be better than DMF affording
3a, with a yield ranged from a minimum of 37% (in glycerol) to
a maximum of 52% (in EtOH).
Table 1. Optimization of the reaction conditions.a
coworkers
described
the
preparation
of
two
O
Me
Me
Me
phenylselanylindoles, starting from indolines.14b Knapp and co-
workers have used aliphatic seleninic acids in reactions with
electron-rich aromatic compounds and nucleosides in acidic
medium.15 Pure benzeneseleninic acid can be easily obtained
by the reaction of diphenyl diselenide with H2O2 under mild
reaction conditions, without any further purification step.16 In
this sense, inspired by the seminal works of Phillips17 on the
chemistry of Se(IV) compounds, and the studies of Sharpless,18
Reich19 and Hevesi14a in the reaction of benzeneseleninic acid
with olefins, we wonder if this bench-stable Se(IV) species
could be a proper selenylating agent in the reaction with
electron-rich arenes and heteroarenes (Scheme 2).
solvent (1.0 mL)
+
N
SePh
N
H
Se
Ph
OH
temperature
time
Me
3a
1a
2a
1a
2a
temp
time
yield
#
solvent
(mmol)
0.25
0.25
0.25
0.25
0.25
0.3
(mmol)
0.25
0.3
(oC)
25
25
70
70
100
70
70
70
70
70
70
70
(h)
24
24
24
24
24
24
24
24
24
24
12
6
(%)b
NR
NR
42
91
80
91
52
37
42
41
95
94
1
2
DMF
DMF
3
0.25
0.3
DMF
4
DMF
5
0.3
DMF
6
0.25
0.25
0.25
0.25
0.25
0.25
0.25
DMF
7
0.3
EtOH
glycerol
PEG-400
DMSO
DMF
8
0.3
R
R
9
0.3
N
SeAr
N
H
R
R
10
11
12
0.3
 simple
 efficient
 TM-catalyst free
 reductant free
3
2
O
DMF
or
SeAr
0.3
or
+
H
Se
70 ºC, 6-15 h
Ar
OH
0.3
DMF
1
a
N
In a round-bottomed flask were added the benzeneseleninic acid 1a, N,N-
N
H
H
5
dimethylaniline 2a and the solvent (1.0 mL). The resulting solution was stirred
4
for 24 h. b Isolated yield obtained by preparative thin layer chromatography.
Scheme 2. This work: arylseleninic acid as an electrophilic selenium
source.
2 | J. Name., 2012, 00, 1-3
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An investigation about the effect of the duration on the optimal conditions, with the aim to prepare 3-selVainewylAirntidcleoOlenslin5e
DOI: 10.1039/D0OB01073A
ongoing of the reaction, was also carried out. Interestingly, (Table 3). Generally, the yields of the 3-selanylindoles 5 were
when reduced to 12 and 6 hours, the desired product 3a was inferior to those of the selanylaniline derivatives 3. The
obtained in 95% and 94% yields, respectively, reducing the behavior of the arylseleninic acids 1 towards indole 4a
formation of side products (Table 1, entries 11 and 12). Thus, followed the same pattern observed in the reactions with
the best reaction condition was setup stirring a mixture of anilines 2.
benzeneseleninic acid 1a (0.3 mmol) and N,N-dimethylaniline
Table 2. Study of the reaction scope in the synthesis of selanylanilines
3.a
2a (0.25 mmol) in DMF (1.0 mL) at 70 oC for 6 h (Table 1, entry
12).
Se
O
Using the optimized reaction conditions, we investigated the
scope and limitations of the protocol by using different
substrates (Table 2). Initially, benzeneseleninic acid 1a was
reacted with the N,N-dialkyl anilines 2b (R = C2H5) and 2c (R =
C4H9), affording the respective products 3b and 3c in 95% and
99% yield, respectively. It was observed that substituted
benzeneseleninic acids were less reactive compared to the
unsubstituted one 1a. For instance, the presence of the
moderately electron-withdrawing chlorine at the para-position
of 4-chlorobenzeneseleninic acid 1b caused a decrease in
reactivity, and 15 hours were required to afford the respective
products 3d (R = CH3), 3e (R = C2H5) and 3f (R = C4H9) in 60%,
61% and 55% yield, respectively (Table 2). A better outcome
was obtained starting from 4-fluorobenzeneseleninic acid 1c (R
= 4-F), which reacted with aniline 2a to give, after 7 h, the
expected selanylaniline 3g in 88% yield. Similar good results
were obtained in the reaction of 1d (R = 3-CF3) with anilines 2b
and 2c, with the expected products 3h and 3i being obtained in
88% and 79% yields after 15 h. Satisfactorily, the protocol
works also for electron-rich substituents, and 4-
methylbenzeneseleninic acid 1e (R = 4-CH3) reacted with
anilines 2a-c under optimized reaction conditions to afford the
products 3j-l in good yields. Even the sterically hindered 2,4,6-
trimethylbenzeneseleninic acid 1f was a good substrate for the
reaction, and products 3m (R1 = CH3) and 3n (R1 = C2H5) were
obtained in 60% and 57% yield, respectively. Unfortunately,
NH2-free aniline was not a good substrate for the reaction, and
the expected product 3o was not observed, even after 24 h of
reaction.
R1
R1
R
Se
DMF
R1
OH
N
H
+
N
R
70 ºC, time
R1
1a-f
2a-c
3a-n
R1
N
SePh
R1
N
F
R1
: R1 = CH3 (6 h, 94%)
: R1 = C2H5 (6 h, 95%)
: R1 = C4H9 (6 h, 99%)
3a
3g
(7 h, 88%)
N
Cl
3b
3c
R1
: R1 = CH3 (15 h, 60%)
: R1 = C2H5 (15 h, 61%)
: R1 = C4H9 (15 h, 55%)
3d
3e
3f
CF3
R1
N
R1
N
R1
R1
: R1 = CH3 (15 h, 60%)
3m
3n
: R1 = C2H5 (15 h, 57%)
: R1 = CH3 (15 h, 88%)
R1
3h
3i
N
: R1 = C2H5 (15 h, 79%)
R1
: R1 = CH3 (15 h, 80%)
3j
H3CO
SePh
H2N
3o
SePh
: R1 = C2H5 (15 h, 71%)
3k
3l
: R1 = C4H9 (15 h, 67%)
3p
(15 h, 9%)
b
(not observed)
a Isolated yields after purification on preparative thin layer chromatography.
b Conversion determined by GC-MS and 1H NMR.
Indeed, the unsubstituted benzeneseleninic acid 1a was more
reactive compared to the substituted ones, affording 3-
(phenylselanyl)-1H-indole 5a in 60% yield after
6 h.
Satisfactorily, the electron-deficient benzeneseleninic acids 1c
(R = 4-F) and 1d (R = 3-CF3) reacted with 4a to give the
respective products 5b and 5c in 61% and 73% yield,
respectively, after 15 h. Electron-donor groups were also
tolerated, and 4-methylbenzeneseleninic acid 1e (R = 4-CH3)
and 2,4,6-trimethylbenzeneseleninic acid 1f (R = 2,4,6-(CH3)3)
afforded the expected 3-selanylindoles 5d and 5e in 56% and
40% yield, respectively, after 15 h (Table 3).
When anisole was used as an electron-rich arene, the expected
(4-methoxyphenyl)(phenyl)selenide 3p was formed in only 9%
yield. The less reactivity of anisole can be explained in the
terms of the difference of electronegativity between oxygen
and nitrogen. Once oxygen is more electronegative, it releases
its lone pair to the aromatic ring harder than does nitrogen,
making the anisole less reactive than anilines in electrophilic
aromatic substitution reactions.20 These are limitations of this
protocol (Table 2).
Table 3. Synthesis of 3-selanylindoles 5.a
Se
H
O
R
Se
DMF
OH
+
R
70 ºC, time
N
N
H
H
4a
5a-e
1a,c-f
F
SePh
Se
Se
CF3
The synthesis of 3-selanylindoles has been extensively
investigated in recent years, with important advances having
been achieved.21 The use of microwave irradiations21a and
photo-catalyzed reactions are notable examples.21b-c However,
some efforts are still welcome to afford more simple and
efficient methods, which circumvent the use of specific
apparatus and reaction conditions. Based on that, we
envisioned to expand the application of benzeneseleninic acid
derivatives 1 as an effective selenium electrophilic source in
reactions using 1H-indole 4a as a nucleophile, under the
N
H
N
N
H
H
5a
(6 h, 60%)
5c
5b
(15 h, 73%)
(15 h, 61%)
Se
Se
N
N
H
H
5e
(15 h, 40%)
5d
(15 h, 56%)
a
Isolated yields after purification on preparative thin layer
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
chromatography.
Initially, benzeneselenenic acid 8 and its anhydride 9 are
View Article Online
formed in situ by the comproportionation of benzeneseleninic
DOI: 10.1039/D0OB01073A
From a mechanistic point of view, an important aspect to
clarify was to determine whether benzeneseleninic acid 1 is
the true electrophilic species, or if it is decomposed into
another Se-based compound, as postulated by Yi and
coworkers in their studies using sodium selenite in the
presence of a reducing agent.12 As mentioned before, the role
of seleninic acid as an intermediate in selenium-catalyzed
oxygen-transfer reactions to alkenes (epoxidation, Baeyer-
Villiger, etc) is well established.1a,13 However, the use of this
species directly as an electrophile in the formation of new C-Se
bonds was scarcely described, being limited to few
examples.13,14,17-19 At a first glance, a possible intermediate of
the reaction between PhSe(O)OH 1a and N,N-dimethylaniline
2a could be the selenoxide 6, formed by elimination of a
molecule of water. However, since there are no reasonable
reducing agents in the reaction medium, the conversion of
selenoxide 6 to the selenide 3a appears not possible. To prove
this, compound 6 was prepared from the reaction of 3a with
m-CPBA22 and submitted to our reaction conditions. After
stirring for 6 h in DMF at 70 oC it remained intact, being totally
recovered, thus discarding the formation of this intermediary
in the reaction (Scheme 3A). In a second experiment, a
solution of benzeneseleninic acid 1a in DMF was stirred for 6 h
at 70 oC, and it was observed that the reaction mixture
gradually became yellow, indicating the presence of diphenyl
diselenide 7, which was observed by TLC and confirmed by GC-
MS analysis (Scheme 3B). To verify if PhSeSePh 7 could be the
selenium source in the reaction, one experiment using 7
instead benzeneseleninic acid 1a in the reaction with aniline
2a was conducted, and both starting materials were recovered
after 6 h (Scheme 3C). Furthermore, the reaction was not
affected by the presence of TEMPO (4 equiv) as a radical
scavenger, indicating that a radical pathway is not involved
(Scheme 3D).
acid 1a and diphenyl diselenide 7,11a,14b,18,19 which in turn is
formed from 1a in the reaction medium, as shown in Scheme
3B. The spontaneous formation of PhSeSePh 7 and PhSeOH 8
(and/or anhydride 9) from benzeneseleninic acid 1a in DMF
was observed by 77Se NMR (SI, Figs. S1 and S2).23 The
comproportionation of benzeneseleninic acid 1a and diphenyl
diselenide 7 could also be observed by 77Se NMR. The peak
intensity of PhSeOH 8/(PhSe)2O 9 ( 1022 ppm) increases with
the time, at the expense of 1a ( 1183 ppm), whose amount
gradually decreases (SI, Figs. S3 and S4). This equilibrium
would be displaced to the right thanks to the consumption of
PhSeOH and (PhSe)2O by the aniline 2a. The reactivity of 8 and
9 is boosted by the acidic medium, forming the respective
protonated species 8’ and 9’. The following step is a classical
electrophilic aromatic substitution of aniline 2a, passing by the
iminium intermediate, to afford the product 3a and water
(from 8 or 8’), or more protonated benzeneseleninic acid 8’ for
a new reaction with 2a. After all, water is the only waste
generated in the reaction, disregarding obviously the
unreacted starting materials.
O
PhSe-SePh
7
Ph Se OH
8
+
Ph Se
O
9
SePh
+
Se
1a
Ph
OH
8
H
O
1a / H+
H
N
+
+
H
N
SePh
Ph Se OH2
2a
N
SePh
8'
H3O+
3a
iminium ion
9
H
N
1a / H+
O
H
PhSe
2a
N
H
O
+
+
2a
8'
Ph Se
SePh
3a
+
N
SePh
9'
iminium ion
Scheme 4. Proposed reaction mechanism.
Control Experiments
O
Experimental procedures
General Information
DMF
N
SePh
N
SePh
A:
B:
70 oC, 6 h
3a
not observed
6
The reactions were monitored by TLC carried out on pre-
coated TLC sheets ALUGRAM® Xtra SIL G/UV254 by using UV
light as visualization agent and the mixture of 5% vanillin in
10% H2SO4 under heating conditions as developing agent.
Merck silica gel (particle size 63-200 m) was used to flash
chromatography, and PTLC Glass Plates L × W 20 cm × 20 cm,
silica gel 60 F254, 1 mm, was used in the preparative thin layer
chromatography. The aryl seleninic acids 1a-f14 and the
selenoxide 618 were prepared according to the literature.
Hydrogen nuclear magnetic resonance spectra (1H NMR) were
obtained at 400 MHz on A Bruker Ascend 400 spectrometer.
The spectra were recorded in CDCl3 solutions. The chemical
shifts are reported in ppm, referenced to tetramethysilane
(TMS) as the external reference. Hydrogen coupling patterns
are described as singlet (s), broad signal (brs) doublet (d),
triplet (t), doublet of doublets (dd), doublet of doublet of
doublets (ddd) and multiplet (m). Coupling constants (J) are
O
DMF
Se
PhSe-SePh
7
1a
+
70 oC, 6 h
Ph
OH
1a
DMF
PhSe-SePh
7
C:
D:
Ph NMe2
no reaction
+
70 oC, 6 h
2a
TEMPO
(4 equiv)
O
Se
Ph NMe2
2a
N
SePh
+
Ph
OH
DMF
70 oC, 6 h
1a
3a
, 90%
Scheme 3. Control experiments and reaction mechanism.
Therefore, based on the outcomes of the experiments
depicted on Scheme 3A-D, and in the reports on the use of
arylseleninic acid in selenylation reactions,11,12,14,18,19
a
plausible reaction mechanism was proposed (Scheme 4).
4 | J. Name., 2012, 00, 1-3
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reported in Hertz. Carbon-13 nuclear magnetic resonance 8.9 Hz, 2H), 7.32 – 7.25 (m, 2H), 7.21 – 7.08 (m, 3H), 6.57 (d, J =
View Article Online
spectra (13C NMR) were obtained at 100 MHz on Bruker 8.9 Hz, 2H), 3.26 (t, J = 7.7 Hz, 4H), 1.62 – 1.51 (m, 4H), 1.35 (h,
DOI: 10.1039/D0OB01073A
Nuclear Ascend 400 spectrometer. The chemical shifts are J = 7.4 Hz, 4H), 0.96 (t, J = 7.3 Hz, 6H). 13C-{1H} NMR (CDCl3, 100
reported in ppm, referenced to the solvent peak of CDCl3. MHz) δ (ppm) 148.3, 137.4, 134.8, 129.6, 128.9, 125.7, 112.4,
Selenium-77 nuclear magnetic resonance spectra (77Se NMR) 111.9, 50.7, 29.3, 20.3, 14.0.
were obtained at 76 MHz on Bruker Nuclear Ascend 400 4-((4-Chlorophenyl)selanyl)-N,N-dimethylaniline (3d).25 Yield:
o
spectrometer. The chemical shifts are reported in ppm, 0.056 g (60%); white solid, mp: 111 – 113 C (Lit.:25 111 – 116
1
referenced to diphenyl diselenide as the external reference. oC). H NMR (CDCl3, 400 MHz) δ (ppm) 7.46 (d, J = 8.8 Hz, 2H),
The HRMS analyses were performed in a Bruker micrOTOF-QII 7.18 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.8
spectrometer equipped with an APCI source operating in Hz, 2H), 2.98 (s, 6H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm)
positive mode. The samples were solubilized in acetonitrile 150.6, 137.1, 133.0, 131.8, 131.0, 129.0, 113.2, 40.2.
and analyzed by direct infusion at a constant flow rate of 180
L/min. The acquisition parameters were capillary: 4000 V, 4-((4-Chlorophenyl)selanyl)-N,N-diethylaniline (3e). Yield: 0.062
end plate offset: -500 V, nebulizer: 1.5 bar, dry gas: 1.5 L min-1, g (61%); yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.42 (d, J
and dry heater: 180 °C. The collision cell energy was set to 5.0 = 8.8 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H),
eV. The mass-to-charge ratio (m/z) data were processed and 6.61 (d, J = 8.8 Hz, 2H), 3.35 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0
analyzed using Bruker Daltonics softwares: Compass Data Hz, 3H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm) 148.1, 137.5,
Analysis and Isotope Pattern.
133.2, 131.6, 130.8, 129.0, 112.4, 111.7, 44.3, 12.5. HRMS
General procedure for the synthesis of the arylseleninic acids (APCI-QTOF) m/z: [M + H]+ calcd for C16H19ClNS, 340.0364;
1a-f24
found, 340.0352.
In a round-bottomed flask were added diselenide (0.5 mmol) and
DCM (3 mL) and the system was cooled with an ice bath (0 °C).
Thus, H2O2 (3.0 equiv) was added dropwise. The result mixture was
stirred at 0 °C until the formation of a white suspension and the
disappearance of the yellow solution. After, the solvent was
evaporated, removing DCM and residual water, being the
precipitate washed several times with hexanes and dried at the
vacuum pump. The freshly dried white solid was directly employed
in the next reaction step as substrate.
N,N-Dibutyl-4-((4-chlorophenyl)selanyl)aniline (3f). Yield: 0.054
g (55%); yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.41 (d, J
= 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H),
6.57 (d, J = 8.4 Hz, 2H), 3.26 (t, J = 7.7 Hz, 4H), 1.63 – 1.51 (m,
4H), 1.35 (sex, J = 7.4 Hz, 4H), 0.96 (t, J = 7.4 Hz, 6H). 13C-{1H}
NMR (CDCl3, 100 MHz) δ (ppm) 148.5, 137.4, 133.2, 131.6,
130.9, 129.0, 112.4, 111.5, 50.7, 29.3, 20.3, 14.0. HRMS (APCI-
QTOF) m/z: [M + H]+ calcd for C20H27ClNSe, 396.0990; found,
396.0998.
4-((4-Fluorophenyl)selanyl)-N,N-dimethylaniline (3g).25 Yield:
0.064 g (88%); white solid, mp: 50 – 55 oC (Lit.:25 49 – 52 oC). 1H
NMR (CDCl3, 400 MHz) δ (ppm) 7.45 (d, J = 8.8 Hz, 2H), 7.31 –
7.23 (m, 2H), 6.93 – 6.86 (m, 2H), 6.65 (d, J = 8.8 Hz, 2H), 2.96
(s, 6H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm) 161.7 (d, J =
245,1 Hz), 150.5, 136.6, 132.1 (d, J = 7.5 Hz,), 128.6 (d, J = 3.2
Hz), 116.1 (d, J = 21.5 Hz), 114.3, 113.2, 40.3.
General procedure for the synthesis of the products 3a-n
In a round-bottomed flask were added arylseleninic acid 1a-f
(0.3 mmol), aniline 2a-c (0.25 mmol) and DMF (1.0 mL). The
mixture was stirring at 70 °C for a specific time for each
starting material (Table 2). After this time, the reaction was
received in water, extracted with ethyl acetate (3 x 10 mL),
washed with brine (2 x 15 mL), dried over MgSO4 and
concentrated under vacuum. Then, the crude was purified by
preparative thin layer chromatography using a mixture of
hexanes/ethyl acetate (97:3) as the eluent.
N,N-Dimethyl-4-((3-(trifluoromethyl)phenyl)selanyl)aniline
o
(3h).25 Yield: 0.076 g (88%); light yellow solid, mp: 45 – 47 C
o
1
(Lit.:25 48 – 52 C). H NMR (CDCl3, 400 MHz) δ (ppm) 7.52 (s,
1H), 7.48 (d, J = 8.8 Hz, 2H), 7.40 – 7.32 (m, 2H), 7.28 – 7.21 (m,
1H), 6.67 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H). 13C-{1H} NMR (CDCl3,
N,N-Dimethyl-4-(phenylselanyl)aniline (3a).25 Yield: 0.065 g
1
(94%); yellow oil. H NMR (CDCl3, 400 MHz) δ (ppm) 7.51 –
7.45 (m, 2H), 7.30 – 7.24 (m, 2H), 7.22 – 7.09 (m, 3H), 6.69 –
6.64 (m, 2H), 2.97 (s, 6H). 13C-{1H} NMR (CDCl3, 100 MHz) δ
(ppm) 150.5, 137.1, 134.6, 129.8, 129.0, 125.8, 113.7, 113.2,
40.3.
100 MHz) δ (ppm) 150.8, 137.5, 136.3, 132.5, 131.1 (q, JC-F
32.2 Hz), 129.1, 125.8 (q, JC-F = 3.9 Hz), 125.2, 122.4 (q, JC-F
3.9 Hz), 113.2, 112.2, 40.2.
=
=
N,N-Diethyl-4-((3-(trifluoromethyl)phenyl)selanyl)aniline (3i).
N,N-Diethyl-4-(phenylselanyl)aniline (3b).25 Yield: 0.087
g
o
1
Yield: 0.075 g (79%); yellow solid, mp: 47 – 50 C. H NMR
(CDCl3, 400 MHz) δ (ppm) 7.53 (s, 1H), 7.45 (d, J = 8.7 Hz, 2H),
7.40 – 7.33 (m, 2H), 7.29 – 7.22 (m, 1H), 6.63 (d, J = 8.7 Hz, 2H),
3.37 (q, J = 7.1 Hz, 4H), 1.18 (t, J = 7.1 Hz, 6H). 13C-{1H} NMR
(CDCl3, 100 MHz) δ (ppm) 148.3, 137.8, 136.5, 132.4, 131.1 (q,
1
(95%); yellow oil. H NMR (CDCl3, 400 MHz) δ (ppm) 7.48 –
7.42 (m, 2H), 7.31 – 7.26 (m, 2H), 7.21 – 7.09 (m, 3H), 3.36 (q, J
= 7.0 Hz, 4H), 1.17 (t, J = 7.0 Hz, 6H). 13C-{1H} NMR (CDCl3, 100
MHz) δ (ppm) 147.9, 137.5, 134.8, 129.6, 128.9, 125.7, 112.4,
112.1, 44.3, 12.5.
JC-F = 32.0 Hz), 129.1, 125.7 (q, JC-F = 3.8 Hz), 123.8 (q, JC-F
=
270.9 Hz), 122.3 (q, JC-F = 3.7 Hz), 112.5, 110.7, 44.3, 12.5.
HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C17H19F3NSe,
374.0630; found, 374.0627.
N,N-Dibutyl-4-(phenylselanyl)aniline (3c).25 Yield: 0.107
g
(99%); brown oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.43 (d, J =
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J. Name., 2013, 00, 1-3 | 5
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MHz) δ (ppm) 136.4, 133.8, 131.2, 130.0, 128.9, 128.6, 125.6,
122.9, 120.8, 120.4, 111.3, 98.2.
View Article Online
DOI: 10.1039/D0OB01073A
N,N-Dimethyl-4-(p-tolylselanyl)aniline (3j).7b Yield: 0.058
g
1
(80%); brown solid, mp: 60 – 65 oC (Lit.:7b 67 – 69 oC). H NMR
(CDCl3, 400 MHz) δ (ppm) 7.45 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 3-((4-Fluorophenyl)selanyl)-1H-indole (5b).9e Yield: 0.044 g
o
o
1
8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 2.95 (61%); white solid, mp: 116-120 C (Lit.:9e 117 – 118 C). H
(s, 6H), 2.27 (s, 3H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm) NMR (CDCl3, 400 MHz) δ (ppm) 8.40 (brs, 1H), 7.62 (d, J = 7.9
150.3, 136.5, 135.8, 130.5, 130.3, 129.8, 114.6, 113.1, 40.3, Hz, 1H), 7.48 – 7.39 (m, 2H), 7.29 – 7.14 (m, 4H), 6.87 – 6.79
20.9.
(m, 2H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm) 161.5 (d, JC-F
244.6 Hz), 136.4, 131.0, 130.7 (d, JC-F = 7.6 Hz), 129.7, 127.9 (d,
=
N,N-Diethyl-4-(p-tolylselanyl)aniline (3k). Yield: 0.056 g (71%); JC-F = 3.1 Hz), 123.0, 120.9, 120.2, 116.0 (d, JC-F = 21.5 Hz),
green oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.42 (d, J = 8.9 Hz, 111.4, 98.6.
2H), 7.22 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.60 (d, J =
8.9 Hz, 2H), 3.35 (q, J = 7.0 Hz, 4H), 2.27 (s, 3H), 1.16 (t, J = 7.0 3-((3-(Trifluoromethyl)phenyl)selanyl)-1H-indole (5c).9e Yield:
o
o
Hz, 6H). 13C-{1H} NMR (CDCl3, 100 MHz) δ (ppm) 147.8, 136.9, 0,062 g (73%), white solid, mp: 75 – 80 C. (Lit.:9e 70 – 71 C).
135.7, 130.4, 129.8, 129.2, 113.0, 112.4, 44.3, 21.0, 12.5. 1H NMR (CDCl3, 400 MHz) δ (ppm) 8.46 (s, 1H), 7.59 (d, J = 7.9
HRMS (APCI-QTOF) m/z: [M + H]+ calcd for C17H22NSe, Hz, 1H), 7.53 (s, 1H), 7.48 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.0 Hz,
320.0823; found, 320.0828.
1H), 7.36 – 7.14 (m, 5H). 13C-{1H} NMR (CDCl3, 100 MHz) δ
(ppm) 136.4, 135.2, 131.7, 131.5, 131.3, 130.9, 130.6, 130.9,
N,N-Dibutyl-4-(p-tolylselanyl)aniline (3l). Yield: 0.062 g (67%); 130.6, 129.6, 129.2, 125.1 (d, JC-F = 4.0 Hz), 123.2, 124.4 (d, JC-F
1
brown oil. H NMR (CDCl3, 400 MHz) δ (ppm) 7.42 (d, J = 8.9 = 4.0 Hz), 121.1, 120.1, 111.5, 97.2.
Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.56 (d,
J = 8.9 Hz, 2H), 3.29 – 3.21 (m, 4H), 2.27 (s, 3H), 1.61 – 1.50 (m, 3-(p-tolylselanyl)-1H-indole (5d).26 Yield: 0.040 g (56%); white
o
o
1
6H), 1.40 – 1.29 (m, 4H), 0.95 (t, J = 7.3 Hz, 6H). 13C-{1H} NMR solid, mp: 104 – 108 C (Lit.:26 104 – 107 C). H NMR (CDCl3,
(CDCl3, 100 MHz) δ (ppm) 148.2, 136.8, 135.7, 130.4, 129.8, 400 MHz) δ (ppm) 8.32 (brs, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.44 –
112.8, 112.4, 50.7, 29.3, 21.0, 20.3, 14.0. HRMS (APCI-QTOF) 7.36 (m, 2H), 7.27 – 7.20 (m, 1H), 7.19 – 7.12 (m, 3H), 6.94 (d, J
m/z: [M + H]+ calcd for C21H30NSe, 376.1469; found, 376.1472.
= 7.9 Hz, 2H), 2.22 (s, 3H). 13C-{1H} NMR (CDCl3, 100 MHz) δ
(ppm) 136.3, 135.5, 130.9, 129.9, 129.7, 129.0, 122.8, 120.7,
4-(Mesitylselanyl)-N,N-dimethylaniline (3m).25 Yield: 0.049 g 120.3, 111.3, 98.6, 20.9.
o
o
1
(60%); brown solid, mp: 57-60 C (Lit.:25 56 – 59 C). H NMR 3-(mesitylselanyl)-1H-indole (5e).26 Yield: 0,031 g (40%); white
(CDCl3, 400 MHz) δ (ppm) 7.06 (d, J = 8.8 Hz, 2H), 6.94 (s, 2H), solid, mp: 135 – 140 C (Lit.:26 134 – 137 C). H NMR (CDCl3,
6.57 (d, J = 8.8 Hz, 2H), 2.88 (s, 6H), 2.46 (s, 6H), 2.27 (s, 3H). 400 MHz) δ (ppm) 8.17 (brs, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.33
13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 149.1, 143.1, 138.3, (d, J = 8.0 Hz, 1H), 7.20 – 7.14 (m, 2H), 7.13 – 7.07 (m, 1H), 6.87
o
o
1
131.2, 128.6, 118.1, 113.6, 40.5, 24.4, 21.0.
(s, 2H), 2.56 (s, 6H), 2.22 (s, 3H). 13C-{1H} NMR (CDCl3, 100
MHz) δ (ppm) 142.5, 137.8, 136.1, 129.6, 128.7, 128.6, 127.9,
N,N-Diethyl-4-(mesitylselanyl)aniline (3n). Yield: 0.049 g (57%); 122.4, 120.2, 120.2, 111.1, 101.1, 24.5, 20.9.
green oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.05 (d, J = 8.8 Hz,
2H), 6.93 (s, 2H), 6.50 (d, J = 8.8 Hz, 2H), 3.26 (q, J = 7.1 Hz,
4H), 2.47 (s, 6H), 2.26 (s, 3H), 1.10 (t, J = 7.1 Hz, 6H). 13C-{1H}
NMR (CDCl3, 100 MHz) δ (ppm) 146.4, 143.1, 138.2, 131.8,
128.6, 116.4, 112.9, 44.3, 24.4, 21.0, 12.5. HRMS (APCI-QTOF)
m/z: [M + H]+ calcd for C19H26NSe, 348.1156; found, 348.1160.
Conclusions
We disclosed herein the use of benzeneseleninic acid
derivatives as electrophilic selenium source in aromatic
substitution reactions, using N,N-substituted anilines and
indole as nucleophiles. The reaction is quite simple, and the
expected selenylated products were selectively obtained in
moderate to excellent yields under mild conditions. An
investigation on the mechanism of the reaction suggests that
the true electrophile is generated in situ from the arylseleninic
acid and diaryl diselenide. This so far underexplored
selenylating agent is bench-stable and ease to handle, does
not requires addictive or auxiliaries, and produces water as the
only waste of the reaction.
General procedure for the synthesis of the products 5a-e
In a round-bottomed flask were added arylseleninic acid 1a,c-f
(0.3 mmol), indole 4a (0.25 mmol) and DMF (1.0 mL). The
mixture was stirring at 70 °C for a specific time for each
starting material (Table 3). After this time, the reaction was
received in water, extracted with ethyl acetate (3 x 10 mL),
washed with brine (2 x 15 mL), dried over MgSO4 and
concentrated under vacuum. Then, the crude was purified by
preparative thin layer chromatography using a mixture of
hexanes/ethyl acetate (90:10) as the eluent.
Conflicts of interest
“There are no conflicts to declare”.
3-(Phenylselanyl)-1H-indole (5a).9e Yield: 0.041 g (60%); white
solid, mp: 134 – 138 C (Lit.:9e 130 – 131 C). H NMR (CDCl3,
400 MHz) δ (ppm) 8.42 (brs, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.50 –
7.40 (m, 2H), 7.30 – 7.04 (m, 7H). 13C-{1H} NMR (CDCl3, 100
o
o
1
6 | J. Name., 2012, 00, 1-3
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6
(a) C. Santi and S. Santoro, Electrophilic Selenium. In
Acknowledgements
View Article Online
Organoselenium Chemistry: SynthesDisOI:a1n0d.103R9e/Dac0tOioBn0s10; 73TA.
Wirth (Ed.). Wiley-VCH: Weinheim, Germany. 2012; pp 1–48.
(b) C. Santi and C. Tidei, Electrophilic selenium/tellurium
reagents: Reactivity and their contribution to Green
Chemistry. In PATAI’S Chemistry of Functional Groups. Vol 4.
This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES)
- Finance Code 001. FAPERGS (PqG 17/2551-0000987-8), CNPq
and FINEP are acknowledged for financial support. We thank
Prof. Thiago Barcellos, from University of Caxias do Sul (Brazil)
for providing the HRMS analysis. This manuscript is part of the
scientific activity of the international network Selenium Sulfur
Redox and Catalysis.
John
Wiley
&
Sons:
New
York,
2013.
DOI:10.1002/9780470682531.pat0720. (c) J. Ścianowski and
Z. Rafiński, Electrophilic Selenium Reagents: Addition
Reactions to Double Bonds and Selenocyclizations. In:
Organoselenium Chemistry: Between Synthesis and
Biochemistry. C. Santi (Ed.). Bentham Science: Sharjah, U.A.E.
2014,
pp
8–60.
Ebook,
DOI:
10.2174/97816080583891140101.
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ARTICLE
Journal Name
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View Article Online
DOI: 10.1039/D0OB01073A
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23 While this manuscript was in preparation, in an excellent
paper on the involvement of Se(VI) species in the Se-
catalyzed epoxidation of alkenes, Back and co-workers
suggested that in solution, peroxyseleninic acid (PhSe(O)O2),
formed from PhSeO2 in the presence of excess of H2O2,
spontaneously decomposes in PhSeOH and O2. This could
explain the presence of a second signal in the 77Se NMR of
1a, in ~1020 ppm, which is due to PhSeOH (Figure S1,
Supporting Information): K. N. Sands, E. M. Rengifo, G. N.
George, I. J. Pickering, B. S. Gelfand and T. G. Back, Angew.
Chem. Int. Ed. 2020, 59, 4283.
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8 | J. Name., 2012, 00, 1-3
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