Synthesis of 2-(Arylselanyl)benzo[ b[chalcogenophenes via Intramolecular Cyclization of Vinyl Selenides

Article abstract of DOI:10.1055/s-0037-1610656

An efficient protocol to access 2-arylselanylbenzo[ b[chalcogenophene derivatives through the Cu(I)-catalyzed annulation of vinyl selenides is described. The key vinyl selenides were easily prepared from properly functionalized 1,1-dibromostyrenes and the

Full text of DOI:10.1055/s-0037-1610656

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
G. Stach et al.
Paper
Synthesis
Synthesis of 2-(Arylselanyl)benzo[b]chalcogenophenes via
Intramolecular Cyclization of Vinyl Selenides
Guilherme Stacha
Thiago J. Peglowa
Juliano A. Roehrsb
Filipe Penteadoa
Thiago Barcellosc
Raquel G. Jacoba
Eder J. Lenardão*a
Gelson Perin*a
Br
Br
Br
CuBr
NaBH4
PEG-400, Ar
YR
SeAr
YR
MeNO2
SeAr
+
r.t. to 50 °C, 1 h
100 °C, Ar
Y
ArSeSeAr
9 examples
60–94% yield
RY = MeO, PrS, BuSe
Y = O, S, Se
0
0
0
0
0-
0
0
1
7-
9
2
0
3-
2
8
9
a Laboratório de Síntese Orgânica Limpa – LASOL, CCQFA, Universidade
Federal de Pelotas – UFPel, P. O. Box 354, 96010-900, Pelotas, RS, Brazil
lenardao@ufpel.edu.br
gelson_perin@ufpel.edu.br
b Instituto Federal de Educação Ciência e Tecnologia Sul-rio-grandense –
IFSul, 96015-360, Pelotas, RS, Brazil
c Laboratório de Biotecnologia de Produtos Naturais e Sintéticos -
Universidade de Caxias do Sul – UCS, Caxias do Sul, RS, Brazil
Received: 04.07.2018
Accepted after revision: 23.08.2018
Published online: 19.09.2018
that benzo[b]thiophene C and benzo[b]furan D derivatives
are able to inhibit the tubulin polymerization, showing the
promising capacity to be applied as anticancer agents, act-
ing mimetically to combretastatin A-4, a powerful naturally
occurring inhibitor of tubulin polymerization (Figure 1).
DOI: 10.1055/s-0037-1610656; Art ID: ss-2018-z0454-op
Abstract An efficient protocol to access 2-arylselanylbenzo[b]chalcog-
enophene derivatives through the Cu(I)-catalyzed annulation of vinyl
selenides is described. The key vinyl selenides were easily prepared
from properly functionalized 1,1-dibromostyrenes and the method al-
lowed the synthesis of 2-arylselanylfurans, -thiophenes, and -seleno-
phenes in moderate to excellent yields.
OMe
MeO
O
MeO
N
O
O
Key words 2-arylselanylbenzo[b]chalcogenophenes, copper catalysis,
annulation
OMe
OH
S
MeO
C
S
HO
Raloxifene A
Heterocycles are among the most important classes of
compounds found in nature, occurring mainly in the form
of alkaloids.1 Their reputation is closely linked to their use
in the pharmaceutical industry; once in 2010, over 80% of
the top small-molecule drugs marketed in the USA con-
tained at least one heterocyclic unit in the structure.1d
In this context, the benzo[b]chalcogenophenes have at-
tracted attention due to their wide range of biological ac-
tivities. For instance, benzo[b]furans are widely present in
nature,2 and their derivatives exhibit a broad range of med-
ically important activities,3 such as antioxidant,3c antihista-
minic,3d PTP-1B inhibitor,3f and against pancreatic cancer.3g
Benzo[b]thiophenes, in turn, are present in the structure of
worldwide marketed drugs, such as, Raloxifene (A), used in
the treatment and prevention of osteoporosis in menopaus-
al women,4 and Zileuton (B), which is used by asthmatic pa-
tients in the prevention of acute asthma attacks.5 In addi-
tion, between 1999 and 2002, Pinney6 and Flynn7 disclosed
OMe
MeO
MeO
HO
O
O
N
NH2
S
OMe
O
Zileuton B
MeO
D
Figure 1 Benzo[b]chalcogenophene derivatives of interest in medici-
nal chemistry
Sartans are a new class of antihypertensive drugs acting
as Ang II receptor antagonists. Examples of thiophene-con-
taining sartan derivatives are milfasartan (E), which has
reached the phase I of clinical trials,8 and eprosartan (F),
marketed in some countries under the tradename Te-
veten®, used in the treatment of arterial hypertension (Fig-
ure 2).9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
G. Stach et al.
Paper
Synthesis
tion conditions, affording 3-substituted 2-organochalcog-
enylbenzo[b]furan derivatives in moderate to excellent
yields (Scheme 1 A). In 2013, Wang and co-workers16 re-
ported the synthesis of 2-chalcogenylbenzo[b]furans via a
Cu(I)-catalyzed tandem annulation of 2-(1,1-dibromovi-
nyl)phenols with diorganyl dichalcogenides. The reaction
was conducted in the presence of t-BuOLi as a base, Mg as
an additive, and DMSO as the solvent. The functionalized
benzofurans were obtained in moderate to very good yields
after 12 hours of reaction at 110 °C (Scheme 1 B).
MeO2C
CO2H
S
N
O
N
N
S
N
N
N
CO2H
N
N
H
Previous work:
A) Zeni:
Eprosartan F
Milfasartan E
E
YR
E+
CO2H
YR
CH2Cl2, r.t.
from 0.3 to 3 h
ref. 15
O
OMe
Se
50–95%
N
O
RY = PhSe, BuSe, PhS, MeS
E+ = I2, ICl, PhSeBr, Br2
N
N
N
B) Wang:
CuI (10 mol%)
Br
CO2H
Mgº (1 equiv)
N
R1
YR2
R1
R2Y)2
N
+
Br
N
Se
tBuOLi (4 equiv)
DMSO, 110 °C, 12 h
sealed tube
O
OH
N
53–80%
H
R
1 = EDG, EWG
R2 = alkyl, aryl
ref. 16
G
H
Y = S (4), Se (5)
(AT1-receptor antagonists)
C) Perin:
YR3
Figure 2 Biologically active sartan derivatives
E
E+
YR3
CH2Cl2, r.t.
from 15 to 38 min
ref. 17
Se
In view of this, between 2007 and 2012, Schiesser and
co-workers10 developed a deep study on the synthesis of se-
lenium-containing sartan derivatives, in order to discover
AT1-receptor antagonists, candidates to new antihyperten-
sive drugs. Among the designed compounds, benzoseleno-
phene derivatives G and H of milfasartan and eprosartan,
respectively, (Figure 2) showed to be excellent AT1-receptor
antagonists compared to the thio-analogues, presenting
good binding ability and therefore quoted as drug candi-
dates for the treatment of hypertension.3d
With regard to the importance of organoselenium com-
pounds, heterocycles bearing a selenium atom on their
structure, in the form of selenides, have been displaying re-
markable performance in biological assays, presenting im-
portant activities, such as antioxidant,11 anticancer,12 anti-
viral,13 and antihelminthic.14
SeBu
Y = S, Se
R3 = alkyl, aryl
E+ = I2, Br2, PhSeBr
This work:
Br
Br
YR4
Br
NaBH4
PEG-400
1
CuBr (15 mol%)
SeAr
SeAr
YR4
+
MeNO2
100 °C, Ar
Y
50 °C, 1 h
Ar
ArSeSeAr
4
2
3
R4Y = MeO, PrS, BuSe
Y = O, S, Se
Scheme 1 Preview of reported methods for the synthesis of 2-selanyl-
benzo[b]chalcogenophenes and our general reaction scheme
Based on what was described above, 2-selanylben-
zo[b]chalcogenophenes can be considered as a promisor
class of compounds, combining two units of biologically
important scaffolds. However, synthetic methodologies to
access such molecular hybrids are still very scarce. In 2009,
Zeni and co-workers15 reported the electrophilic cyclization
of 2-chalcogenealkynyl anisole, promoted by different elec-
trophiles, such as I2, ICl, Br2, and PhSeBr, under mild reac-
Recently, we have described the synthesis of 3-substi-
tuted 2-organochalcogenylbenzo[b]selenophenes, via an
electrophilic cyclization of 1-(2-chalcogenylethynyl)-2-bu-
tylselenanybenzenes promoted by I2, Br2, and PhSeBr in di-
chloromethane as the solvent.17 The desired selenophenes
were obtained in moderate to excellent yields in short reac-
tion time at room temperature (Scheme 1 C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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G. Stach et al.
Paper
Synthesis
Table 1 (continued)
On the other hand, 1,1-dibromoalkenes are versatile
building blocks in organic synthesis, widely applied in sev-
eral transformations.18 In this context, we have recently de-
scribed a robust protocol for easily accessing (E)-1-bromo-
1-selenanylalkenes and ketene selenoacetals starting from
1,1-dibromoalkenes.19
Entry
Alkene 1
R1 2
Product 3
Yield
(%)b
Br
Se
F
3
1a
F, 2c
80
SeBu
Thus, aiming to expand the use of (E)-1-bromo-1-ar-
ylselenoalkenes 3 as a versatile intermediate in organic syn-
thesis, herein we describe our results on the Cu(I)-catalyzed
annulation of properly functionalized alkenes 3, affording
the respective 2-arylselanylbenzo [b]chalcogenophenes 4
(Scheme 1, bottom panel). The key intermediates 3 were
prepared by the reaction of 1,1-dibromoalkenes 1 with di-
organyl diselenides.19
Our initial studies were focused in the synthesis of the
substrates 3, the synthetic precursors of the title chalcog-
enophenes 4. Based on the methodology developed by us in
2016,19 the 1-(2,2-dibromovinyl)-2-chalcogenylbenzenes
1a–c were subjected to the reaction with diaryl diselenides
2 in the presence of NaBH4 as a reducing agent and PEG-400
as the solvent. After 1 hour at 50 °C under argon atmo-
sphere, the respective (E)-1-bromo-1-arylselenoalkenes
3a–i were selectively formed (see Supporting Information
for NMR spectra) in good to very good yields (Table 1). The
high selectivity in the formation of the (E)-1-bromo-1-
arylselenoalkenes 3a–i (>99% of E-isomer) is similar to that
observed starting from unsubstituted 1,1-dibromo-
alkenes.19 This outcome indicates that the presence of the
o-chalcogen substituent in 1 did not influence the selectivi-
ty of the reaction, with the E-isomers of 3a–i being the only
observed products by GC.
3c
Br
Br
Br
Se
4
5
6
7
8
9
H, 2a
Me, 2b
F, 2c
78
OMe
OMe
1b
1b
3d
Br
Se
Me
76
84
85
76
78
OMe
3e
Br
Se
F
1b
OMe
3f
Br
Br
Br
Se
H, 2a
Me, 2b
F, 2c
SPr
SPr
1c
1c
3g
Br
Se
Me
SPr
Table 1 Synthesis of the Synthetic Precursors (E)-3a–ia
3h
Br
Br
Br
Se)2
NaBH4
Br
YR
Se
YR
R1
Se
F
+
1c
SPr
R1
PEG-400, Ar
r.t. to 50 °C, 1 h
1a–c
2a–c
3a–i
3i
a The reaction was performed using 1,1-dibromoalkene 1 (0.5 mmol), dior-
ganyl diselenide 2 (0.25 mmol), and NaBH4 (0.75 mmol) as reducing agent
in PEG-400 (3 mL) as solvent at 50 °C, under argon atmosphere.
Entry
Alkene 1
R1 2
Product 3
Yield
(%)b
b Yields are given for isolated products after column chromatography.
Br
Br
Br
SeBu
Se
1
H, 2a
88
There was no substantial influence of electronic effects
in the aromatic ring of the diaryl diselenides 2a–c and
equally good yields were obtained starting from electron-
rich and electron-deficient diselenides. Correspondingly,
similar outcomes were observed regardless of the organo-
chalcogen appending group in the vinyl dibromide (SeBu
1a, OMe 1b, or SPr 1c), showing the robustness of the meth-
odology in the synthesis of 3 (Table 1).
SeBu
3a
1a
1a
Br
Se
Me
2
Me, 2b
74
SeBu
3b
With a well-established general method to access the
starting materials 3a–i in hand, the o-seleno-substituted
(E)-1-bromo-1-phenylselenoalkene 3a was selected as a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
G. Stach et al.
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Synthesis
standard substrate and a careful optimization study to ac-
cess the desired compound 4a via a copper-catalyzed annu-
lation was performed. Initially, CuBr (30 mol%) was used as
the catalyst in MeNO2 as the solvent and, after 24 hours un-
der argon atmosphere at refluxing temperature, the title
benzoselenophene 4a was obtained in 95% yield (Table 2,
entry 1).
iodine in this reaction (Table 2, entry 1 vs entry 6). In addi-
tion, Cu(II) species were also employed as catalysts, with
Cu(OAc)2 affording the respective product 4a in 44% yield,
while CuBr2 efficiently catalyzed the reaction, affording 4a
in 95% yield, confirming the best performance of bromide
salts (entries 7 and 8). Considering that CuBr is cheaper
than CuBr2, it was chosen as the catalyst for the reaction.
Hence, the catalyst loading was reduced to 20, 15, 10, 5, and
1 mol%, and it was observed that no substantial decrease in
the reaction yield was observed using 20 or 15 mol% (90%
yield of 4a, entries 9 and 10).
Table 2 Optimization Study to the Cu-Catalyzed Annulation of 3aa
Br
The effect of the reaction temperature was also signifi-
cant. When the reaction was performed at 75 °C, a consid-
erable decrease in the reaction yield was observed, with 4a
being obtained in only 35% (Table 2, entry 14). At room
temperature, no product was detected after 24 hours, and
the starting material 3a was recovered (entry 15). Finally,
the reaction was prolonged up to 40 hours under reflux
(100 °C) and 4a was obtained in 92% yield, similar to that
obtained in 24 hours (entry 16 vs entry 10).
Thus, the best reaction conditions for the copper-cata-
lyzed annulation of the substrate 3a to give 4a, was defined
as using CuBr (15 mol%) as the catalyst, MeNO2 as the sol-
vent, under argon atmosphere and refluxing conditions, for
24 hours (Table 2, entry 10). With the best reaction condi-
tions in hand, our efforts were concentrated in the study of
the reaction scope, aiming to prepare a variety of 2-selanyl-
benzo[b]chalcogenophenes 4a–i (Table 3).
Initially, the ortho-seleno-substituted (E)-1-bromo-1-
arylselenoalkenes 3b,c, bearing electron-releasing (Me) and
electron-withdrawing group (F), were subjected to the an-
nulation under the optimized conditions. As shown in Table
3, the presence of the methyl group positively influences
the reaction, and 2-(4-tolylselanyl)benzo[b]selenophene
(4b) was obtained in 94% yield after 16 hours (Table 3, entry
2). In contrast, the electron-withdrawing fluorine caused
an increase in the reaction time, and 38 hours were neces-
sary to obtain the expected benzoselenophene 4c (R1 = F) in
60% yield (entry 3).
Very similar results were obtained when the method
was expanded to the annulation of the o-methoxy- and o-
propylthio-substituted (E)-1-bromo-1-arylselenoalkenes
3d–f and 3g–i. Good to very good yields of the respective 2-
arylselanylbenzo[b]furans 4d–f and 2-arylselanylben-
zo[b]thiophenes 4g–i were obtained under the optimized
reaction conditions (Table 3, entries 4 to 9).
copper salt
Se
Se
SeBu
solvent, Ar
reflux, 24 h
Se
3a
4a
Entry
Solvent
Cu salt (mol%)
Yield (%)b
1
2
MeNO2
DMSO
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (30)
CuBr (30)
CuI (30)
95
–
3
DMF
50
10
7
4
MeCN
5c
6
PEG-400
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
76
44
95
92
90
85
56
30
35
–
7
Cu(OAc)2 (30)
CuBr2 (30)
CuBr (20)
CuBr (15)
CuBr (10)
CuBr (5)
8
9
10
11
12
13
14d
15e
16f
CuBr (1)
CuBr (15)
CuBr (15)
CuBr (15)
92
a Reaction was performed using a mixture of 3a (0.15 mmol), the copper
salt, and solvent (3 mL), under argon at reflux for 24 h.
b Yields of isolated product, after column chromatography.
c Reaction at 90 °C.
d Reaction at 75 °C.
e Reaction at r.t.
f After 40 h of reaction.
Based on this result, CuBr (30 mol%) was set as the cata-
lyst and other organic solvents were tested, at their respec-
tive reflux temperatures, such as DMSO, DMF, and MeCN
(Table 2, entries 2–4). As shown in Table 2, none of them
was more effective than MeNO2 in this annulation reaction,
affording poor to moderate yields of product 4a. Additional-
ly, PEG-400 was used as a non-conventional solvent at 90
°C, affording 4a in only 7% yield (entry 5), thus confirming
MeNO2 as the better solvent for this transformation.
Next, different copper catalysts, both Cu(I) and Cu(II)
salts, were tested. Initially, CuI was used as an alternative
Cu(I) specie, but the reaction yield decreased from 95 to
76%, showing that bromide is a better counterion than
The same electronic effect was observed, with the elec-
tron-poor fluoro-containing substrates 3f and 3i being less
reactive. The unsubstituted starting materials 3d and 3g (R1
= H) were cyclized to 2-(phenylselanyl)benzofuran 4d and
2-(phenylselanyl)benzo[b]thiophene 4g in 80% and 81%
yield, respectively, after 24 hours (Table 3, entries 4 and 7).
In the presence of an EDG (R1 = Me), the expected products
4e and 4h were obtained in 85% and 84% yield, respectively,
after 16 hours (entries 5 and 8). The presence of an EWG
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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G. Stach et al.
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Synthesis
(R1 = F) negatively affects the reaction, as observed for the
products 4f and 4i in 63% and 72% yields after 38 hours of
seleno-substituted analogue 3c, affording the respective
reaction (entries 6 and 9).
Table 3 Synthesis of 2-Selanylbenzo[b]chalcogenophenes 4a–ia
R1
Br
CuBr (15 mol%)
Se
YR
R1
Se
MeNO2 (3 mL)
reflux, Ar
time
Y
4a–i
3a–i (0.15 mmol)
Entry
1
Vinyl selenide 3
Time (h)
24
Product 4
Yield (%)b
Br
Se
90
Se
SeBu
Se
4a
3a
Me
Br
Se
Me
2
16
94
SeBu
Se
Se
3b
4b
F
Br
Se
F
3
4
5
38
24
16
60
80
85
SeBu
Se
Se
3c
4c
Br
Se
Se
OMe
O
3d
4d
Me
Br
Se
Me
OMe
Se
O
3e
4e
F
Br
Se
F
6
7
38
24
63
81
OMe
Se
O
3f
4f
Br
Se
Se
SPr
S
3g
4g
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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G. Stach et al.
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Synthesis
Table 3 (continued)
Entry
Vinyl selenide 3
Time (h)
16
Product 4
Yield (%)b
Me
Br
Se
Me
8
9
84
SPr
Se
S
3h
4h
F
Br
Se
F
38
72
SPr
Se
S
3i
4i
a The reaction was performed using 3a–i (0.15 mmol) and CuBr (15 mol%) as the catalyst in MeNO2 (3 mL) as the solvent at 100 °C under argon atmosphere.
b Yields are given for isolated products after column chromatography.
Br
SePh
Br
Based on previous works17,20 and in our own observa-
tions, a proposed mechanism for the Cu(I)-catalyzed annu-
lation of 3a is depicted in Scheme 2. Initially, an isomeriza-
tion step is needed to the conversion of the E-isomer 3a to
the Z-isomer 3a′, which presents a more suitable configura-
tion to undergo an oxidative addition to the coordination
sphere of Cu(I) specie, leading to the selenonium interme-
diate I. To confirm this hypothesis [the pre-isomerization
(E)-3a → (Z)-3a], a control experiment using pure (E)-1-
bromo-1-(phenylselanyl)-2-phenylethene (6) was conduct-
ed under the optimized reaction conditions (CuBr/MeNO2
under reflux) and, after 24 hours, 45% of the E-isomer was
isomerized to the Z-isomer (determined by GC/MS analy-
sis), confirming that the reactive specie is formed in situ
(see Supporting Information for experimental details and
GC chromatograms). Then, an Ullmann-type coupling af-
fords the intermediate II, releasing the copper catalyst and
bromide. Finally, bromide acts as a nucleophile, attacking
the butyl group via an SN2 mechanism, releasing the de-
sired product 4a as a leaving group and affording 1-bro-
mobutane as a by-product (Scheme 2).
SePh
isomerization
SeBu
SeBu
3a
3a'
E-isomer
Z-isomer
reactive isomer
3a'
SePh
Cu(I)Ln
Se
4a
BuBr
+
SePh
SePh
Cu(Br)Ln
Se
Se
I
II
Bu
Bu
Br
Cu(I)Ln
+
Br
Scheme 2 A plausible mechanism for the formation of 4a
In conclusion, we have developed an efficient method-
ology to access 2-arylselanylbenzo[b]chalcogenophene de-
rivatives through a Cu(I)-catalyzed annulation of properly
substituted (E)-1-aryl-1-bromoselenoalkenes. This is the
first general protocol to access seleno-functionalized ben-
zo[b]chalcogenophenes in moderate to excellent yields us-
ing easily available starting materials.
TMS as internal standard. Standard abbreviations are used to describe
1H coupling patterns. Coupling constants (J) are reported in Hz. 13C
NMR spectra were recorded on a Bruker Ascend 400 spectrometer at
100 MHz. The chemical shifts (δ) are reported in ppm, referenced to
the solvent peak (CDCl3). The high-resolution atmospheric pressure
chemical ionization (APCI-QToF) analyses were performed on a
Bruker Daltonics micrOTOF-Q II instrument operating in the positive
ion detection mode. For data acquisition and processing, Compass 1.3
for micrOTOF-Q II software (Bruker Daltonics, USA) was used. Melting
point (mp) values were measured in a Marte PFD III instrument with
a 0.1 °C precision.
Pre-coated TLC sheets ALUGRAM® Xtra SIL G/UV254 using UV light and
acidic ethanolic vanillin solution (5% in 10% H2SO4) were used to fol-
low the reaction progress. Aldrich technical grade silica gel (pore size
60 Å, 230–400 mesh) was used for flash chromatography. 1H NMR
spectra were recorded in CDCl3 on a Bruker Ascend 400 spectrometer
at 400 MHz. Chemical shifts are reported in ppm, referenced against
(E)-1-Aryl-1-bromoselenoalkenes 3a–i;19 General Procedure
To a solution of the appropriate diaryl diselenide 2a–c (0.25 mmol) in
PEG-400 (1 mL) under argon atmosphere was added NaBH4 (0.75
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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G. Stach et al.
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Synthesis
mmol) at r.t. and the mixture was stirred for 30 min. Then, the re-
spective 1,1-dibromoalkene 1a–c21 (0.5 mmol) was added and the
temperature was slowly raised to 50 °C. The reaction progress was
monitored by TLC. After 1 h, the reaction mixture was quenched with
H2O (10 mL) and the mixture was extracted with EtOAc (3 × 15 mL).
The combined organic phases were dried (MgSO4) and the solvent
was evaporated under reduced pressure. The required product was
isolated by column chromatography using hexane as the eluent.
MS: m/z (%) = 370 (20.9), 368 (28.4), 289 (19.3), 274 (31.9), 194
(100.0), 131 (63.7), 89 (51.6), 77 (38.3).
HRMS (APCI-QTOF): m/z calcd for C15H13BrOSe [M + H]+: 368.9393;
found: 368.9396.
(E)-1-Bromo-2-(2-methoxyphenyl)vinyl-4-tolylselane (3e)
Yield: 0.145 g (76%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.68 (s, 1 H), 7.45–7.39 (m, 3 H), 7.32–
7.28 (m, 1 H), 7.11 (d, J = 7.9 Hz, 2 H), 6.95 (t, J = 7.4 Hz, 1 H), 6.88–
6.85 (m, 1 H), 3.83 (s, 3 H), 2.33 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 156.6, 138.3, 136.7, 133.9, 129.9,
129.8, 129.7, 126.8, 125.7, 120.0, 110.4, 110.1, 55.4, 21.2.
(E)-{1-Bromo-2-[2-(butylselanyl)phenyl]vinyl}phenylselane (3a)
Yield: 0.209 g (88%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.65 (s, 1 H), 7.45–7.39 (m, 3 H), 7.30–
7.19 (m, 4 H), 7.17–7.13 (m, 2 H), 2.82 (t, J = 7.3 Hz, 2 H), 1.61 (quint,
J = 7.3 Hz, 2 H), 1.36 (sext, J = 7.3 Hz, 2 H), 0.84 (t, J = 7.3 Hz, 3 H).
MS: m/z (%) = 384 (65.6), 382 (81.9), 303 (70.4), 288 (57.3), 208 (99.0),
131 (100.0), 89 (66.2), 77 (22.4).
HRMS (APCI-QTOF): m/z calcd for C16H15BrOSe [M + H]+: 382.9550;
13C NMR (CDCl3, 100 MHz): δ = 141.2, 138.9, 133.7, 131.8, 131.3,
130.1, 129.7, 129.1, 128.7, 128.2, 126.3, 111.3, 31.9, 27.5, 23.0, 13.6.
found: 382.9540.
MS: m/z (%) = 395 (M+ – 79Br, 14.0), 338 (8.3), 317 (25.2), 261 (25.8),
258 (37.7), 182 (50.8), 180 (27.4), 89 (23.9), 77 (16.2), 57 (100.0).
HRMS (APCI-QTOF): m/z calcd C18H19BrSe2 [M + H]+: 474.9079; found:
474.9072.
(E)-1-Bromo-2-(2-methoxyphenyl)vinyl-4-fluorophenylselane
(3f)
Yield: 0.162 g (84%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.67 (s, 1 H), 7.51–7.46 (m, 2 H), 7.38–
7.36 (m, 1 H), 7.30 (td, J = 8.0, 1.6 Hz, 1 H), 7.01–6.93 (m, 3 H), 6.86 (d,
J = 8.2 Hz, 1 H), 3.82 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 162.9 (d, J = 247.1 Hz), 156.5, 136.9,
136.2 (d, J = 8.1 Hz), 129.82, 129.75, 125.5, 125.1 (d, J = 3.5 Hz), 120.0,
116.2 (d, J = 21.7 Hz), 110.4, 109.8, 55.3.
(E)-{1-Bromo-2-[2-(butylselanyl)phenyl]vinyl}-4-tolylselane (3b)
Yield: 0.181 g (74%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.61 (s, 1 H), 7.44–7.40 (m, 1 H), 7.33
(d, J = 8.0 Hz, 2 H), 7.30–7.28 (m, 1 H), 7.19–7.13 (m, 2 H), 7.05 (d,
J = 8.0 Hz, 2 H), 2.83 (t, J = 7.3 Hz, 2 H), 2.27 (s, 3 H), 1.61 (quint, J = 7.3
Hz, 2 H), 1.37 (sext, J = 7.3 Hz, 2 H), 0.85 (t, J = 7.3 Hz, 3 H).
MS: m/z (%) = 388 (45.3), 386 (58.7), 307 (42.4), 292 (42.4), 212 (61.6),
131 (100.0), 89 (51.7), 77 (14.8).
HRMS (APCI-QTOF): m/z calcd for C15H12BrFOSe [M]+: 385.9221;
13C NMR (CDCl3, 100 MHz): δ = 140.3, 139.0, 138.5, 134.3, 131.9,
131.3, 129.9, 129.7, 128.6, 126.4, 126.3, 112.1, 32.0, 27.5, 23.0, 21.3,
13.6.
found: 385.9230.
MS: m/z (%) = 409 (M+ – 79Br, 13.6), 352 (14.1), 317 (28.3), 272 (50.1),
261 (32.4), 182 (42.0), 180 (23.1), 89 (30.8), 77 (3.6), 57 (100.0).
HRMS (APCI-QTOF): m/z calcd for C19H21BrSe2 [M + H]+: 488.9235;
found: 488.9237.
(E)-{2-[2-Bromo-2-(phenylselanyl)vinyl]phenyl}propylsulfane
(3g)
Yield: 0.175 g (85%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.84 (s, 1 H), 7.63–7.57 (m, 2 H), 7.45–
7.35 (m, 6 H), 7.27 (td, J = 7.4, 1.2 Hz, 1 H), 2.97 (t, J = 7.3 Hz, 2 H), 1.77
(sext, J = 7.3 Hz, 2 H), 1.13 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 140.0, 137.1, 136.1, 133.6, 130.1,
129.7, 129.1, 128.7, 128.5, 128.1, 125.3, 111.1, 35.6, 22.4, 13.5.
(E)-{2-[2-Bromo-2-(4-fluorophenyl)selanyl]vinylphenyl}butylsel-
ane (3c)
Yield: 0.197 g (80%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.66 (s, 1 H), 7.50–7.46 (m, 3 H), 7.33–
7.30 (m, 1 H), 7.26–7.22 (m, 2 H), 6.99 (t, J = 8.7 Hz, 2 H), 2.90 (t, J = 7.3
Hz, 2 H), 1.69 (quint, J = 7.3 Hz, 2 H), 1.44 (sext, J = 7.3 Hz, 2 H), 0.92 (t,
J = 7.3 Hz, 3 H).
MS: m/z (%) = 333 (M+ – 79Br, 17.4), 290 (8.0), 257 (28.2), 213 (32.9),
210 (45.3), 176 (32.0), 134 (100.0), 89 (19.5), 77 (11.7), 43 (55.5).
HRMS (APCI-QTOF): m/z calcd for C17H17BrSSe [M + H]+: 412.9478;
found: 412.9473.
13C NMR (CDCl3, 100 MHz): δ = 163.0 (d, J = 247.3 Hz), 140.4, 138.8,
136.5 (d, J = 8.1 Hz), 131.7, 131.4, 129.7, 128.7, 126.2, 124.6 (d, J = 3.2
Hz), 116.3 (d, J = 21.8 Hz), 111.8, 31.9, 27.4, 23.0, 13.5.
MS: m/z (%) = 413 (M+
261 (21.8), 182 (56.3), 180 (31.6), 89 (26.0), 77 (1.1), 57 (100.0).
–
79Br, 7.9), 355 (3.9), 317 (23.6), 276 (15.0),
(E)-{2-[2-Bromo-2-(4-tolylselanyl)vinyl]phenyl}propylsulfane
(3h)
Yield: 0.162 g (76%); yellowish oil.
HRMS (APCI -QTOF): m/z calcd for C18H18BrFSe2 [M + H]+: 492.8985;
found: 492.8981.
1H NMR (CDCl3, 400 MHz): δ = 7.70 (s, 1 H), 7.40 (d, J = 8.0 Hz, 2 H),
7.36–7.32 (m, 2 H), 7.27 (dt, J = 7.4, 0.9 Hz, 1 H), 7.18 (dt, J = 7.4, 0.9
Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 2.87 (t, J = 7.3 Hz, 2 H), 2.33 (s, 3 H),
1.67 (sext, J = 7.3 Hz, 2 H), 1.03 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 139.1, 138.4, 137.2, 136.0, 134.2,
129.9, 129.7, 128.6, 126.4, 125.3, 111.9, 35.6, 22.4, 21.2, 13.5.
(E)-1-Bromo-2-(2-methoxyphenyl)vinylphenylselane (3d)
Yield: 0.143 g (78%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.65 (s, 1 H), 7.47–7.42 (m, 2 H), 7.35
(d, J = 7.5 Hz, 1 H), 7.26–7.20 (m, 4 H), 6.87 (t, J = 7.5 Hz, 1 H), 6.79 (d,
J = 8.3 Hz, 1 H), 3.77 (s, 3 H).
MS: m/z (%) = 347 (M+ – 79Br, 17.9), 304 (17.6), 257 (32.6), 224 (100.0),
213 (41.0), 176 (33.6), 134 (86.9), 89 (29.4), 77 (4.9), 43 (75.5).
13C NMR (CDCl3, 100 MHz): δ = 156.6, 137.7, 133.4, 130.6, 129.8,
129.79, 129.1, 128.0, 125.7, 120.1, 110.5, 109.3, 55.4.
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G. Stach et al.
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HRMS (APCI-QTOF): m/z calcd for C18H19BrSSe [M + H]+: 426.9634;
found: 426.9633.
13C NMR (CDCl3, 100 MHz): δ = 162.7 (d, J = 246.5 Hz), 145.2, 142.5,
134.6, 134.5 (d, J = 7.9 Hz), 130.1, 126.4 (d, J = 3.4 Hz), 125.1, 125.0,
124.78, 124.76, 116.6 (d, J = 21.7 Hz).
(E)-{2-[2-Bromo-2-(4-fluorophenylselanyl)vinyl]phenyl}propyl-
MS: m/z (%) = 356 (34.1), 276 (100.0), 196 (62.0), 89 (27.4), 77 (0.9).
sulfane (3i)
HRMS (APCI-QTOF): m/z calcd for C14H9FSe2 [M]+: 355.9019; found:
355.9031.
Yield: 0.168 g (78%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.61 (s, 1 H), 7.43–7.39 (m, 2 H), 7.26–
7.19 (m, 3 H), 7.11 (td, J = 7.4, 1.2 Hz, 1 H), 6.94–6.89 (m, 2 H), 2.80 (t,
J = 7.3 Hz, 2 H), 1.60 (sext, J = 7.3 Hz, 2 H), 0.96 (t, J = 7.3 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 163.0 (d, J = 247.3 Hz), 139.2, 136.9,
136.4 (d, J = 8.1 Hz), 136.2, 129.7, 128.7, 128.3, 125.3, 124.7 (d, J = 3.4
Hz), 116.3 (d, J = 21.6 Hz), 111.6, 35.5, 22.4, 13.5.
MS: m/z (%) = 351 (M+ – 79Br, 13.8), 308 (7.6), 257 (27.2), 228 (47.1),
213 (28.7), 176 (30.1), 134 (100.0), 89 (22.9), 77 (2.2), 43 (64.4).
HRMS (APCI-QTOF): m/z calcd for C17H16BrFSSe [M + H]+: 430.9384;
found: 430.9389.
2-(Phenylselanyl)benzofuran (4d)
Yield: 0.033 g (80%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.55–7.53 (m, 1 H), 7.49–7.45 (m, 3 H),
7.29–7.19 (m, 5 H), 7.02 (d, J = 0.8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 157.5, 143.6, 131.6, 129.8, 129.4,
128.5, 127.5, 124.8, 122.9, 120.7, 115.8, 111.3.
MS: m/z (%) = 274 (22.9), 194 (100.0), 165 (25.1), 89 (10.0), 77 (9.1).
HRMS (APCI-QTOF): m/z calcd for C14H10OSe [M]+: 273.9897; found:
273.9904.
2-Arylselanylbenzo[b]chalcogenophenes 4a–i; General Procedure
2-(4-Tolylselanyl)benzofuran (4e)
To a two-necked round-bottomed flask, equipped with magnetic stir-
ring and a reflux condenser under argon atmosphere was added a
solution of the respective (E)-1-bromo-1-arylselenoalkene 3a–i (0.15
mmol) in MeNO2 (3 mL). Then, CuBr (15 mol%) was added and the
temperature was raised to the reflux temperature. After the time in-
dicated in Table 3, the reaction mixture was poured into H2O (30 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo, and the required
product was isolated by column chromatography using hexane as the
eluent.
Yield: 0.037 g (85%); yellowish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.53–7.50 (m, 1 H), 7.45–7.40 (m, 3 H),
7.25 (td, J = 7.3, 1.2 Hz, 1 H), 7.20 (td, J = 7.3, 1.2 Hz, 1 H), 7.07 (d,
J = 7.9 Hz, 2 H), 6.96 (d, J = 0.6 Hz, 1 H), 2.30 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 157.4, 144.4, 137.8, 132.3, 130.2,
128.6, 125.7, 124.6, 122.9, 120.5, 115.0, 111.2, 21.1.
MS: m/z (%) = 288 (20.3), 208 (100.0), 179 (5.6), 89 (11.7), 77 (2.4).
HRMS (APCI-QTOF): m/z calcd for C15H12OSe [M]+: 288.0053; found:
288.0068.
2-(Phenylselanyl)benzo[b]selenophene (4a)
2-[(4-Fluorophenyl)selanyl]benzofuran (4f)
Yield: 0.046 g (90%); yellowish solid; mp 73–74 °C.
Yield: 0.028 g (63%); reddish oil.
1H NMR (CDCl3, 400 MHz): δ = 7.54–7.44 (m, 4 H), 7.27 (td, J = 7.3, 1.2
Hz, 1 H), 7.22 (td, J = 7.3, 1.2 Hz, 1 H), 7.00–6.94 (m, 3 H).
1H NMR (CDCl3, 400 MHz): δ = 7.72 (d, J = 7.9 Hz, 1 H), 7.66 (d, J = 7.9
Hz, 1 H), 7.63 (s, 1 H), 7.47–7.45 (m, 2 H), 7.28–7.24 (m, 1 H), 7.22–
7.15 (m, 4 H).
13C NMR (CDCl3, 100 MHz): δ = 162.6 (d, J = 246.4 Hz), 157.4, 143.8,
134.3 (d, J = 8.0 Hz), 128.5, 124.9, 123.9 (d, J = 3.5 Hz), 123.0, 120.7,
116.6 (d, J = 21.9 Hz), 115.3, 111.2.
13C NMR (CDCl3, 100 MHz): δ = 145.4, 142.6, 135.3, 132.2, 131.8,
129.5, 129.4, 127.6, 125.2, 125.0, 124.8, 124.7.
MS: m/z (%) = 338 (37.2), 258 (100.0), 178 (53.3), 89 (22.4), 77 (12.9).
HRMS (APCI-QTOF): m/z calcd for C14H10Se2 [M]+: 337.9113; found:
337.9132.
MS: m/z (%) = 292 (18.3), 212 (100.0), 183 (25.4), 89 (9.4), 77 (1.9).
HRMS (APCI-QTOF): m/z calcd for C14H9FOSe [M]+: 291.9803; found:
291.9806.
2-(4-Tolylselanyl)benzo[b]selenophene (4b)
2-(Phenylselanyl)benzo[b]thiophene (4g)
Yield: 0.050 g (94%); yellowish solid; mp 75–77 °C.
Yield: 0.035 g (81%); yellowish solid; mp 57–58 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.68–7.62 (m, 2 H), 7.43 (s, 1 H), 7.40–
7.37 (m, 2 H), 7.26–7.19 (m, 2 H), 7.17–7.13 (m, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 143.8, 140.2, 132.2, 131.7, 131.4,
1H NMR (CDCl3, 400 MHz): δ = 7.67 (d, J = 7.9 Hz, 1 H), 7.60 (d, J = 7.9
Hz, 1 H), 7.55 (s, 1 H), 7.40–7.36 (m, 2 H), 7.24–7.20 (m, 1 H), 7.14–
7.10 (m, 1 H), 7.01 (d, J = 7.9 Hz, 2 H), 2.23 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 145.0, 142.7, 137.9, 134.0, 132.6,
130.8, 130.2, 128.1, 125.1, 124.8, 124.6, 124.5, 21.1.
129.3, 127.3, 126.9, 124.6, 124.4, 123.3, 121.8.
MS: m/z (%) = 290 (26.8), 210 (100.0), 89 (8.2), 77 (6.9).
HRMS (APCI-QTOF): m/z calcd for C14H10SSe [M]+: 289.9668; found:
289.9683.
MS: m/z (%) = 352 (35.9), 272 (100.0), 192 (18.5), 89 (20.2), 77 (2.6).
HRMS (APCI-QTOF): m/z calcd for C15H12Se2 [M + H]+: 352.9348;
found: 352.9135.
2-(4-Tolylselanyl)benzo[b]thiophene (4h)
2-[(4-Fluorophenyl)selanyl]benzo[b]selenophene (4c)
Yield: 0.038 g (84%); yellowish solid; mp 85–86 °C.
Yield: 0.032 g (60%); yellowish solid; mp 75–76 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.62 (t, J = 7.2 Hz, 2 H), 7.37 (s, 1 H),
7.32 (d, J = 7.9 Hz, 2 H), 7.23–7.15 (m, 2 H), 6.97 (d, J = 7.9 Hz, 2 H),
2.20 (s, 3 H).
1H NMR (CDCl3, 400 MHz): δ = 7.77 (d, J = 7.9 Hz, 1 H), 7.71 (d, J = 7.9
Hz, 1 H), 7.65 (s, 1 H), 7.55–7.52 (m, 2 H), 7.34–7.30 (m, 1 H), 7.25–
7.20 (m, 1 H), 6.98 (t, J = 8.7 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

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G. Stach et al.
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13C NMR (CDCl3, 100 MHz): δ = 143.5, 140.2, 137.7, 132.2, 131.1,
130.1, 128.0, 127.6, 124.4, 124.3, 123.1, 121.7, 21.1.
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MS: m/z (%) = 304 (23.4), 224 (100.0), 89 (8.1), 77 (1.5).
HRMS (APCI-QTOF): m/z calcd for C15H12SSe [M]+: 303.9825; found:
303.9842.
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2-[(4-Fluorophenyl)selanyl]benzo[b]thiophene (4i)
Yield: 0.033 g (72%); yellowish solid; mp 54–55 °C.
(8) Salimbeni, A.; Canevotti, R.; Paleari, F.; Poma, D.; Caliari, S.; Fici,
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Gleason, J. G.; Hill, D. T.; Morgan, T. M.; Peishoff, C. E.; Aiyar, N.;
Brooks, D. P.; Fredrickson, T. A.; Ohlstein, E. H.; Ruffolo, R. R.;
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1H NMR (CDCl3, 400 MHz): δ = 7.72 (t, J = 6.9 Hz, 2 H), 7.50–7.47 (m, 3
H), 7.34–7.27 (m, 2 H), 6.95 (t, J = 8.5 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 162.5 (d, J = 246.4 Hz), 143.6, 140.1,
134.1 (d, J = 7.9 Hz), 131.5, 127.4, 125.9 (d, J = 3.4 Hz), 124.7, 124.5,
123.3, 121.8, 116.5 (d, J = 21.3 Hz).
MS: m/z (%) = 308 (26.9), 228 (100.0), 89 (9.9), 77 (1.5).
HRMS (APCI-QTOF): m/z calcd for C14H9FSSe [M]+: 307.9574; found:
307.9579.
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Funding Information
This study was financed in part by the Coordenação de Aperfeiçoa-
mento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code
001. CNPq, FAPERGS and FINEP are thanked for financial support.
)(
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610656.
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