Cyclization of Diaryl(hetaryl)alkynes under Selenobromination Conditions: Regioselectivity and Mechanistic Studies

Article abstract of DOI:10.1002/ejoc.201500431

The cyclization of substituted diaryl(hetaryl)alkynes with in-situ-prepared SeBr₄ has been achieved. The use of an alkene additive as a bromine scavenger gives simple access to functionalized benzo[b]selenophene and selenophenothiophene derivatives from commercially available or easily accessible starting materials. The reactions can be performed in air without the use of moisture-sensitive reagents, dry solvents, or an inert atmosphere. Mechanistic studies confirmed a regioselective anti 1,2-addition in the selenobromination step, and a subsequent electrophilic substitution in the aromatic ring to complete the cyclization. The cyclization of substituted diaryl(hetaryl)alkynes with in-situ-prepared SeBr₄ has been achieved. The use of an alkene additive as a bromine scavenger gives simple access to functionalized benzo[b]selenophene and selenophenothiophene derivatives from commercially available or easily accessible starting materials.

Full text of DOI:10.1002/ejoc.201500431

FULL PAPER
DOI: 10.1002/ejoc.201500431
Cyclization of Diaryl(hetaryl)alkynes under Selenobromination Conditions:
Regioselectivity and Mechanistic Studies
Edgars Paegle,[a] Sergey Belyakov,[a] Marina Petrova,[a] Edvards Liepinsh,[a] and
Pavel Arsenyan*[a]
Keywords: Synthetic methods / Cyclization / Selenium / Heterocycles / Alkynes / Regioselectivity
The cyclization of substituted diaryl(hetaryl)alkynes with in-
situ-prepared SeBr4 has been achieved. The use of an alkene
additive as a bromine scavenger gives simple access to func-
tionalized benzo[b]selenophene and selenophenothiophene
derivatives from commercially available or easily accessible
starting materials. The reactions can be performed in air
without the use of moisture-sensitive reagents, dry solvents,
or an inert atmosphere. Mechanistic studies confirmed a re-
gioselective anti 1,2-addition in the selenobromination step,
and a subsequent electrophilic substitution in the aromatic
ring to complete the cyclization.
systems as organic semiconductors in various optoelec-
tronic devices has been an inspiration for numerous stud-
Introduction
In both medicinal chemistry[1] and materials science,[2] ies.[2]
fused selenophene-ring-containing systems have been intri-
Since the introduction of alkene additives as bromine
guing subjects of research. Although the heterocyclic scavengers,[4] the cyclization of aryl(thienyl)alkyne deriva-
benzo[b]selenophene system has not been found in natural tives in the presence of in-situ-prepared SeBr4 (SeO2 + HBr)
compounds to date, it is regarded as a bioisostere of has become one of the most straightforward methods for
naphthalene, benzofuran, benzothiophene, and indole.[3] the synthesis of a wide variety of benzo[b]selenophenes and
Recently,[1a] it has been shown that the selenium analogue selenophenothiophenes. Nevertheless, no studies on the cy-
of raloxifene, which is a selective estrogen-receptor modula- clization of symmetrically or unsymmetrically substituted
tor (SERM) that is used for the prevention of osteoporosis diaryl(hetaryl)alkynes (Scheme 1) have been reported to
in postmenopausal women and to reduce the incidence of date. Electrophilic selenium reagents, including selenium
breast cancer, shows a considerably higher cytotoxic activity halides, react with CϵC triple bonds by 1,2-addition, but
against various cancer cell lines, while also providing better the regio- and stereoselectivity strongly depends on the sub-
normal/malignant cell selectivity than the original drug. stitution patterns of the substrates and the reaction condi-
Furthermore, the results of in vivo studies on BALB/c fe- tions. In the case of PhSeCl(Br),[5] anti 1,2-addition was ob-
male mice with the 4T1 cell induced breast cancer model served, and the corresponding halovinylselenylbenzenes
showed that the selenium analogue of raloxifene is able to were usually formed with a substantial excess of one re-
suppress estrogen-dependent tumor growth, whereas no gioisomer due to regioselectivity. Nevertheless, the addition
such effect was observed for raloxifene itself. Additionally, of PhSeCl to arylferrocenylethynes[6a] led to the formation
in materials science, the potential applicability of these of two regioisomers in different ratios, and no regioselectiv-
Scheme 1. Cyclization of diarylalkynes under selenobromination conditions (EWG = electron-withdrawing group; EDG = electron-
donating group).
ity was observed in reactions of phenylselenylfluoride[6b]
[a] Department of Medicinal Chemistry, Latvian Institute of
with unsymmetrical alkynes. Additional contradictory re-
Organic Synthesis,
sults have been reported in the case of selenium halides.
Quite recently, Amosova[7] and coworkers showed that sel-
enium mono-, di-, and tetrahalides react with acetylene in
a stereoselective manner to give the corresponding anti ad-
Aizkraukles 21, Riga, LV-1006, Latvia
E-mail: pavel.arsenyan@lycos.com
www.osi.lv
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500431.
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FULL PAPER
dition products. On the other hand, in Braverman’s[8] stud- mination of the triple bond of the starting material. None-
ies, the addition of SeCl2, SeBr2, or SeCl4 to propargyl theless, using 1.5 equiv. of SeO2 and 1.0 equiv. of cyclohex-
alcohols involved syn stereochemistry and an anti-Markov- ene, and allowing the reaction to proceed for 24 h at room
nikov orientation. Furthermore, reactions of selenium hal- temperature, 2a was formed exclusively, and was easily iso-
ides with diethynylsilane and germane systems[9] can lead lated in 84% yield (Table 1, entry 1). As expected, the elec-
to sequential intermolecular anti and intramolecular syn tronic nature of the substituents attached to the aromatic
additions. Regarding the mechanism of the selenohalogena- rings strongly influenced the progress of the reaction. Thus,
tion step, cationic selenirenium species have been wide- upon cyclization of dimethoxy derivative 1b in the absence
ly[5a,5e,6a,10] postulated as a key intermediates, and their of the alkene additive, an approximately 1:1 mixture of the
existence has been proved by single-crystal X-ray diffraction desired benzo[b]selenophene derivative (i.e., 2b) and the cor-
analysis.[5a] Additionally, it has been suggested that the for- responding product of bromination of the triple bond was
mation of the selenophene heterocyclic system by the cycli- obtained, and conditions analogous to the cyclization of 1a
zation of aryl(hetaryl)alkyne derivatives under selenohalo- did not sufficiently suppress the side reaction. It seems that
genation conditions[4,11] involves the regioselective anti 1,2- the presence of strongly electron-donating methoxy groups
addition of the selenium halide to the CϵC triple bond, and the resulting increase in electron density on the triple
and subsequent intramolecular electrophilic substitution in bond drives the equilibrium towards bromination. The opti-
the aromatic ring. However, no mechanistic studies have mal reaction conditions were achieved when 4.0 equiv. of
been performed to date to prove this claim.
SeO2 and 3.0 equiv. of cyclohexene were used, providing cy-
Considering that the cyclization of commercially avail- clization product 2b in 50% yield (Table 1, entry 2). In-
able or easily prepared diaryl(hetaryl)alkynes could provide spired by the fact that the cyclization of phenylproparg-
direct access to the corresponding 2-aryl(hetaryl)benzo[b]- ylamines[11g] proceeds without bromination of the triple
selenophenes, and that the cyclization of unsymmetric sub- bond in the starting material, even in the absence of an
strates would provide useful information concerning the re- alkene additive, we attempted the cyclization of 1b in the
gioselectivity of the selenobromination step, we were moti- presence of triethylamine as an external base. However, no
vated to further explore this topic.
significant changes in the product yield or the ratio of sele-
nobromination to bromination were observed. However, be-
cause such an excessive amount of SeO2 was used for the
cyclization of 1b, a large amount of elemental selenium pre-
Results and Discussion
To investigate the reactions of in-situ-prepared SeBr4 cipitated upon quenching of the reaction mixture. Never-
(SeO2 + HBr) with various substituted diaryl(hetaryl)alk- theless, in the presence of triethylamine (4.0 equiv.), no pre-
ynes, compounds 1a–m and 3a–g were used as substrates cipitation was observed, which facilitated the isolation of
(Schemes 2 and 3). The required diaryl(hetaryl)alkynes (i.e., product 2b. It should be mentioned that 2b has been used
1b–l, 3a–g), and (cyclohex-1-en-1-ylethynyl)benzene (1m) elsewhere as a key precursor for the preparation of selenium
were easily prepared by Sonogashira-type coupling proto- analogues of raloxifene.[1a] A very distinctive reaction was
cols (for the procedure used to prepare the starting materi- observed in the case of difluoro derivative 1c. Despite the
als, see the Supporting Information), and the results of the fact that the use of 2.0 equiv. of SeO2 and 1.5 equiv. of cy-
cyclization reactions are summarized in Table 1. Analo- clohexene resulted in the complete consumption of the
gously to recently reported reactions of phenylpropargyl starting material (i.e., 1c) after stirring at room temperature
alcohol derivatives,[4] selenobromination of commercially for 3 d, no bromination of the triple bond of the starting
available 1,2-diphenylethyne (1a) in the absence of a cyclo- material was observed, and product 2c was easily isolated
hexene additive as a bromine scavenger led to the formation in 64% yield (Table 1, entry 3). This observation can be ex-
of a nearly inseparable mixture (approximately 9:1) of the plained by the decreased nucleophilicity of the triple bond
desired cyclization product [i.e., 3-bromo-2-phenylbenzo[b]- resulting from the inductive electron-withdrawing effect of
selenophene (2a)] and a side-product originating from bro- the fluorine atoms. This conclusion was further supported
Scheme 2. Cyclization of diaryl(hetaryl)alkynes 1a–l and (cyclohex-1-en-1-ylethynyl)benzene (1m).
Scheme 3. Cyclization of dihetarylalkynes 3a–g.
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Cyclization of Diaryl(hetaryl)alkynes
Table 1. Cyclization of diaryl(hetaryl)alkynes 1a–l and 3a–g and (cyclohex-1-en-1-ylethynyl)benzene (1m).[a]
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Table 1. (Continued)
[a] Reactions were carried out on a scale of up to 1.12 mmol of 1a–1m and 3a–3g; 0.43 mL of HBr (48%) was used per 1.0 mmol of
selenium dioxide. [b] Et3N (4.0 equiv.) additive was used. [c] An inseparable mixture of products was obtained. [d] A mixture of two
inseparable regioisomers was obtained. [e] Cyclohex-2-enone (1.5 equiv.) was used instead of cyclohexene. [f] 0.27 mL of HBr (48%) was
used per 1.0 mmol of selenium dioxide. [g] Cyclohex-2-enone (1.5 equiv.) was used instead of cyclohexene in the presence of Et3N
(1.0 equiv.) additive.
by the negligible reaction of diarylalkyne 1d in the presence yield (Table 1, entry 7). Next, we tried to achieve the cycli-
of an alkene additive. We have previously shown[4] that zation of substrates bearing two different electron-with-
SeBr4 can react directly with an alkene additive by bromi- drawing groups. As was expected in the case of the cycliza-
nating the double bond, which may be the main reaction in tion of 1h, no bromination of the triple bond of the starting
the case of the strongly deactivated 1d. Nevertheless, when material was observed, but very poor regioselectivity led to
the reaction was conducted in the absence of cyclohexene, the formation of both possible regioisomers, which we were
no bromination of the triple bond of the starting material not able to separate (Table 1, entry 8). Additionally, com-
was detected, and the corresponding cyclization product plete regioselectivity of the cyclization was not achieved in
(i.e., 2d) was isolated in very good yield (84%; Table 1, en- the presence of one strongly electron-withdrawing group
try 4). Next, we examined the cyclization of unsymmetri- (Table 1, entries 9 and 10). Thus, the cyclizations of sub-
cally substituted diarylalkynes, which can theoretically lead strates 1i and 1j led to the formation of 5:1 and 10:1 mix-
to the formation of two regioisomers (Table 1, entries 5–13). tures of regioisomers, respectively. However, the minor re-
In the case of methoxy-substituted derivative 1e, a large gioisomers were easily separated by recrystallization, and
amount of the product of bromination of the triple bond the corresponding cyclization products (i.e., 2i and 2j) were
was observed, as well as poor regioselectivity. As a result, obtained in moderate yields. The cyclization of phenyl-
a complex mixture of inseparable products was obtained ethynyl pyridines 1k and 1l proceeded with complete re-
(Table 1, entry 5). Nevertheless, even the slightly electron- gioselectivity, and the corresponding products (i.e., 2k and
accepting fluorine atom in 1f promoted complete regiose- 2l) were isolated in 57 and 66% yields, respectively (Table 1,
lectivity, and product 2f was obtained in 55% yield (Table 1, entries 11 and 12). Finally, we attempted the cyclization of
entry 6). However, such polarized triple bonds also have a 1m, which contains an aromatic C(sp2) on one side of the
quite pronounced affinity for the addition of bromine; triple bond, and an aliphatic C(sp2) on the other. An unex-
therefore, 3.0 equiv. of SeO2 and 3.0 equiv. of cyclohexene pected outcome was obtained in this case, as complete re-
were used to achieve the optimal reaction conditions. Very gioselectivity was achieved, and the selenophene ring
similar results were obtained in the case of diarylalkyne 1g, formed towards the nonaromatic side of substrate 1m. As a
which gave benzo[b]selenophene derivative 2g in a 58% result, the corresponding 3-bromo-2-phenyl-4,5,6,7-tetra-
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Cyclization of Diaryl(hetaryl)alkynes
hydrobenzo[b]selenophene (2m) was obtained in 58% yield
(Table 1, entry 13).
The reactions of dihetarylalkynes 3a–3g were regio-
specific in all cases, and as a result, the corresponding sele-
nophenothiophene derivatives (i.e., 4a–4g) were obtained in
moderate yields (Table 1, entries 14–20). For 3a and 3b, op-
timal reaction conditions were achieved when 1.2 equiv. of
SeO2 and 1.5 equiv. of cyclohexene were used. Although no
bromination of the triple bond of the starting material was
detected, slight α-bromination of the thiophene ring was
observed. Nevertheless, the corresponding cyclization prod-
ucts (i.e., 4a and 4b) were isolated in 28 and 40% yields,
respectively (Table 1, entries 14 and 15). Even more pro-
nounced α-bromination occurred in the cyclization of 3c,
but the reaction was somewhat cleaner in the presence of
Figure 1. Molecular structure of 3,3Ј-(3,5-dibromodiseleno-
1.0 equiv. of trimethylamine. As a result, selenophenothio- pheno[3,2-b:2Ј,3Ј-d]thiophene-2,6-diyl)dipyridine (4g). Displace-
ment ellipsoids are drawn at the 50% probability level, and
hydrogen atoms are shown as small spheres of arbitrary radius.
phene derivative 4c was obtained in a 33% yield (Table 1,
entry 16). To simplify the isolation of pure 4c, cyclohex-2-
enone was used instead of cyclohexene as a bromine scaven-
ger. In the case of unsymmetrically substituted derivative
3d, the α-positions of the thiophene rings are blocked, pre-
venting the bromination of the thiophene rings. However,
similarly to what was observed for the cyclization of di-
arylalkynes 1f and 1g (Table 1, entries 6 and 7), quite pro-
nounced bromination of the triple bond of the starting ma-
terials occurred. Therefore, a greater excess of SeO2
(4.0 equiv.) and cyclohexene (3.0 equiv.) was necessary, and
the corresponding cyclization product (i.e., 4d) was isolated
in 38% yield (Table 1, entry 17). Although slight α-bromin-
ation of the thiophene ring also occurred during the cycliza-
tion of 3e and 3f, selenopheno[2,3-b]thiophene derivatives
4e and 4f were obtained in moderate yields (39 and 32%,
respectively) (Table 1, entries 18 and 19). The cyclization of
2,5-bis(pyridin-3-ylethynyl)thiophene (3g) provided a suc-
cessful example of biscyclization. In the presence of
3.0 equiv. of SeO2 and 2.4 equiv. of cyclohexene, the reac-
tion proceeded for 4 d, and fused heterocyclic system 4g
was obtained in 40% yield (Table 1, entry 20). No chroma-
tographic methods were necessary for the purification of
the product, and the structure of 4g was unambiguously
confirmed by X-ray analysis. Figure 1 shows a projection of
two interacting molecules of 4g along the monoclinic axis.
In the crystal structure, the molecules lie in general posi-
tions, and the symmetrical parts of the molecules have dif-
ferent surroundings. For one of the pyridyl groups, all of
the intermolecular contacts correspond to sums of the van
der Waals radii, whereas the second pyridine ring partici-
pates in a strong σ-hole N-1Ј···Br-1 bonding with a distance
of 3.034(3) Å. There are also weak intermolecular σ-hole
interactions between selenium (Se-7) and bromine (Br-2)
atoms, with a distance of 3.607(2) Å. These interactions
lead to the formation of molecular chains along the [100]
crystallographic direction.
intermediate 7, and product 2c allowed us to directly moni-
tor the progress of the reaction by 19F NMR spectroscopy
in dioxane using D2O as an internal standard (Figure 2,
Scheme 4). In the absence of an alkene additive, the reac-
tion of 1c reached completion after 24 h, and a mixture of
cyclization product 2c and the corresponding triple bond
bromination adduct was obtained. Furthermore, we were
not able to detect any intermediates. However, when the
reaction was performed in the presence of 2.0 equiv. of
SeO2 and 1.0 equiv. of cyclohexene, the cyclization process
was significantly slowed. The complete disappearance of
the resonance at δ = –111.31 ppm due to starting material
1c (Figure 2, A) was observed after 24 h. At this point, only
one major product was observed in the reaction mixture
Figure 2. Cyclization of 1c monitored by 19F NMR spectroscopy
in dioxane using D2O as an internal standard. A) resonance signal
due to starting material 1c; B) 19F NMR spectrum of the reaction
mixture after 24 h, showing intermediate 7 as the major compo-
nent; C) 19F NMR spectrum of the reaction mixture after 48 h;
D) 19F NMR spectrum of the reaction mixture after 72 h, showing
The exceptionally slow reaction of difluoro-substituted
derivative 1c provided an excellent opportunity to study the
stepwise mechanism of the cyclization process under condi-
tions identical to those described in Table 1. The presence
of fluorine atoms in the structures of starting material 1c, cyclization product 2c as the major component.
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Scheme 4. Proposed mechanism for the cyclization of 1c.
(Figure 2, B). This product showed two resonances at δ = 7. Nevertheless, the equivalent of molecular bromine ex-
–112.84 and –116.04 ppm in the 19F NMR spectra (Fig- pelled during the cyclization process poisons starting mate-
ure 2, B). In addition, the 77Se NMR spectrum of the reac- rial 1c by bromination of the triple bond. On the other
tion mixture was recorded, and only one major resonance hand, in the presence of cyclohexene, the equivalent of bro-
at δ = 916 ppm was observed. The similarity of the chemical mine formed from intermediate 6 is transferred to the scav-
shift of this resonance to that of commercially available enger, and 1,2-dibromocyclohexane is formed along with
PhSeBr (δ = 888 ppm in dioxane/D2O) led us to conclude the vinylselenylbromide intermediate 7 (Scheme 4, D). The
1
that after 24 h of stirring, vinylselenylbromide intermediate structure of intermediate 7 was confirmed by H, 13C, 19F,
7 had been formed almost exclusively. After 48 h of stirring, and 77Se NMR spectroscopic data. The formation of 1,2-
the slow disappearance of intermediate 7 and the formation dibromocyclohexane was observed by GC–MS analysis of
of cyclization product 2c was observed (Figure 2, C). Fi- the reaction mixture, and it was also isolated in pure form.
nally, after 72 h, benzo[b]selenophene derivative 2c was the By quenching the reaction mixture with brine and ethyl
major component of the reaction mixture (Figure 2, D). acetate after 24 h of stirring, diselenide derivative 8 was iso-
Product 2c also shows two distinct resonances in its 19F lated in 42% yield. Apparently, an aqueous work-up led to
NMR spectrum at δ = –110.64 and –112.80 ppm.
the disproportionation of intermediate 7, and subsequent
The experimental data discussed above allowed us to Se–Se bond formation. The fact that diselenide 8 was iso-
confirm certain aspects of the cyclization mechanism under lated solely as an E,E stereoisomer (Figure 3) provides un-
selenobromination conditions (Scheme 4). Considering the ambiguous evidence of stereospecific anti 1,2-addition in
study of Poleschner and Seppelt,[5a] there is good reason to the selenobromination step (Scheme 4, A,B). As observed
believe that the addition of SeBr4 to a triple bond of 1c by monitoring the cyclization of 1c using 19F NMR spec-
occurs through a cationic selenirenium type intermediate 5 troscopy (Figure 2, C,D), intermediate 7 is slowly converted
(Scheme 4, A). As the presence of this type of intermediate into the desired product (i.e, 2c) through intramolecular
can only be detected by low-temperature techniques,[5a] it is electrophilic substitution in the aromatic ring. More evi-
not surprising that intermediate 5 was not detected during dence for the existence of intermediate 7 was provided by
our room-temperature experiments. Unfortunately, due to the oxidative addition of Br2 to diselenide 8 (Scheme 4, G).
the relatively high melting point of dioxane, low-tempera- When 1.0 equiv. of Br2 was added to a dioxane solution of
ture studies are not feasible in this case. The selenobromina- diselenide 8, the diselenide was completely converted into
tion step (Scheme 4, A,B) is crucial for achieving a regiose- vinylselenylbromide 7 in less than 1 h, and the slow forma-
lective synthesis in the case of unsymmetrical substrates. It tion of the cyclization product 2c (Scheme 4H) was ob-
seems that the nucleophilic attack of the bromide anion oc- served again. Moreover, no side-products were formed dur-
curs at the carbon bearing the lowest electron density. A ing this experiment. Finally, as mentioned previously, SeBr4
more polarized triple bond leads to more pronounced re- can react directly with an alkene additive by bromination
gioselectivity. The faster cyclization in the absence of an of the double bond (Scheme 4I). Thus, the presence of
alkene additive (Scheme 4, C) could be explained by the fact SeBr2 species in the reaction mixture should not be categor-
that more electrophilic SeIV species 6 are involved in the ically denied. To confirm the formation of selenium(II)
SEAr step compared to the corresponding SeII intermediate bromide, the reaction was monitored directly in an NMR
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Cyclization of Diaryl(hetaryl)alkynes
cation. Thin-layer chromatography (TLC) was performed using
Merck Silica gel 60 F254 plates, which were visualized using UV
(254 nm) fluorescence. Zeochem silica gel (ZEOprep 60/35–70 mi-
crons –SI23501) was used for column chromatography. 1H, 13C, 19F,
and 77Se NMR spectra were recorded with a Varian 400 Mercury
spectrometer at 400.0, 100.58, 376.21, and 76.37 MHz, respectively,
at 298 K in CDCl3. The 1H chemical shifts were calibrated using
the residual CHCl3 signal (δ = 7.26 ppm), 13C shifts were calibrated
using the CDCl3 signal (δ = 77.0 ppm), and 77Se shifts were cal-
ibrated using the dimethyl selenide signal (δ = 0.0 ppm). Melting
tube. After the reactants [in-situ-prepared selenium(IV)
bromide and cyclohexene] were mixed, a broad resonance
at δ = 950 ppm in the 77Se NMR spectra was observed. This
signal can probably be assigned to SeBr2. The selenium(II)
bromide was unstable in aqueous dioxane, and dispropor-
tionated over the next 0.5 h. Then 77Se signals at δ = 728,
411, and 406 ppm were detected, and could be assigned to
selenium polybromides SenBrm.[12,13] Because an example of
3-bromo-2-phenylbenzo[b]selenophene synthesis in the re-
action of diphenylethyne with SeBr2 has been demonstrated points were determined with a “digital melting-point analyser”
previously,[11e] partial participation of this pathway
(Fisher).
3-Bromo-2-phenylbenzo[b]selenophene (2a):[14] Selenium dioxide
(186 mg, 1.68 mmol) was dissolved in hydrogen bromide (48%;
0.72 mL), and the mixture was stirred at room temperature for
15 min. A solution of diphenylethyne (1a; 200 mg, 1.12 mmol) and
cyclohexene (110 mg, 1.34 mmol) in dioxane (4.0 mL) was added
dropwise, and the reaction mixture was stirred at room temperature
for 24 h. The reaction mixture was then quenched with ethyl acetate
(50 mL) and water (20 mL). The mixture was stirred for 15 min at
room temperature, then the organic phase was separated, and the
aqueous phase was extracted with ethyl acetate (2ϫ 30 mL). The
combined organic extracts were dried with anhydrous sodium sulf-
ate, and concentrated under vacuum. The crude product was puri-
fied by flash chromatography on silica gel using petroleum ether as
eluent to give 2a (315 mg, 84%). 1H NMR (400 MHz, CDCl3): δ
= 7.97–7.93 (m, 1 H, 4-CH), 7.89–7.85 (m, 1 H, 7-CH), 7.72–7.67
(m, 2 H, 2Ј,6Ј-CH), 7.52–7.39 (m, 4 H, 6,3Ј,4Ј,5Ј-CH), 7.39–7.33
(m, 1 H, 5-CH) ppm.
(Scheme 4, J,K) should be under consideration.
Figure 3. Molecular structure of 1,2-bis[(E)-2-bromo-1,2-bis(4-
fluorophenyl)vinyl] diselenide (8). Displacement ellipsoids are
drawn at the 50% probability level, and hydrogen atoms are shown
as small spheres of arbitrary radius.
3-Bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]selenophene
(2b):[1a] Selenium dioxide (373 mg, 3.36 mmol) was dissolved in
hydrogen bromide (48%; 1.44 mL), and the mixture was stirred at
room temperature for 15 min. A solution of bis(4-methoxyphenyl)-
ethyne (1b; 200 mg, 0.839 mmol), cyclohexene (207 mg,
2.52 mmol), and triethylamine (0.47 mL, 3.36 mmol) in dioxane
Conclusions
The first examples of regioselective addition of in-situ-
prepared SeBr4 to diaryl(hetaryl)alkynes are reported. This
approach represents the most straightforward access to 2-
aryl(hetaryl)-3-bromobenzo[b]selenophenes and selenophe-
nothiophenes. The regioselectivity is strongly affected by (4.0 mL) was added dropwise, and the reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was then
quenched with ethyl acetate (50 mL) and water (20 mL). The mix-
ture was stirred for 15 min at room temperature, then the organic
phase was separated, and the aqueous phase was extracted with
ethyl acetate (2ϫ 30 mL). The combined organic phases were dried
with anhydrous sodium sulfate, and concentrated under vacuum.
The crude product was purified by flash chromatography on silica
gel using a mixture of petroleum ether and ethyl acetate (40:1) as
eluent. In the first fractions, a solid precipitate appeared, which
was not collected (almost exclusively contained the corresponding
the electronic nature of the aromatic rings. A more polar-
ized triple bond leads to higher regioselectivity, and as a
general rule, cyclization is favoured on the side of the more
electron-rich aromatic ring. The presence of electron-donat-
ing groups or a strongly polarized triple bond leads to an
increased tendency for bromination, but a greater excess of
SeBr4 can significantly suppress the poisoning of the start-
ing material. On the other hand, strongly electron-with-
drawing groups completely prevented the bromination of
the triple bond of the starting material, even in the absence dibromo derivative). After evaporation of the solvents, a pale yel-
low oil was obtained, which slowly crystallized upon standing at
room temperature. This material was recrystallized from a mixture
of an alkene additive. Experimental evidence confirmed
stereospecific anti 1,2-addition in the selenobromination
step and subsequent intramolecular electrophilic substitu-
tion on the aromatic ring to be the main contributors to
the cyclization mechanism.
Further work in this research field will be dedicated to
the application of the developed method to the construction
of more advanced selenophene-ring-containing molecular
scaffolds as core structures of potential nonlinear optical
materials.
1
of petroleum ether and ethyl acetate to give 2b (166 mg, 50%). H
NMR (400 MHz, CDCl3): δ = 7.79 (d, 1 H, 3JH,H = 8.8 Hz, 4-CH),
4
7.64–7.59 (m, 2 H, 2Ј,6Ј-CH), 7.35 (d, 1 H, JH,H = 2.3 Hz, 7-CH),
4
3
7.07 (dd, 1 H, JH,H = 2.3, JH,H = 8.8 Hz, 5-CH), 7.00–6.96 (m, 2
H, 3Ј,5Ј-CH), 3.89 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3) ppm.
3-Bromo-6-fluoro-2-(4-fluorophenyl)benzo[b]selenophene
(2c):[1a]
Starting from bis(4-fluorophenyl)ethyne (1c), and following a
method analogous to that used for the cyclization of 1a, but using
2.0 equiv. of selenium dioxide and 1.5 equiv. of cyclohexene, and
running the reaction for 72 h gave 2c (222 mg, 64%). 1H NMR
4
3
(400 MHz, CDCl3): δ = 7.88 (dd, 1 H, JH,F = 5.1, JH,H = 8.8 Hz,
Experimental Section
4
4-CH), 7.66–7.61 (m, 2 H, 3Ј,5Ј-CH), 7.57 (dd, 1 H, JH,H = 2.3,
General Remarks: Unless otherwise stated, all reagents were pur-
chased from commercial suppliers and used without further purifi-
3JH,F = 8.0 Hz, 7-CH), 7.23 (ddd, 1 H, 4JH,H = 2.3, 3JH,H = 8.8 Hz,
3JH,F = 8.8 Hz, 5-CH), 7.19–7.13 (m, 2 H, 2Ј,6Ј-CH) ppm.
Eur. J. Org. Chem. 2015, 4389–4399
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4395

E. Paegle, S. Belyakov, M. Petrova, E. Liepinsh, P. Arsenyan
3-Bromo-2-[4-(methoxycarbonyl)phenyl]benzo[b]seleno- from a mixture of petroleum ether and ethyl acetate to give 2i
FULL PAPER
Methyl
1
phene-6-carboxylate (2d): Selenium dioxide (57 mg, 0.510 mmol)
was dissolved in hydrogen bromide (48%; 0.22 mL), and the mix-
ture was stirred at room temperature for 15 min. A suspension of
dimethyl 4,4Ј-(ethyne-1,2-diyl)dibenzoate (1d; 100 mg, 0.340 mmol)
in dioxane (6.0 mL) was added, and the reaction mixture was
stirred at room temperature for 24 h. The reaction mixture was
quenched with ethyl acetate (100 mL) and water (40 mL). The mix-
ture was stirred for 15 min at room temperature, then the organic
phase was separated, and the aqueous phase was extracted with
ethyl acetate (2ϫ 50 mL). The combined organic phases were dried
with anhydrous sodium sulfate, and concentrated under vacuum.
The crude product was purified by column chromatography on sil-
ica gel using mixture of petroleum ether, dichloromethane, and
ethyl acetate (13:7:1) as eluent to give 2d (130 mg, 84%) as a white
solid, m.p. 175–176 °C. 1H NMR (600 MHz, CDCl3): δ = 8.59 (dd,
(201 mg, 57%), m.p. 122–123 °C. H NMR (400 MHz, CDCl3): δ
= 10.08 (s, 1 H, CHO), 8.00–7.95 (m, 3 H, 2,6-CH, 4Ј-CH), 7.91–
7.85 (m, 3 H, 3,5-CH, 7Ј-CH), 7.55–7.49 (m, 1 H, 6Ј-CH), 7.43–
7.37 (m, 1 H, 5Ј-CH) ppm. 13C NMR (100.58 MHz, CDCl3): δ =
191.6, 141.0, 140.8, 139.2, 138.8, 135.9, 130.5, 129.8, 126.4, 126.3,
125.8, 125.2, 108.1 ppm. MS (EI, 70 eV): m/z (%) = 364 (100)
[M]+. C15H9BrOSe (364.10): calcd. C 49.48, H 2.49; found C 49.30,
H 2.51.
Methyl 4-(3-Bromobenzo[b]selenophen-2-yl)benzoate (2j): Starting
from 1j, and following a method analogous to that used for the
cyclization of 1a, except that the reaction was run for 30 h, and a
mixture of petroleum ether and ethyl acetate (1:0Ǟ40:1) was used
as eluent. To remove the minor regioisomer, the product was recrys-
tallized from a mixture of petroleum ether and ethyl acetate to give
1
2j (214 mg, 64%), m.p. 125–126 °C. H NMR (400 MHz, CDCl3):
5
4
4
1 H, JH,H = 0.6, JH,H = 2.4 Hz, 7Ј-CH), 8.15 (dd, 1 H, JH,H
=
δ = 8.17–8.08 (m, 2 H, 2,6-CH), 7.99–7.93 (m, 1 H, 4Ј-CH), 7.90–
7.84 (m, 1 H, 7Ј-CH), 7.81–7.73 (m, 2 H, 3,5-CH), 7.54–7.47 (m, 1
H, 6Ј-CH), 7.41–7.34 (m, 1 H, 5Ј-CH), 3.96 (s, 3 H, OCH3) ppm.
13C NMR (100.58 MHz, CDCl3): δ = 166.6, 140.8, 139.5, 139.2,
139.1, 130.0, 129.8, 129.7, 126.3, 126.1, 125.7, 125.2, 107.7,
2.4, 3JH,H = 12.6 Hz, 5Ј-CH), 8.16–8.12 (m, 2 H, 3,5-CH), 8.00 (dd,
5
3
1 H, JH,H = 0.6, JH,H = 12.6 Hz, 4Ј-CH), 7.80–7.75 (m, 2 H, 2,6-
CH), 3.98 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 166.6, 166.5, 144.2, 143.5, 139.0, 138.7,
130.4, 129.8 (2 C), 127.5, 127.0, 126.6, 126.1, 107.6, 52.4, 52.3 ppm.
MS (EI, 70 eV): m/z (%) = 452 (100) [M]+. C18H13BrO4Se (452.16):
calcd. C 47.81, H 2.90; found C 47.60, H 2.95.
52.2 ppm. MS (EI, 70 eV): m/z (%)
=
394 (100) [M]+.
C16H11BrO2Se (394.13): calcd. C 48.76, H 2.81; found C 48.67,
H 3.15.
3-Bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]selenophene
(2f):
General Method for the Cyclization of Phenylethynylpyridines 1k
and 1l: Selenium dioxide (497 mg, 4.48 mmol) was dissolved in
hydrogen bromide (48%; 1.92 mL), and the mixture was stirred at
room temperature for 15 min. A solution of 1k or 1l (200 mg,
1.12 mmol) and cyclohexene (276 mg, 3.36 mmol) in dioxane
(4.0 mL) was added dropwise, and the reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was quenched
with dichloromethane (100 mL) and saturated aqueous sodium
hydrogen carbonate solution (50 mL). The mixture was stirred for
30 min at room temperature, then the organic phase was separated,
and aqueous phase was extracted with dichloromethane (2ϫ
50 mL). The combined organic phases were dried with anhydrous
sodium sulfate, and concentrated under vacuum. The crude prod-
uct was purified by flash chromatography on silica gel using mix-
ture of petroleum ether and ethyl acetate (20:1Ǟ5:1) as eluent to
give 2k or 2l.
Starting from 1-fluoro-4-[(4-methoxyphenyl)ethynyl]benzene (1f),
and following a method analogous to that used for the cyclization
of 1a, but using 3 equiv. of selenium dioxide and cyclohexene. A
mixture of petroleum ether and dichloromethane (0:1Ǟ20:3) was
used as eluent. The product was then recrystallized from a mixture
of petroleum ether and ethyl acetate to remove traces of the corre-
sponding dibromo derivative, to give 2f (187 mg, 55%) as a white
1
solid, m.p. 114–115 °C. H NMR (400 MHz, CDCl3): δ = 7.80 (d,
3JH,H = 8.8 Hz, 1 H), 7.67–7.60 (m, 2 H, 3Ј,5Ј-CH), 7.36 (d, 1 H,
4JH,H = 2.3 Hz, 7-CH), 7.18–7.11 (m, 2 H, 2Ј,6Ј-CH), 7.08 (dd, 1
4
3
H, JH,H = 2.3 Hz, JH,H = 8.8 Hz, 5-CH), 3.90 (s, 3 H, OCH3)
ppm. 13C NMR (100.58 MHz, CDCl3): δ = 162.6 (d, JC,F
249.1 Hz), 158.4, 139.9, 136.2, 134.6, 131.6 (d, JC,F = 8.2 Hz),
=
1
3
4
2
131.1 (d, JC,F = 3.5 Hz), 126.7, 115.6 (d, JC,F = 21.8 Hz), 114.7,
108.4, 106.3 (d, 5JC,F = 0.8 Hz), 55.7 ppm. 19F NMR (376.21 MHz,
4
3
CDCl3): δ = –112.7 (tt, JH,F = 5.5, JH,F = 8.5 Hz) ppm. MS (EI,
70 eV): m/z (%) = 384 (100) [M]+. C15H10BrFOSe (384.11): calcd.
C 46.90, H 2.62; found C 46.82, H 2.69.
2-(3-Bromobenzo[b]selenophen-2-yl)pyridine (2k): White solid
1
(214 mg, 57%), m.p. 134–135 °C. H NMR (400 MHz, CDCl3): δ
= 8.65–8.62 (m, 1 H, 6-CH), 8.61–8.56 (m, 1 H, 3-CH), 7.99–7.94
4-(3-Bromo-6-methoxybenzo[b]selenophen-2-yl)benzaldehyde (2g):
Starting from 4-[(4-methoxyphenyl)ethynyl]benzaldehyde (1g), and
following a method analogous to that used for the cyclization of 1b,
but without using the triethylamine additive, and using a mixture of
petroleum ether and dichloromethane (1:1) as eluent gave 2g
(194 mg, 58%) as a pale grey solid, m.p. 154–155 °C. 1H NMR
(400 MHz, CDCl3): δ = 10.07 (s, 1 H, CHO), 7.97–7.92 (m, 2 H,
2,6-CH), 7.87–7.83 (m, 2 H, 3,5-CH), 7.84 (d, 1 H, 3JH,H = 8.8 Hz,
4Ј-CH), 7.37 (d, 1 H, JH,H = 2.3 Hz, 7Ј-CH), 7.10 (dd, 1 H, JH,H
= 2.3, 3JH,H = 8.8 Hz, 5Ј-CH), 3.90 (s, 3 H, OCH3) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 191.5, 158.7, 141.1, 140.3, 135.6, 135.5,
134.7, 130.3, 129.8, 127.1, 115.0, 108.3, 107.5, 55.7 ppm. MS (EI,
70 eV): m/z (%) = 394 (100) [M]+. C16H11BrO2Se (394.13): calcd.
C 48.76, H 2.81; found C 48.44, H 3.01.
(m, 1 H, 4Ј-CH), 7.90–7.86 (m, 1 H, 7Ј-CH), 7.80 (ddd, 1 H, 4JH,H
3
3
= 1.8, JH,H = 8.0 Hz, JH,H = 8.0 Hz, 4-CH), 7.49–7.44 (m, 1 H,
4
6Ј-CH), 7.39–7.34 (m, 1 H, 5Ј-CH), 7.27 (ddd, 1 H, JH,H = 0.8,
3JH,H
=
5.0 Hz, JH,H
=
8.0 Hz, 5-CH) ppm. 13C NMR
3
(100.58 MHz, CDCl3): δ = 152.7, 149.6, 142.9, 142.1, 139.1, 136.4,
126.2, 125.3 (2 C), 123.1, 121.7, 106.1 ppm. MS (EI, 70 eV): m/z
(%) = 337 (100) [M]+. HRMS (ESI): calcd. for C13H9BrNSe+ [M
+ H]+ 337.9078; found 337.9090. C13H8BrNSe (337.08): calcd.
C 46.32, H 2.39, N 4.16; found C 46.13, H 2.52, N 4.08.
4
4
3-(3-Bromobenzo[b]selenophen-2-yl)pyridine (2l): White solid
1
(248 mg, 66%), m.p. 75–76 °C. H NMR (400 MHz, CDCl3): δ =
4
4
8.92 (d, 1 H, JH,H = 2.0 Hz, 2-CH), 8.65 (dd, 1 H, JH,H = 1.6,
3JH,H = 4.9 Hz, 6-CH), 8.03–7.99 (m, 1 H, 4-CH), 7.97–7.94 (m, 1
H, 4Ј-CH), 7.90–7.86 (m, 1 H, 7Ј-CH), 7.54–7.49 (m, 1 H, 6Ј-CH),
7.42–7.37 (m, 2 H, 5,5Ј-CH) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 150.2, 149.4, 140.6, 139.1, 137.0, 136.3, 131.3, 126.3,
126.1, 125.8, 125.2, 123.2, 108.3 ppm. MS (EI, 70 eV): m/z (%) =
337 (100) [M]+. HRMS (ESI): calcd. for C13H9BrNSe+ [M + H]+
4-(3-Bromobenzo[b]selenophen-2-yl)benzaldehyde (2i): Starting from
1i, and following a method analogous to that used for the cycliza-
tion of 1a, except that the reaction was run for 30 h, and a mixture
of petroleum ether and ethyl acetate (1:0Ǟ40:1) was used as eluent.
To remove the minor regioisomer, the product was recrystallized
4396
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4389–4399

Cyclization of Diaryl(hetaryl)alkynes
337.9078; found 337.9080. C13H8BrNSe (337.08): calcd. C 46.32, upon standing at room temperature to give a greenish yellow solid,
1
H 2.39, N 4.16; found C 46.20, H 2.45, N 4.02.
m.p. 56–57 °C. H NMR (400 MHz, CDCl3): δ = 7.41–7.38 (m, 3
H, 2,3Ј,5Ј-CH), 7.34 (d, 1 H, 3JH,H = 5.2 Hz, 3-CH), 7.10 (dd, 1 H,
3JH,H = 3.8, 3JH,H = 5.2 Hz, 4Ј-CH) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 143.7, 136.7, 135.2, 133.7, 127.3, 127.2, 127.1, 126.7,
123.2, 100.6 ppm. MS (EI, 70 eV): m/z (%) = 348 (100) [M]+.
C10H5BrS2Se (348.13): calcd. C 34.50, H 1.45, S 18.42; found
C 34.31, H 1.41, S 18.14.
3-Bromo-2-phenyl-4,5,6,7-tetrahydrobenzo[b]selenophene
(2m):
Starting from (cyclohex-1-en-1-ylethynyl)benzene (1m), and follow-
ing a method analogous to that used for the cyclization of 1a, but
3.0 equiv. of SeO2 and 1.5 equiv. of cyclohex-2-enone were used,
and the reaction was run for 1 h. A mixture of petroleum ether and
dichloromethane (50:1) was used as eluent to give 2m (216 mg,
58%) as a pale grey amorphous solid, m.p. 56–58 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.62–7.55 (m, 2 H, 2Ј,6Ј-CH), 7.43–7.31
(m, 3 H, 3Ј,4Ј,5Ј-CH), 2.90–2.82 (m, 2 H, 4-CH2), 2.60–2.53 (m, 2
5-(6-Bromo-2-methylselenopheno[3,2-b]thiophen-5-yl)thiophene-2-
carbaldehyde (4d): Starting from 5-[(5-methylthiophen-2-yl)ethyn-
yl]thiophene-2-carbaldehyde (3d), and following a method analo-
gous to that used for the cyclization of 1b, but without the triethyl-
amine additive, and using a mixture of petroleum ether and ethyl
acetate (40:1Ǟ10:1) as eluent, gave 4d (129 mg, 38%) as a yellow
H, 7-CH2), 1.91–1.82 (m,
4
H, 5,6-CH2) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 141.3, 138.3, 137.0, 135.5, 129.3, 128.3,
127.8, 110.4, 28.2, 27.8, 23.7, 22.5 ppm. MS (EI, 70 eV): m/z (%) =
340 (100) [M]+. C14H13BrSe (340.12): calcd. C 49.44, H 3.85; found
C 49.55, H 4.01.
1
solid, m.p. 182–183 °C. H NMR (400 MHz, CDCl3): δ = 9.90 (s,
3
1 H, CHO), 7.70 (d, 1 H, JH,H = 4.0 Hz, 3-CH), 7.42 (d, 1 H,
4
3JH,H = 4.0 Hz, 4-CH), 7.03 (q, 1 H, JH,H = 1.2 Hz, 3Ј-CH), 2.61
General Method for the Cyclization of Thiophen-2-ylethynylpyrid-
ines 3a and 3b: Following a method analogous to that used for the
cyclization of 1k and 1l, but using 1.2 equiv. of selenium dioxide
and 1.5 equiv. of cyclohexene.
4
(d, 3 H, JH,H = 1.2 Hz, CH3) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 182.7, 146.6, 144.7, 142.6, 142.3, 136.1, 135.3, 131.7,
127.0, 121.4, 103.4, 16.4 ppm. MS (EI, 70 eV): m/z (%) = 390 (100)
[M]+. C12H7BrOS2Se (390.17): calcd. C 36.94, H 1.81, S 16.44;
found C 36.80, H 1.85, S 16.21.
2-(6-Bromoselenopheno[3,2-b]thiophen-5-yl)pyridine (4a): Pale yel-
low solid (104 mg, 28%), m.p. 158–159 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.58–8.54 (m, 1 H, 6-CH), 8.46–8.43 (m, 1 H, 3-CH),
2-(4-Bromoselenopheno[2,3-b]thiophen-5-yl)pyridine (4e): Selenium
dioxide (144 mg, 1.30 mmol) was dissolved in hydrogen bromide
(48%; 0.36 mL), and the mixture was stirred at room temperature
for 15 min. The resulting selenium tetrabromide solution was
cooled to 0 °C, and a solution of 2-(thiophen-3-ylethynyl)pyridine
(3e; 200 mg, 1.08 mmol) and cyclohexene (108 mg, 1.30 mmol) in
dioxane (4.0 mL) was added dropwise. Then the reaction mixture
was slowly allowed to reach room temperature, and stirring was
continued at room temperature for 24 h. The reaction mixture was
quenched with dichloromethane (100 mL) and saturated aqueous
sodium hydrogen carbonate solution (50 mL). The mixture was
stirred for 30 min at room temperature, then the organic phase was
separated, and aqueous phase was extracted with dichloromethane
(2ϫ 50 mL). The combined organic phases were dried with anhy-
drous sodium sulfate, and concentrated under vacuum. The crude
product was purified by flash chromatography on silica gel using a
mixture of petroleum ether and ethyl acetate (1:0Ǟ40:1) as eluent
to give 4e (mixed with a small amount of the α-brominated prod-
uct; 144 mg, 39%) as a pale yellow solid, m.p. 150–151 °C. 1H
4
3
3
7.75 (ddd, 1 H, JH,H = 1.8, JH,H = 7.8 Hz, JH,H = 7.8 Hz, 4-
3
3
CH), 7.42 (d, 1 H, JH,H = 5.3 Hz, 2Ј-CH), 7.39 (d, 1 H, JH,H
5.3 Hz, 3Ј-CH), 7.22 (ddd, 1 H, JH,H = 0.8, JH,H = 4.9, JH,H
=
=
4
3
3
7.8 Hz, 5-CH) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 152.6,
149.6, 144.9, 144.2, 136.4 (2 C), 127.8, 123.8, 122.7, 119.6,
100.0 ppm. MS (EI, 70 eV): m/z (%) = 343 (100) [M]+. HRMS
(ESI): calcd. for C11H7BrNSSe+ [M + H]+ 343.8642; found
343.8639. C11H6BrNSSe (343.10): calcd. C 38.51, H 1.76, N 4.08,
S 9.35; found C 38.38, H 1.83, N 3.79, S 9.26.
3-(6-Bromoselenopheno[3,2-b]thiophen-5-yl)pyridine (4b): Pale grey
1
solid (148 mg, 40%), m.p. 85–86 °C. H NMR (400 MHz, CDCl3):
4
4
δ = 8.89 (d, 1 H, JH,H = 2.2 Hz, 2-CH), 8.62 (dd, 1 H, JH,H
=
3
1.6, JH,H = 4.9 Hz, 6-CH), 8.01–7.97 (m, 1 H, 4-CH), 7.46 (d, 1
3
3
H, JH,H = 5.2 Hz, 2Ј-CH), 7.40 (d, 1 H, JH,H = 5.2 Hz, 3Ј-CH),
7.40–7.36 (m, 1 H, 5-CH) ppm. 13C NMR (100.58 MHz, CDCl3):
δ = 149.7, 149.2, 143.6, 137.9, 136.3, 135.4, 131.3, 127.4, 123.3,
101.8 ppm. MS (EI, 70 eV): m/z (%) = 343 (100) [M]+. HRMS
(ESI): calcd. for C11H7BrNSSe+ [M + H]+ 343.8642; found
343.8645. C11H6BrNSSe (343.10): calcd. C 38.51, H 1.76, N 4.08,
S 9.35; found C 38.33, H 1.81, N 3.92, S 9.16.
5
4
NMR (400 MHz, CDCl3): δ = 8.54 (ddd, 1 H, JH,H = 1.0, JH,H
= 1.8, 3JH,H = 4.9 Hz, 6-CH), 8.51–8.47 (m, 1 H, 3-CH), 7.75 (ddd,
1 H, 4JH,H = 1.8, JH,H = 7.8, JH,H = 7.8 Hz, 4-CH), 7.43 (d, 1 H,
3
3
6-Bromo-5-(thiophen-2-yl)selenopheno[3,2-b]thiophene (4c): Selen-
ium dioxide (175 mg, 1.58 mmol) was dissolved in hydrogen brom-
ide (48%; 0.43 mL), and the mixture was stirred at room tempera-
ture for 15 min, then the solution was cooled to 15 °C. A solution
of bis(thiophen-2-yl)ethyne (3c; 200 mg, 1.05 mmol), cyclohex-2-
enone (152 mg, 1.58 mmol), and triethylamine (146 μL, 1.05 mmol)
in dioxane (4.0 mL) was added dropwiseto the cooled selenium tet-
rabromide solution, and the reaction mixture was stirred at room
temperature for 24 h. The reaction mixture was quenched with
ethyl acetate (50 mL) and water (20 mL). The mixture was stirred
for 15 min at room temperature, then the organic phase was sepa-
rated, and aqueous phase was extracted with ethyl acetate (2ϫ
30 mL). The combined organic phases were dried with anhydrous
sodium sulfate, and concentrated under vacuum. The crude prod-
uct was purified by flash chromatography on silica gel using petro-
leum ether as eluent. The resulting fractions were divided into three
parts. The first contained brominated products, but the last ones
were pure product. After evaporation of the solvent, 4c (121 mg,
33%) was obtained as a greenish yellow oil that slowly crystallized
3JH,H = 5.3 Hz, 2Ј-CH), 7.31 (d, 1 H, JH,H = 5.3 Hz, 3Ј-CH), 7.22
3
(ddd, 1 H, 4JH,H = 1.2, 3JH,H = 4.9 Hz, 3JH,H = 7.8 Hz, 5-CH) ppm.
13C NMR (100.58 MHz, CDCl3): δ = 152.7, 150.1, 149.5, 145.3,
136.5, 134.8, 128.7, 122.7 (2 C), 119.6, 101.0 ppm. MS (EI, 70 eV):
m/z (%) = 343 (100) [M]+. HRMS (ESI): calcd. for C11H7BrNSSe+
[M + H]+ 343.8642; found 343.8646. C11H6BrNSSe (343.10): calcd.
C 38.51, H 1.76, N 4.08, S 9.35; found C 38.13, H 1.68, N 3.78,
S 9.12.
3-(4-Bromoselenopheno[2,3-b]thiophen-5-yl)pyridine (4f): Starting
from 3-(thiophen-3-ylethynyl)pyridine (3f), and following a method
analogous to that used for the cyclization of 3a and 3b, except that
upon addition of the dioxane solution to the solution of selenium
tetrabromide, the reaction mixture was cooled to 0 °C, and then
slowly allowed to reach room temperature, gave 4f (118 mg, 32%)
as a pale yellow solid, m.p. 137–138 °C. 1H NMR (400 MHz,
4
CDCl3): δ = 8.89–8.85 (m, 1 H, 2-CH), 8.63 (dd, 1 H, JH,H = 1.5,
3JH,H = 4.8 Hz, 6-CH), 7.96 (ddd, 1 H, 4JH,H = 2.0, 4JH,H = 2.0 Hz,
3
3JH,H = 8.0 Hz, 4-CH), 7.49 (d, 1 H, JH,H = 5.2 Hz, 2Ј-CH), 7.38
Eur. J. Org. Chem. 2015, 4389–4399
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4397

E. Paegle, S. Belyakov, M. Petrova, E. Liepinsh, P. Arsenyan
FULL PAPER
(dd, 1 H, JH,H = 4.8, JH,H = 8.0 Hz, 5-CH), 7.33 (d, 1 H, JH,H the H, 13C, 19F, 77Se NMR spectra, and crystallographic data for
= 5.2 Hz, 3Ј-CH) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 149.9, compounds 2b, 2f, 2k, 2l, 4g, and 8.
149.3, 148.5, 138.5, 136.5, 133.3, 131.2, 129.2, 123.3, 122.4,
3
3
3
1
103.0 ppm. MS (EI, 70 eV): m/z (%)
=
343 (100) [M]+.
Acknowledgments
C11H6BrNSSe (343.10): calcd. C 38.51, H 1.76, N 4.08, S 9.35;
found C 38.15, H 1.90, N 3.97, S 9.01.
Financial support for this work provided by the Latvian Council
of Science (grant number 447/2012) is gratefully acknowledged.
3,3Ј-(3,5-Dibromodiselenopheno[3,2-b:2Ј,3Ј-d]thiophene-2,6-diyl)-
dipyridine (4g): Selenium dioxide (234 mg, 2.10 mmol) was dis-
solved in hydrogen bromide (48%; 0.90 mL), and the mixture was
stirred at room temperature for 15 min. A solution of 3g (200 mg,
0.698 mmol) and cyclohexene (114 mg, 1.40 mmol) in dioxane
(12 mL) was then added dropwise, and the resulting mixture was
stirred at room temperature for 96 h. The reaction mixture was
quenched with dichloromethane (300 mL) and aqueous NaOH
solution (1 m; 100 mL). The mixture was stirred at room tempera-
ture for 1 h, then the organic phase was separated, and the aqueous
phase was extracted with dichloromethane (100 mL). The com-
bined organic phases were dried with anhydrous Na2SO4, and con-
centrated under reduced pressure. The crude product was purified
by adding ethyl acetate (30 mL), and stirring at room temperature
for 30 min. After decantation of the solvent, this washing pro-
cedure was repeated twice. The resulting pure product was dried
under vacuum to give 4g (170 mg, 40%) as a yellow solid, m.p.
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1
4
Ͼ 245 °C. H NMR (400 MHz, CDCl3): δ = 8.93 (d, 1 H, JH,H
2.0 Hz, 2,2Ј-Py-CH), 8.66 (dd, 1 H, JH,H = 1.6, JH,H = 4.9 Hz),
=
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3
3831–3840.
4
4
3
8.05 (ddd, 1 H, JH,H = 2.0, JH,H = 2.0, JH,H = 8.0; 4 Hz, 4Ј-Py-
CH), 7.44 (dd, 1 H, 3JH,H = 4.9, 3JH,H = 8.0; 5 Hz, 5Ј-Py-CH) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 149.5, 149.4, 144.3, 138.0,
136.5, 131.6, 131.0, 123.5, 102.8 ppm. MS (EI, 70 eV): m/z (%) =
603 (100) [M + 1]+. HRMS (ESI): calcd. for C18H9Br2N2SSe2+ [M
+ H]+ 602.7178; found 602.7185. C18H8Br2N2SSe2 (602.06): calcd.
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S 5.17.
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1,2-Bis[(E)-2-bromo-1,2-bis(4-fluorophenyl)vinyl] Diselenide (8): Fol-
lowing a method analogous to that used for the cyclization of 1c,
but running the reaction for 24 h, and using a mixture of petroleum
ether and dichloromethane (10:1) as eluent gave 8 (146 mg, 42%) as
a pale yellow crystalline solid, m.p. 196–197 °C (crystallized from
dichloromethane by slow evaporation at room temperature). 1H
NMR (400 MHz, CDCl3): δ = 7.25–7.19 (m, 4 H), 7.00–7.08 (m,
1
12 H) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 162.9 (d, JC,F
1
4
= 250.5 Hz), 162.1 (d, JC,F = 248.6 Hz), 136.3 (d, JC,F = 3.6 Hz),
4
3
3
136.2 (d, JC,F = 3.6 Hz), 131.4 (d, JC,F = 8.4 Hz), 131.2 (d, JC,F
5
2
= 8.7 Hz), 131.2 (d, JC,F = 0.6 Hz), 116.7 (m), 115.4 (d, JC,F
=
21.7 Hz), 115.0 (d, JC,F = 21.7 Hz) ppm. 19F NMR (376.21 MHz,
2
4
3
CDCl3): δ = –110.6 (tt, JH,F = 5.5, JH,F = 8.5 Hz), –112.7 (tt,
4JH,F = 6.1, 3JH,F = 8.2 Hz) ppm. 77Se NMR (76.37 MHz, dioxane/
D2O): δ = 575.7 ppm. C28H16Br2F4Se2 (746.15): calcd. C 45.07,
H 2.16; found C 44.78, H 2.31.
Crystallographic Data: Diffraction data were collected at low tem-
perature with a Nonius KappaCCD diffractometer using graphite-
monochromated Mo-Kα radiation (λ = 0.71073 Å). The crystal
structures of 2b, 2f, 2k, 2l, 4g, and 8 were solved by direct meth-
ods[15a] and refined by full-matrix least-squares.[15b,15c]
CCDC-1048489 (for 2b), 1048491 (for 2f), 1048490 (for 2k),
1048492 (for 2l), 1048495 (for 4g), 048493 (for 8) contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Supporting Information (see footnote on the first page of this arti-
cle): methods for the preparation of starting materials, copies of
4398
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4389–4399

Cyclization of Diaryl(hetaryl)alkynes
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Received: April 3, 2015
Published Online: June 5, 2015
Eur. J. Org. Chem. 2015, 4389–4399
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4399