An approach to the selenobromination of aryl(thienyl)alkynes: Access to 3-bromobenzo[b]selenophenes and selenophenothiophenes

Article abstract of DOI:10.1002/ejoc.201402095

A novel approach for the cyclization of arylalkynes with selenium(IV) bromide prepared in situ has been elaborated. The use of an alkene additive as a bromine scavenger provides a convenient synthetic pathway for the synthesis of a wide variety of 3-bromobenzo[b]selenophenes. Reactions can be performed open to air without the use of moisture-sensitive reagents, anhydrous solvents, or an inert atmosphere. Selenobromination of ethynylthiophenes has been applied for the preparation of selenopheno[3,2-b]- and selenopheno[2,3-b]thiophenes. The molecular structures of representative derivatives have been confirmed by X-ray crystallographic analysis. The use of an alkene additive as a bromine scavenger under selenobromination conditions provides a convenient synthetic pathway for the synthesis of a wide variety of 3-bromobenzo[b]selenophenes in moderate to high yields. The reactions are not moisture-sensitive and do not require an inert atmosphere. Selenobromination of ethynylthiophenes enables the preparation of selenopheno[b]thiophenes. Copyright

Full text of DOI:10.1002/ejoc.201402095

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201402095
An Approach to the Selenobromination of Aryl(thienyl)alkynes: Access to
3-Bromobenzo[b]selenophenes and Selenophenothiophenes
Edgars Paegle,[a] Sergey Belyakov,[a] and Pavel Arsenyan*[a]
Keywords: Heterocycles / Selenophenes / Selenium / Bromination / Cyclization
A novel approach for the cyclization of arylalkynes with
selenium(IV) bromide prepared in situ has been elaborated.
The use of an alkene additive as a bromine scavenger pro-
vides a convenient synthetic pathway for the synthesis of a
wide variety of 3-bromobenzo[b]selenophenes. Reactions
can be performed open to air without the use of moisture-
sensitive reagents, anhydrous solvents, or an inert atmo-
sphere. Selenobromination of ethynylthiophenes has been
applied for the preparation of selenopheno[3,2-b]- and
selenopheno[2,3-b]thiophenes. The molecular structures of
representative derivatives have been confirmed by X-ray
crystallographic analysis.
presence of iodine and other electrophiles.[6a] The most im-
portant advantages of this methodology are mild reaction
conditions, regioselectivity, and high product yields, and it
is the only general method available for the preparation of
3-iododerivatives. However, starting materials for this cycli-
zation are prepared by using a rather low yielding, three-
step procedure. Moreover, only a limited number of the re-
quired iodoanilines are commercially available, and the syn-
thesis of appropriately substituted substrates is quite com-
plex. Another option is the reaction of phenylacetylene de-
rivatives with selenium tetrahalogenides (SeCl4 and SeBr4)
generated in situ.[9] This methodology has been known for
more than 30 years, but the scope of useful substrates re-
mains quite poor. Cyclizations have been achieved by using
phenyl- and naphthylpropiolic acids,[9a,9c,9e] phenylpropiolic
acid amide[9f] and sulfonamide,[9a] phenylethynylphosphonic
acid,[9d] and phenylpropargylic amines.[9b] The cyclization
reaction is regarded as a two-step process (Scheme 1).[9e]
The first step involves anti addition of selenium tetrahalide
(SeCl4 or SeBr4) to a triple bond, forming a selenohaloge-
nated intermediate, followed by intramolecular cyclization
through an SEAr mechanism, while one equivalent of
hydrogen halide and halogen molecule is expelled.
Based on the above idea and on our experience with thio-
phene and selenophene chemistry,[3c,3d] in the present study
we focused on the construction of benzo[b]selenophene,
selenopheno[3,2-b]- and -[2,3-b]thiophene rings by treat-
ment of ethynylarenes with SeBr4 prepared in situ. Because
a range of phenylacetylene derivatives are either commer-
ciallyavailableoreasilypreparedfromthecorrespondingaryl-
halogenides and terminal alkynes, we were inspired to de-
velop this protocol. Considering that the corresponding
bromo derivatives are more useful for further modifications
through different types of transition-metal-catalyzed reac-
tions, we focused our attention on cyclization under seleno-
bromination conditions.
Introduction
During the last decade benzo[b]selenophenes have at-
tracted increasing attention in both medicinal chemistry
and materials science. Although the benzo[b]selenophene
heterocyclic system has not been found in natural com-
pounds, it is considered to be a bioisoster of naphthalene,
benzofurane, benzothiophene, and indole.[1] It has been
shown that benzo[b]selenophene analogues of milfasartan
and eprosartan (compounds used for treatment of hyperten-
sion) are excellent AT1 receptor antagonists, and selenium
analogues exhibit higher activity than the corresponding
benzo[b]thiophene derivatives.[2] Our own research work on
synthesis and antiproliferative activity studies of 2,3-disub-
stituted benzo[b]selenophene derivatives has shown that
these compounds exhibit medium or low acute cytotoxic
effect on normal cells without causing changes in cell mor-
phology.[3a,3b] Furthermore, fused selenophene ring con-
taining systems have attracted much interest because of
their potential application as organic semiconductors in
various optoelectronic devices.[4]
Although there are a number of more or less general
methods for the preparation of benzo[b]selenophenes,[5–10]
only two methods are applicable for the synthesis of 3-halo
derivatives, which are extremely useful for further modifica-
tions through different kinds of cross-coupling protocols. In
2006, Larock and co-workers published their studies on the
cyclization of 1-(1-alkynyl)-2-(methylseleno)arenes in the
[a] Department of Medicinal Chemistry, Latvian Institute of
Organic Synthesis,
Aizkraukles 21, Riga 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.201402095.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
E. Paegle, S. Belyakov, P. Arsenyan
FULL PAPER
Scheme 1. Ethynylarenes cyclization mechanism under selenohalogenation conditions.
dioxane as solvent (Table 1, entry 4). All attempts to sepa-
rate 2 from 2a were unsuccessful, so it was crucial to find a
methodology that would avoid formation of 2a.
Results and Discussion
As previously[9a] mentioned, cyclization of phenylacetyl-
ene derivatives in the presence of water is higher yielding
and less time-consuming than the corresponding reactions
under anhydrous conditions.[11] The standard protocol in-
volves dropwise addition of arylalkyne solution in ethers
(diethyl ether or dioxane) to a freshly prepared aqueous
solution of selenium(IV) bromide, or vice versa. The aque-
ous solution of selenium(IV) bromide is simply prepared by
treatment of selenium dioxide with an appropriate amount
of concentrated hydrobromic acid.
Because phenylacetylene (1) is the simplest and most
readily available arylalkyne, and because no successful ex-
amples of its cyclization under the given conditions have
been shown so far, we selected this compound as our first
model (Scheme 2, Table 1). Brief examination of this reac-
tion under previously described conditions[9e] led us to con-
clude that four main products were formed (Table 1, en-
try 1). Simultaneously with the expected cyclization product
2, both stereoisomers of dibromo derivative 2a and divinyl
selenide 2b were formed (approximate mass ratio 2:2:1).
Moreover, considerable amounts of minor unidentified side
Table 1. Optimization of reaction conditions for the cyclization of
1.[a]
Entry
SeO2
Akene additive (equiv.)
Product mass ratio [%][h]
[equiv.]
2
2a
2b
1[b]
2[c]
3[d]
4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
1.2
–
–
–
–
–
–
43
55
59
60
34
68
96 (45)
90
82
75
52
92
97 (46)
97 (51)
97 (60)
70
39
40
38
38
61
28
Ͻ 1
4
10
21
45
4
Ͻ 1
Ͻ 1
Ͻ 1
26
18
5
3
2
5
4
3
6
8
4
3
4
2
2
2
4
5[e]
6[f]
7[g]
8
cyclohexene (1.0)
cyclohexene (0.8)
cyclohexene (0.6)
cyclohexene (0.4)
allyl alcohol (1.0)
3,4-dihydro-2H-pyran (1.0)
cyclohex-2-enone (1.0)
cyclohex-2-enone (1.2)
cyclohex-2-enone (1.0)
isophorone (1.0)
9
10
11
12
13
14
15
16
products were detected, and all attempts to isolate pure 2 [a] Reaction conditions (unless otherwise stated): phenylacetylene 1
(200 mg), dioxane (12 mL), 48% HBr (0.43 mL), selenium dioxide
from such a complex mixture were unsuccessful. Although
(1.0 mmol). [b] Reaction performed in 3 mL dioxane. [c] Reaction
alteration of the addition sequence did not affect cyclization
performed in 6 mL dioxane. [d] Reaction performed in 9 mL of di-
oxane. [e] Et2O was used as solvent. [f] THF was used as solvent.
of phenylpropargylic amines,[9b] in this case it was impor-
tant that the solution of 1 in dioxane was added to aqueous
SeBr4 solution, because the reverse addition led to a more
complex mixture of products accompanied by more pro-
nounced formation of 2b. Because the structure of 2b corre-
sponds to addition of two phenylacetylene (1) units to one
selenium(IV) bromide molecule, more diluted conditions
[g] For isolation of 2 the reaction was performed on a 5.0 g scale
of 1. [h] Determined by GC–MS. [i] Isolated yield shown in paren-
theses.
Table 2. Optimization of reaction conditions for cyclization of 3a.[a]
were employed (Table 1, entries 2–4). In this way, the ap- Entry SeO2
Cyclohexene
[equiv.] [equiv.]
Product mass ratio [%][b]
4a[c]
5
6
pearance of minor side products was completely prevented
and the formation of divinyl selenide 2b was suppressed to
a minimum (Table 2, entry 4). Further dilution did not con-
siderably reduce the formation of 2b further. Notably, use
of diethyl ether instead of dioxane drastically increased the
amount of 2a formed (Table 1, entry 5). Despite the fact
that the formation of 2a was suppressed by approximately
8% by performing the reaction in tetrahydrofuran (THF)
1
2
3
4
5
1.2
1.2
1.5
2.0
4.0
–
62 (42)
99 (62)
Ͼ 99 (76)
72 (48)
73 (46)
38
1
Ͻ 1
11
1
–
–
–
17
26
1.0
1.2
–
–
[a] Reaction conditions (unless otherwise stated): 3a (300 mg), di-
oxane (6 mL), 48% HBr (0.43 mL), selenium dioxide (1.0 mmol).
[b] Determined by GC–MS. [c] Isolated yield is shown in paren-
(Table 1, entry 6), cleaner reaction was achieved by using theses.
Scheme 2. Cyclization of 1.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
Selenobromination of Aryl(thienyl)alkynes
Because the formation of 2a could be explained by reac- without the use of anhydrous solvents or an inert atmo-
tion of 1 with the bromine expelled during the cyclization sphere. The last time the synthesis of 2 was reported
process (Scheme 1), we examined the use of a selective (1974),[11b] the approach employed selective debromination
bromine scavenger that, under the given reaction condi- of 2,3-dibromobenzo[b]selenophene.
tions, would be inactive to SeBr4. We were pleased to find
Recently, two papers[12] have been published by Braver-
that, in the presence of one equivalent of cyclohexene, for- man and co-workers regarding reactions of propargyl
mation of 2a was almost completely prevented and, as a alcohols with selenium di- and tetrahalides under an-
result, a nearly 1:1 mixture of 2 and 1,2-dibromocyclo- hydrous conditions, but no successful results were obtained
hexane was obtained (Table 1, entry 7). Although, separa- for the preparative synthesis of benzo[b]selenophenes. Be-
tion of these compounds by chromatographic methods cause highly versatile substrates could be obtained for fur-
turned out to be rather difficult, 2 was isolated in high pu- ther modifications, we were encouraged to explore the cycli-
rity by distillation under reduced pressure. We noticed that zation of these derivatives. Commercially available 3-phen-
the use of a decreased amount of cyclohexene led to the ylpropargyl alcohol (3a) was chosen as a model compound
formation of larger quantities of 2a (Table 1, entries 8–10). for optimization of the reaction conditions (Scheme 3,
On the other hand, when a larger amount of alkene additive Table 2). As expected, a large amount of the corresponding
was employed, no 2a formed, however, the yield of 2 de- dibromo derivative 5 was formed in the absence of alkene
creased. In the presence of 2.0 equiv. cyclohexene almost no additive (Table 2, entry 1). Although the separation of 4a
cyclization product was observed, and 1,2-dibromocyclo- from 5 was rather complex, pure 4a was isolated in 42%
hexane was formed as a main product, which indicates that yield. Nevertheless, in the presence of one equivalent of
under the given reaction conditions the alkene additive re- cyclohexene, the formation of 5 was nearly completely pre-
acts with SeBr4. Because, in this case, no cyclization took vented and product 4a was obtained (62%) (Table 2, en-
place, it was presumed that selenium(IV) bromide itself try 2). When 1.5 equiv. selenium(IV) oxide and 1.2 equiv.
could serve as a brominating agent. Such a hypothesis was cyclohexene were used, the yield of 4a increased to 76%
confirmed by performing the reaction in the absence of 1. (Table 1, entry 3). We found that the formation of 5 could
As a result, 1,2-dibromocyclohexane was obtained as al- be effectively prevented when a large excess of SeO2 was
most sole product. To adapt the methodology for small- used (Table 2, entries 4 and 5). Such an approach is not
scale synthesis, we looked for alternative bromine scaven- only economically disadvantageous, but also another side
gers that would form more polar adducts that would be product, 6, was formed as a result of oxidation of the
easier to separate from 2 (Table 1, entries 11–16). Allyl hydroxymethyl group of 4a. Aldehyde 6 was also obtained
alcohol turned out to be rather ineffective because a large by oxidation of 4a with manganese(IV) oxide (Scheme 3).
amount of 2a as well as other unidentified side products
Optimized reaction conditions (Table 2, entry 3) were
were formed (Table 1, entry 11). 2,3-Dihydropyrane ap- applied to the cyclization of substituted phenylpropargyl
peared to be slightly less active than cyclohexene and, con- alcohols (Scheme 4). Arylalkynes 3b, 3c, and 3e–i were suc-
sequently, only 4% 2b was formed (Table 1, entry 12). Fi- cessfully obtained in a single step from the corresponding
nally, cyclohexenone showed excellent activity and selectiv- aryl bromides and terminal alkynes by using Sonogashira
ity, providing easy isolation of pure 2 in 46% yield (Table 1, cross-coupling reactions (see the Supporting Information).
entry 13). Notably, the use of 1.5 equiv. SeO2 and 1.2 equiv. By cyclization of dimethyl-substituted 3b and cyclohexyl
cyclohexenone did not dramatically alter the product yield derivative 3c, the corresponding benzo[b]selenophenes 4b
(Table 1, entry 14). However, when the amount of selenium and 4c were obtained in very good yields. Although the
dioxide was increased to 2.0 equiv. and only 1.0 equiv. cy- formation of 4d was detected by GC–MS, all attempts to
clohexenone was used, 2 was isolated in 60% yield (Table 1, isolate pure product were unsuccessful; failure in this case
entry 15). With the aim of finding a less expensive alterna- can possibly be explained by steric hindrance imparted by
tive to cyclohexenone, we attempted to use isophorone but, the phenyl groups. As previously reported,[9e] the outcome
presumably for steric reasons, this turned out to be ineffec- of the reaction depends strongly on the nature of the sub-
tive (Table 1, entry 16).
stituents in the aromatic ring. Even in the presence of an
Thus, a potential precursor for the synthesis of more alkene additive, cyclization of para-methoxy-substituted 3e
complex benzo[b]selenophene derivatives can be obtained in led to the formation of an inseparable mixture of 4e and
a single step directly from commercially available materials the corresponding dibromo derivative. In the case of ortho-
Scheme 3. Cyclization of 3a and oxidation of 4a to 6.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
E. Paegle, S. Belyakov, P. Arsenyan
FULL PAPER
Scheme 4. Cyclization of phenylpropargyl alcohols 3b–j. Reaction conditions (unless otherwise stated): 3b–j (300 mg), dioxane (6 mL),
48% HBr (0.43 mL), selenium dioxide (1.0 mmol). [a] Product was isolated with 10% premix of 7-methoxy isomer. [b] SeO2 (2.0 equiv.)
and cyclohexene (1.0 equiv.) were used and reaction time was 72 h.
methoxy-substituted 3g, only a trace amount of the cycliza- more attractive for attack by the bromine molecule. Particu-
tion product 4g was detected (GC–MS), with the major larly, in the case of 3g, direct bromination of the triple bond
product being the corresponding dibromo derivative. No almost completely overcomes the selenobromination.
bromination of the triple bond of the starting material was
To broaden the substrate scope of the reaction further,
observed in the cyclization of 3f but, unfortunately, the re- we attempted the cyclization of thienylpropargyl alcohols,
action suffered from a lack of complete regioselectivity. which could lead to formation of selenopheno[3,2-b]- and
Compound 4f was formed as a major regioisomer (approxi- selenopheno[2,3-b]thiophenes (Scheme 5). Although elec-
mately 90%), but we were not able to separate this from the trophilic cyclization of 3-alkynyl-2-organylselenothio-
corresponding 7-methoxy derivative. The presence of the phenes[13] serves as a powerful tool for the preparation of
other regioisomer could not be established by GC–MS 4-haloselenopheno[2,3-b]thiophenes, no convenient meth-
analysis because the mixture appears as a single signal, but odologies are available for the synthesis of 6-haloseleno-
1
it could be readily recognized by H NMR spectroscopy. A pheno[3,2-b]thiophenes.
strongly electron-withdrawing group in the para-position of
Similarly to phenylpropargyl alcohols 3b, 3c, and 3e–j,
3h favors the corresponding cyclization product, and 4h was substrates 7a–h were prepared in one step from the corre-
easily isolated in 88% yield. Similarly, para-fluoro derivative sponding bromothiophenes and terminal alkynes under the
3i underwent clean cyclization to give 4i in very good yield. Sonogashira protocol (see the Supporting Information).
Interesting results were found in the cyclization of ortho- When previously optimized reaction conditions (Table 2,
fluoro-substituted 3j. Although seven days were required entry 3) were applied to the cyclization of 7a, a complex
for complete consumption of starting material, no forma- mixture of products was obtained. Along with cyclization
tion of the corresponding dibromo derivative was observed. product 8a, not only was a large amount of the correspond-
Use of 2.0 equiv. SeO2 and 1.0 equiv. cyclohexene reduced ing dibromo derivative formed, but bromination at the α-
the reaction time to 72 h, and 4j was isolated in 49% yield. position of thiophene ring was also detected. No better re-
In the case of meta-fluoro-substituted 3k, the reaction pro- sults were obtained by increasing the amount of alkene ad-
ceeded with complete regioselectivity and the correspond- ditive, however, α-bromination was almost completely pre-
ing cyclization product 4k was isolated in 83% yield.
vented when only 2.4 equiv. of hydrogen bromide was used
From the results obtained for the cyclization of substi- per 1.0 equiv. SeO2. In this case, formation of the corre-
tuted phenylpropargyl alcohol derivatives 3a–k (Scheme 4), sponding dibromo derivative was also considerably sup-
it is quite clear that the failure of the cyclization of para- pressed, however, formation of SeBr4 in situ is open to
and ortho-methoxy substituted compounds 3e and 3g is not question. The isolation of pure 8a was unsuccessful, but
due to deactivation towards the intramolecular SEAr step treatment of 7b with selenium(IV) oxide (1.2 equiv.) and
(Scheme 1), as reported[9e] for the cyclization of phenylpro- cyclohexene (1.2 equiv.) led to the formation of seleno-
piolic acid derivatives. More likely, the presence of an elec- pheno[3,2-b]thiophene derivative 8b in 34% yield. As ex-
tron-donating group increases the electron density on the pected, formation of the cyclization product 8c was not de-
CϵC triple bond of the starting material, thus making it tected, probably because of steric hindrance. When α-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
Selenobromination of Aryl(thienyl)alkynes
Scheme 5. Cyclization of thienylpropargyl alcohols 7a–h. Reaction conditions (unless otherwise stated): 7a–h (300 mg), dioxane (6.0 mL),
48% HBr (0.27 mL), selenium dioxide (1.0 mmol). [a] Reaction conditions were those used for the cyclization of phenyl-
propargyl alcohols 3a–i. [b] During addition of thienylethynyl alcohol 7f–g solution to SeBr4 the reaction mixture was cooled to 0 °C.
methyl-substituted 7d was submitted to the conditions used
for cyclization, only a trace amount of 8d was observed by
GC–MS, and the corresponding dibromo derivative was
formed as a major product. Because in this case no α-
bromination could take place, we tried to employ reaction
conditions analogous to the cyclization of phenylpropargyl
alcohol derivatives (Table 2, entry 3), but no better results
were achieved. In general, the reactivity of 2-alkynylthio-
phenes 7a–d was similar to methoxy-substituted 3e and 3g
(Scheme 4). On the other hand, the presence of a strongly
electron-withdrawing formyl group activates 7e towards
cyclization. As a result, under previously optimized condi-
tions (Table 2, entry 3) cyclization of 7e proceeded without
formation of the corresponding dibromo derivative and
product 8e was isolated in 66% yield. Completely different
reactivity was observed in the case of 3-alkynylthiophenes
7f and 7g. Although α-bromination in the thiophene ring
was not completely avoided, no formation of the corre-
sponding dibromo derivative was observed, and seleno-
pheno[2,3-b]thiophenes 8f and 8g were obtained in moder-
ate yields. As expected, diphenyl-substituted 7h did not
form any cyclization product.
For representative derivatives 4b, 8b, and 8g single-crys-
tal X-ray analysis data were obtained. Molecular structures
with thermal ellipsoids and atomic labels are shown in Fig-
ure 1. The crystal structures of 4b, 8b, and 8g are isomor-
phous and each asymmetric unit consists of two indepen-
dent molecules. These compounds form tetramers by means
of O–H···OЈ and OЈ–HЈ···O intermolecular hydrogen bonds.
The lengths of these bonds in the structures of 4b, 8b, and
8g are 2.742(4)/2.801(4) Å, 2.740(7)/2.787(7) Å, and
2.729(7), 2.803(8) Å, respectively.
Figure 1. Molecular structures of 4b, 8b, and 8g.
reaction proceeded for 36 h and ester derivative 10b was
Other C(sp)-substituted arylalkynes were also subjected isolated in 71% yield.
to cyclization (Scheme 6). Very good yield was obtained by
The longer reaction time required for these reactions is
selenobromination of hept-1-ynylbenzene (9a). Because of probably a result of the decrease in nucleophilicity of the
the low polarity of 10a, cyclohex-2-enone was used as alk- triple bond in the initial compounds. It should be noted
ene additive. Considerably slower reaction was observed in that previously reported[9e] cyclization of the corresponding
the cyclization of ethyl phenylpropiolate (9b). By using methyl ester provided the cyclization product in only 17%
2.0 equiv. selenium dioxide and 1.2 equiv. cyclohexene the yield. Although no bromination of the CϵC triple bond of
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
E. Paegle, S. Belyakov, P. Arsenyan
FULL PAPER
Conclusions
A new approach for the cyclization of readily accessible
aryl(thienyl)alkynes under selenobromination conditions
has been elaborated. The method provides convenient syn-
thetic access to a wide variety of 3-bromobenzo[b]seleno-
phenes and, for the first time, selenobromination is appli-
cable for the preparation of selenophenothiophenes. By
cyclization of commercially available substrates, the 3-
bromobenzo[b]selenophene heterocyclic framework can be
obtained in one step without the use of anhydrous solvents
or an inert atmosphere. A significant limitation of the elab-
orated methodology is extensive bromination of the CϵC
triple bond of the starting material, or lack of regioselectiv-
ity, when electron-donating groups bearing aryl(tienyl)alk-
ynes are subjected to cyclization. Nevertheless, unsubsti-
tuted and ethynyl arenes bearing an electron-withdrawing
group are highly favored and even meta-fluoro derivative 3k
was cyclized with complete regioselectivity in very good
yield. The presence of an electron-withdrawing group in the
α-position of the thiophene ring is essential for highly ef-
ficient preparation of 6-bromoselenopheno[3,2-b]thio-
phenes. So far, this is the only methodology available for
the preparation of this type of derivative.
Scheme 6. Cyclization of C(sp)-substituted arylalkynes 10a–d. Re-
action conditions (unless otherwise stated): arylalkyne 10a–d
(200 mg), 48% HBr (0.43 mL), SeO2 (1.0 mmol). [a] Cyclohex-2-
enone was used as alkene additive. [b] SeO2 (2.0 equiv.) and cyclo-
hexene (1.2 equiv.) were used and the reaction time was 36 h.
[c] SeO2 (2.0 equiv.) and cyclohex-2-enone (2.0 equiv.) were used;
complete desilylation was achieved by the use of TBAF (0.5 equiv.).
the starting material was observed, cyclization of aldehyde
9c led to aldehyde derivative 6 in only 11% yield, which is
close to that previously reported.[9e] Nevertheless, aldehyde
6 can be obtained in better yield by using a two-step pro-
cedure (Scheme 3). Finally, cyclization of phenylethynyltri-
methylsilane (9d) was attempted, however, as expected, the
TMS group was not sufficiently stable to survive under the
given reaction conditions, so partial desilylation occurred.
Complete desilylation was achieved by treatment of the re-
action mixture with 0.5 equiv. tetrabutylammonium
fluoride (TBAF). As a result, 2-unsubstituted 3-bromo-
benzo[b]selenophene (2) was obtained in 44% yield. In this
case, it was essential to use equimolar amounts of SeO2 and
alkene additive, because in the presence of a subequimolar
amount of alkene additive the TMS group was partially re-
placed by bromine, leading to a premix of the correspond-
ing 2,3-dibromo derivative.
Further work in this area will be directed towards to bis-
and tris-cyclizations, as well as to regioselective cyclization
of diaryl(hetaryl)alkynes.
Experimental Section
General Remarks: Unless otherwise stated, all reagents were pur-
chased from commercial suppliers and used without further purifi-
cation. Thin-layer chromatography (TLC) was performed using
MERCK Silica gel 60 F254 plates and visualized by UV (254 nm)
fluorescence. ZEOCHEM silica gel (ZEOprep 60/35–70 microns –
Propan-2-ole derivatives 4b and 4h–k can serve as power-
ful precursors for 2-unsubstituted frameworks. For exam-
ple, by deacetonation[14] of 4i, 3-bromo-6-fluorobenzo[b]-
selenophene (11) was obtained in good yield (Scheme 7).
1
SI23501) was used for column chromatography. H, 13C, 19F, and
77Se NMR spectra were recorded with a Varian 400 Mercury spec-
trometer at 400.0, 100.58, 376.21, and 76.37 MHz, respectively, at
1
298 K in CDCl3. The H chemical shifts are given relative to resid-
ual CHCl3 signal (δ = 7.26 ppm), 13C shifts are relative to CDCl3
(δ = 77.0 ppm), and 77Se relative to dimethyl selenide (δ = 0.0 ppm).
The melting points were determined with a “Digital melting point
analyser” (Fisher), and the results are given without correction.
Diffraction data were collected with a Nonius Kappa CCD dif-
fractometer using graphite monochromated Mo-Kα radiation (λ =
0.71073 Å). The crystal structures were solved by direct methods
and refined by full-matrix least-squares.
Large-Scale Procedure Using Cyclohexene as Alkene Additive:
Selenium dioxide (6.52 g, 58.8 mmol) was dissolved in 48% hydro-
gen bromide (25.3 mL) and stirred at room temp. for 15 min. A
Scheme 7. Deacetonation of 4i.
solution of
1 (5.00 g, 49.0 mmol) and cyclohexene (4.03 g,
A wide range of modifications can be envisioned for 11,
because the C–Br bond is available for different kinds of
transition-metal-catalyzed processes, C-2 is active in electro-
philic aromatic substitution, and it is well-known that
fluorine is an excellent leaving group for nucleophilic aro-
matic substitution, which would allow insertion of electron-
donating groups (for example alkoxy) in positions that are
forbidden during cyclization process.
49.0 mmol) in dioxane (300 mL) was added dropwise, and the reac-
tion mixture was stirred at room temp. for 24 h. Then reaction was
quenched with ethyl acetate (500 mL) and water (200 mL). After
stirring for 15 min, the organic phase was separated and the aque-
ous phase was extracted with ethyl acetate (2ϫ 150 mL). The com-
bined organic phases were washed with brine (200 mL), dried with
anhydrous sodium sulfate, and concentrated under reduced pres-
sure. The residue was subjected to column chromatography on sil-
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
Selenobromination of Aryl(thienyl)alkynes
ica gel (petroleum ether) to give a mixture of 2 and 1,2-dibromocy-
clohexane (approximately 1:1) as a colorless oil. Product 2 (5.73 g,
45%) was isolated by fractionated distillation.
1.87–1.96 (m, 2 H, 2,6-CH), 1.68–1.82 (m, 5 H, 3,4,5-CH), 1.30–
1.47 (m, 1 H, 4-CH) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
154.0, 142.1, 137.1, 125.1, 125.0 (2 C), 124.9, 101.4, 75.4, 35.6, 24.9,
21.7 ppm. MS (EI, 70 eV): m/z (%) = 358 (57) [M]+, 236 (100).
C14H15BrOSe (358.14): calcd. C 46.95, H 4.22; found C 46.85,
H 4.25.
3-Bromobenzo[b]selenophene (2):[15] Colorless oil; b.p. 120 °C
2
(10 Torr). 1H NMR (400 MHz, CDCl3): δ = 7.97 (s, JH,Se
=
44.8 Hz, 1 H, 2-CH), 7.88–7.94 (m, 2 H, 4,7-CH), 7.46–7.52 (m, 1
H, 6-CH), 7.34–7.40 (m, 1 H, 5-CH) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 139.4, 139.2, 125.7, 125.4, 125.3, 125.2, 124.7,
109.4 ppm. 77Se NMR (76.37 MHz, CDCl3): δ = 533.8 (s) ppm.
MS (EI, 70 eV): m/z (%) = 260 (100) [M]+. C8H5BrSe (259.99):
calcd. C 36.96, H 1.94; found C 36.54, H 1.79.
2-(3-Bromo-5-methoxybenzo[b]selenophen-2-yl)propan-2-ol
(4f):
Eluent: petroleum ether/ethyl acetate (40:1Ǟ5:1); isolated with pre-
mix of minor regioisomer (approximately 10%); Overall yield:
65%; colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.68 [d, 3JH,H
4
= 8.6 Hz, 1 H, 7-CH], 7.32 [d, JH,H = 2.5 Hz, 1 H, 4-CH], 6.95
3
[dd, 4JH,H = 2.5, JH,H = 8.6 Hz, 1 H, 6-CH], 3.90 (s, 3 H, OCH3),
Small-Scale Procedure Using Cyclohex-2-enone as Alkene Additive:
Selenium dioxide (435 mg, 3.92 mmol) was dissolved in 48% hydro-
gen bromide (1.69 mL) and stirred at room temp. for 15 min. A
solution of 1 (200 mg, 1.96 mmol) and cyclohex-2-enone (188 mg,
1.96 mmol) in dioxane (12 mL) was added dropwise, and the reac-
tion mixture was stirred at room temp. for 24 h. The reaction was
quenched with ethyl acetate (50 mL) and water (20 mL). After stir-
ring for 15 min, the organic phase was separated and the aqueous
phase was extracted with ethyl acetate (2ϫ 30 mL). The combined
organic phases were washed with brine (40 mL), dried with an-
hydrous sodium sulfate, and concentrated under reduced pressure.
The crude product was purified by column chromatography on sil-
ica gel (petroleum ether) to give 2 (306 mg, 60%).
2.64 (br. s, 1 H, OH), 1.83 (s, 6 H, CH3) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 155.0, 143.0, 128.5, 125.9, 114.9, 107.9,
104.9, 101.3, 74.3, 55.6, 29.2 ppm. 77Se NMR (76.37 MHz, CDCl3):
δ = 537.8 ppm. MS (EI, 70 eV): m/z (%) = 348 (11) [M]+, 330 (100)
[M – H2O]+. C10H9BrO2Se (320.04): calcd. C 37.53, H 2.83; found
C 37.44, H 2.94.
Methyl
3-Bromo-2-(2-hydroxypropan-2-yl)benzo[b]selenophene-6-
carboxylate (4h): Eluent: petroleum ether/ethyl acetate
(20:1Ǟ10:3), yield 88%; white solid; m.p. 137–138 °C (petroleum
ether/ethyl acetate). 1H NMR (400 MHz, CDCl3): δ = 8.53 [dd,
4
4
5JH,H = 0.6, JH,H = 1.6 Hz, 1 H, 7-CH], 8.07 [dd, JH,H = 1.6,
3JH,H = 8.4 Hz, 1 H, 5-CH], 7.85 [dd, JH,H = 0.6, JH,H = 8.4 Hz,
1 H, 4-CH], 3.96 (s, 3 H, OCH3), 2.77 (br. s, 1 H, OH), 1.84 (s, 6
H, CH3) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 166.9, 158.6,
145.5, 136.8, 127.0, 126.5, 126.0, 124.8, 101.6, 74.5, 52.3, 29.0 ppm.
MS (EI, 70 eV): m/z (%) = 376 (43) [M]+, 361 (100) [M –
CH3]+. C13H13BrO3Se (376.11): calcd. C 41.52, H 3.48; found
C 41.58, H 3.49.
5
3
Cyclization of Phenylpropargylalcohol Derivatives 3a–c, 3f, 3h, 3i,
and 3k: Typical Procedure for 3a: Selenium dioxide (378 mg,
3.41 mmol) was dissolved in 48% hydrogen bromide (1.47 mL) and
stirred at room temp. for 15 min. A solution of 3a (300 mg,
2.27 mmol) and cyclohexene (223 mg, 2.72 mmol) in dioxane
(6.0 mL) was added dropwise, and the reaction mixture was stirred
at room temp. for 24 h. The reaction was quenched with ethyl acet-
ate (80 mL) and water (30 mL). After stirring for 15 min, the or-
ganic phase was separated and the aqueous phase was extracted
with ethyl acetate (2ϫ 50 mL). The combined organic phases were
washed with brine (50 mL), dried with anhydrous sodium sulfate,
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (petroleum ether–
ethyl acetate, 40:1Ǟ5:1) to give 4a (501 mg, 76%).
2-(3-Bromo-6-fluorobenzo[b]selenophen-2-yl)propan-2-ol (4i): Elu-
ent: petroleum ether/ethyl acetate (40:1Ǟ10:1); Yield: 85%; pale-
1
4
yellow oil. H NMR (400 MHz, CDCl3): δ = 7.77 (dd, JH,F = 5.0,
3JH,H = 8.9 Hz, 1 H, 4-CH), 7.53 (dd, JH,H = 2.4, JH,F = 8.1 Hz,
4
3
4
3
3
1 H, 7-CH), 7.16 (ddd, JH,H = 2.4, JH,H = 8.9, JH,F = 8.9 Hz, 1
H, 5-CH), 2.60 (br. s, 1 H, OH), 1.82 (s, 6 H, CH3) ppm. 13C NMR
1
(100.58 MHz, CDCl3): δ = 160.8 (d, JC,F = 247.6 Hz), 153.0 (d,
4JC,F = 3.5 Hz), 138.4 (d, 5JC,F = 1.6 Hz), 137.8 (d, 3JC,F = 9.0 Hz),
6
126.3 (m), 113.8 (m), 111.4 (m), 100.8 (d, JC,F = 0.8 Hz), 74.3,
(3-Bromobenzo[b]selenophen-2-yl)methanol (4a):[16] White solid;
29.2 ppm. 19F NMR (376.21 MHz, CDCl3): δ = –116.7 (m) ppm.
MS (EI, 70 eV): m/z (%) = 336 (8) [M]+, 318 (66) [M – H2O]+,
159 (100). C11H10BrFOSe (336.06): calcd. C 39.31, H 3.00; found
C 39.18, H 3.05.
1
m.p. 104–106 °C. H NMR (400 MHz, CDCl3): δ = 7.81–7.87 (m,
2 H, 4,7-CH), 7.42–7.48 (m, 1 H, 6-CH), 7.29–7.35 (m, 1 H, 5-
CH), 4.99 (s, 2 H, CH2), 2.26 (br. s, 1 H, OH) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 143.3, 140.1, 138.2, 125.6, 125.4, 125.3,
125.0, 105.7, 62.2 ppm. MS (EI, 70 eV): m/z (%) = 290 (64)
[M]+, 183 (100). C9H7BrOSe (290.02): calcd. C 37.27, H 2.43;
found C 37.20, H 2.46.
2-(3-Bromo-5-fluorobenzo[b]selenophen-2-yl)propan-2-ol (4k): Elu-
ent: petroleum ether/ethyl acetate (40:1Ǟ10:1), yield 83%; white
crystalline solid; m.p. 84–85 °C (petroleum ether). 1H NMR
4
(400 MHz, CDCl3): δ = 7.74 (dd, JH,F = 5.0, 3JH,H = 8.7 Hz, 1 H,
4
3
7-CH), 7.53 (dd, JH,H = 2.5, JH,F = 10.0 Hz, 1 H, 4-CH), 7.06
2-(3-Bromobenzo[b]selenophen-2-yl)propan-2-ol (4b): Eluent: petro-
leum ether/ethyl acetate (40:1Ǟ5:1), yield 89%; white solid; m.p.
119–121 °C (petroleum ether/ethyl acetate). 1H NMR (400 MHz,
CDCl3): δ = 7.86–7.80 (m, 2 H, 4,7-CH), 7.47–7.40 (m, 1 H, 6-
CH), 7.34–7.28 (m, 1 H, 5-CH), 2.63 (br. s, 1 H, OH), 1.82 (s, 6 H,
CH3) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 153.5, 141.9,
137.0, 125.1 (2 C), 125.0, 101.7, 74.3, 29.2 ppm. 77Se NMR
(76.37 MHz, CDCl3): δ = 548.2 ppm (s) ppm. MS (EI, 70 eV): m/z
(%) = 318 (45) [M]+, 303 (100) [M – CH3]+. C11H11BrOSe (318.07):
calcd. C 41.54, H 3.49; found C 41.49, H 3.51.
4
3
3
(ddd, JH,H = 2.5, JH,H = 8.7, JH,F = 8.7 Hz, 1 H, 6-CH), 2.57
(br. s, 1 H, OH), 1.83 (s, 6 H, CH3) ppm. 13C NMR (100.58 MHz,
1
3
CDCl3): δ = 161.6 (d, JC,F = 242.1 Hz), 156.6, 143.5 (d, JC,F
=
4
3
9.0 Hz), 131.9 (d, JC,F = 1.9 Hz), 126.4 (d, JC,F = 9.0 Hz), 113.7
2
2
4
(d, JC,F = 24.5 Hz), 111.1 (d, JC,F = 24.1 Hz), 100.9 (d, JC,F
=
4.3 Hz), 74.4, 29.1 ppm. 19F NMR (376.21 MHz, CDCl3): δ =
–117.4 (m) ppm. MS (EI, 70 eV): m/z (%) = 336 (45) [M]+, 321
(100) [M – CH3]+. C11H10BrFOSe (336.06): calcd. C 39.31, H 3.00;
found C 39.22, H 3.04.
Cyclization of 3j: Methodology was analogous to cyclization of 3a
except SeO2 (2.0 equiv.) and cyclohexene (1.0 equiv.) were used and
the reaction was run for 72 h.
1-(3-Bromobenzo[b]selenophen-2-yl)cyclohexanol (4c): Eluent: pe-
troleum ether/ethyl acetate (40:1Ǟ5:1), yield 83%; white solid; m.p.
67–68 °C (petroleum ether). 1H NMR (400 MHz, CDCl3): δ =
7.89–7.81 (m, 2 H, 4Ј,7Ј-CH), 7.48–7.41 (m, 1 H, 6Ј-CH), 7.34–7.27 2-(3-Bromo-4-fluorobenzo[b]selenophen-2-yl)propan-2-ol (4j): Elu-
(m, 1 H, 5Ј-CH), 2.62 (br. s, 1 H, OH), 2.59–2.44 (m, 2 H, 2,6-CH), ent: petroleum ether/ethyl acetate (40:1Ǟ10:1), yield 49%; white
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
E. Paegle, S. Belyakov, P. Arsenyan
solid; m.p. 103–104 °C (petroleum ether). 1H NMR (400 MHz, 2-(4-Bromoselenopheno[2,3-b]thiophen-5-yl)propan-2-ol (8g): Elu-
FULL PAPER
4
3
CDCl3): δ = 7.61 (dd, JH,H = 0.9, JH,H = 7.9 Hz, 1 H, 7-CH), ent: petroleum ether/ethyl acetate (40:1Ǟ10:1), yield 39%; white
4
3
3
7.22 (ddd, JH,F = 4.5, JH,H = 7.9, JH,H = 7.9 Hz, 1 H, 6-CH),
crystalline solid; m.p. 103–104 °C (petroleum ether/ethyl acetate).
4
3
3
3
7.06 (ddd, JH,H = 0.9, JH,H = 7.9, JH,F = 12.4 Hz, 1 H, 5-CH),
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, JH,H = 5.2 Hz, 1 H, 2-
2.54 (br. s, 1 H, OH), 1.84 (s, 6 H, CH3) ppm. 13C NMR
CH), 7.21 (d, JH,H = 5.2 Hz, 1 H, 3-CH), 2.50 (br. s, 1 H, OH),
3
1
(100.58 MHz, CDCl3): δ = 158.5 (d, JC,F = 256.5 Hz), 154.5 (d,
1.80 (s, 6 H, CH3) ppm. 13C NMR (100.58 MHz, CDCl3): δ =
155.1, 149.5, 130.6, 128.2, 122.1, 74.3, 29.4 ppm. MS (EI, 70 eV):
m/z (%) = 324 (8) [M]+, 306 (71) [M – H2O]+, 147 (100).
C9H9BrOSSe (324.09): calcd. C 33.35, H 2.80; found C 33.30,
5JC,F = 1.2 Hz), 139.7 (d, 4JC,F = 2.7 Hz), 130.0 (d, 3JC,F = 9.7 Hz),
3
4
2
125.5 (d, JC,F = 7.8 Hz), 121.1 (d, JC,F = 4.7 Hz), 111.6 (d, JC,F
= 21.8 Hz), 95.9 (d, JC,F = 4.3 Hz), 74.7, 28.8 ppm. 19F NMR
4
(376.21 MHz, CDCl3): δ = –117.7 (m) ppm. MS (EI, 70 eV): m/z H 2.81.
(%) = 336 (46) [M]+, 321 (100) [M – CH3]+. C11H10BrFOSe
(336.06): calcd. C 39.31, H 3.00; found C 39.25, H 3.04.
Cyclization of Hept-1-yn-1-ylbenzene (9a): Method was analogous
to cyclization of 3a, except cyclohex-2-enone was used as alkene
additive.
Cyclization of 2-Methyl-4-thiophen-2-ylbut-3-yn-2-ol (7b): Selenium
dioxide (240 mg, 2.16 mmol) was dissolved in 48% hydrogen brom-
ide (0.60 mL) and stirred at room temp. for 15 min. A solution of
7b (300 mg, 1.80 mmol) and cyclohexene (177 mg, 2.16 mmol) in
dioxane (6.0 mL) was added dropwise to a cooled (10 °C) solution
of selenium(IV) bromide, and the reaction mixture was stirred at
room temp. for 24 h. The reaction was quenched with ethyl acetate
(80 mL) and water (30 mL). After stirring for 15 min, the organic
phase was separated and the aqueous phase was extracted with
ethyl acetate (2ϫ 50 mL). The combined organic phases were
washed with brine (50 mL), dried with anhydrous sodium sulfate,
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate, 50:3) and recrystallized (petroleum ether) to give 8b
(198 mg, 34%).
3-Bromo-2-pentylbenzo[b]selenophene (10a): Eluent: petroleum
ether, yield 82%; colorless oil. 1H NMR (400 MHz, CDCl3): δ =
7.82–7.78 (m, 2 H, 4,7-CH), 7.45–7.40 (m, 1 H, 6-CH), 7.30–7.26
(m, 1 H, 5-CH), 3.03–2.96 (m, 2 H, 1Ј-CH2), 1.79–1.69 (m, 2 H,
2Ј-CH2), 1.48–1.33 (m, 4 H, 3Ј,4Ј-CH2), 0.95–0.89 (m, 3 H,
CH3) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 144.3, 140.3,
125.3, 125.2, 125.0, 124.9, 107.4, 32.2, 31.3, 30.8, 22.4, 14.0 ppm.
MS (EI, 70 eV): m/z (%) = 330 (39) [M]+, 273 (100) [M – C4H9]+.
C13H15BrSe (330.13): calcd. C 47.30, H 4.58; found C 47.38,
H 4.43.
Cyclization of Ethyl 3-Phenylpropiolate (9b): Method was analo-
gous to cyclization of 3a, except SeO2 (2.0 equiv.) and cyclohexene
(1.2 equiv.) were used and the reaction was run for 36 h.
Ethyl 3-Bromobenzo[b]selenophene-2-carboxylate (10b): Eluent: pe-
troleum ether/ethyl acetate (1:0Ǟ40:1); Yield: 71%; white solid;
m.p. 177–178 °C (petroleum ether/ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ = 8.10–8.06 (m, 1 H, 4-CH), 7.89–7.85 (m, 1
2-(6-Bromoselenopheno[3,2-b]thiophen-5-yl)propan-2-ol (8b): Pale-
yellow crystalline solid; m.p. 111–112 °C. 1H NMR (400 MHz,
3
3
CDCl3): δ = 7.33 (d, JH,H = 5.2 Hz, 1 H, 2-CH), 7.30 (d, JH,H
=
5.2 Hz, 1 H, 3-CH), 2.49 (br. s, 1 H, OH), 1.80 (s, 6 H, CH3) ppm.
13C NMR (100.58 MHz, CDCl3): δ = 154.5, 144.2, 133.0, 125.6,
123.4, 95.9, 74.1, 29.4 ppm. MS (EI, 70 eV): m/z (%) = 324 (39)
[M]+, 309 (100) [M – CH3]+. C9H9BrOSSe (324.09): calcd. C 33.35,
H 2.80; found C 33.28, H 2.84.
3
H, 7-CH), 7.53–7.44 (m, 2 H, 5,6-CH), 4.42 (q, JH,H = 7.2 Hz, 2
3
H, CH2),1.43 (t, JH,H = 7.2 Hz, 3 H, CH3) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 162.5, 140.7, 140.4, 129.6, 128.1, 127.8,
125.8, 125.6, 116.3, 61.9, 14.3 ppm. MS (EI, 70 eV): m/z (%) = 332
(81) [M]+, 287 (100) [M – OC2H5]+. C11H9BrO2Se (332.05): calcd.
C 39.79, H 2.73; found C 39.71, H 2.77.
Cyclization of 5-(3-Hydroxy-3-methylbut-1-ynyl)thiophene-2-carbal-
dehyde (7e): Methodology was analogous to the cyclization of 3a.
Cyclization of 3-Phenylpropiolaldehyde (9c): Method was analogous
to the cyclization of 3a.
6-Bromo-5-(2-hydroxypropan-2-yl)selenopheno[3,2-b]thiophene-2-
carbaldehyde (8e): Eluent: petroleum ether/ethyl acetate
(40:1Ǟ4:1), yield 66%; pale-yellow solid; m.p. 127–128 °C (petro-
leum ether/ethyl acetate). 1H NMR (400 MHz, CDCl3): δ = 9.93
(s, 1 H, cabonyl-CH), 7.97 (s, 1 H, 3-CH), 2.72 (br. s, 1 H, OH),
1.81 (s, 6 H, CH3) ppm. 13C NMR (100.58 MHz, CDCl3): δ =
183.2, 162.6, 151.4, 142.9, 132.7, 132.6, 96.6, 74.5, 29.0 ppm. MS
(EI, 70 eV): m/z (%) = 352 (38) [M]+, 337 (100) [M – CH3]+.
C10H9BrO2SSe (352.10): calcd. C 34.11, H 2.58; found C 34.00,
H 2.60.
3-Bromobenzo[b]selenophene-2-carbaldehyde (6):[17] Eluent: petro-
leum ether/ethyl acetate (1:0Ǟ40:1), yield 11%; pale-yellow solid;
m.p. 106–107 °C (petroleum ether/ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ = 10.20 (s, 1 H, carbonyl-CH), 8.13–8.08 (m,
1 H, 4-CH), 7.94–7.90 (m, 1 H, 7-CH), 7.46–7.55 ppm (m, 2 H,
5,6-CH) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 186.1, 141.2,
140.1, 139.5, 129.1, 127.2, 126.3, 126.1, 120.3 ppm. MS (EI, 70 eV):
m/z (%) = 288 (100) [M]+. C9H5BrOSe (288.00): calcd. C 37.53,
H 1.75; found C 37.46, H 1.83.
General Method for Cyclization of 8f and 8g: Methodology was
analogous to cyclization of 8b, except the reaction mixture was co-
oled to 0 °C (ice bath) during addition of dioxane solution, then
slowly (within 2 h) allowed to reach room temp. and stirred for an
additional 24 h.
Cyclization of Trimethyl(phenylethynyl)silane (9d): Selenium dioxide
(255 mg, 2.30 mmol) was dissolved in 48% hydrogen bromide
(0.99 mL) and stirred at room temp. for 15 min. A solution of 9d
(200 mg, 1.15 mmol) and cyclohex-2-enone (221 mg, 2.30 mmol) in
dioxane (6.0 mL) was added dropwise, and the reaction mixture
(4-Bromoselenopheno[2,3-b]thien-5-yl)methanol (8f): Eluent: petro- was stirred at room temp. for 24 h. The reaction was quenched with
leum ether/ethyl acetate (40:1Ǟ10:1); Yield: 56%; white crystalline
ethyl acetate (50 mL) and water (20 mL). After stirring for 15 min,
the organic phase was separated and the aqueous phase was ex-
tracted with ethyl acetate (2ϫ 20 mL). The combined organic
phases were washed with brine (20 mL), dried with anhydrous so-
dium sulfate, and concentrated under reduced pressure. The residue
was dissolved in dioxane (5.0 mL), tetrabutylammonium fluoride
(150 mg, 0.575 mmol) was added and reaction mixture was stirred
at 110 °C overnight. After complete desilylation (monitored by
solid; m.p. 92–93 °C (petroleum ether/ethyl acetate). 1H NMR
3
(400 MHz, CDCl3): δ = 7.42 (d, JH,H = 5.2 Hz, 1 H, 2-CH), 7.23
(d, 3JH,H = 5.2 Hz, 1 H, 3-CH), 4.90 (d, 3JH,H = 4.8 Hz, 2 H, CH2),
3
2.23 (t, JH,H = 4.8 Hz, 1 H, OH) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 147.5, 144.8, 132.6, 128.9, 121.6, 101.3, 61.8 ppm. MS
(EI, 70 eV): m/z (%) = 296 (100) [M]+. C7H5BrOSSe (296.04): calcd.
C 28.40, H 1.70; found C 28.40, H 1.78.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
Selenobromination of Aryl(thienyl)alkynes
[4]
GC–MS), solvent was evaporated under reduced pressure and the
crude product was purified by column chromatography on silica
gel (petroleum ether) to give 2 (132 mg, 44%).
a) K. Takimiya, Y. Kunugi, Y. Konda, H. Ebata, Y. Toyoshima,
T. Otsubo, J. Am. Chem. Soc. 2006, 128, 3044–3050; b) T. Yam-
amoto, K. Takimiya, J. Am. Chem. Soc. 2007, 129, 2224–2225;
c) H. Ebata, E. Miyazaki, T. Yamamoto, K. Takimiya, Org.
Lett. 2007, 9, 4499–4502.
For the most recently published methodology, see: B. Wu, N.
Yoshikai, Angew. Chem. Int. Ed. 2013, 52, 10496–10499.
For methodologies involving electrophilic cyclization of 1-(1-
alkynyl)-2-(organylseleno)arenes, see: a) T. Kesherwani, S. A.
Worlikar, R. C. Larock, J. Org. Chem. 2006, 71, 2307–2312; b)
S. Mehta, J. P. Waldo, R. C. Larock, J. Org. Chem. 2009, 74,
1141–1147; c) R. Sanz, V. Guilarte, E. Hernando, A. M. San-
juán, J. Org. Chem. 2010, 75, 7443–7446.
Oxidation of (3-Bromobenzo[b]selenophen-2-yl)methanol (4a): A
solution of 4a (200 mg, 0.690 mmol) in anhydrous THF (10 mL)
was added dropwise to a stirred suspension of manganese(IV) oxide
(240 mg, 2.76 mmol) and stirring was continued at room temp. for
24 h. Precipitates were removed by filtration and the filtrate was
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel (petroleum ether/ethyl
acetate, 1:0Ǟ40:1) to give 6 (106 mg, 53%).
[5]
[6]
Deacetonation of 2-(3-Bromo-6-fluorobenzo[b]selenophen-2-yl)prop-
an-2-ol (4i): A mixture of 4i (0.760 g, 2.26 mmol) and anhydrous
potassium phosphate (0.575 g, 2.71 mmol) in anhydrous DMSO
(8.0 mL) was barbotated with argon and stirred at 80 °C for 24 h.
After usual workup, the crude product was purified by flash
chromatography on silica gel (petroleum ether) to give 11 (0.446 g,
71%).
[7]
[8]
For PtCl2 and AuCl catalyzed cyclizations of 1-(1-alkynyl)-2-
(organylseleno)arenes, see: T. Sato, I. Nakamura, M. Terada,
Eur. J. Org. Chem. 2009, 32, 5509–5512.
For methodologies involving reactions of o-bromo(chloro)alk-
ynylarenes, see: a) T. Kashiki, S. Shinamura, M. Kohara, E.
Miyazaki, K. Takimiya, M. Ikeda, H. Kuwabara, Org. Lett.
2009, 11, 2473–2475; b) H. Sashida, K. Sadamori, T. Tsuchiya,
Synth. Commun. 1998, 28, 713–728.
For methodologies involving reactions of phenylacetylene de-
rivatives with selenium tetrahalogenides, see: a) Yu. V. Migal-
ina, S. V. Galla-Bobik, V. G. Lendel, V. I. Staninets, Khim. Get-
erotsikl. Soedin. 1981, 1283; b) V. G. Lendel, V. I. Pak, V. V.
Petrus, M. Yu. Kiyak, Yu. V. Migalina, Khim. Geterotsikl. Soe-
din. 1990, 1331–1334; c) Yu. L. Zborovskii, V. I. Staninets,
L. B. Saichenko, Zh. Org. Khim. 1992, 4, 760–763; d) Yu. L.
Zborovskii, V. F. Levon, V. I. Staninets, Zh. Obshch. Khim.
1994, 64, 1567; e) Yu. L. Zborovskii, V. F. Levon, V. I. Stani-
nets, Zh. Obshch. Khim. 1996, 66, 1847–1850; f) V. F. Levon,
Yu. L. Zborovskii, V. I. Staninets, Zh. Obshch. Khim. 1998, 68,
288–291.
3-Bromo-6-fluorobenzo[b]selenophene (11): White solid; m.p. 50–
[9]
1
2
51 °C. H NMR (400 MHz, CDCl3): δ = 7.89 (s, JH,Se = 45.8 Hz,
4
3
1 H, 2-CH), 7.82 (dd, JH,F = 5.0, JH,H = 8.8 Hz, 1 H, 4-CH),
7.61 (dd, 4JH,H = 2.4, JH,F = 8.1 Hz, 1 H, 7-CH), 7.22 (ddd, 4JH,H
3
3
3
= 2.4, JH,H = 8.8, JH,F = 8.8 Hz, 1 H, 5-CH) ppm. 13C NMR
(100.58 MHz, CDCl3): δ = 161.1 (1JC,F = 248.3 Hz), 140.2 (d, 3JC,F
= 9.3 Hz), 135.8 (d, 5JC,F = 1.6 Hz), 126.5 (d, 3JC,F = 9.0 Hz), 124.2
4
2
2
(d, JC,F = 3.5 Hz), 114.1 (d, JC,F = 24.1 Hz), 112.0 (d, JC,F
=
24.9 Hz), 108.7 (d, JC,F = 0.8 Hz) ppm. 19F NMR (376.21 MHz,
CDCl3): δ = –116.2 (m) ppm. MS (EI, 70 eV): m/z (%) = 278 (90)
[M]+, 199 (45) [M – Br]+, 107 (100). C8H4BrFSe (277.98): calcd. C
34.57, H 1.45; found C 34.53, H 1.51.
6
[10]
For methodologies of conceptually different syntheses, see: a)
M. V. Karkhelikar, S. S. Racharlawar, S. M. Salian, B. Sridhar,
P. R. Likhar, J. Organomet. Chem. 2012, 706–707; b) H.
Hommes, H. D. Verkruijsse, L. Brandsma, J. Chem. Soc.,
Chem. Commun. 1981, 8, 366–367; c) J. Kurita, M. Ishii, S.
Yasuike, T. Tsuchiya, Chem. Pharm. Bull. 1994, 42, 1437–1441;
d) J. Kurita, M. Ishii, S. Yasuike, T. Tsuchiya, J. Chem. Soc.,
Chem. Commun. 1993, 17, 1309–1310; e) C. D. Rosa, M. Knee-
teman, P. Mancini, Tetrahedron Lett. 2007, 48, 7075–7078; f)
N. N. Magdesieva, V. A. Vdovin, Khim. Geterotsikl. Soedin.
1971, 1640–1644; g) A. E. Jakobs, L. E. Christiaens, M. J.
Renson, Tetrahedron 1994, 50, 9315–9324; h) E. A. Jakobs,
L. E. Christiaens, M. J. Renson, Heterocycles 1992, 34, 1119–
1132; i) S. W. Wright, R. L. Corbett, Tetrahedron Lett. 1993,
34, 2875–2878; j) A. Dari, L. E. Christiaens, M. J. Renson, Het-
erocycles 1992, 34, 1737–1748; k) N. N. Magdesieva, V. A. Vdo-
vin, Khim. Geterotsikl. Soedin. 1970, 1475–1480; l) L. Laitem,
P. Thibaut, L. Christiaens, J. Heterocycl. Chem. 1976, 13, 469–
473; m) J.-M. Webert, D. Cagniant, P. Cagniant, G. Kirsch, J.-
V. We b e r, J. Heterocycl. Chem. 1983, 20, 49–53; n) K. Kloc, J.
Mlochowski, Tetrahedron Lett. 2001, 42, 4899–4902; o) K.
Kloc, M. Osajda, J. Mlochowski, Chem. Lett. 2001, 8, 826–
827; p) R. Lisiak, J. Mochowski, Synth. Commun. 2009, 39,
4271–4281; q) M. Cherif, P. Cotelle, J.-P. Catteau, Heterocycles
1992, 34, 1749–1758; r) P. Kaszynski, D. A. Dougherty, J. Org.
Chem. 1993, 58, 5209–5220.
Crystallographic Data: Diffraction data were collected at low tem-
perature with a Nonius Kappa CCD diffractometer using graphite
monochromated Mo-Kα radiation (λ = 0.71073 Å). The crystal
structures of 4b, 8b and 8g were solved by direct methods[18a] and
refined by full-matrix least-squares.[18b,18c]
CCDC-967670 (for 4b), -967165 (for 8b), and -967166 (for 8g) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Methods for the preparation of ethynylarenes, copies of the
1H, 13C, 19F, 77Se NMR spectra, and crystallographic data for com-
pounds 4b, 8b, and 8g.
Acknowledgments
The financial support for this work provided by Latvian Council
of Science (447/2012) is gratefully acknowledged.
[1] R. Lisiak, J. Mochowski, Synth. Commun. 2009, 39, 4271–
4281.
[11]
[12]
a) R. Riley, Y. Flato, P. McIntyre, J. Org. Chem. 1963, 15,
1138–1139; b) T. Q. Minh, L. Christiaens, M. Renson, Bull.
Soc. Chim. France. 1974, 9, 2239–2242; c) I. V. Smirnov-
Zamkov, Yu. L. Zborovskii, Zh. Org. Khim. 1977, 13, 667; d)
I. V. Smirnov-Zamkov, Yu. L. Zborovskii, V. I. Staninets, Zh.
Org. Khim. 1979, 15, 1782.
a) S. Braverman, M. Cherkinskya, R. Janaa, Y. Kalendara, M.
Sprechera, J. Phys. Org. Chem. 2010, 23, 1114–1120; b) S. Brav-
erman, T. Pechenick-Azizi, H. E. Gottlieb, M. Sprecher, Syn-
thesis 2011, 577–584.
[2] M. K. Staples, R. L. Grange, J. A. Angus, J. Ziogas, N. P. H.
Tan, M. K. Taylor, C. H. Schiesser, Org. Biomol. Chem. 2011,
9, 473–479.
[3] a) P. Arsenyan, E. Paegle, S. Belyakov, I. Shestakova, E. Jasch-
enko, I. Domracheva, J. Popelis, Eur. J. Med. Chem. 2011, 46,
3434–3443; b) P. Arsenyan, J. Vasiljeva, I. Shestakova, I. Dom-
racheva, S. Belyakov, Chem. Heterocycl. Compd. 2014, 49,
1674–1680; c) P. Arsenyan, O. Pudova, E. Lukevics, Tetrahe-
dron Lett. 2002, 43, 4817–4819; d) P. Arsenyan, J. Vasiljeva, S.
Belyakov, Mendeleev Commun. 2014, 24, 32–34.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
E. Paegle, S. Belyakov, P. Arsenyan
FULL PAPER
[13]
[17] a) G. Kirsch, S. Deprets, Z. Naturforsch. B 2006, 61, 427–430;
b) Yu. L. Zborovskii, V. F. Levon, V. I. Staninets, Zh. Obshch.
Khim. 1996, 66, 1847–1850.
A. L. Stein, J. da Rocha, P. H. Menezes, G. Zeni, Eur. J. Org.
Chem. 2010, 705–710.
For methodology of deacetonation, see: E. Shirakawa, T. Kita-
bata, H. Otsuka, T. Tsuchimoto, Tetrahedron 2005, 61, 9878–
9885.
[14]
[18] a) A. Altomare, M. Burla, M. Camalli, G. Cascarano, C. Gia-
covazzo, A. Guagliardi, A. Moliterni, R. Spagna, J. Appl. Crys-
tallogr. 1999, 32, 115–119; b) S. Mackay, W. Dong, C. Edwards,
A. Henderson, C. J. Gilmore, N. Stewart, K. Shankland, A.
Donald, maXus, Integrated Crystallography Software, 2003,
Bruker-Nonius and University of Glasgow; c) G. M. Sheldrick,
Acta Crystallogr., Sect. A 2008, 64, 112–122.
[15] a) N. Komppa, J. Prakt. Chem. 1934, 2, 229–231; b) N. N.
Magdesiewa, V. A. Vdovin, Chem. Heterocycl. Compd. 1972, 8,
13–17; c) T. Q. Minh, L. Christiaens, M. Renson, Bull. Soc.
Chim. Fr. 1974, 9, 2239–2242.
[16] L. Christiaens, R. Dufour, M. Renson, Bull. Soc. Chim. Belg.
1970, 79, 143–149.
Received: February 27, 2014
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42095
/KAP1
Date: 06-05-14 17:41:42
Pages: 11
Selenobromination of Aryl(thienyl)alkynes
Selenium Chemistry
E. Paegle, S. Belyakov,
P. Arsenyan* ................................... 1–11
An Approach to the Selenobromination of
Aryl(thienyl)alkynes: Access to 3-Bromo-
benzo[b]selenophenes and Selenopheno-
thiophenes
The use of an alkene additive as a bromine
scavenger under selenobromination con-
ate to high yields. The reactions are not
moisture-sensitive and do not require an
inert atmosphere. Selenobromination of
ethynylthiophenes enables the preparation
of selenopheno[b]thiophenes.
ditions provides
a convenient synthetic
Keywords: Heterocycles / Selenophenes /
Selenium / Bromination / Cyclization
pathway for the synthesis of a wide variety
of 3-bromobenzo[b]selenophenes in moder-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11