Synthesis of 2,3-dihydroselenophene and selenophene derivatives by electrophilic cyclization of homopropargyl selenides

Article abstract of DOI:10.1021/ol1003753

Figure presented The synthesis of several highly functionalized 2,3-dihydroselenophenes from homopropargyl selenides via electrophilic cyclization is described. Electrophiles such as I₂, ICl, and PhSeBr were used in a simple process employing CH₂Cl₂ as solvent at room temperature, which gave the cyclized products in high yields. 4-Iodo-2,3-dihydroselenophenes obtained by this methodology were submitted to a dehydrogenation reaction using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to give 3-iodoselenophenes. 4-Iodo-5-phenyl-2,3-dihydroselenophene was also submitted to the thiol copper-catalyzed and Heck-type reactions giving the desired products under mild reaction conditions.

Full text of DOI:10.1021/ol1003753

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1952-1955
Synthesis of 2,3-Dihydroselenophene
and Selenophene Derivatives by
Electrophilic Cyclization of
Homopropargyl Selenides
Ricardo F. Schumacher,† Alisson R. Rosa´rio,† Ana Cristina G. Souza,†
Paulo H. Menezes,‡ and Gilson Zeni*,†
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o Farmacolo´gica e Toxicolo´gica de
Organocalcogeˆnios, CCNE, UFSM, 97105-900, Santa Maria, RS, Brazil, and
UniVersidade Federal de Pernambuco, Departamento de Qu´ımica Fundamental,
Recife, Pernambuco, Brazil, 50670-901
gzeni@pq.cnpq.br
Received February 12, 2010
ABSTRACT
The synthesis of several highly functionalized 2,3-dihydroselenophenes from homopropargyl selenides via electrophilic cyclization is described.
Electrophiles such as I2, ICl, and PhSeBr were used in a simple process employing CH2Cl2 as solvent at room temperature, which gave the
cyclized products in high yields. 4-Iodo-2,3-dihydroselenophenes obtained by this methodology were submitted to a dehydrogenation reaction
using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to give 3-iodoselenophenes. 4-Iodo-5-phenyl-2,3-dihydroselenophene was also submitted
to the thiol copper-catalyzed and Heck-type reactions giving the desired products under mild reaction conditions.
Selenophene heterocycles and their derivatives have numer-
ous uses in the fields of biochemistry, physical organic
chemistry, materials chemistry and organic synthesis. For
example, selenophene oligomers are compounds of current
interest because many of them show photoenhanced biologi-
cal activities1 and alpha-type chalcogenophene oligomers,
such as 5,2′:5′,2′′-thiophene, produce crystalline, and elec-
troconductive polythiophenes in electrochemical polymeriza-
tions.2 Thus, a wide variety of oligomers and related
chalcogen compounds including mixed thiophene-pyrrole
oligomers, have been synthesized mainly with the expectation
of obtaining excellent precursor compounds for molecular
devices and electroconductive polymers.3 In addition, sele-
nophenes are widely studied agents with a diverse array of
biological effects, these include antioxidant action,4 anti-
nociceptive5 and antiinflammatory properties,6 as well as
efficacy as maturation inducing agents.7 A great number of
these heterocycles have been synthesized and their chemistry
has attracted a good deal of interest and activity from a
(3) Okutan, M. M.; Yerli, Y.; San, S. E.; Yy´lmaz, F.; Gu¨naydy´n, O.;
Durak, M. Synth. Met. 2007, 157, 368.
† CCNE.
(4) Meotti, F. C.; Silva, D. O.; Santos, A. R. S.; Zeni, G.; Rocha, J. B. T.;
Nogueira, C. W. EnViron. Toxicol. Pharmacol. 2003, 37, 37.
(5) Gonc¸ales, C. E. P.; Araldi, D.; Panatieri, R. B.; Rocha, J. B. T.;
Zeni, G.; Nogueira, C. W. Life Sci. 2005, 76, 2221.
‡ Universidade Federal de Pernambuco.
(1) Ismail, M. A.; Boykin, D. W.; Stephens, C. E. Tetrahedron Lett.
2006, 47, 795. (b) Chemistry and Biology of Naturally-occurring Acetylenes
and Related Compounds; Lam, J., Breteler, H., Arnason, T., Hansen, L.,
Eds.; Elsevier: Amsterdam, 1988.
(6) (a) Zeni, G.; Lu¨dtke, D. S.; Nogueira, C. W.; Panatieri, R. B.; Braga,
A. L.; Silveira, C. C.; Stefani, H. A.; Rocha, J. B. T. Tetrahedron Lett.
2001, 42, 8927. (b) Zeni, G.; Nogueira, C. W.; Panatieri, R. B.; Silva, D. O.;
Menezes, P. H.; Braga, A. L.; Silveira, C. C.; Stefani, H. A.; Rocha, J. B. T.
Tetrahedron Lett. 2001, 42, 7921.
(2) (a) Nakayama, J.; Konishi, T. Heterocycles 1988, 27, 1731. (b)
Kuroda, M.; Nakayama, J.; Hoshino, M.; Furusho, N.; Kawata, T.; Ohba,
S. Tetrahedron 1993, 49, 3735.
10.1021/ol1003753  2010 American Chemical Society
Published on Web 03/29/2010

variety of standpoints such as structures, stereochemistry,
reactivities, and applications to organic synthesis.8 However,
the synthetic study of a partially saturated version, 2,3-
dihydroselenophene derivatives of selenophenes, has been
surprisingly limited.9 In the context of heterocycles, the
transition-metal catalyzed cyclization reaction of simple
acyclic precursors is one of the most attractive ways to
directly construct complicated molecules under mild condi-
tions.10 In this way, palladium is one of the most common
transition metals used,11 although it sometimes displays
intolerance to some functionalities or proceeds with a lack
of regioselectivity. On the other hand, the electrophilic
cyclization appears as an alternative route to generate highly
functionalized heterocycles. This methodology takes advan-
tage, in the most of cases, by the presence of an halogen
atom suitable to suffer further transformations. This cycliza-
tion has been used as an efficient tool in the synthesis of
highly substituted indoles,12 furans,13 thiophenes,14 sele-
nophenes,15 benzo[b]furans,16 benzo[b]thiophenes,17 ben-
zo[b]selenophenes,18 lactones,19 and pyrroles,20 employing
electrophiles, like I2, ICl or chalcogen derivatives. Among
the known protocols for the synthesis of dihydrothiophenes,
Flynn and co-workers have reported that the reaction of
homopropargyl sulfides with iodine gave the title compounds
in almost quantitative yields.14 The superiority of this method
was proved by the high yields of the desired products, the
tolerance for various substituents, and successful applications
to synthesis of analogues of combretastatin A-4, a prodrug,
which exhibits potent pharmacological activities. Inspired by
Flynn’s reaction, we extended this method to access new
2,3-dihydroselenophenes 3a-r and to examine their ability
as precursors of 3-iodoselenophenes.
We initially focused on experiments to find a route which
gave the required starting materials, the homopropargylic
selenides, in good yields. We envisioned that this route could
start with the introduction of a chalcogen group in the
homopropargyl tosylates and subsequent functionalization of
the terminal alkyne. For the introduction of the chalcogen
group, we chose the substitution reaction in the homoprop-
argyl alcohol protected as tosylate, using selenolate anion
as nucleophile.21 Thus, the addition of butylselenolate (easily
prepared by reaction of n-BuLi with elemental selenium, in
THF at 0 °C) to a solution of tosylate 1 in THF at room
temperature for 6 h, gave the selenide 2f in high yield. With
the subunit 2f in hand to the functionalization of terminal
alkynes, we first generated the lithium acetylide intermediate
by reaction of terminal alkyne 2f with 1 equiv of n-BuLi, in
THF at -78 °C for 1 h, followed by the addition of an
electrophile (Scheme 1). By this method, we prepared a
number of novel homopropargylic selenides 2g-r and
applied these new compounds as starting materials in the
electrophilic cyclization reactions (Table 1).22
Scheme 1. Synthesis of Homopropargyl Selenides
(7) (a) Srivastava, P. C.; Robins, R. K. J. Med. Chem. 1983, 26, 445.
(b) Streeter, D. G.; Robins, R. K. Biochem. Biophys. Res. Commun. 1983,
115, 544. (c) Kirsi, J. J.; North, J.; McKernan, P. A.; Murray, B. K.;
Canonico, P. G.; Huggins, J. W.; Srivastava, P. C.; Robins, R. K. Antimicrob.
Agents Chemother. 1983, 24, 353.
The conditions for the cyclization were optimized by
varying parameters such as solvent, reaction temperature,
amount and identity of electrophile sources. For these studies,
the reaction of homopropargyl selenide 2a with iodine was
chosen as a model system. To identify the solvent potentially
suitable for the cyclization, we first chose MeOH, hexane,
MeCN, THF, and CH2Cl2. For this process, CH2Cl2 was the
most effective solvent giving the cyclized product in 93%
yield. The study to screen the electrophile source showed
that ICl (3a) and PhSeBr (3a′) (1.1 equiv) gave the target
products in 70 and 62% yields, respectively. It is important
to note that when the amount of electrophile was increased
from 1.1 to 2.0 equiv a decrease in the yield was observed.
After optimizing the reaction parameters, the functional group
tolerance was explored. The results are presented in Table
1. Many functional groups were compatible with the reaction
conditions. In general, all the reactions proceeded smoothly
with good results. Most importantly, the cyclization turned
out to be general with respect of a diverse array of
functionalities. The experiments showed that the electrophilic
cyclization of substrate having an aromatic ring directly
bonded to the terminal alkyne was not sensitive to the
electronic effects of the substituents. For example, the
(8) (a) Stein, A. L.; Alves, D.; da Rocha, J. T.; Nogueira, C. W.; Zeni,
G. Org. Lett. 2008, 10, 4983. (b) Alves, D.; Prigol, M.; Nogueira, C. W.;
Zeni, G. Synlett 2008, 6, 914. (c) Bui, C. T.; Flynn, B. L. J. Comb. Chem.
2006, 8, 163.
(9) (a) Sommen, G. L.; Linden, A.; Heimgartner, H. Lett. Org. Chem.
2007, 4, 7. (b) Sasaki, S.; Adachi, K.; Yoshifuji, M. Org. Lett. 2007, 9,
1729.
(10) For a special issue in Chemical Reviews, see Chem. ReV. 2004,
104, Issue 5.
(11) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Zeni,
G.; Larock, R. C. Chem. ReV. 2006, 106, 4644. (c) Gill, G. S.; Grobelny,
D. W.; Chaplin, J. H.; Flynn, B. L. J. Org. Chem. 2008, 73, 1131.
(12) (a) Halim, R.; Scammells, P. J.; Flynn, B. L. Org. Lett. 2008, 10,
1967. (b) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243.
(13) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769.
(14) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med.
Chem. Lett. 2001, 11, 2341.
(15) Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org. Chem.
2007, 72, 6726.
(16) (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292.
(b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999,
1432.
(17) (a) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377. (b) Yue,
D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.; Verdier-
Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(18) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006,
71, 2307.
(19) (a) Bellina, F.; Colzi, F.; Mannina, L.; Rossi, R.; Viel, S. J. Org.
Chem. 2003, 68, 10175. (b) Biagetti, M.; Bellina, F.; Carpita, A.; Viel, S.;
Mannina, L.; Rossi, R. Eur. J. Org. Chem. 2002, 1063. (c) Bellina, F.;
Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857.
(20) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin
Trans. 1 2002, 622.
(21) Zeni, G.; Stracke, M. P.; Nogueira, C. W.; Braga, A. L.; Menezes,
P. H.; Stefani, H. A. Org. Lett. 2004, 6, 1135.
(22) For preparation of compounds 2a-e, see the Supporting Informa-
tion.
Org. Lett., Vol. 12, No. 9, 2010
1953

Table 1. Products of Iodo Cyclizationa
a Reactions were performed using the selenide 2 (0.25 mmol), I2 (1.1 equiv) in CH2Cl2 at room temperature. b Isolated yield after column chromatography.
aromatic ring having either neutral 2a, electron-donating
2b-c or electronwithdrawing 2d substituents gave the
cyclized products in very similar yields (Table 1, entries
1-4). In addition to aromatic rings, the reaction with
heteroaromatic thiophene also led to the formation of the
desired product in 82% yield (Table 1, entry 5). By contrast,
when the reaction was carried out with homopropargyl
selenides with a hydrogen atom or an alkyl group in the
terminal position, a little decrease in the yields was observed,
and the cyclized products were obtained in 67 and 60%
yields, respectively (Table 1, entries 6 and 7). In the case of
substrates with propargyl alcohols, our reaction system was
also suitable for the cyclization of both hindered and
nonhindered chains, giving the desired cyclized products in
good yields (Table 1, entries 8-10). Finally, it is worth
mentioning that, through our methodology, it was possible
to prepare a series of difunctionalized selenophene rings, such
as 3l-r (Table 1, entries 12-18). This result is significant
particular when one considers that there are many ways to
transform the resulting functionalities into other substituents.
We believe that the mechanism of this cyclization reaction
involves; (i) coordination of the carbon-carbon triple bond
to I2 to generate an iodonium intermediate a, which activates
the triple bond toward nucleophilic attack, (ii) antinucleo-
philic attack of the selenium atom on the activated iodonium
intermediate to produce the salt b, and (iii) facile removal
of the alkyl group via SN2 displacement by the iodide anion
present in the reaction mixture to generate the 4-iodo-2,3-
dihydroselenophene product and one molecule of n-BuI
(Scheme 2).
Since selenophene derivatives exhibit a broad range of
biological activities and applications as intermediates in
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Org. Lett., Vol. 12, No. 9, 2010

give the corresponding products 4 in good yields. It is
interesting to note that the oxidation reaction tolerated a
variety of functional groups, such as halides, hydroxyl, and
butylseleno groups (Table 2, entries 2-6).
Scheme 2. Plausible Mechanism
In order to complete our investigation and to further prove
the potential of 2,3-dihydroselenophene derivatives as pre-
cursors for increasing molecular complexity, we tested the
reactivity of these compounds toward thiol and Heck cross-
coupling via copper- or palladium-catalyzed reactions. In this
way, the reaction of 3a with benzenethiol, using CuI as
catalyst in dioxane, afforded the product 5a in 80% (isolated
yield). In addition, the reaction of 3a with methyl acrylate
or styrene gave the corresponding Heck products 5b and 5c
in 75 and 50% yields, respectively (Scheme 3).
Table 2. Aromatization of 2,3-Dihydroselenophenes with DDQ
Scheme 3
.
Thiol and Heck Cross-Coupling using 3a as
Substratea
a Method A: CuI (10 mol %), benzenethiol (1.2 equiv) in dioxane at
100 °C. Method B: Pd(OAc)2 (5 mol %), n-BuNI (1 equiv), Na2CO3 (2.5
equiv), methyl acrylate (1.2 equiv, 5b) or styrene (1.2 equiv, 5c), DMF,
100 °C.
In summary, we have explored the electrophilic cyclization
of easily accessible alkynyl selenides establishing a route to
2,3-dihydroselenophene derivatives 3 in good yields. The
reaction could be carried out using different electrophiles in
CH2Cl2 at room temperature. The reaction works well with
a wide range of substituents, such as aryl, heteroaryl, alkyl,
propargyl alcohol, and halogen groups in the homopropargyl
selenides. 4-Iodo-2,3-dihydroselenophenes obtained by this
methodology were submitted to a dehydrogenation reaction
using DDQ to give 3-iodoselenophenes in high yields. In
addition, 2,3-dihydroselenophene derivatives 3 were submit-
ted to a copper-catalyzed thiol cross-coupling reaction and
Heck-type reaction giving the desired products in moderate
to good yields.
a Yield of isolated product after column chromatography.
organic synthesis, we wondered if it would be possible to
prepare selenophenes directly from 2,3-dihydroselenophenes.
Otsubo and co-workers have reported that 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) is a useful promoter for the
oxidation of 5,6-dihydroseleno[2,3-d]-1,3-dithiole-2-thione
to aromatic seleno[2,3-d]-1,3-dithiole-2-thione.23 Gratify-
ingly, we found that the reaction of 2,3-dihydroselenophenes
3a (1 equiv) with DDQ (2 equiv) in toluene at 90 °C gave
the selenophene 4a in 77% yield (Table 2, entry 1). As
demonstrated in Table 2, the reaction of DDQ with other
2,3-dihydroselenophenes was also carried out smoothly to
Acknowledgment. We are grateful to CNPq (CNPq/
INCT-catalise), CAPES (SAUX), and FAPERGS for finan-
cial support. CNPq is also acknowledged for a fellowship
(to G.Z. and R.F.S.).
Supporting Information Available: Spectroscopic data
for all new compounds and detailed experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(23) Jigami, T.; Takimiya, K.; Otsubo, T. J. Org. Chem. 1998, 63, 8865.
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