Copper iodide-catalyzed cyclization of (Z)-chalcogenoenynes

Article abstract of DOI:10.1021/ol802060f

(Chemical Equation Presented) We present here our results of the efficient copper-catalyzed cyclizations of chalcogenoenynes and establish a route to obtain 3-substituted chalcogenophenes in good to excellent yields. In addition, the obtained chalcogenophenes were readily transformed to more complex products using the palladium-catalyzed cross-coupling reactions with boronic acids to give Suzuki-type products in good yields.

Full text of DOI:10.1021/ol802060f

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4983-4986
Copper Iodide-Catalyzed Cyclization of
(Z)-Chalcogenoenynes
Andre´ L. Stein, Diego Alves,* Juliana T. da Rocha, Cristina W. Nogueira, and
Gilson Zeni*
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o, Toxicolo´gica e Farmacolo´gica de
Organocalcogenios-CCNE-UFSM, 97105-900-Santa Maria, RS, Brazil
gzeni@quimica.ufsm.br
Received September 3, 2008
ABSTRACT
We present here our results of the efficient copper-catalyzed cyclizations of chalcogenoenynes and establish a route to obtain 3-substituted
chalcogenophenes in good to excellent yields. In addition, the obtained chalcogenophenes were readily transformed to more complex products
using the palladium-catalyzed cross-coupling reactions with boronic acids to give Suzuki-type products in good yields.
Chalcogenide compounds have found such wide utility
because their effects on an extraordinary number of very
different reactions, including many carbon-carbon bond
formations,1 under relatively mild reaction conditions. In
addition, they have become attractive synthetic targets
because of their chemo-, regio-, and stereoselective reac-
tions,2 use in a wide variety of functional groups, thus
avoiding protection group chemistry, and useful biological
activities.3 The selenium group can be introduced in an
organic substrate via both nucleophile and electrophile
reagents. After being introduced in an organic substrate, the
organoselenium group can easily be removed by selenoxide
syn elimination4 and [2,3] sigmatropic rearrangement.5
Conversely, the carbon-selenium bond can also be replaced
by a carbon-hydrogen,6 carbon-halogen,7 carbon-lithium,8
or carbon-carbon bond.9
Among chalcogenides, the chalcogenophene derivatives
play an important role in organic synthesis because of their
excellent electrical properties and environmental stability.
Chalcogenophene oligomers are compounds of current inter-
est because many of them show photoenhanced biological
activities,10 and R-type chalcogenophene oligomers, such as
5,2′:5′,2′′-terthiophene, produce crystalline, electroconductive
polythiophenes on electrochemical polymerizations.11 Thus,
a wide variety of oligomers and related chalcogen compounds
including mixed thiophene-pyrrole oligomers have been
synthesized mainly with expectation of obtaining excellent
(5) (a) Reich, H. J. J. Org. Chem. 1975, 40, 2570. (b) Sharpless, K. B.;
Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.
(1) (a) Zeni, G.; Ludtke, D. S.; Panatieri, R. B.; Braga, A. L. Chem.
ReV. 2006, 106, 1032. (b) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc. Chem.
Res. 2003, 36, 731.
(6) Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976, 30, 2643.
(7) Sevrin, M.; Dumont, W.; Hevesi, L. D.; Krief, A. Tetrahedron Lett.
1976, 30, 2647.
(2) (a) Organoselenium Chemistry. In Topics in Current Chemistry 208;
Wirth, T., Ed.; Springer-Verlag: Heidelberg, 2000. (b) Krief, A. In
ComprehensiVe Organometallic Chemistry II; Abel, E. V., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon Press: New York, 1995; Vol. 11, Chapter
13. (c) Paulmier, C. Selenium Reagents and Intermediates in Organic
Synthesis. In Organic Chemistry Series 4; Baldwin, J. E., Ed.; Pergamon
Press: Oxford, 1986. (d) Petragnani, N. Tellurium in Organic Synthesis;
Academic Press: London, 1994.
(8) (a) Seebach, D.; Peleties, N. Chem. Ber. 1972, 105, 511. (b) Seebach,
D.; Beck, A. K. Angew. Chem., Int. Ed. Engl. 1974, 13, 806. (c) Reich,
H. J.; Shah, S. K. J. Am. Chem. Soc. 1975, 97, 3250.
(9) Silveira, C. C.; Braga, A. L.; Vieira, A. S.; Zeni, G. J. Org. Chem.
2003, 68, 662.
(10) Chemistry and Biology of Naturally-Occurring Acetylenes and
Related Compounds; Lain, J., Breteler, H., Arnason, T., Hansen, L., Eds.;
Elsevier: Amsterdam, 1988.
(3) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. ReV. 2004, 104,
6255.
(11) (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.
(4) (a) Huguet, J. L. AdV. Chem. Ser. 1967, 345. (b) Sharpless, K. B.;
Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 22, 1979.
10.1021/ol802060f CCC: $40.75
Published on Web 10/01/2008
2008 American Chemical Society

precursor compounds for molecular devices and electrocon-
ductive polymers. In addition, chalcogenophenes are widely
studied agents with a diverse array of biological effects.
These include potent antitumor and antiviral activity, as well
as efficacy as a maturation inducing agent.12
development of an optimum set of reaction conditions. In
this way, the optimization process was performed using
telluroenyne 1a and diphenyl diselenide. Thus, a mixture of
1a (0.25 mmol) and diphenyl diselenide (1.1 equiv), utilizing
DMSO (3 mL) as a solvent at 110 °C, was reacted with
different copper salts (10 mol %). The results showed that
the cyclization of 1a was best catalyzed by CuI. Using this
catalyst, the desired product 2a was obtained in 79% yield.
Other copper salts such as CuCl, CuCN, CuCl2, CuBr2,
Cu(OAc)2, and Cu(OTf)2 were less effective. Remarkably,
diphenyl deselenide alone could not promote this reaction
in the absence of the copper catalyst, and 1a was recovered
quantitatively. In comparison, treatment of enyne 1a with a
catalytic amount of CuI in the absence of diphenyl deselenide
led to no detectable consumption of the starting material.
This observation suggested that a complex PhSe/CuI16 should
be required for the catalytic conversion of 1a to 2a.
Regarding the influence of the solvent in this cyclization,
optimal results were achieved using DMSO. Other solvents
(THF, DMF, MeCN, toluene, CH2Cl2, and dioxane) gave
the desired product 2a in unacceptable yields (less than 20%).
Since the accomplishment of this reaction probably is
dependent on the nature of the group directly linked to the
chalcogen atom, we decided to explore this influence using
different aryl and alkyl groups, and the results are shown in
Scheme 2. A closer inspection of these results revealed that
In addition, great progress has been made in carbon-hetero-
atom bond formation via the cross-coupling reaction of
heteroatom compounds with halides using a copper-catalyzed
system.13 These improvements are certainly a consequence
of the studies regarding the effects of several ligands, such
as aliphatic diamines, 1,10-phenanthroline, amino acids and
their derivatives, and others. These important findings allow
the use of common organic solvents (dichloromethane,
chloroform, toluene, benzene, DMF, and DMSO) and weaker
bases (K2CO3, Cs2CO3, and K3PO4), and they also allow the
use of not only aryl iodide but also aryl bromides and
chlorides. After that, these reactions became more attractive,
and nowadays they can be carried out at lower temperatures,
under milder conditions, and using a catalytic amount of the
copper salts. Besides, the transition-metal-catalyzed reactions
of organoselenium compounds have been growing, and
highly selective transformations of chalcogen compounds
have been developed by using palladium or copper cata-
lysts.14
To our knowledge, the use of Cu-catalyzed cyclization of
enynes remains unexplored. In this paper, we present our
contribution to this field by developing a general and mild
protocol for the seleno- and tellurophene synthesis via
reaction of enynes with diorganoyl dichalcogenides, cata-
lyzed by CuI. Not only does this method give access to C-3-
substituted selenophenes, unavailable by existing one-pot
cyclization techniques, but it also holds a promise for a quick
assembly of tellurium heterocyclic compounds via a two-
component cyclization/coupling strategy (Scheme 1).
Scheme 2. Syntheis of Tellurophenes
Scheme 1. General Scheme
the reaction with telluroenynes having an alkyl group bonded
at the tellurium atom gave the tellurophene derivatives in
good yields, although the yield was lower for telluroenynes
with a methyl or ethyl group. Nonetheless, performing the
reaction with teluroenyne 1d, which has an aryl group bonded
at the tellurium atom, the desired product was not observed,
even under long reaction time. These results demonstrated
that the efficiency of the chalcogenophene formation could
significantly depend on the steric effects and that this
cyclization reaction occurs only with chalcogenenynes having
a Y-Csp3 bond.
The starting (Z)-chalcogenoenyne 1 was readily available
by using the process of hydrochalcogenation of alkynes.15
Our initial studies on the cyclization have focused on the
(12) (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. (d) Goldstein, B. M.; Leary, J. F.; Farley,
B. A.; Marquez, V. E.; Rowley, P. T. Blood 1991, 78, 593. (e) Jayaram,
H. N.; Dion, R. L.; Glazer, R. I.; Johns, D. G.; Robins, R. K.; Srivastava,
P. C.; Cooney, D. A. Biochem. Pharmacol. 1982, 31, 2371.
Our investigation of the generality and scope of the
reaction is summarized in Table 1. Inspection of results
demonstrates that the reaction worked well for a variety of
diaryl diselenides. Both hindered (2g and 2h) and nonhindred
(14) (a) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii,
P. V. J. Organomet. Chem. 2000, 605, 96. (b) Beletskaya, I. P.; Ananikov,
V. P. Pure Appl. Chem. 2007, 79, 1041.
(13) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421. (b) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald,
S. L. J. Org. Chem. 2004, 69, 5578. (c) Shafir, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 8742. (d) Shafir, A.; Lichtor, P. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3490. (e) Zhang, D.; Liu, Z.; Yum, E. K.;
Larock, R. C. J. Org. Chem. 2007, 72, 251.
(15) Zeni, G.; Stracke, M. P.; Nogueira, C. W.; Braga, A. L.; Menezes,
P. H.; Stefani, H. A. Org. Lett. 2004, 6, 1135.
(16) (a) Taniguchi, N. J. Org. Chem. 2007, 72, 1241. (b) Taniguchi,
N.; Onami, T. J. Org. Chem. 2004, 69, 915.
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Org. Lett., Vol. 10, No. 21, 2008

uents in the aromatic ring. For example, diaryl diselenides
with a CF3 substituent (2f) or with a Cl (2d) gave similar
yields than diaryl diselenides with a methyl group (2b). It is
worth mentioning that, through our methodology, it was
possible to prepare highly functionalized selenophenes, using
as substrate not only diaryl diselenides (2a-2i) but also
diaryl ditelurides (2j,2k) and sulfide (2m). Notably, dialkyl
diselenide (2n) and dialkyl ditelluride (2o) delivered the
desired tellurophenes in moderated yields.
Table 1. Telluroenynes Cyclization Catalized by CuI/ArYYAra
In an attempt to broaden the scope of our methodology,
the possibility of performing the reaction with selenoenynes
instead of telluroenynes was also investigated. Thus, the
standard reaction condition applied to prepare the tel-
luroenynes was also tested for selenoenynes (Table 2). The
reaction is tolerant of both electron-donating and electron-
Table 2. Selenoenynes Cyclization Catalized by CuI/ArYYAra
a Reaction conditions: telluroenyne (0.5 mmol), diorganoyl dichalco-
genide (1.1 equiv), CuI (10 mol %) in DMSO (3 mL) at 110 °C for 10 h.
b Yields of isolated products.
a Reaction conditions: selenoenyne (0.5 mmol), diorganoyl dichalco-
genide (1.1 equiv), CuI (10 mol %) in DMSO (3 mL) at 110 °C for 10 h.
b Yields of isolated products.
(2a) diaryl diselenides gave the desired tellurophene in good
yields. A closer inspection of the results revealed that the
reaction is not sensitive to electronic effects of the substit-
Org. Lett., Vol. 10, No. 21, 2008
4985

withdrawing groups on the aromatic ring, including sensitive
chlorine. Excellent yield was also obtained in cyclization of
the terminal selenoenynes which gave selenophene 3i with
no substituent at the 5 position.
chalcogen atom on the activated triple bond to produce the
chalcogen salt, (d) the Cu(I) anionic complex formations
[CuI(YAr)]-, and (e) nucleophilic attack of selenolate anion
on the alkyl group bonded to the chalcogen atom (Scheme
4).
We believe that this approach to chalcogenophenes should
prove quite useful in synthesis, particularly when one
considers that there are many ways to transform the resulting
functionalities into other substituents. For instance, the
resulting tellurophene 2o should be a particularly useful
intermediate in many transition-metal-catalyzed processes,
such as Sonogashira, Suzuki, Stille, Heck, and Ullmann
cross-couplings.1 In view of this, the potential of tellurophene
derivatives as precursors for increasing molecular complexity
via palladium-catalyzed reactions has been briefly investi-
gated (Scheme 3). For example, compound 2o underwent
Scheme 4. Proposed Reaction Mechanism
Scheme 3. Suzuki Cross-Coupling of Selenophenes
In conclusion, we have described simple and efficient
copper-catalyzed cyclizations of chalcogenoenynes and
established a route to obtain 3-substituted chalcogenophene
in good to excellent yields. In addition, using the reactions
with boronic acid, we were able to convert chalcogenophenes
to Suzuki-type products in good yields. We believe that this
approach to chalcogenophenes should prove quite useful in
synthesis, particularly when one considers that there are many
ways to transform the resulting tellurium and selenium
functionalities into other substituents. A scale-up experiment
was carried out to show the practicability of the method to
provide chalcogenophenes having different substituents.
Preliminary mechanistic studies support the proposed mech-
anism, and the results of additional investigations that are
ongoing in our laboratory will be reported in due course.
palladium cross-coupling with boronic acids,17 and aryltri-
fluoroborates18 gave the corresponding 3-aryltellurophenes
5a and 5b in excellent yields.
Our working mechanism for the copper-catalyzed conver-
sion of chalcogenoenynes to chalcogenophene is based on
experimental data obtained: (1) in all cases, we isolated the
BuYAr as byproduct; (2) the reaction does not work with
Cu(0) catalyst; (3) no product was obtained when a sp2
carbon was bonded to the chalcogen atom; and (4) no product
was obtained in the absence of both copper salt and
dichalcogenides, then it could involve (a) CuI into the Y-Y
bond to give a Cu(III)-tetracoordinated square-planar sele-
nolate,19 (b) alkyne coordination to the metal center to give
the cationic organo-Cu(III) complex, (c) anti-attack of the
Acknowledgment. We are grateful to CNPq, CAPES
(SAUX), and FAPERGS for financial support. CNPq is also
acknowledged for a fellowship (to G.Z. and A.L.S.).
(17) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(18) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(19) Vicente, J.; Herrero, P. G.; Sa´nchez, Y. G.; Jones, P. G.; Bautista,
D. Eur. J. Inorg. Chem. 2006, 115.
OL802060F
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Org. Lett., Vol. 10, No. 21, 2008