Electrophilic cyclization of 3-alkynyl-4-chalcogen-2-H-chromenes: Synthesis of 3-halo-chalcogenophene[3,2-c]chromene derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.11.049

An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electrophilic cyclization reaction of 3-alkynyl-4-chalcogen-2H- chromene using I₂, PhSeBr, and BuTeBr₃ as electrophilic sources. The cyclizatio

Full text of DOI:10.1016/j.tetlet.2010.11.049

Tetrahedron Letters 52 (2011) 388–391
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Electrophilic cyclization of 3-alkynyl-4-chalcogen-2-H-chromenes: synthesis
of 3-halo-chalcogenophene[3,2-c]chromene derivatives
Adriane Sperança a, Benhur Godoi a, Michael Daniel Costa a, Paulo Henrique Menezes b, Gilson Zeni a,
⇑
a Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicidade de Organocalcogênios, CCNE, UFSM, Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
b Universidade Federal de Pernambuco, Departamento de Química Fundamental, Recife, Pernambuco 50670-901, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 3-halo-chalcogenophene[3,2-c]chromene has been accomplished via electro-
philic cyclization reaction of 3-alkynyl-4-chalcogen-2H-chromene using I2, PhSeBr, and BuTeBr3 as elec-
trophilic sources. The cyclization reaction proceeded cleanly under mild reaction conditions, and 3-
halochalcogen-chromenes were formed in good yields. In addition, the obtained 3-iodo-chalcogenoph-
ene-chromenes were readily transformed to more complex products using a metal–halogen exchange
reaction with n-BuLi and trapping the lithium-intermediate formed with aldehyde, furnishing the desired
secondary alcohol in good yield. Conversely, using the palladium catalyzed cross-coupling reactions with
terminal alkynes and boronic acid, we were able to obtain the Sonogashira and Suzuki type products in
good yields.
Received 2 October 2010
Revised 5 November 2010
Accepted 9 November 2010
Available online 3 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Chalcogenides are widely studied agents with a diverse array of
biological effects.1 These include potent antitumor and antiviral
activities as well as efficacy as a maturation inducing agent.2
Among chalcogenides, the fused chalcogenophene derivatives play
an important role in organic synthesis because of their excellent
electrical properties and environmental stability. Chalcogenophene
oligomers are compounds of current interest because many of
them show photoenhanced biological activities3 and crystalline
polymerizations.4 Thus, a wide variety of oligomers and related
chalcogen compounds including mixed thiophene-pyrrole oligo-
mers have been synthesized mainly with the expectation of obtain-
ing excellent precursor compounds for molecular devices and
electroconductive polymers.5
The derivatives of multiple heterocycles are valued not only for
their rich and varied chemistry, but also for many important bio-
logical properties.5 The synthesis of multiple heterocycles has also
attracted considerable attention because of their use for the syn-
thesis of a variety of functional materials for electronic devices.6,7
However, little is known about the multiple Se-(S)-chromene nu-
cleus with different features and applications in the literature,
and there are only a few reports of a generally useful synthesis
of multiple seleno-thiophenes.8
benzo[b]selenophenes,9g thiophenes,9h furans,9i and pyrroles9j
among others9k–v have been accessed using this protocol.9
These and especially the knowledge that multiple Se-(S)-chro-
mene nuclei are promising candidates for biological active com-
pounds or pharmaceuticals prompted us to develop a complete
investigation on the electrophilic cyclization of 3-alkynyl-4-chal-
cogen-2H-chromenes 1 to obtain the 3-halo-chalcogenophene-
chromenes 2 as the sequence showed in Scheme 1.
The starting 3-alkynyl-4-chalcogen-2H-chromene 1 was readily
available by Sonogashira cross-coupling reactions of 3-iodo-4-
chalcogen-2H-chromene derivatives with different terminal
alkynes.10
As preliminary studies, we examined the feasibility of the elec-
trophilic cyclization reaction with I2 and ICl, as electrophilic
sources, by using 3-phenylethynyl-6-methyl-4-butylselenyl-2H-
chromene 1a as substrate, in order to determine the optimum
reaction conditions (Table 1). Treatment of 1a with I2 (2 equiv),
using THF as solvent at room temperature furnished the cyclized
product 2a in 70% yield (Table 1, entry 1). Encouraged by this
result, we further investigated the reaction behavior with other
solvents and electrophilic sources with the aim to improve the pro-
tocol. To identify the solvent potentially suitable for the cycliza-
In the context of heterocycles, electrophilic cyclization of unsat-
urated compounds has proved to be an efficient method for one-step
construction of a substituted heterocyclic unit.5 Important heterocy-
cles, such as indoles,9a,b benzo[b]furans,9c,d benzo[b]thiophenes,9e,f
I
O
O
R
I2(2eq)
CH2Cl2, r.t
R2
Y
YR1
R2
R
2
1
Y = S, Se; R = aryl, alkyl; R1 = Me, butyl;R2 = alkyl, aryl, alcohol
⇑
Corresponding author.
E-mail address: gzeni@pq.cnpq.br (G. Zeni).
Scheme 1. General scheme.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.049

A. Sperança et al. / Tetrahedron Letters 52 (2011) 388–391
389
Table 1
general, all the reactions proceeded smoothly with good results.
Most importantly, the cyclization turned out to be general with re-
spect to a diverse array of functionalities. The experiments showed
that the electrophilic cyclization of substrates having aryl or alkyl
group bonded to alkyne formed the desired products in similar
yields (Table 2, entries 1 and 2). In addition, the reaction with
bulky alkyl substituents also led to the formation of the desired
product, however, a decrease in the yield was observed (Table 2,
entry 3). A significant decrease in yield of 3-halo-chalcogenophene
chromene was also observed when the reaction was performed
with a bulky propargyl alcohol derivative (Table 2, entry 4). In
the case of substrates with different substituents in the chromene
ring, our reaction system was also suitable for the cyclization of
both naphtho and aryl substituents giving the desired cyclized
products in good yields (Table 2, entries 8 and 9). In addition to
the use of I2 as electrophile source, the reaction with BuTeBr3
and PhSeBr also led to the formation of the desired products in
58% and 60% yield, respectively (Table 2, entries 14 and 15). This
result is significant particularly when one considers that there
are many ways to transform the resulting tellurium and selenium
functionalities into other substituents. It is also worth noting that
this reaction can be performed using not only selenium as the
nucleophile but also sulfur groups (Table 2, entries 10–13).
This approach to 3-halo-chalcogenophene-chromenes 2 pro-
vides a very useful synthesis of various substituted 3-chromenes
via elaboration of the resulting iodide functionality into other
substituents. For instance, the resulting 3-iodo-chalcogenophene-
chromenes 2 are particularly useful intermediates in many palla-
dium-catalyzed processes, such as Sonogashira, Suzuki, and Heck
cross couplings. In view of this, compound 2 was treated under
standard Sonogashira,11 Suzuki12 conditions, providing the corre-
sponding coupling products 3 and 4, respectively, in moderate to
good yields (Scheme 2).
Effect of reaction conditions for the cyclization reaction
E
O
O
E+
Ph
Se
solvent, r.t
2a
SeBu
Ph
1a
Entry
E+
E+ (equiv)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
I2
I2
I2
I2
I2
I2
ICl
ICl
ICl
2.0
2.0
1.1
3.0
2.0
2.0
1.1
1.5
2.0
THF
70
73
94
97
99
nr
86
63
49
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
CH2Cl2
CH2Cl2
CH2Cl2
a
Yields were determined by GC analysis.
R2
I
O
O
Pd(PPh3)2Cl2 (1mol%)
R1
R1
CuI (1.5 mol%), Et3N (2 mL)
Y
Y
r.t.
2
3a-c
3a: Y=Se; R1=Ph; R2=CH(CH3)2OH; (50%)
3j: Y=S; R1=Ph; R2=CH(CH3)2OH; (40%)
1
2
3k:
Y=S; R =n-Bu; R =Ph; (66%)
I
O
O
Pd(PPh3)2Cl2 (5 mol%)
C6H7B(OH)2, K2CO3/H2O,
DMF, 100° C
Ph
Ph
Y
Y
In addition to the palladium catalyzed cross coupling reactions,
we have carried out the halogen-lithium exchange reaction of
product 2j with n-butyllithium. Metal–halogen exchange reactions
have great importance in synthetic organic chemistry, particularly
with respect to the formation of new C–C bonds.13 Analogous to
the well-known metal-halogen exchange reactions, which lead to
a lithium intermediate, we extended this finding to obtain an inter-
mediate 3-lithio-chalcogenophene-chromene 5j. In this way, per-
forming the reaction of 2j with n-BuLi (1 equiv) in a mixture of
hexane (2 mL) and THF (2 mL) at À78 °C followed by the addition
of aldehyde (1 equiv), the secondary alcohol 6j was obtained in
60% yield (Scheme 3).
2
4a-b
Y=Se; (80%)
4a:
4b: Y=S; (65%)
Scheme 2. Reactivity of 2 toward Sonogashira and Suzuki cross-coupling.
tion, we chose CH2Cl2, MeCN, and hexane. For this process, CH2Cl2
was the most effective solvent giving the cyclized product in 99%
yield (Table 1, entry 5). The study to screen the electrophile source
showed that ICl gave the target products in lower yields than I2
(Table 1, entries 7–9). It is important to note that when the amount
of I2 was increased from 1.0 to 3.0 equiv the desired product was
obtained in similar yields (Table 1, entry 4). The analysis of the
optimized reactions revealed that the optimum conditions for this
electrophilic cyclization were the use of 4-butylselenyl-2H-chro-
mene 1a (0.25 mmol), I2 (2.0 equiv) in CH2Cl2 (5 ml) at room tem-
perature. Using this methodology we were able to prepare 3-iodo-
selenopheno[3,2-c]chromene 2a in almost quantitative yield.
After optimizing the reaction parameters, the functional group
tolerance was explored. The results are presented in Table 2. Many
functional groups were compatible with the reaction conditions. In
In summary, we have demonstrated the electrophilic cycliza-
tion reaction of 3-alkynyl-4-chalcogen-2H-chromenes with differ-
ent electrophilic sources under exceptionally mild conditions and
established a route to obtain 3-halo-chalcogenophene-chromenes
2
in good yields. The 3-iodo-4-chalcogenophene-chromenes
obtained by electrophilic cyclization appear highly promising as
intermediates for the preparation of more highly substituted
structures. In fact, using the palladium catalyzed cross-coupling
reactions with terminal alkynes and boronic acids we were able
to convert the 3-iodo-4-chalcogenophene-chromene in highly
O
I
Li
H
OH
O
O
O
n -BuLi
(1equiv)
C6H5
C6H5
C6H5
S
S
THF/hexane
S
hexane
78° C
15 min
-78° C
r.t.
10 min
2j
6j (60%)
5j
Scheme 3. Reactivity of 2j toward n-BuLi followed by aldehyde.

390
A. Sperança et al. / Tetrahedron Letters 52 (2011) 388–391
Table 2
Table 2 (continued)
Scope and generality of the electrophilic cyclization of 3-halo-chalcogenophene[3,2-
c]chromene
Entry
12
Substrate
Product yieldsa (%)/time
I
I
O
O
O
O
I2 (2eq)
R
C6H5
R2
S
CH2Cl2, r.t
Y
2a-o
R2
O
YR1
1a-n
Entry
R
2l (55) 15 min
SCH3
1l
C6H5
n-Bu
C6H5
Substrate
Product yieldsa (%)/time
I
O
I
O
O
n-Bu
S
C6H5
Se
1
2
13
C6H5
SeBu
1a
O
2m (65) 2 h
SCH3
1m
2a (84) 30 min
I
O
TeBu
C6H5
O
O
n-Bu
Se
n-Bu
SeBu
1b
O
Se
2n (58) 2 h
14
15
2b (75) 1 h
I
SeBu
O
1n
SePh
C6H5
3
O
Se
SeBu
2c (65) 1 h
1n
1c
Se
2o (60) 15 min
O
I
O
a
Yields are given for isolated products.
OH
Se
4
5
SeBu
OH
2d (50) 1h 30 min
1d
O
I
O
substituted multiple chalcogenophenes in good yields. Conversely,
3-iodo-4-chalcogenophene-chromene was treated under metal–
halogen exchange conditions with n-BuLi, and trapping the inter-
mediates with aldehydes provided the corresponding secondary
alcohol in good yields. We believe that this approach to 3-iodo-
4-chalcogenophene-chromenes should prove quite useful in syn-
thesis, particularly when one considers that there are many ways
to transform the resulting halogen, tellurium, and selenium func-
tionalities into other substituents.
C6H4-p -Me
Se
SeBu
1e
C6H4-p-Me
2e (77) 3 h
I
O
O
n-Bu
Se
2f (86) 15 min
6
SeBu
n-Bu
1f
Acknowledgments
I
O
O
We are grateful to CNPq, CAPES (SAUX) and FAPERGS (Pronex-
10/0005-1), for financial support. CNPq is also acknowledged for
the fellowships (to G.Z. and A.S.).
C6H5
Se
7
8
2g (84) 30 min
C6H5
SeBu
1g
O
I
Supplementary data
O
C6H5
Se
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.049.
SeBu
1h
C6H5
2h
(75) 2 h
I
References and notes
O
O
1. (a) Gonzalez, J. L.; Stephens, C. E.; Wenzler, T.; Brun, R.; Tanious, F. A.; Wilson,
W. D.; Barszcz, T.; Werbovetz, C. A.; Boykin, D. W. Eur. J. Med. Chem. 2007, 42,
552; (b) Naesens, L.; Stephens, C. E.; Andrei, G.; Loregian, A.; De Bolle, L.;
Snoeck, R.; Sowell, J. W.; De Clercq, E. Antivir. Res. 2006, 72, 60.
2. (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, B. 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. L.; Johns, D. G.; Robins, R. K.; Srivastava, P.
C.; Cooney, D. A. Biochem. Pharmacol. 1982, 31, 2371.
3. (a) 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.
4. (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.
C6H5
C6H5
9
10
11
Se
C6H5
SeBu
1i
2i (74) 3 h
C6H5
O
I
O
C6H5
S
C6H5
SMe
1j
O
2j (80) 30 min
I
O
n-Bu
S
SMe
1k
n-Bu
2k
(50) 2 h

A. Sperança et al. / Tetrahedron Letters 52 (2011) 388–391
391
5. (a) Manetti, F.; Santucci, A.; Locatelli, G. A.; Maga, G.; Spreafico, A.; Serchi, T.;
Orlandini, M.; Bernardini, G.; Caradonna, N. P.; Spallarossa, A.; Brullo, C.;
Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Hoffmann, O.; Bologna, M.;
Angelucci, A.; Botta, M. J. Med. Chem. 2007, 50, 5579; (b) Naya, S.; Ohtoshi, H.;
Nitta, M. J. Org. Chem. 2006, 71, 176; (c) Wendt, J. A.; Deeter, S. D.; Bove, S. E.;
Knauer, C. S.; Brooker, R. M.; Augelli-Szafran, C. E.; Schwarz, R. D.; Kinsora, J. J.;
Kilgore, K. S. Bioorg. Med. Chem. Lett. 2007, 17, 5396.
6. (a) Skotheim, T. A.; Elsenbaumer, R. L.; Reynolds, J. R. Handbook of Conducting
Polymers, 2nd ed.; Dekker: New York, 1998; (b) Nalwa, H. S. Handbook of
Conductive Materials and Polymers; Wiley: New York, 1997; (c) Kraft, A.;
Grimsdale, A.; Holmes, A. B. Angew. Chem., Int. Ed. 1998, 37, 403.
1769; (j) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1
2002, 622; (k) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437;
(l) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936; (m) Yue, D.; Della Ca, N.;
Larock, R. C. Org. Lett. 2004, 6, 1581; (n) Yao, T.; Larock, R. C. J. Org. Chem. 2005,
70, 1432; (o) Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511; (p)
Zhou, C.; Dubrovsky, A. V.; Larock, R. C. J. Org. Chem. 2006, 71, 1626; (q) Waldo,
J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203; (r) Arcadi, A.; Cacchi, S.; Giuseppe, S.
D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409; (s) Dabdoub, M. J.; Dabdoub,
V. B.; Pereira, M. A. J. Org. Chem. 1996, 61, 9503; (t) Bellina, F.; Biagetti, M.;
Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857; (u) Peng, A.; Ding, Y. J. Am.
Chem. Soc. 2003, 125, 15006; (v) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999,
40, 7193.
7. Arbizzani, C.; Catellani, M.; Mastragostino, M.; Cerroni, M. G. J. Electroanal.
Chem. 1997, 423, 23.
10. (a) Godoi, B.; Sperança, A.; Back, F. D.; Brandão, R.; Nogueira, C. W.; Zeni, G. J.
Org. Chem. 2009, 74, 3469; (b) Sperança, A.; Godoi, B.; Souza, A. C. G.; Zeni, G.
Tetrahedron Lett. 2010, 51, 36.
11. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
12. Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.
13. (a) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1; (b) Knochel, P.;
Dohle, W.; Gommerman, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu,
V. A. Angew. Chem., Int. Ed. 2003, 42, 4302; (c) Parham, W. E.; Bradsher, C. K. Acc.
Chem. Res. 1982, 15, 300; (d) Rogers, H. R.; Houk, J. J. Am. Chem. Soc. 1982, 104,
522; (e) Rieke, R. D.; Lee, J.; Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R. J. Org.
Chem. 2000, 65, 5428; (f) Slocum, D. W.; Carroll, A.; Dietzel, P.; Eilerman, S.;
Culver, J. P.; McClure, B.; Brown, S.; Holman, R. W. Tetrahedron Lett. 2006, 47,
865; (g) Oshima, K.; Inoue, A.; Kitagawa, K.; Shinokubo, H. J. Org. Chem. 2001,
66, 4333.
8. (a) Sommen, G.; Comel, A.; Kirsch, G. Phosphorus, Sulfur and Silicon and the
Related Elements 2005, 180, 939; (b) Sommen, G.; Comel, A.; Kirsch, G. Synthesis
2004, 451; (c) Yasuike, S.; Kurita, J.; Tsuchiya, T. Heterocycles 1997, 45, 1891; (d)
Kazuo Takimiya, K.; Konda, Y.; Ebata, H.; Niihara, N.; Otsubo, T. J. Org. Chem.
2005, 70, 10569.
9. (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed.
2003, 42, 2406; (b) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2006, 71, 62; (c)
Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292; (d) Arcadi, A.; Cacchi,
S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432; (e) Yue, D.; Larock, R. C.
J. Org. Chem. 2002, 67, 1905; (f) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5,
4377; (g) Kesharwani, T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71,
2307; (h) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med. Chem. Lett.
2001, 11, 2341; (i) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7,