Synthesis of organochalcogen propargyl aryl ethers and their application in the electrophilic cyclization reaction: An efficient preparation of 3-halo-4-chalcogen-2H-benzopyrans

Article abstract of DOI:10.1021/jo900307k

We herein described the synthesis of various organochalcogen propargyl aryl ethers via reaction of lithium acetylide intermediate with electrophilic chalcogen (sulfur, selenium, tellurium) species. Various aryl and alkyl groups directly bonded to the chal

Full text of DOI:10.1021/jo900307k

Synthesis of Organochalcogen Propargyl Aryl Ethers and Their
Application in the Electrophilic Cyclization Reaction: An Efficient
Preparation of 3-Halo-4-Chalcogen-2H-Benzopyrans
Benhur Godoi,† Adriane Speranc¸a,† Davi F. Back,‡ Ricardo Branda˜o,†
Cristina W. Nogueira,† and Gilson Zeni*,†
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o Farmacolo´gica e Toxicolo´gica de Organocalcogeˆnios and
Laborato´rio de Materiais Inorgaˆnicos, CCNE, UniVersidade Federal de Santa Maria, Santa Maria - Rio
Grande do Sul - Brazil - 97105-900
gzeni@pq.cnpq.br
ReceiVed February 11, 2009
We herein described the synthesis of various organochalcogen propargyl aryl ethers via reaction of lithium
acetylide intermediate with electrophilic chalcogen (sulfur, selenium, tellurium) species. Various aryl
and alkyl groups directly bonded to the chalcogen atom were used as electrophile. The results revealed
that the reaction does not significantly depend on the electronic effects of substituents in the aromatic
ring bonded to the chalcogen atom of the electrophilic chalcogen species. Additional versatility in this
process was demonstrated with respect to a diverse array of functionality in the aromatic ring at propargyl
aryl ethers. These propargyl aryl ethers, bearing the chalcogen group, underwent highly selective
intramolecular cyclizations when treated with I2 or ICl affording 3-iodo-4-chalcogen-2H-benzopyrans.
The results demonstrated that the cyclization efficiency was significantly influenced by the steric effects
of aromatic ring, since the cyclization reaction gave low yields with aromatic rings having a substituent
at orto position than those having no substituent. The reactivity of 3-iodo-4-chalcogen-2H-benzopyrans
was also studied. 4-Selenobutyl benzopyrans were treated under Neghishi cross-coupling conditions
providing the corresponding 3-aryl benzopyran derivatives in good yields. In addition, using the copper
catalyzed cross-coupling reactions with thiols, in the absence of any cocatalyst, we were able to introduce
a thiol function in 3-iodo-benzopyran derivatives.
Introduction
ReViews journal that was devoted to this field.3 Among
heterocycles, the six-membered oxygenated heterocycles, or
pyrans, are probably one of the most common structural motifs
spread across natural products, from simple glucose to structur-
In recent years, there has been increased interest in the
synthesis of heterocycles due to the number of these compounds
that show antidepressant, antihypertensive, and hypoglycemic
activities as well as other biological effects.1 The literature
contains a variety of synthetic approaches to the heterocycle
ring structures, much of which has been compiled into com-
prehensive reviews,2 including a special issue in the Chemical
(1) (a) Sebille, S.; Gall, D.; de Tullio, P.; Florence, X.; Lebrun, P.; Pirotte,
B. J. Med. Chem. 2006, 49, 4690. (b) Madrid, P. B.; Liou, A. P.; DeRisi, J. L.;
Guy, R. K. J. Med. Chem. 2006, 49, 4535. (c) Heinrich, T.; Bo¨ttcher, H.;
Schiemann, K.; Holzemann, G.; Schwarz, M.; Bartoszyk, G. D.; Amsterdam,
C.; Greiner, H. E.; Seyfried, C. A. Bioorg. Med. Chem. 2004, 12, 4843. (d)
Tang, L.; Yu, J.; Leng, Y.; Feng, Y.; Yang, Y.; Ji, R. Bioorg. Med. Chem. Lett.
2003, 13, 3437.
† Laborato´rio de S´ıntese, Reatividade, Avaliac¸a˜o Farmacolo´gica e Toxico-
lo´gica de Organocalcogeˆnios.
(2) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Zeni, G.;
Larock, R. C. Chem. ReV. 2007, 107, 303.
‡ Laborato´rio de Materiais Inorgaˆnicos.
(3) See Chem. ReV. 2004, 104, Issue 5.
10.1021/jo900307k CCC: $40.75
Published on Web 04/03/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3469–3477 3469

Godoi et al.
SCHEME 1
ally complex metabolites present in the structure of several
biologically interesting compounds. In particular, 2H-benzopy-
rans are present in a variety of compounds that possess important
pharmaceutical and biological applications, such as Dau-
richromenic acid that exhibits anti-HIV activities4 and Coutar-
eagenin that is known to present antidiabetic properties.5
Therefore, the synthesis of 2H-benzopyran derivatives and their
properties have been thoroughly reported in the literature. The
synthetic methods to obtain multiple substituted 2H-benzopyran
can be basically divided into two classes. The first approach is
based on a construction of the 2H-benzopyran nucleus after the
substituents have been installed and properly functionalized. The
second approach is based on a preformed 2H-benzopyran to
which carbon substituents are attached in successive order. In
this context, electrophilic cyclizations of suitable unsaturated
systems have been frequently utilized to construct a wide range
of carbocycles and heterocycles.6 Important heterocycles, such
as indoles,7a,b benzo[b]furans,7c,d benzo[b]thiophenes,6g,7e
benzo[b]selenophenes,7f thiophenes,7g furans,6e pyrroles,7h and
benzopyrans,6a have been accessed using this protocol.
In addition, the introduction of chalcogen group into organic
molecules has found such wide utility because their effects on
an extraordinary number of very different reactions. They have
become attractive synthetic targets because of their chemo-,
regio-, and stereoselective reactions,8 use in a wide variety of
functional groups, avoiding protection group chemistry, and
useful biological activities.9 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 groups can easily be removed by
selenoxide syn elimination10 and [2, 3] sigmatropic rearrange-
ment.11 The carbon-selenium bond can also be replaced by a
carbon-hydrogen,12 carbon-halogen,13 carbon-lithium,14 or
carbon-carbon bond.15
gies for the synthesis of substituted telluro and selenophenes.16
There are several reasons for this; they have a widely varied
synthetic organochemical potential. The chalcogen atom exer-
cises a stabilizing effect on neighboring positive as well as
negative charges. This makes the carbon responsive toward both
nucleophilic and electrophilic attack an extremely useful feature
for organic synthetic purposes. Recently, Larock and co-
workers6a reported an elegant synthesis of 2H-benzopyrans via
electrophilic cyclization of propargylic aryl ethers. In this study,
they were able to introduce an alkyl or aryl group at 4-position
and the iodine moiety at 3-position of benzopyran. A possible
extension of this interesting chemistry envisions that the
introduction of chalcogen substituent at 4-position at benzopy-
rans could provide a versatile synthetic handle for further
functionalization as well as lead to increased rates of cyclization.
To the best of our knowledge, there is no protocol describing
the introduction, at the same time, of both halogen and chalcogen
at 3 and 4-positions of benzopyran, respectively, using orga-
nochalcogen propargyl aryl ethers as substrate via electrophilic
cyclization reactions. The difference of the reactivity between
halogen and chalcogen functionality can constitute as a synthetic
approach to the preparation of benzopyran compounds. In this
study, we optimized the preparation of organochalcogen pro-
pargyl aryl ethers 2, and investigated their applications as
substrate in the electrophilic cyclization reactions to obtain
3-halo-4-chalcogen-2H-benzopyrans 3 (Scheme 1).
Results and Discussion
Heterocycles containing chalcogen play an important role in
organic synthesis, especially in the development of methodolo-
To the preparation of propargyl aryl ethers 1, we chose the
known reaction of phenol with propargyl bromide in the
presence of K2CO3 in acetone at reflux for 24 h.17 To the
introduction of selenophenyl group, we first generated the
lithium acetylide intermediated by reaction of propargyl aryl
ethers 1a-i with 1.1 equiv of n-BuLi, in THF at -78 °C for
1 h, followed by the reaction with an electrophilic selenium
species. By this way, we prepared a number of novel orga-
nochalcogen propargyl aryl ethers, and the generality and scope
of the reaction is summarized in Table 1.
(4) (a) Zhendong, J.; Ying, K. Total synthesis of daurichromenic acid. PCT
Int. Appl. WO 2004058738, 2004. (b) Iwata, N.; Wang, N.; Yao, X.; Kitanaka,
S. J. Nat. Prod. 2004, 67, 1106. (c) Hu, H.; Harrison, T. J.; Wilson, P. D. J.
Org. Chem. 2004, 69, 3782.
(5) Korec, R.; Sensch, K. H.; Zoukas, T. Arzneim.-Forsch. 2000, 50, 122.
(6) (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem.
2007, 72, 1347. (b) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c)
Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763. (d)
Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71, 236. (e) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (f) Barluenga, J.;
Trincado, M.; Marco-Arias, M.; Ballesteros, A.; Rubio, E.; Gonzalez, J. M. Chem.
Commun. 2005, 2008. (g) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377.
(h) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437. (i)
Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
Table 1 illustrates the introduction of chalcogen group at
terminal triple bond of the propargyl aryl ethers. Various aryl
(7) (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) Kesharwani,
T.; Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2006, 71, 2307. (g) Flynn,
B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med. Chem. Lett. 2001, 11,
2341. (h) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans.
1 2002, 622.
(8) (a) Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem.
2009, 1649. (b) In Organoselenium Chemistry; Wirth, T., Ed.; Topics in Current
Chemistry 208; Springer-Verlag: Heidelberg, 2000. (c) Krief, A. In Compre-
hensiVe Organometallic Chemistry II; Abel, E. V., Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon Press: New York, 1995; Vol. 11, Chapter 13. (d) Paulmier,
C. In Selenium Reagents and Intermediates in Organic Synthesis; Baldwin, J. E.,
Ed.; Organic Chemistry Series 4; Pergamon Press: Oxford, 1986.
(9) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. ReV. 2004, 104, 6255.
(10) (a) Huguet, J. L. AdV. Chem. Ser. 1967, 345. (b) Sharpless, K. B.; Young,
M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 22, 1979.
(12) Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976, 30, 2643.
(13) Sevrin, M.; Dumont, W.; Hevesi, L. D.; Krief, A. Tetrahedron Lett.
1976, 30, 2647.
(14) (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.
(15) Silveira, C. C.; Braga, A. L.; Vieira, A. S.; Zeni, G. J. Org. Chem.
2003, 68, 662.
(16) (a) Barros, O. S. R.; Favero, A.; Nogueira, C. W.; Menezes, P. H.; Zeni,
G. Tetrahedron Lett. 2006, 47, 2179. (b) Prediger, P.; Moro, A. V.; Nogueira,
C. W.; Savegnago, L.; Rocha, J. B. T.; Zeni, G. J. Org. Chem. 2006, 71, 3786.
(c) Barros, O. S. R.; Nogueira, C. W.; Stangherlin, E. C.; Menezes, P. H.; Zeni,
G. J. Org. Chem. 2006, 71, 1552. (d) Zeni, G. Tetrahedron Lett. 2005, 46, 2647.
(e) Panatieri, R. B.; Reis, J. S.; Borges, L. P.; Nogueira, C. W.; Zeni, G. Synlett
2006, 18, 3161. (f) Stein, A. L.; Alves, D.; Rocha, J. T.; Nogueira, C. W.; Zeni,
G. Org. Lett. 2008, 10, 4983. (g) Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni,
G. J. Org. Chem. 2007, 72, 6726.
(17) Bach, P.; Nilsson, K.; Wallberg, A.; Bauer, U.; Hammerland, L. G.;
Peterson, A.; Svensson, T.; Oesterlund, K.; Karis, D.; Boije, M.; Wensbo, D.
Bioorg. Med. Chem. Lett. 2006, 16, 4792.
(11) (a) Reich, H. J. J. Org. Chem. 1975, 40, 2570. (b) Sharpless, K. B.;
Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154.
3470 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Organochalcogen Propargyl Aryl Ethers
TABLE 1. Synthesis of Organochalcogen Propargyl Aryl Ethers 2a
and alkyl groups directly bonded to the chalcogen atom were
used as electrophile, under the same reaction conditions
described in Table 1. Interestingly, all entries provided the
corresponding organochalcogen propargyl aryl ethers in accept-
able yields. Aromatic ring connected to the selenium atom
having a neutral (Table 1, entries 1-9), electron-donating (Table
1, entry 10), or electron-withdrawing group (Table 1, entry 11)
formed the desired product in similar yields. These results
revealed that the reaction does not significantly depend on the
electronic effects of substituents in the aromatic ring bonded to
the selenium atom of the electrophilic selenium species. The
use of a bulky group, such as naphthalene (Table 1, entry 12),
proceeded smoothly within 3 h, affording the corresponding
organochalcogen propargyl aryl ether in 60% yield. In addition
to aromatic rings, the reactions with alkyl group directly bonded
to the selenium atom also led to the formation of the desired
products (Table 1, entries 13-15). It is also worth noting that
this reaction can be performed using tellurium and sulfur groups
as electrophile source to functionalize the terminal alkynes under
extremely mild conditions (Table 1, entries 16-19). Most
importantly, this method turned out to be general with respect
to a diverse array of functionality in the aromatic ring at
propargyl aryl ethers. Satisfactorily, all propargyl aryl ethers
tested were effective in the preparation of the corresponding
organochalcogen propargyl aryl ethers. These compounds are
yellow oils, odorless, very stable, which can be easily purified
and stored in the laboratory. In addition, using this protocol,
we were able to prepare the organochalcogen propargyl aryl
ethers on a large scale (10 mmol).
After the successful investigation of the preparation of
organochalcogen propargyl aryl ethers 2a-s, we then turned
our attention to use these compounds in the electrophilic
cyclization reactions. The model substrate, arylseleno propargyl
aryl ether 2a, was considered appropriate for studying the scope
of the method. Initial experiments focused on the use of I2 as
electrophilic reagent in CH3NO2 as solvent in the presence of
NaHCO3 as base, using the same reaction conditions described
by Larock.6a In this way, I2 (3 equiv)/CH3NO2 (3 mL) and
subsequently NaHCO3 (2 equiv) were added to a solution of
2a (0.25mmol) in CH3NO2 (2 mL) at room temperature.
Unfortunately, these conditions failed to give the desired
cyclization product. Indeed, complete recovery of the starting
material, even under forcing conditions, led to the conclusion
that the solvent was critical for the success of this cyclization
reaction. In view of this disappointing result, we further
investigated the reaction behavior with different solvents and
electrophilic sources aiming to improve the protocol. The
outcome of this study and an investigation of other reaction
parameters are depicted in Table 2.
The presence of a base was crucial for a clean, high-yielding
reaction. It is presumed to neutralize the byproduct HI of the
electrophilic cyclization, which can also react with the acetylenic
selenide and generate the corresponding vinylic iodide.18 For
this reason, in our experiments, we investigated the influence
of some inexpensive bases. As listed in Table 2, when the
reaction was carried out using KOH, Na2CO3, Cs2CO3, and
CH3COONa, the target product was not obtained nor was it
obtained in moderated yields, even though a long reaction time
was used (24 h). The best result was obtained using NaHCO3,
which gave the desired product 3a in 83% yield (Table 2, entries
a Reaction performed in the presence of 1 (5mmol), n-BuLi (1.1
equiv), R2YBr (1.1 equiv) in THF (30 mL).
(18) Comasseto, J. V.; Menezes, P. H.; Stefani, H. A.; Zeni, G.; Braga, A. L.
Tetrahedron 1996, 52, 9687.
J. Org. Chem. Vol. 74, No. 9, 2009 3471

Godoi et al.
TABLE 2. Influence of Reaction Conditions on the Iodo
Cyclization of Arylseleno Propargyl Aryl Ethers 2a
Thus the careful analysis of the optimized reactions revealed
that the optimum condition for the I2 cyclization reactions was
the addition of NaHCO3 (0.5 mmol), at room temperature, to a
solution of 0.25 mmol of selenophenyl propargyl aryl ether 2a
in 3 mL of THF. After that, 3 equiv of I2 in 2 mL of THF was
gradually added at room temperature.
In the course of our investigation into the eletrophilic
cyclization of organochalcogen propargyl aryl ethers, we found
that treatment of arylseleno propargyl aryl ether 2a with the
standard conditions using ICl instead of I2 resulted in the
formation of cyclized product 3a only in 18% yield (Table 3,
entry 1). In the Larock’s condition6a and in our earlier study on
the iodocyclization of functionally substituted alkynes,16g using
ICl as electrophile source, the use of lower temperature (-25
°C) proved to be better than the use of room temperature. In an
attempt to obtain an improvement in the yield of this cyclization,
the change of the temperature from room temperature to -25
°C and a variety of conditions were investigated, including,
solvent and bases. As shown in Table 3, of the bases
investigated, Na2CO3, CH3COONa, Cs2CO3 and KOH provided
similar results giving the products in moderated yields (Table
3, entries 2-5). Interestingly, it was found that in the absence
of base, the reaction reached completion in 83% yield (Table
3, entry 6). With regard to the solvent, the reaction worked
equally well in THF and DMF giving the cyclized product in
83% and 80% yield respectively (Table 3, entries 6 and 7). We
also examined other solvents in place of THF such as DMF,
CH3NO2, CH2Cl2, EtOH, CH3CN and hexane which gave the
desired products in moderate yields (Table 3, entries 7-12). It
was pointed out that the amount of ICl also played an important
role in the reaction. Not only the increase the amount of ICl to
3.0 equiv (Table 3, entry 16) but also the reduction to 1.0 equiv
(Table 3, entry 13) was not better than 1.5 equiv (Table 3, entry
6). Thus, we concluded that our optimized conditions to ICl
cyclizations is the addition of a mixture of ICl (1.5 equiv) in
THF (2 mL), at -25 °C, to a solution of 0.25 mmol of the
selenophenyl propargyl aryl ether 2a in 3 mL of THF. The
reaction mixture was allowed to stir at this temperature for
2 h. After obtaining our best conditions using either I2 or
ICl, we studied the scope of this reaction to various
organochalcogen propargyl aryl ethers and the results are
summarized in Table 4.
entry
solvent
base (equiv)
I2 (equiv)
yield (%)
1
2
3
4
5
6
7
8
CH3NO2
CH2Cl2
Hexane
EtOH
DMF
THF
CH3CN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
Na2CO3 (2)
CH3COONa (2)
Cs2CO3 (2)
KOH (2)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
1.2
1.5
2.0
3.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
traces
-
-
25
50
83
83
23
26
48
68
70
47
20
5
23
50
50
55
42
9
10
11
12
13
14
15
16
17
18
19
20
None
NaHCO3 (1.2)
NaHCO3 (1.5)
NaHCO3 (3)
6-7). It is important to note that in the absence (Table 2, entry
17), in excess (Table 2, entry 20), or when the amount of base
is reduced from 2.0 to 1.2 equiv (Table 2, entries 18 and 19),
a decrease in the yield was also observed. Regarding the
influence of the solvent, the best results were achieved using
THF and CH3CN, which furnished the desired product 3a in
83% yield (Table 2, entries 6-7). We observed that EtOH and
DMF were less effective since the product 3a was obtained in
poor yields (Table 2, entries 4-5). The use of CH2Cl2 and
hexane failed to produce the electrophilic cyclization product
(Table 2, entries 2-3). We also studied the influence of the
amount of electrophilic source; it was observed that reducing
the amount of I2 from 3 to 1 equiv decreased the yield
significantly (Table 2, entries 8-11), while an increase in the
number of equivalents of I2 to 3.5 caused a slight decrease in
the yield to 70% (Table 2, entry 12). The large excess of I2
required for the cyclization can be justified by the initial
formation of an organochalcogen (IV) species due to the great
affinity of the chalcogen atom for I2. It is well described that
chalcogen alkynes react very fast and quantitatively with halogen
to form a species of selenium (IV) known as dihalo organoch-
alcogen.19 For this reason, different from the mechanism
proposed by Larock,6a in which the starting materials were free
of chalcogen atoms, we believe that the first step of this
cyclization involves the usual reaction of organochalcogen
propargyl aryl ethers with I2 to give the selenium (IV) species
a; after that the cyclization process follows: (i) coordination of
the carbon-carbon triple bond to the electrophilic reagent to
generate the iodonium intermediate b, (ii) attack of the electron
from the aromatic ring on the activated triple bond to produce
the species c, and (iii) the removal of a proton restores the
aromatic ring giving the cyclized organochalcogen (IV) species
d which is reduced to organochalcogen (II) species by sodium
thiosulfate (Scheme 2).
Studies defining the scope and limitations of this reaction
led us to a good understanding of this process. First, to determine
the real influence of the substituent at aromatic ring of phenol,
we keep the selenophenyl group directly bonded to triple bond
invariable. The results demonstrated that the cyclization ef-
ficiency was significantly influenced by the steric effects of
aromatic ring, since the cyclization reaction gave low yields
with aromatic rings having a substituent at ortho position than
those having no substituent (Table 4, entries 3-6). We also
observed that the reaction is not sensitive to electronic effects
of aromatic ring. For example, phenol with a MeO, an electron-
donating group, gave similar yields than phenol with a Cl, an
electron-withdrawing group (Table 4, entries 9-10). In addition,
the reactions of chalcogen propargyl aryl ethers containing
different substituents at aryl group directly bonded to the
selenium atom have also been investigated. Our experiments
showed that the reaction with selenium having aryl, aryl
substituted and alkyl groups gave the benzopyran derivatives
in similar yields (Table 4, entries 16-22). By contrast, when
the reaction was carried out with chalcogen propargyl aryl ethers
(19) (a) Lang, E. S.; Casagrande, G. A.; de Oliveira, G. M.; Ledesma, G. N.;
Lemos, S. S.; Castellano, E. E.; Abram, U. Eur. J. Inorg. Chem. 2006, 958. (b)
Boyle, P. D.; Godfrey, S. M. Coord. Chem. ReV. 2001, 223, 265.
3472 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Organochalcogen Propargyl Aryl Ethers
SCHEME 2
TABLE 3. Influence of Reaction Conditions on the ICl Cyclization
of Arylseleno Propargyl Aryl Ethers 2a
the five versus six membered ring, it is important to point out
that the unique product obtained during the curse of this
cyclization was the six-membered benzopyran, which was
determined by X-ray diffraction analysis (see the Supporting
Information). This high selectivity is due to the presence of the
selenium atom directly bonded to carbon of the triple bond.
This selenium atom exerts a high stabilization of the positive
charge in the carbon one of the iodonium intermediate b
(Scheme 2), forcing the subsequent attack into this carbon.
Concerning the tellurium group directly bonded at the triple
bond of propargyl aryl ethers 2r and 2s, we found some
limitations in this methodology. For example no reaction was
observed with propargyl aryl ethers bearing an alkyltellurium
group (Table 4, entry 30). Unfortunately, all conditions tested
were found to be ineffective and neither I2 nor ICl was effective
to produce the cyclized product. In these cases we obtained
alkyne iodine 4 (Scheme 3). Based on these results and with
the knowledge that the Csp-tellurium bond exhibits an easier
heterolytic cleavage than the carbon-sulfur and carbon-selenium
bonds, due to the large volume and greater ionic character of
the tellurium atom and the easy polarization of the bonds,20 we
assumed that the product 4 was formed via a tellurium IV
intermediate a. Thus, the great affinity between tellurium and
iodine atoms gave the telluride IV b;21 nucleophilic attack of
iodide anion on the alkyl group bonded to the tellurium atom16g
produces a tellurium electrophilic species c, which via displace-
ment of the stable tellurium tetraiodide gave the alkynyl iodide
4 (Scheme 3). Concerning the propargyl aryl ether 2s bearing
an arylltellurim group, which has a Csp2-Te bond unable to
nucleophilic attack of iodide, we did not observe the formation
of alkynyl iodide. In this case, only the starting material was
recovered after the reaction quenching with sodium thiosulfate.
Additional limitation in our method was observed when
compound 2e (Table 4, entry 8), which has a methoxyl group
in the para-position of aromatic ring, was reacted with I2 giving
as product an almost equimolar mixture of the two compounds,
the cyclized 3f in 50% yield and no cyclized 5 in 45% yield.
By contrast, the reaction with propargyl aryl ether having a
methoxyl group at meta-position of the aromatic ring gave only
the expected cyclized product in excellent yield and total
stereoselection (Table 4, entry 9). These results are a conse-
quence of the two possible pathways. Mechanistically, we
believe that one of them involves the usual cyclization reactions
as described in Scheme 2. The second mechanistic hypothesis,
involves the formation of hydroxylated uncyclized product 5,
via intermediates e and f as showed in Scheme 4. The iodonium
entry
solvent
base (equiv)
ICl (equiv)
yield (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
DMF
CH3NO2
CH2Cl2
EtOH
CH3CN
Hexane
THF
THF
THF
THF
NaHCO3 (2)
Na2CO3 (2)
CH3COONa (2)
Cs2CO3 (2)
KOH (2)
none
none
none
none
none
none
none
none
none
none
none
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.2
2.0
3.0
18
37
56
35
52
83
80
10
45
60
63
62
40
40
68
60
9
10
11
12
13
14
15
16
having a sulfur group a decrease in the yields was observed
and the cyclized products were obtained in 50% yields (Table
4, entries 23-25). Meanwhile, with the purpose to evaluate the
possibility to introduce one more different function at C-3 of
the benzopyran ring, we tested the behavior of chalcogen
propargyl aryl ethers using PhSeBr and BuTeBr3 as electrophile
source. The reaction of propargyl aryl ethers 2a with BuTeBr3
in CH3CN, at room temperature, gave the benzopyran with a
BuTe group at C-3 (Table 4, entry 26). This result is significant
particularly when one considers that there are many ways to
transform the resulting tellurium functionalities into other
substituents. Interestingly, although it is known that PhSeBr can
act as efficient PhSe+ donors to the alkyne triple bond,6h,7f
herein under our conditions no cyclized benzopyran derivative
was isolated (Table 4, entry 27).
To study the regiochemistry of cyclization, the reaction was
carried out with organochalcogen propargyl aryl ethers having
Cl (2f), 2-naphthalene (2g) and MeO (2e) substituent at meta
position to the oxygen moiety. Placing a less bulky Cl in the
meta position gave two regioisomers 3f and 3f′ (Table 4, entry
10), which were easily separable by chromatograph column.
On the other hand, an electron-donating CH3O and a stericaly
bulky 2-naphthalene substituent gave only the regioisomer 3e
and 3h, respectively, as sole product (Table 4, entries 9 and
13). These results showed that our method is highly regiose-
lective since, only in the case of 2f, which has a halogen
substituent, was detected a mixture of regioisomers. Regarding
(20) Tellurium in Organic Synthesis; Petragnani, N., Ed.; Academic Press:
London, 1994.
(21) Hope, E. G.; Kemmitt, T.; Levason, W. Organometallics 1988, 7, 78.
J. Org. Chem. Vol. 74, No. 9, 2009 3473

Godoi et al.
TABLE 4.
Synthesis of the 3-Halo-4-chalcogen-2H-benzopyran Derivatives 3 via Electrophilic Cyclization Using I2 and ICla
a I2 cyclization performed in the presence of 2 (0.25mmol), NaHCO3 (2 equiv), I2 (3 equiv) in THF (5 mL), at room temperature. The ICl cyclization
was performed in the presence of 2 (0.25mmol), ICl (1.5 equiv) in THF, at -25 °C. b Reaction performed in the presence of 2a (0.25mmol), BuTeBr3
(1.1 equiv) in CH3CN, at room temperature. c Reaction performed in the presence of 2a (0.25mmol), PhSeBr (1.5 equiv) in CH2Cl2 (5 mL), at room
temperature.
intermediate is formed followed by a nucleophilic attack of
iodide anion on the methyl group bonded to the oxygen atom16g
producing the intermediate f, which is impeded to give the
cyclized product.
3474 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Organochalcogen Propargyl Aryl Ethers
SCHEME 3
tellurium) species. Various aryl and alkyl groups directly bonded
to the chalcogen atom were successful used as electrophile. The
results revealed that the reaction does not significantly depend
on the electronic effects of substituents in the aromatic ring
bonded to the selenium atom of the electrophilic chalcogen
species. Additional versatility in this process was demonstrated
with respect to a diverse array of functionality in the aromatic
ring at propargyl aryl ethers. These propargyl aryl ethers, bearing
the chalcogen group, underwent highly selective intramolecular
cyclizations when treated with I2 or ICl affording 3-iodo-4-
chalcogen-2H-benzopyrans. The results demonstrated that the
cyclization efficiency was significantly influenced by the steric
effects of aromatic ring, since the cyclization reaction gave low
yields with aromatic rings having a substituent at the orto
position than those having no substituent. The reactivity of
3-iodo-4-chalcogen-2H-benzopyrans was also studied. 4-Sele-
nobutyl benzopyrans were treated under Negishi cross-coupling
conditions providing the corresponding 3-aryl benzopyran
derivatives in good yields. In addition, using the copper
catalyzed cross-coupling reactions with thiols, in the absence
of any cocatalyst, we were able to introduce a thiol function in
3-iodo-benzopyran derivatives.
Although the intermediates from this mechanism could not
be isolated, we carried out a new experiment to get additional
observations that support the mechanism described in Scheme
4. We prepared, purified hydroxyled propargyl aryl ether 5 and
used as starting material in the I2 addition reaction, under our
standard reaction conditions. After 24 h we recovered only the
starting material 5 quantitatively as the product. These results
strongly suggest that the reaction of this substrate with iodide
does not allow the cyclized product even that using an excess
of iodide, reflux and long reaction time (Scheme 5).
Experimental Section
We believe that this approach to 3-halo-4-chalcogen-2H-
benzopyrans should prove quite useful in synthesis, particularly
when one considers that there are many ways to transform the
resulting functionalities into other substituents. The applicability
of the above cyclization product to the synthesis of more
functionalized benzopyran can be verified by transition metal-
catalyzed processes, such as Sonogashira,22 Suzuki,23 Stille,24
Heck,25 Negishi26 and Ullmann27 cross-couplings. In addition,
this reaction associated with the nickel-catalyzed cross-coupling
of selenides15 can also contribute to an interesting alternative
route to the preparation of more functionalized benzopyrans.
In view of this, the potential of chalcogen-2H-benzopyran
derivatives as precursors for increasing molecular complexity
via palladium and copper catalyzed reactions has been briefly
investigated (Scheme 6). For example, compound 3m under
Neghishi cross-coupling with different organozinc species gave
the corresponding products 6a, 6b and 6c in 80%, 77% and
70%, respectively. In addition, the reaction of 3m with aryl
thiols, using just CuI as catalyst in dioxane, afforded the resultant
products 7a, 7b and 7c in good isolated yields (Scheme 6).
General Procedure for the Preparation of the Organochal-
cogen Propargyl Aryl Ethers 2a-s. To a solution of the
appropriate propargyl aryl ether (5 mmol) in dry THF (30 mL) at
-78 °C, under argon atmosphere was added drop by drop, n-BuLi
(2.2 mL of a 2.5 M solution in hexane, 5.5 mmol). After 1 h at this
temperature, the appropriate organochalcogen electrophile (R2SBr,
R2SeBr, R2TeBr; 5.5 mmol) in THF (5 mL) was added. The mixture
was stirred at room temperature for 3 h. After this time, the mixture
was diluted with ethyl acetate (60 mL) and washed with saturated
aq NH4Cl (30 mL) and water (3 × 30 mL). The organic phase was
separated, dried over MgSO4, and concentrated under vacuum.
4-Methylphenyl 3-Phenylselenylprop-2-yn-1-yl Ether (2a).
Purified by flash chromatography and eluted with hexane/ethyl
acetate (95:5). Yield: 0.827 g (55%). 1H NMR: CDCl3, 200 MHz,
δ(ppm): 7.50-7.45 (m, 2H), 7.34-7.26 (m, 3H), 7.10 (d, J ) 8.0
Hz, 2H), 6.93-6.86 (m, 2H), 4.87 (s, 2H), 2.30 (s, 3H). 13C NMR:
CDCl3, 100 MHz, δ(ppm): 155.4, 130.7, 129.8, 129.4, 129.2, 127.2,
114.9, 99.8, 98.9, 68.1, 57.0, 20.4. MS (EI, 70 eV) m/z (relative
intensity): 299 (9), 218 (6), 192 (26), 144 (27), 114 (100), 102
(21), 76 (29), 51 (15). Anal. (%) Calcd for C16H14OSe: C 63.79, H
4.68. Found: C 63.33, H 4.22.
2-Methylphenyl 3-Phenylselenylprop-2-yn-1-yl Ether (2b).
Purified by flash chromatography and eluted with hexane/ethyl
acetate (95:5). Yield: 0.767 g (51%). 1H NMR: CDCl3, 200 MHz,
δ(ppm): 7.49-7.43 (m, 2H), 7.33-7.07 (m, 5H), 6.98-6.86 (m,
2H), 4.91 (s, 2H), 2.25 (s, 3H). 13C NMR: CDCl3, 100 MHz,
δ(ppm): 155.8, 130.8, 129.5, 129.2, 128.1, 127.3, 127.2, 126.6. MS
(EI, 70 eV) m/z (relative intensity): 299 (5), 192 (31), 156 (3), 144
(13), 114 (100), 102 (16), 76 (21). Anal. (%) Calcd for C16H14OSe:
C 63.79, H 4.68. Found: C 64.12, H 4.91.
Conclusion
We have shown the synthesis of various organochalcogen
propargyl aryl ethers via reaction of the lithium acetylide
intermediated with electrophilic chalcogen (sulfur, selenium,
(22) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 864.
(23) (a) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749. (b) Molander, G. A.;
Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(24) (a) Scott, W. J.; Pen˜a, M. R.; Sward, K.; Stoessel, S. J.; Stille, J. K. J.
Org. Chem. 1985, 50, 2302. (b) Fugami, K.; Kosugi, M. Cross-coupling Reactions
2002, 219, 87.
(25) (a) Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259. (b)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(26) (a) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (b) Negishi,
E.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
(27) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Altman,
R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779. (c) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578. (d) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (e) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727.
General Procedure for the I2 Cyclization. To a solution of
organochalcogen propargyl aryl ethers appropriate (0.25 mmol) in
3 mL of THF, was added at room temperature, NaHCO3 (0.5 mmol).
After that, was added gradually I2 (3 equiv) in 2 mL of THF. The
reaction mixture was allowed to stir at room temperature for the
time shown in Table 4. Excess I2 was removed by washing with
saturated aq Na2S2O3. The product was then extracted by ethyl
acetate (3 × 5 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under vacuum to yield the
crude product. 3-Iodo-6-methyl-4-phenylselenyl-2H-benzopyran
(3a): Purified by flash chromatography and eluted with hexane/
1
ethyl acetate (95:5). Yield: 0.088 g (83%). H NMR: CDCl3, 400
J. Org. Chem. Vol. 74, No. 9, 2009 3475

Godoi et al.
SCHEME 4
SCHEME 5
SCHEME 6
crude product. 3-Iodo-8-tert-Butyl-4-phenylselenyl-2H-benzopy-
ran (3c): Purified by flash chromatography and eluted with hexane/
ethyl acetate (95:5). Yield: 0.070 g (60%). H NMR: CDCl3, 400
1
MHz, δ(ppm): 7.51-7.49 (m, 1H), 7.35-7.32 (m, 2H), 7.21-7.14
(m, 4H), 6.75 (t, J ) 7.8 Hz, 1H), 4.93 (s, 2H), 1.35 (s, 9H). 13C
NMR: CDCl3, 100 MHz, δ(ppm): 151.9, 137.9, 134.6, 131.3, 130.2,
129.3, 127.6, 127.4, 126.6, 124.9, 121.5, 104.7, 75.9, 34.5, 29.7.
MS (EI, 70 eV) m/z (relative intensity): 468 (4), 465 (83), 339 (66),
284 (37), 260 (88), 202 (10), 183 (11), 155 (27), 144 (10), 127
(100), 114 (66), 109 (21), 76 (33), 56 (70), 41 (26). HRMS calcd
for C19H19IOSe: 469.4696. Found: 469.4692. 3-Iodo-6-methoxyl-
4-phenylselenyl-2H-benzopyran (3d): Purified by flash chroma-
tography and eluted with hexane/ethyl acetate (90:10). Yield: 0.055
g (50%). 1H NMR: CDCl3, 200 MHz, δ(ppm): 7.38-7.33 (m, 2H),
7.25-7.17 (m, 3H), 7.09 (d, J ) 2.8 Hz, 1H), 6.77-6.62 (m, 2H),
4.93 (s, 2H), 3.57 (s, 3H). 13C NMR: CDCl3, 100 MHz, δ(ppm):
154.5, 147.3, 134.3, 130.8, 130.5, 129.5, 129.4, 126.9, 124.0, 114.2,
105.4, 97.9, 75.9, 55.6. MS (EI, 70 eV) m/z (relative intensity):
443 (2), 439 (92), 313 (43), 283 (22), 253 (5), 234 (100), 202 (8),
192 (30), 158 (45), 153 (11), 116 (32), 101 (19), 88 (63), 76 (24).
Anal. (%) Calcd for C16H13IO2Se: C 43.37, H 2.96. Found: C 43.45,
H 3.02.
Procedure for the BuTeBr3 Cyclization. To a Schlenck tube,
under argon, containing a solution of organochalcogen propargyl
aryl ethers 2a (0.25 mmol) in CH3CN (1.5 mL) was added, at room
temperature, the BuTeBr3 (0.28 mmol). The reaction was stirred
for 1 h, after that was added 2 mL of EtOH 95% and NaBH4 (0.5
mmol) was added gradually. The reaction mixture was allowed to
stir at room temperature for 1 h. After this, the mixture was diluted
with ethyl acetate (15 mL) and washed with water (3 × 5 mL) and
saturated solution of NaCl (10 mL). The organic phase was
separated, dried over MgSO4, and concentrated under vacuum.
3-Butyltelluryl-6-methyl-4-phenylselenyl-2H-benzopyran (3r):
Purified by flash chromatography and eluted with hexane/ethyl
acetate (95:5). Yield: 0.048 g (40%). 1H NMR: CDCl3, 400 MHz,
δ(ppm): 7.37-7.14 (m, 6H), 6.90-6.86 (m, 1H), 6.69 (d, J ) 8.0
Hz, 1H), 4.81 (s, 2H), 2.71 (t, J ) 7.4, 2H), 2.16 (s, 3H), 1.79
(quint, J ) 7.3 Hz, 2H), 1.40 (sext, J ) 7.5 Hz, 2H), 0.92 (t, J )
7.2 Hz, 3H). 13C NMR: CDCl3, 100 MHz, δ(ppm): 151.1, 131.1,
131.0, 129.5, 129.4, 129.3, 128.5, 128.1, 127.6, 126.4, 124.4, 115.4,
70.7, 34.1, 25.2, 20.7, 13.4, 7.6. MS (EI, 70 eV) m/z (relative
intensity): 481 (2), 424 (19), 337 (46), 278 (62), 250 (40), 204
(100), 189 (13), 154 (8), 146 (26), 134 (27), 114 (8), 72 (56), 43
(34). Anal. (%) Calcd for C20H22OSeTe: C 49.53, H 4.21. Found:
C 49.29, H 4.31.
MHz, δ(ppm): 7.36-7.32 (m, 3H), 7.21-7.15 (m, 3H), 6.92-6.89
(m, 1H), 6.70 (d, J ) 8.3 Hz, 1H), 4.95 (s, 2H), 2.14 (s, 3H). 13C
NMR: CDCl3, 100 MHz, δ(ppm): 151.1, 134.1, 131.4, 131.1, 130.3,
129.8, 129.3, 126.6, 123.2, 115.7, 105.3, 75.8, 20.6. MS (EI, 70
eV) m/z (relative intensity): 427 (15), 301 (21), 221 (71), 157 (18),
144 (15), 115 (100), 102 (3), 77 (94), 63 (44), 51 (71). Anal. (%)
Calcd for C16H13IOSe: C 44.99, H 3.07. Found: C 45.21, H 3.23.
3-Iodo-8-methyl-4-phenylselenyl-2H-benzopyran (3b): Purified
by flash chromatography and eluted with hexane/ethyl acetate
(95:5). Yield: 0.058 g (55%). 1H NMR: CDCl3, 400 MHz, δ(ppm):
7.42-7.40 (m, 1H), 7.34-7.31 (m, 2H), 7.21-7.13 (m, 3H),
7.00-6.98 (m, 1H), 6.69 (t, J ) 7.8 Hz, 1H), 5.00 (s, 2H), 2.18 (s,
3H). 13C NMR: CDCl3, 100 MHz, δ(ppm): 151.3, 134.4, 131.4,
131.2, 130.2, 129.3, 127.2, 126.6, 125.4, 123.1, 121.4, 104.8, 75.7,
15.5. MS (EI, 70 eV) m/z (relative intensity): 426 (2), 423 (30),
298 (61), 283 (16), 218 (67), 202 (8), 176 (32), 155 (10), 143 (18),
114 (100), 88 (18), 76 (18). HRMS calcd for C16H13IOSe: 427.9176.
Found: 427.9190.
General Procedure for the ICl Cyclization. To a solution of
appropriate organochalcogen propargyl aryl ethers (0.25 mmol) in
3 mL of THF was added gradually ICl (1.5 equiv) in 2 mL of THF
at -25 °C. The reaction mixture was allowed to stir at this
temperature for the time shown in Table 4 and washed with
saturated aq Na2S2O3. The organic product was extracted by ethyl
acetate (3 × 5 mL). The combined organic layers were dried over
anhydrous MgSO4 and concentrated under vacuum to yield the
General Procedure for the Palladium-Catalyzed Coupling
Reaction of 3m with Organozinc Reagents. To a Schlenck tube,
under argon, containing a solution of 3m (0.25 mmol) in THF (3
mL) and Pd(PPh3)2Cl2 (10 mol%), was added the organozinc
compound (0.75 mmol) in THF (2 mL), previously prepared.28 The
yellow mixture was stirred at room temperature for 24 h. The
reaction mixture was then quenched with aqueous NH4Cl (5 mL),
3476 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Organochalcogen Propargyl Aryl Ethers
washed with CH2Cl2 (3 × 5 mL), dried with MgSO4 and the solvent
removed under vacuum.
furyl-6-methyl-4-butylselenyl-2H-benzopyran (7a): Purified by
flash chromatography and eluted with hexane/ethyl acetate
(90:10). Yield: 0.063 g (65%). 1H NMR: CDCl3, 200 MHz, δ(ppm):
7.50-7.27 (m, 6H), 6.98-6.94 (m, 1H), 6.75 (d, J ) 8.0 Hz, 1H),
4.48 (s, 2H), 2.79 (t, J ) 7.1 Hz, 2H), 2.34 (s, 3H), 1.72-1.58 (m,
2H), 1.51-1.33 (sext, J ) 7.2 Hz, 2H), 0.88 (t, J ) 7.3 Hz, 3H).
13C NMR: CDCl3, 100 MHz, δ(ppm): 151.4, 135.2, 132.9, 131.4,
131.2, 129.4, 129.3, 128.5, 127.7, 126.2, 124.3, 115.7, 68.4, 32.2,
28.0, 22.7, 20.8, 13.5. MS (EI, 70 eV) m/z (relative intensity): 389
(7), 386 (100), 329 (65), 278 (9), 248 (31), 222 (49), 143 (63), 114
(60), 88 (10), 76 (9), 56 (6). Anal. (%) Calcd for C20H22OSSe: C
61.69, H 5.69. Found: C 61.85, H 5.91.
3-Phenyl-6-methyl-4-butylselenyl-2H-benzopyran (6a). Puri-
fied by flash chromatography and eluted with hexane/ethyl acetate
(90:10). Yield: 0.071 g (80%). 1H NMR: CDCl3, 400 MHz, δ(ppm):
7.57 (s, 1H), 7.42-7.29 (m, 5H), 6.98-6.95 (m, 1H), 6.80 (d, J )
8.0 Hz, 1H), 4.86 (s, 2H), 2.43 (t, J ) 7.3 Hz, 2H), 2.33 (s, 3H),
1.39 (quint, J ) 7.6 Hz, 2H), 1.16 (sext, J ) 7.6 Hz, 2H), 0.74 (s,
3H). 13C NMR: CDCl3, 50 MHz, δ(ppm): 151.7, 140.7, 139.2,
131.0, 129.4, 128.9, 128.8, 128.0, 124.1, 122.7, 115.7, 70.3, 31.6,
27.2, 22.4, 20.8, 13.4. MS (EI, 70 eV) m/z (relative intensity): 357
(4), 354 (51), 298 (100), 252 (3), 218 (90), 189 (14), 176 (37), 163
(14), 150 (10), 114 (14), 101 (6), 57 (3). Anal. (%) Calcd for
C20H22OSe: C 67.22, H 6.21. Found: C 67.45, H 6.47.
General Procedure for the Copper-Catalyzed Coupling
Reaction of 3m with Aryl Thiols. To a Schlenck tube, under argon,
containing a solution of 3m (0.25 mmol) in dioxane (2 mL) was
added the appropriate aryl thiol (0.3 mmol) in 0.5 mL of dioxane.
After that was added the CuI (10 mol%) and Et3N in 0.5 mL of
dioxane. The mixture was kept under reflux for 12 h. After this
time, the mixture was diluted with ethyl acetate (10 mL) and washed
with saturated brine (3 × 20 mL). The organic phase was separated,
dried over MgSO4, and concentrated under vacuum. 3-Phenylsul-
Acknowledgment. We thank the following agencies for
support: FAPERGS, CNPq, CAPES (SAUX) and UFSM.
CAPES is also acknowledged for a PhD fellowship (B.G.). G.Z.
is the recipient of CNPq fellowship. We thank the LMI (Prof.
Ernesto Lang) for support of crystal X-ray results.
Supporting Information Available: Experimental proce-
dures, additional experimental details for the preparation of all
compounds and 1H and 13C NMR spectra for all reaction
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
(28) (a) Zeni, G.; Alves, D.; Braga, A. L.; Stefani, H. A.; Nogueira, C. W.
Tetrahedron Lett. 2004, 45, 4823. (b) Alves, D.; Schumacher, R. F.; Branda˜o,
R.; Nogueira, C. W.; Zeni, G. Synlett 2006, 7, 1035.
JO900307K
J. Org. Chem. Vol. 74, No. 9, 2009 3477