Palladium-catalyzed Suzuki cross-coupling of 2-haloselenophenes: Synthesis of 2-arylselenophenes, 2,5-diarylselenophenes, and 2-arylselenophenyl ketones

Article abstract of DOI:10.1021/jo0601056

We present herein our results on the Suzuki coupling reaction of 2-haloselenophenes with boronic acids catalyzed by palladium salt and describe a new route established to prepare 2-arylselenophenes and 2,5-diarylselenophenes in good yields. The reaction p

Full text of DOI:10.1021/jo0601056

Palladium-Catalyzed Suzuki Cross-Coupling of 2-Haloselenophenes:
Synthesis of 2-Arylselenophenes, 2,5-Diarylselenophenes, and
2-Arylselenophenyl Ketones
Patr´ıcia Prediger,† Ange´lica V. Moro,† Cristina W. Nogueira,† Lucielli Savegnago,†
Paulo Henrique Menezes,‡ Joa˜o B. T. Rocha,† and Gilson Zeni*,†
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o Farmacolo´gica e Toxicolo´gica de Organocalcogeˆnios,
CCNE, UniVersidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brazil 97105-900, and
Departamento de Qu´ımica Fundamental, UniVersidade Federal de Pernambuco, Recife, PE,
Brazil 50670-901
gzeni@quimica.ufsm.br
ReceiVed January 18, 2006
We present herein our results on the Suzuki coupling reaction of 2-haloselenophenes with boronic acids
catalyzed by palladium salt and describe a new route established to prepare 2-arylselenophenes and 2,5-
diarylselenophenes in good yields. The reaction proceeded cleanly under mild conditions and was
performed with aryl boronic acids bearing electron-withdrawing, electron-donating, and neutral substituents,
in the presence of Pd(OAc)2, K2CO3/H2O in DME. In addition, by this protocol unsymmetrical aryl
ketones were also obtained from 2-iodoselenophene and boronic acids via a carbonylative process.
Introduction
being the key stage in the synthesis of many currently interesting
heterocycle-incorporated compounds, have proved to proceed
generally and effectively.4 More recently, significant advances
have been made in the use of organoboron reagents as coupling
partners in a number of palladium-mediated carbon-carbon
bond formation. Among them, the use of potassium organotri-
fluoroborates, as the organoboron coupling partner, has some
advantages in comparison to boronic acids and boronic esters,
such as being more nucleophilic, stable in the air, crystalline
as solids, and easily prepared.5
In the past decade, there have been developments in pal-
ladium-catalyzed coupling systems as a consequence of great
interest in the development of coupling substrates that are more
economic, more easily accessible, and reactive even under mild
conditions. In this way, the palladium-catalyzed cross-coupling
reactions of aryl halides or triflates with boronic acids, com-
monly referred to as Suzuki reactions, are a powerful, versatile,
and popular tool for selective construction of carbon-carbon
bonds.1 The palladium-catalyzed Suzuki cross-coupling reaction
of aryl halides with boronic acids and esters has become a
common and convenient synthetic method in organic chemistry
for biaryl compounds.2 Many examples of Suzuki coupling
reactions between heterocyclic halides and phenyl boronic acids
that have appeared in the literature over the past two decades,3
Organoselenium compounds have become attractive synthetic
targets because of their chemo-, regio-, and stereoselective
reactions and their useful biologic activities.6 Furthermore,
(2) (a) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J., Eds.; Wiley-VHC: Weinheim, 1998. (b) Lloyd-
Williams, P.; Giralt, E. Chem. Soc. ReV. 2001, 30, 145-157.
† Universidade Federal de Santa Maria.
(3) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
‡ Universidade Federal de Pernambuco.
(4) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126,
5074-5075. (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, 7921-7923. (c) Zeni, G.; Lu¨dtke, D. S.;
Nogueira, C. W.; Panatieri, R. B.; Braga, A. L.; Silveira, C. C.; Stefani,
H.; Rocha, J. B. T. Tetrahedron Lett. 2001, 42, 8927-8930.
(1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. Pure Appl. Chem. 1985, 57, 1749-1758. (c) Suzuki, A. Pure
Appl. Chem. 1991, 63, 419-422. (d) Suzuki, A. Pure Appl. Chem. 1994,
66, 213-222. (e) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(f) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-2208.
10.1021/jo0601056 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/13/2006
3786
J. Org. Chem. 2006, 71, 3786-3792

Pd-Catalyzed Suzuki Cross-Coupling of 2-Haloselenophenes
SCHEME 1
SCHEME 2
TABLE 1. Effects of Palladium Catalysts on Cross-Coupling of 1a
and 2a
organoselenium compounds can usually be used with a wide
variety of functional groups, thus avoiding protection group
chemistry.7 Organoselenium chemistry developed rapidly, mainly
in the area of selenocarbohydrates, selenoamino acids, and
selenopeptides. The selenium group can be introduced in an
organic substrate via both nucleophile and electrophile reagents.
After being introduced in an organic substrate, the organo-
selenium group can easily be removed by selenoxide syn
elimination8 and [2,3] sigmatropic rearrangement.9 In addition,
the carbon-selenium bond can also be replaced by a carbon-
hydrogen,10 carbon-halogen,11 carbon-lithium,12 or carbon-
carbon bond.13
Our continuing interest in the synthesis14 and applications15
of organochalcogenides in organic synthesis prompted us to
examine a procedure to prepare 2-arylselenophenes by the
boronic acid coupling reaction with 2-haloselenophene in the
presence of palladium salt (Scheme 1).
entry
palladium catalyst (mol %)
time (h)
yield (%)
1
2
3
4
5
6
PdCl2(PPh3)2 (5)
Pd(PPh3)4 (5)
PdCl2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (3)
Pd(OAc)2 (1)
1.5
1
2
1
1
70
65
84
94
95
68
1
give 2-(lithium)selenophene derivatives. The treatment of
2-(lithium)selenophene with iodine led to the formation of
2-iodoselenophene 1a, isolated in 60% yield after purification
(Scheme 2).17 The 2-bromoselenophene 1b was prepared by the
bromination of selenophene 4 with NBS in a mixture of CH2-
Cl2 and AcOH in 62% yield (Scheme 2).18
Since our initial studies have focused on the development of
an optimum set of reaction conditions, the coupling reaction of
boronic acid with 2-iodoselenophene was examined to optimize
the reaction conditions. In this way, 2-iodoselenophene 1a (0.5
mmol) and p-tolylboronic acid (0.7 mmol) in DME were treated
at room temperature with different palladium catalysts. After
30 min at this temperature, a solution of K2CO3 (2.4 mmol) in
H2O (1.2 mL) was added and the mixture was refluxed for
different reaction times (Table 1).
Results and Discussion
The starting 2-iodoselenophene 1a was readily available by
using the metalation of selenophene16 4 with n-butyllithium to
(5) (a) Molander, G. A.; Petrillo, D. E.; Landzberg, N. R.; Rohanna, J.
C.; Biolatto, B. Synlett 2005, 1763-1766. (b) Molander, G. A.; Figueroa,
R. Aldrichimica Acta 2005, 38, 49-56. (c) Molander, G. A.; Felix, L. A.
J. Org. Chem. 2005, 70, 3950-3956. (d) Molander, G. A.; Yun, C. S.;
Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534-5539. (e)
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302-4314. (f)
Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67,
8416-8423. (g) Molander, G. A.; Reviro, M. R. Org. Lett. 2002, 4, 107-
109.
(6) (a) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. ReV. 2004,
104, 6255-6285. (b) Nogueira, C. W.; Quinhonhes, E. B.; Jung, E. A. C.;
Zeni, G.; Rocha, J. B. T. Inflammation Res. 2003, 52, 56-63.
(7) (a) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products
Synthesis; CIS: Philadelphia, 1984. (b) Paulmier, C. Selenium Reagents
and Intermediates in Organic Synthesis; Pergamon: Oxford, 1986. (c) Patai,
S.; Rappoport, Z. The Chemistry of Organic Selenium and Tellurium
Compounds; Wiley: New York, 1986; Vol 1. (d) Liotta, D. Organoselenium
Chemistry; Wiley: New York, 1987. (e) Krief, A.; Hevesi, L. Organose-
lenium Chemistry I; Springer: Berlin, 1988. (f) Back, T. G. Organoselenium
Chemistry: A Practical Approach; Oxford University Press: Oxford, 1999.
(g) Reich, H. J. Acc. Chem. Res. 1979, 12, 22-30. (h) Liotta, D. Acc. Chem.
Res. 1984, 17, 28-34. (i) Wirth, T. Organoselenium Chemistry-Modern
DeVelopments in Organic Synthesis; Top. Curr. Chem. 208; Spring-
Verlag: Heidelberg, 2000. (j) Mugesh, G.; Singh, H. B. Acc. Chem. Res.
2002, 35, 226-236.
(8) (a) Huguet, J. L. AdV. Chem. Ser. 1967, 345-351. (b) Sharpless, K.
B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 22, 1979-1982.
(9) (a) Reich, H. J. J. Org. Chem. 1975, 40, 2570-2572. (b) Sharpless,
K. B.; Lauer, R. F. J. Am. Chem. Soc. 1972, 94, 7154-7155.
(10) Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976, 30,
2643-2646.
(11) Sevrin, M.; Dumont, W.; Hevesi, L. D.; Krief, A. Tetrahedron Lett.
1976, 30, 2647-2650.
(12) (a) Seebach, D.; Peleties, N. Chem. Ber. 1972, 105, 511-520. (b)
Seebach, D.; Beck, A. K. Angew. Chem., Int. Ed. Engl. 1974, 13, 806-
807. (c) Reich, H. J.; Shah, S. K. J. Am. Chem. Soc. 1975, 97, 3250-3252.
(13) Silveira, C. C.; Braga, A. L.; Vieira, A. S.; Zeni, G. J. Org. Chem.
2003, 68, 662-665.
As shown in Table 1, palladium catalysts such as PdCl2,
PdCl2(PPh3)2, and Pd(PPh3)4 exhibit moderate to good catalytic
activity in this reaction (Table 1, entries 1-3). However, with
3 mol % of Pd(OAc)2 (Table 1, entry 5), the reaction was
completed in a short time (1 h) and an excellent yield of product
was obtained (95%). It is intriguing that the reaction proceeds
much better with Pd(II) than with a Pd(0), but it is reasonable
since the reduction of Pd(II) can occur with the boronic acid. It
is important to note that when the amount of catalyst is reduced
from 3 to 1 mol % a decrease in the yield was observed (Table
1, entries 5 and 6), while the increase from 3 to 5 mol % did
not improve the yield (Table 1, entries 4 and 5). The catalytic
study also showed that in the absence of palladium catalyst there
was no reaction even after the reaction mixture was stirred for
72 h.
We also observed that the nature of the base was critical for
the success of the coupling. The reaction of 2-iodoselenophene
1a (0.5 mmol) with p-tolylboronic acid (0.7 mmol) and Pd-
(OAc)2 (3 mol %) in DME was refluxed with different bases
as shown in Table 2. The use of AcOK, AcOLi, and t-BuCO2-
(15) (a) Zeni, G.; Braga, A. L.; Stefani, H. A. Acc. Chem. Res. 2003,
36, 731-738. (b) Zeni, G.; Panatieri, R. B.; Lissner, E.; Menezes, P. H.;
Braga, A. L.; Stefani, H. A. Org. Lett. 2001, 3, 819-821.
(16) Selenophene was prepared according to Gronowitz, S.; Frejd, T.;
Moberg-Ogard, A.; Trege, L. J. Heterocycl. Chem. 1976, 13, 1319-1320.
(17) Takahashi, K.; Tarutani, S. Heterocycles 1996, 43, 1927-1935.
(18) Nakayama, J.; Dong, H.; Sawada, K.; Ishii, A.; Kumakura, S.
Tetrahedron 1996, 52, 471-478.
(14) (a) Moro, A. V.; Nogueira, C. W.; Barbosa, N. B. V.; Menezes, P.
H.; Rocha, J. B. T.; Zeni, G. J. Org. Chem. 2005, 70, 5257-5268. (b)
Zeni, G.; Stracke, M. P.; Nogueira, C. W.; Braga, A. L.; Menezes, P. H.;
Stefani, H. A. Org. Lett. 2004, 6, 1135-1138. (c) Zeni, G.; Barros, O. S.
D.; Moro, A. V.; Braga, A. L.; Peppe, C. Chem. Commun. 2003, 1258-
1259. (d) Barros, O. S. D.; Lang, E. S.; Peppe, C.; Zeni, G. Synlett 2003,
1725-1727.
J. Org. Chem, Vol. 71, No. 10, 2006 3787

Prediger et al.
TABLE 2. Study of Base and Solvent Effects on Cross-Coupling
Reaction
TABLE 3. Coupling Products Obtained Using 2-Iodoselenophene
with Boronic Acids
entry
solvent
DME
base
AcOK
AcOLi
t-BuCO2Li
Cs2CO3
Na2CO3
KOH
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
24
24
24
12
24
1
1
1
2
12
1
18
19
38
84
61
90
87
95
38
35
28
46
75
DME
DME
DME
DME
DME
DME
DME
1,4-dioxane
THF
toluene
H2O
DMF
24
1
Li afforded unsatisfactory yields (Table 2, entries 1-3), while
an aqueous solution of Cs2CO3 (Table 2, entry 4) led to a high
yield of the cross-coupling product. Due to the high cost of
Cs2CO3, we turned our attention to the study of other bases.
When the reaction was carried out with inorganic bases such
as Na2CO3, KOH, and K3PO4, the coupling product was
obtained in moderate to good yields (Table 2, entries 5-7). To
our satisfaction, the use of an aqueous solution of K2CO3, an
inexpensive base, resulted in the coupled product in 95% yield.
Another interesting aspect of this reaction is that when dry bases
were used in place of an aqueous solution only a trace amount
of product was obtained.
Regarding the influence of the solvent in this coupling
reaction, optimal results were achieved using DME (Table 2,
entry 8). By using DMF (Table 2, entry 13) moderate yield
was obtained, while other solvents such as 1,4-dioxane, THF,
toluene, and H2O (Table 2, entries 9-12) furnished a small
amount of the desired arylated product.
Thus, the careful analysis of the optimized reactions revealed
that the optimum conditions for this cross-coupling procedure
were the addition of a solution of 2-iodoselenophene 1a (0.5
mmol) in DME (5 mL) to a mixture of Pd(OAc)2 (3 mol %)
and p-tolylboronic acid (0.7 mmol) at room temperature. After
30 min at this temperature, a solution of K2CO3 (2.4 mmol) in
H2O (1.2 mL) was added and the mixture was refluxed for 1 h.
Using this reaction condition, we were able to prepare 2-p-
tolylselenophene 3a in 95% yield. To demonstrate the efficiency
of this reaction, we explored the generality of our method
extending the conditions to other boronic acids; the results are
summarized in Table 3.
Inspections of Table 3 show that the reaction worked well
for a variety of boronic acids. Satisfactorily, all boronic acids
tested were effective, although poor yields were observed in
more hindered boronic acids (Table 3, entries 5 and 6).
Next, we extended our standard catalytic system, used to the
coupling reaction described in Table 3, to the reaction of
2-bromoselenophene 1b with boronic acids, but unfortunately,
the system gave lower yields than the corresponding iodides
1a (Table 4, entry 4). Then, we focused our attention to find a
new catalytic system that could deliver the product of the
reaction between 2-bromoselenophene and boronic acid in
acceptable yields. Toward this end, we used a variety of
catalysts, solvents, and bases. After a series of experiments, we
found that when the catalytic system was changed to Pd(PPh3)4
(3 mol %), using toluene as solvent and changing the base to
Na2CO3, the yield was greatly improved (Table 4, entry 4). Thus,
the careful analysis of the optimized reactions revealed that the
optimum conditions for this cross-coupling reaction were the
3788 J. Org. Chem., Vol. 71, No. 10, 2006

Pd-Catalyzed Suzuki Cross-Coupling of 2-Haloselenophenes
TABLE 4. Coupling Product Using 2-Bromoselenophene and
Boronic Acids
SCHEME 3
boronic acid. For example, boronic acid bearing a Me substituent
at the ortho position gave worse yield than no substituted boronic
acid (Table 4, entries 2 and 1, respectively).
After that, the possibility of generating 2,5-diarylselenophenes
was also investigated. As illustrated in Scheme 3, the cross-
coupling reaction of 2,5-diiodoselenophene 519 and boronic
acids, under the same reaction conditions described for 2-iodo-
selenophene, led to the substituted diaryl selenophene derivatives
6a-c in good yields (Scheme 3). We investigated the optimum
conditions and found that it was only necessary to change the
boronic acid amount from 0.7 to 1.4 equiv to give the dual
Suzuki coupling with 2,5-diiodoselenophene.
Having optimized the reaction conditions for direct coupling
of 2-iodoselenophene or 2-bromoselenophene with boronic
acids, we turned our attention to carbonylative cross-coupling
reactions using 2-iodoselenophene, boronic acids, and carbon
monoxide (Table 5).
Palladium-catalyzed carbonylative cross-coupling is an at-
tractive approach to the formation of unsymmetrically substi-
tuted biaryl ketones.20 Aryl halides with various coupling
partners have found success, including stannanes,21 magne-
sium,22 aluminum,23 silanes,24 and boronic acids.25 Drawbacks
to this approach often involve significant amounts of biaryl
coupled products, the result of coupling without carbon mon-
oxide insertion. The forms of the palladium catalysts, ligands,
bases, additives, solvents, and temperature have been reported
to have an effect on the amount of ketone versus biaryl formed.
To the best of our knowledge, however, no carbonylative cross-
coupling reaction using 2-haloselenophene as substrate, to
prepare unsymmetrical ketones, has been described thus far.
Thus, the standard reaction condition applied to direct coupling
of 2-bromoselenophene with boronic acids was also tested for
the carbonylative process. Accordingly, the treatment of 2-iodo-
selenophene (0.5 mmol) with organoboronic acids (0.75 mmol)
(19) 2,5-Diiodoselenophene was prepared according to Zeni, G.; Noguei-
ra, C. W.; Silva, D. O.; Menezes, P. H.; Braga, A. L.; Stefani, H. A.; Rocha,
J. B. T. Tetrahedron Lett. 2003, 44, 685-688, using I2 instead of Te0.
(20) Schoenberg, I.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39,
3318-3326.
a Yields in parentheses correspond to reactions performed in Pd(OAc)2
(3 mol %), K2CO3 (2.4 mmol) in H2O (1.2 mL) and DME (5 mL).
(21) (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1988, 110,
1557-1565. (b) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J. Org.
Chem. 1996, 61, 9082-9083. (c) Morera, E.; Ortar, G. Bioorg. Med. Chem.
Lett. 2000, 10, 1815-1818. (d) Ceccarelli, S.; Piarulli, U.; Gennari, C. J.
Org. Chem. 2000, 65, 6254-6256.
addition of Pd(PPh3)4 (3 mol %) to a mixture of 2-bromosele-
nophene 1b (0.5 mmol) and boronic acids (0.75 mmol) in
toluene (3.5 mL). After that, a solution of Na2CO3 (2.2 mmol)
in H2O (1.2 mL) was added and the mixture was refluxed. To
demonstrate the efficiency of this reaction, we extended the
conditions to other boronic acids (Table 4). In general, all of
the reactions proceeded smoothly with good yields. Most
importantly, the coupling turned out to be general with respect
to a diverse array of functionality. The reaction showed
compatibility with ketone, nitro, ester, and halogen groups. A
closer inspection of the results revealed that the reaction is
sensitive to the steric effect of the aromatic ring attached in the
(22) Yamamoto, M.; Kohara, T.; Yamamoto, A. Chem. Lett. 1976, 1217-
1220.
(23) Bumagin, N. A.; Ponomaryov, A. B.; Beletskaya, I. P. Tetrahedron
Lett. 1985, 26, 4819-4822.
(24) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Tetrahedron 1992, 48,
2113-2119.
(25) (a) Langstrom, B.; Ishiyama, T.; Kizaki, H.; Miyaura, N.; Suzuki,
A. Tetrahedron Lett. 1993, 34, 7595-7598. (b) Rahman, O.; Llop, J.
Langstro¨m, B. Eur. J. Org. Chem. 2004, 2004, 2674-2678. (c) Ishiyama,
T.; Kizaki, H.; Hayashi, T.; Suzuki, A.; Miyaura, N. J. Org. Chem. 1998,
63, 4726-4731.
J. Org. Chem, Vol. 71, No. 10, 2006 3789

Prediger et al.
TABLE 5. Carbonylative Coupling of 1a with 2 to Give 7
Catalyzed by Pd(PPh3)4
4-chlorophenylboronic acid with 2-iodoselenophene to provide
only the ketone in 69% yield, without any Ullmann-type reaction
product observed (Table 5, entry 3). To the best of our
knowledge, aryl chloride could react with boronic acids to afford
biaryl products using palladium catalysts.26 In our case, the
chlorine substituent was not affected.
Conclusion
In summary, we have explored the carbon-carbon bond
formation via Suzuki coupling reaction of 2-haloselenophenes
with boronic acids catalyzed by palladium salt and established
a new route to prepare 2-arylselenophenes in good yields. The
reaction proceeded cleanly under mild reaction conditions and
was performed with aryl boronic acids bearing electron-
withdrawing, electron-donating, and neutral substituents, in the
presence of Pd(OAc)2 and K2CO3/H2O in DME. In addition,
by this protocol unsymmetrical aryl ketones were also obtained
from 2-iodoselenophene and boronic acids via a carbonylative
process. The pharmacological activities of these compounds are
under study in our laboratory. Analysis of the 1H and 13C NMR
spectra showed that all the obtained products presented data in
full agreement with their assigned structures.
Experimental Section
General Procedure for the Preparation of the Arylsele-
nophenes from 2-Iodoselenophene. The solution of 2-iodosele-
nophene (0.128 g, 0.5 mmol) in DME (5 mL) was added to
Pd(OAc)2 (0,003 g, 3 mol %) and boronic acid (0.7 mmol), under
argon. The resulting solution was stirred for 30 min at room
temperature. After this time, a solution of K2CO3 (2.4 mmol, 0.309
g) in H2O (1.2 mL) was added. The mixture was then heated at
reflux for the time indicated in Table 3, cooled to room temperature,
diluted with dichloromethane (20 mL), and washed with brine (2
× 20 mL). The organic phase was separated, dried over MgSO4,
and concentrated under vacuum. The residue was purified by flash
chromatography and eluted with hexane/ethyl acetate (95:5) or
hexane.
1
2-Phenylselenophene (3b). Yield: 0.079 g (77%). H NMR:
CDCl3, 400 MHz, δ (ppm): 7.89 (d, J ) 5.55 Hz, 1H), 7.53 (d, J
) 7.75 Hz, 2H), 7.42 (d, J ) 4.10 Hz, 1H), 7.34-7.30 (m, 3H),
7.27-7.24 (m, 1H). 13C NMR: CDCl3, 100 MHz, δ (ppm): 150.8,
136.4, 130.5, 129.9, 128.8, 127.5, 126.3, 125.2. MS (EI, 70 eV)
m/z (relative intensity): 210 (25), 208 (99), 128 (100), 115 (38),
102 (35). HRMS Calcd for C10H8Se: 207.9791. Found: 207.9796.
1
2-p-Tolylselenophene (3a). Yield: 0.104 g (95%). H NMR:
CDCl3, 400 MHz, δ (ppm): 7.87 (d, J ) 5.55 Hz, 1H), 7.44 (d, J
) 8.04 Hz, 2H), 7.39 (d, J ) 3.51 Hz, 1H), 7.29-7.26 (m, 1H),
7.14 (d, J ) 8.04 Hz, 2H), 2.34 (s, 3H). 13C NMR: CDCl3, 100
MHz, δ (ppm): 150.9, 137.4, 133.7, 130.5, 129.5, 129.3, 126.3,
124.7, 21.1. MS (EI, 70 eV) m/z (relative intensity): 224 (22), 222
(96), 182 (56), 167 (31), 141 (100), 115 (68). HRMS Calcd for
C11H10Se: 221.9948. Found: 221.9953.
in the presence of Pd(PPh3)4 (3 mol %), a solution of Na2CO3
(2.2 mmol) in H2O (1.2 mL) under carbon monoxide atmosphere
(balloon), and toluene (3 mL) at 110 °C for 12 h afforded
unsymmetrical ketones. The scope and limitations of this
carbonylative cross-coupling process are summarized in Table
5.
The presence of different functional groups is compatible with
the carbonylation reaction. It is noteworthy that the reaction is
sensitive to the electronic nature of functional groups present
in the aromatic ring of boric acids, since the reactions with
boronic acids bearing a neutral and an electron-rich group gave
the desired product in good yields (Table 5, entries 1-3).
However, aryl boronic acids bearing strong electron-withdrawing
groups in the aromatic ring (Table 5, entries 6 and 7) did not
give the carbonylative products; in this case, only significant
amounts of the direct coupling products were observed. When
we performed this reaction with hindered boronic acid, the
carbonylation product was obtained in moderate yield (Table
5, entry 4). Differentiation in the reactivity between chlorine
and boron atoms of boronic acids can be seen by coupling of
2-(4-Methoxyphenyl)selenophene (3c). Yield: 0.098 g (83%).
1H NMR: CDCl3, 400 MHz, δ (ppm): 7.84 (d, J ) 5.55 Hz, 1H),
7.47 (d, J ) 8.77 Hz, 2H), 7.32 (d, J ) 3.65 Hz, 1H), 7.28-7.26
(m, 1H), 6.88 (d, J ) 8.77 Hz, 2H), 3.81 (s, 3H). 13C NMR: CDCl3,
100 MHz, δ (ppm): 159.3, 150.7, 130.5, 129.3, 128.7, 127.6, 124.1,
114.3, 55.3. MS (EI, 70 eV) m/z (relative intensity): 240 (17), 238
(100), 223 (90), 195 (4), 115 (88). HRMS Calcd for C11H10OSe:
237.9897. Found: 237.9903.
2-(Selenophen-2-yl)thiophene (3d). Yield: 0.085 g (80%). 1H
NMR: CDCl3, 400 MHz, δ (ppm): 7.85 (d, J ) 5.55 Hz, 1H),
7.31 (d, J ) 3.65 Hz, 1H), 7.25-7.19 (m, 2H), 7.12 (d, J ) 3.65
(26) (a) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101-
2104. (b) LeBlond, C. R.; Andrews, A. T.; Sowa, J. R.; Sun, Y. Org. Lett.
2001, 3, 1555-1557.
3790 J. Org. Chem., Vol. 71, No. 10, 2006

Pd-Catalyzed Suzuki Cross-Coupling of 2-Haloselenophenes
Hz, 1H), 7.00-6.98 (m, 1H). 13C NMR: CDCl3, 100 MHz, δ
(ppm): 130.2, 129.7, 129.5, 127.8, 126.7, 125.9, 124.5, 124.4. MS
(EI, 70 eV) m/z (relative intensity): 214 (85), 134 (100), 121 (10),
108 (20), 89 (23). HRMS Calcd for C8H6SSe: 213.9355. Found:
213.9361.
CDCl3, 100 MHz, δ (ppm): 149.4, 137.4, 133.7, 129.6, 125.9,
125.6, 21.1. MS (EI, 70 eV) m/z (relative intensity): 312 (100),
309 (26), 215 (26), 154 (20), 115 (27), 101 (10), 89 (7). HRMS
Calcd for C18H16Se: 312.0417. Found: 312.0424.
2,5-Bis-(3-(trifluoromethyl)phenyl)selenophene (6c). Yield:
1
1
2-o-Tolylselenophene (3e). Yield: 0.060 g (55%). H NMR:
0.151 g (72%). H NMR: CDCl3, 400 MHz, δ (ppm): 7.80 (s,
CDCl3, 400 MHz, δ (ppm): 8.02 (d, J ) 5.55 Hz, 1H), 7.39-7.37
2H), 7.71 (d, J ) 7.64 Hz, 2H), 7.57-7.49 (m, 6H). 13C NMR:
CDCl3, 100 MHz, δ (ppm): 149.0, 136.8, 131.5 (q, J ) 32.53 Hz),
129.5, 129.3, 127.4, 124.3 (q, J ) 3.53 Hz), 123.9 (q, J ) 272.68
Hz), 122.6 (q, J ) 3.53 Hz). MS (EI, 70 eV) m/z (relative
intensity): 420 (100), 418 (48), 340 (13), 270 (16), 210 (16). HRMS
Calcd for C18H10F6Se: 419.9852. Found: 419.9858.
(m, 1H), 7.33-7.31 (m, 1H), 7.26-7.18 (m, 4H), 2.41 (s, 3H). 13
C
NMR: CDCl3, 100 MHz, δ (ppm): 149.4, 136.3, 135.7, 130.7,
130.6, 130.5, 129.6, 128.6, 127.7, 125.8, 29.7. HRMS Calcd for
C11H10Se: 221.9948. Found: 221.9955.
1
2-Mesitylselenophene (3f). Yield: 0.039 g (32%). H NMR:
CDCl3, 400 MHz, δ (ppm): 8.04 (d, J ) 5.55 Hz, 1H), 7.31-7.29
(m, 1H), 6.93-6.92 (m, 3H), 2.31 (s, 3H), 2.14 (s, 6H). 13C NMR:
CDCl3, 100 MHz, δ (ppm): 148.1, 137.6, 133.1, 130.9, 130.2,
129.5, 128.6, 128.1, 21.0, 20.8. MS (EI, 70 eV) m/z (relative
intensity): 252 (14), 250 (74), 235 (32), 169 (100), 155 (41), 128
(29), 115 (26). HRMS Calcd for C13H14Se: 250.0261. Found:
250.0266.
2-(3-(Trifluoromethyl)phenyl)selenophene (3g). Yield: 0.099
g (72%). 1H NMR: CDCl3, 400 MHz, δ (ppm): 7.98 (d, J ) 5.55
Hz, 1H), 7.78 (s, 1H), 7.69 (d, J ) 7.75 Hz, 1H), 7.58-7.43 (m,
2H), 7.45 (t, J ) 7.75 Hz, 1H), 7.33-7.31 (m, 1H). 13C NMR:
CDCl3, 100 MHz, δ (ppm): 148.9, 137.2, 131.5 (q, J ) 32.53 Hz),
131.2, 130.7, 129.6, 129.4, 126.4, 124.0 (q, J ) 3.53 Hz), 123.9
(q, J ) 272,68 Hz), 122.9 (q, J ) 3.53 Hz). MS (EI, 70 eV) m/z
(relative intensity): 276 (100), 196 (48), 175 (13), 146 (23), 126
(10), 115 (11). HRMS Calcd for C11H7F3Se: 275.9665. Found:
275.9671.
2-(3-Nitrophenyl)selenophene (3h). Yield: 0.081 g (65%). 1H
NMR: CDCl3, 400 MHz, δ (ppm): 8.38 (s, 1H), 8.10 (d, J ) 7.89
Hz, 1H), 8.04 (d, J ) 5.55 Hz, 1H), 7.83 (d, J ) 7.60 Hz, 1H),
7.57 (d, J ) 3.51 Hz, 1H), 7.52 (t, J ) 8.04 Hz, 1H), 7.37-7.34
(m, 1H). 13C NMR: CDCl3, 100 MHz, δ (ppm): 167.7, 147.6,
138.1, 132.3, 131.9, 130.8, 129.8, 127.1, 121.9, 120.7. MS (EI, 70
eV) m/z (relative intensity): 253 (9), 207 (7), 127 (14), 115 (100).
HRMS Calcd for C10H7NO2Se: 252.9642. Found: 252.9648.
2,5-Bis-phenylselenophene (6a). Yield: 0.078 g (55%). 1H
NMR: CDCl3, 400 MHz, δ (ppm): 7.56 (d, J ) 7.60 Hz, 4H),
7.44 (s, 2H), 7.38-7.23 (m, 6H). 13C NMR: CDCl3, 100 MHz, δ
(ppm): 149.9, 136.4, 128.9, 127.6, 126.2, 126.1. MS (EI, 70 eV)
m/z (relative intensity): 284 (100), 280 (22), 203 (53), 142 (14),
101 (30). HRMS Calcd for C16H12Se: 284.0104. Found: 284.0110.
General Procedure for the Synthesis of Diaryl Ketones from
2-Iodoselenophene. A dried Schlenk flask containing Pd(PPh3)4
(0.017 g, 3 mol %) and boronic acid (0.75 mmol) was evacuated
and connected to an atmosphere of argon. 2-Iodoselenophene (0.128
g, 0.5 mmol), toluene (3 mL), and aqueous Na2CO3 (1.1 mL of
solution 2 M in H2O, 2.17 mmol) were added. After removal of
argon atmosphere, the system was purged with CO three times using
a balloon. The mixture was stirred at 110 °C under carbon monoxide
atmosphere (balloon) for 12 h. The resulting mixture was quenched
by addition of NH4Cl solution (10 mL) and then extracted with
EtOAc (3 × 10 mL). The combined organic extracts were dried
with MgSO4, filtered, and evaporated under reduced pressure. The
crude products were purified by flash column chromatography
(EtOAc/hexane, 20:80).
Selenophen-2-yl(p-tolyl)methanone (7a). Yield: 0.101 g (81%).
1H NMR: CDCl3, 400 MHz, δ (ppm): 8.40 (d, J ) 5.55 Hz, 1H),
7.83 (d, J ) 3.95 Hz, 1H), 7.76 (d, J ) 8.04 Hz, 2H), 7.42-7.39
(m, 1H), 7.28 (d, J ) 8.04 Hz, 2H), 2.43 (s, 3H). 13C NMR: CDCl3,
100 MHz, δ (ppm): 189.0, 150.7, 139.9, 136.8, 130.5, 130.1, 129.3,
129.0, 128.8, 21.5. MS (EI, 70 eV) m/z (relative intensity): 252
(13), 250 (69), 159 (74), 119 (100), 91 (75). HRMS Calcd for
C12H10OSe: 249.9897. Found: 249.9904.
1-(4-(Selenophen-2-yl)phenyl)ethanone (3i). Yield: 0.094 g
1
(76%). H NMR: CDCl3, 400 MHz, δ (ppm): 8.02 (d, J ) 5.55
Hz, 1H), 7.93 (d, J ) 8.33 Hz, 2H), 7.62 (d, J ) 8.33 Hz, 2H),
7.58 (d, J ) 3.51 Hz, 1H), 7.35-7.33 (m, 1H), 2.59 (s, 3H). 13C
NMR: CDCl3, 100 MHz, δ (ppm): 197.2, 149.2, 140.7, 135.8,
131.8, 130.8, 129.1, 126.8, 126.1, 26.5. MS (EI, 70 eV) m/z (relative
intensity): 250 (9), 235 (100), 207 (5), 126 (25), 115 (99). HRMS
Calcd for C12H10OSe: 249.9897. Found: 249.9905.
(4-Methoxyphenyl)(selenophen-2-yl)methanone (7b). Yield:
1
0.107 g (80%). H NMR: CDCl3, 400 MHz, δ (ppm): 8.38 (d, J
) 5.55 Hz, 1H), 7.87 (d, J ) 8.77 Hz, 2H), 7.82 (d, J ) 3.65 Hz,
1H), 7.41-7.39 (m, 1H), 6.96 (d, J ) 8.77 Hz, 2H), 3.86 (s, 3H).
13C NMR: CDCl3, 100 MHz, δ (ppm): 187.9, 162.9, 150.7, 139.4,
136.2, 132.0, 131.4, 130.4, 130.2, 55.3. MS (EI, 70 eV) m/z (relative
intensity): 266 (53), 264 (29), 251 (13), 159 (38), 135 (100), 77
(40). HRMS Calcd for C12H10O2Se: 265.9846. Found: 265.9852.
2-(4-Chlorophenyl)selenophene (3j). Yield: 0.113 g (94%). 1H
NMR: CDCl3, 400 MHz, δ (ppm): 7.91 (d, J ) 5.55 Hz, 1H),
7.44 (d, J ) 8.33 Hz, 2H), 7.42-7.38 (m, 1H), 7.30-7.27 (m,
3H). 13C NMR: CDCl3, 100 MHz, δ (ppm): 149.3, 134.9, 130.6,
130.4, 128.9, 128.1, 127.5, 125.6. MS (EI, 70 eV) m/z (relative
intensity): 244 (6), 242 (100), 162 (69), 126 (26), 115 (27). HRMS
Calcd for C10H7ClSe: 241.9401. Found: 241.9407.
General Procedure for the Preparation of the Bis-arylsele-
nophene from 2,5-Diiodoselenophene. The solution of 2,5-
diiodoselenophene (0.096 g, 0.25 mmol) in DME (5 mL) was added,
under argon, to a mixture of Pd(OAc)2 (0.003 g, 6 mol %) and
boronic acid (0.7 mmol). The resulting solution was stirred for 30
min at room temperature. After this time, the solution was added
to the solution of K2CO3 (2.4 mmol, 0.309 g) in H2O (1.2 mL).
The mixture was then heated at reflux for the time indicated in
Scheme 3, cooled to room temperature, diluted with dichlo-
romethane (20 mL), and washed with brine (2 × 20 mL). The
organic phase was separated, dried over MgSO4, and concentrated
under vacuum. The residue was purified by flash chromatography
and eluted with hexane/ethyl acetate (95:5) or hexane.
(4-Chlorophenyl)(selenophen-2-yl)methanone (7c). Yield: 0.093
g (69%). 1H NMR: CDCl3, 400 MHz, δ (ppm): 8.45 (d, J ) 5.55
Hz, 1H), 7.81-7.77 (m, 3H), 7.45 (d, J ) 8.48 Hz, 2H), 7.43-
7.40 (m, 1H). 13C NMR: CDCl3, 100 MHz, δ (ppm): 188.0, 149.9,
140.7, 138.4, 137.1, 135.9, 130.7, 130.5, 128.6. MS (EI, 70 eV)
m/z (relative intensity): 270 (52), 159 (100), 139 (40), 111 (42),
75 (38). HRMS Calcd for C11H7ClOSe: 269.9351. Found: 269.9357.
Mesityl(selenophen-2-yl)methanone (7d). Yield: 0.074 g (53%).
1H NMR: CDCl3, 400 MHz, δ (ppm): 8.42 (d, J ) 5.55 Hz, 1H),
7.49 (d, J ) 3.97 Hz, 1H), 7.33-7.29 (m, 1H), 6.88 (s, 2H), 2.31
(s, 3H), 2.17 (s, 6H). 13C NMR: CDCl3, 100 MHz, δ (ppm): 193.9,
151.4, 141.2, 138.5, 137.4, 134.0, 130.9, 128.2, 128.1, 21.0, 19.2.
MS (EI, 70 eV) m/z (relative intensity): 280 (18), 278 (89), 197
(100), 169 (33), 147 (26), 119 (25), 91 (40). HRMS Calcd for
C14H14OSe: 278.0210. Found: 278.0216.
Phenyl(selenophen-2-yl)methanone (7e). Yield: 0.049 g (42%).
1H NMR: CDCl3, 400 MHz, δ (ppm): 8.42 (d, J ) 5.55 Hz, 1H),
7.84-7.79 (m, 3H), 7.59-7.41 (m, 1H), 7.49-7.41 (m, 3H). 13C
NMR: CDCl3, 100 MHz, δ (ppm): 189.3, 150.4, 140.3, 137.3,
132.0, 130.6, 129.9, 129.0, 128.3. MS (EI, 70 eV) m/z (relative
2,5-Bis-p-tolylselenophene (6b). Yield: 0.148 g (95%). 1H
NMR: CDCl3, 400 MHz, δ (ppm): 7.44 (d, J ) 7.65 Hz, 4H),
7.36 (s, 2H), 7.14 (d, J ) 7.61 Hz, 4H), 2.34 (s, 6H). 13C NMR:
J. Org. Chem, Vol. 71, No. 10, 2006 3791

Prediger et al.
intensity): 238 (12), 236 (64), 159 (100), 105 (53), 77 (10), 51
(5). HRMS Calcd for C11H8OSe: 235.9740. Found: 235.9744.
Supporting Information Available: Experimental procedures,
additional experimental details for the preparation, and 1H and 13
C
NMR spectra for all reaction products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the following agencies for
support: FAPERGS, CNPq, CAPES, and UFSM. CNPq is also
acknowledged for a Ms fellowship (P.P.). G.Z. is the recipient
of a CNPq fellowship.
JO0601056
3792 J. Org. Chem., Vol. 71, No. 10, 2006