3-Iodoselenophene derivatives: a versatile substrate for Negishi cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2007.11.070

3-Iodoselenophene derivatives undergo a direct Negishi cross-coupling reaction with several organozinc compounds in the presence of a catalytic amount of Pd(PPh₃)₄ in THF at room temperature. This cross-coupling reaction proceeded cl

Full text of DOI:10.1016/j.tetlet.2007.11.070

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Tetrahedron Letters 49 (2008) 538–542
3-Iodoselenophene derivatives: a versatile substrate
for Negishi cross-coupling reaction
Ricardo F. Schumacher, Diego Alves, Ricardo Brandao,
˜
Cristina W. Nogueira and Gilson Zeni*
ˆ
Laborato´rio de Sı´ntese, Reatividade, Avaliac¸a˜o Farmacolo´gica e Toxicolo´gica de Organocalcogenios, CCNE, UFSM,
Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
Received 8 October 2007; revised 12 November 2007; accepted 13 November 2007
Available online 19 November 2007
Abstract—3-Iodoselenophene derivatives undergo a direct Negishi cross-coupling reaction with several organozinc compounds in
the presence of a catalytic amount of Pd(PPh3)4 in THF at room temperature. This cross-coupling reaction proceeded cleanly under
mild conditions and permitted the formation of polyaromatic compounds in good yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Transition-metal catalyzed cross-coupling reactions
between Csp2-centers have been extensively used for
preparing pharmaceuticals and agrochemical intermedi-
ates.1 In this context, there have been developments in
palladium-catalyzed coupling systems as a consequence
of the great interest in the development of coupling sub-
strates that are more economic, more easily accessible,
and reactive even under mild conditions. In this line,
the palladium-catalyzed cross-coupling of organozinc
compounds with organic electrophiles, known as the
Negishi reaction, has become an extremely powerful
tool for the construction of carbon–carbon bonds.2
Functionalized organozinc compounds are also impor-
tant tools for allowing easy access to polyfunctional aro-
matic and heteroaromatic compounds.3 On the other
hand, chalcogenide compounds have found such wide
utility because their effects on an extraordinary number
of very different reactions, including many carbon–
carbon bond formations, under relatively mild reaction
conditions4 and useful biological activities.5 Among
chalcogenide compounds, the chalcogenophene deriva-
tives play an important role in organic synthesis because
many of them show biological activities.6 Halochalco-
genophenes are important derivatives that provide an
opportunity for further functionalization. In particular,
2-iodo- and bromoselenophenes are useful as substrates
in a variety of C–C, C–N, and C–S bond forming
reactions.7
To the best of our knowledge no Negishi cross-coupling
reaction using 3-haloselenophene as substrate in the
preparation of sp2–sp2 or sp2–sp carbon–carbon bond
has been described so far. Our continuing interest in
the palladium-catalyzed Negishi cross-coupling reac-
tions of organochalcogen8 prompted us to examine the
cross-coupling reaction of 3-iodoselenophenes 1a–c with
organozinc chlorides 2a–l to obtain selenophene deriva-
tives 3a–q (Scheme 1).
The starting 3-iodoselenophene was readily available by
using the electrophilic cyclization protocol of (Z)-seleno-
enynes. The treatment of (Z)-selenoenyne with iodine
in CH2Cl2 lead to the formation of the 3-iodoseleno-
phene 1a, isolated in 93% yield after purification
(Scheme 2).9
R2
I
[Pd]
R2-ZnCl
R1
R
R1
R
Se
Se
THF
1a-c
2a-l
3a-q
Keywords: Palladium; Negishi reaction; Cross-coupling; Halo-
R = R1 = alkyl, aryl; R2= aryl, heteroaryl, alkynyl
selenophene.
*
Corresponding author. Tel.: +55 55 220 8140; fax: +55 55 220
8031; e-mail: gzeni@quimica.ufsm.br
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.070

R. F. Schumacher et al. / Tetrahedron Letters 49 (2008) 538–542
539
Ph
I
Br
I2 (1.1 eq)
n-C4H9Se
CH2Cl2
5 min., r.t.
Ph
Ph
Se
1) BuLi / THF
-78 ˚C / 45 min.
2) ZnCl2 / THF
Ph
1a
93%
Scheme 2.
-78 ˚C
r.t.
ZnCl Pd(PPh3)4 (1%)
Our initial efforts were devoted to the selection of a suit-
able catalyst system for an efficient coupling. In this
way, 2,5-diphenyl-3-iodoselenophene 1a and p-tolylzinc
chloride 2a were used as standard substrates. Thus, a
mixture of 3-iodoselenophene 1a (0.25 mmol), p-tolyl-
zinc chloride 2a (0.75 mmol) (prepared in situ by reac-
tion of 4-bromotoluene with n-BuLi in THF at À78 ꢁC
followed by the addition of ZnCl2) in THF, at room
temperature was reacted with different palladium cata-
lysts and the results are shown in Table 1.
THF; r. t.
I
Ph
Ph
Se
3a
95%
2a
Ph
Ph
Se
1a
Scheme 3.
To demonstrate the efficiency of this cross-coupling
reaction, we explored the generality of our method
extending the coupling reaction to other aryl, heteroaryl,
and alkynylzinc chlorides as well as to other 3-iodoselen-
ophenes and the results are summarized in Table 2.
As shown in Table 1, all catalysts of Pd(0) and Pd(II)
tested, such as PdCl2(PhCN)2, PdCl2(PPh3)2, PdCl2,
Pd(OAc)2, Pd(PPh3)4, Pd(dba)2, and Pd(dppe)2, in
10 mol % exhibit a poor to good catalytic activity but
the best result was obtained using Pd(PPh3)4 which gave
the desired product 3a in 88% yield (Table 1, entry 7). It
is important to note that when the amount of catalyst is
reduced from 10 to 1 mol %, an increase in the yield was
observed (Table 1, entries 7–9). The influence of other
parameters such as the amount of the organozinc
compound in this reaction was also investigated. We
observed that this cross-coupling reaction required the
use of an excess of organozinc reagent (3 equiv). When
1.5 or 2 equiv of compound 2a was used unsatisfactory
yields of 3a were obtained (Table 1, entries 10 and 11).
Inspection of Table 2 shows that the reaction worked
well for a variety of organozinc chlorides. A closer
inspection of the results revealed that the reaction is
not sensitive to the electronic effects in organozinc chlo-
ride. A wide range of groups attached to the arylzinc
chloride, such as electron-rich, neutral, and poor groups
were cross-coupled efficiently under these conditions
and produced the functionalized products in good to
excellent yields. However, the reaction was sensitive to
the steric effect of the aromatic ring attached in the
arylzinc chloride. For example, arylzinc chloride bearing
o-tolyl and naphthyl groups gave a lower yield of the
desired products (Table 2, entries 2 and 6). Organozinc
reagents having heteroaromatics such as 2-furyl and
2-thienyl groups afforded the corresponding products
3i and 3j in satisfactory isolated yields (Table 2, entries
9 and 10).
Thus, the careful analysis of the optimized reactions
revealed that the optimum conditions for the cross-
coupling were found to be the use of 2,5-diphenyl-3-
iodoselenophene 1a (0.25 mmol) and p-tolylzinc chloride
2a (0.75 mmol), Pd(PPh3)4 (1 mol %), in THF (3 mL), at
room temperature. Under these conditions we were able
to prepare 2,5-diphenyl-3-p-tolylselenophene 3a in 95%
yield (Scheme 3).10
Alkynylzinc compounds could also be coupled in good
yields (Table 2, entries 11 and 12).
In an attempt to broaden the scope of our methodology,
the possibility of performing the reaction using other
3-iodoselenophenes was also investigated. As illustrated
in Table 2, the cross-coupling reaction of 1b–c with
arylzinc chlorides, under the same reaction conditions,
led to the corresponding coupling products 3m–q in
good yields (Table 2, entries 13–17).
Table 1. Reaction conditions optimizationa
Entry
Catalyst (mol %)
R2-ZnCl (equiv)
Yield 3a (%)
1
2
3
Pd(OAc)2 (10)
PdCl2(PPh3)2 (10)
PdCl2 (10)
3
3
3
50
55
45
60
33
20
88
90
95
82
40
4
5
6
7
8
9
10
11
PdCl2(PhCN)2 (10)
Pd(dba)2 (10)
Pd(dppe)2 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (1)
Pd(PPh3)4 (1)
Pd(PPh3)4 (1)
3
3
3
3
3
3
2
1.5
The 3-alkynylselenophenes obtained by this protocol
appear highly promising as intermediates for the prepa-
ration of more highly substituted selenophenes. In this
context, we have carried out the synthesis of vinylic
telluride 4 using compound 3r as a starting material,
which was obtained using the procedure described here
in 58% yield. Many classes of organotellurium com-
pounds have been prepared and studied to date, vinylic
tellurides are certainly the most useful and promising
a Reactions were performed in the presence of 1a (0.25 mmol), using
THF (3 mL) as solvent at room temperature for 24 h.

540
R. F. Schumacher et al. / Tetrahedron Letters 49 (2008) 538–542
Table 2. Coupling products using 3-iodoselenophenes 1a–c and
organozinc reagents 2a–la
Table 2 (continued)
Entry R2-ZnCl
Product 3
Yieldb
(%)
R2
I
Pd(PPh3)4 (1 mol %)
OMe
2
R
R1
R -ZnCl
R
R1
Se
Se
THF
MeO
1a-c
2a-l
3a-q
8
60
R = R1 = alkyl, aryl; R2 = aryl, heteroaryl, alkynyl
ZnCl
2h
Ph
Se
Ph
3h
Entry R2-ZnCl
Product 3
Yieldb
(%)
S
ZnCl
9
93
72
1
S
95
ZnCl
Ph
Se
Ph
2i
2a
Ph
Se
Ph
3i
3a
O
ZnCl
10
11
12
O
Ph
Se
Ph
2
65
2j
ZnCl
3j
Ph
Se
Ph
2b
3b
C5H11
Cl
C5H11
ZnCl
Cl
75
2k
Ph
Se
Ph
3
70
ZnCl
3k
2c
Ph
Se
Ph
3c
Ph
Ph
ZnCl
Cl
75
Cl
2l
Ph
Ph
Se
3l
4
82
ZnCl
Ph
Ph
Se
2d
2e
3d
13
70c
ZnCl
5
71
2a
C4H9
C4H9
Se
ZnCl
Ph
Ph
Ph
Ph
Ph
Ph
3m
Se
3e
Cl
Cl
14
76c
ZnCl
6
35
ZnCl
2c
C4H9
C4H9
Se
2f
Se
3f
3n
CF3
15
70c
7
70
F3C
ZnCl
ZnCl
C4H9
C4H9
Se
2e
Se
3g
2g
3o

R. F. Schumacher et al. / Tetrahedron Letters 49 (2008) 538–542
541
Table 2 (continued)
Entry
R2-ZnCl
Supplementary data
Product 3
Yieldb
(%)
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.11.070.
16
73c
ZnCl
References and notes
2a
Ph
Se
C4H9
1. (a) Miyaura, N. Cross-Coupling Reactions. A Practical
Guide; Springer: Berlin, 2002; (b) Diederich, F.; Stang, P.
J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 1998.
3p
Cl
2. (a) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979;
(b) Negishi, E. In Handbook of Organopalladium Chemis-
try for Organic Synthesis; Wiley and Sons: New York,
2002; Vols. 1 and 2; (c) Li, J. J.; Gribble, G. W. Palladium
in Heterocyclic Chemistry. In Tetrahedron Organic Chem-
istry Series; Pergamon: Amsterdam, 2000; Vol. 20; (d)
Negishi, E.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G.
Aldrichim. Acta 2005, 38, 71–88.
3. (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117;
(b) Staubitz, A.; Dohle, W.; Knochel, P. Synthesis 2003,
233; (c) Gommermann, N.; Koradin, C.; Knochel, P.
Synthesis 2002, 2143; (d) Knochel, P.; Millot, N.; Rodri-
guez, A. L. Org. React. 2001, 58, 417.
Cl
17
90c
ZnCl
2c
Ph
Se
C4H9
3q
a Reactions were performed in the presence of 1a–c (0.25 mmol), 2a–l
(0.75 mmol), using THF (3 mL) as solvent at room temperature for
24 h.
b The yields are given for isolated products.
c Reaction time 30 h.
4. (a) Zeni, G.; Ludtke, D. S.; Panatieri, R. B.; Braga, A. L.
Chem. Rev. 2006, 106, 1032; (b) Zeni, G.; Braga, A. L.;
Stefani, H. A. Acc. Chem. Res. 2003, 36, 731.
5. Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev.
2004, 104, 6255.
6. Chemistry and Biology of Naturally-occurring Acetylenes
and Related Compounds; Lain, J., Breteler, H., Arnason,
T., Hansen, L., Eds.; Elsevier: Amsterdam, 1988.
7. (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.; Savegn-
ago, 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.
compounds in view of the usefulness in the organic syn-
thesis, including in the synthesis of natural products.11
Thus, 3-alkynylselenophene 3r was reacted with NaOH
in toluene under reflux for 4 h. Then the terminal alkyne
generated in situ reacts with BuTeTeBu and NaBH4 in
ethanol, under reflux, to give the corresponding vinylic
telluride 4 (Scheme 4).12
In summary, we have explored the Negishi cross-cou-
pling reaction of 3-iodoselenophene derivatives with sev-
eral organozinc compounds in the presence of catalytic
amount of Pd(PPh3)4 under mild reaction conditions
(room temperature) and established a new route to
obtain polyaromatic compounds in good to excellent
yields. Analysis of the 1H and 13C NMR spectra showed
that all the obtained products presented data in full
agreement with their assigned structures.
8. (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.; Brandao, R.; Nogueira, C.
˜
W.; Zeni, G. Synlett 2006, 7, 1035.
9. Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org.
Chem. 2007, 72, 6726.
10. General procedure for the cross-coupling reaction. A 10 mL
Schlenk tube, equipped with a magnetic bar, rubber
septum and argon, containing previously prepared the
organozinc compound (0.75 mmol),8 was charged sequen-
tially with the 3-iodoselenophene derivative (0.25 mmol)
and Pd(PPh3)4 (0.0028 g, 0.0025 mmol). The yellow mix-
ture was stirred at room temperature and the reaction time
Acknowledgments
We are grateful to FAPERGS, CAPES (SAUX) and
CNPq for financial support. CNPq are also acknowl-
edged for the fellowships (R.F.S. and G.Z.).
OH
TeBu
1) NaOH, toluene, reflux
2) BuTe)2, NaBH4, EtOH
Ph
Ph
Ph
Ph
Se
Se
3r
4
Scheme 4.

542
R. F. Schumacher et al. / Tetrahedron Letters 49 (2008) 538–542
was determined monitoring the reaction by TLC. The
intensity) m/z: 358 (100), 282 (71), 204 (35), 128 (63),
111 (44), 77 (29). HRMS calcd for C22H15ClSe: 394.0027.
Found: 394.0032.
reaction mixture was then quenched with aqueous NH4Cl
(5 mL), washed with CH2Cl2 (3 · 5 mL), dried with
MgSO4 and the solvent removed under vacuum. The
products were purified by column chromatography.
Selected spectral and analytical data for 3c: yield:
11. (a) Zeni, G.; Panatieri, R. B.; Lissner, E.; Menezes, P. H.;
Braga, A. L.; Stefani, H. A. Org. Lett. 2001, 3, 819; (b)
Alves, D.; Nogueira, C. W.; Zeni, G. Tetrahedron Lett.
2005, 46, 8761; (c) Marino, J. P.; McClure, M. S.; Holub,
D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc.
2002, 124, 1664.
1
0.068 g (70%). H NMR: (400 MHz, CDCl3): d 7.57–7.53
(m, 4H), 7.44 (s, 1H), 7.39–7.22 (m, 10H). 13C NMR:
(100 MHz, CDCl3): d 148.83, 144.45, 139.50, 136.04,
135.92, 135.84, 132.78, 130.43, 129.20, 128.96, 128.90,
128.53, 127.57, 127.49, 126.19, 126.02. MS (relative
12. Alves, D.; Reis, J. S.; Luchese, C.; Nogueira, C. W.; Zeni, G.
Eur. J. Org. Chem., in press, doi:10.1002/ejoc.2007.00.707.