3-Iodo-4-chalcogen-2H-benzopyran as a convenient precursor for the sonogashira cross-coupling: synthesis of 3-alkynyl-4-chalcogen-2H-benzopyrans

Article abstract of DOI:10.1016/j.tetlet.2009.09.058

3-Iodo-4-chalcogen-2H-benzopyran derivatives underwent a direct Sonogashira cross-coupling reaction with several terminal alkynes in the presence of a catalytic amount of Pd(PPh₃)₂Cl₂ with CuI as a co-catalyst, using Et₃N as base and solvent. This cross-coupling reaction proceeded cleanly under mild conditions and was performed with propargylic alcohols, propargylic ethers, as well as alkyl and aryl alkynes, furnishing the correspondent 3-alkynyl-4-chalcogen-2H-benzopyrans in good yields.

Full text of DOI:10.1016/j.tetlet.2009.09.058

Tetrahedron Letters 51 (2010) 36–39
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
3-Iodo-4-chalcogen-2H-benzopyran as a convenient precursor
for the sonogashira cross-coupling: synthesis of 3-alkynyl-4-chalcogen-2H-
benzopyrans
*
Adriane Sperança, Benhur Godoi, Ana C. G. Souza, Gilson Zeni
Laboratório de Síntese, Reatividade, Avaliação Farmacológica e Toxicidade de Organocalcogênios, CCNE, UFSM, Santa Maria, Rio Grande do Sul CEP 97105-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Revised 10 September 2009
Accepted 10 September 2009
Available online 13 September 2009
3-Iodo-4-chalcogen-2H-benzopyran derivatives underwent a direct Sonogashira cross-coupling reaction
with several terminal alkynes in the presence of a catalytic amount of Pd(PPh3)2Cl2 with CuI as a co-cat-
alyst, using Et3N as base and solvent. This cross-coupling reaction proceeded cleanly under mild condi-
tions and was performed with propargylic alcohols, propargylic ethers, as well as alkyl and aryl
alkynes, furnishing the correspondent 3-alkynyl-4-chalcogen-2H-benzopyrans in good yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzopyrans
Palladium
Sonogashira cross-coupling
Transition-metal-catalyzed cross-coupling reactions between
Csp2-centers have been extensively used for selective construction
of carbon–carbon bonds, in particular, for the formation of struc-
tural units found in natural products, pharmaceuticals, and electri-
cal conductors.1 In this context, palladium-catalyzed coupling
systems have been developed as a consequence of the great inter-
est in the increase 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 terminal alkynes, commonly referred to
as Sonogashira reactions, are powerful, versatile, and popular tools
for selective construction of the new carbon–carbon bonds.2 To
this reaction that is generally co-catalyzed by copper salts, an
amine as a base and a phosphine as a ligand for palladium are also
typically included. Recent advances of Sonogashira reactions,
including the development of conditions with metals other than
palladium3 and a copper-free protocol4 have been described. Of
the variety of reactions that fall in this category, the preparation
of conjugated enyne, and enediyne systems as well as heterocycles
represent a great area of investigation.5 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 structurally complex metabolites
present in the structure of several biologically interesting com-
pounds. In particular, 2H-benzopyrans are present in a variety of
compounds that possess important pharmaceutical and biological
applications, such as daurichromenic acid that exhibits anti-HIV
activity,6 and coutareagenin that is known to present antidiabetic
property.7 To the best of our knowledge, there is no protocol
describing the introduction of alkyne and chalcogen at 3 and 4-
positions of benzopyran, respectively, using 3-iodo-4-chalcogen-
2H-benzopyrans as a substrate in the Sonogashira cross-coupling.
The applicability of the selectivity of these two functionalities
can constitute as a synthetic approach to the preparation of biolog-
ical active benzopyran compounds. Combining the knowledge that
our group has accumulated in the synthesis of heterocycles con-
taining a chalcogen8 with the opportunity for further functionali-
zation in these compounds, herein we suggest an entirely new
approach that focuses on the application of 3-iodo-4-chalcogen-
2H-benzopyrans 1a–c as substrates in the Sonogashira cross-cou-
pling to give 3-alkynyl-4-chalcogen-2H-benzopyrans (Scheme 1).
Initially, to optimize the reaction conditions, we examined the
reaction between 3-iodo-4-(1-buthylselenyl)-2H-benzopyran 1a9
and phenyl acetylene 2a in the presence of a variety of Pd(II) or
Pd(0) catalysts with various solvents, using bases and CuI
(1.5 mol %).
A comparison of the effectiveness of catalysts showed that
Pd(PPh3)2Cl2 and Pd(PPh3)4 were effective (Table1, entries 1 and
5), whereas Pd(PhCN)2Cl2, PdCl2, and Pd(OAc)2 were less active (Ta-
ble1, entries 2–4). It is important to note that when the amount of
catalyst was reduced from 2 to 0.5 mol % there was no change in
the catalytic effect (Table 1, entries 7 and 8). However when the
reaction was carried out in the absence of CuI the coupling product
was not observed (Table 1, entry 9). In addition to using Et3N as
base and solvent, we tried other solvents and bases. The reaction
* Corresponding author. Tel.: +55 55 3220 9611; fax: +55 55 3220 8978.
E-mail address: gzeni@pq.cnpq.br (G. Zeni).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.058

A. Sperança et al. / Tetrahedron Letters 51 (2010) 36–39
37
O
O
R
Pd(PPh3)2Cl2 (1mol%)
R
R2
H
+
I
CuI (1.5 mol%), Et3N, r.t.
2a-i
3a-u
1a-c
YR1
YR1
R2
Y = S, Se; R = Me, naphthyl; R1 = Me, butyl; R2 =alkyl, aryl, alcohol, ether
Scheme 1.
Table 1
in dioxane and DMF formed not only 3a in 45% and 32% yields,
respectively, but also side products, while in that reaction involv-
ing MeOH and CH3CN, 3a was found almost exclusively (Table 1,
entries 10–13). Replacement of Et3N with other bases such as pirr-
olidyne, Cs2CO3, NaOH, and K2CO3 went equally well or worse (Ta-
ble 1, entries 14–17).
Influence of reaction conditions on the formation of 3-alkynyl-4-chalcogen-2H-
benzopyran 3a
O
O
[Pd], CuI (1.5mol%)
Et3N, r.t., 24 h
Ph
H
+
I
2a
1a
3a
SeBu
SeBu
Ph
Good to excellent yields could be obtained from the Sonogash-
ira coupling reactions across a wide range of alkynes and 3-iodo-4-
chalcogen-2H-benzopyran derivatives using the established reac-
tion conditions10 (Table 2).
S. No.
[Pd] (mol %)
Solvent (mL)
Base (equiv)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PdCl2(PPh3)2 (2)
PdCl2(PhCN)2 (2)
PdCl2 (2)
Pd(Oac)2 (2)
Pd(PPh3)4 (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
—
—
—
—
—
—
—
—
—
Et3N
Et3N
Et3N
99
49
54
67
87
—
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 terminal alkynes, we keep the chalcogen-2H-benz-
opyran 1a invariable. The cross-coupling worked well with respect
to alkynes having aryl, aryl substituted and alkyl groups (Table 2,
entries 1–4). Both hindered and nonhindered propargyl alcohols
gave the desired 3-alkynyl-4-2H-benzopyrans in moderated to
good yields (Table 2, entries 5–9). In an attempt to broaden the
scope of our methodology, the possibility of performing the reac-
tion with other 3-iodo-4-chalcogen-2H-benzopyrans was also
investigated. Then the substrates 1b and 1c, which have a methyl-
thio group in the 4-position of the benzopyran ring, were also
cross-coupled efficiently, under the same reaction conditions (Ta-
ble 2, entries 10–21).
—
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (0.5)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
PdCl2(PPh3)2 (1)
98
97
b
Et3N (2)
—
Dioxane (1.5)
MeOH (1.5)
CH3CN (1.5)
DMF (1.5)
MeOH (2)
MeOH (2)
MeOH (2)
MeOH (2)
45
95
86
32
60
95
76
83
Et3N
Pirrolidyne (2)
Cs2CO3 (2)
NaOH (2)
K2CO3 (2)
a
Yields are given by GC analysis.
Reaction was performed in the absence of CuI.
b
Table 2
Synthesis of 3-alkynyl-4-chalcogen-2H-benzopyrans 3a–ua
O
O
R
R
Pd(PPh3)2Cl2 (1mol%)
R2
H
+
I
CuI (1.5 mol%)
Et3N (2 mL)
r.t.
2a-k
YR1
YR1
R2
3a-u
1a-c
S. No.
Substrate
Alkyne (equiv)
Product yieldb (%)/time
O
O
1
I
BuSe
2a (1.2)
SeBu
3a (99)/12h
1a
C6H5
2
1a
R2 = C6H4-Me-p
3b (57)/12 h
2b (1.2)
2c (3)
3
4
1a
1a
R2 = n-Bu
3c (55)/12 h
R2 = t-Bu
3d (60)/10 h
2d (1.2)
(continued on next page)

38
A. Sperança et al. / Tetrahedron Letters 51 (2010) 36–39
Table 2 (continued)
S. No.
Substrate
Alkyne (equiv)
Product yieldb (%)/time
5
1a
R2 = CH2OH
OH
3e (52)/14 h
2e (3)
OH
6
7
1a
1a
R2 = (CH2)2OH
3f (47)/14 h
2f (3)
OH
R2 = C(CH3)2OH
3g (73)/13 h
2g (1.2)
8
9
1a
1a
R2 = C(CH2)OHCH2CH3
3h (33)/13 h
OH
2h (3)
R2 = OH-c-C6H10
3u (91)/15 h
OH
2i (1.2)
O
O
10
2a (1.2)
I
MeS
SMe
3j (83)/12h
1b
C6H5
11
12
13
1b
1b
1b
2c (3)
2e (3)
2f (3)
R2 = n-Bu
3k (82)/16 h
R
2 = CH2OH
3l (72)/15 h
R
2 = (CH2)2OH
3m (81)/16 h
OH
14
15
1b
1b
R2 = (CH2)4OH
3n (71)/15 h
2j (3)
2g (3)
R
2 = C(CH3)2OH
3o (82)/16 h
O
16
1b
R2 = CH2O-tolyl-p
3p (75)/15 h
2k
O
O
17
18
2a (1.2)
I
MeS
SMe
1c
3q (85)/14h
C6H5
1c
2c (3)
R2 = n-Bu
3r (80)/15 h

A. Sperança et al. / Tetrahedron Letters 51 (2010) 36–39
39
Table 2 (continued)
S. No.
Substrate
Alkyne (equiv)
Product yieldb (%)/time
19
20
21
1c
1c
1c
2e (3)
2f (3)
2g (3)
R
2 = CH2OH
3s (67)/15 h
2 = (CH2)2OH
3t (84)/16 h
2 = C(CH3)2OH
3u (91)/15 h
R
R
a
Reactions were performed by using 1a–c (0.25 mmol), alkyne a–k, Pd(PPh3)2Cl2 (1 mol %), and CuI (1.5 mol %) in Et3N (2 mL), under room temperature.
Yields of 3a–u are given for isolated products.
b
2. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467; (b)
Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627;
For a review, see: (c) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
3. Wang, L.; Li, P.; Zhang, Y. Chem. Commun. 2004, 514.
4. (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39,
2632; (b) Soheili, A.; Albaneze-Wlker, J.; Murry, J.; Dormer, P.; Hughes, D. Org.
Lett. 2003, 5, 4191.
5. (a) Vicente, J.; Abad, J. A.; Lopez-Serrano, J.; Jones, P. G.; Najera, C.; Botella-
Segura, L. Organometallics 2005, 24, 5044; (b) Chinchilla, R.; Najera, C.; Yus, M.
Chem. Rev. 2004, 104, 2667; (c) Bellina, F.; Falchi, E.; Rossi, R. Tetrahedron 2003,
59, 9091; (d) Biagetti, M.; Bellina, F.; Carpita, A.; Rossi, R. Tetrahedron Lett. 2003,
44, 607; (e) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L. Tetrahedron
2003, 59, 2067.
OH
O
O
TeBu
BuTeTeBu, NaBH4
EtOH, reflux, 6h
SMe
4o (55%)
SMe
OH
3o
Scheme 2.
6. (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.
7. Korec, R.; Sensch, K. H.; Zoukas, T. Arzneim. Forsch. 2000, 50, 122.
8. (a) Alves, D.; Luchese, C.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2007, 72, 6726; (b)
Stein, A. L.; Alves, D.; Rocha, J. T.; Nogueira, C. W.; Zeni, G. Org. Lett. 2008, 10, 4983.
9. (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72,
1347; (b) The best condition for the I2 cyclization reactions was the addition of
We believe that this approach to 3-alkynyl-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. In view of this,
the potential of these products as precursors for increasing molec-
ular complexity via hydrotelluration reaction has been briefly
investigated.11 For example, the compound 3o was reacted with
BuTeTeBu and NaBH4 in ethanol under reflux temperature for
6 h, affording, the corresponding vinylic telluride 4o, in 55% yield
(Scheme 2). Vinyl tellurides are useful intermediates in organic
synthesis,12 including the synthesis of natural products by using
cross-coupling reactions.13
We have described that 3-iodo-4-chalcogen-2H-benzopyrans
were versatile units for the Sonogashira cross-coupling in the prep-
aration of 3-alkynyl-4-chalcogen-2H-benzopyrans. This cross-cou-
pling reaction proceeded cleanly under mild conditions and was
performed with propargylic alcohols, propargylic ethers, as well
as alkyl and aryl alkynes. The product obtained was effective for
subsequent hydrotelluration reaction at triple bond giving the
vinylic telluride in moderate yield. The studies in the structure–
activity relationship and pharmacological activity of these com-
pounds are in progress and will appear in a specialized journal
soon.
NaHCO3 (0.5 mmol), at room temperature, to
a solution of 0.25 mmol of
selenophenyl propargyl aryl ethers in 3 mL of THF. After that, 3 equiv of I2 in
2 mL of THF was gradually added at room temperature. The reaction mixture
was allowed to stir at room temperature for 1 h
O
O
I2 (3 equiv), NaHCO3 (2 equiv)
THF, r. t.
R
R
I
SeR1
SeR1
10. General procedure for the cross-coupling reaction: To a Schlenck tube, under
argon, containing an appropriate 3-iodo-4-chalcogen-2H-benzopyran
(0.25 mmol) in Et3
N
(1.5 mL) was added Pd(PPh3)2Cl2 (0.0017 g,
0.0025 mmol). The resulting solution was stirred for 5 min at room
temperature. After this time the CuI (0.0007 g, 0.0036 mmol) was added and
the solution was stirred for an additional 20 min. After that, appropriate
terminal alkyne (0.3 mmol) dissolved in 0.5 mL of Et3N was then added
dropwise, and the reaction mixture was stirred at room temperature for the
required time. After this the mixture was diluted with dichloromethane
(20 mL), and washed with brine (3 Â 20 mL). The organic phase was separated,
dried over MgSO4, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel using ethyl acetate/hexane as the eluent.
Selected spectral and analytical data for: 3-p-tolylethynyl-6-methyl-4-
butylselenyl-2H-benzopyran (3b). Yield: 0.056 g (57%). 1H NMR: (CDCl3,
400 MHz) d (ppm): 7.50 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz,
2H), 6.96–6.94 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.73 (s, 2H), 2.91 (t, J = 7.1 Hz,
2H), 2.36 (s, 3H), 2.31 (s, 3H), 1.66 (quint, J = 7.3 Hz, 2H), 1.41 (sext, J = 7.3 Hz,
2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR: (CDCl3, 100 MHz), d (ppm): 151.6, 138.8,
131.3, 131.1, 130.2, 129.9, 129.1, 128.7, 123.9, 121.2, 120.0, 115.8, 98.8, 68.6,
32.3, 27.9, 22.7, 21.5, 20.7, 13.5. MS (EI, 70 eV) m/z (relative intensity): 395 (6),
392 (64), 335 (85), 256 (100), 212 (26), 187 (4), 114 (13), 57 (2). Anal. Calcd for
C23H24OSe: C, 69.65; H, 5.93. Found: C, 69.87; H, 6.12.
Acknowledgments
We are grateful to CNPq/INCT-catalise, CAPES (SAUX), and FA-
PERGS, for financial support. CNPq is also acknowledged for the fel-
lowships (to G.Z. and B.G.).
References and notes
11. Comasseto, J. V.; Barrientos-Astigarraga, R. E. Aldrichim. Acta 2000, 33, 66.
12. (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.
13. Zeni, G.; Panatieri, R. B.; Lissner, E.; Menezes, P. H.; Braga, A. L.; Stefani, H. A.
Org. Lett. 2001, 3, 819.
1. (a) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48, 2452; (b) Miyaura,
N. Cross-Coupling Reactions.
A Practical Guide; Springer: Berlin, 2002; (c)
Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 1998.