Synthesis of 3-aryl-4-chalcogen-2H-benzopyrans from 3-iodo-4-chalcogen-2H-benzopyrans using a Suzuki cross-coupling

Article abstract of DOI:10.1016/j.tetlet.2009.07.008

The Suzuki cross-coupling reaction of 3-iodo-4-chalcogen-2H-benzopyran derivatives with a variety of organoboron compounds in the presence of catalytic amount of palladium salt is described. This cross-coupling reaction proceeded cleanly and was performed

Full text of DOI:10.1016/j.tetlet.2009.07.008

Tetrahedron Letters 50 (2009) 5326–5328
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Synthesis of 3-aryl-4-chalcogen-2H-benzopyrans from
3-iodo-4-chalcogen-2H-benzopyrans using a Suzuki cross-coupling
*
Benhur Godoi, José S. S. Neto, Adriane Sperança, Carmine Ines Acker, Cristina W. Nogueira, 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:
The Suzuki cross-coupling reaction of 3-iodo-4-chalcogen-2H-benzopyran derivatives with a variety of
organoboron compounds in the presence of catalytic amount of palladium salt is described. This cross-
coupling reaction proceeded cleanly and was performed with aryl boronic acids bearing electron-with-
drawing, electron-donating, and neutral substituents, furnishing the corresponding products in moderate
to good yields.
Received 20 April 2009
Revised 30 June 2009
Accepted 1 July 2009
Available online 8 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The synthesis of heterocycles has attracted much attention in
recent years due to their interesting biological properties.1 Substi-
tuted six-membered oxygenated heterocycles or pyrans play key
pharmacophore functions in many pharmaceuticals.2 In addition
to the diverse biological activity of the naturally occurring com-
pounds, synthetically derived benzopyrans also exhibit significant
bioactivity.3
The most used strategies for the synthesis of multiple substi-
tuted 2H-benzopyran involve: (a) the construction of the 2H-benz-
opyran nucleus after the substituents have been installed and
properly functionalized; (b) a preformed 2H-benzopyran to which
carbon substituents are attached in successive order.
In connection with a project directed at the preparation of novel
3,4-disubstituted benzopyran derivatives, we reasoned that 3-
iodo-4-chalcogen-2H-benzopyran 1, easily prepared from organ-
ochalcogen propargyl aryl ethers, via electrophilic cyclization pro-
tocol,4 could become a valuable starting material on Suzuki cross-
coupling reactions (Scheme 1).
Suzuki cross-coupling reactions of various heteroaryl deriva-
tives have been well documented.5 However, the application of
this protocol to 3-iodo-4-chalcogen-2H-benzopyran remains lar-
gely unexplored,6 consequently it is necessary to design a simple,
efficient, and versatile method for the construction of benzopyran
rings having two different groups at 3- and 4-positions.
For preliminary optimization of the cross-coupling reaction
conditions, 3-iodo-6-methyl-4-(1-butylselenyl)-2H-benzopyran 1a
and phenylboronic acid 2a were chosen as standard substrates.
Thus, the reaction of 1a (0.25 mmol) and arylboronic acid 2a
(0.5 mmol) was performed under 60 °C, using different palladium
catalysts, solvents, and bases (Table 1).
Pd(PPh3)2Cl2 10 mol % which gave the desired product 3a in 91%
yield (Table 1; entry 1). It is important to note that when the
amount of catalyst was reduced from 10 to 5 mol %, an increase
in the yield was observed and the product 3a was obtained quan-
titatively (Table 1, entry 8). However, using less than 5 mol % of
Pd(PPh3)2Cl2 a decrease in the yield of the coupling product was
observed. Our experiments also showed that in the absence of cat-
alysts the formation of the product was not detected, in this case
the starting material was recovered (Table 1, entry 7).
Regarding the influence of the solvent, the best results were
achieved using a mixture of DMF/H2O, which furnished the desired
product 3a in 99% yield (Table 1, entry 8). By using DMSO, MeOH,
dioxane, hexane, and THF moderate to good yields were also ob-
tained (Table 1, entries 9–13). The presence of base was crucial
for a clean, high-yielding reaction. For this reason, in our experi-
ments we investigated the influence of organic and inorganic
bases. As listed in Table 1, when the reaction was carried out using
K3PO4, Cs2CO3, NaOH, and pyrrolidine the target product was ob-
tained in moderate yields (Table 1, entries 15–18). The best result
was obtained using K2CO3, which gave the desired product 3a in
99% yield (Table 1, entry 8). When the amount of K2CO3 was re-
duced from 2 to 1 equiv a significant decrease in the yield was ob-
served (Table 1, entry 20). When the Suzuki reaction was carried
out in the absence of base the coupling product was not obtained
(Table 1, entry 19). Careful analysis of the optimized reactions re-
vealed that the optimum conditions for this coupling reaction were
the use of Pd(PPh3)2Cl2 (5 mol %), 3-iodo-6-methyl-4-(1-butylsele-
nyl)-2H-benzopyran 1a (0.25 mmol), phenylboronic acid 2a
O
O
Pd(PPh3)2Cl2 (5 mol%),
K2CO3/H2O, DMF, 60 ºC
R
R
+
ArB(OH)2
As shown in Table 1, both Pd(0) and Pd(II) catalysts with differ-
ent ligands were tested, the best result was obtained using
I
Ar
2a-j
3a-p
1a-c
SeR1
SeR1
(30-99%)
* Corresponding author.
E-mail address: gzeni@pq.cnpq.br (G. Zeni).
Scheme 1. General scheme.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.008

B. Godoi et al. / Tetrahedron Letters 50 (2009) 5326–5328
5327
Table 1
Table 2
Optimization of reaction conditions for the formation of 3a
Palladium-catalyzed formation of 3-aryl-4-chalcogen-2H-benzopyrans 3a–p
O
O
O
O
Pd(PPh3)2Cl2 (5 mol%)
K2CO3 (2 equiv)/H2O (1 mL)
DMF, 60 ºC
[Pd], base/H2O
R
R
+
R2B(OH)2
+
PhB(OH)2
solvent, 60 ºC, 6h
R2
I
I
Ph
2a
2a-j
(2 equiv)
1a
3a
SeR1
YR1
3a-p
SeBu
SeBu
1a-c
(0.25 mmol)
#
[Pd] (mol %)
Solvent
Base (equiv)
Yielda (%)
#
Substrate
Organoboron
Product yield (%)a/time
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
PdCl2(PPh3)2 (10)
PdCl2(PhCN)2 (10)
PdCl2 (10)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Dioxane
MeOH
THF
Hexane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K3PO4 (2)
Cs2CO3 (2)
NaOH (2)
91
83
71
73
71
86
—
>99
69
51
80
72
96
16b
80
48
64
21
—
O
O
Pd(Oac)2 (10)
B(OH)2
Pd(acac)2 (10)
Pd(PPh3)4 (10)
—
1
I
SeBu
2a
SeBu
1a
3a (99)/1.5h
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
O
B(OH)2
2
3
4
5
6
7
8
9
1a
SeBu
2b
3b (73)/1.5h
O
Pyrrolidine (2)
—
K2CO3 (1)
K2CO3 (2)
MeO
B(OH)2
43
1a
1a
1a
1a
1a
1a
1a
23c
SeBu
2c
OMe
CF3
a
3c (64)/2h
Yields are given by GC analysis.
Reaction carried out in the absence of water.
Reaction carried out under room temperature.
b
c
O
B(OH)2
(2 equiv) in DMF (5.0 mL), and H2O (1.0 mL) at room temperature.
After that, the base K2CO3 (2 equiv) was added and the mixture
was heated at 60 °C for 6 h. Using this reaction condition we were
able to prepare 3-aryl-4-chalcogen-2H-benzopyran 3a in quantita-
tive yield. In order to demonstrate the efficiency of this protocol,
we explored the generality of our method extending the conditions
to other 3-iodo-4-chalcogen-2H-benzopyran compounds 1a–c
with different arylboronic acids 2a–j and the results are summa-
rized in Table 2.7
First, to determine the real influence of the substituent at aro-
matic ring of boronic acids, we kept the substrate 1a invariable.
The results revealed that the reaction is not sensitive to the elec-
tronic effect of the aromatic ring attached in the boron atom. For
example, arylboronic acid bearing an electron-donating group
methoxyl at the para position gave a very similar yield than the
arylboronic acid bearing an electron-withdrawing group CF3 (Table
2; entry 3 vs entry 4). Differentiation in the reactivity between hal-
ogen and boron atoms can be seen by coupling shown in the exper-
iments described in table 1, entries 8 and 9, which provide only the
Suzuki product, without any homo-coupling product. To the best of
our knowledge, aryl halogen could react with boronic acids in the
presence of palladium catalysts to afford biaryl products.8 In our
case, the halogen substituent was not affected. In an attempt to
broaden the scope of our methodology, the possibility of perform-
ing the reaction with other 3-iodo-4-chalcogen-2H-benzopyran
was also investigated. Then the substrates 1b and 1c, which have
a selenophenyl group in the 4-position of the benzopyran ring,
were also cross-coupled efficiently, under the same reaction condi-
tions (Table 2; entries 12–16).
SeBu
F3C
2d
2e
3d (65)/3h
O
B(OH)2
NO2
SeBu
O2N
3e (74)/3h
O
B(OH)2
O
SeBu
O
2f
3f (70)/2h
O
O
B(OH)2
SeBu
O
2g
3g (77)/2h
O
Br
B(OH)2
SeBu
2h
2i
Br
Cl
3h (96)/2h
More recently, significant advances have been made in the use
of organoboron reagents as coupling partners in a number of palla-
dium-mediated carbon–carbon bond formations. Among them, the
use of potassium organotrifluoroborates, as the organoboron cou-
pling 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.9
O
Cl
B(OH)2
SeBu
3i (93)/2h
(continued on next page)

5328
B. Godoi et al. / Tetrahedron Letters 50 (2009) 5326–5328
Table 2 (continued)
Acknowledgments
#
Substrate
Organoboron
Product yield (%)a/time
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.).
O
10
1a
B(OH)2
SeBu
References and notes
2j
3j (85)/2h
1. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (b) Arcadi, A.; Cacchi, S.; Di
Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409; (c) Masters, K. S.;
Flynn, B. L. J. Org. Chem. 2008, 73, 8081; (d) Halim, R.; Scarnmells, P. J.; Flynn, B.
L. Org. Lett. 2008, 10, 1967; (e) Bui, C. T.; Flynn, B. L. J. Comb. Chem. 2006, 8, 163;
(f) Sebille, S.; Gall, D.; de Tullio, P.; Florence, X.; Lebrun, P.; Pirotte, B. J. Med.
Chem. 2006, 49, 4690; (g) Madrid, P. B.; Liou, A. P.; DeRisi, J. L.; Guy, R. K. J. Med.
Chem. 2006, 49, 4535; (h) Heinrich, T.; Böttcher, H.; Schiemann, K.; Holzemann,
G.; Schwarz, M.; Bartoszyk, G. D.; Amsterdam, C.; Greiner, H. E.; Seyfried, C. A.
Bioorg. Med. Chem. 2004, 12, 4843; (i) Tang, L.; Yu, J.; Leng, Y.; Feng, Y.; Yang, Y.;
Ji, R. Bioorg. Med. Chem. Lett. 2003, 13, 3437.
2. (a) Jin, Z.; Kang, Y. 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.
3. Korec, R.; Sensch, K. H.; Zoukas, T. Arzneim. Forsch. 2000, 50, 122.
4. (a) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72,
1347; (b) Godoi, B.; Speranca, A.; Back, D. F.; Brandao, R.; Nogueira, C. W.; Zeni,
G. J. Org. Chem. 2009, 74, 3469; (c) The best 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 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
S
11
12
13
1a
BF3K
S
SeBu
3k (48)b/2h
2k
O
O
I
2a
SePh
SePh
3l (82)/1.5h
1b
O
CF3
1b
2d
2j
SePh
3m (55)/6h
O
14
15
1b
O
O
SePh
I2 (3 equiv), NaHCO3 (2 equiv)
THF, r. t.
R
R
3n (30)/6h
I
SeR1
SeR1
O
O
5. (a) Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (b)Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; (c)Metal-Catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; (d)Cross-coupling
Reactions: A Practical Guide; Miyaura, N., Ed.Topics in Current Chemistry Series
219; Springer: New York, 2002; (e) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
2a
I
SePh
SePh
1c
3o (70)/2h
6. Frigoli, M.; Moustrou, C.; Samat, A.; Guglielmetti, R. Eur. J. Org. Chem. 2003,
2799.
O
7. General procedure for the cross-coupling reaction: To a solution of appropriate
3-iodo-4-chalcogen-2H-benzopyran (0.25 mmol) in DMF (5 mL) were added the
Pd(PPh3)2Cl2 (0.003 g, 5 mol %) and boronic acid (0.5 mmol) under argon. The
resulting solution was stirred for 30 min at room temperature. After this time, a
solution of K2CO3 (0.5 mmol, 0.254 g) in H2O (1 mL) was added. The mixture was
then heated at 60 °C for the time indicated in Table 2, cooled to room
temperature, diluted with dichloromethane (20 mL), and washed with brine
(2 Â 20 mL). The organic phase was separated, dried over MgSO4, and
concentrated under vacuum. The residue was purified by flash chromato-
graphy. Selected spectral and analytical data for 3-phenyl-6-methyl-4-
butylselenyl-2H-benzopyran (6a): Yield: 0.087 g (99%). 1H NMR: CDCl3,
400 MHz, d (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, d
(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.
16
1c
2d
CF3
SePh
3p (55)/2h
a
Yields are given for isolated products.
Reaction carried out at 100 °C.
b
In this way, substrate 1a underwent palladium cross-coupling
with thienyl trifluoroborates furnishing the corresponding 3-thie-
nyl-4-butylselenyl-2H-benzopyran 3k in moderate yield (Table 2,
entry 11).
In summary, we have explored the Suzuki cross-coupling reac-
tion of arylboronic acids with 3-iodo-4-chalcogen-2H-benzopyran
derivatives using a catalytic amount of PdCl2(PPh3)2. The reaction
proceeded cleanly under mild reaction conditions, short reaction
time, and was performed with aryl boronic acids bearing elec-
tron-withdrawing, electron-donating, and neutral substituents. It
is important to point out that this route permits an easy and effi-
cient access to highly substituted benzopyran. The pharmacologi-
cal activity of these compounds is in progress and will appear in
a specialized journal soon.
8. (a) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005, 7, 2101; (b) LeBlond, C. R.;
Andrews, A. T.; Sowa, J. R.; Sun, Y. Org. Lett. 2001, 3, 1555.
9. (a) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74, 973; (b)
Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275; (c) Molander, G. A.;
Petrillo, D. E.; Landzberg, N. R.; Rohanna, J. C.; Biolatto, B. Synlett 2005, 1763;
(d) Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49; (e) Molander, G.
A.; Felix, L. A. J. Org. Chem. 2005, 70, 3950; (f) Molander, G. A.; Yun, C. S.;
Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534; (g) Molander, G. A.;
Biolatto, B. J. Org. Chem. 2003, 68, 4302; (h) Molander, G. A.; Katona, B. W.;
Machrouhi, F. J. Org. Chem. 2002, 67, 8416; (i) Molander, G. A.; Reviro, M. R.
Org. Lett. 2002, 4, 107.