Synthesis of 2-(2-arylethenyl)-5-arylfurans by regioselective palladium(0)-catalyzed coupling reactions of 2-(2-bromo-2-nitroethenyl)-5- bromofuran

Article abstract of DOI:10.1055/s-2006-950271

The Suzuki reaction of 2-(2-bromo-2-nitroethenyl)-5-bromofuran, readily available from furfural, resulted in regioselective attack onto the furan moiety. The alkenyl moiety could be functionalized in a second Suzuki reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950271

2812
LETTER
Synthesis of 2-(2-Arylethenyl)-5-arylfurans by Regioselective Palladium(0)-
Catalyzed Coupling Reactions of 2-(2-Bromo-2-nitroethenyl)-5-bromofuran
S
ynthesisof 2-(2-A
a
rylethenyl
n
)-5-arylfuran
g
s
Thanh Tuan,a,b Dang Thanh Tung,a Peter Langer*a,c
a
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Institut für Biochemie, Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 23 August 2006
and subsequent bromination (Scheme 2).13 It has been
shown that compound 3 possesses interesting biological
activity and its derivatization is, therefore, of considerable
interest.13e Furfural represents an inexpensive, green start-
ing material which is produced in large scale by acid-me-
diated hydrolysis of plant-derived polysaccharides
(sustainable development).
Abstract: The Suzuki reaction of 2-(2-bromo-2-nitroethenyl)-5-
bromofuran, readily available from furfural, resulted in regioselec-
tive attack onto the furan moiety. The alkenyl moiety could be func-
tionalized in a second Suzuki reaction.
Key words: catalysis, furans, green chemistry, heterocycles, palla-
dium, regioselectivity
O
CHO
Furans are of considerable pharmacological relevance and
occur in a variety of natural products.1,2 A number of syn-
thetic approaches to furans have been reported.2–9 Bach
and coworkers reported an interesting approach to 2,3-di-
substituted furans by regioselective palladium(0)-cata-
lyzed coupling reactions of 2,3-dibromofurans.10 The
success of these transformations relies on the fact that the
oxidative addition of the palladium(0) complex onto car-
bon atom C-2 of the furan is faster than onto C-3
(Scheme 1).11 Herein, we wish to report what are, to the
best of our knowledge, the first regioselective palladi-
um(0)-catalyzed coupling reactions of 2-(2-bromoalke-
nyl)-5-bromofurans which contain both a furyl and an
alkenyl bromide function (Scheme 1). These reactions
should be of considerable interest, since the starting mate-
rials are readily available and the products are pharmaco-
logically relevant and represent useful intermediates for
further synthetic transformations (e.g. electrocyclic ring-
closure reactions).12
Biomass
1
i
O
O
ii
Br
NO2
NO2
Br
3
2
Scheme 2 Synthesis of (Z)-2-(2-bromo-2-nitroethenyl)-5-bromo-
furan (3). Reagents and conditions: i, CH3NO2, NaOH, H2O; i, 1) Br2,
AcOH; 2) pyridine.
The Suzuki reaction of 3 (1.2 equiv) with various boronic
acids (1.0 equiv) resulted in regioselective coupling of the
furan rather than the alkenyl moiety to give the 2-(2-bro-
mo-2-nitroethenyl)-5-arylfurans 4a–i (Scheme 3).14 The
reaction proceeded without E/Z-isomerization of the dou-
1st attack
O
O
O
O
Ar1
Ar1 B(OH)2
Br
Br
Br
NO2
NO2
i
Br
Br
Br
nd attack
Br
st attack
3
4a–i
1
2
2nd attack
Ar1 B(OH)2
ii
Ar2 B(OH)2
iii
Scheme 1 Regioselectivity of palladium(0)-catalyzed coupling re-
actions.
O
Ar1
O
Ar1
NO2
NO2
Ar2
Ar1
As a starting point for our studies we chose (Z)-2-(2-bro-
mo-2-nitroethenyl)-5-bromofuran (3) which is readily
5a–g
6a–e
available by Henry reaction of furfural with nitromethane Scheme 3 Suzuki reactions of 3. Reagents and conditions: i, 3 (1.2
equiv), Ar1B(OH)2 (1.0 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (2.0
equiv), solvent (see Table 1); ii, 3 (1.0 equiv), Ar1B(OH)2 (2.0 equiv),
Pd(PPh3)4 (5 mol%), K3PO4 (4.0 equiv), solvent (see Table 2); iii, 4a–
i (1.0 equiv), Ar2B(OH)2 (1.0 equiv), Pd(PPh3)4 (3 mol%), K3PO4 (2.0
equiv), solvent (see Table 3).
SYNLETT 2006, No. 17, pp 2812–2814
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950271; Art ID: D20906ST
1
7
.1
0
.2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-(2-Arylethenyl)-5-arylfurans
2813
Table 1 Synthesis of 2-(2-Bromo-2-nitroethenyl)-5-arylfurans 4a–i
Entry
4
a
a
a
a
a
b
b
b
c
d
d
e
f
Ar1
Solvent–H2O (6:1)
Temp (°C)
90
Yield of 4 (%)a
1
Ph
Toluene
90
76
73
70
78
83
69
38
64
93
56
67
52
75
77
87
84
2
Ph
Toluene
20
3
Ph
THF
20
4
Ph
1,4-Dioxaneb
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
90
5
Ph
90
6
4-(HO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
3,5-Me2C6H3
3,5-Me2C6H3
4-(EtO)C6H4
1-Naphthyl
1-Naphthyl
3,4,5-(MeO)3C6H2
2-Thienyl
4-MeC6H4
90
7
90
8
90
9
1,4-Dioxane
Toluene
90
10
90
11
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
90
12
90
13
90
14
f
90
15
g
h
i
1,4-Dioxane
1,4-Dioxane
Toluene
90
16
90
17
90
a Isolated yields.
b Without addition of H2O.
ble bond. The structure and configuration of the products equiv) with various arylboronic acids (1.0 equiv) allowed
was proved by spectroscopic methods and by X-ray crys- the synthesis of 2-(2-aryl-2-nitroethenyl)-5-phenylfurans
tal structure analyses. During the optimization, the sto- 6a–e, which contain two different aryl groups (Table 3).
ichiometry, temperature, solvent, and the presence of The formation of 5a–g and 6a–e proceeded, as expected
water played an important role (Table 1). The reaction of for Suzuki reactions, without E/Z-isomerization of the
3 (1.0 equiv) with 2.0 equivalents of boronic acids result- double bond.
ed in double coupling and formation of the 2-(2-aryl-2-ni-
troethenyl)-5-arylfurans 5a–g containing two identical
aryl groups (Table 2). The Suzuki reaction of 4a (1.0
Acknowledgment
We thank Prof. Nilo Castañedo for a gift of compound 3. Financial
support by the state of Vietnam (MOET scholarship for Dang
Thanh Tuan and Dang Thanh Tung) is gratefully acknowledged.
Table 2 Synthesis of 2-(2-Aryl-2-nitroethenyl)-5-arylfurans 5a–g
5
a
b
c
d
e
f
Ar1
Solvent–H2O (6:1) Yield of 5 (%)a
Table 3 Synthesis of 2-(2-Aryl-2-nitroethenyl)-5-arylfurans 6a–e
Ph
Toluene
67
69
64
86
87
82
42
6
Ar1
Ar2
Solvent–H2O
(6:1)
Yield of 6
(%)a
4-(MeO)C6H4
2-(MeO)C6H4
3,5-Me2C6H3
4-(EtO)C6H4
4-MeC6H4
2-Thienyl
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
a
b
c
Ph
Ph
Ph
Ph
Ph
1-Naphthyl
3,5-Me2C6H3
4-MeC6H4
Toluene
63
74
79
75
57
Toluene
Toluene
d
4-(MeO)C6H4
2-Thienyl
1,4-Dioxane
Toluene
Toluene
e
g
1,4-Dioxane
a Isolated yields (all reactions were carried out at 90 °C).
a Isolated yields (all reactions were carried out at 90 °C).
Synlett 2006, No. 17, 2812–2814 © Thieme Stuttgart · New York

2814
D. T. Tuan et al.
LETTER
(9) For furan syntheses from our laboratory, see: (a) Bellur, E.;
Langer, P. J. Org. Chem. 2005, 70, 10013. (b) Bellur, E.;
Görls, H.; Langer, P. Eur. J. Org. Chem. 2005, 2074.
(c) Holtz, E.; Langer, P. Synlett 2004, 1805.
(10) Bach, T.; Krüger, L. Eur. J. Org. Chem. 1999, 2045.
(11) For a review of regioselective cross-coupling reactions of
poly-halogenated heterocycles, see: Schröter, S.; Stock, C.;
Bach, T. Tetrahedron 2005, 61, 2245.
(12) For example, see: Samori, S.; Hara, M.; Ho, T.-I.; Tojo, S.;
Kawai, K.; Endo, M.; Fujitsuka, M.; Majima, T. J. Org.
Chem. 2005, 70, 2708; and references cited therein.
(13) For the synthesis of 2, see: (a) Mampreian, D. M.; Hoveyda,
A. H. Org. Lett. 2004, 16, 2829. (b) Kinderman, S. S.;
Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H.
E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70,
5519. (c) Mahmood, S. Y.; Lallemand, M.-C.; Sader-
Bakaouni, L.; Charton, O.; Verite, P.; Dufat, H.; Tillequin,
F. Tetrahedron 2004, 60, 5105. For compound 3, see:
(d) Estrada, E.; Gómez, M.; Castañedo, N.; Pérez, C. J. Mol.
Struct. (THEOCHEM) 1999, 468, 193. (e) Gonzalez-Diaz,
H.; Agueero, G.; Cabrera, M. A.; Molina, R.; Santana, L.;
Uriarte, E.; Delogu, G.; Castañedo, N. Bioorg. Med. Chem.
Lett. 2005, 15, 551; and references cited therein.
References and Notes
(1) Römpp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
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Silva, E. D.; de Costa, M. S. L.; Djura, P. J. Aust. J. Chem.
1983, 36, 371. (b) Subba, R. G. S. R.; Ravindranath, B.;
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68, 6810. (f) Schoedel, R.; Spiteller, G. Liebigs Ann. Chem.
1987, 459. (g) Bauer, S.; Spiteller, G. Helv. Chim. Acta
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Kanemasa, S.; Suga, H. Bull. Chem. Soc. Jpn. 1988, 61,
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(m) Previtera, L.; Merola, D.; Monaco, P. Phytochemistry
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(q) Schulz, S.; Steffensky, M.; Roisin, Y. Liebigs Ann. 1996,
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(14) General Procedure for the Synthesis of 2-(2-Bromo-2-
nitroethenyl)-5-arylfurans 4a–i.
To a toluene solution (3 mL) of 3 (0.356 g, 1.2 mmol) was
added Pd(PPh3)4 (0.042 g, 3 mol%) at 20 °C. After stirring
for 30 min, the arylboronic acid (1.0 mmol), K3PO4 (2.0
mmol) and H2O (0.5 mL) were added. The mixture was
stirred at 90 °C for 8 h. After cooling to ambient
temperature, the mixture was diluted with EtOAc, dried
(Na2SO4), and filtered through a short Celite® pad. The
solution was concentrated in vacuo and the residue was
purified by column chromatography (silica gel, n-heptane–
EtOAc = 20:1 to 5:1).
(3) For reviews of furan syntheses, see: (a) Friedrichsen, W. In
Comprehensive Heterocyclic Chemistry, Vol. 2; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier:
Amsterdam, 1996, 359–363; and references cited therein.
(b) König, B. In Science of Synthesis, Vol. 9; Thieme:
Stuttgart, 2001, 183–285.
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Synthesis of 2-[(Z)-2-bromo-2-nitrovinyl]-5-(4-ethoxy-
phenyl)furan (4e).
Starting with 3 (0.356 g, 1.2 mmol) and (4-
ethoxyphenyl)boronic acid (1.0 mmol), 4e was isolated
(0.226 g, 67%) as a red solid; mp 127–128 °C. 1H NMR (300
MHz, CDCl3): d = 1.42 (t, 3J = 7.2 Hz, 3 H, CH3), 4.05 (q,
3J = 7.2 Hz, 2 H, OCH2CH3), 6.76 (d, 3J = 3.8 Hz, 1 H,
furan), 6.92 (d, 3J = 8.7 Hz, 2 H, Ar), 7.38 (d, 3J = 3.8 Hz,
1 H, furan), 6.92 (d, 3J = 8.7 Hz, 2 H, Ar), 8.53 (s, CH).
13C NMR (75 MHz, CDCl3): d = 14.8 (CH2CH3), 63.6
(OCH2CH3), 107.7 (CH), 115.1, 115.1, 126.8, 126.8 (CH,
Ar), 124.2, 124.6 (CH, furan), 122.2, 123.9, 145.7, 159.9,
161.1 (C). IR (KBr): 3432 (m), 3050 (m), 2971 (w), 1603 (s),
1599 (s), 1467 (s), 1280 (s), 1235 (s), 1177 (s), 1035 (s), 964
(s) cm–1. MS (EI, 70 eV): m/z (%) = 339 (30) [M+, 81Br], 337
(31) [M+, 79Br], 258 (100), 227 (10), 212 (23), 184 (37), 183
(29), 155 (17), 131 (22), 77 (8), 69 (11). HRMS (EI, 70 eV):
m/z calcd for C14H12O4NBr [M+, 79Br]: 336.9944; found:
336.9939. All products gave satisfactory spectroscopic data
and correct elemental analyses and/or high-resolution mass
data.
Kanematsu, K. J. Org. Chem. 1993, 58, 3960.
Synlett 2006, No. 17, 2812–2814 © Thieme Stuttgart · New York