Efficient synthesis of 5-nitro-benzo[b]furans via 2-bromo-4-nitro-phenyl acetates

Article abstract of DOI:10.1016/j.tetlet.2010.03.072

Acetylation/Sonogashira cross-coupling reaction/cyclization has been carried out in one-pot using a Na₂PdCl₄/2-(di-tert-butylphosphino)-N-phenylindole/CuI system in TMEDA to give 5-nitro-2-substituted benzo[b]furans in excellent yields. We also describe the extension of this method to 4-EWG-2-bromo-phenols obtaining 2,5-disubstituted-benzo[b]furans in good yields.

Full text of DOI:10.1016/j.tetlet.2010.03.072

Tetrahedron Letters 51 (2010) 2824–2827
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of 5-nitro-benzo[b]furans via
2-bromo-4-nitro-phenyl acetates
*
Antonella Bochicchio, Lucia Chiummiento , Maria Funicello, Maria Teresa Lopardo, Paolo Lupattelli
Dipartimento di Chimica, Università degli Studi della Basilicata, Via N. Sauro, 85, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Acetylation/Sonogashira cross-coupling reaction/cyclization has been carried out in one-pot using a
Na2PdCl4/2-(di-tert-butylphosphino)-N-phenylindole/CuI system in TMEDA to give 5-nitro-2-substituted
benzo[b]furans in excellent yields. We also describe the extension of this method to 4-EWG-2-bromo-
phenols obtaining 2,5-disubstituted-benzo[b]furans in good yields.
Received 11 February 2010
Revised 15 March 2010
Accepted 17 March 2010
Available online 21 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In memoriam of Professor Antonio Mario
Tamburro, great man and tireless scientist
Keywords:
5-Nitro-benzo[b]furans
2-Br-phenyl acetates
Sonogashira reaction
Pd catalyst
Heteroannulation
protection
path b
O2N
I
O2N
I
Benzo[b]furan derivatives are found abundantly in nature and
are well known to possess various biological activities.1–3 Benzo[b]-
furan-based molecules have been also disclosed as the inhibitors of
b-amyloid (Ab) aggregation4 and cyclooxygenase-2 (COX-2).5 Conse-
quently, there is an increasing interest in the synthesis of compounds
containing benzo[b]furan moiety and a number of synthetic methods
for their synthesis have been described in the literature.6
5-Nitro-benzofurans possess antibacterial and anti-cancer
activities and recently have been used as a synthetical precursor
of the new antiarrhythmic agent, dronedarone.7 In connection with
our research for the synthesis of biologically active compounds, we
decided to evaluate a Sonogashira-based process8 to access to 5-ni-
tro-2-substituted-benzo[b]furans. They have been mostly obtained
using Pd-catalyzed reactions: via a one-pot annulation of terminal
alkynes and 2-iodophenols (path a)9 or via cyclization of 2-alkynyl-
phenols, prepared in three steps including O-protection, Sonogash-
ira coupling, and O-deprotecting (path b),10 (Scheme 1).
OP
OH
one-pot
path a
R
1. cross-coupling
2. deprotection
R
annulation
R
O2N
O2N
cyclization
R
O
OH
Scheme 1. General routes to 5-nitro-benzo[b]furans.
Ph
O2N
O2N
Br
+
Na2PdCl4, L,
Ph
2a
OH
OH
CuI, TMEDA,80 °C
1a
3a 0%
Ac2O,
Py, rt
However, to the best of our knowledge, there are no examples
of the synthesis of benzofurans using 2-bromo-4-nitrophenol
derivatives as substrates.
Recently, highly efficient Sonogashira couplings have been ob-
tained on aryl and heteroaryl bromides using 0.5 mol % of Na2PdCl4
in the presence of 1 mol% of 2-(di-tert-butyl phosphino)-N-indole
O2N
Br
O2N
Na PdCl , L,
2a,
2
4
1a
+
Ph
O
OAc
CuI, TMEDA,80 °C
4a
53%
1b
47%
96%
Scheme 2. Reactions of 2-bromo-4-nitrophenol derivatives with phenylacetylene
2a.
as the ligand, with CuI as the co-catalyst and tetramethylethylene-
* Corresponding author. Tel.: +39 0971 202255; fax: +39 0971 202223.
E-mail address: lucia.chiummiento@unibas.it (L. Chiummiento).
diamine (TMEDA) as the solvent at 80 °C.11
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.072

A. Bochicchio et al. / Tetrahedron Letters 51 (2010) 2824–2827
2825
Table 1
Sonogashira coupling of 2-bromo-4-nitrophenyl acetate (1b) with phenylacetylene (2a) under various conditionsa
"Pd", CuI,
solvent, 80°C
O2N
Br
O2N
+
Ph
2a
Ph
O
OAc
1b
4a
Entry
Equiv of 2a
Pd source
Solvent
t (h)
4a Yieldb (%)
1
2
3
4
1.2
4
4
4
1.2
2
Na2PdCl4/L
Na2PdCl4/L
Na2PdCl4/L
PdCl2(PPh3)2
PdCl2(PPh3)2
Na2PdCl4/L
TMEDA
TMEDA
Et3N
TMEDA
Et3N
5
1
7
4
24
8
47
98
98
23
5
Tracec
0c
6d
TMEDA
a
Reactions were carried out with 1b (1 equiv), phenylacetylene 2a, ‘Pd’ (0.5 mol %), ligand (1 mol %), CuI (1 mol %) in solvent (1 M) at 80 °C and were monitored by TLC and
GC–MS analysis.
b
Isolated yield.
Compound 1a was obtained as the product.
Reaction was carried out without CuI.
c
d
Herein we report the first application of the latter conditions for
the synthesis of 5-nitro-2-substituted benzofurans using 2-bromo-
4-nitro-phenol acetates as substrates. Firstly we examined this
reaction protocol on 2-bromo-4-nitrophenol 1a with phenylacety-
lene 2a. However, no reaction occurred (Scheme 2).
This result shows that 1b can indeed afford the coupling prod-
uct, which then undergoes in situ deacetylation followed by het-
eroannulation. The in situ deacetylation of the phenol group can
be ascribed to the presence of the nitro group at the para position
as well as to the basicity of TMEDA. In order to optimize the results
avoiding the competitive deprotection reaction on 1b, we used an
excess of 2a. More than 2 equiv was necessary to obtain 4a in high
selectivity (98% yield after 1 h, Table 2, entry 2). Na2PdCl4 in Et3N
also gave 4a in high yield, but with longer reaction time (entry
3). It should be noted that PdCl2(PPh3)2, used as the catalyst, affor-
ded 4a in only 23% yield if used in the TMEDA and only trace in
Et3N (Table 1, entries 4 and 5). With the aim of reducing the
It has been shown by Kotschy and co-workers12 that acetylated
bromophenols give very good results in terms of cross-coupling
products if used in Sonogashira reaction, so we decided to use
the acetate derivative 1b as the substrate. The reaction of the latter
with 2a (1.2 equiv) gave after 5 h a mixture of the deacetylated
bromide 1a (53%) and benzo[b]furan 4a (47%, Scheme 2 and Ta-
ble 1, entry 1).
Table 2
One-pot synthesis of 2,5-disubstituted-benzofurans (4) starting from 2-bromo-4-substituted phenols (1a, 5a–8a)a
2
,Na2PdCl4, L
X
X
Br
AcBr,TMEDA,
THF, rt, 5 min
X
Br
R
CuI, TMEDA,
80°C
OH
OAc
O
1b, 5b-8b
1a, 5a-8a
4
Entry
1
X
Bromide
Alkyne 2
t (h)
Benzofuran 4
Yieldb (%)
99
O2N
NO2
1a
2a
1.5
O
O
4a
OMe
OMe
OMe
O2N
2
NO2
1a
9
79
OMe
2b
4b
O2N
O2N
NC
OH
OH
3
4
5
6
NO2
NO2
CN
1a
1a
5a
5a
7
99c
97
O
2c
4c
C6H13
2d
C6H13
4
O
4d
2a
2c
5.5
23
94
O
4e
NC
OH
CN
89c
O
4f
(continued on next page)

2826
A. Bochicchio et al. / Tetrahedron Letters 51 (2010) 2824–2827
Table 2 (continued)
Entry
X
Bromide
Alkyne 2
t (h)
Benzofuran 4
Yieldb (%)
90
NC
C6H13
7
CN
5a
2d
16
O
4g
OHC
AcO
8
9
CHO
H
6a
7a
8a
2a
2a
2a
26
12
14
24
O
4h
87e
23e
O
4i
10d
OH
O
4j
a
Reactions were carried out with 1a, 5a–8a (1 equiv), acetyl bromide (1 equiv), TMEDA (1 equiv), THF (1 M), 2 (4 equiv), Na2PdCl4 (0.5 mol %), 2-(di-tert-butyl phosphino)-
N-indole (1 mol %), CuI (1 mol %) in TMEDA (1 M) at 80 °C and were monitored by TLC and GC–MS analysis. All products were characterized by NMR spectroscopy and mass
spectrometry (EI MS).
b
All yields are isolated yields after column chromatography.
Conversion evaluated by GC–MS analysis.
c
d
Reaction was carried out with 2 equiv of acetyl bromide and 8 equiv in all of 2a.
e
After 10 h was added KOtBu (2 equiv) to convert the cross-coupling products 9 and 10 into the cyclic ones.
Glazer-type oxidative dimerization of terminal alkyne due to the
presence of copper(I) co-catalyst, the copper-free condition was
tested without any success (Table 1, entry 6).
AcO
The one-pot acetylation/coupling/cyclization of 2-bromo-4-
nitrophenol 1a to 4a was equally successful.13 Acetylation of 1a
was complete in 5 min at room temperature (monitored by TLC)
using acetyl bromide (1 equiv), TMEDA (1 equiv), and THF (1 M).
After the addition of 2a (4 equiv), TMEDA (1 M), and the catalyst
system the Sonogashira coupling/cyclization reached full conver-
sion in less than 2 h affording 4a in 99% yield (starting from 1a, en-
try 1 in Table 2).
The generality of this protocol was then investigated under the
optimized reaction conditions. Table 2 shows that several commer-
cial alkynes can react with bromide 1a to give compounds 4b–d in
very good yields (entries 2–4). It can be noted that bromide 1b was
completely transformed into 4c only when 1.2 equiv of 2c was
used (Table 2, entry 3), but significant decomposition during the
purification occurred.
Encouraged by these results we further investigated the reac-
tion of EWG-substituted bromides under similar conditions. When
the substituents were the cyano- and the formyl-group acetates 5b
and 6b afforded benzofurans 4e and 4h in 94% and 24% yields,
respectively. The formation of 4h was in competition with the
hydrolysis of the acetyl group of 6b, as the other product of the
reaction was the deacetylated bromophenol 6a.
10
OAc
OAc
9
Figure 1. Cross-coupling products 9 and 10.
as switches of the reaction direction. Phenols bearing electron-
withdrawing groups led exclusively to the target benzofurans
while their analogues with electron-donating substituents (or
without any substituent) gave previously the cross-coupling prod-
ucts and after the addition of a base the desired cyclic ones.
4-EWG-2-bromophenols are valuable synthetic tools for a one-
pot preparation of 2,5-disubstituted-benzofurans using Na2PdCl4/
L/CuI/TMEDA system.
Further investigations to utilize this method and these com-
pounds for more complex molecules are currently underway in
our laboratory.
Acknowledgment
The authors gratefully acknowledge University of Basilicata for
financial support.
Unfortunately but unsurprisingly, unsubstituted o-bromophe-
nol 7a and 2-bromo-1,4-dihydroxybenzene 8a gave under these
reaction conditions lower yields of benzofurans 4i and 4j along
with cross-coupling products 9 and 10 (Fig. 1). Adding 2 equiv of
KOtBu in the same vessel compounds 9 and 10 were converted into
benzofurans 4i and 4j (87% and 23% yields, respectively; Table 2
entries 9 and 10). In the case of the reaction of 8b the main reaction
product corresponded to the fully hydrolyzed bromide 8a.
From the results obtained, it is clear that substrates 1a and 5a
are the most reactive in these coupling/cyclization sequences.
Although 4 equiv of alkynes has been used, this protocol provides
a facile access to a large number of 5-nitro-2-substituted-benzofu-
rans in excellent yields, starting from commercially available aryl
bromide 1a and alkynes 2a–d.
References and notes
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
2. McCallion, G. D. Curr. Org. Chem. 1999, 3, 67–76.
3. (a) Gubin, J.; de Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux, J.;
Rossels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1993,
36, 1425–1433; (b) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.;
Komoriya, S. J. Med. Chem. 1994, 37, 1200–1207; (c) De Luca, L.; Nieddu, G.;
Porcheddu, A.; Giacomelli, G. Curr. Med. Chem. 2009, 16, 1–20.
4. (a) Twyman, L. J.; Allsop, D. Tetrahedron Lett. 1999, 40, 9383–9384; (b) Allsop,
D.; Gibson, G.; Martin, I. K.; Moore, S.; Turnbull, S.; Twyman, L. J. Bioorg. Med.
Chem. Lett. 2001, 11, 255–257.
5. Huang, H.-C.; Chamberlain, T. S.; Seibert, K.; Koboldt, C. M.; Isakson, P. C.; Reitz,
D. B. Bioorg. Med. Chem. Lett. 1995, 5, 2377–2380.
6. For recently developed methods for benzofurans synthesis see: (a) Fiandanese,
V.; Bottalico, D.; Marchese, G.; Punzi, A.; Quarta, M. R.; Fittipaldi, M. Synthesis
2009, 3853–3859; (b) Tsuchikama, K.; Hashimoto, Y.-K.; Endo, K.; Shibataa, T.
Adv. Synth. Catal. 2009, 351, 2850–2854; (c) Menon, R. S.; Findlay, A. D.;
Bissember, A. C.; Banwell, M. G. J. Org. Chem. 2009, 74, 8901–8903; (d) Honey,
M. A.; Blake, A. J.; Campbell, I. B.; Judkins, B. D.; Moodya, C. J. Tetrahedron 2009,
The synthesis of benzo[b]furans is strongly limited by the nat-
ure of the substituents on the aromatic ring, which can be regarded

A. Bochicchio et al. / Tetrahedron Letters 51 (2010) 2824–2827
2827
65, 8995–9001; (e) Barluenga, J.; Gómez, A.; Santamaría, J.; Tomás, M. J. Am.
Chem. Soc. 2009, 131, 14628–14629; (f) Hari, Y.; Kondo, R.; Date, K.; Aoyama, T.
Tetrahedron 2009, 65, 8708–8713; (g) Hashmi, A. S. K.; Wölfle, M. Tetrahedron
2009, 65, 9021–9029; (h) Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.;
Zhao, K. Org. Lett. 2009, 11, 4978–4981; (i) Kim, I.; Kim, K.; Choi, J. J. Org. Chem.
2009, 74, 8492–8495; (j) Manarin, F.; Roehrs, J. A.; Mozzaquatro Gay, R.;
Brandão, R.; Menezes, P. H.; Nogueira, C. W.; Zeni, G. J. Org. Chem. 2009, 74,
2153–2162; (k) Kanazawa, C.; Goto, K.; Terada, M. Chem. Commun. 2009, 5248–
5250; (l) Jacubert, M.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.
Tetrahedron Lett. 2009, 50, 3588–3592; (m) Martínez, C.; Àlvarez, R.;
Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083–1086; (n) Okitsu, T.; Nakazawa,
D.; Taniguchi, R.; Wada, A. Org. Lett. 2008, 10, 4967–4970; (o) Kim, I.; Lee, S.-H.;
Lee, S. Tetrahedron Lett. 2008, 49, 6579–6584; (p) Eidamshaus, C.; Burch, J. D.
Org. Lett. 2008, 10, 4211–4214; (q) Csekei, M.; Novak, Z.; Kotschy, A.
Tetrahedron 2008, 64, 8992–8996; (r) De Luca, L.; Giacomelli, G.; Nieddu, G. J.
Comb. Chem. 2008, 10, 517–520; (s) Sakai, N.; Uchida, N.; Konakahara, T.
Tetrahedron Lett. 2008, 49, 3437–3440; (t) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi,
S.-F.; Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525–1528; (u) Gabriele, B.;
Mancuso, R.; Salerno, G. J. Org. Chem. 2008, 73, 7336–7341; (v) Cacchi, S.;
Fabrizi, G.; Goggiamani, A. Curr. Org. Chem. 2006, 10, 1423–1455; (w) Nan, Y.;
Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297–299.
10. (a) Dai, W.-M.; Lai, K. W. Tetrahedron Lett. 2002, 43, 9377–9380; (b) Liang, Y.;
Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Li, J.-H. Org. Lett 2006, 8, 3017–
3020.
11. Torborg, C.; Zapf, A.; Beller, M. ChemSusChem 2008, 1, 1–7.
12. Novák, Z.; Timari, G.; Kotschy, A. Tetrahedron 2003, 59, 7509–7513.
13. General procedure for the one-pot synthesis of 2,5-disubstituted-benzofurans. AcBr
(1 equiv) was added dropwise to
a solution of bromophenol 1a, 5a–8a
(1 equiv) and TMEDA (1 equiv) in dry THF and the resulting mixture was
stirred at room temperature for 5 min. After total conversion of starting
bromophenol to the corresponding acetylated product 1b, 5b–8b (monitored
by TLC), the flask was charged with Na2PdCl4 (0.5 mol %), 2-(di-tert-butyl
phosphino)-N-indole (1 mol%), and copper iodide (1 mol %). TMEDA (1 M) and
the acetylene substrates 2a–e (4 equiv) were added successively under argon
atmosphere and the resulting mixture was stirred at 80 °C. After cooling to
room temperature, water was added and the mixture was extracted with
diethyl ether. The combined organic phases were dried over anhydrous Na2SO4
and filtered. The solvent was removed under reduced pressure and the crude
was purified by silica gel column chromatography to provide the desired
products 4a–h in moderate to excellent yields (24–99%). Compounds 4i and 4j
were obtained by base-promoted cyclization of acetylated alkynylphenols 9
and 10. Two equivalents of KOtBu were added in the same pot for 2 h before
cooling the mixture. 2-(3,5-Dimethoxy-phenyl)-5-nitro-benzo[b]furan 4b. Yield
79%; (found: C, 64.18; H, 4.70. C16H13NO5 requires C, 64.21; H, 4.68); pale
7. (a) Powers, L. J.; Mertes, M. P. J. Med. Chem. 1970, 13, 1102–1105; (b) Castelain,
P.; Hendrickx, B.; Tromelin, A.; Demerseman, P.; Moens, W. Mutat. Res. Genetic
Toxicol. 1992, 280, 9–15; (c) Asoh, K.; Kohchi, M.; Hyoudoh, I.; Ohtsuka, T.;
Masubuchi, M.; Kawasaki, K.; Ebiike, H.; Shiratori, Y.; Fukami, T. A.; Kondoh, O.;
Tsukaguchi, T.; Ishii, N.; Aoki, Y.; Shimma, N.; Sakaitani, M. Bioorg. Med. Chem.
Lett. 2009, 19, 1753–1757; (d) Diouf, O.; Durand, T.; Lemeune, S.; Marcoux, J.-F.;
Frison, N.; Larquetoux, L.; Folleas, B. Patent: WO 2008/139057.
8. Various catalyst systems have been applied in Sonogashira cross-coupling
reaction, including palladium monophosphine system, palladacycles, chelating
diphosphine, diamine, and P,N ligands, as well as carbene ligands. Reviews: (a)
Sonogashira, K.. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002; Vol. I, p
493; (b) Farina, V. Adv. Synth. Catal. 2004, 346, 1553–1558; (c) Negishi, E.-I.;
Anastasia, L. Chem. Rev. 2003, 103, 1979–2018; (d) Sonogashira, K. J. Organomet.
Chem. 2002, 653, 46–49; (e) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874–
922; (f) Doucet, H.; Hierso, J.-C. Angew. Chem. 2007, 119, 850–886; Angew.
Chem. Int. Ed. 2007, 46, 834–871.
yellow solid; mp 178–180 °C;
m
(KBr, cmÀ1) 3020, 1562, 1260, 1138, 1113; dY
(500 MHz, CDCl3) 3.91 (6H, s, OCH3), 6.55 (1H, s, CH), 7.04 (2H, s, CH), 7.14 (1H,
s, CH), 7.62 (1H, d, J 9.0, CH), 8.24 (1H, d, J 9.0, CH), 8.56 (1H, s, CH); dC
(125 MHz, CDCl3) 55.5, 101.9, 102.1, 103.4, 111.4, 117.3, 120.2, 129.5, 130.8,
144.3, 157.5, 159.0, 161.2; m/z (EI) M+ 299 (100), 283 (5), 269 (10), 253 (15). 2-
Hexyl-5-nitro-benzo[b]furan 4d. Yield 97%; (found: C, 68.30; H, 5.69. C14H17NO3
requires C, 68.00; H, 5.66); yellow oil;
m
(KBr, cmÀ1) 3018, 1592, 1524, 1346,
1265, 754; dY (500 MHz, CDCl3) 0.89 (3H, m, CH3), 1.35 (6H, m, CH2), 1.75 (2H,
m, CH2), 2.81 (2H, t, J 8, CH2), 6.52 (1H, s, CH), 7.47 (1H, d, J 8.8, CH), 8.16 (1H, d,
J 8.8, CH), 8.42 (1H, s, CH); dC (125 MHz, CDCl3) 14.1, 22.5, 28.5, 28.8, 31.5,
102.6, 110.9, 116.6, 119.2, 128.8, 129.4, 130.9, 157.6, 163.5; m/z (EI) M+ 247
(50), 176 (100), 130 (70), 95 (98). 2-Hexyl-benzo[b]furan-5-carbonitrile 4g. Yield
90%; (found: C, 79.40; H, 7.57. C15H17NO requires C, 79.26; H, 7.54); pale
yellow oil;
m
(KBr, cmÀ1) 2190, 1590, 1340, 790, 720; dY (500 MHz, CDCl3) 0.88
(3H, t, J 6.8, CH3), 1.32 (6H, m, CH2), 1.73 (2H, m, CH2), 2.77 (2H, t, J 8, CH2), 6.41
(1H, s, CH), 7.45 (2H, s, CH), 7.78 (1H, s, CH); dC (125 MHz, CDCl3) 14.1, 22.5,
27.4, 28.4, 28.8, 31.5, 101.7, 106.2, 111.8, 119.7, 125.0, 126.9, 129.7, 156.4,
162.5; m/z (EI) M+ 227(30), 156 (100), 95(70).
9. (a) Pal, M.; Subramanian, V.; Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44,
8221–8225; (b) Djakovitch, L.; Rollet, P. Adv. Synth. Catal. 2004, 346, 1782–
1792; (c) Rollet, P.; Kleist, W.; Dufaud, V.; Djakovitch, L. J. Mol. Catal. A: Chem.
2005, 241, 39–51; (d) Palimkar, S. S.; More, V. S.; Srinivasan, K. V. Ultrason.
Sonochem. 2008, 15, 853–862.