2,5,7-Trisubstituted benzo[b]furans through a copper- and/or palladium-catalyzed assembly and functionalization process

Article abstract of DOI:10.1016/j.tetlet.2011.07.122

A straightforward approach to the synthesis of 2,5,7-trisubstituted benzo[b]furans from 2-bromo- and 2-chloro-6-iodo-4-substituted phenols through a consecutive copper- and/or palladium-catalyzed assembly and functionalization process is described. Functionalization at the C(7) position is carried out by Suzuki-Miyaura cross-coupling and C-N bond forming reactions.

Full text of DOI:10.1016/j.tetlet.2011.07.122

Tetrahedron Letters 52 (2011) 5149–5152
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2,5,7-Trisubstituted benzo[b]furans through a copper- and/or
palladium-catalyzed assembly and functionalization process
Antonio Arcadi a, , Federico Blesi a, , Sandro Cacchi b,à, Giancarlo Fabrizi b,à, Antonella Goggiamani b,à
⇑
a Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università di L’Aquila, Via Vetoio, 67010 L’Aquila, Italy
b Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward approach to the synthesis of 2,5,7-trisubstituted benzo[b]furans from 2-bromo- and 2-
chloro-6-iodo-4-substituted phenols through a consecutive copper- and/or palladium-catalyzed assem-
bly and functionalization process is described. Functionalization at the C(7) position is carried out by
Suzuki–Miyaura cross-coupling and C–N bond forming reactions.
Received 20 June 2011
Revised 18 July 2011
Accepted 26 July 2011
Available online 4 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Palladium
Cross-couplings
Benzo[b]furans
Benzo[b]furans are important heterocycles with widespread
occurrence in nature that exhibit interesting biological activities
and potential pharmaceutical applications.1 As a result, they are
an attractive synthetic target2 and a variety of methods have been
developed to prepare specific structures characterized by given
pharmacological qualities.3 In recent years, transition metal-cata-
lyzed reactions played a remarkable role in this area. Particularly,
palladium-4 and copper5-catalyzed reactions, including combina-
torial approaches6 as well as solid phase synthesis,7 have been
widely employed in the construction of the benzo[b]furan core
providing functional group tolerance, simplified procedures and
improved yields. However, procedures for the synthesis of 2,5,7-
trisubstituted benzo[b]furans are scarcely described in the litera-
ture8 and the development of simple and general methods for their
preparation is a subject of great interest.
As part of our studies devoted to the construction of the ben-
zo[b]furan skeleton,9 we envisaged that readily available 2-bromo-
and 2-chloro-6-iodo-4-substituted phenols might represent suit-
able building blocks for the synthesis of 2,5,7-trisubstituted ben-
zo[b]furans through a process that involves the assembly of the
benzo[b]furan ring followed by its functionalization at the C(7) po-
sition (Scheme 1). Our planning included a domino alkynylation/
endo-dig cyclization reaction and the functionalization at the C(7)
R
I
R
R
Ar
Ar
O
O
OH
X
Nu
Nu = Ar1 , NR2; X = Br, Cl
X
Scheme 1. Retrosynthetic representation of the synthesis of 2,5,7-trisubstituted
benzo[b]furans from 2-halo-6-iodo-4-substituted phenols.
position via Suzuki–Miyaura cross-coupling and C–N bond forming
reactions.
To the best of our knowledge, a similar approach to 2,5,7-trisub-
stituted benzo[b]furans has been described for the synthesis of
benzo[b]furans containing 7-alkynyl substituents.10 The reaction
proceeds through an initial Sonogashira cross-coupling/cyclization
reaction of 4-nitro-2,6-diiodophenol with terminal alkynes fol-
lowed by an in situ Sonogashira cross-coupling of the resultant
7-iodobenzo[b]furan intermediates with terminal alkynes. The
process, however, seems to be limited to the synthesis of 7-alkynyl
derivatives as it cannot be stopped at the 7-iodobenzo[b]furan
stage. We hypothesized that substituting one of the iodo atoms
on the starting phenol with a bromine or chlorine atom should al-
low for the selective synthesis of 7-halobenzo[b]furans, thus pro-
viding access to otherwise inaccessible benzo[b]furan derivatives.
From a synthetic perspective, the C–Br/C–Cl bond would be an
invaluable handle for modulating reactivity, manipulating site
selectivity, and greatly expanding the breadth of potential target
compounds that might be accessible, for example by transition
metal-catalyzed reactions.
⇑
Corresponding author. Fax: +39 08 6243 4203.
E-mail addresses: arcadi@univaq.it, antonio.arcadi@univaq.it (A. Arcadi),
giancarlo.fabrizi@uniroma1.it (G. Fabrizi).
Fax: +39 08 6243 4203.
Fax: +39 06 4991 2780.
à
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.122

5150
A. Arcadi et al. / Tetrahedron Letters 52 (2011) 5149–5152
Table 2
NBS or NCS
Synthesis of 7-halo-2-phenyl-5-substituted benzo[b]furans 4a
R
AlCl3
I
R
R
I2, Ag2SO4
rt, EtOH
98%
Entry
3
Time (h)
Yield% of 4b
rt, CH2Cl2
95%
OH
OH
OH
1
2
3
4
5
3b
3b
3d
3e
3f
4
4
4
4
3
4b (63)c
4b (65)
4d (68)
4e (63)
X
2a-f
X
1a-c
3a-f
1a: R = Ph
1b: R = CH3
1c: R = F
3a: R = Ph, X = Cl
3b: R = Ph, X = Br
3c: R = CH3, X = Cl
3d: R = CH3, X = Br
3e: R = F, X = Cl
3f: R = F, X = Br
d
4f (78)
a
Unless otherwise stated, reactions were carried out on a 2 mmol scale using
6 mL of 1,4-dioxane at 120 °C, using 1 equiv of 3a, 1.5 equiv of phenyl acetylene,
0.10 equiv of CuI, 0.2 equiv of -proline, and 2 equiv of K2CO3.
L
b
Yields refer to single run and are for isolated products.
In the presence of K3PO4.
Toluene was used as a the solvent.
c
Scheme 2. Synthesis of 2-bromo- and 2-chloro-6-iodo-4-substituted phenols.
d
R
I
R
cat
lower toxicity and cost of copper catalysts. A number of ligands
have been examined for this type of reaction.13 We initially used
the Cu(I) complex Cu(phen)(PPh3)2]NO3 developed by Venkatar-
aman et al. and applied to the synthesis of 2-aryl-
benzo[b]furans.13j,14 Under their conditions 4a was isolated in
good yields (entries 5–7). Nevertheless, we subsequently found
Ar
Ar
O
OH
X
X
3
4
Scheme 3. Synthesis of 7-halo-2-aryl-5-substituted benzo[b]furans.
that similar results could be obtained by using the simpler CuI/L-
proline combination developed by Ma et al. and successfully em-
ployed in the N-arylation of aryl bromides15 and in the synthesis
of 2-arylindoles from terminal alkynes and 2-bromoalkynyltrifluo-
roacetanilides.16 1,4-Dioxane, toluene, and DMF were proved suit-
able solvents (entries 8–10) with this catalyst system and K2CO3 or
K3PO4 or Cs2CO3 were equally effective as bases (entries 11–13).
Herein we describe some preliminary results that should have
broad implications as a general synthetic strategy to 2,5,7-trisub-
stituted benzo[b]furans.
The starting 2-bromo- and 2-chloro-6-iodo-4-substituted phe-
nols 3a–f were prepared in high yields from commercially avail-
able 4-substituted phenols 1a–c according to the sequence
outlined in Scheme 2.11
Initial studies were directed toward searching for the best con-
ditions to convert 3 and terminal alkynes into the corresponding
benzo[b]furan derivatives 4 (Scheme 3). 2-Chloro-6-iodo-4-phen-
ylphenol 3a and phenyl acetylene were selected as the model
system.
Some results of our screening are summarized in Table 1. No
benzo[b]furan formation was observed using PdCl2(PPh3)2, CuI,
and Et2NH in DMF at room temperature (entry 1). Increasing the
reaction temperature to 50 °C gave 4a only in moderate yield (en-
try 2). A similar result was obtained with NH(Pr-i)2 as the base (en-
try 3). Interestingly, 4a was isolated in good yield when Pd2(dba)3
was used as the Pd(0) source in the presence of the bulky P(Bu-t)3
ligand generated in situ from the robust BF4HP(Bu-t)3 salt12 under
copper-free conditions (entry 4).
The CuI/L-proline catalytic system was then used when we ex-
plored other 2-halo-6-iodo-4-substituted phenols.17 As shown by
the results listed in Table 2, benzo[b]furans 4 were isolated in good
to high yield.
The arylation at the C(7) position of 4 through the Suzuki–Miya-
ura cross-coupling was next investigated. The Suzuki–Miyaura
cross-coupling has been widely used for the functionalization of
benzo[b]furans.4 Nevertheless, the functionalization at the C(7) po-
sition has been rarely described. To the best of our knowledge,
Moody et al.18 reported one example of this chemistry showing
that 2,7-diphenylbenzo[b]furan could be prepared either directly
by the reaction of phenyl boronic acid with 2-phenyl-7-bro-
mobenzo[b]furan or indirectly by the conversion of 2-phenyl-7-
bromobenzo[b]furan into the corresponding boronic acid followed
by reaction with bromobenzene (Scheme 4).
Therefore, it appeared of interest to us to investigate the scope
and generality of a route to benzo[b]furans bearing an aryl
substituent at the C(7) position based on the Suzuki–Miyaura
cross-coupling. Our studies were directed toward the use of
Further optimization revealed that the best results could be ob-
tained by using copper catalysis. Recently, copper-catalyzed alky-
nylation of aryl halides has gained a growing attention due to its
Table 1
Optimization of the reaction conditions for the synthesis of 4a from 3aa
Entry
Catalytic System (equiv)
Solvent
Base
Temperature (°C)
Time (h)
Yield% of 4ab
1
2
3
4
5
6
7
8
9
10
11
12
13
PdCl2(PPh3)2 (0.02)/CuI (0.04)
PdCl2(PPh3)2 (0.02)/CuI (0.04)
PdCl2(PPh3)2 (0.02)/CuI (0.04)
Pd2(dba)3 (0.025), BF4HP(Bu-t)3 (0.05)
Cu(phen)(PPh3)2]NO3 (0.10)
Cu(phen)(PPh3)2]NO3 (0.10)
Cu(phen)(PPh3)2]NO3 (0.10)
DMF
DMF
DMF
DMSO
Toluene
Toluene
Toluene
Toluene
DMF
Et2NH
Et2NH
NH(Pr-i)2
Cs2CO3
K2CO3
Cs2CO3
K3PO4
K3PO4
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
rt
50
50
60
110
110
110
120
120
120
120
120
120
24
48
48
48
2
2
2
1
1
1
2
2
1
4a (—)
4a (53)
4a (50)
4a (68)
4a (73)
4a (74)
4a (73)
4a (75)
4a (68)
4a (69)
4a (70)
4a (73)
4a (75)
CuI(0.10)/
CuI(0.10)/
CuI(0.10)/
CuI(0.10)/
CuI(0.10)/
CuI(0.10)/
L-proline (0.20)
L-proline (0.20)
L-proline (0.20)
L-proline (0.20)
L-proline (0.20)
L-proline (0.20)
DMSO
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
a
Reactions were carried out on a 2 mmol scale using 6 mL of solvent, using 1 equiv of 3a, 1.5 equiv of phenyl acetylene, and 2 equiv of base.
Yields refer to single run and are for pure isolated products.
b

A. Arcadi et al. / Tetrahedron Letters 52 (2011) 5149–5152
5151
Table 4
PhB(OH)2
Pd(PPh3)4
Na2CO3
PhBr
Pd(PPh3)4
Na2CO3
aq. DME
67%
Amination of 7-chlorobenzo[b]furans 4a
Ph
Ph
Ph
aq. DME
81%
Y
O
O
O
Br
Ph
B(OH)2
N
H
R
R
Scheme 4. Synthesis of 2,7-diphenylbenzo[b]furan.
Pd2(dba)3/XPhos
Ph
Ph
toluene, NaOBu-t
O
O
80 ºC
X
N
Y
Pd2(dba)3
SPhos
R
R
K3PO4
ArB(OH)2
Ph
Ph
1,4-dioxane,
100 ºC
O
O
Cl
Ar
Entry
4
Y
Time (h)
Yield% of 6b
6ba 71
4a,c,e
5
1
2
3
4
5
4b
4d
4d
4e
4f
CH2
CH2
NH
CH2
CH2
12
12
40
12
12
Scheme 5. Palladium-catalyzed cross-coupling of 7-chlorobenzo[b]furan deriva-
tives with aryl boronic acids.
6da
6db
6ec
6fc
99
60c
71
71
a
Table 3
Unless otherwise stated, reactions were carried out on a 0.35 mmol scale using
Synthesis of 7-aryl-2-phenyl-5-substituted benzo[b]benzofurans 5 from 7-chloro-
1 mL of toluene at 80 °C, using 1.0 equiv of 4, 10 equiv of the nitrogen nucleophile,
0.025 equiv of Pd2(dba)3, 0.10 equiv of XPhos, and 2 equiv of NaOBu-t.
benzo[b]furans 4 and arylboronic acidsa
b
Yields refer to single run and are for isolated products.
In the presence of 5 equiv of piperazine.
Entry
4
Ar
Time (h)
Yield% of 5b
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4a
4a
4a
4a
4c
4c
4c
4c
4c
4e
4e
4e
4e
4e
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
2
3
2
3
4
2
3
2
3
3
2
3
2
2
3
5aa (99)
5ab (99)
5ac (99)
5ad (99)
5ae (99)
5ca (95)
5cb (95)
5cc (99)
5cd (95)
5ce (99)
5ea(99)
5eb (95)
5ec (99)
5ed (95)
5ee (98)
mobenzo[b]furan with N-Boc-piperazine in the presence of
Pd(dba)2, P(o-tol)3, and NaOBu-t in toluene at 100 °C followed by
a deprotection step with trifluoroacetic acid.21
In summary, this paper describes a straightforward general pro-
tocol for the synthesis of 2,5,7-trisubstituted benzo[b]furans from
readily available 2-bromo- and/or 2-chloro-6-iodo-4-substituted-
phenols. A comparison of the copper and palladium catalysis
shows that both transition metals are suitable catalysts for the site
selective sequential alkynylation/cyclization process. Pd2(dba)3/
SPhos and Pd2(dba)3/XPhos catalysts achieve very efficiently the
consecutive functionalization at the C(7) position of benzo[b]fur-
ans. Extension of this protocol will be disclosed in a forthcoming
full paper.
a
Reactions were carried out on a 0.4 mmol scale using 2 mL of 1,4-dioxane at
100 °C, using 1.0 equiv of 4, 1.5 equiv of arylboronic acids, 0.04 equiv of Pd2(dba)3,
0.04 equiv of SPhos, and 3 equiv of K3PO4.
b
Yields refer to single run and are for isolated products.
Acknowledgments
The authors are grateful for financial support from the Consor-
zio di Ricerca per l’Innovazione Tecnologica, la Qualità e la Sicu-
rezza degli Alimenti S.C.R.L. (Grant No. 28497/2006) and from
Sapienza, Università di Roma.
7-chlorobenzo[b]furans as coupling partners of boronic acids. In-
deed, the preparation of 7-benzo[b]furan-7-yl boronic acids in-
volves the utilization of butyllithium, a synthetic approach that
has important deficiencies in terms of flexibility and functional
group tolerance when a highest degree of functionalization on
the benzo[b]furan ring is required. After a brief optimization study,
we found that under the same conditions used for the preparation
of 2-arylhydroxytyrosol derivatives,11 7-chlorobenzo[b]furans
4a,c,e could give the corresponding 7-arylbenzo[b]furans 5 in al-
most quantitative yields (Scheme 5).19 As shown in Table 3, the
reaction can be applied to a variety of neutral, electron-rich, and
electron-poor arylboronic acids. Heteroarylboronic acids can also
be successfully used.
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J.; Xue, Q.-W.; Chung, J.-L.; Chen, S.-C.; Chen, Y.-J. Tetrahedron 2010, 66, 7755–
7761; Sparteine: 6b; triphenylphosphine: (m) Okuro, K.; Furuune, M.; Enna,
M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 4716–4721; (n) Guan, J. T.;
Yu, G.-A.; Chen, L.; Weng, T. Q.; Yuan, J. J.; Liu, S. H. Appl. Organomet. Chem
2009, 23, 75–77; (o) Lin, C.-H.; Wang, Y.-J.; Lee, C.-F. Eur. J. Org. Chem. 2010,
4368–4371; (p) XantPhos: 6c
(0.036 g, 0.192 mmol), L-proline (0.044 g, 0.384 mmol), and K3PO4 (0.815 g,
3.84 mmol) in toluene (6 mL), phenylacetylene (0.309 mL, 2.88 mmol) was
added and the mixture was stirred at 120 °C for 1 h. After cooling, the reaction
mixture was dried under reduced pressure and the residue was purified by
flash chromatography (SiO2, 50 g; n-hexane/ethyl acetate 98/2 v/v) to give
0.375 mg of 4d: 68% yield; mp 102–3 °C; IR (KBr) 3100, 3048, 1461, 761,
684 cmÀ1 1H NMR (CDCl3) 7.91 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.38
;
(t, J = 7.2 Hz, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.01 (s, 1H), 2.45 (s, 3H); 13CNMR
(CDCl3) 156.7, 150.4, 134.1, 130.4, 130.0, 128.9, 128.1, 128.3, 125.1, 120.0,
103.3, 101.6, 21.1; MS m/z (relative intensity) 288 (M+[81Br], 100), 286
(M+[79Br], 100), 207 (52), 178 (46); Anal. Calcd for C15H11BrO C, 62.74; H, 3.86;
Br, 27.83. Found C, 62.59; H, 3.84; Br, 27.31.
18. Moody, C. J.; Doyle, K. J.; Elliot, M. C.; Mowlem, T. J. J. Chem. Soc. Perkin Trans. 1
1997, 2413–2420.
19. General procedure for the palladium-catalyzed cross-coupling of 7-chlorobenzo
[b]furans (4a,c,e) with arylboronic acids: A solution of 2-phenyl-5-methyl-7-
chlorobenzo[b]furan 4c (0.100 g, 0.41 mmol), 3-carbomethoxyphenyl boronic
acid (0.112 g, 0.62 mmol), Pd2(dba)3 (0.0075 g, 0.0082 mmol), SPhos (0.0067 g,
0.0164 mmol), and K3PO4 (0.261 g, 1.23 mmol) in 1,4-dioxane (2 mL) was
stirred at 100 °C for 2 h. After cooling, the reaction mixture was dried under
reduced pressure and the residue was purified by flash chromatography (SiO2,
50 g; n-hexane/ethyl acetate 90:10 v/v) to give 0.133 g of 5ca 95% yield; mp
130–1 °C; IR (KBr) 3100, 1708, 761, 690 cmÀ1 1H NMR (CDCl3) d 8.69 (s, 1H),
;
8.21 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 6.63 (t,
J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.40–7.29 (m, 5H), 7.04 (s, 1H), 4.02 (s,
3H), 2.54 (s, 3H); 13CNMR (CDCl3) d 194.3, 167.1, 156.2, 150.4, 136.9, 133.0,
132.8, 130.6, 130.4, 130.3, 129.6, 128.8, 128.7, 128.61, 128.57, 124.9, 123.5,
120.6, 101.2, 52.2, 21.4; MS m/z (relative intensity) 343 (M+, 100); Anal. Calcd
for C23H18O3 C, 80.68; H, 5.30. Found C, 80.59; H, 5.33.
20. General procedure for the palladium-catalyzed amination reaction of 7-
halobenzo[b]furans (4b,d,e,f): A solution of 2-phenyl-5-methyl-7-bromobenzo
[b]furan 4d (0.100 g, 0.34 mmol), Pd2(dba)3 (0.0078 g, 0.0085 mmol), XPhos
(0.0162 g, 0.034 mmol), NaOBu-t (0.065 g, 0.68 mmol), and piperidine
(0.337 mL, 3.4 mmol) in toluene (11 mL) was stirred at 80 °C for 24 h. After
cooling, the reaction mixture was dried under reduced pressure and the
residue was purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl
acetate 85:15 v/v) to give 0.133 g of 6da 99% yield; mp 139–40 °C; IR (KBr)
3100, 2921, 1596, 765, 690 cmÀ1 1H NMR (CDCl3) d 7.87 (d, J = 8.4 Hz, 2H),
;
7.46 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.2 Hz, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 6.62 (s,
1H), 3.37 (bt, J = 5.2 Hz, 4H), 2.43 (s, 3H), 1.91–1.85 (m, 4H), 1.72–1.65 (m, 2H);
13CNMR (CDCl3) d 155.0, 145.2, 137.8, 133.2, 130.8, 130.3, 128.7, 128.2, 124.8,
113.3, 113.1, 51.4, 26.2, 24.6, 21.8; MS m/z (relative intensity) 291 (M+, 100),
235 (13), 207 (17); Anal. Calcd for C20H21NO3 C, 82.44; H, 7.26; N, 4.81. Found
C, 81.95; H, 7.28; N, 4.78.
14. (a) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4,
4727–4729.
15. Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542–4546.
16. Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844–4850.
21. Kerrigan, F.; Martin, C.; Thomas, G. H. Tetrahedron Lett. 1998, 39, 2219–2222.