Domino synthesis of 2-arylbenzo[b]furans by copper(II)-catalyzed coupling of o-iodophenols and aryl acetylenes

Article abstract of DOI:10.1016/j.tet.2010.01.026

A wide range of 2-arylbenzo[b]furans are synthesized through domino intermolecular C_(aryl)-C_(alkynyl) bond formation followed by intramolecular C_(alkynyl)-O bond forming cyclization via copper(II)-catalyzed coupling of o-iodophenols and aryl terminal acetylenes. This method requires neither expensive palladium catalyst nor oxophilic phosphine ligands, can tolerate different functional groups. The methodology is successfully utilized in formal synthesis of β-amyloid aggregation inhibitor 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl) benzofuran.

Full text of DOI:10.1016/j.tet.2010.01.026

Tetrahedron 66 (2010) 2077–2082
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Domino synthesis of 2-arylbenzo[b]furans by copper(II)-catalyzed coupling of
o-iodophenols and aryl acetylenes
*
E.A. Jaseer, D.J.C. Prasad, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of 2-arylbenzo[b]furans are synthesized through domino intermolecular C(aryl)–C(alkynyl)
bond formation followed by intramolecular C(alkynyl)–O bond forming cyclization via copper(II)-catalyzed
coupling of o-iodophenols and aryl terminal acetylenes. This method requires neither expensive palla-
dium catalyst nor oxophilic phosphine ligands, can tolerate different functional groups. The methodology
Received 13 November 2009
Received in revised form
24 December 2009
Accepted 7 January 2010
Available online 20 January 2010
is successfully utilized in formal synthesis of
b-amyloid aggregation inhibitor 5-chloro-3-[4-(3-diethyl-
aminopropoxy)benzoyl]-2-(4-methoxyphenyl) benzofuran.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Coupling reaction
Benzofuran
Diamine ligands
Sonogashira coupling
1. Introduction
Easily available metal salts of copper13–17 or iron18 will be the
ideal replacement for expensive palladium. Particularly, copper-
catalyzed domino19 intermolecular Sonogashira coupling between
o-iodophenols and aryl acetylenes followed by 5-endo-dig cycliza-
tion is the alternative for palladium catalyzed benzo[b]furan syn-
thesis, which is not much explored in literature. The pioneerring
work by Castro14a using stoichiometric quantities of copper acety-
lide followed by Owen14b using 60 mol % Cu2O in pyridine solvent
made significant progress for copper catalyzed benzo[b]furan syn-
thesis. Recently, CuI-PPh3 catalyst developed by Miura15 and CuI-
DABCO by Heng Li16a were also shown to catalyze the formation of
benzo[b]furans from o-iodophenols and aryl terminal acetylenes.
Venkataraman et al. demonstrated that CuNO3 along with PPh3 and
1,10-phenanthroline successfully used as efficient catalyst for ben-
zo[b]furan synthesis.17 However, these advances in the field of
copper complex catalyzed benzo[b]furan synthesis is not sufficient
as most of the catalysts still require harsh reaction conditions such
as high temperatures (ꢀ120 ꢁC),14–16 the requirement of stoichio-
metric quantities of copper catalysts,14a poor substrate scope,14–16
still need of oxophilic phosphine ligands15,17 and low to moderate
yields14b,15 have generally limited the utility of copper catalyst.
As part of our ongoing research toward copper catalyzed oxida-
tion chemistry,20 very recently we reported copper complex cata-
lyzed arylation of alcohols, phenols, indoles, thiols, and terminal
alkynes through C(aryl)–O bond formation, C(aryl)–N bond formation
(N-arylation of indoles), C(aryl)–S bond formation, C(aryl)–C bond
formation and their applications in heterocycle synthesis.21 Thus, it
was a natural extension for us to investigate the BINAM-copper
Numerous synthetically challenging and medicinally important
chemicals contain benzo[b]furan moiety as structural units.1 Some
of the properties of pharmaceutically active molecules, which con-
tains benzo[b]furans are antitumor properties,2 inhibition of protein
phosphatase 1B,3 5-HT2 and 5-HT3 antagonist activity,4 inhibition of
5-lipoxygenase (5-LO),4b and antifungal properties.5 Therefore these
type of compounds can be used for treatment of cancer, cardio-
vascular disease, type-2 diabetes, migraines, dementia and
anxiety.2–5 Traditional synthetic methods are often multistep re-
actions such as dehydrative cyclization of
a-(phenoxy)alkyl
ketones,6 cyclofragmentation of oxiranes,7 acidic dehydration of
o-hydroxybenzyl ketones,8 base mediated decarboxylation of
o-acylphenoxyacetic acids and esters9 and reaction of phenols with
a
-acylsulfoxides.10 However, these multi-step traditional methods
suffered with limited substrate scope and do not tolerate several
functional groups. Palladium catalyzed benzo[b]furan formation
from the corresponding o-ethynylphenol11 or o-iodophenols12 and
aryl terminal acetylenes used to be the method of choice. But the
high costs of palladium salts, high oxophillicity associated with
phosphine ligands, and tedious multistep processes involved in the
synthesis of these ligands have made to look for alternative method
particularly for large scale reactions.
* Corresponding author. Tel.: þ91 44 2257 4229; fax: þ91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.026

2078
E.A. Jaseer et al. / Tetrahedron 66 (2010) 2077–2082
catalyzed domino Sonogashira coupling followed by 5-endo-dig
cyclization from coupling between o-iodophenols and aryl acety-
lenes to synthesize benzo[b]furans (Scheme 1).
product. In less polar solvent like toluene, it provided highest iso-
lated yield with required cyclized product 3 as almost single
product. So it is clear that the oxidative homo coupling product 4 is
I
Cu complex (cat.)
R
+
R
base, solvent
O
R'
OH
R'
Scheme 1.
2. Results and discussion
favored in polar solvents, such as DMSO, DMF, and expected cy-
clization product 3 through domino Sonogashira coupling followed
by 5-endo-dig cyclization favored in non-polar solvent such as
toluene. Similarly the yield also increased by decreasing the po-
larity of the solvent.
In preliminary studies, we used 20 mol % of N,N0-dibenzyl-1,10-
binaphthyl-2,20-diamine L1 (dibenzyl-BINAM) (Fig. 1) as ligand
with 20 mol % of Cu(OTf)2 for the coupling of o-iodophenol with
phenyl acetylene in DMSO at 110 ꢁC. After 36 h the coupling re-
action provided just 5% isolated yield with 21:79 mixture of re-
quired 2-phenylbenzo[b]furan 3 through domino Sonogashira
coupling followed by 5-endo-dig cyclization and 1,3-diyne 4
through oxidative homo coupling of phenyl acetylene (Table 1,
entry 1). When the solvent DMSO was replaced by DMF, the yield
was increased to 13% yield with 28:72 mixture of 2-phenyl-
benzo[b]furan 3 and 1,3-diyne 4 (entry 2). Then the coupling re-
action were carried out in acetonitrile, THF, and 1,4-dioxane
solvents and the isolated yield increased to 41–55% with gradually
increasing the required 2-phenylbenzo[b]furans 3 up to 91:09
(entries 3–5). Surprisingly, when the reaction was carried out in
less polar solvent such as toluene, the reaction took only 32 h for
completion and yielded 90% isolated yield in favor of 98:02 of re-
quired phenylbenzo[b]furan 3 (entry 6).
The reaction was screened with several BINAM based ligands,
copper salts, bases and different ratio of catalyst to increase the
efficiency of the coupling reactions and the results are summarized
inTable 2. Replacing ligand L1 by L2, L3, and L4 in toluene took more
timeforcompletionandthe isolated yield decreasedto52%, 47%, and
41%, respectively (Table 2, entries 2–4). Although several copper
salts catalyzed the reaction, Cu(OTf)2 turned out to be the copper salt
of choice in view of isolated yield (entry 1). When the reaction was
carried out without any ligand, it provided only 35% yield for the
cyclized product 3 (entry 10). K2CO3 as base gave the best yields of
product in comparison with Cs2CO3 (entry 1 vs entry11). Then the
reactionwas carried out with different ratios of L1 and Cu(OTf)2, and
it was found that 20 mol % of ligand L1-copper combination was the
most effective catalytic system (entry 1 vs entries 12–14).
Table 2
Effect of Cu salts, bases and different ratio of catalyst
NR1R2
NR1R2
L1: R = H; R = Bn L2: R = R = H
Entry
Ligands
Cu salts
Time (h)
Yielda (%)
1
2
1
2
L3: R = H; R = Me
L4: R = R = Me
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L1
L1
L1
L1
L1
ꢂ
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
CuSO4
Cu(OAc)2.H2O
CuCl2
32
48
52
52
30
52
53
49
50
52
50
66
68
69
90
52
47
41
78
76
74
76
68
1
2
1
2
Figure 1. BINAM based ligands for copper catalyzed 2-arylbenzo[b]furan synthesis.
Table 1
Effect of the solvents
9
CuBr
10
11
12
13
14
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
35
L1
L1
L1
L1
62b
52c
74d
56e
Entry
Solvent
Time (h)
Yielda (%)
3:4b
a
Isolated yield.
Cs2CO3 is used as base.
Ratio of Cu(OTf)2 and L1 is 10:20 mol %.
Ratio of Cu(OTf)2 and L1 is 10:10 mol %.
Ratio of Cu(OTf)2 and L1 is 5:10 mol %.
1
2
3
4
5
6
DMSO
DMF
36
36
56
64
55
32
05
13
55
41
64
90
21:79
28:72
62:38c
70:30c
91:09c
98:02
b
c
Acetonitrile
THF
1,4-Dioxane
Toluene
d
e
a
Yield of 30.
Usingtheabovementionedoptimizedconditions,weinitiatedour
b
Determined by GC analysis using hp5 regular column (flowrate: H280 ml/m, air
investigations into the scope of the L1-Cu(OTf)2 complex catalyzed
domino Sonogashira coupling followed by 5-endo-dig cyclization for
the synthesis of 2-aryl substituted benzo[b]furans and the results are
summarized in Table 3. Various o-iodophenols reacted with several
kindsofterminalalkynestogivethecorresponding2-arylsubstituted
benzo[b]furans under mild reaction conditions. We found that
o-iodophenols containing electron-releasing groups (entries 8 and 9)
as well as electron-withdrawing groups (entries 10–13) reacted with
terminal aryl alkynes to give corresponding benzo[b]furans. The
250 ml/m, oven temperature: 60–250 ꢁC).
c
Reaction was carried out in pressure tube.
It is very clear that polar solvents such as DMSO and DMF pro-
vide poor yield and oxidative homo coupling product as major
product. When comparatively moderate polar solvents such as
acetonitrile, THF, and 1,4-dioxane are used, the isolated yield in-
creased gradually and yielded required cyclized product 3 as major

E.A. Jaseer et al. / Tetrahedron 66 (2010) 2077–2082
2079
o-iodophenols containing electron-withdrawing groups provided
comparatively better yields for benzofurans than o-iodophenols
containing electron-releasing groups (entries 8 and 9 vs 10–13).
Similarly, terminal alkynes containing electron-releasing groups
(entries 2–5) as well as electron-withdrawing groups (entries 6 and
7) reacted with o-iodophenols to give corresponding benzofurans.
However, the terminal alkynes containing electron-releasing groups
yielded comparatively better yields for benzofurans than alkynes
containing electron-withdrawing group (entries 2–5 vs 6 and 7).
Alkyl acetylene such as 2-(prop-2-ynyloxy)tetrahydro-2H-pyran
failed to provide expected 2-alkyl substituted benzofuran.
give 70% of product 4-chloro-2-iodophenol 17, which was used as
starting material to couple with p-methoxyphenyl acetylene 18 in the
presenceofcatalyticamountof L1-Cu(OTf)2 complex to give 5-chloro-
2-(4-methoxyphenyl)benzofuran 19 with 80% isolated yield.
Acylation of product 19 with acid chloride 20 in the presence of SnCl4
gave 56% of acylated product 21. Replacement of bromo group by
diethylamine will provide the target molecule b-amyloid aggregation
inhibitor 22.23
Table 3
Coupling of o-iodophenols with terminal aryl alkynes catalyzed by L1-Cu(OTf)2
complex
Entry Iodophenols Aryl acetylenes
Products
Time Yielda
(h) (%)
1
2
32
39
90
83
Scheme 2. Formal synthesis of
b-amyloid aggregation inhibitor 22 using L1-CuI
catalyzed 2-arylbenzo[b]furan formation is the key step.
3
49
77
3. Conclusion
6
In summary, we have described an efficient, experimentally
simple, and economically attractive copper catalyzed synthesis of
awide range of 2-arylbenzo[b]furans through domino intermolecular
C(aryl)–C(alkynyl) bondformationfollowedbyintramolecularC(alkynyl)–O
bond formation from coupling of o-iodophenols with aryl acetylenes.
o-Iodophenols containing electron-withdrawing groups provided
comparatively better yields for benzofurans than o-iodophenols
containing electron-releasing groups. Similarly, the aryl terminal
alkynes containing electron-releasing groups yielded compara-
tively better yields for benzo[b]furans than alkynes containing
electron-withdrawing group. This methodology can be success-
4
5
6
22
39
24
80
82
60
CF3
O
9
7
8
9
38
36
30
48
60
48
fully applied to the formal synthesis of
b-amyloid aggregation
inhibitor 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-
methoxyphenyl)benzofuran.
10
11
36
70
4. Experimental
4.1. General
28
28
91
90
All reactions were carried out in reaction tubes under nitrogen
atmosphere. Substituted o-Iodophenols, Ligands L2, L3, and L4 were
made using literature procedures. o-Iodophenol, aryl acetylenes, and
copper(II) triflate were purchased from Aldrich Chemical Company.
Potassium carbonate are purchased from Spectrochem India Private
Limited and used without further purification. All other reagents are
commercially available and were used without further purification.
Toluene was purchased from SRL Chemicals, India and dried over
sodium. Reaction temperatures were controlled by Varivolt tem-
perature modulator. Thin-layer chromatography (TLC) was per-
formed using Merck silica gel 60 F254 precoated plates (0.25 mm) and
visualized by UV fluorescence quenching. Silica gel for chromatog-
raphy (particle size 100–200 mesh) was purchased from SRL India.
1H and 13C NMR spectra were recorded on a Bruker 400 MHz in-
Cl
I
12
OH
13
26
87
a
Isolated yield.
2.1. Formal synthesis of b-amyloid aggregation inhibitor
Aftersuccessfulcompletionofawiderangeof2-arylbenzo[b]furan
synthesis in the presence of L1-Cu(OTf)2, we successfully applied the
same protocol for formal synthesis of a potent b-amyloid aggregation
inhibitor22 5-chloro-3-[4-(3-diethyl aminopropoxy)benzoyl]-2-
(4-methoxyphenyl)benzofuran 22 where 2-arylbenzo[b]furan
formation is the key step (Scheme 2). Commercially available
p-chlorophenolwasiodinated byNaOCl/NaIandNaOHinmethanolto
strument. 1H NMR spectra were reported relative to Me4Si (
0.0 ppm) or residual CHCl3
7.26 ppm). 13C NMR were reported
relative to CDCl3 77.16 ppm). FTIR spectra were recorded on
a Nicolet 6700 spectrometer and are reported in frequency of
d
(d
(d

2080
E.A. Jaseer et al. / Tetrahedron 66 (2010) 2077–2082
absorption (cmꢂ1). High resolution mass spectra (HRMS) were
recorded on Q-Tof Micro mass spectrometer. The Gas chromatogra-
phy was a Agilent 6890N series with a HP capillary column.
3069, 3038, 1450, 1259 cmꢂ1; 1H NMR (400 MHz, CDCl3)
s), 8.00 (1H, d, J¼7.6 Hz), 7.64–7.50 (4H, m), 7.36–7.28 (1H, m), 7.26–
7.22 (1H, m), 7.08 (1H, s); 13C NMR (100 MHz, CDCl3)
155.2, 154.3,
d 8.10 (1H,
d
131.7, 131.4, 129.5, 129.0, 128.0, 125.1, 125.1, 123.4, (q, J¼3.9 Hz),
121.8, 121.8 (q, J¼3.9 Hz), 121.4, 111.5, 102.8; HRMS [MNa]þ Calcu-
lated for C15H9ONaF3 285.0503, found 285.0504.
4.2. Typical experimental procedure (Table 3, entry 1)
Typical Experimental Procedure: Dibenzyl-BINAM (23.2 mg,
0.05 mmol), Cu(OTf)2 (18.1 mg, 0.05 mmol), K2CO3 (103.7 mg,
0.75 mmol), and o-iodophenol (55 mg, 0.25 mmol) were taken in
a 10 mL reaction tube capped with a septum. The tube was evac-
uated and back-filled with nitrogen. Toluene (3 mL) was added to
the reaction mixture at room temperature. Then the resulting so-
4.2.6. 2-(4-Fluorophenyl)benzo[b]furan (10). Light yellow solid, mp
120–122 ꢁC (lit. 122–124 ꢁC)26; Rf 0.6 (5% ethyl acetate/hexanes);
FTIR (neat) 3058, 2927, 839, 736 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.86–7.80 (2H, m), 7.57 (1H, d, J¼8 Hz), 7.51 (1H, d, J¼8 Hz),
7.31–7.20 (2H, m), 7.17–7.10 (2H, m), 6.94 (1H, s); 13C NMR
(100 MHz, CDCl3)
lution refluxed, followed by phenyl acetylene (33
mL, 0.3 mmol)
d
163.0 (d, J¼247.1 Hz), 155.2, 155.0, 129.3, 126.9
addition at refluxing temperature and the septum was replaced
with a glass stopper and the reaction mixture was refluxed until the
complete disappearance of o-iodophenol (TLC), then the reaction
mixture was allowed to cool to room temperature and the solvent
was evaporated. The crude residue was purified by column chro-
matography on silica gel using hexane as the eluent to afford 2-
phenylbenzofuran 3 (43.7 mg, 90%) as a white solid. Mp 119 ꢁC (lit.
120 ꢁC)17; Rf 0.64 (hexanes); FTIR (neat) 3052, 2925, 2853, 1456,
(d, J¼8 Hz), 124.4, 123.2, 121.0, 116.0 (d, J¼21.8 Hz), 111.3, 101.1;
HRMS [MH]þ Calculated for C14H10FO 213.0716, found 213.0718.
4.2.7. 5-Methyl-2-phenyl-benzo[b]furan (11). White solid, mp
131–133 ꢁC (lit. 129 ꢁC)27; Rf 0.58 (hexanes); FTIR (neat) 3062, 2920,
2855, 1444, 1266 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.89–7.83 (2H,
m), 7.49–7.30 (5H, m), 7.09 (1H, dd, J¼8.4, 2 Hz), 2.44 (3H, s), 6.95
(1H, s); 13C NMR (100 MHz, CDCl3)
d 156.2, 153.5, 132.5, 130.8, 129.5,
1258 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.87 (2H, d, J¼7.6 Hz), 7.59
128.9, 128.6, 125.7, 125.0, 120.9, 110.8, 101.2, 21.5; HRMS [MH]þ
Calculated for C15H13O 209.0966, found 209.0964.
(1H, d, J¼7.6 Hz), 7.53 (1H, d, J¼8.0 Hz), 7.45 (2H, t, J¼8 Hz), 7.35
(1H, t, J¼7.6 Hz), 7.32–7.20 (2H, m), 7.03 (1H, s); 13C NMR (100 MHz,
CDCl3)
d
156.1, 155.0, 130.6, 129.4, 128.9, 128.7, 125.1, 124.4, 123.1,
4.2.8. 5-tert-Butyl-2-phenyl-benzo[b]furan (12). White solid, mp
100–102 ꢁC (lit. 102–103 ꢁC)28; Rf 0.63 (hexanes); FTIR (neat) 3061,
121.0, 111.3, 101.4; HRMS [MNa]þ Calculated for C14H10ONa
217.0629, found 217.0625.
2957, 2866, 1474, 1278 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.88–7.84
(2H, m), 7.59 (1H, d, J¼2 Hz), 7.48–7.42 (3H, m), 7.38–7.32 (2H, m),
7.00 (1H, s), 1.38 (9H, s); 13C NMR (100 MHz, CDCl3)
156.2, 153.3,
4.2.1. 2-p-Tolyl-benzo[b]furan (5). White solid, mp 124–125 ꢁC (lit.
126–128 ꢁC)12g; Rf 0.64 (hexanes); FTIR (neat) 3029, 2917, 2852,
d
146.1, 130.8, 129.0, 128.9, 128.5, 125.0, 122.4, 117.2, 110.6, 101.6, 34.9,
32.0; HRMS [MH]þ Calculated for C18H19O 251.1436, found 251.1432.
1451, 1258 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.75 (2H, d, J¼8 Hz),
7.57–7.53 (1H, m), 7.50 (1H, d, J¼8 Hz), 7.28–7.18 (4H, m), 6.95 (1H,
s), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3)
156.3, 154.9, 138.7,
d
4.2.9. 5-Chloro-2-phenyl-benzo[b]furan (13). White solid, mp
154 ꢁC (lit.156 ꢁC)29; Rf 0.68 (hexanes); FTIR (neat) 3086, 2922,1452,
129.5, 129.6, 127.9, 125.0, 124.1, 123.0, 120.9, 111.2, 100.7, 21.5; HRMS
[MH]þ Calculated for C15H13O 209.0966, found 209.0968.
1274 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.89–7.82 (2H, m), 7.55 (1H,
d, J¼2 Hz), 7.50–7.41 (3H, m), 7.41–7.35 (1H, m), 7.23 (1H, dd, J¼8.8,
2 Hz), 6.97 (1H, s); 13C NMR (100 MHz, CDCl3)
157.6, 153.4, 130.7,
4.2.2. 2-m-Tolyl-benzo[b]furan (6). White solid, mp 74–75 ꢁC (lit.
75–76 ꢁC)24; Rf 0.68 (hexanes); FTIR (neat) 3039, 2922, 2852, 1451,
d
130.1, 129.1, 129.0, 128.6, 125.2, 124.5, 120.6, 112.3, 100.9; HRMS
[MH]þ Calculated for C14H10ClO 229.0420, found 229.0423.
1257 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.70 (1H, s), 7.67 (1H, d,
J¼7.6 Hz), 7.60–7.55 (1H, m), 7.52 (1H, d, J¼7.6 Hz), 7.33 (1H, t,
J¼7.6 Hz), 7.30–7.19 (2H, m), 7.17 (1H, d, J¼7.6 Hz), 7.01(1H, s), 2.43
4.2.10. 5-Chloro-2-p-tolyl-benzo[b]furan (14). White solid, mp
175–176 ꢁC (lit. 177–178 ꢁC)10; Rf 0.83 (hexanes); FTIR (neat) 3029,
(3H, s); 13C NMR (100 MHz, CDCl3)
d 156.3, 155.0, 138.6, 130.5, 129.5,
129.4, 128.8, 125.7, 124.3, 123.0, 122.3, 121.0, 111.3, 101.3, 21.6; HRMS
2915, 2857, 1444, 1263 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.72 (2H,
[MH]þ Calculated for C15H13O 209.0966, found 209.0968.
d, J¼8.0 Hz), 7.50 (1H, d, J¼2 Hz), 7.40 (1H, d, J¼8.4 Hz), 7.24 (2H, d,
J¼8 Hz), 7.20 (1H, dd, J¼8.8, 2 Hz), 6.87 (1H, s), 2.39 (3H, s); 13C
4.2.3. 2-(4-Methoxy-phenyl)-benzo[b]furan (7). White solid, mp
148–150 ꢁC (lit. 146–147 ꢁC)12g; Rf 0.2 (hexanes); FTIR (neat) 3054,
NMR (100 MHz, CDCl3) d 157.8, 153.3, 139.3, 130.9, 129.7, 128.5,
127.4, 125.1, 124.2, 120.4, 112.1, 100.2, 21.5; HRMS [MH]þ Calculated
for C15H13OCl 244.0655, found 244.0661.
3006, 2961, 2837, 1454, 1250 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
7.83–7.77 (2H, m), 7.54 (1H, d, J¼8.4 Hz), 7.49 (1H, d, J¼8 Hz),
7.28–7.17 (2H, m), 7.01–6.94 (2H, m), 6.88 (1H, s), 3.85 (3H, s); 13C
4.2.11. 5-Chloro-2-m-tolyl-benzo[b]furan (15). White solid, mp
98–100 ꢁC; Rf 0.89 (hexanes); FTIR (neat) 3109, 3059, 3038, 2920,
NMR (100 MHz, CDCl3)
d 160.1, 156.2, 154.8, 129.6, 126.6, 123.9,
123.5, 123.0, 120.7, 114.4, 111.1, 99.8, 55.5; HRMS [MH]þ Calculated
for C15H13O2 225.0916, found 225.0918.
2860, 1443, 1261 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.67 (1H, s),
7.64 (1H, d, J¼7.6 Hz), 7.53 (1H, d, J¼2.4 Hz), 7.42 (1H, d, J¼8.4 Hz),
7.34 (1H, t, J¼7.6 Hz), 7.22 (1H, dd, J¼8.8, 2 Hz), 7.19 (1H, d,
J¼7.6 Hz), 6.93 (1H, s), 2.42 (3H, s); 13C NMR (100 MHz, CDCl3)
4.2.4. 2-(4-Pentyl-phenyl)-benzo[b]furan (8). White solid, mp 89–
90 ꢁC; Rf 0.65 (hexanes); FTIR (neat) 2956, 2928, 2856, 1452,
d
157.8, 153.4, 138.7, 130.8, 130.0, 130.0, 128.9, 128.6, 125.8, 124.4,
1256 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.78 (2H, d, J¼8 Hz),
122.4, 120.5, 112.2, 100.8, 21.6; HRMS [MH]þ Calculated for
C15H13OCl 244.0655, found 244.0658.
7.59–7.55 (1H, m), 7.51 (1H, d, J¼8 Hz), 7.29–7.19 (4H, m), 6.97 (1H,
s), 2.64 (2H, t, J¼8 Hz), 1.70–1.59 (2H, m), 1.42–1.28 (4H, m), 0.90
(3H, t, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d
156.4, 154.9, 143.8,
4.2.12. 5-Chloro-2-(4-pentyl-phenyl)-benzo[b]furan (16). White
solid, mp 147–149 ꢁC; Rf 0.71 (hexanes); FTIR (neat) 2931, 2858,
129.5, 129.0, 128.1, 125.1, 124.1, 123.0, 120.9, 111.2, 100.7, 35.9, 31.6,
31.2, 22.7, 14.2; HRMS [MH]þ Calculated for C19H21O 265.1592,
found 265.1589.
1444 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.73 (2H, d, J¼8 Hz), 7.50
(1H, d, J¼2.4 Hz), 7.40 (1H, d, J¼8.8 Hz), 7.25 (2H, d, J¼8.0 Hz), 7.20
(1H, dd, J¼8.8, 2 Hz), 6.87 (1H, s), 2.63 (2H, t, J¼7.6 Hz), 1.64 (2H,
quint, J¼7.6 Hz), 1.41–1.27 (4H, m), 0.90 (3H, t, J¼7.2 Hz); 13C NMR
4.2.5. 2-(3-(Trifluoromethyl)-phenyl)-benzo[b]furan (9). White solid,
mp 65–67 ꢁC (lit. 67.2–67.6 ꢁC)25; Rf 0.8 (hexanes); FTIR (neat) 3110,
(100 MHz, CDCl3)
d 157.9, 153.3, 144.4, 130.9, 129.1, 128.5, 127.6,

E.A. Jaseer et al. / Tetrahedron 66 (2010) 2077–2082
2081
125.2, 124.2, 120.4, 112.1, 100.2, 35.9, 31.6, 31.1, 22.7, 14.2; HRMS
[MH]þ Calculated for C19H20OCl, 299.1203; found 299.1201.
taken in a reaction tube capped with a septum. The tube was evac-
uated and back-filled with nitrogen. Toluene (3 mL) was added to the
reaction mixture at room temperature. Then the resulting solution
4.3. Formal synthesis of 5-chloro-3-[4-(3-diethylamino-
propoxy)-benzoyl]-2-(4-methoxyphenyl)-benzofuran
refluxed, followed by 1-ethynyl-4-methoxybenzene 18 (311 mL,
2.4 mmol) addition at refluxing temperature and the septum was
replaced with a glass stopper and the reaction mixture was refluxed
until the complete disappearance of o-iodophenol (TLC). Then the
reaction mixture was allowed to cool to room temperature and the
solvent was evaporated. The crude residue was purified by column
chromatography on silica gel using hexane as the eluent to afford
5-chloro-2-(4-methoxyphenyl)-benzofuran 19 (413.6 mg, 80%) as
white solid. Mp 164–165 ꢁC (lit.166–167 ꢁC)10; Rf 0.60 (hexanes); FTIR
(neat) 3036, 2918, 2851, 1485, 1266 cmꢂ1; 1H NMR (400 MHz, CDCl3)
4.3.1. 4-Chloro-2-iodophenol (17)30. White solid, mp 77 ꢁC (lit.
78 ꢁC); Rf 0.38 (5% ethyl acetate/hexanes); FTIR (neat) 3315,
3086 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.63 (1H, d, J¼2.4 Hz), 7.22
(1H, dd, J¼8.8, 2.4 Hz), 6.92 (1H, d, J¼8.8 Hz), 5.28 (1H, s); 13C NMR
(100 MHz, CDCl3):
d 153.9, 137.3, 130.3, 126.2, 115.8, 85.6.
4.3.2. 4-(3-Bromopropoxy)benzoyl chloride (20)23
.
d
7.78 (2H, d, J¼8.8 Hz), 7.50 (1H, d, J¼2 Hz), 7.40 (1H, d, J¼8.8 Hz), 7.19
(1H, dd, J¼8.6, 2 Hz), 6.98 (2H, d, J¼8.8 Hz), 6.82 (1H, s), 3.86 (3H, s);
13C NMR (100 MHz, CDCl3)
d 160.5, 157.7, 153.2, 131.0, 128.5,
126.7, 124.0, 123.0, 120.2, 114.5, 112.0, 99.3, 55.5; GC–MS EIþ:
m/z¼258.0259.
4.3.2.5. 5-Chloro-3-[4-(3-bromopropoxy)benzoyl]-2-(4-methoxy-
phenyl) benzofuran (21).23. Stannic chloride (469 mg, 1.8 mmol)
was added to a stirred solution of 5-chloro-2-(4-methoxyphenyl)-
benzofuran 19 (388 mg, 1.5 mmol) and 4-(3-bromopropox-
y)benzoyl chloride 20 (500 mg, 1.8 mmol) in benzene (12 mL) at
room temperature under nitrogen atmosphere, and the stirring was
continued at the same temperature for 24 h. The reaction mixture
was quenched by the addition of water. The organic layer was dried
over anhydrous Na2SO4, and was concentrated under the reduced
pressure. The residue was purified by column chromatography
using ethyl acetate/hexanes as eluents. The reaction provided 21
(420 mg, 56%) as a oily liquid, Rf 0.38 (10% ethyl acetate/hexanes);
FTIR (neat): 2924, 1646, 1601, 1504, 1447, 1366, 1308, 1258, 1173,
4.3.2.1. Methyl 4-(3-bromopropoxy)benzoate (20a). In a 100 mL
two neck round bottom flask equipped with reflux condenser
methyl p-hydroxy benzoate (1.52 g, 10 mmol), 1,3-dibromopropane
(3.23 g, 16 mmol), and K2CO3 (1.66 g, 12 mmol) were taken, acetone
(30 mL) was added to the round bottom flask. The contents were
refluxed for 20 h. The reaction mixture was cooled to room tem-
perature, the crude product was purified by column chromatogra-
phy on silica gel using ethyl acetate/hexanes as eluents. The
reaction provided 64% yield (1.74 g) of methyl 4-(3-bromopropoxy)
benzoate 20a as white solid, mp 64–65 ꢁC; Rf 0.64 (10% ethyl ace-
tate/hexanes); FTIR (neat): 2948, 1718, 1606, 1510, 1435, 1256, 1169,
1108, 1038 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 8.01–7.97 (2H, m),
6.92 (2H, d, J¼8.8 Hz), 4.16 (2H, t, J¼6.0 Hz), 3.88 (3H, s), 3.60 (2H, t,
1030 cmꢂ1
;
1H NMR (400 MHz, CDCl3):
d
7.76 (2H, d, J¼8.8 Hz),
J¼6.0 Hz), 2.34 (2H, quint, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3):
7.61–7.55 (2H, m), 7.41–7.37 (2H, m), 7.23–7.19 (1H, m), 6.80–6.75
d
166.9, 162.5, 131.7, 123.0, 114.2, 65.6, 52.0, 32.3, 29.8; HRMS [MH]þ
(4H, m), 4.09 (2H, t, J¼6.0 Hz), 3.74 (3H, s), 3.67 (2H, t, J¼6.0 Hz),
Calculated. for C11H14O3Br, 273.0126; found 273.0125.
2.18 (2H, quint, J¼6.0 Hz); 13C NMR (100 MHz, CDCl3)
d 190.5, 163.2,
161.1,158.3,152.1,132.4,130.7,130.4,130.0,129.5, 125.2,121.8,120.9,
114.7, 114.5, 114.2, 112.2, 64.7, 55.5, 32.2, 29.8; HRMS [MH]þ Cal-
culated for C25H21O4ClBr, 499.0312; found 499.0307.
4.3.2.2. 4-(3-Bromopropoxy)benzoic acid (20b). In
a 50 mL
round bottom flask methyl 4-(3-bromopropoxy)benzoate 20a
(1.36 g, 5 mmol), NaOH (1.20 g, 30 mmol) were taken, methanol
(10 mL) and water (5 mL) was added to the round bottom flask. The
contents were stirred for 4 h at room temperature. Then, the
methanol was evaporated and the reaction mixture was washed
with methylene chloride. The aqueous layer was acidified to pH 1
with concentrated hydrochloric acid, extracted with ethyl acetate,
and dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure, and the residue was recrystallized from iso-
propanol to give 4-(3-Bromopropoxy)benzoic acid 20b (1.19 g, 92%)
as white solid, mp 154–156 ꢁC; Rf 0.82 (50% ethyl acetate/hexanes);
Acknowledgements
We thank DST (Project No.: SR/S1/OC-06/2008), New Delhi for
the financial support. EAJ thanks CSIR, New Delhi for SRF and DJC
Prasad thanks UGC, New Delhi. We thank DST, New Delhi, for the
funding toward the 400 MHz NMR instrument to the department of
chemistry, IIT Madras under the IRPHA scheme and ESI-MS facility
under the FIST programme.
FTIR (neat): 2985,1737,1680,1607,1511,1430,1246,1171,1047 cmꢂ1
1H NMR (400 MHz, CDCl3)
8.07 (2H, d, J¼8.8 Hz), 6.96 (2H, d,
;
Supplementary data
d
J¼8.8 Hz), 4.19 (2H, t, J¼6.0 Hz), 3.61 (2H, t, J¼6.4 Hz), 2.35 (2H, quint,
J¼6.0 Hz); 13C NMR (100 MHz, CDCl3):
d 171.8, 163.3, 132.6, 122.1,
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2010.01.026.
114.4, 65.7, 32.3, 29.8; HRMS [MH]þ Calculated for C10H12O3Br,
258.9970; found 258.9965.
References and notes
4.3.2.3. 4-(3-Bromopropoxy)benzoyl chloride (20). In
a 5 mL
1. Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon: New York, NY, 1984; Vol. 4.
2. Erber, S.; Ringshandl, R.; von Angerer, E. Anti-Cancer Drug Des. 1991, 6, 417.
3. Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W. X.; McDevitt, R.;
Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med. Chem.
2000, 43, 1293.
round bottom flask 4-(3-bromopropoxy)benzoic acid 20b (516 mg,
2 mmol) was taken to this 1 mL of thionyl chloride added and
refluxed for 90 min. The reaction was monitored by TLC, excess
thionyl chloride was removed under reduced pressure to give
4-(3-bromopropoxy)benzoyl chloride 20 (500 mg) was used for the
next step in its crude form without further purification.
4. (a) Watanabe, Y.; Yoshiwara, H.; Kanao, M. J. Heterocycl. Chem. 1993, 30, 445;
(b) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67.
5. (a) McAllister, G. D.; Hartley, R. C.; Dawson, M. J.; Knaggs, A. R. J. Chem. Soc.,
Perkin Trans. 1 1998, 3453; (b) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.;
Veitch, N. C.; Hall, D. R. Tetrahedron 2006, 62, 4214.
6. (a) Wright, J. B. J. Org. Chem. 1960, 25, 1867; (b) Royer, R.; Bisagni, E.; Hudry, C.;
Cheutin, A.; Desvoye, M. L. Bull. Soc. Chim. Fr. 1963, 1003; (c) Pene, C.;
4.3.2.4. 5-Chloro-2-(4-methoxyphenyl)-benzofuran
benzyl-BINAM (185.6 mg, 0.4 mmol), Cu(OTf)2 (144.7 mg, 0.4 mmol),
K2CO3 (830 mg, 6 mmol), and o-iodophenol (508 mg, 2.0 mmol) were
(19). Di-

2082
E.A. Jaseer et al. / Tetrahedron 66 (2010) 2077–2082
Demerseman, P.; Cheutin, A.; Royer, R. Bull. Soc. Chim. Fr. 1966, 586; (d) Kawase,
16. (a) Li, J. H.; Li, J. L.; Wang, D. P.; Pi, S. F.; Xie, Y. X.; Zhang, M. B.; Hu, X. C. J. Org.
Chem. 2007, 72, 2053; (b) Wu, M.; Mao, J.; Guo, J.; Ji, S. Eur. J. Org. Chem. 2008,
4050.
Y.; Takata, S.; Hikishima, E. Bull. Soc. Chim. Jpn. 1971, 44, 749; (e) Horaguchi, T.;
Iwanami, H.; Tanaka, T.; Hasegawa, E.; Shimizu, T. J. Chem. Soc., Chem. Commun.
1991, 44.
7. Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A. Angew. Chem., Int. Ed.
2000, 39, 1093.
17. (a) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4,
4727; (b) Saejueng, P.; Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706.
18. Carril, M.; Correa, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 4862.
19. A domino reaction or cascade reaction or tandem reaction is a consecutive
series of organic reactions which often proceed via highly reactive in-
termediates. It allows the organic synthesis of complex multinuclear molecules
from a single precursor. The substrate contains many functional groups that
take part in chemical transformations one at the time. Often a functional group
is generated in situ from the previous chemical transformation. For recent
reviews, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Or-
ganic Synthesis; Wiley-VCH, VerlagGmbH: Weinheim, 2006; (b) Tietze, L. F.
Chem. Rev. 1996, 96, 115.
20. (a) Mannam, S.; Kumar, S. A.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253;
(b) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 1083; (c) Mannam, S.;
Sekar, G. Tetrahedron Lett. 2008, 49, 2457; (d) Kumar, S. A.; Mannam, S.; Mu-
thupandi, P.; Sekar, G. Chem.d Eur. J. 2009, 15, 1086.
21. (a) Naidu, A. B.; Jaseer, E. A.; Sekar, G. J. Org. Chem. 2009, 74, 3675; (b) Rao, R. K.;
Naidu, A. B.; Sekar, G. Org. Lett. 2009, 11, 1923; (c) Naidu, A. B.; Sekar, G. Tet-
rahedron Lett. 2008, 49, 3147; (d) Naidu, A. B.; Ragunath, O. R.; Prasad, D. J. C.;
Sekar, G. Tetrahedron Lett. 2008, 49, 1057; (e) Rao, R. K.; Naidu, A. B.; Jaseer, E. A.;
Sekar, G. Tetrahedron 2009, 65, 4619; (f) Prasad, D. J. C.; Naidu, A. B.; Sekar, G.
Tetrahedron Lett. 2009, 50, 1411; (g) Thakur, K. G.; Jaseer, E. A.; Naidu, A. B.;
Sekar, G. Tetrahedron Lett. 2009, 50, 2865.
22. Howlett, D. R.; Perry, A. E.; Godfrey, F.; Swatton, J. E.; Jennings, K. H.; Spitzfaden, C.;
Wadsworth, H.; Wood, S. J.; Markwell, R. E. Biochem. J. 1999, 340, 283.
23. Choi, H. D.; Seo, P. J.; Son, B. W.; Kang, B. W. Arch. Pharm. Res. 2003, 26, 985.
24. Csekei, M.; Novak, Z.; Kotschy, A. Tetrahedron 2008, 64, 8992.
25. Furstner, A. W.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
26. (a) Chittimalla, S. K.; Chang, T. C.; Liu, T. C.; Hsieh, H. P.; Liao, C. C. Tetrahedron
2008, 64, 2586; (b) Zhang, Y.; Xin, Z. J.; Xue, J. J.; Li, Y. Chin. J. Chem. 2008, 26,
1461.
27. Kasahara, A.; Izumi, T.; Yodono, M.; Saito, R.; Takeda, T.; Sugawara, J. Bull. Chem.
Soc. Jpn. 1973, 46, 1220.
28. Eicher, T.; Schneider, V. Synthesis 1989, 372.
29. Vallet, D. C.; Ilotse, J. B.; Dayan, M. M.; Motho, D. Tetrahedron Lett. 1979, 20, 1109.
30. Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55, 5287.
8. (a) Adams, R.; Whitaker, L. J. Am. Chem. Soc. 1956, 78, 658; (b) Kalyana-
sundaram, M.; Rajagopalan, K.; Swaminathan, S. Tetrahedron Lett. 1980, 21, 4391.
9. (a) Muller, A.; Meszaros, M.; Kormendy, K. J. Org. Chem. 1954, 19, 472;
(b) Horaguchi, T.; Tanemura, K.; Suzuki, T. J. Heterocycl. Chem. 1988, 25, 39;
(c) Horaguchi, T.; Kobayashi, H.; Miyazawa, K.; Hasegawa, E.; Shimizu, T.
J. Heterocycl. Chem. 1990, 27, 935; (d) Boehm, T. L.; Showalter, H. D. H. J. Org.
Chem. 1996, 61, 6498.
10. Kim, Y. W.; Choi, H. D.; Seo, P. J.; Son, B. W. J. Korean Chem. Soc. 2001, 45, 391
Recent reports for benzofuran synthesis are; (a) Gabriele, B.; Mancuso, R.;
Salerno, G. J. Org. Chem. 2008, 73, 7336; (b) Huang, X. C.; Liu, Y. L.; Liang, Y.;
Pi, S. F.; Wang, F.; Li, J. H. Org. Lett. 2008, 10, 1525; (c) Sakai, N.; Uchida, N.;
Konakahara, T. Tetrahedron Lett. 2008, 49, 3437; (d) Fiandanese, V.; Bottalico, D.;
Marchese, G.; Punzi, A. Tetrahedron 2008, 64, 53; (e) Gabriele, B.; Mancuso, R.;
Salerno, G.; Costa, M. Adv. Synth. Catal. 2006, 348, 1101; (f) Gabriele, B.; Man-
cuso, R.; Salerno, G.; Costa, M. J. Org. Chem. 2007, 72, 9278.
11. (a) Arcadi, A.; Cacchi, S.; DelRosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem.
1996, 61, 9280; (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432; (c) Cacchi, S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101;
(d) Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000, 2, 297.
12. (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Synthesis 1986, 749; (b) Torii, S.; Xu, L. H.;
Okumoto, H. Synlett 1992, 515; (c) Dyker, G. J. Org. Chem. 1993, 58, 6426; (d)
Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270; (e)
Fancelli, D.; Fagnola, M. C.; Severino, D.; Bedeschi, A. Tetrahedron Lett. 1997, 38,
2311; (f) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1
1997, 2815; (g) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017.
13. For reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428; (b) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (c) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337; (d) Dehli, J. R.; Legros, J.;
Bolm, C. Chem. Commun. 2005, 973.
14. (a) Castro, C. E.; Gauchan, E. J.; Owsley, D. C. J. Org. Chem.1966, 31, 4071; (b) Doad,
G. J. S.; Barltrop, J. A.; Petty, C. M.; Owen, T. C. Tetrahedron Lett. 1989, 30, 1597.
15. Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,
4716.