A new synthesis of 2-aryl/alkylbenzofurans by visible light stimulated intermolecular Sonogashira coupling and cyclization reaction in water

Article abstract of DOI:10.1016/j.tetlet.2012.08.078

A visible light induced rapid one pot intermolecular Sonogashira coupling and 5-endo-dig cyclization in water of ortho-halophenols and terminal alkynes catalyzed by [Pd] have been developed to furnish 2-aryl/alkyl benzofurans in good yields sans Ru or Ir

Full text of DOI:10.1016/j.tetlet.2012.08.078

Tetrahedron Letters 53 (2012) 5883–5886
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Tetrahedron Letters
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A new synthesis of 2-aryl/alkylbenzofurans by visible light stimulated
intermolecular Sonogashira coupling and cyclization reaction in water
⇑
Somnath Ghosh , Jhantu Das, Forid Saikh
Department of Chemistry, Jadavpur University, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A visible light induced rapid one pot intermolecular Sonogashira coupling and 5-endo-dig cyclization in
water of ortho-halophenols and terminal alkynes catalyzed by [Pd] have been developed to furnish 2-
aryl/alkyl benzofurans in good yields sans Ru or Ir complexes or any other additives.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 July 2012
Revised 16 August 2012
Accepted 17 August 2012
Available online 29 August 2012
Keywords:
Intermolecular photochemical Sonogashira
coupling
5-endo-Dig cyclization
Halophenols
Alkynes
Water
2-Arylbenzofurans are important naturally occurring oxygen
heterocycles known for their various biological activities1 and a
number of benzofuran core units containing natural products are
available in nature.2 For example, pterofuran,3 isopterofuran,4 vig-
nafuran,5 6-demethylvignafuran6 and so forth are of interest, as
several have been recognized as antifungal phytoalexins. Hence,
these molecules, for a long time, are attractive target for the syn-
thesis by organic chemists and various methodologies7 have been
developed ever since the synthesis of 2-phenylbenzofuran was first
reported by Dilthey and Quint8 in 1931 and later on by Yates9 in
1952.
Sunlight is clean, abundantly available, and most importantly,
environmentally friendly in all respects. In overall solar spectrum
visible light (390–750 nm) accounts for 43%. As such, any natural
reaction in vivo efficiently utilizes solar energy and converts it into
chemical energy. As many organic compounds do not absorb visi-
ble light efficiently, visible-light photoredox catalysts such as
ruthenium or iridium polypyridyl complexes have been employed
to propel energy from visible light into organic molecules for C–C
bond-formation.20–22 Moreover, the use of light accelerates certain
reactions in organic synthesis. Such photochemical activation of
substrate without additional reagents very often minimizes the
formation of byproducts; and for this reason, photochemical reac-
tions occupy an interesting position in the realm of green chemis-
try. These concepts have been successfully employed in many
organic syntheses employing visible light or sunlight or UV light,
for example, Suzuki–Miyaura and Stille-type coupling reactions,23
Nazarov cyclization,24 Wittig reaction,25,26 Heck reaction27 etc.
and excellent reviews28,29 on photochemical reactions have been
published.
Palladium catalyzed Sonogashira reaction10 of terminal alkynes
and 2-iodo/bromo phenols followed by cyclization reaction has la-
ter become a popular strategy for the synthesis of 2-alkyl/aryl-
benzofurans. A variety of reaction conditions have been used for
this purpose, such as, Pd(PPh3)2Cl2/CuI in THF,11 Pd(PPh3)2Cl2/CuI
in Et3N,12 FeCl3 in toluene under refluxing condition,13
Pd(PPh3)2Cl2/CuI in DMF,14 and also from 2-chlorophenol.15
On the other hand, palladium catalyzed Sonogashira reactions
in water16 under thermal condition or under UV light17 and by
using a Ru/bipyridine complex as energy transfer agent under vis-
ible light18 have been reported. Application of this reaction for the
synthesis of substituted benzofurans is also available in the litera-
ture.19 However, most of these reactions need prolonged reaction
time or phase transfer catalyst, or external additives.
We have been carrying out the synthesis of benzofurans30,31 for
over a period of time and recently, we have reported an efficient
methodology for the synthesis of title compounds by intramolecu-
lar photochemical Wittig reaction,26a (Eq. 1, Fig. 1). Our enduring
interest in this arena has led us to devise a visible light induced
palladium catalyzed, copper-free Sonogashira reaction in water
for the synthesis of 2-aryl/alkylbenzofurans in an environmentally
friendly condition (Eq. 2, Fig. 1).
⇑
Corresponding author. Tel./fax: +91 033 2414 6223.
E-mail address: ghoshsn@yahoo.com (S. Ghosh).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.078

5884
S. Ghosh et al. / Tetrahedron Letters 53 (2012) 5883–5886
Previous work:
CH2PPh3Br
O C
CCl4 / Et3N / hν
(1)
O
Ar / R
Ar / R
MW / Et3N
Neutral Al2O3
O
This study:
R
R
X
[Pd] / ligand / Et3N
H2O, visible light
Ar/ R1
(2)
+
Ar/ R1
OH
O
X = Br, I
Figure 1. Visible light catalyzed synthesis of 2-aryl/alkyl benzofurans.
ylphosphine at various mole percent (mol %), the reaction failed
to produce benzofuran. Addition of cuprous chloride as a co-cata-
lyst also did not improve the yield of the product and 1,4-diphe-
nyl-but-1,3-diyne was obtained by coupling of phenyl acetylene
itself. The optimum reaction condition requires the use of
palladium chloride (10 mol %) and triphenylphosphine (20 mol %)
in conjunction with triethylamine (4 mmol) for ortho-iodophenol
and phenyl acetylene each 1 mmol (Table 1, entry 6). It is pre-
sumed that triethyl amine (in excess) acts not only as a base but
also as a co-solvent to help the organic substrates to disperse in
water.
These experimental observations indicate that the catalytic
amount of Pd(PPh3)2Cl2 or Pd(PPh3)4 is generated in the reaction
mixture when PPh3 and PdCl2 are preheated at the beginning. Once
Sonogashira process commences, the reaction may proceed
through Pd(0) via a radical path under light (Scheme 2), thereby
shortening the reaction time. Mechanistically, it may be proposed
that in the first step, ortho-iodophenol reacts with Pd(0) under
photo irradiation to afford aryl radical (I) and Pd(1)I via one elec-
tron transfer32 that further couples with Pd(1)I to give aryl palla-
dium intermediate (II); and gives the coupling product (IV)
through an intermediate (III). In this pathway, a rather unfamiliar
Pd(1)I-type species may be involved that may exist in equilibrium
with PdI dimer17,33 under photochemical condition.34 Finally the
intramolecular cyclization of IV gives 2-phenylbenzofuran (1a).
When this optimized reaction condition was applied to substi-
tuted ortho-iodo/bromophenols and different terminal aliphatic
1. PdCl2 (10 mol%)
2. PPh3 (20 mol%)
Et3N, H2O, hν
R
R
X
Ar/ R1
+
Ar/ R1
OH
O
1
a :
c :
e :
b :
R = H, X = I/Br, Ar = C6H5
R = CH3, X = Br, Ar = C6H5
d :
f :
R = H, X = I, Ar = (p-OCH3)C6H5
R = Cl, X = Br, Ar = (p-OCH3)C6H5
R = Cl, X = Br, R1 = C6H13
R = Cl, X = Br, Ar =C6H5
R = CH3, X = Br, Ar = (p-OCH3)C6H5
g :
R = H, X = I, Ar = (p-Cl)C6H5
h :
Scheme 1. Visible light catalyzed Sonogashira coupling and cyclization reaction of
ortho-halophenols and terminal alkynes in water.
Table 1
Optimization of reaction condition
Ph
1.
2. PdCl2
3. ligand
I
O
Et3N, H2O, hν
OH
Entry
PdCl2 (mol %)
Ligand (mol %)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
2
2
5
10
10
10
10
10
10
PPh3, 5
PPh3, 5
60
60
9
12
33
43
54
63
62
0
PPh3, 10
PPh3, 20
PPh3, 20
PPh3, 20
PPh3, 20
bdba, 20
bopd, 20
120
60
90
105
120
105
105
Δ
Pd(PPh3)2Cl2
PdCl2
PPh3
0
Pd(PPh3)4
[Pd]
Bold value indicates the optimized condition for reaction.
a
Isolated yield after column chromatographic separation over silica gel.
dba: Dibenzylidene acetone; opd: ortho-phenylenediamine.
b
I
[Pd]/hν
Ph
OH
O
Ph
The present procedure for the synthesis of 2-substituted benzo-
1a
furans (1) consists of photo-irradiation of substituted ortho-iodo/
bromophenols and terminal alkynes in the presence of palladium
chloride, triphenyl phosphine and triethyl amine in water and after
subsequent work-up, the products are obtained in reasonably good
yields (49–77%) by chromatography over silica gel in a highly pure
state. The reaction proceeds through two consecutive steps: the
Sonogashira coupling reaction mediated by PdCl2 and PPh3 as a
ligand, followed by 5-endo-dig cyclization to give the products
(Scheme 1).
In order to optimize the reaction condition, we carried out the
reaction under visible light by varying the amount of PdCl2, ligand,
base and also the reaction time using ortho-iodophenol and phenyl
acetylene (Table 1). For example, when dibenzylidene acetone or
ortho-phenylenediamine was used as a ligand in place of triphen-
Ph
[Pd]/hν
hν
[Pd(1)I]2
Pd(1)I
OH
Pd
IV
[Pd]
Ph
PdI
OH
Pd(1)I
Ph
HI
OH
OH
I
II
III
Scheme 2. Plausible mechanism for the synthesis of 2-aryl/alkylbenzofurans.

S. Ghosh et al. / Tetrahedron Letters 53 (2012) 5883–5886
5885
Table 2
Results of visible light catalyzed Sonogashira coupling and cyclization reaction of ortho-halophenols and terminal alkynes
Entry
Halophenol
Alkyne
2-Aryl/alkylbenzofuransa
Yieldb (%)
I
Ph
1
O
63
57
OH
Br
1a
Ph
Ph
2
3
O
OH
1a
H3C
Cl
Br
H C
3
49
63
O
OH
1b
Br
OH
Ph
Cl
4
5
O
1c
I
H3CO
H3CO
O
71
53
58
OH
1d
OCH
3
Br
OH
H3C
H C
3
O
6
7
1e
OCH
3
Br
Cl
Cl
H3CO
O
OH
1f
OCH
3
I
Cl
O
8
9
51
77
OH
1g
Cl
Cl
Br
Cl
CH
O
3
OH
1h
a
All products were characterized by their satisfactory spectral data and also by comparison with the literature data (vide Supplementary data).
Yield refers to combined amounts of first and second crops of crystallized products obtained after chromatography (for 1 h: only chromatographically separated yield as it
b
is liquid).
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or aromatic alkynes, 2-substituted benzofurans were formed in
very good yield (Table 2) and the reaction smoothly occurred in
both cases.
In conclusion, we have developed a rapid, visible light induced
one pot two reactions (Sonogashira and 5-endo-dig cyclization) for
the synthesis of 2-alkyl/arylbenzofurans in an environmentally
friendly nature’s solvent like water. The present methodology35 is
an improvement over existing ones in terms of efficiency and time
of reaction.
Acknowledgments
The authors wish to thank the University Grants Commission
and the Council of Scientific and Industrial Research, Government
of India to the authors (J.D. & F.S.) and partly funded by the Centre
for Advance Studies, and DST-PURSE program of the Department of
Chemistry, Jadavpur University.
Supplementary data
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08.078.
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35. Method: Palladium chloride (17.7 mg, 10 mol %), triphenylphosphine (52.4 mg,
20 mol %) distilled water (25 mL) were taken in an Erlenmeyer flask and heated
on water bath for 10 min followed by cooling at room temperature. Afterwards,
2-halophenols and terminal alkynes were added followed by addition of
triethylamine (400 mg, 4 mmol). The reaction mixture was irradiated with a
150 W tungsten lamp (Philips India Ltd) for 1 h and 45 min. After the reaction
was complete (monitored by TLC), the product was isolated, by Et2O (20 mL)
and purified by column chromatography on silica gel (2% ethyl acetate in light
petrol, 60–80 °C) and crystallized further from appropriate solvents. 2-(n-
Hexyl)-5-chloro-benzofuran (1 h): Colorless liquid. 1H NMR (500 MHz, CDCl3,
22 °C) d 7.43 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 8.8, 2.0,
2.5 Hz, 1H), 6.32, (s, 1H), 2.75 (t, J = 7.5 Hz, 2H), 1.72 (m, 2H), 1.32 (m, 9H) ppm;
13C NMR (125 MHz, CDCl3, 22 °C) d 161.5, 153.1, 130.5, 128.2, 123.2, 119.9,
111.7, 101.6, 31.6, 29.0, 28.6, 27.6, 22.7, 14.1 ppm. HRMS (ESI) m/z [M+H]+,
calcd. for C14H17ClO 237.1047; found 237.2703.