A practicable environmentally benign one-pot synthesis of 2-arylbenzofurans at room temperature

Article abstract of DOI:10.1039/c2gc16181h

An environmentallyfriendly one-pot synthesis of 2-arylbenzofurans under ambient temperature has been developed. It features an ortho-hydroxyl group assisted Wittig reaction of substituted salicylaldehyde followed by an in situ oxidative cyclization. Its advantages include readily available and non-hazardous materials, benign reaction conditions (room temperature, green solvent and one-pot manner), easy work-up and high overall yields. Utilizing this methodology, various 2-aryl-benzofurans including four natural products have been synthesized. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2gc16181h

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 695
www.rsc.org/greenchem
PAPER
A practicable environmentally benign one-pot synthesis of 2-arylbenzofurans
at room temperature†
Lian-Yan Liao, Gang Shen, Xue Zhang and Xin-Fang Duan*
Received 21st September 2011, Accepted 24th November 2011
DOI: 10.1039/c2gc16181h
An environmentallyfriendly one-pot synthesis of 2-arylbenzofurans under ambient temperature has been
developed. It features an ortho-hydroxyl group assisted Wittig reaction of substituted salicylaldehyde
followed by an in situ oxidative cyclization. Its advantages include readily available and non-hazardous
materials, benign reaction conditions (room temperature, green solvent and one-pot manner), easy work-
up and high overall yields. Utilizing this methodology, various 2-aryl-benzofurans including four natural
products have been synthesized.
usually carried out using either strong bases such as n-BuLi,17
Introduction
(Me3Si)2NNa,10d t-BuOK18 or other organic bases such as
DBN,19 along with the relatively harsh conditions.
Herein we report an environmentally friendly Wittig reaction
The benzofuran motif is widely presented in natural products
and biologically active compounds.1 It has drawn extensive
attention due to its broad range of biological activities with sig-
nificant pharmaceutical potentials in anticancer,2 antiviral,3 anti-
fungal,4 and immunosuppressive,5 etc. To date, various
methodologies have been developed to prepare benzofuran-con-
taining analogs, including: (a) metal-mediated Sonogashira
couplings,6 C–C7 or C–O8 arylation reactions and oxidative aro-
matic C–O bond formation;9 (b) oxidative cyclization of o-vinyl-
phenols;10 (c) dehydration of α-phenoxy ketones;11 (d)
intramolecular McMurry couplings12 or Wittig reactions.13 Gen-
erally, the application of these reported methodologies has been
limited by several factors: (a) unavailable starting materials; (b)
relatively harsh reaction conditions; (c) expensive transition-
metal catalysts; and (d) multiple steps and low yields.
Previously we have reported a two-step synthesis of benzofur-
ans. It involved a selective cross-McMurry coupling of the sub-
stituted salicylaldehyde with an aromatic aldehyde, followed by
the oxidative cyclization.14 One major challenge of this synthetic
protocol is the difficult separation of the ortho-vinylphenols
from the by-products produced during the cross-McMurry coup-
lings. Therefore, it is highly desirable to develop a convenient
and eco-friendly synthesis of the ortho-vinylphenols. We
believed that this could be achieved through the Wittig reaction
of a readily available substituted salicylaldehyde with triphenyl-
phosphonium. Although a number of reports have discussed
improving the green credentials of Wittig reactions using a sol-
ventless procedure15 or using aqueous media,16 the Wittig reac-
tions of salicylaldehyde or protected salicylaldehyde were
of substituted salicylaldehyde without protecting groups. The
reaction was achieved in high yield at room temperature using
KOH in an environmentally benign solvent (PEG-600). Utilizing
this greener Witttig reaction, a facile one-pot synthesis of 2-aryl-
benzofurans has also been developed.
Results and discussion
Our initial studies started with the Wittig reaction of salicylalde-
hyde (1a) with benzylphosphonium chloride (2a) in the presence
of several readily available inorganic bases. As shown in
Table 1, Na2CO3, K2CO3, K3PO4, LiOH, and NaOH could
promote the reaction to some extent at room temperature
(Table 1, entries 1–5). Here the best results were obtained when
using KOH as a base (Table 1, entries 6–9), while the solvent
effect indicated that better results were obtained with the non-
polar solvent, such as toluene or hexane (Table 1, entries 10–14).
It is usually considered that at least two equivalents of base
are needed to promote the Wittig reaction of the unprotected sali-
cylaldehyde, one for neutralizing OH and one to deprotonate the
triphenylphosphonium.17,18 Nevertheless, our experiments
demonstrated that this Wittig reaction could proceed in high
yield using only 1.2 equivalents of KOH (Table 1, entries 8 and
14). We rationalized that the hydroxyl group of the salicylalde-
hyde could play a role that assists the Wittig reaction, as illus-
trated in Scheme 1. In contrast to the general impression that
protecting groups are usually required for any acidic protons
(OH, NH, etc.) on either ylide or carbonyl components, in this
case the corresponding Wittig reaction can be conducted under
milder conditions than those without the ortho-hydroxyl group.
This rationale has been further confirmed by the fact that the
reaction of the potassium salt of salicylaldehyde with benzylpho-
sphonium chloride also afforded the corresponding alkene in
College of Chemistry, Beijing Normal University, Beijing, 100875,
China. E-mail: xinfangduan@vip.163.com; Fax: +86-10-58802075
†Electronic supplementary information (ESI) available: Characterization
data for known benzofurans and NMR spectra for all compounds. See
DOI: 10.1039/c2gc16181h
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 695–701 | 695

View Online
Table 1 Effect of solvents, bases and hydroxyl group on the Wittig reaction at ambient temperaturea
Entry
Aldehyde
Phosphonium salt
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1a (R = o-OH)
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b (R = o-OK)
1c (R = o-OMe)
1d (R = m-OH)
1e (R = p-OH)
1f (R = H)
1f
2a (Ar = Ph; X = Cl)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Na2CO3 (2.0 eq.)
K2CO3 (2.0 eq.)
K3PO4 (2.0 eq.)
LiOH·H2O (2.0 eq.)
NaOH (2.0 eq.)
KOH (2.0 eq.)
KOH (1.5 eq.)
KOH (1.2 eq.)
KOH (1.1 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
—
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
EtOH
44
45
67
58
79
89
89
89
85
45
45
58
68
86
88
9
10
11
12
13
14
15
16
17
18
19
20
DMF
CH3CN
CH2Cl2
hexane
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
KOH (1.2 eq.)
78c
NRd
NRd
NRd
NRd
2a
2a
2b (Ar = o-HOC6H4; X = Br)
2c (Ar = m-HOC6H4; X =Cl)
a The mole ratio of aldehyde (1) to phosphonium salt (2) was 1 : 1.1. b Isolated yield. c Only 10–20% conversion was observed after overnight stirring
at ambient temperature, and the yield was obtained after heating at reflux for 8 h. d No reaction (NR) was observed after overnight stirring at ambient
temperature or at reflux (above 8 h).
and yields were inconsistent. The best yield obtained was 53%
(Table 2, entry 1). Similarly the results from using aqueous
media were not ideal either (Table 2, entries 2 and 3). Next,
given the fact that polyethylene glycol (PEG) has been proven to
be a green solvent21 and has been widely used in biotechnology
and medicine,22 we tested the Wittig reaction in this benign
Scheme 1 ortho-Hydroxyl group assisted Wittig reaction.
solvent. Among the PEGs screened, the reaction in
PEG-600 gave a better result with a shorter reaction time and in
higher yield at room temperature (Table 2, entries 4–7). Mean-
high yield (88%) (Table 1, entry 15). In contrast, the Wittig reac-
tion of 2-MeOPhCHO with benzylphosphonium chloride went
slowly at room temperature and only afforded the desired
product after heating at reflux for 8 h (Table 1, entry 16). No pro-
ducts were observed for the reactions of 3- or 4-hydroxybenzal-
dehyde with benzylphosphonium chloride (Table 1, entries 17
and 18) or PhCHO with 2- or 3-hydroxybenzylphosphonium
bromide (Table 1, entries 19 and 20), even after the reaction mix-
tures were stirred at reflux temperature for 8 h. These experimen-
tal data correlated well with our proposed mechanism.
while, it was found that the recovered PEG-600 can be re-used
several times (up to five times) without losing its activity
(Table 2, entry 7). This condition was also applied to the other
substrates (Table 2, entries 9–13), and as expected, the corre-
sponding o-vinylphenols were obtained in high yields as well. It
was noted that the ester group was tolerable even if KOH was
used in the reactions (Table 2, entry 10).
We also carried out the Wittig reaction on a larger scale
(10 mmol of 1a, 11 mmol of 2a, 12 mmol of KOH, 50 mL of
PEG-600), the yield was almost identical to that obtained in the
small scale (∼86%). This demonstrated the potential of a large
scale application for this protocol. Additionally, the post-Wittig
reaction did not involve any organic solvent. After the reaction
time, the mixture was directly poured into water and acidified
with aqueous HCl solution. The resulting precipitate was col-
lected and the filtrate was concentrated to recover the PEG-600.
The crude products were subjected to further purification either
through recrystallization (Table 2, entries 6, 10, 11) or by flash
column chromatography. The newly formed triphenylphosphine
oxide was also collected in high yield, which can be reduced
back to triphenylphosphine if needed.23
Overall, compared with the reported procedures,17,18 the afore-
mentioned Wittig reaction of salicylaldehyde can be carried out
under significantly milder conditions (e.g. with only 1.2 eq. of
KOH at room temperature). Since organic solvents are usually
one of largest contributors to the magnitude of the Wittig reac-
tion E factor,20 in order to improve the green credentials of this
Wittig reaction, we attempted to conduct the reaction in a
solvent-free manner or in an eco-friendly solvent. In the solvent-
free case, the neat reaction mixture was pulverized with a pestle
and mortar at ambient temperature. Repeated tests indicated that
the reactions in solid phase went very slowly at room temperature
696 | Green Chem., 2012, 14, 695–701
This journal is © The Royal Society of Chemistry 2012

View Online
Table 2 Wittig reactions of the unprotected salicylaldehyde in the solid phase or in an eco-friendly solventa
Entry
Aldehyde
Phosphonium salt
Solvent
Conditions
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
—
H2O
H2O
RT, 12 h
RT, 20 h
80 °C, 16 h
RT, 38 h
RT, 36 h
RT, 12 h
RT, 12 h
RT, 48 h
RT, 17 h
RT, 12 h
RT, 16 h
RT, 14 h
RT, 16 h
53
34
63
76
PEG-300
PEG-400
PEG-600
PEG-600d
PEG-800
PEG-600
PEG-600
PEG-600
PEG-600
PEG-600
75
86(73)c
85e,83f
82
9
1b
1a
1a
2a
86
10
11
12
13
2d (Ar = 4-MeOOCC6H4; X = Cl)
2e (Ar = 4-MeOC6H4; X = Cl)
2a
2e
89(76)c
85(71)c
87
1g (R = 3-OMe)
1g
86
a The mole ratio of aldehyde (1), phosphonium salt (2) and KOH was 1 : 1.1 : 1.2. b Isolated yield. c Yields in parenthesis were obtained after
purification based on recrystallization. d Recovered PEG-600. e Yield was obtained when recovered PEG-600 was used for up to three times. f Yield
was obtained when recovered PEG-600 was used for 4–5 times.
Utilizing this Wittig reaction, we further developed the one-
pot synthesis of 2-arylbenzofuran in an eco-friendly manner.
This was achieved through the Wittig reaction of substituted
salicylaldehyde with triphenylphosphonium, followed by in situ
Conclusions
We have developed an environmentally friendly Wittig reaction
of the substituted salicylaldehyde without any protecting groups.
The reaction proceeded via an ortho-hydroxyl-assisted mechan-
ism. Its advantages include: the use of a green solvent at room
temperature, easy work-up and high yields. Based on this green
Wittig reaction, a one-pot synthesis of 2-arylbenzofurans has
also been developed in an eco-friendly manner. The one-pot syn-
thetic approach features readily available and non-hazardous
oxidative cyclization of the resulting o-vinylphenols. Here
10a,14
I2/K2CO3
was chosen for the oxidative cycliztion because
iodine is an inexpensive, non-toxic, readily available reagent.
The generality and flexibility of this approach has been well
established (Table 3). Corresponding Wittig reactions proceeded
smoothly in most cases, and electron-donating groups, such as
MeO– was beneficial to the oxidative cyclization of o-vinylphe-
nols, leading to higher overall reaction yields. Corresponding
work-up was very straightforward and similar to the Wittig
reaction.
This one-pot synthetic approach offers one of the most practi-
cable, effective and environmentally benign protocols for the
preparation of 2-arylbenzofurans. Its advantages include: readily
available and non-hazardous materials, benign reaction con-
ditions (room temperature, green solvent and one-pot manner),
easy work-up and high overall yields. In addition, this approach
does not require the use of transition metal catalysts. Because it
is very challenging to prepare halogen (especially iodine)-incor-
porated benzofurans through metal-mediated Sonogashira coup-
lings,6 C–C7 or C–O8 arylation reactions, our current protocol
should address this limitation to readily yield the halogen-con-
taining benzofurans (Table 3 entries 13–17).
Finally we applied this protocol to the synthesis of several
naturally occurring benzofuran compounds. Corsifuran C,24 iso-
lated from Corsinia coriandrina as an origin of stilbenoid, was
made using the one-pot reaction providing the desired product in
91% yield (Table 3, entry 9). Erythbidin E,25 cicerfuran10d,14a
and ebenfuran I26 were readily prepared in only two steps, start-
ing from the Wittig reactions of benzyloxy-substituted salicylal-
dehydes (1h–1p) with benzylphosphonium chlorides (2nand2o),
followed by the deprotection step (illustrated in Scheme 2).
Scheme 2 Total synthesis of cicerfuran, ebenfuran I and erythbidin E.
Green Chem., 2012, 14, 695–701 | 697
This journal is © The Royal Society of Chemistry 2012

View Online
Table 3 One-pot synthesis of 2-arylbenzofuran at ambient temperature in PEG-600
Entry
1
Aldehyde
Phosphonium salt
Product (yield)a
1a
2e
2
3
1a
1a
2f (Ar = 4-MeC6H4)
2g (Ar = 3,4-(MeO)2C6H3)
4
1a
2h (Ar = 3,4-(OCH2O)C6H3)
5
6
1a
1g
2i (Ar = thiophen-2-yl)
2e
7
8
1g
2a
1h (R = 4-MeO)
2j (Ar = 3-MeO-4-OBnC6H3)
9
1i (R = 5-MeO)
2e
2f
10
1i
11
12
13
14
1j (R = 4-BnO)
1k (R = 5-Me)
1l (R = 5-Cl)
1m (R= 5-Br)
2a
2k (Ar = 4-ClC6H4
2e
2l (Ar = 4-BnOC6H4)
698 | Green Chem., 2012, 14, 695–701
This journal is © The Royal Society of Chemistry 2012

View Online
Table 3 (Contd.)
Entry
15
Aldehyde
Phosphonium salt
Product (yield)a
1n (R = 5-I)
2e
16
17
1n
2l
1o (R = 5-Br-3-MeO)
2g
18
1p (R = 4-MeO-5-OBn)
2m (Ar = 2-BnO-4-MeC6H3)
a Overall isolated yield. b The yields were obtained after further purification either by flash column chromatography or through recrystallization (in
parenthesis).
materials, benign reaction conditions (room temperature, green
solvent and one-pot manner), easy work-up and high overall
yields. Following this methodology, various 2-arylbenzofurans
including four natural products have been readily synthesized.
back to triphenylphosphine according to the reported method.23
The filtrate was evaporated and the resulting residue was further
purified by recrystallization or chromatography on silica gel
column to give desired product 3.
Experimental
General procedure for the one-pot synthesis of the
2-arylbenzofurans
All reagents required for this study were purchased from com-
mercial sources. H and 13C NMR spectra were recorded at 400
1
A mixture of salicylaldehyde (1, 1.0 mmol), benzyltriphenylpho-
sphonium chloride (2, 1.1 mmol) and KOH (82 mg, 1.2 mmol)
in PEG-600 (5 mL) was stirred at room temperature until the
reaction was completed (monitored by TLC). The mixture was
diluted with 5 mL of PEG-600, and finely ground anhydrous
K2CO3 (1.1 g, 8.0 mmol) was added. The stirring was continued
for 2–3 h before iodine (2.1 g, 8.0 mmol) was added. After the
oxidative cyclization was complete (monitored by TLC), the
mixture was poured into water (50 mL), and treated with satu-
rated aqueous NaHSO3 to remove the unreacted iodine. The
obtained solid and mother liquor were dealt with in the same
way as described in the general procedure for the Wittig reaction.
The desired 2-arylbenzofurans 4 were obtained after the work-up
described above.
and 100 MHz, respectively, on a Bruker Avance DPX 400
(400 MHz) spectrometer in CDCl3 using TMS as an internal
standard. MS were recorded on a TRACE mass spectrometer. IR
spectra were recorded on a Vaatar 360 FT-IR spectrometer.
Melting points are uncorrected.
General procedure for the Wittig reaction of (substituted)
salicylaldehyde in PEG-600
To 10 mL of PEG-600, salicylaldehyde (1, 2.0 mmol), benzyltri-
phenylphosphonium chloride or bromide (2, 2.2 mmol) and
KOH (164 mg, 2.4 mmol) was added. The mixture was stirred at
room temperature until the reaction was completed (monitored
by TLC). The reaction mixture was poured into water (50 mL),
acidified to pH 2–3 with a 2 N HCl aqueous solution, after
which a (sticky) solid was formed (Note: when the solid was
sticky, silica gel (∼5 g) was added and stirred for 0.5 h). The
mother liquor was filtered off and subjected to vacuum distilla-
tion to recover the PEG-600. The filtered solid was treated with
light petroleum–ethyl acetate at reflux temperature. After it was
cooled to room temperature, the precipitated triphenylphosphine
oxide was obtained in over 90% yield, which should be reduced
Characterization data for unreported 2-arylbenzofurans
2-(4-(Benzyloxy)-3-methoxyphenyl)-6-methoxybenzofuran (4hj)
White solid; m.p. = 118–120 °C; 1H NMR (CDCl3, 400 MHz) δ
7.46 (d, J = 7.4 Hz, 2H), 7.35–7.43 (m, 4H), 7.30–7.34 (m, 2H),
7.07 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.86 (dd, J1 =
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 695–701 | 699

View Online
2-(2,4-Bis(benzyloxy)phenyl)-5-(benzyloxy)-6-methoxy-
benzofuran (4pn)
8.5 Hz, J2 = 2.1 Hz, 1H), 6.83 (s, 1H), 5.21 (s, 2H), 4.0 (s, 3H),
3.87 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 157.7, 155.6,
155.1, 149.7, 148.2, 136.9, 128.6, 127.9, 127.2, 124.2, 122.7,
120.7, 117.3, 114.0, 111.7, 108.1, 99.9, 95.8, 70.9, 56.0, 55.7;
MS (AP) m/z 361 (M + H)+. Anal. calcd for C23H20O4: C,
76.65; H, 5.59; Found: C, 76.53; H, 5.71.
White solid; m.p. = 157.1–158.5 °C. 1H NMR (CDCl3,
400 MHz) δ 7.92 (d, J = 9.3 Hz, 1H), 7.30–7.50 (m, 15H), 7.09
(s, 1H), 7.03 (s, 1H), 6.99 (s, 1H), 6.69–6.70 (m, 2H), 5.19 (s,
2H), 5.15 (s, 2H), 5.08 (s, 2H), 3.94 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 159.4, 156.2, 151.6, 148.9, 148.4, 145.3, 137.4,
136.6, 136.5, 128.7, 128.6, 128.4, 128.1, 127.7, 127.6, 127.5,
127.4, 121.8, 113.6, 106.1, 105.8, 104.7, 100.8, 95.4, 71.9, 70.5,
70.2, 56.3; MS (AP) m/z 543 (M + H)+. Anal. Calc. for
C36H30O5: C, 79.68; H, 5.57; Found: C, 79.34; H, 5.80.
2-(4-(Benzyloxy)phenyl)-5-bromobenzofuran (4ml)
White solid; m.p. = 197–199 °C; 1H NMR (400 MHz, CDCl3) δ
7.79 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 7.32–7.48 (m, 7H), 7.05
(d, J = 4.8 Hz, 2H), 6.83 (s, 1H), 5.13 (s, 2 H); 13C NMR
(100 MHz, CDCl3) δ 159.5, 157.3, 153.5, 136.6, 131.5, 128.7,
128.2, 127.5, 127.5, 126.6, 126.5, 123.2, 123.0, 115.9, 115.3,
99.1, 70.1; MS (EI) m/z 380 (M+, 40%), 287 (35%), 179 (45%),
91 (100%); Anal. calcd for C21H15BrO2: C, 66.51; H, 3.99;
Found: C, 66.27; H, 3.98.
Acknowledgements
We gratefully acknowledge National Nature Science Foundation
of China (20672014 and 21072022), Fundamental Research
Funds for the Central Universities, Beijing Key Subject Program
and Dr Yao Ma for revising this manuscript.
2-(4-(Benzyloxy)phenyl)-5-iodobenzofuran (4nl)
Notes and references
White solid; m.p. = 187.7–189.3 °C; 1H NMR (CDCl3,
400 MHz) δ 7.80 (d, J = 1.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H),
7.44 (dd, J1 = 8.6 Hz, J2 = 1.6 Hz, 1H), 7.31–7.40 (m, 4H), 7.27
(d, J = 7.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.8
Hz, 2H), 6.73 (s, 1H), 5.05(s, 2H); 13C NMR (CDCl3,
100 MHz) δ 159.1, 156.2, 153.3, 136.7, 132.1, 132.0, 129.0,
128.4, 127.7, 126.4, 121.9, 115.3, 113.3, 99.4, 99.3, 87.2, 69.3;
MS (AP) m/z 427 (M + H)+; Anal. calcd for C21H15IO2: C,
59.17; H, 3.55; Found: C, 59.26; H, 3.78.
1 A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Comprehensive Hetero-
cyclic Chemistry II, Pergamon Press, Oxford, 1996, vol. 2, p. 259.
2 (a) E. Navarro, S. J. Alonso, J. Trujillo, E. Jorge and C. Perez, J. Nat.
Prod., 2001, 64, 134; (b) J. D. Lambert, R. O. Meyers,
B. N. Timmermann and R. T. Dorr, Cancer Lett., 2001, 171, 47;
(c) A. Banskota, Y. Tezuka, K. Midorikawa, K. Matsushige and
S. Kadota, J. Nat. Prod., 2000, 63, 1277.
3 (a) S. A. Galal, A. S. Abd El-All, M. M. Abdallah and H. I. El-Diwani,
Bioorg. Med. Chem. Lett., 2009, 19, 2420; (b) J. Craigo, M. Callahan,
R. C. C. Huang and A. L. DeLucia, Antiviral Res., 2000, 47, 19.
4 H. S. Deokar, P. Puranik and V. M. Kulkarni, Med. Chem. Res., 2009, 18,
206.
5 M. Gordaliza, M. Castro, J. M. Corral, M. Lopez-Vazquez, A.
S. Feliciano and G. T. Faircloth, Bioorg. Med. Chem. Lett., 1997, 7,
2781.
6 For selected recent references, see: (a) M. A. Berliner, E. M. Cordi,
J. R. Dunetz and K. E. Price, Org. Process Res. Dev., 2010, 14, 180;
(b) M. Csekei, Z. Novak and A. Kotschy, Tetrahedron, 2008, 64, 8992;
(c) O. Takashi, N. Daisuke, T. Rie and W. Akimori, Org. Lett., 2008, 10,
4967.
7 (a) E. Masaru, U. Masahiro, O. Yoshiteru and K. Yoshinori, Tetrahedron
Lett., 2007, 48, 8918; (b) L.-C. Campeau, M. Parisien, A. Jean and
K. Fagnou, J. Am. Chem. Soc., 2006, 128, 581; (c) L.-C. Campeau,
P. Thansandote and K. Fagnou, Org. Lett., 2005, 7, 1857.
8 (a) J. Farago and A. Kotschy, Synthesis, 2009, 85; (b) L. Ackermann and
L. T. Kaspar, J. Org. Chem., 2007, 72, 6149; (c) M. C. Willis, D. Taylor
and A. T. Gillmore, Tetrahedron, 2006, 62, 11513; (d) M. Carril,
R. SanMartin, I. Tellitu and E. Dominguez, Org. Lett., 2006, 8, 1467;
(e) Y. Fang and C. Li, J. Org. Chem., 2006, 71, 6427; (f) C.-Y. Chen and
P. G. Dormer, J. Org. Chem., 2005, 70, 6964.
5-(Benzyloxy)-2-(2-(benzyloxy)-4-methoxyphenyl)-6-methoxy
benzofuran (4pm)
White solid; m.p. = 157.1–158.5 °C; 1H NMR (CDCl3,
400 MHz) δ 7.93 (d, J = 8.2 Hz, 1H), 7.31–7.51 (m, 10H), 7.10
(s, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.61 (d, J = 7.8 Hz, 2H), 5.21
(s, 2H), 5.16 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H). 13C NMR
(CDCl3, 100 MHz) δ 160.2, 156.2, 151.6, 148.8, 148.3, 145.3,
137.4, 136.5, 128.7, 128.5, 127.7, 127.6, 127.4, 121.8, 113.4,
105.7, 105.1, 104.6, 100.0, 95.4, 71.9, 70.5, 56.3, 55.4; MS
(AP) m/z 467 (M + H)+. Anal. Calc. for C30H26O5: C, 77.24; H,
5.62; Found: C, 77.20; H, 5.71.
9 (a) Z. D. Liang, W. Z. Hou, Y. F. Du, Y. L. Zhang, Y. Pan, D. Mao and
K. Zhao, Org. Lett., 2009, 11, 4978; (b) X. W. Guo, R. Yu, H. J. Li and
Z. P. Li, J. Am. Chem. Soc., 2009, 131, 17387.
10 For I2-mediated cyclization, see: (a) C. F. Pan, J. Yu, Y. Q. Zhou,
Z. Y. Wang and M. M. Zhou, Synlett, 2006, 1657; . For the cyclization
using DDQ, see: (b) K. Takeshi and I. Koji, Heterocycles, 2005, 65,
1641; (c) M. Fujita, G. Z. Qi, U. H. Verkerk, T. L. Dzwiniel,
R. McDonald and J. M. Stryker, Org. Lett., 2004, 6, 2653; . For other
reagents, see: (d) S. N. Aslam, P. C. Stevenson, S. J. Phythian, N.
C. Veitch and D. R. Hall, Tetrahedron, 2006, 62, 4214.
11 (a) Q. Shen, Q. Peng, J. L. Shao, X. L. Liu, Z. H. Huang, X. Z. Pu,
L. Ma, Y. M. Li, A. S. C. Chan and L. Q. Gu, Eur. J. Med. Chem., 2005,
40, 1307; (b) M. Jørgensen, F. C. Krebs and K. Bechgaard, J. Org.
Chem., 2000, 65, 8783.
12 (a) S. Rele, S. Talukdar, A. Banerji and S. Chattopadhyay, J. Org. Chem.,
2001, 66, 2990; (b) A. Furstner and A. Hupperts, J. Am. Chem. Soc.,
1995, 117, 4468.
2-(2,4-Bis(benzyloxy)phenyl)-6-methoxybenzofuran (4hn)
White solid; m.p. = 130.5–132.1 °C. 1H NMR (CDCl3,
400 MHz) δ 7.88 (d, J = 9.2 Hz, 1H), 7.26–7.44 (m, 11H), 7.02
(s, 1H), 6.97 (d, J = 1.4 Hz, 1H), 6.75 (dd, J1 = 8.5 Hz, J2 = 2.2
Hz, 1H), 6.62 (dd, J1 = 5.6 Hz, J2 = 2.2 Hz, 2H), 5.12 (s, 2H),
5.02 (s, 2H), 3.79 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
159.5, 157.6, 156.3, 154.6, 151.5, 136.6, 136.4, 128.7, 128.6,
128.2, 128.1, 127.7, 127.6, 127.5, 123.3, 120.8, 113.5, 106.1,
111.3, 106.1, 104.4, 100.8, 95.6, 70.5, 70.2, 55.7; MS (AP) m/z
437 [(M + H)+, 100], 179 (34). Anal. Calc. for C29H24O4: C,
79.80; H, 5.54; Found: C, 79.40; H, 5.44.
700 | Green Chem., 2012, 14, 695–701
This journal is © The Royal Society of Chemistry 2012

View Online
13 (a) M. L. N. Rao, D. K. Awasthi and D. Banerjee, Tetrahedron Lett.,
2010, 51, 1979; (b) Y. Yuan, H.-B. Men and C. Lee, J. Am. Chem. Soc.,
2004, 126, 14720.
(b) N. A. Colabufo, F. Berardi, R. Perrone, S. Rapposelli, M. Digiacomo
and A. Balsamo, J. Med. Chem., 2006, 49, 6607.
20 R. A. Sheldon, Chem. Ind., 1992, 903.
14 (a) X. F. Duan, J. Zeng, Z. B. Zhang and G. F. Zi, J. Org. Chem., 2007, 72,
10283; (b) X. F. Duan, G. Shen and Z. B. Zhang, Synthesis, 2010, 1181.
15 (a) T Thiemann, M. Watanabe, Y. Tanakaa and S. Mataka, New J. Chem.,
2004, 28, 578; (b) V. P. Balema, J. W. Wiench, M. Pruski and
V. K. Pecharsky, J. Am. Chem. Soc., 2002, 124, 6244.
21 (a) S. G. Konda, V. T. Humne and P. D. Lokhande, Green Chem., 2011,
13, 2354; (b) J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers,
Green Chem., 2005, 7, 64.
22 J. M. Harris, Polyethylene glycol Chemistry: Biotechnical and Biomedic-
inal Applications, Plenum Press, New York, 1992.
16 (a) J. McNulty and D. McLeod, Chem.–Eur. J., 2011, 17, 8794;
(b) J. McNulty, P. Das and D. McLeod, Chem.–Eur. J., 2010, 16, 6756;
(c) J. McNulty and P. Das, Tetrahedron Lett., 2009, 50, 5737.
17 (a) O. O. Fadeyi, R. N. Daniels, S. M. DeGuire and C. W. Lindsley, Tet-
rahedron Lett., 2009, 50, 3084; (b) E. L. Pearson, L. C. H. Kwan, C.
I. Turner, G. A. Jones, A. C. Willis, M. N. Paddon-Row and M.
S. Sherburn, J. Org. Chem., 2006, 71, 6099; (c) C. W. Johannes, M.
S. Visser, G. S. Weatherhead and A. H. Hoveyda, J. Am. Chem. Soc.,
1998, 120, 8340.
23 M. Berthod, A. Favre-Reguillon, J. Mohamad, G. Mignani, G. Docherty
and M. Lemaire, Synlett, 2007, 1545.
24 (a) L. M. Geary and P. G. Hultin, Org. Lett., 2009, 11, 5478; (b) I. Kim,
K. Kim and J. Choi, J. Org. Chem., 2009, 74, 8492; (c) S. H. Reuss and
W. A. Koenig, Phytochemistry, 2004, 65, 3113.
25 (a) H. Tanaka, H. Hattori, M. Sato, R. Yamaguchi, T. Fukai, T. Tanaka
and E. Sakai, Heterocycles, 2007, 71, 1779; (b) J. L. Ingham and P.
M. Dewick, Phytochemistry, 1978, 17, 535.
26 (a) M. Halabalaki, X. Alexi, N. Aligiannis, M. N. Alexis and A.
L. Skaltsounis, J. Nat. Prod., 2008, 71, 1934; (b) M. Halabalaki,
N. Aligiannis, Z. Papoutsi, S. Mitakou, P. Moutsatsou, C. Sekeris and
A. L. Skaltsounis, J. Nat. Prod., 2000, 63, 1672.
18 M. J. Schultz and M. S. Sigman, J. Am. Chem. Soc., 2006, 128, 1460.
19 (a) R. Kikumoto, H. Hara, K. Ninomiya, M. Osakabe, M. Sugano,
H. Fukami and Y. Tamao, J. Med. Chem., 1990, 33, 1818;
This journal is © The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 695–701 | 701