Synthesis of 5,5′-bis-benzofurans and 5-arylbenzofurans

Article abstract of DOI:10.1016/j.tet.2013.02.031

A facile synthetic route of the tandem Claisen rearrangement/aerobic Wacker-type oxidative cyclization toward 5,5′-bis-benzofurans 2 and 5-arylbenzofurans 3 starting with bis-allyl aryl ethers 4 or allyl aryl ethers 5 with good yields is described. Skelet

Full text of DOI:10.1016/j.tet.2013.02.031

Tetrahedron 69 (2013) 2933e2940
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 5,50-bis-benzofurans and 5-arylbenzofurans
*
Meng-Yang Chang , Shin-Ying Lin, Chieh-Kai Chan
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthetic route of the tandem Claisen rearrangement/aerobic Wacker-type oxidative cyclization
toward 5,50-bis-benzofurans 2 and 5-arylbenzofurans 3 starting with bis-allyl aryl ethers 4 or allyl aryl
ethers 5 with good yields is described. Skeletons 4 or 5 was prepared from 4,40-biphenol (1) in moderate
total yields via the known protocol.
Received 17 December 2012
Received in revised form 25 January 2013
Accepted 4 February 2013
Available online 13 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aerobic Wacker-type oxidation
Bis-benzofurans
4,40-Biphenol
Bis-allylphenols
1. Introduction
During the last decade, the development of effective routes for
the synthesis of large structural libraries of different benzannulated
heterocycles has been an important course for modern organic
synthesis.1 Among these transformations, the palladium-catalyzed
one-pot reaction has become a powerful and efficient tool to access
a versatile class of functionalized cycloadducts that have been
useful in the discovery of new drugs. A number of review articles
have highlighted fascinating researches based on the Wacker-type
reaction.2e6 In continuation of our recent investigation of 4,40-
biphenol (1) for preparing several benzannulated molecules,7
substituted 5,50-bis-benzofurans 2 or 5-arylbenzofurans 3 are
prepared by one-pot PdII/CuII-mediated tandem annulation of bis-
allyl aryl ethers 4 or allyl aryl ethers 5 via an easy synthetic pro-
cedure of Claisen rearrangement and Wacker-type oxidative
cyclization.
Scheme 1. Metal ion-catalyzed synthetic routes of benzofurans.
Substituted benzofurans have played an important role in or-
ganic synthesis due to their high reactivity and suitability.8e10 Most
of the relevant literature on one-pot synthesis of substituted ben-
zofurans is focused on transition metal-catalyzed oxidative cycli-
zation. Common transition metal-catalyzed one-pot synthetic
routes for making the skeleton of benzofuran include in-
termolecular, intramolecular ynol or enol cyclization,9 as shown in
Scheme 1.
After a further comparison of literature reports on the synthesis
of benzofurans,9 we find that this PdII/CuII system catalyzing intra-
molecular aerobic Wacker-type oxidative cyclization of allylphenols
has been mentioned in a few reports,10 and is becoming an attractive
candidate for the construction of substituted 5,50-bis-benzofurans 2
or 5-arylbenzofurans 3 with molecular oxygen (O2) as the co-
oxidant. From information gleaned in literature reports, we specu-
late that molecular oxygen may control this reaction to generate
different kinds of products; it should provide different results in the
assumed catalytic cycles under the Wacker-type oxidative reaction.
There have been extensive studies on the preparation of function-
alized benzofurans, owing to their prevalence in a variety of de-
rivatives possessing important physical and biological properties.11
* Corresponding author. Tel.: þ886
7 3121101x2220; e-mail addresses:
mychang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.031

2934
M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
Table 1
However, as yet, there have been very few efficient syntheses of
skeletons of 5,50-bis-benzofurans 2 or 5-aryl-benzofurans 3 bearing
the appropriate groups.12,13 The retrosynthetic synthesis of skeletons
2 or 3 is shown in Scheme 2.
One-pot Wacker-type cyclization of bis-allyl aryl ether 4aa,b
Me
Me
OH
O
O
Me
catalyst, CuCl , oxidants
2
4a
+
+
THF / MeOH (v/v = 9/1),
Na CO (2.5 equiv), rt
2
3
Me
Me
O
2a
OH
OH
2a-1
2a-2
Me
Entry Catalyst (mol %), CuCl2, oxidants (equiv)
Yield (%) 2a/2a-1/2a-2
1
2
3
4
5
6
PdCl2(MeCN)2 (10), CuCl2 (1.5), air
35/29/30c
PdCl2(MeCN)2 (10), CuCl2 (1.5), t-BuO2H (1.0) d/<10/80d
PdCl2(MeCN)2 (10), CuCl2 (1.5), DDQ (1.0)
PdCl2(MeCN)2 (10), CuCl2 (1.5), CAN (1.0)
PdCl2(MeCN)2 (10), CuCl2 (1.5), OxoneÒ (1)
d/<10/42c,d
d/<10/56c,d
d/d/85d
Scheme 2. Representative example for synthesis of compound 2a or 3a from
4,40-biphenol (1).
PdCl2(MeCN)2 (10), CuCl2 (1.5), PhI(OAc)2 (1) d/d/81d
7
8
9
10
11
12
13
PdCl2(MeCN)2 (10), CuCl2 (1.5), O2
PdCl2(MeCN)2 (20), CuCl2 (1.5), O2
PdCl2(MeCN)2 (5), CuCl2 (1.5), O2
PdCl2(MeCN)2 (10), CuCl2 (0), O2
RuCl2(PPh3)3 (10), CuCl2 (1.5), O2
Pd(OAc)2 (10), CuCl2 (1.5), O2
PdCl2 (10), CuCl2 (1.5), O2
80/d/dd
75/d/dd
72/d/dd
25/30/33d
71/15/dd
65/22/dd
75/10/dd
2. Results and discussion
With our experience in using the O-allyl group for employing
4,40-biphenol (1) for the synthesis of molecules, we believe that it
may be possible to develop this one-pot methodology for preparing
the skeletons of 5,50-bis-benzofurans 2 or 5-aryl-allylbenzofurans
3. As shown in Scheme 3, a facile route was employed to create
skeletons 2 and 3, starting with 4,40-biphenol (1) or 40-methoxy-
biphenyl-4-ol (1a) via (1) O-allylation of compound 1 or 1a with
allyl or crotyl bromide (R1¼H/Me) in the boiling acetone, (2) Claisen
rearrangement of compounds 4ae4b or 5ae5b with the refluxing
decalin (for 6ae6b, 3e4 h; for 7ae7b 8e10 h), (3) hydrogenation of
compounds 6ae6b or 7ae7b with H2 and 10% Pd/C in EtOAc at rt,
and (4) O-allylation of compounds 8ae8b or 9ae9b with allyl or
crotyl bromide (R2¼H/Me) in boiling acetone. Under the above
four-step reaction conditions, compounds 4ae4f and 5ae5f were
isolated from compounds 1 and 1a with acceptable total yields.
As shown in Table 1, the PdII/CuII system mediated one-pot
Claisen rearrangement/Wacker-type oxidative cyclization of
model compound 4a was further studied; it created three structural
skeletons of bis-benzofuran 2a (35%), benzofuran with a styrenyl
motif 2a-1 (29%), and biphenol with two styrenyl groups 2a-2 (30%)
a
The reactions were run on a 1.0 mmol scale with starting material 4a.
b
The products 2a, 2a-1, and 2a-2 were >95% pure as determined by 1H NMR
analysis.
c
The unknown products (for entry 3, 30%; entry 4, 24%) were obtained.
The starting material 4a (for entries 2e6, 5e10%; for entries 7e13, <5%) was
d
recovered.
at rt for 8 h under the co-solvent (THF/MeOH¼9/1) condition (entry
1). After screening different conditions, we found that the PdII/CuII
system mediated Wacker-type oxidation of substrate 4a with five
different oxidants (t-BuO2H, DDQ, CAN, OxoneÒ and PhI(OAc)2),
provided these major migrated olefins. As shown in entries 2e6,
compound 2a was not isolated in the product mixture; starting
material 4a, products 2a-1 or 2a-2, and an unknown mixture, were
isolated at different ratios.
OH
O
R
1
O
R
R
1
OH
R
1
OH
1
K CO , Br
R
1
decalin, reflux
2
3
or
or
(for 4a~4b, from 1;
for 5a~5b, from 1a)
(for 6a~6b, 8~10 h;
for 7a~7b, 3~4 h)
OR
O
R
OMe
R
OH
O
7a, R = H (86%)
R
1
1
1
1, R = H
1a, R = Me
4a, R = H (88%)
5a, R = H (68%)
1
6a, R = H (89%)
1
1
1
K CO , MeI
2
3
4b, R = Me (84%) 5b, R = Me (72%)
6b, R = Me (80%)
7b, R = Me (78%)
1
1
1
1
H , Pd/C, EtOAc
2
R
1
OH
R
OH
R
O
R
R
1
O
R
2
1
1
2
K CO , Br
R
2
2
3
or
or
R
OH
O
9a, R = H (92%)
R
1
R
O
R
O
R
1
1
1
2
4c, R = R = H (86%)
5c, R = R = H (89%)
8a, R = H (98%)
1
2
1
1
2
1
1
4d, R = H, R = Me (90%)
5d, R = H, R = Me (92%)
8b, R = Me (95%)
9b, R = Me (94%)
1
1
2
2
1
4e, R = Me, R = H (88%)
5e, R = Me, R = H (84%)
1 2
1
2
4f, R = R = Me (84%)
5f, R = R = Me (80%)
1 2
1
2
4g, R =H, R = Ph (82%)
1
2
Scheme 3. Synthesis of bis-allyl aryl ethers 4 and allyl aryl ethers 5.

M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
2935
From the above results, we found that molecular oxygen should
be an important oxidant for synthesizing the skeleton of benzofu-
ran. To our delight, by adjusting the molecular oxygen (by the
bubbled method) as the oxidant, the isolated yield of product 2a
(80%) was noticeably enhanced (entry 7). After the amount of
PdCl2(MeCN)2 was increased two-fold or half-fold, product 2a
provided similar yields (for entry 8, 75%; for entry 9, 72%). Without
the addition of CuCl2, a mixture of products 2a, 2a-1, and 2a-2 was
isolated in similar ratios (entry 10). When changing the catalyst
from PdCl2(MeCN)2 to RuCl2(PPh3)3, Pd(OAc)2 or PdCl2, product 2a
provided a poorer yield (entries 11e13) along with trace amounts of
product 2a-1. We inferred that the optimized one-pot process for
synthesizing bis-benzofuran 2a would involve the PdCl2(MeCN)2/
CuCl2/O2 system.
Based on the experimental results, a possible reaction mecha-
nism is shown in Scheme 4. How is product 2a produced? Initially,
complexation of PdCl2(MeCN)2 with terminal olefin of substrate 4a
yields intermediate A. Intermediate B should be afforded via
intramolecular 5-exo-trig cyclization. This is followed by a b-hy-
dride elimination on the skeleton of intermediate B, generating
intermediate C is generated. After isomerization of intermediate C,
olefinic migration affords product 2a. Subsequently, Pd(0) is recy-
cled into PdCl2(MeCN)2 by using CuCl2 and O2, which is regenerated
by forming CuCl and HCl in situ.14
Changing the substituents (R1 and R2) of skeletons 4 and 5, six
5,50-bis-benzofurans 2ae2f and six 5-arylbenzofurans 3ae3f were
isolated with 40%e80% and 82%e49% yields via the above-
mentioned one-pot oxidative protocol as shown in Table 2. In
comparison with the isolated yields of products with different
substituents, it was found that the yields of products 2ee2f and
3ee3f (R1¼Me, entries 5e6 and 11e12) were slightly poorer than
those for the other analogues 2ae2d and 3ae3d (entries 1e4 and
Scheme 4. A possible mechanism for synthesizing product 2a.
7e10). For the one-pot reaction of compound 4g, however, at-
tempts to obtain the skeleton of benzofuran were unsuccessful (see
equation 1). The structural frameworks of compounds 2b and 3b
were constructed using single-crystal X-ray analysis (Fig. 1).15
Single-crystal X-ray diffraction analysis was employed to de-
termine the constitution and relative configuration of the isolated
product. According to the above procedure, skeletons 4 and 5 were
constructed by PdCl2(MeCN)2/CuCl2/O2 system mediated annula-
tion of skeletons 2 and 3 with different substituents.
Table 2
One-pot synthetic route toward 5,50-bis-benzofurans 2 and 5-arylbenzofurans 3a,b
Me
Me
Me
Me
O
R
R
O
R
O
R
R
O
R
O
R
O
O
R
1
O
1
1
2
1
1
2
1
R
1
R
2
R
R
2
1
PdCl (MeCN) , CuCl
2
2
2
or
or
or
or
or
or
Na CO , O , THF / MeOH
2
3
2
R
1
R
2
O
O
O
R
R
O
R
OMe
O
R
R
OMe
O
R
1
1
1
2
1
1
Me
2a~2b
Me
4a~4b
4c~4f
5a~5b
5c~5f
2c~2f
3a~3b
3c~3f
Entry
Reactants 4/5
Products 2/3
Entry
Reactants 4/5
Products 2/3
Entry
Reactants 4/5
Products 2/3
Me
Me
Me
O
Me
O
Me
O
O
O
O
1
5
9
O
O
O
Me
O
Me
OMe
OMe
Me
Me
4a
2a/80%
4e
2e/52%
5c
3c/74%
Me
Me
Me
O
Me
O
O
Me
Me
O
Me
O
Me
O
Me
Me
Me
2
6
10
Me
Me
O
O
Me
O
Me
Me
O
Me
OMe
OMe
Me
Me
4b
2b/75%
4f
2f/40%
5d
3d/62%
(continued on next page)

2936
M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
Table 2 (continued )
Entry
Reactants 4/5
Products 2/3
Entry
Reactants 4/5
Products 2/3
Entry
11
Reactants 4/5
Products 2/3
Me
Me
Me
O
O
O
Me
O
O
Me
O
3
7
O
O
OMe
OMe
OMe
OMe
Me
4c
2c/78%
5a
3a/82%
5e
3e/58%
Me
Me
Me
O
O
Me
O
Me
Me
O
Me
O
Me
O
Me
Me
Me
4
8
12
Me
O
O
Me
OMe
OMe
OMe
OMe
Me
4d
2d/70%
5b
3b/74%
5f
3f/49%
a
For the optimal reaction conditions: (i) skeleton 4 or 5 (1.0 mmol), PdCl2(MeCN)2 (26 mg, 10 mol %), CuCl2 (200 mg, 1.5 mmol), Na2CO3 (265 mg, 2.5 mmol), O2 (bubbled),
THF/MeOH (v/v¼9/1, 10 mL), rt, 10 h.
b
The isolated products were>95% pure as determined by 1H NMR analysis.
was further studied, as shown in Scheme 5. Compound 10 was
prepared in 80% yield from the PdII/CuII system mediated one-pot
combination of compound 7b.
Scheme 5. Synthesis of compound 10.
3. Conclusion
A synthetic methodology for producing functionalized 5,50-bis-
benzofurans 2 and 5-arylbenzofurans 3 has been successfully pre-
sented from the one-pot facile PdCl2/CuCl2-mediated reaction of
Fig. 1. X-ray structures of compounds 2b and 3b.
substituted bis-allylphenols 4 or 5-aryl-allylphenols 5 with the in-
volvement of molecular oxygen. This resulted in acceptable to good
yields via a tandem process of Claisen rearrangement and Wacker-
type oxidative cyclization. The overall preparation procedures for
synthesizing the functionalized skeletons of benzofurans are simple.
4. Experimental section
4.1. General
Equation 1. One-pot reaction of compound 4g.
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
To further examine the reaction of compound 6a with the
PdCl2(MeCN)2/CuCl2/O2 system, we found that product 2a provided
with 92% yield. In comparison with two routes, the two-step
transformation of Claisen rearrangement and aerobic Wacker-
type oxidative cyclization (4a 6a 2a) provided a similar yield
(82% for two-steps) to that of a one-pot conversion process (4a 2a,
80%). Under the above conditions, the reaction for compound 7b
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with a SMP3 melting apparatus. 1H and 13C NMR
spectra were recorded on a Varian INOVA-400 spectrometer oper-
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (
d)
are reported in parts per million (ppm) and the coupling constants

M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
2937
(J) are given in Hertz. High resolution mass spectra (HRMS) were
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHN-OS-Rapid
Analyzer or Elementar Vario EL III.
found 375.2326; 1H NMR (200 MHz, CDCl3):
6.44 (s, 2H), 3.22e3.17 (m, 2H), 2.45 (s, 6H), 1.86e1.78 (m, 4H), 1.43 (d,
J¼7.2 Hz, 6H), 0.93 (t, J¼7.2 Hz, 6H).
d
7.54 (s, 2H), 7.29 (s, 2H),
4.2.6. 7,70-Di-sec-butyl-2,3,20,30-tetramethyl[5,50]bibenzofuranyl
(2f). Yield¼40% (160 mg); Colorless gum; IR (CHCl3) 2940, 1482,
1273, 1113, 952 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C28H35O2
4.2. A representative procedure of skeleton 2 or 3 is as follows
403.2637, found 403.2636; 1H NMR (400 MHz, CDCl3):
d 7.44 (d,
J¼1.6 Hz, 2H), 7.28 (d, J¼1.6 Hz, 2H), 3.23e3.18 (m, 2H), 2.43 (d,
J¼0.4 Hz, 6H), 2.22 (d, J¼0.8 Hz, 6H), 1.84e1.75 (m, 4H), 1.43 (d,
J¼6.8 Hz, 6H), 0.93 (t, J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
PdCl2(MeCN)2 (26 mg, 10 mol %), CuCl2 (200 mg, 1.5 mmol), and
Na2CO3 (265 mg, 2.5 mmol) were added to a solution of skeleton 4
or 5 (1.0 mmol) in the co-solvent of THF and MeOH (20 mL, v/v¼9/
1) at rt. Then oxygen was bubbled into the mixture for 2 h, and
stirring occurred at rt for 8 h. The residue was diluted with water
(2 mL) and the mixture was extracted with EtOAc (3ꢀ20 mL). The
combined organic layers were washed with brine, dried, filtered,
and evaporated to afford crude product. Purification on silica gel
(hexanes/EtOAc¼10/1e6/1) afforded skeleton 2 or 3.
d
151.39 (2ꢀ), 150.45 (2ꢀ), 137.10 (2ꢀ), 130.64 (2ꢀ), 130.31 (2ꢀ),
121.11 (2ꢀ), 114.77 (2ꢀ), 109.95 (2ꢀ), 36.30 (2ꢀ), 29.81 (2ꢀ), 20.56
(2ꢀ), 12.46 (2ꢀ), 11.95 (2ꢀ), 8.10 (2ꢀ).
4.2.7. 5-(4-Methoxyphenyl)-2-methylbenzofuran (3a). Yield¼82%
(195 mg); mp¼128e129 ꢁC (recrystallized from hexanes and EtOAc);
IR (CHCl3) 2939,1466,1243,1147, 966 cmꢂ1; HRMS (ESI, Mþþ1) calcd
1
for C16H15O2 239.1072, found 239.1074; H NMR (400 MHz, CDCl3):
4.2.1. 2,20-Dimethyl[5,50]bibenzofuranyl (2a). Yield¼80% (210 mg);
mp¼141e143 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
2935, 1493, 1270, 1120, 958 cmꢂ1; HRMS (ESI, Mþþ1) calcd for
d
7.62 (dd, J¼0.4, 1.6 Hz, 1H), 7.55 (d, J¼9.2 Hz, 2H), 7.44 (dt, J¼0.8,
8.4 Hz, 1H), 7.39 (dd, J¼1.6, 8.4 Hz, 1H), 6.99 (d, J¼9.2 Hz, 2H), 6.41 (t,
J¼1.2 Hz, 1H), 3.86 (s, 3H), 2.48 (d, J¼1.2 Hz, 3H); 13C NMR (100 MHz,
C18H15O2 263.1072, found 263.1077; 1H NMR (400 MHz, CDCl3):
d
7.67
CDCl3):
d
158.74, 156.03, 154.05, 135.74, 134.47, 129.68, 128.34 (2ꢀ),
(t, J¼1.2 Hz, 2H), 7.45 (br s, 4H), 6.42 (s, 2H), 2.49 (d, J¼1.2 Hz, 6H); 13C
122.38, 118.17, 114.11 (2ꢀ), 110.60, 102.74, 55.31, 14.11; Anal. Calcd for
NMR (100 MHz, CDCl3):
d
156.03(2ꢀ),154.10 (2ꢀ),136.76 (2ꢀ),129.65
C16H14O2: C, 80.65; H, 5.92. Found: C, 80.88; H, 6.12.
(2ꢀ), 123.01 (2ꢀ), 118.84 (2ꢀ), 110.55 (2ꢀ), 102.76 (2ꢀ), 14.12 (2ꢀ).
4.2.8. 5-(4-Methoxyphenyl)-2,3-dimethylbenzofuran (3b). Yield¼74%
(186 mg); mp¼132e133 ꢁC (recrystallized from hexanes and EtOAc);
IR (CHCl3) 2938, 1469, 1245, 1143, 966 cmꢂ1; HRMS (ESI, Mþþ1)
calcd for C17H17O2 253.1229, found 253.1230; 1H NMR (400 MHz,
4.2.2. 2,3,20,30-Tetramethyl[5,50]bibenzofuranyl (2b). Yield¼75% (217
mg); mp¼157e158 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2939, 1501, 1274, 1122, 961 cmꢂ1; HRMS (ESI, Mþþ1) calcd
for C20H19O2 291.1385, found 291.1389; 1H NMR (400 MHz, CDCl3):
CDCl3):
d
7.57 (d, J¼9.2 Hz, 2H), 7.58e7.55 (m,1H), 7.40e7.38 (m, 2H),
d
7.62 (s, 2H), 7.47 (dd, J¼1.2, 8.4 Hz, 2H), 7.42 (d, J¼8.0 Hz, 2H), 2.42
7.00 (d, J¼9.2 Hz, 2H), 3.87 (s, 3H), 2.41 (d, J¼0.8 Hz, 3H), 2.20 (d,
(s, 6H), 2.21 (s, 6H); 13C NMR (100 MHz, CDCl3):
d
153.17 (2ꢀ), 151.10
J¼0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 158.72, 153.13, 151.11,
(2ꢀ), 136.52 (2ꢀ), 130.91 (2ꢀ), 122.98 (2ꢀ), 117.32 (2ꢀ), 110.34 (2ꢀ),
109.92 (2ꢀ), 11.87 (2ꢀ), 7.97 (2ꢀ); Anal. Calcd for C20H18O2: C, 82.73;
H, 6.25. Found: C, 82.98; H, 6.45. Single-crystal X-ray diagram:
crystal of 2b was grown by slow diffusion of EtOAc into a solution of
2b in CH2Cl2 to yield colorless prisms. The compound crystallizes in
the monoclinic crystal system, space group P 1 21/c 1, a¼17.2542(17)
135.35, 134.64, 130.93, 128.35 (2ꢀ), 122.31, 116.66, 114.11 (2ꢀ),
110.39, 109.87, 55.32, 11.83, 7.91; Anal. Calcd for C17H16O2: C, 80.93;
H, 6.39. Found: C, 81.23; H, 6.62. Single-crystal X-ray diagram: crystal
of 3b was grown by slow diffusion of EtOAc into a solution of 3b in
CH2Cl2 to yield colorless prisms. The compound crystallizes in the
ꢀ
monoclinic crystal system, space group P 1 21/n 1, a¼7.0591(4) A,
3
3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
A, b¼6.7387(7) A, c¼13.1842(12) A, V¼1499.1(3) A , Z¼4,
b¼7.2045(4) A, c¼25.9203(15) A, V¼1312.44(13) A , Z¼4,
dcalcd¼1.286 g/cm3, F(000)¼616, 2
q
range 1.21e26.37ꢁ, R indices (all
dcalcd¼1.277 g/cm3, F(000)¼536, 2
q
range 1.58e26.52ꢁ, R indices (all
data) R1¼0.0617, wR2¼0.1398.
data) R1¼0.0506, wR2¼0.1039.
4.2.3. 2,20-Dimethyl-7,70-dipropyl[5,50]bibenzofuranyl (2c). Yield¼78%
(270 mg); mp¼63e64 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2933, 1494, 1272, 1122, 960 cmꢂ1; HRMS (ESI, Mþþ1) calcd
for C24H27O2 347.2011, found 347.2015; 1H NMR (400 MHz, CDCl3):
4.2.9. 2-Methyl-5-(4-propoxyphenyl)-7-propylbenzofuran (3c). Yield
¼74% (228 mg); mp¼81e83 ꢁC (recrystallized from hexanes and
EtOAc); IR (CHCl3) 2935, 1462, 1240, 1143, 964 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C21H25O2 309.1855, found 309.1856; 1H NMR
d
7.54 (d, J¼1.6 Hz, 2H), 7.30 (d, J¼1.6 Hz, 2H), 6.42 (d, J¼1.2 Hz, 2H),
(400 MHz, CDCl3):
d
7.52 (d, J¼8.8 Hz, 2H), 7.44 (d, J¼2.0 Hz, 1H), 7.20
2.95 (t, J¼7.6 Hz, 4H), 2.51 (d, J¼0.8 Hz, 6H),1.92e1.82 (m, 4H), 1.08 (t,
(d, J¼1.6 Hz, 1H), 6.97 (d, J¼8.8 Hz, 2H), 6.38 (d, J¼1.2 Hz, 1H), 3.97 (t,
J¼6.4 Hz, 2H), 2.89 (t, J¼7.6 Hz, 2H), 2.47 (d, J¼0.8 Hz, 3H), 1.87e1.79
(m, 4H), 1.07 (t, J¼6.8 Hz, 3H), 1.02 (t, J¼7.6 Hz, 3H); 13C NMR
J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
155.47 (2ꢀ), 152.86 (2ꢀ),
d
137.01 (2ꢀ),129.01 (2ꢀ),125.43 (2ꢀ),123.29 (2ꢀ),116.37 (2ꢀ),102.93
(2ꢀ), 32.07 (2ꢀ), 23.17 (2ꢀ), 14.20 (2ꢀ), 14.14 (2ꢀ).
(100 MHz, CDCl3):
d 158.21, 155.54, 152.83, 135.77, 134.59, 129.28,
128.31 (2ꢀ), 125.53, 122.63, 115.71, 114.66 (2ꢀ), 102.90, 69.59, 32.03,
4.2.4. 2,3,20,30-Tetramethyl-7,70-dipropyl[5,50]bibenzofuranyl
(2d). Yield¼70% (262 mg); mp¼70e71 ꢁC (recrystallized from hex-
anes and EtOAc); IR (CHCl3) 2938, 1493, 1271, 1121, 956 cmꢂ1; HRMS
23.11, 22.63, 14.21, 14.11, 10.54.
4.2.10. 2,3-Dimethyl-5-(4-propoxyphenyl)-7-propylbenzofuran
(3d). Yield¼62% (200 mg); Viscous gum; IR (CHCl3) 2934, 1467,
1243, 1152, 958 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C22H27O2
1
(ESI, Mþþ1) calcd for C26H31O2 375.2324, found 375.2328; H NMR
(400 MHz, CDCl3):
d
7.43 (d, J¼2.0 Hz, 2H), 7.27 (d, J¼2.0 Hz, 2H), 2.90
(t, J¼7.6 Hz, 4H), 2.41 (s, 6H), 2.20 (s, 6H), 1.86e1.80 (m, 4H), 1.03 (t,
323.2011, found 323.2013; 1H NMR (200 MHz, CDCl3):
d 7.57 (d,
J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d
151.83 (2ꢀ), 150.57 (2ꢀ),
J¼9.2 Hz, 2H), 7.42 (s, 1H), 7.22 (s, 1H), 6.99 (d, J¼9.2 Hz, 2H), 3.99 (t,
J¼6.8 Hz, 2H), 2.91 (t, J¼7.2 Hz, 2H), 2.47 (s, 3H), 2.22 (s, 3H),
1.88e1.75 (m, 4H), 1.10 (t, J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H).
136.82 (2ꢀ), 130.50 (2ꢀ), 125.26 (2ꢀ), 123.32 (2ꢀ), 114.86 (2ꢀ),
110.03 (2ꢀ), 32.02 (2ꢀ), 23.24 (2ꢀ), 14.16 (2ꢀ), 11.94 (2ꢀ), 8.12 (2ꢀ).
4.2.5. 7,70-Di-sec-butyl-2,20-dimethyl[5,50]bibenzofuranyl (2e). Yield
¼52% (195 mg); Colorless viscous gum; IR (CHCl3) 2942, 1488, 1273,
1116, 955 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C26H31O2 375.2324,
4.2.11. 5-(4-Butoxyphenyl)-7-sec-butyl-2-methylbenzofuran
(3e). Yield¼58% (195 mg); Viscous gum; IR (CHCl3) 2941, 1462, 1240,
1142, 956 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C23H29O2 337.2168,

2938
M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
found 337.2170; 1H NMR (400 MHz, CDCl3):
d
7.51 (d, J¼8.8 Hz, 2H),
reaction mixture was stirred at reflux for 10 h. The reaction was
7.43 (d, J¼1.6 Hz, 1H), 7.19 (d, J¼2.0 Hz, 1H), 6.87 (d, J¼8.8 Hz, 2H),
6.37 (d, J¼0.8 Hz, 1H), 4.01 (t, J¼6.4 Hz, 2H), 3.20e3.15 (m, 1H), 2.46
(d, J¼1.2 Hz, 3H), 1.88e1.70 (m, 4H), 1.56e1.45 (m, 2H), 1.39 (d,
J¼7.2 Hz, 3H), 1.39 (t, J¼7.2 Hz, 3H), 0.91 (t, J¼7.2 Hz, 3H); 13C NMR
traced by TLC until compound 1 or 1a and compounds 8ae8b or
9ae9b was consumed. The reaction mixture was cooled to rt,
concentrated, and extracted with EtOAc (3ꢀ60 mL). The combined
organic layers were washed with brine, dried, filtered and evapo-
rated to afford crude product under reduced pressure. Purification
on silica gel (hexanes/EtOAc¼15/1e10/1) afforded skeleton 4 or 5.
(100 MHz, CDCl3):
d 158.22, 155.41, 152.41, 144.88, 135.86, 134.76,
130.56, 128.34 (2ꢀ), 120.33, 115.57, 114.66 (2ꢀ), 102.86, 67.78, 36.15,
31.38, 29.78, 20.50, 19.27, 14.23, 13.86, 12.36.
4.4.1. 4,40-Bis-allyloxybiphenyl (4a). Compound 4a is a known
compound and the analytical data are consistent with those in the
literature.7c Yield¼88% (1.17 g).
4.2.12. 5-(4-Butoxyphenyl)-7-sec-butyl-2,3-dimethylbenzofuran
(3f). Yield¼49% (172 mg); Viscous gum; IR (CHCl3) 2940, 1459,
1239, 1139, 960 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C24H31O2
351.2324, found 351.2328; 1H NMR (200 MHz, CDCl3):
d
7.57 (d,
4.4.2. 4,40-Bis-but-2-enyloxybiphenyl (4b). Compound 4b is
a known compound and the analytical data are consistent with
those in the literature.7c Yield¼84% (1.23 g).
J¼9.2 Hz, 2H), 7.42 (s, 1H), 7.22 (s, 1H), 6.99 (d, J¼9.2 Hz, 2H), 4.04 (t,
J¼6.8 Hz, 2H), 3.22e3.17 (m, 1H), 2.46 (s, 3H), 2.22 (s, 3H), 1.91e1.74
(m, 4H), 1.60e1.51 (m, 2H), 1.38 (d, J¼7.2 Hz, 3H), 1.35 (t, J¼7.2 Hz,
3H), 0.88 (t, J¼7.2 Hz, 3H).
4.4.3. 4,40-Bis-allyloxy-3,30-dipropyl-biphenyl (4c). Yield¼86% (151
mg); mp¼102e103 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2968, 2870, 1642, 1460, 1232, 1132, 926 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C24H31O2 351.2324, found 351.2339; 1H NMR
4.3. A representative procedure of skeleton 6 or 7 is as follows
Decalin (8 mL) was added to a solution of compounds 4ae4b or
5ae5b (0.7 mmol) at rt. The reaction mixture was stirred at reflux for
(400 MHz, CDCl3):
d
7.33 (s, 2H), 7.33e7.30 (m, 2H), 6.86 (dd, J¼1.2,
8.8 Hz, 2H), 6.13e6.04 (m, 2H), 5.47e5.42 (m, 2H), 5.30e5.26 (m, 2H),
4.57 (dt, J¼1.6, 4.8 Hz, 4H), 2.69e2.65 (m, 4H),1.72e1.62 (m, 4H), 0.98
3e4 h (for 5ae5b
7ae7b) or 8e10 h (for 4ae4b
6ae6b). The
reaction was traced by TLC until compounds 4ae4b or 5ae5b was
consumed. The reaction mixture was cooled to rt. Decalin was evap-
orated to afford crude product under reduced pressure. Purification on
silica gel (hexanes/EtOAc¼8/1e4/1) afforded compounds 6ae6b or
7ae7b.
(t, J¼6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d
155.55 (2ꢀ), 133.67
(2ꢀ), 133.48 (2ꢀ), 131.58 (2ꢀ), 128.52 (2ꢀ), 124.88 (2ꢀ), 116.67 (2ꢀ),
111.74 (2ꢀ), 68.73 (2ꢀ), 32.60 (2ꢀ), 23.13 (2ꢀ), 14.17 (2ꢀ).
4.4.4. 4,40-Bis-but-2-enyloxy-3,30-dipropylbiphenyl (4d). Yield¼90%
(170 mg); mp¼85e86 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2978, 2872, 1640, 1462, 1235, 1128, 933 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C26H35O2 379.2637, found 379.2643; 1H NMR
4.3.1. 3,30-Diallyl-biphenyl-4,40-diol (6a). Yield¼89% (166 mg);
mp¼81e82 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
3310, 2957, 2877,1636,1461,1240,1141, 911 cmꢂ1; HRMS (ESI, Mþþ1)
calcd for C18H19O2 267.1385, found 267.1391; 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
7.32 (s, 2H), 7.32e7.30 (m, 2H), 6.87 (dd, J¼1.2,
8.8 Hz, 2H), 5.90e5.82 (m, 2H), 5.77e5.70 (m, 2H), 4.50 (d, J¼5.6 Hz,
CDCl3):
d
7.31e7.28 (m, 4H), 6.85 (d, J¼8.0 Hz, 2H), 6.10e6.00 (m, 2H),
4H), 2.67e2.64 (m, 4H),1.77 (dd, J¼1.2, 5.6 Hz, 6H), 1.71e1.62 (m, 4H),
5.23e5.16 (m, 4H), 5.05 (br s, 2H), 3.46 (d, J¼6.0 Hz, 4H); 13C NMR
0.98 (t, J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
155.76 (2ꢀ),133.42
d
(100 MHz, CDCl3):
d
153.20 (2ꢀ), 136.32 (2ꢀ), 133.87 (2ꢀ), 128.80
(2ꢀ), 131.59 (2ꢀ), 129.15 (2ꢀ), 128.43 (2ꢀ), 126.63 (2ꢀ), 124.84 (2ꢀ),
111.92 (2ꢀ), 68.87 (2ꢀ), 32.50 (2ꢀ), 23.09 (2ꢀ),17.86 (2ꢀ), 14.15 (2ꢀ);
Anal. Calcd for C26H34O2: C, 82.49; H, 9.05. Found: C, 82.80; H, 9.32.
(2ꢀ), 126.14 (2ꢀ), 125.47 (2ꢀ), 116.62 (2ꢀ), 116.11 (2ꢀ), 35.29 (2ꢀ);
Anal. Calcd for C18H18O2: C, 81.17; H, 6.81. Found: C, 81.30; H, 6.62.
4.3.2. 3,30-Bis-(1-methylallyl)biphenyl-4,40-diol
(6b). Yield¼80%
4.4.5. 4,40-Bis-allyloxy-3,30-di-sec-butylbiphenyl
(4e). Yield¼88%
(165 mg); Colorless gum; IR (CHCl3) 3318, 2967, 2870,1646,1458,1239,
(166 mg); Viscous gum; IR (CHCl3) 2972, 2861, 1639, 1470, 1242,
1140, 918 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C20H23O2 295.1698, found
1133, 932 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C26H35O2 379.2637,
295.1710; 1H NMR (400 MHz, CDCl3):
d
7.31 (s, 2H), 7.31e7.29 (m, 2H),
found 379.2638; 1H NMR (200 MHz, CDCl3):
d 7.35e7.22 (m, 4H),
6.89e6.85 (m, 2H), 6.19e6.11 (m, 2H), 5.30 (br s, 2H), 5.27e5.19 (m,
6.89 (d, J¼7.8 Hz, 2H), 6.16e6.03 (m, 2H), 5.46e5.42 (m, 2H),
5.30e5.24 (m, 2H), 4.57 (d, J¼4.8 Hz, 4H), 3.22e3.16 (m, 2H),
1.75e1.60 (m, 4H), 1.20 (d, J¼7.2 Hz, 6H), 0.92 (t, J¼7.2 Hz, 6H).
4H), 3.80e3.74 (m, 2H), 1.45 (d, J¼7.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3):
d
152.79 (2ꢀ), 142.27 (2ꢀ), 134.10 (2ꢀ), 130.57 (2ꢀ), 126.55
(2ꢀ), 125.91 (2ꢀ), 116.45 (2ꢀ), 114.41 (2ꢀ), 37.85 (2ꢀ), 18.78 (2ꢀ).
4.4.6. 4,40-Bis-but-2-enyloxy-3,30-di-sec-butylbiphenyl (4f). Yield¼
84% (171 mg); Viscous gum; IR (CHCl3) 2977, 2872, 1644, 1461,
1233, 1132, 924 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C28H39O2
4.3.3. 3-Allyl-40-allyloxybiphenyl-4-ol (7a). Compound 7a is
a known compound and the analytical data are consistent with
those in the literature.7c Yield¼86% (160 mg).
407.2950, found 407.2953; 1H NMR (400 MHz, CDCl3):
d 7.33e7.28
(m, 4H), 6.88 (d, J¼8.4 Hz, 2H), 5.89e5.81 (m, 2H), 5.77e5.70 (m,
2H), 4.48 (dd, J¼1.2, 5.6 Hz, 4H), 3.21e3.13 (m, 2H), 1.76 (dd, J¼1.2,
6.4 Hz, 6H), 1.73e1.54 (m, 4H), 1.25 (d, J¼7.2 Hz, 6H), 0.88 (t,
4.3.4. 40-But-2-enyloxy-3-(1-methylallyl)biphenyl-4-ol (7b). Com-
pound 7b is a known compound and the analytical data are con-
sistent with those in the literature.7c Yield¼78% (161 mg).
J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d
155.40 (2ꢀ), 136.38
(2ꢀ), 133.92 (2ꢀ), 129.12 (2ꢀ), 126.65 (2ꢀ), 125.48 (2ꢀ), 124.62
(2ꢀ), 112.20 (2ꢀ), 69.09 (2ꢀ), 33.85 (2ꢀ), 29.87 (2ꢀ), 20.49 (2ꢀ),
17.85 (2ꢀ), 12.27 (2ꢀ).
4.4. A representative procedure of skeleton 4 or 5 is as follows
K2CO3 (for 1 or 1a, 2.8 g, 20.0 mmol; for 8ae8b or 9ae9b,
280 mg, 2.0 mmol) was added to a solution of compound 1 or 1a
(5.0 mmol) or compounds 8ae8b or 9ae9b (0.5 mmol) in acetone
(for 1 or 1a, 100 mL; for 8ae8b or 9ae9b, 10 mL) at rt. The reaction
mixture was stirred at rt for 10 min. Allyl bromide (for 1 or 8ae8b,
3.0 mmol; for 1a or 9ae9b, 1.5 mmol), crotyl bromide (for 1 or
8ae8b, 3.0 mmol; for 1a or 9ae9b, 1.5 mmol) or cinnamyl chloride
(for 8a, 3.0 mmol) was added to the reaction mixture at rt. The
4.4.7. 40-But-2-enyloxy-3-(1-methylallyl)biphenyl-4-ol
(4g). Com-
pound 4g is a known compound and the analytical data are consistent
with those in the literature.7c Yield¼82% (206 mg).
4.4.8. 4-Allyloxy-40-methoxybiphenyl (5a). Yield¼68% (816 mg);
mp¼136e137 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2975, 2871, 1640, 1451, 1222, 1125, 912 cmꢂ1; HRMS (ESI,

M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
2939
Mþþ1) calcd for C16H17O2 241.1229, found 241.1236; 1H NMR
125.36, 124.50, 114.65 (2ꢀ), 112.22, 69.09, 67.75, 33.72, 31.36, 29.87,
(400 MHz, CDCl3):
d
7.49e7.44 (m, 4H), 6.97 (m, 4H), 6.12e6.03 (m,
20.53, 19.26, 17.88, 13.86, 12.25.
1H), 5.43 (dq, J¼1.6, 17.2 Hz, 1H), 5.30 (dq, J¼1.6, 10.4 Hz, 1H), 4.56
(dt, J¼1.2, 6.4 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3):
4.5. A representative procedure of skeleton 8 or 9 is as follows
d
158.68, 157.69, 133.60, 133.41, 133.31, 127.69 (2ꢀ), 127.66 (2ꢀ),
117.65, 114.97 (2ꢀ), 114.13 (2ꢀ), 68.87, 55.30.
Palladium on activated carbon (10%, 5 mg) was added to a so-
lution of skeleton 6 or 7 (1.0 mmol) in EtOAc (20 mL) at rt. Then
hydrogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hex-
anes/EtOAc¼6/1e3/1) afforded skeleton 8 or 9.
4.4.9. 4-But-2-enyloxy-40-methoxybiphenyl (5b). Yield¼92% (1.17 g);
mp¼129e131 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
2970, 2872, 1633, 1446, 1218, 1135, 931 cmꢂ1; HRMS (ESI, Mþþ1)
calcd for C17H19O2 255.1385, found 255.1388; 1H NMR (400 MHz,
CDCl3):
d 7.48e7.42 (m, 4H), 6.98e6.92 (m, 4H), 5.90e5.83 (m, 1H),
5.78e5.71 (m, 1H), 4.48 (dt, J¼1.2, 6.0 Hz, 2H), 3.82 (s, 3H), 1.76 (dd,
4.5.1. 3,30-Dipropylbiphenyl-4,40-diol (8a). Yield¼98% (265 mg);
mp¼115e116 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 3323, 2973, 2867, 1655, 1450, 1231, 1143, 963 cmꢂ1; HRMS
(ESI, Mþþ1) calcd for C18H23O2 271.1698, found 271.1703; 1H NMR
J¼0.8, 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 158.65, 157.81,
133.41, 130.56, 127.67 (2ꢀ), 127.64 (2ꢀ), 126.08, 114.92 (2ꢀ), 114.22,
114.11 (2ꢀ), 68.75, 55.28, 17.84.
(400 MHz, CDCl3):
d
7.30 (d, J¼2.4 Hz, 2H), 7.26 (dd, J¼2.4, 8.0 Hz,
4.4.10. 4-Allyloxy-40-propoxy-3-propylbiphenyl (5c). Yield¼89% (138
mg); Colorless gum; IR (CHCl3) 2965, 2882, 1634, 1450, 1224, 1130,
923 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C21H27O2 311.2011, found
2H), 6.81 (d, J¼8.0 Hz, 2H), 4.80 (s, 2H), 2.64 (t, J¼7.6 Hz, 4H),
1.75e1.66 (m, 4H),1.02 (t, J¼7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d
152.52 (2ꢀ), 133.85 (2ꢀ), 128.68 (2ꢀ), 128.55 (2ꢀ), 125.31 (2ꢀ),
311.2021; 1H NMR (400 MHz, CDCl3):
d
7.49e7.45 (m, 2H), 7.34e7.31
115.46 (2ꢀ), 32.20 (2ꢀ), 23.02 (2ꢀ), 14.05 (2ꢀ).
(m, 2H), 6.97e6.93 (m, 2H), 6.87 (d, J¼8.0 Hz, 1H), 6.14e6.04 (m, 1H),
5.48e5.42 (m, 1H), 5.31e5.27 (m, 1H), 4.58 (dt, J¼1.6, 4.8 Hz, 2H), 3.96
(t, J¼6.4 Hz, 2H), 2.70e2.66 (m, 2H), 1.88e1.79 (m, 2H), 1.72e1.63 (m,
2H), 1.06 (t, J¼7.6 Hz, 3H), 0.99 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
4.5.2. 3,30-Di-sec-butylbiphenyl-4,40-diol (8b). Yield¼95% (283 mg);
mp¼113e114 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
3329, 2968, 2863, 1651, 1442, 1238, 1146, 958 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C20H27O2 299.2011, found 299.2012; 1H NMR
CDCl3):
d 158.14, 155.60, 133.64, 133.55, 133.23, 131.61, 128.47, 127.70
(2ꢀ), 124.82, 116.69, 114.67 (2ꢀ), 111.76, 69.56, 68.73, 32.57, 23.10,
(400 MHz, CDCl3):
d
7.30 (d, J¼2.4 Hz, 2H), 7.23 (dd, J¼2.4, 8.4 Hz,
22.62, 14.16, 10.54.
2H), 6.79 (d, J¼8.4 Hz, 2H), 4.74 (s, 2H), 3.04e2.95 (m, 2H), 1.78e1.58
(m, 4H), 1.29 (d, J¼7.2 Hz, 6H), 0.91 (t, J¼7.2 Hz, 6H); 13C NMR
4.4.11. 4-But-2-enyloxy-40-propoxy-3-propylbiphenyl (5d). Yield¼92%
(149 mg); mp¼83e84 ꢁC (recrystallized from hexanes and EtOAc); IR
(CHCl3) 2974, 2878, 1632, 1440, 1228, 1141, 931 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C22H29O2 325.2168, found 325.2170; 1H NMR
(100 MHz, CDCl3):
d
152.09 (2ꢀ), 134.28 (2ꢀ), 133.38 (2ꢀ), 125.70
(2ꢀ), 124.96 (2ꢀ), 115.55 (2ꢀ), 34.26 (2ꢀ), 29.83 (2ꢀ), 20.44 (2ꢀ),
12.24 (2ꢀ).
(400 MHz, CDCl3):
d
7.50e7.46 (m, 2H), 7.34e7.29 (m, 2H), 6.99e6.94
4.5.3. 40-Propoxy-3-propylbiphenyl-4-ol (9a). Yield¼92% (248 mg);
Colorless gum; IR (CHCl3) 3315, 2983, 2877, 1668, 1452, 1239, 1154,
958 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C18H23O2 271.1698, found
(m, 2H), 6.88 (d, J¼8.0 Hz, 1H), 5.91e5.83 (m, 1H), 5.79e5.72 (m, 1H),
4.51 (dt, J¼1.2, 5.6 Hz, 2H), 3.96 (t, J¼6.4 Hz, 2H), 2.69e2.64 (m, 2H),
1.89e1.81 (m, 2H), 1.78 (dd, J¼1.2, 6.0 Hz, 3H), 1.73e1.63 (m, 2H), 1.07
(t, J¼7.6 Hz, 3H), 0.99 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
271.1702; 1H NMR (400 MHz, CDCl3):
d 7.49e7.45 (m, 2H), 7.32 (d,
J¼2.4 Hz, 1H), 7.27 (dd, J¼2.4, 8.4 Hz, 1H), 6.98e6.94 (m, 2H), 6.81
(d, J¼8.4 Hz,1H), 4.80 (br s,1H), 3.97 (t, J¼6.4 Hz, 2H), 2.67e2.63 (m,
2H), 1.89e1.80 (m, 2H), 1.75e1.66 (m, 2H), 1.07 (t, J¼7.2 Hz, 3H), 1.02
d
158.12, 155.81, 133.63, 133.07, 131.63, 129.17, 128.36, 127.67 (2ꢀ),
126.57, 124.78, 114.67 (2ꢀ), 111.91, 69.56, 68.84, 32.47, 23.05, 22.61,
17.86, 14.13, 10.53.
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 158.12, 152.57,
133.60, 133.51, 128.65, 128.57, 127.67 (2ꢀ), 125.24, 115.47, 114.69
(2ꢀ), 69.60, 32.18, 22.98, 22.59, 14.05, 10.52.
4.4.12. 4-Allyloxy-40-butoxy-3-sec-butylbiphenyl (5e). Yield¼84%
(142 mg); Viscous gum; IR (CHCl3) 2963, 2863, 1641, 1449, 1223,
1145, 940 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C23H31O2 339.2324,
4.5.4. 40-Butoxy-3-sec-butylbiphenyl-4-ol (9b). Yield¼94% (280 mg);
mp¼92e93 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
3322, 2979, 2876, 1659, 1450, 1241, 1156, 957 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C20H27O2 299.2011, found 299.2013; 1H NMR
found 339.2325; 1H NMR (400 MHz, CDCl3):
d
7.47 (d, J¼8.8 Hz,
2H), 7.35 (d, J¼2.4 Hz, 1H), 7.30 (dd, J¼2.4, 8.4 Hz, 1H), 6.94 (d,
J¼9.2 Hz, 2H), 6.87 (d, J¼8.4 Hz, 1H), 6.13e6.04 (m, 1H), 5.45 (dq,
J¼1.6, 17.2 Hz, 1H), 5.28 (dq, J¼1.6, 10.8 Hz, 1H), 4.56 (dt, J¼1.6,
4.8 Hz, 2H), 3.99 (t, J¼6.4 Hz, 2H), 3.21e3.16 (m, 1H), 1.82e1.46
(m, 6H), 1.25 (d, J¼7.2 Hz, 3H), 0.99 (t, J¼7.2 Hz, 3H), 0.88 (t,
(400 MHz, CDCl3):
d
7.49 (d, J¼8.8 Hz, 2H), 7.36 (d, J¼2.4 Hz,1H), 7.26
(dd, J¼2.4, 8.4 Hz, 1H), 6.98 (d, J¼8.8 Hz, 2H), 6.81 (d, J¼8.4 Hz, 1H),
4.97 (br s, 1H), 4.03 (t, J¼6.4 Hz, 2H), 3.06e3.01 (m, 1H), 1.85e1.63
(m, 4H), 1.59e1.49 (m, 2H), 1.31 (d, J¼7.2 Hz, 3H), 1.02 (t, J¼7.2 Hz,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 158.18, 155.25,
136.39, 133.81, 133.71, 133.50, 127.74 (2ꢀ), 125.46, 124.54, 116.73,
114.68 (2ꢀ), 112.05, 58.98, 67.76, 33.88, 31.37, 29.87, 20.46, 19.26,
13.86, 12.26.
3H), 0.93 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 158.11,
152.17, 133.80, 133.75, 133.47, 127.71 (2ꢀ), 125.61, 124.82, 115.58,
114.71 (2ꢀ), 67.81, 34.11, 31.32, 29.81, 20.46, 19.23, 13.83, 12.20.
4.4.13. 4-But-2-enyloxy-40-butoxy-3-sec-butylbiphenyl
(5f). Yield¼84% (148 mg); Viscous gum; IR (CHCl3) 2965, 2871,
1635, 1452, 1221, 1144, 935 cmꢂ1; HRMS (ESI, Mþþ1) calcd for
C24H33O2 353.2481, found 353.2484; 1H NMR (400 MHz, CDCl3):
4.6. In Table 1 and entry 1 (no involvement of oxygen)
Pd(MeCN)2Cl2 (26 mg, 10 mol %), CuCl2 (200 mg, 1.5 mmol) and
Na2CO3 (265 mg, 2.5 mmol) were added to a solution of compound
4a or 7b (1.0 mmol) in the co-solvent of THF and MeOH (20 mL, v/
v¼9/1) at rt. The residue was diluted with water (2 mL) and the
mixture was extracted with EtOAc (3ꢀ20 mL). The combined or-
ganic layers were washed with brine, dried, filtered and evaporated
to afford crude product. Purification on silica gel (hexanes/
EtOAc¼10/1e6/1) afforded compounds 2a, 2a-1, and 2a-2 or 10.
d
7.47 (d, J¼8.8 Hz, 2H), 7.34 (d, J¼2.4 Hz,1H), 7.30 (dd, J¼2.4, 8.4 Hz,
1H), 6.95 (d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.4 Hz,1H), 5.91e5.82 (m,1H),
5.78e5.71 (m, 1H), 4.50 (dt, J¼1.6, 5.6 Hz, 2H), 4.00 (t, J¼6.4 Hz, 2H),
3.22e3.14 (m, 1H), 1.83e1.47 (m, 9H), 1.25 (d, J¼6.8 Hz, 3H), 1.00 (t,
J¼7.2 Hz, 3H), 0.88 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
158.13, 155.45, 136.44, 133.86, 133.33, 129.20, 127.73 (2ꢀ), 126.60,

2940
M.-Y. Chang et al. / Tetrahedron 69 (2013) 2933e2940
Y.; Zhao, J.; Xue, W.; Li, Y.; Larock, R. C.; Shi, F. Tetrahedron Lett. 2011, 52, 3797;
(e) Wang, M.; Li, D.; Zhou, W.; Wang, L. Tetrahedron 2012, 68, 1926.
4. For aerobic aza-Wacker-type cyclizations, see: (a) Yang, G.; Zhang, W. Org. Lett.
2012, 14,168; (b) Zhang, Z.; Zhang, J.; Tan, J.; Wang, Z. J. Org. Chem. 2008, 73, 5180;
(c) Alladoum, J.; Vrancken, E.; Mageney, P.; Roland, S.; Kadouri-Puchot, C. Org. Lett.
2009, 11, 3746; (d) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75,
3900; (e) Peng, P.; Tang, B.-X.; Pi, S.-F.; Liang, Y.; Li, J.-H. J. Org. Chem. 2009, 74,
3569; (f) Chen, C.-C.; Chin, L.-Y.; Yang, S.-C.; Wu, M.-J. Org. Lett. 2010, 12, 5652.
5. For aerobic Wacker-type cyclizations, see: (a) Zanoni, G.; Porta, A.; Meriggi, A.;
Franzini, M.; Vidari, G. J. Org. Chem. 2002, 67, 6064; (b) Kawamura, Y.; Kawano,
Y.; Matsuda, T.; Ishiobi, Y.; Hosokawa, T. J. Org. Chem. 2009, 74, 3048; (c) Zhou,
P.; Zheng, M.; Jiang, H.; Li, Z.; Qi, C. J. Org. Chem. 2011, 76, 4759; (d) Weng, F.;
Wang, C.; Xu, B. Tetrahedron Lett. 2010, 51, 2593.
6. For aerobic Wacker-type reactions, see: (a) Ren, W.; Xia, Y.; Ji, S.-J.; Zhang, Y.;
Wan, X.; Zhao, J. Org. Lett. 2009, 11, 1841; (b) Mitsudome, T.; Umetani, T.; Mori,
K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2006, 47, 1425.
7. (a) Chang, M.-Y.; Lee, T.-W.; Lin, S.-Y. Tetrahedron 2013, 69, 228; (b) Chang, M.-Y.;
Lee, T.-W.; Wu, M.-H. Heterocycles 2012, 85, 1607; (c) Chang, M.-Y.; Lee, T.-W.;
Wu, M.-H. Org. Lett. 2012, 14, 2198.
4.6.1. 4-(2-Methylbenzofuran-5-yl)-2-propenylphenol (2a-1). Yield¼
29% (77 mg); Colorless viscous gum; IR (CHCl3) 3328, 2978, 2874,
1677, 1454, 1242, 1148, 920 cmꢂ1; HRMS (ESI, Mþþ1) calcd for
C18H17O2 265.1229, found 265.1232; 1H NMR (400 MHz, CDCl3):
d
7.60 (d, J¼1.6 Hz, 1H), 7.53 (d, J¼2.4 Hz, 1H), 7.42 (d, J¼8.4 Hz, 1H),
7.37 (dd, J¼2.0, 8.4 Hz, 1H), 7.33 (dd, J¼2.0, 8.4 Hz, 1H), 6.86 (d,
J¼8.0 Hz,1H), 6.64 (dq, J¼2.0,15.6 Hz,1H), 6.39 (t, J¼0.8 Hz,1H), 6.29
(dq, J¼6.4, 15.6 Hz, 1H), 6.06 (s, 1H), 2.47 (d, J¼1.2 Hz, 3H), 1.95 (dd,
J¼1.6, 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 156.05, 154.07,
151.58, 135.82, 134.75, 129.65, 128.64, 126.92, 126.39, 125.39, 125.17,
122.40, 118.19, 115.93, 110.57, 102.73, 18.94, 14.12.
4.6.2. 3,30-Dipropenylbiphenyl-4,40-diol (2a-2). Yield¼30% (80 mg);
mp¼94e95 ꢁC (recrystallized from hexanes and EtOAc); IR (CHCl3)
3328, 2972, 2878, 1655, 1438, 1241, 1143, 947 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C18H19O2 267.1385, found 267.1388; 1H NMR
8. For recent reviews on the syntheses of benzofurans, see: (a) Li, J. J.; Gribble,
G. W. Palladium in Heterocyclic Chemistry; Pergamon: Amsterdam, Nether-
lands, 2000; (b) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; (c) Liao, Y.; Hu, Y.; Wu, J.;
Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z. Curr. Med. Chem. 2003, 10, 2285; (d)
Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285; (e) Alonso, F.; Beletskaya, I. P.;
Yus, M. Chem. Rev. 2004, 104, 3079.
(400 MHz, CDCl3):
d
7.46 (d, J¼2.4 Hz, 2H), 7.27 (dd, J¼2.4, 8.0 Hz, 2H),
6.83 (d, J¼8.4 Hz, 2H), 6.62 (dq, J¼2.0, 15.6 Hz, 2H), 6.27 (dq, J¼6.4,
15.6 Hz, 2H), 5.09 (br s, 2H), 1.94 (dd, J¼1.6, 6.8 Hz, 6H); 13C NMR
(100 MHz, CDCl3):
d
151.55 (2ꢀ), 133.81 (2ꢀ), 128.66 (2ꢀ), 126.32
9. For recent transition metal-catalyzed one-pot efficient syntheses of benzofu-
rans, see: (a) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Li, J.-H. Org.
Lett. 2006, 8, 3017; (b) Varela-Fernandez, A.; Gonzalez-Rodriguez, C.; Varela, J.
A.; Castedo, L.; Saa, C. Org. Lett. 2009, 11, 5350; (c) Arcadi, A.; Cacchi, S.; Di
Giuseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409; (d) Protti, S.;
Fagnoni, M.; Albini, A. J. Org. Chem. 2012, 77, 6473; (e) Ghosh, S.; Das, J.; Saikh, F.
Tetrahedron Lett. 2012, 53, 5883; (f) Liu, Y.; Yao, B.; Deng, C.-L.; Tang, R.-Y.;
Zhang, X.-G.; Li, J.-H. Org. Lett. 2011, 13, 1126; (g) Gabriele, B.; Mancuso, R.;
Salerno, G. J. Org. Chem. 2008, 73, 7336; (h) Arcadi, A.; Blesi, F.; Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Marinelli, F. Tetrahedron 2013, 69, 1857.
10. For other representative papers on the Pd-catalyzed one-pot synthesis of benzo
[b]furans, see: (a) Arcadi, A.; Marinelli, F.; Cacchi, S. Synthesis 1986, 749; (b)
Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta, S. K. J. Chem. Soc., Chem. Com-
mun. 1992, 41; (c) Torii, S.; Xu, L. H.; Okumoto, H. Synlett 1992, 515; (d) Can-
diani, I.; Debernardinis, S.; Cabri, W.; Marchi, M.; Bedeschi, A.; Penco, S. Synlett
1993, 269; (e) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem.
1995, 60, 3270; (f) Monteiro, N.; Arnold, A.; Balme, G. Synlett 1998, 1111; (g)
Bishop, B. C.; Cottrell, I. F.; Hands, D. Synthesis 1997,1315; (h) Kundu, N. G.; Pal, M.;
Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans. 1 1997, 2815; (i) Lutjens, H.;
Scammells, P. J. Synlett 1999, 1079; (j) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67,
1905.
(2ꢀ), 125.75 (2ꢀ), 125.37 (2ꢀ), 125.19 (2ꢀ), 115.93 (2ꢀ), 18.93 (2ꢀ).
4.6.3. 4-[4-(2,3-Dimethylbenzofuran-5-yl)phenoxy]butan-2-one
(10). Yield¼80% (246 mg); mp¼103e104 ꢁC (recrystallized from
hexanes and EtOAc); IR (CHCl3) 2948, 1760, 1672, 1518, 1277, 1142,
973 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C20H21O3 309.1491, found
309.1493; 1H NMR (400 MHz, CDCl3):
d
7.54 (d, J¼8.4 Hz, 2H),
7.54e7.52 (m, 1H), 7.38e7.37 (m, 2H), 6.97 (d, J¼8.8 Hz, 2H), 4.28 (t,
J¼6.4 Hz, 2H), 2.93 (t, J¼6.4 Hz, 2H), 2.39 (d, J¼0.4 Hz, 3H), 2.26 (s,
3H), 2.17 (d, J¼0.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 206.41,
157.66, 153.14, 151.14, 135.26, 134.95, 130.92, 128.36 (2ꢀ), 122.29,
116.67, 114.75 (2ꢀ), 110.38, 109.87, 62.99, 43.02, 30.52, 11.84, 7.93.
Acknowledgements
The authors would like to thank the National Science Council of
11. For biological properties of benzofurans, see: (a) Monte, A. P.; Marona-Lew-
icka, D.; Cozzi, N. V.; Nichols, D. E. J. Med. Chem. 1993, 36, 3700; (b) Monte, A.
P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D. B.; Nelson, D. L.;
Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997, 40, 2997; (c) Janusz, J. M.;
Young, P. A.; Scherz, M. W.; Enzweiler, K.; Wu, L. I.; Gan, L.; Pikul, S.; McDow-
Dunham, K. L.; Johnson, C. R.; Senanayake, C. B.; Kellstein, D. E.; Green, S. A.;
Tulich, J. L.; Rosario-Jansen, T.; Magrisso, I. J.; Wehmeyer, K. R.; Kuhlenbeck, D. L.;
Eichhold, T. H.; Dobson, R. L. M. J. Med. Chem. 1998, 41, 1124; (d) Piters, L.;
van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G. J. Med. Chem.
1999, 42, 5475; (e) Shi, G. Q.; Dropinski, J. F.; Zhang, Y.; Santini, C.; Sahoo, S. P.;
Berger, J. P.; MacNaul, K. L.; Zhou, G. C.; Agrawal, A.; Alvaro, R.; Cai, T. Q.;
Hernadez, M.; Wright, S. D.; Moller, D. E.; Heck, J. V.; Meinke, P. T. J. Med. Chem.
2005, 48, 5589; (f) Kataoka, K.; Shiota, T.; Takeyasu, T.; Minoshima, T.;
Watanabe, K.; Tanaka, H.; Mochizuki, T.; Taneda, K.; Ota, M.; Tanabe, H.;
Yamaguchi, H. J. Med. Chem. 1996, 39, 1262; (g) Luize, P. S.; Ueda-Nakamura, T.;
Filho, B. P. D.; Cortez, D. A. G.; Nakamura, C. V. Biol. Pharm. Bull. 2006, 29, 2126; (h)
Saku, O.; Saki, M.; Kurokawa, M.; Ikeda, K.; Takizawa, T.; Uesaka, N. Bioorg. Med.
Chem. Lett. 2010, 20, 1090.
the Republic of China for its financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.031.
Scanned photocopies of spectral data and crystallographic data of
compounds 2b and 3b (CIF) were supported.
References and notes
1. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Comprehensive
Heterocyclic Chemistry III; Elsevier: New York, NY, 2008.
2. For reviews on the Wacker reaction, see: (a) Muzart, J. Tetrahedron 2005, 61,
5955; (b) Muzart, J. Tetrahedron 2007, 63, 7505; (c) Punniyamurthy, T.; Velus-
amy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329; (d) Takacs, J. M.; Jiang, X.-T. Curr.
Org. Chem. 2003, 7, 369; (e) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285; (f)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Scottocrnola, S. Chem. Rev. 2007, 107,
5318; (g) Tsuji, J. Pure Appl. Chem. 1999, 71, 1539; (h) Cornell, C. N.; Sigman, M. S.
Inorg. Chem. 2007, 46, 1903; (i) Kotov, V.; Scaborough, C. C.; Stahl, S. S. Inorg.
Chem. 2007, 46, 1910.
12. (a) Demerseman, P.; Royer, R. Bull. Soc. Chim. Fr. 1970, 2253; (b) Mathai, T. J.
India Chem. Soc. 1966, 43, 133.
13. (a) Ota, T.; Hasegawa, S.; Inoue, S.; Sato, K. J. Chem. Soc., Perkin Trans. 1 1988,
3029; (b) For synthesis of garcifuran B, see: Kelly, T. R.; Szabados, A.; Lee, Y.-J. J.
Org. Chem. 1997, 62, 428.
14. Chen, P.-Y.; Huang, K.-S.; Tsai, C.-C.; Wang, T.-P.; Wang, E.-C. Org. Lett. 2012, 14,
4930.
15. CCDC 913059 (3b) and 913060 (2b) contain the supplementary crystallographic
data for this paper. This data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; fax: 44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
3. For representative papers on the Wacker-type reactions, see: (a) Teo, P.;
Wickens, Z. K.; Dong, G.; Grubbs, R. H. Org. Lett. 2012, 14, 3237; (b) Yuan, C.;
Hollingsworth, R. I. Tetrahedron Lett. 2011, 52, 5421; (c) Abrams, J. N.; Zhao, Q.;
Ghiviriga, I.; Minaruzzaman. Tetrahedron 2012, 68, 423; (d) Wu, C.; Li, P.; Fang,