tert-BuOK-mediated carbanion-yne intramolecular cyclization: Synthesis of 2-substituted 3-benzylbenzofurans

Article abstract of DOI:10.1016/j.tet.2011.09.144

A mild, efficient, and regioselective carbanion-yne intramolecular cyclization mediated by t-BuOK for the synthesis of 2-substituted 3-benzylbenzofurans is developed. It was started from o-iodophenol (1), based on O-alkylation, and the Sonogashira reaction in sequence to produce 2-(2-phenylethynylphenoxy)-1-arylalkanones (5). An intramolecular carbanion-yne 5-exo-dig cyclization reaction of 5, which was mediated by t-BuOK, yielded title benzofurans in good yields.

Full text of DOI:10.1016/j.tet.2011.09.144

Tetrahedron 67 (2011) 9291e9297
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
tert-BuOK-mediated carbanioneyne intramolecular cyclization: synthesis
of 2-substituted 3-benzylbenzofurans
,
Po-Yuan Chen a, Tzu-Pin Wang a, Keng-Shiang Huang b, Chai-Lin Kao a, Jui-Chi Tsai a, Eng-Chi Wang a
*
a Department of Medicinal & Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild, efficient, and regioselective carbanioneyne intramolecular cyclization mediated by t-BuOK for
the synthesis of 2-substituted 3-benzylbenzofurans is developed. It was started from o-iodophenol (1),
based on O-alkylation, and the Sonogashira reaction in sequence to produce 2-(2-phenylethynyl-
phenoxy)-1-arylalkanones (5). An intramolecular carbanioneyne 5-exo-dig cyclization reaction of 5,
which was mediated by t-BuOK, yielded title benzofurans in good yields.
Received 22 February 2011
Received in revised form 29 September 2011
Accepted 30 September 2011
Available online 6 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
o-Iodophenol
Sonogashira reaction
Carbanioneyne intramolecular cyclization
5-exo-dig Cyclization
2-Substituted 3-benzylbenzofurans
1. Introduction
strategy for benzofurans using phase-transfer-catalyzed meth-
odology (Scheme 1).
The carbonecarbon bond formation, an important synthetic
strategy for constructing various benzocarbocyclic and benzohe-
terocyclic compounds, has been well documented in literatures.
For instance, strategies for intramolecular carbonecarbon bond
formation which mainly reported were the intramolecular Heck
reaction for medium-sized oxa-heterocycles,1 for including cou-
marins,2 tetrahydroanthracenes,3 as well as others.4 Because
benzofurans exhibited diverse biological activities, such as anti-
bacterial and antifungal,5 antitumor and antiviral,6 anticonvul-
sant and anti-inflammatory,7 and antileishmanial activity,8 the
development of a mild, diverse, efficient, and practical route for
the synthesis of benzofuranoides is requisite and significant from
the view-points of synthetic and medicinal chemistry. Up to
present various approaches for the synthesis of benzofuran, such
as palladium-catalyzed enolate arylation with o-bromophenols,9
palladium-catalyzed reactions of propargylic carbonates with
nucleophiles,10 a one-pot sequential Sonogashira coupling,11 and
ring-closing metathesis12 have been disclosed. Recently, Terada,
et al.13a developed an excellent method using phosphazene base-
catalyzed an intramolecular carbonecarbon bond cyclization in
DMSO (dimethyl sulfoxide) for the synthesis of 2-substitued
3-benzylbenzofurans and Hu et al.13b also reported the similar
O
phosphazene
DMSO
O
R
R
PTC
Cs2CO3, CH3CN
Scheme 1. Intramolecular cyclization of o-alkynylphenyl ether mediated by phos-
phazene13a or PTC/cesium carbonate13b to generate benzofuran.
However, those methods described above have encountered
some disadvantages. Such as, phosphazene used by Terada’s
method as reaction base is complicated in structure and very ex-
pensive in price and DMSO utilized as reaction solvent is a high
boiling point solvent and is difficult to remove. Moreover, the se-
lected PTC (phase transfer catalyst) and base for cyclization re-
ported by Hu et al. to yield benzofurans, which is variable with
reaction condition and lacking of straightforward, are disadvan-
tages. Moreover those reported methods to prepare benzofurans
with limited substituents and insufficient investigation for insight
into this carbanioneyne cyclization are drawbacks. Recently we
have successfully reported a carbanioneolefin cyclization which
mediated by potassium tert-butoxide for diverse chroman de-
rivatives (Scheme 2).14
* Corresponding author. E-mail address: enchwa@kmu.edu.tw (E.-C. Wang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.144

9292
P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
as follows. In 1H-NMR spectrum, a doublet methyl signal with
coupling constant J¼6.8 Hz at 1.80 and a quartet one-proton signal
with coupling constant J¼6.8 Hz at 5.39 indicating the presence of
eCH(CH3)COe group were found in 3d. A triplet methyl signal with
R1
R2
R4
R1
R4
d
t-BuOK
ref 14a
d
O
R2
O
R3
O
R3
O
O
coupling constant J¼8.0 Hz at
at
constant J¼8.0, 4.8 Hz at
d
1.20, a multiplet two-protons signal
d
2.17, and a double doublet one-proton signal with coupling
OCH3
OCH3
CH3
H3CO
R
H3CO
R
d 5.16 indicating the presence of
t-BuOK
ref 14b
eCH(CH2CH3)COe group were found in 3e. The selected 1H NMR
spectral data described above are consistent with the data required
for 3aee. Other spectral data including IR, 1H NMR, 13C NMR, EIMS,
and EA are all equally matched with the data needed for 3aee.
Then, compound 3 was, respectively, allowed to react with phe-
nylacetylene (4a), and p-methylphenylacetylene (4b), in the pres-
ence of CuI, Pd(PPh3)2Cl2, and diisopropylamine to undergo the
Sonogashira reaction15 to give 2-(2-phenylethynylphenoxy)-1-
arylethanones (5aeh) in 76e84% yields. The appearance of CeC
triple bond at 2216e2218 cmꢀ1 and carbonyl group at
1692e1703 cmꢀ1 in the spectra of IR in 5aeh indicated the suc-
cessful work of the Sonogashira reaction. Spectral data, such as 1H
NMR, 13C NMR, EIMS, HRMS, and EA are all consistent with the data
required for 5aeh. In order to figure out the optimized reaction of
base-mediated the carbanioneyne cyclization, compound 5c was
utilized as model to react with various bases and under various
conditions. The results obtained were depicted in Table 1.
O
O
O
Scheme 2. Carbanioneolefin cyclization mediated by potassium tert-butoxide to yield
chroman derivatives.
In these studies we found both 2-phenylvinylphenoxy and
2-phenylallylphenoxy intermediates could be, respectively, medi-
ated by potassium tert-butoxide to undergo carbanioneolefin
intramolecular 6-endo-trig cyclization with regiospecificity to yield
chroman derivatives. Thus, we would like to extend our previous
studies to investigate the cyclization of carbanioneyne mediated by
potassium tert-butoxide. Herein, we report the result to build up
various 2-substituted 3-benzylbenzofurans from intramolecular
carbanioneyne 5-exo-dig cyclization by two different pathways,
which briefly mediated by potassium tert-butoxide (Scheme 3).
R1
Table 1
Treatment of 5c with various bases (1.2 equiv), solvents (10 mL), and temperature to
examine the yield of 6c
I
I
R
i
R
ii
R2
R2
OH
O
O
O
O
OCH3
5
1
3
a. R=R1=R2=H;
a. R=R2=H; b. R=CH3, R2=H;
c. R=OCH3, R2=H;
d. R=H, R2=CH3;
b. R=CH3, R1=R2=H;
c. R=OCH3, R1=R2=H;
d. R=R2=H, R1=CH3;
e. R=R1=CH3, R2=H;
f. R=OCH3, R1=CH3, R2=H;
g. R=R1=H, R2=CH3;
OCH3
Conditions
e. R=H, R2=C2H5
O
O
O
O
h. R=R1=H, R2=C2H5
Entry
Base
Solvent
Temp (ꢁC)
Timea (h)
Yieldb (%)
R1
1
2
3
4
5
6
7
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaOEt
NaOEt
NaNH2
THF
THF
CH2Cl2
t-BuOH
EtOH
THF
rt
1.5
0.5
1.5
1
3
4
80
88
76
R
Reflux
Reflux
Reflux
rt
rt
rt
a. R=R1=H;
iii
b. R=CH3, R1=H
c. R=OCH3, R1=H;
d. R=H, R1=CH3
e. R=R1=CH3;
82
33c
47c
51
R2 = H
O
O
THF
4
f. R=OCH3, R1=CH3
6a-f
a
5
Determined by monitoring the consumption of starting material with TLC.
Isolated by column chromatography.
Recovery of starting material.
b
c
iii
R2 = CH3, C2H5
g. R2=CH3; h. R2=C2H5
R2
From the experimental results obtained at Table 1, we found that
O
compound 5c can be briefly and efficiently cyclized using t-BuOK in
refluxing THF (entry 2) to yield benzofurans with regioselectivity
and in high yields (80e88%), via an intramolecular 5-exo-dig car-
banioneyne cyclization. In monitoring by TLC, we found when
sodium amide was used as base to give not only the desired product
but also other unidentified by-products in this cyclization. When
sodium ethoxide was used as base, the longer reaction time and
lower yield than that of t-BuOK were found (entries 5 and 6). Thus,
in this cyclization, the trend of base in the reactivity in THF is po-
tassium tert-butoxide>sodium amide>sodium ethoxide (entries 1,
6, and 7). Meanwhile the trend of solvent for this cyclization is
THF>t-BuOH>CH2Cl2 (entries 2, 3, and 4). Therefore, the cycliza-
tion of 2-(2-phenylethynylphenoxy)-1-arylethanones (5aef) to
yield a series of 2-aroyl-3-benzylbenzofurans (6aef) is achieved
using the optimum condition (t-BuOK in refluxing THF), which
obtained from our experimental results. The chemical structures of
6g-h
Scheme 3. Intramolecular carbanioneyne 5-exo-dig type cyclization reaction medi-
ated by t-BuOK to generate 2-aroyl-3-benzylbenzofurans. Reagents and reaction con-
dition: (i) 2-bromoacetophenones (2aee), K2CO3, acetone, reflux 2e3 h, 87e91%; (ii)
Pd(PPh3)2Cl2, CuI, phenylacetylene (4a), p-methylphenylacetylene (4b), (iPr)2NH, THF,
reflux 3 h, 76e84%; (iii) t-BuOK, THF, reflux 0.5 h, 80e88%.
2. Results and discussion
As a general procedure, the reaction of o-iodophenol (1) with
2-bromoacetophenones (2aee) in the presence of K2CO3 afforded
2-(2-iodophenoxy)arylethanones (3aee) in yields of 87e91%. The
typical absorption of IR at 1673e1698 cmꢀ1 exhibited the presence
of C]O group in the molecules of 3aee, and the methylene protons
with singlet signals at
found in the structure 3aec. The elucidation of structures 3dee are
d
5.24e5.32 in 1H NMR were commonly

P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
9293
compounds 6aef are fully supported by their spectral data, such as
1H NMR, 13C NMR, EIMS, HRMS, and EA. The % yields, selected
physical and spectral data of 2-aroyl-3-benzylbenzofurans (6aef)
are summarized in Table 2.
allowed to react with tert-BuOK at the same reaction condition.
After quenching with dilute HCl, 3-benzyl-2-methylbenzofuran
(6g) and 3-benzyl-2-ethylbenzofuran (6h) were obtained in 86
and 85% yields, together with benzoic acid, which was isolated in
yields of 82e80%. Apparently, the benzofurans (6g,h), which were
obtained underwent the different reaction pathway than that of
6aef. Thus, it can be developed as a new strategy for the synthesis
of 2-alkyl-3-benzylbenzofurans. The structural elucidation of 3-
benzyl-2-methylbenzofuran (6g), as an example, was determined
by its spectral data. For instances, no carbonyl absorption and no
CeC triple bond were found in IR spectrum. Furthermore, one
Table 2
Selected physical and spectral data of 2-aroyl-3-benzylbenzofurans (6aef)
Compd Yield (%) Mp (ꢁC)
IR
HRMSa
EAa (C%; H%)
(cmꢀ1
)
6a
6b
6c
6d
6e
6f
80
83
88
83
85
87
94e95
1644
1638
1637
1644
1642
1638
Calcd 312.1150 Calcd 84.59: 5.16
Found 312.1152 Found 84.39; 5.18
Calcd 326.1307 Calcd 84.64; 5.56
Found 326.1306 Found 84.67; 5.56
Calcd 342.1256 Calcd 80.68; 5.30
Found 342.1257 Found 80.51; 5.28
Calcd 326.1307 Calcd 84.64; 5.56
Found 326.1310 Found 84.56; 5.55
Calcd 340.1363 Calcd 84.68; 5.92
Found 340.1363 Found 84.55; 5.96
Calcd 356.1412 Calcd 80.88; 5.66
Found 356.1414 Found 80.56; 5.63
(96e98)13a
119e120
singlet signal with three protons at
methyl group, and one singlet signal with two protons at
exhibiting the presence of benzylic protons, and another nine ar-
omatic protons with multiplet at
7.1e7.4 were found in the 1H
NMR spectrum. Two sp3 carbons, one at
12.0 and the other one at
29.6, and twelve sp2 carbons were observed in 13C NMR spectrum.
d
2.4 indicating the presence of
d
4.0
98e99
d
118e119
111e112
120e121
d
d
In addition, molecular ion m/z 222 found in EIMS and m/z 222.1042
found in HRMS further verified the correctness of compound 6g.
The structure of 6h is elucidated as the same procedures as for 6g.
In the previous study,18 3-benzyl-2-ethylbenzofuran (6h), prepared
from 2-ethylbenzofuran via benzoylation, reduction, and de-
oxygenation, was found to be an essential building block for ben-
zofuranyloxadiazolidine-3,5-diones, which played an important
role as PAI-1 inhibitor (plasminogen activator inhibitor-1) for
treatment of disorders related to fibrinolytic system impairment.
However, methods for preparing 2-ethylbenzofuran reported were
not readily accessible.19 Therefore our method for 3-benzyl-2-
ethylbenzofuran (6h) has great advantages over the existing pro-
tocol described above. Thus, in this study, we have successfully
established a novel strategy not only for 6g,h but also could be
applied for other 2-alkyl-3-benzylbenzofurans. The elucidation of
by-product benzoic acid is confirmed simply by comparing with
commercial available authentic sample. The result shown is con-
sistent with IR spectrum and correctness in melting-point [mp for
benzoic acid: 121e124 ꢁC, found: 123e124 ꢁC]. The interpretation
of reaction mechanism of formation 6g,h from 5g,h could be ra-
tionally illustrated as follows (Scheme 5). Initially, (i) the bulky base
t-BuOK due to steric hindrance could not abstract the proton
nearby the carbonyl group but underwent the nucleophilic addition
by attacking the carbonyl group of 5g,h to give transient 5g,h-1, (ii)
because of much hindrance in 5g,h-1, tert-butyl benzoate was
eliminated and generated a carbanion which spontaneously un-
derwent 5-exo-dig cyclization to yield transient 5g,h-2, (iii) after
protonation and deprotonation process, the resulting 5g,h-3 was
aromatized to construct the stable benzofuran ring to generate
transient benzylic anion 5g,h-4, (iv) the forming benzylic anion
a
Data measured from Southern Precious Instrumental Center of NSC, Taiwan.
Based on the obtained results, the reaction mechanism of this
type of 5-exo-dig carbanioneyne cyclization could be rationally
proposed as follows (Scheme 4).
R1
R1
R1
R
K
R
R
t-BuOK
t-BuOH
H
O
H
O
K
O
O
O
O
5a-f
R1
I
II
R1
R1
R
R
R
K
t-BuOH
t-BuOK
O
O
O
O
O
O
H
K
III
IV
V
R1
R
t-BuOK
t-BuOH
O
O
6a-f
Scheme 4. The mechanism of an intramolecular carbanioneyne 5-exo-dig cyclization
for 2-aroyl-3-benzylbenzofurans.
One of the hydrogen, which is nearby the carbonyl group was
abstracted by t-BuOK to yield a carbanion (I), and followed by un-
dergoing intramolecular carbanioneyne 5-exo-dig cyclization re-
action to generate carbanion II. The unstable transient anion II is
subsequently converted into anion III, which is stabilized by an
enolate IV via a protonationedeprotonation process mediated by t-
BuOH and t-BuOK. Then, the C-2 in IV picked up a proton from t-
BuOH to generate V. The transient V further undergoes a process of
deprotonationeprotonation mediated by t-BuOK and t-BuOH to
yield the stable aromatic benzofuran ring. According to the pro-
posed mechanism, the overall reaction, 1 equiv t-BuOK is required
for this cyclization which matches with the requirement (1.2 equiv)
of base in experiments. On the other hand, 2-(2-(2-phenylethynyl)
phenoxy)-1-phenylpropan-1-one (5g) and (2-(2-phenylethynyl)
phenoxy)-1-phenylbutan-1-one (5h), which bearing a methyl
O
C6H5
C6H5
C6H5
C6H5
OBut
O
K
R
R
t-BuOK
R
C6H5
O
O
O
C6H5
O K
O
5 g-h-2
5 g-h-1
5 g-h
C6H5
H
C6H5
C6H5
C6H5
O
H
K
H
H
O
OH
R
+
R
R
O
O
O
O
C6H5
K
6g. R = CH3
6h. R = C2H5
;
5 g-h-4
5 g-h-3
Scheme 5. The proposed mechanism for the formation of 6g and 6h from 5g and 5h,
group and ethyl group at the a-position of the carbonyl group were
respectively.

9294
P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
which is bulky and strong base, immediately attacked one of the
proton of tert-butyl group in tert-butyl benzoate to cause elimina-
tion and to yield potassium benzoate and isobutene, and (v) after
quenching with dilute HCl solution, 2-alkyl-3-benzylbenzofuran
(6g,h) and benzoic acid were produced, but isobutene
[bp¼ꢀ6.9 ꢁC] was lost in the reaction for the lower boiling point.
In order to illustrate the rationality of the proposed mechanism,
tert-butyl benzoate prepared from known procedure,20 was
allowed to react with potassium tert-butoxide in refluxing THF.
After monitoring by TLC to make sure the consumption of starting
material (it took 20 min), the reaction mixture was quenched with
dilute HCl. Benzoic acid was obtained in 88% yield (Scheme 6).
t-BuOK-mediated carbanioneolefin to undergo 6-endo-trig cycli-
zation to yield chroman derivatives but carbanioneyne to undergo
5-exo-dig cyclization to yield benzofuran derivatives.
4. Experimental
4.1. General
Melting points (Yanaco micro melting-point apparatus) were
uncorrected. 1H NMR and 13C NMR spectra were obtained on
a Varian Unity plus 400 Spectrometer. Chemical shifts were mea-
sured in parts per million with respect to TMS. IR spectra were run
on a PerkineElmer spectrometer. Elemental analyses were recor-
ded on a Heraeus CHNeO Rapid analyzer. Mass spectra were
recorded on a Chem/hp/middle spectrometer connected to a Hew-
lett Packard series II model gaseliquid chromatography. HRMS
spectra were performed on a JEOL JMS SX/SX 102A instrument.
Silica gel (230e400 mesh) for column chromatography and pre-
coated silica gel plates (60 F254) for TLC were purchased from E.
Merck Co. UV light (254 nm) was used to detect spots on TLC plates
after development.
OH
H+
C6H5
t-BuOK
O
C6H5
O
O
THF, reflux
Scheme 6. Reaction of tert-butyl benzoate with t-BuOK, and workup in acidic condi-
tion to yield benzoic acid.
Based on experimental result obtained above, tert-butyl ben-
zoate reacted with bulky base to undergo elimination to yield
benzoic acid could be confirmed. In contrast, tert-butyl benzoate
treated with acid to yield benzoic acid and isobutylene via elimi-
nation has been previously reported,21 and can be interpreted as
follows (Scheme 7).
4.2. General procedure for the preparation of 2-(2-
iodophenoxy)-1-arylethanone (3aee)
2-Iodophenol (1) (2.2 g, 10 mmol) dissolved in acetone (40 mL)
was added with 2-bromoacetophenones (2aee) (12 mmol) and
anhydrous K2CO3 (2.07 g, 15 mmol). The resulting mixture was
stirred and refluxed for 2e3 h, then cooled to room temperature,
and filter. The filtrate was concentrated in vacuo to give crude
product. After purification with column chromatography (ethyl
acetate/n-hexane¼1:15), pure of 2-(2-iodophenoxy)-1-aryletha-
nones 3aee were yielded.
H
O
C6H5
O
H+
CH3
C6H5
O
C6H5
O
+
O
HO
H3C
CH2
H
4.2.1. 2-(2-Iodophenoxy)-1-phenylethanone (3a). Compound 3a
(2.94 g, 87%) was obtained as colorless crystals; mp 123e124 ꢁC
(lit.16 mp 123 ꢁC), Rf¼0.43 (ethyl acetate/n-hexane¼1:4); IRmax
-H+
(gas)
(neat) cmꢀ1: 1685 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 5.32 (s,
Scheme 7. Reaction of tert-butyl benzoate with acid to yield benzoic acid.
2H, ArOCH2COe), 6.74 (dd, J¼8.4, 1.2 Hz, 2H, ArH), 7.25 (td, J¼8.4,
1.6 Hz, 1H, ArH), 7.50 (td, J¼6.8, 1.6 Hz, 2H, ArH), 7.62 (ddt, J¼8.4,
6.8,1.2 Hz,1H, ArH), 7.79 (dd, J¼8.0,1.6 Hz,1H, ArH), 8.04 (dd, J¼8.4,
Thus, our proposed mechanism for yielding 2-alkyl-3-
benzylbenzofurans (6g,h) from 5g,h also could be rationally illus-
trated, even could not capture isobutylene gas. Both for the syn-
thesis of 2-aroyl-3-benzylbenzofurans and for 2-alkyl-3-
benzylbenzofurans, were briefly established which is different
from previous studies by Terada,13a Liu,13b and Liang,17 with dif-
ferent bases or catalyst.
1.2 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 72.0, 86.4, 112.6,
123.5, 128.4, 128.8, 129.4, 134.0, 134.4, 139.8, 156.8, 194.1; EIMS
(70 eV) m/z (rel intensity, %) 338 (Mþ, 2), 212 (19), 211 (100),106 (6),
105 (42), 91 (6), 77 (25); HRMS calcd for C14H11IO2: 337.9804.
Found: 337.9804. Anal. Calcd for C14H11IO2: C, 49.73; H, 3.28. Found:
C, 49.77; H, 3.24.
3. Conclusion
4.2.2. 2-(2-Iodophenoxy)-1-p-tolylethanone (3b). Compound 3b
(3.20 g, 91%) was obtained as colorless crystals; mp 132e133 ꢁC,
In this study we have established two concise and efficient
synthetic routes, one for 2-aroyl-3-benzylbenzofurans and the
other for 2-alkyl-3-benzylbenzofurans. It started from o-iodophe-
nol to prepare 2-phenylethynylphenoxy derivatives as key in-
termediates by the Sonogashira coupling. The key intermediates
(5aef) were mediated by t-BuOK to go through an intramolecular
carbanioneyne 5-exo-dig cyclization to give 2-aroyl-3-
benzylbenzofurans (6aef) in good yields and with regiospeci-
ficity. On the other hand, the intermediates (5g,h), which have an
Rf¼0.46 (ethyl acetate/n-hexane¼1:4); IRmax (neat) cmꢀ1
:
1698 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 2.43 (s, 3H,
ArCH3), 5.29 (s, 2H, ArOCH2COe), 6.73 (dd, J¼8.4, 1.2 Hz, 2H, ArH),
7.23 (td, J¼7.6, 1.6 Hz, 1H, ArH), 7.29 (dd, J¼8.4, 0.4 Hz, 1H, ArH),
7.79 (dd, J¼7.6, 1.6 Hz, 1H, ArH), 7.94 (dd, J¼8.4, 1.6 Hz, 2H, ArH);
13C NMR (CDCl3, 100 MHz)
d 21.8, 72.0, 86.39, 112.6, 123.4, 128.5,
129.4, 129.5, 131.9, 139.8, 145.0, 156.8, 193.7; EIMS (70 eV) m/z (rel
intensity, %) 352 (Mþ, 1), 226 (17), 225 (100), 120 (8), 119 (46), 91
(23), 65 (7); HRMS calcd for C15H13IO2: 351.9960. Found:
351.9961. Anal. Calcd for C15H13IO2: C, 51.16; H, 3.72. Found: C,
51.07; H, 3.76.
alkyl group at the a-position were cyclized by t-BuOK to undergo
another intramolecular carbanioneyne 5-exo-dig cyclization with
stereoselectivity to yield 2-alkyl-3-benzylbenzofurans (6g,h) by
going through another mechanism, i.e., additioneeliminatione
cyclization processes. In conclusion, we found that t-BuOK can be
diversely and efficiently applied for not only carbanioneolefin but
also carbanioneyne cyclization. Moreover, we also found that
4.2.3. 2-(2-Iodophenoxy)-1-(4-methoxyphenyl)ethanone
(3c). Compound 3c (3.31 g, 90%) was obtained as colorless crystals;
mp 108e109 ꢁC (lit.,16 no mp data), Rf¼0.45 (ethyl acetate/n-
hexane¼1:4); IRmax (neat) cmꢀ1: 1673 cmꢀ1 (C]O); 1H NMR

P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
9295
(CDCl3, 400 MHz)
d
3.87 (s, 3H, ArOCH3), 5.24 (s, 2H, ArOCH2COe),
for C22H16O2: 312.1150. Found: 312.1152. Anal. Calcd for C22H16O2:
C, 84.59; H, 5.16. Found: C, 84.36; H, 5.24.
6.75 (dd, J¼8.4, 1.2 Hz, 2H, ArH), 6.96 (dd, J¼7.2, 2.0 Hz, 2H, ArH),
7.24 (td, J¼8.0,1.6 Hz,1H, ArH), 7.77 (dd, J¼8.0,1.6 Hz,1H, ArH), 8.04
(dd, J¼8.8, 2.0 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d
55.5, 71.9,
4.3.2. 2-(2-Phenylethynylphenoxy)-1-p-tolylethanone
86.3, 112.5, 114.0, 123.3, 127.4, 129.4, 130.8, 139.7, 156.8, 164.1.8,
192.7; EIMS (70 eV) m/z (rel intensity, %) 368 (Mþ, 0.2), 242 (16),
241 (100), 137 (22), 135 (81), 121 (14), 77 (15); HRMS calcd for
C15H13IO3: 367.9909. Found: 367.9911. Anal. Calcd for C15H13IO3: C,
48.93; H, 3.56. Found: C, 48.72; H, 3.50.
(5b)17. Compound 5b (1.30 g, 80%) was obtained as brown liquid
(lit.17); Rf¼0.56 (ethyl acetate/n-hexane¼1:3); IRmax (neat) cmꢀ1
:
1698 cmꢀ1 (C]O), 2217 cmꢀ1 (C^C); 1H NMR (CDCl3, 400 MHz)
d
2.36 (s, 3H, ArCH3), 5.29 (s, 2H, OCH2COAr), 6.84 (dd, J¼8.4, 0.8 Hz,
1H, ArH), 6.96 (td, J¼8.4, 0.8 Hz,1H, ArH), 7.23 (m,1H, ArH), 7.29 (m,
3H, ArH), 7.44 (m, 2H, ArH), 7.50 (dd, J¼7.6, 1.6 Hz, 1H, ArH), 7.96
4.2.4. 2-(2-Iodophenoxy)-1-phenylpropan-1-one (3d). Compound
3d (3.13 g, 89%) was obtained as colorless crystals; mp 115e116 ꢁC
(lit.,16 no mp data), Rf¼0.45 (ethyl acetate/n-hexane¼1:4); IRmax
(dd, J¼8.0, 1.6 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.6, 71.9,
85.5, 93.9, 112.8, 113.3, 121.5, 123.4, 128.0, 128.1, 128.6, 129.4, 129.6,
131.5, 132.1, 133.5, 144.7, 158.5, 194.2; EIMS (70 eV) m/z (rel in-
tensity, %) 326 (Mþ, 100), 311 (18), 221 (16), 207 (42), 178 (15), 119
(95), 91 (36); HRMS calcd for C23H18O2: 326.1307. Found: 326.1309.
(neat) cmꢀ1: 1677 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 1.80 (d,
J¼6.8 Hz, 3H, ArOCHCH3COAr), 5.39 (q, J¼6.8 Hz, 1H,
ArOCHCH3eCOAr), 6.67 (m, 2H, ArH), 7.17 (ddd, J¼8.0, 7.2, 1.6 Hz,
1H, ArH), 7.46 (td, J¼8.8, 2.0 Hz, 2H, ArH), 7.57 (ddd, J¼8.8, 7.2,
1.6 Hz, 1H, ArH), 7.75 (dd, J¼8.0, 1.6 Hz, 1H, ArH), 8.13 (dd, J¼8.4,
4.3.3. 1-(4-Methoxyphenyl)-2-(2-phenylethynylphenoxy)-ethanone
(5c). Compound 5c (1.42 g, 83%) was obtained as colorless crystals;
mp 100e101 ꢁC; Rf¼0.49 (ethyl acetate/n-hexane¼1:3); IRmax
(neat) cmꢀ1: 1692 cmꢀ1 (C]O), 2216 cmꢀ1 (C^C); 1H NMR (CDCl3,
1.6 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 19.0, 78.8, 86.9, 113.0,
123.2, 128.7, 129.1, 129.4, 133.7, 136.8, 139.8, 156.2, 198.6; EIMS
(70 eV) m/z (rel intensity, %) 352 (Mþ, 11), 247 (64), 226 (20), 225
(100), 121 (38), 106 (23), 78 (18).
400 MHz)
d 3.81 (s, 3H, OCH3), 5.27 (s, 2H, OCH2COAr), 6.90 (dd,
J¼8.8, 0.8 Hz, 1H, ArH), 6.98 (td, J¼8.4, 0.8 Hz, 1H, ArH), 7.26 (td,
J¼8.4,1.6 Hz,1H, ArH), 7.31 (m, 3H, ArH), 7.45 (m, 2H, ArH), 7.51 (dd,
J¼7.6, 1.6 Hz, 1H, ArH), 8.10 (dd, J¼8.8, 2.0 Hz, 2H, ArH); 13C NMR
4.2.5. 2-(2-Iodophenoxy)-1-phenylbutan-1-one (3e). Compound 3e
(3.18 g, 87%) was obtained as colorless crystals; mp 128e129 ꢁC,
(CDCl3, 100 MHz)
d 55.4, 72.1, 85.6, 93.87, 112.8, 113.3, 113.9, 121.6,
Rf¼0.43 (ethyl acetate/n-hexane¼1:4); IRmax (neat) cmꢀ1
:
123.5, 127.8, 128.1, 128.2, 129.6, 131.1, 131.6, 133.5, 158.6, 164.0,
193.3; EIMS (70 eV) m/z (rel intensity, %) 342 (Mþ, 53), 311 (8), 237
(24), 165 (8), 136 (10), 135 (100), 77 (13); HRMS calcd for C23H18O3:
342.1256. Found: 342.1256. Anal. Calcd for C23H18O3: C, 80.68; H,
5.30. Found: C, 80.70; H, 5.36.
1693 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d
1.20 (t, J¼7.6 Hz, 3H,
ArOCH(CH2CH3)COAr), 2.17 (m, 2H, ArOCH(CH2CH3)COAr), 5.16 (dd,
J¼8.0, 4.8 Hz, 1H, ArOCH(CH2CH3)COAr), 6.59 (dd, J¼8.4, 1.2 Hz, 1H,
ArH), 6.65 (td, J¼8.0, 1.6 Hz, 1H, ArH), 7.14 (ddd, J¼8.8, 7.2, 1.6 Hz,
1H, ArH), 7.46 (td, J¼8.8, 1.6 Hz, 2H, ArH), 7.57 (ddd, J¼8.4, 6.8,
1.2 Hz, 1H, ArH), 7.75 (dd, J¼8.0, 1.6 Hz, 1H, ArH), 8.14 (dd, J¼8.4,
4.3.4. 1-Phenyl-2-(2-p-tolylethynylphenoxy)ethanone
(5d). Compound 5d (1.28 g, 79%) was obtained as brown crystals;
mp 97e98 ꢁC; Rf¼0.55 (ethyl acetate/n-hexane¼1:3); IRmax
(neat) cmꢀ1: 1699 cmꢀ1 (C]O), 2218 cmꢀ1 (C^C); 1H NMR (CDCl3,
1.2 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 10.4, 26.9, 84.1, 86.5,
112.4,123.0, 128.7,129.1, 129.4, 133.7, 134.0, 139.7, 156.2, 198.5; EIMS
(70 eV) m/z (rel intensity, %) 366 (Mþ, 15), 261(100), 241(31),
134(55), 109(18), 105(18), 78(20); HRMS calcd for C16H15IO2:
366.0117. Found: 366.0120. Anal. Calcd for C16H15IO2: C, 52.48; H,
4.13. Found: C, 52.45; H, 4.07.
400 MHz)
d 2.35 (s, 3H, ArCH3), 5.34 (s, 2H, OCH2COAr), 6.85 (d,
J¼8.4 Hz, 1H, ArH), 6.97 (td, J¼8.4, 0.8 Hz, 1H, ArH), 7.11 (d, J¼8.0 Hz,
1H, ArH), 7.24 (td, J¼8.0,1.6 Hz,1H, ArH), 7.46 (m, 2H, ArH), 7.50 (dd,
J¼7.6, 2.0 Hz, 2H, ArH), 7.57 (tt, J¼8.4, 0.8 Hz, 1H, ArH), 8.07 (dd,
4.3. General procedure for the preparation of 5aeh
J¼8.4, 1.6 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.5, 72.1, 84.8,
94.2, 113.0, 113.7, 120.3, 121.7, 128.5, 128.7, 129.0, 129.4, 131.5, 133.5,
133.7, 134.6, 138.2, 158.4, 194.7; EIMS (70 eV) m/z (rel intensity, %)
326 (Mþ, 41), 222 (18), 221 (100), 179 (15), 178 (40), 105 (29), 77
(16); HRMS calcd for C23H18O2: 326.130. Found: 326.1307. Anal.
Calcd for C23H18O2: C, 84.64; H, 5.56. Found: C, 84.38; H, 5.53.
Bis(triphenylphosphine)palladium(II)
chloride
(0.14
g,
0.2 mmol), CuI (0.05 g, 0.26 mmol), and diisopropylamine
(1.27 mL, 9 mmol) in THF (25 mL) was stirred and added 3aee
(5 mmol) and arylacetylenes (4a,b) (7.5 mmol) in drops. The re-
action mixture was stirred and heated to reflux for 3 h. After
cooling, the solution was quenched with saturated NH4Cl solution
and extracted with CH2Cl2 (5ꢂ20 mL). The combined organic
layers were washed with brine (20 mL), and dried over MgSO4
and was filtered, concentrated in vacuo in sequences. The ob-
tained residue was purified from flash column chromatography
(ethyl acetate/n-hexane¼1:5) to afford the desired compound
5aeh.
4.3. 5. 1-p-Tolyl-2-(2-p-tolylethynylphenoxy)ethanone
(5e). Compound 5e (1.41 g, 83%) was obtained as colorless crystals;
mp 116e117 ꢁC; Rf¼0.53 (ethyl acetate/n-hexane¼1:3); 1693 cmꢀ1
(C]O), 2217 cmꢀ1 (C^C); 1H NMR (CDCl3, 400 MHz)
d 2.36 (s, 3H,
ArCH3), 2.38 (s, 3H, ArCH3), 5.31 (s, 2H, OCH2COAr), 6.85 (d,
J¼8.4 Hz,1H, ArH), 6.97 (td, J¼8.4, 0.8 Hz,1H, ArH), 7.12 (d, J¼8.0 Hz,
1H, ArH), 7.24 (m, 3H, ArH), 7.34 (dd, J¼8.0, 1.6 Hz, 2H, ArH), 7.49
(dd, J¼7.6, 1.6 Hz, 1H, ArH), 7.97 (dd, J¼8.0, 1.6 Hz, 2H, ArH); 13C
4. 3.1. 1-Phenyl-2-(2-phenylethynylphenoxy)ethanone
(5a). Compound 5a (1.19 g, 76%) was obtained as brown crystals;
mp 95e96 ꢁC (lit.13a mp 90e92 ꢁC); Rf¼0.53 (ethyl acetate/n-
hexane¼1:3); IRmax (neat) cmꢀ1: 1702 cmꢀ1 (C]O), 2217 cmꢀ1
NMR (CDCl3, 100 MHz) d 21.5, 21.7, 72.1, 84.8, 94.1, 112.9, 113.6,
120.4, 121.6, 128.7, 129.0, 129.4, 131.5, 132.2, 133.5, 138.2, 144.7,
158.5, 194.4; EIMS (70 eV) m/z (rel intensity, %) 340 (Mþ, 32), 221
(78), 205 (15), 178 (37), 119 (100), 91 (52), 65 (15); HRMS calcd for
C24H20O2: 340.1463. Found: 340.1465. Anal. Calcd for C24H20O2: C,
84.68; H, 5.92. Found: C, 84.32; H, 5.98.
(C^C); 1H NMR (CDCl3, 400 MHz)
d 5.32 (s, 2H, OCH2COAr), 6.84
(dd, J¼8.4, 0.8 Hz, 1H, ArH), 6.97 (td, J¼8.4, 0.8 Hz,1H, ArH), 7.24 (m,
1H, ArH), 7.30 (m, 3H, ArH), 7.44 (m, 4H, ArH), 7.50 (dd, J¼7.6,1.6 Hz,
1H, ArH), 7.55 (tt, J¼8.8, 1.2 Hz, 1H, ArH), 8.05 (dd, J¼8.0, 1.6 Hz, 2H,
4.3.6. 1-(4-Methoxyphenyl)-2-(2-p-tolylethynylphenoxy)-ethanone
(5f). Compound 5f (1.50 g, 84%) was obtained as colorless crystals;
mp 125e126 ꢁC; Rf¼0.53 (ethyl acetate/n-hexane¼1:3); IRmax
(neat) cmꢀ1: 1703 cmꢀ1 (C]O), 2216 cmꢀ1 (C^C); 1H NMR (CDCl3,
ArH); 13C NMR (CDCl3, 100 MHz)
d 71.9, 86.5, 93.9, 112.8, 113.3,
121.6, 123.4, 128.1, 128.2, 128.4, 128.7, 129.6, 131.5, 133.5, 133.7,
134.5, 158.4, 194.5; EIMS (70 eV) m/z (rel intensity, %) 312 (Mþ, 57),
208 (18), 207 (100), 179 (21),178 (32),106 (68), 78 (34); HRMS calcd
400 MHz)
d 2.35 (s, 3H, ArCH3), 3.80 (s, 3H, OCH3), 5.25 (s, 2H,

9296
P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
OCH2COAr), 6.86 (d, J¼8.4 Hz, 1H, ArH), 6.89 (dd, J¼8.8, 2.0 Hz, 2H,
ArH), 6.96 (td, J¼8.4, 0.8 Hz, 1H, ArH), 7.11 (d, J¼7.6 Hz, 2H, ArH),
7.24 (m, 1H, ArH), 7.35 (dd, J¼8.0, 1.6 Hz, 2H, ArH), 7.49 (dd, J¼8.0,
2.0 Hz, 1H, ArH), 8.09 (dd, J¼8.8, 2.0 Hz, 2H, ArH); 13C NMR (CDCl3,
119e120 ꢁC; Rf¼0.45 (ethyl acetate/n-hexane¼1: 5); IRmax
(neat) cmꢀ1: 1638 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 2.46 (s,
3H, ArCH3), 4.54 (s, 2H, ArCH2), 7.22 (m, 4H, ArH), 7.36 (dd, J¼8.8,
0.8 Hz, 2H, ArH), 7.37 (dd, J¼8.4, 0.8 Hz, 2H, ArH), 7.45 (td, J¼8.4,
1.2 Hz, 1H, ArH), 7.55 (td, J¼8.8, 1.2 Hz, 2H, ArH), 8.04 (dd, J¼8.0,
100 MHz) d 21.5, 55.4, 72.1, 84.9, 94.1, 112.8,113.5,113.9, 120.4, 121.5,
127.7,129.0, 129.4, 131.0,131.5,133.4,138.2,158.5,163.9,193.3; EIMS
(70 eV) m/z (rel intensity, %) 356 (Mþ, 28), 237 (10), 221 (22), 178
(15), 136 (9), 135 (100), 77 (13); HRMS calcd for C24H20O3: 356.1412.
Found: 356.1409. Anal. Calcd for C24H20O3: C, 80.88; H, 5.66. Found:
C, 80.80; H, 5.67.
1.6 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.7, 30.5, 112.3, 122.1,
123.4, 126.3, 127.9, 128.5, 128.7, 129.1, 130.0, 135.1, 139.2, 143.6,
148.6, 154.4, 185.5; EIMS (70 eV) m/z (rel intensity, %) 326 (Mþ, 23),
325 (9), 312 (23), 311 (100), 310 (6), 233 (6), 205 (8); HRMS calcd for
C23H18O2: 326.1307. Found: 326.1306. Anal. Calcd for C23H18O2: C,
84.64; H, 5.56. Found: C, 84.67; H, 5.56.
4.3.7. 1-Phenyl-2-(2-phenylethynylphenoxy)propan-1-one
(5g). Compound 5g (1.27 g, 78%) was obtained as pale yellow solid;
mp 96e97 ꢁC (lit.,17 mp 94.9e96.7 ꢁC), Rf¼0.53 (ethyl acetate/n-
hexane¼1:3); IRmax (neat) cmꢀ1: 1695 cmꢀ1 (C]O), 2216 cmꢀ1
4.4.3. 3-Benzyl-2-(4-methoxybenzoyl)benzofuran (6c). Compound
6c (0.30 g, 88%) was obtained as colorless crystals; mp 98e99 ꢁC;
Rf¼0.45 (ethyl acetate/n-hexane¼1:5); IRmax (neat) cmꢀ1
:
(C^C); 1H NMR (CDCl3, 400 MHz)
d
1.80 (d, J¼6.8 Hz, 3H, eCH(CH3)
1637 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 3.90 (s, 3H, OCH3),
COe), 5.51 (q, J¼6.8 Hz, 1H, eCH(CH3)COe), 6.83 (d, J¼8.4 Hz, 1H,
ArH), 6.94 (td, J¼8.4, 0.8 Hz, 1H, ArH), 7.19 (ddd, J¼8.4, 7.6, 1.6 Hz,
1H, ArH), 7.34 (m, 3H, ArH), 7.40 (m, 2H, ArH), 7.50 (m, 4H, ArH),
4.54 (s, 2H, ArCH2), 7.01 (dd, J¼8.8, 2.0 Hz, 2H, ArH), 7.22 (m, 4H,
ArH), 7.37 (d, J¼8.8 Hz, 2H, ArH), 7.44 (td, J¼8.4, 1.2 Hz, 1H, ArH),
7.55 (m, 2H, ArH), 8.18 (dd, J¼9.2, 1.6 Hz, 2H, ArH); 13C NMR (CDCl3,
8.17 (dd, J¼8.4, 1.2 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d
18.94
100 MHz) d 30.5, 55.5, 112.2, 113.6, 122.0, 123.4, 126.3, 127.8, 128.4,
78.84, 85.78, 93.81, 113.9, 114.3, 121.7, 123.6, 128.1, 128.3, 128.6,
129.2, 129.6, 131.5, 133.6, 134.0, 137.1, 158.0, 198.9; EIMS (70 eV) m/z
(rel intensity, %) 326 (Mþ, 92), 283 (24), 221 (100), 178 (24), 165
(20), 105 (23), 103 (20).
128.5, 128.7, 130.4, 132.4, 139.2, 148.7, 154.3, 163.4, 184.2; EIMS
(70 eV) m/z (rel intensity, %) 342 (Mþ, 40), 341 (17), 327 (19), 325
(12), 312 (28), 311 (100), 265 (9); HRMS calcd for C23H18O3:
342.1256. Found: 342.1257. Anal. Calcd for C23H18O3: C, 80.68; H,
5.30. Found: C, 80.51; H, 5.28.
4.3.8. 1-Phenyl-2-(2-phenylethynylphenoxy)butan-1-one
(5h). Compound 5h (1.34 g, 79%) was obtained as yellow liquid,
4.4.4. 2-Benzoyl-3-(4-methylbenzyl)benzofuran (6d). Compound 6d
(0.27 g, 83%) was obtained as colorless crystals; mp 118e119 ꢁC;
Rf¼0.52 (ethyl acetate/n-hexane¼1:3); IRmax (neat) cmꢀ1
:
1698 cmꢀ1 (C]O), 2217 cmꢀ1 (C^C); 1H NMR (CDCl3, 400 MHz)
Rf¼0.45 (ethyl acetate/n-hexane¼1:5); IRmax (neat) cmꢀ1
:
d
1.19 (t, J¼7.6 Hz, 3H, ArOCH(CH2CH3)COAr), 2.18 (m, 2H,
1644 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 2.28 (s, 3H, ArCH3),
ArOCH(CH2CH3)COAr), 5.26 (dd, J¼7.6, 5.2 Hz, 1H, ArOCH(CH2CH3)
COAr), 6.75 (d, J¼8.4 Hz, 1H, ArH), 6.91 (td, J¼8.4, 1.2 Hz, 1H, ArH),
7.16 (ddd, J¼8.0, 7.6, 2.0 Hz, 1H, ArH), 7.32 (m, 3H, ArH), 7.42 (m, 2H,
ArH), 7.47 (dd, J¼8.0, 2.0 Hz, 1H, ArH), 7.54 (m, 3H, ArH), 8.18 (dd,
4.50 (s, 2H, ArCH2), 7.07(d, J¼7.6 Hz, 2H, ArH), 7.25 (td, J¼8.0, 1.2 Hz,
4H, ArH), 7.44 (td, J¼8.4, 1.2 Hz, 2H, ArH), 7.51 (m, 2H, ArH), 7.59 (m,
2H, ArH), 8.10 (dd, J¼8.4, 1.2 Hz, 2H, ArH); 13C NMR (CDCl3,
100 MHz)
d 21.0, 30.0, 112.2, 122.1, 123.4, 128.0, 128.3, 128.4, 128.6,
J¼8.8, 1.2 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d
14.1, 22.6, 26.9,
129.2, 129.4, 129.8, 132.7, 135.8, 136.0, 137.7, 148.2, 154.4, 185.9;
EIMS (70 eV) m/z (rel intensity, %) 326 (Mþ, 100), 325 (55), 311 (26),
309 (14), 234 (14), 205 (14), 178 (12); HRMS calcd for C23H18O2:
326.1307. Found: 326.1310. Anal. Calcd for C23H18O2: C, 84.64; H,
5.56. Found: C, 84.56; H, 5.55.
31.6, 84.0, 93.7, 113.5, 121.3, 128.1, 128.3, 128.6, 128.7, 129.1, 129.6,
131.5,133.5,133.6,134.3,158.3,198.9; EIMS (70 eV) m/z (rel intensity,
%) 340 (Mþ, 100), 325 (44), 311 (39), 235 (56), 165 (26), 132 (31), 131
(95); HRMS calcd for C24H20O2: 340.1463. Found: 340.1460.
4.4. General procedure for the preparation of 2-aroyl-3-
arylbenzofuran (6aef)
4.4.5. 2-(4-Methylbenzoyl)-3-(4-methylbenzyl)benzofuran
(6e). Compound 6e (0.29 g, 85%) was obtained as colorless crystals;
mp 111e112 ꢁC; Rf¼0.42 (ethyl acetate/n-hexane¼1:5); IRmax
To a stirred solution of compounds 5aef (1 mmol) in anhydrous
THF (10 mL) was added potassium tert-butoxide (1.2 mmol), and
the mixture were stirred and refluxed for 30 min. After cooling, the
solution was quenched with saturated NH4Cl solution, and
extracted with CH2Cl2 (5ꢂ20 mL). The combined organic layers
were washed with brine (20 mL) and dried over MgSO4 was filtered,
evaporated, and the residue was purified by column chromatog-
raphy (ethyl acetate/n-hexane¼1:20) to give 6aef.
(neat) cmꢀ1: 1642 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 2.28 (s,
3H, ArCH3), 2.46 (s, 3H, ArCH3), 4.49 (s, 2H, ArCH2), 7.07 (d,
J¼8.0 Hz, 2H, ArH), 7.24 (dd, J¼8.0, 0.8 Hz, 3H, ArH), 7.32 (d,
J¼8.0 Hz, 2H, ArH), 7.44 (td, J¼8.4, 1.2 Hz, 1H, ArH), 7.53 (dd,
J¼8.4 Hz, 1H, ArH), 7.57 (dd, J¼8.0, 0.8 Hz, 1H, ArH), 8.03 (d,
J¼8.0 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.0, 21.7, 30.0,
112.2, 122.1, 123.4, 127.9, 128.5, 128.6, 129.0, 129.2, 130.0, 135.1,
135.8, 136.1, 143.6, 148.4, 154.3, 185.5; EIMS (70 eV) m/z (rel in-
tensity, %) 340 (Mþ, 23), 326 (25), 325 (100), 233 (12), 205 (21), 189
(11), 91 (23); HRMS calcd for C24H20O2: 340.1463. Found: 340.1463.
Anal. Calcd for C24H20O2: C, 84.68; H, 5.92. Found: C, 84.55; H, 5.96.
4.4.1. 2-Benzoyl-3-benzylbenzofuran (6a). Compound 6a (0.25 g,
80%) was obtained as yellow crystals; mp 94e95 ꢁC (lit.13a mp
96e98 ꢁC); Rf¼0.46 (ethyl acetate/n-hexane¼1:5); IRmax
(neat) cmꢀ1: 1644 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d
4.54 (s,
4.4.6. 2-(4-Methoxybenzoyl)-3-(4-methylbenzyl)benzofuran
(6f). Compound 6f (0.31 g, 87%) was obtained as colorless crystals;
mp 120e121 ꢁC; Rf¼0.43 (ethyl acetate/n-hexane¼1:5); IRmax
2H, ArCH2), 7.21 (m, 4H, ArH), 7.40 (m, 4H, ArH), 7.54 (m, 4H, ArH),
8.10 (dd, J¼8.4, 1.2 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 30.4,
112.2, 122.1, 123.4, 126.3, 128.0, 128.3, 128.5, 128.6, 128.7, 129.1,
129.8, 132.7, 137.7, 139.1, 148.3, 154.4, 185.8; EIMS (70 eV) m/z (rel
intensity, %) 312 (Mþ, 100), 311 (65), 297 (15), 296 (15), 235 (11), 178
(14), 77 (12); HRMS calcd for C22H16O2: 312.1150. Found: 312.1152.
Anal. Calcd for C22H16O2: C, 84.59; H, 5.16. Found: C, 84.38; H, 5.18.
(neat) cmꢀ1: 1638 cmꢀ1 (C]O); 1H NMR (CDCl3, 400 MHz)
d 2.29 (s,
3H, ArCH3), 3.91 (s, 3H, OCH3), 4.50 (s, 2H, ArCH2), 7.01 (dd, J¼9.2,
2.0 Hz, 2H, ArH), 7.07 (d, J¼8.0 Hz, 2H, ArH), 7.25 (m, 3H, ArH), 7.44
(td, J¼8.4, 1.2 Hz, 1H, ArH), 7.55 (m, 2H, ArH), 8.17 (dd, J¼8.8, 2.0 Hz,
2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.0, 30.0, 55.5, 112.2, 113.6,
113.9, 122.1, 123.3, 127.7, 128.5, 128.6, 128.7, 129.2, 130.5, 132.4,
135.8, 136.2, 154.3, 163.4, 184.2; EIMS (70 eV) m/z (rel intensity, %)
356 (Mþ, 43), 341 (19), 326 (28), 325 (100), 221 (15), 205 (21), 77
4.4.2. 3-Benzyl-2-(4-methylbenzoyl)-benzofuran (6b). Compound
6b (0.27 g, 83%) was obtained as
a colorless crystals; mp

P.-Y. Chen et al. / Tetrahedron 67 (2011) 9291e9297
9297
(22); HRMS calcd for C24H20O3: 356.1412. Found: 356.1414. Anal.
Acknowledgements
Calcd for C24H20O3: C, 80.88; H, 5.66. Found: C, 80.56; H, 5.63.
The research grants from the National Science Council of Taiwan
(NSC-99-2113-M-037-007) are grateful. We also thank the anony-
mous reviewers for their valuable comments to improve the quality
of this work.
4.5. General procedure for the preparation of 2-alkyl-3-
benzylbenzofuran (6g,h) from 5g,h
The reaction procedure is the same for preparation of 6aef,
which described above. At the end of reaction (it took 30 min),
which was monitored by TLC analysis, the reaction mixture was
cooled to room temperature and acidified by 2% HCl until the color
change of Congo red paper from red to blue. The resulting mixture
was extracted with dichloromethane (20 mLꢂ3). The organic layers
were combined and washed with brine, dried with anhydrous
magnesium sulfate, filtered, and concentrated in vacuo, in se-
quences. The resulting residue was purified by silica gel column
chromatography. Eluted with n-hexane/ethyl acetate (5:1) to give
2-alkyl-3-benzyl-benzofurans (6g,h), and eluted with n-hexane/
ethanol (5:1) to yield benzoic acid (82e80%).
References and notes
1. Majumdar, K. C.; Chattopadhyay, B.; Ray, K. Tetrahedron Lett. 2007, 48, 7633e7636.
2. Chang, C. P.; Pradiuldi, S. V.; Hong, F. E. Inorg. Chem. Commun. 2009, 12, 596e598.
3. Sengupta, S.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. Tetrahedron Lett.
2005, 46, 1515e1519.
4. (a) Ray, D.; Paul, S.; Brahma, S.; Ray, J. K. Tetrahedron Lett. 2007, 48, 8005e8008;
(b) Sant’Ana, D. P.; Pinho, V. D.; Maior, MC. L. S.; Costa, P. R. R. Tetrahedron Lett.
2009, 50, 3753e3755; (c) Mehta, G.; Harish, M.; Shinde, H. M. Tetrahedron Lett.
2003, 44, 7049e7053; (d) Ferreira, B. R. V.; Pirovani, R. V.; Souza-Filho, L. G.;
Coelho, F. Tetrahedron 2009, 65, 7712e7717; (e) Donaldson, L. R.; Haigh, D.;
Hulme, A. N. Tetrahedron 2008, 64, 4468e4477.
5. (a) Abdel-Aziz, H. A.; Mekawey, A. A. I. Eur. J. Med. Chem. 2009, 44, 4985e4997;
(b) Aslam, S. N.; Stevenson, P. C.; Kokubun, T.; Hall, D. R. Microbiol. Res. 2009,
164, 191e195.
6. Galal, S. A.; Abd El-All, A. S.; Abdallah, M. M.; El-Diwani, H. I. Bioorg. Med. Chem.
Lett. 2009, 19, 2420e2428.
7. Dawood, K. M.; Abdel-Gawad, H.; Rageb, E. A.; Ellithey, M.; Mohamed, H. A.
Bioorg. Med. Chem. 2006, 14, 3672e3680.
8. Miert, S. V.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemiere, g.; Pieters,
L. Bioorg. Med. Chem. 2005, 13, 661e669.
9. Eidamshaus, C.; Burch, J. D. Org. Lett. 2008, 10, 4211e4214.
10. Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron Lett. 2004, 45,
1861e1864.
11. Csekei, M.; Novak, Z.; Kotschy, A. Tetrahedron 2008, 64, 8992e8996.
12. Tsai, T. W.; Wang, E. C.; Huang, K. S.; Li, S. R.; Wang, Y. F.; Lin, Y. L.; Chen, Y. H.
Heterocycles 2004, 63, 1771e1781.
13. (a) Kanazawa, C.; Goto, K.; Terada, M. Chem. Commun. 2009, 5248e5250; (b)
Hu, J.; Wu, L. Y.; Wang, X. C.; Hu, Y. Y.; Niu, Y. N.; Liu, X. Y.; Yang, S.; Liang, Y. M.
Adv. Synth. Catal. 2010, 352, 351e356.
14. (a) Chen, L.-Y.; Li, S.-R.; Chen, P. Y.; Tsai, I.-L.; Hsu, C. L.; Lin, H. P.; Wang, T. P.;
Wang, E.-C. Tetrahedron Lett. 2009, 50, 5748e5750; (b) Li, S.-R.; Shu, C.-J.; Chen,
L.-Y.; Chen, H.-M.; Chen, P. Y.; Wang, E.-C. Tetrahedron 2009, 65, 8702e8707.
15. Songashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467e4470.
16. Kraus, G. A.; Schroeder, J. D. Synlett 2005, 2504e2506.
17. Wang, Z. Q.; Liang, Y.; Lei, Y.; Zhou, M. B.; Li, J. H. Chem. Commun. 2009,
5232e5244.
4.5.1. 3-Benzyl-2-methylbenzofuran (6g). Compound 6g (0.19 g,
86%) was obtained as a yellow liquid; Rf¼0.49 (ethyl acetate/n-
hexane¼1:5); 1H NMR (CDCl3, 400 MHz)
d 2.40 (s, 3H, CH3), 3.95 (s,
2H, ArCH2), 7.09 (m, 1H, ArH), 7.16 (m, 3H, ArH), 7.23 (m, 4H, ArH),
7.37 (d, J¼8.0 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz)
d 12.01,
29.60, 110.5,119.1, 122.1, 123.1, 126.1, 128.3, 128.4, 129.4, 129.6, 139.8,
151.5, 154.0; EIMS (70 eV) m/z (rel intensity, %) 222 (Mþ, 100), 221
(16), 208 (24), 207 (72), 179 (14), 179 (13), 145 (15), HRMS calcd for
C16H14O: 222.1045. Found: 222.1042.
4.5.2. 3-Benzyl-2-ethylbenzofuran (6h)18. Compound 6h (0.20 g,
85%) was obtained as a yellow liquid; Rf¼0.46 (ethyl acetate/n-
hexane¼1:5); 1H NMR (CDCl3, 400 MHz)
d
1.28 (t, J¼7.6 Hz, 3H,
eCH2CH3), 2.78 (q, J¼7.6 Hz, 2H, eCH2CH3), 3.98 (s, 2H, CH2C6H5),
7.09 (m, 1H, ArH), 7.17 (m, 3H, ArH), 7.24 (m, 4H, ArH), 7.39 (d,
J¼8.0 Hz, 1H, ArH); 13C NMR (CDCl3, 100 MHz)
d 12.9, 19.9, 29.5,
18. Mahmoud, E. H.; Malamas, M. S. U.S. Pat. Appl. Publ. US 20050070585 A1, 2005.
19. He, Z.; Yudin, A. K. Org. Lett. 2006, 8, 5829e5832.
20. Wright, S. W.; Hageman, D. L.; Wright, A. S.; McClure, L. D. Tetrahedron Lett.
1997, 38, 7345e7348.
21. Altschul, R.; Herbert, J. J. Am. Chem. Soc. 1948, 70, 351e354.
110.6, 112.1, 119.3,122.6, 123.1, 126.1, 128.2, 128.4, 129.6, 139.9, 154.0,
156.5; EIMS (70 eV) m/z (rel intensity, %) 236 (Mþ, 100), 221 (14),
208 (12), 207 (30), 193 (22), 178 (14), 115 (9), HRMS calcd for
C17H16O: 236.1201. Found: 236.1204.