Synthesis of 7-Allylated Benzofuran Derivatives from o-Allyloxyethynylbenzene via Claisen Rearrangement and TBAF-Catalyzed Annulation

Article abstract of DOI:10.1002/ejoc.201801800

The 7-allylated benzofuran derivatives were synthesized via a continuous reaction of Claisen rearrangement and annulation using o-allyloxyetynylbenzene as starting material. In addition, it was observed that annulation of o-alkynylphenol proceeded under mild conditions when carried out in the presence of a catalytic amount of TBAF. Furthermore, these continuous reactions could be achieved in a one-pot reaction and afforded not only 7-allylbenzofurans but also 7-alkenylbenzofurans by controlling the reaction temperature and time of the annulation. Finally, we demonstrated that 7-allylbenzofuran and 7-alkenylbenzofuran could be converted into 7-(2-formylvinyl)benzofuran and 7-formylbenzofuran derivatives, respectively. Therefore, various 7-substituted benzofuran derivatives could be synthesized according to this synthetic strategy.

Full text of DOI:10.1002/ejoc.201801800

A Journal of
Accepted Article
Title: Synthesis of 7-Allylated Benzofuran Derivative from o
Allyloxyethynylbenzene via Claisen Rearrangement and TBAF
Catalyzed Annulation
Authors: Kohei Watanabe, Takashi Mino, Chihiro Masuda, Yasushi
Yoshida, and Masami Sakamoto
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801800
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 7-Allylated Benzofuran Derivative from
o-Allyloxyethynylbenzene via Claisen Rearrangement and
TBAF-Catalyzed Annulation
Dr. Kohei Watanabe,[a] Prof. Dr. Takashi Mino,*[a],[b] Chihiro Masuda,[a] Prof. Dr. Yasushi Yoshida,[a],[b]
Prof. Dr. Masami Sakamoto[a],[b]
Abstract: We found that 7-allylated benzofuran derivatives via
a
reported that Pd-catalyzed tandem reaction via Sonogashira
continuous reaction of Claisen rearrangement and annulation using an o-
allyloxyetynylbenzene derivatives as starting material. In addition, it was
observed that annulation of o-alkynylphenol proceeded under mild
conditions when carried out in the presence of a catalytic amount of TBAF.
Furthermore, these continuous reactions could be achieved in a one-pot
reaction and afforded not only 7-allylbenzofurans but also 7-
alkenylbenzofurans by controlling the reaction temperature and time of the
annulation reaction. Finally, we demonstrated that 7- allylbenzofuran and
7-alkenylbenzofuran could be converted to 7-(2-formylvinyl)benzofuran
and 7-formylbenzofuran derivatives, respectively. Therefore, various 7-
substituted benzofuran derivatives could be synthesized according to this
synthetic strategy.
coupling of 2,6-diiodophenol with terminal alkynes and
annulation
of
o-alkynylphenol
afforded
the
7-alkynylbenzofuran derivatives (Scheme 1a).[6] In 2011, the
Arcadi group also reported that a tandem reaction via
Sonogashira coupling of 2-bromo-6-iodephenol and
annulation
afforded
7-bromobenzofuran
derivatives.
Moreover, they also reported that a Pd-catalyzed coupling
reaction of this product with arylboronic acids afforded 7-
arylbenzofuran derivatives (Scheme 1b).[7] These synthetic
strategies required a halogen atom at the corresponding
position of the starting material. Therefore, finding a synthetic
methodology of 7-substituted benzofuran remains
challenge.
a
Introduction
R
R
I
The benzofuran core structure is one of the most important
structures because various natural products and
pharmacologically active compounds include a benzofuran
skeleton.[1] In particular, 7-substituted benzofuran derivatives
are known to be useful bioactive compounds.[2] For examples,
various groups have reported the isolation of the 7-allylated
benzofuran derivatives from the morus plants and that some
of them have various bioactivities.[3] Moreover, the Arafa
group synthesized 7-allylated benzofuran derivatives and
found out specific bioactivity such as inhibition of GSK-3β
from one of their compounds.[4] Therefore, a synthetic
methodology of 7-substituted benzofurans, especially 7-
allylated derivatives, is important and highly desired.
Although various synthetic methodologies of 7-substituted
indole derivatives via C-H activation using a directing group
on the nitrogen atom have been reported,[5] the synthetic
methodology for 7-substituted benzofuran is extremely
limited. This is because, unlike a nitrogen atom, an oxygen
atom cannot possess a directing group. As a result, there
have been only two reports on synthetic methodology of
7-substituted benzofuran derivatives. In 2003, the Pal group
O
Pd cat.
(a)
OH
X = I
Pal
(2003)
X
R
R
X = Br, Cl
Arcadi
(2011)
Pd cat.
ArB(OH)2
Pd cat.
R
R
(b)
O
O
Ar
X
Scheme 1. Previous reports for the synthesis of 7-substituted benzofuran.
Previously, we reported an effective synthetic
methodology of o-allyloxyethynylbenzene derivatives via a
Cu-catalyzed
Suzuki-Miyaura
coupling
reaction
of
dibromoalkene derivatives.[8] Moreover, we reported
transformations of this substrate for access to various
heterocyclic compounds such as benzofuran and
benzopyran derivatives.[8a,9]
On the other hand, classical Claisen rearrangement
under heat conditions or high pressure is known to be a
powerful strategy for the transformation of allyloxy
compounds to o-allylphenol derivatives.[10] Actually, the
Schmidt group reported that tandem Claisen rearrangement
and annulation under heat conditions afforded heterocyclic
compounds such as 6-allylated chromone derivatives.[11]
Moreover, the Rizzacasa group applied Claisen
[a]
[b]
Department of Applied Chemistry and Biotechnology, Graduate
School of Engineering, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
E-mail: tmino@faculty.chiba-u.jp
http://chem.tf.chiba-u.jp/gacb06/index.html
Molecular Chirality Research Center, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
rearrangement at high temperature to synthesize
chalcomoracin.[12] As another example of Claisen
rearrangement, the Feng group developed Ni-catalyzed
Claisen rearrangement.[13] They reported that Ni-catalyzed
Claisen rearrangement of allyl vinyl ether derivatives
afforded allyl substituted β-ketoesters.[13a] Moreover, they
also reported that a tandem intermolecular reaction of alkynyl
esters with allylic alcohols via hydroalkoxylation and Claisen
rearrangement promoted by an Ni/Au catalyst system
afforded α-allyl-β-ketoesters.[13b] On the other hand, the Wipf
group reported that Claisen rearrangement proceeded
without harsh conditions or a transition metal catalyst by
utilizing Lewis acid such as an aluminum reagents.[14] After
this reaction was reported, some groups have used this
rearrangement in the presence of Et2AlCl to prepare a
precursor that could synthesize useful compounds.[15]
as
a
Lewis acid in hexane afforded 2-allyl-4-methyl-6-
(phenylethynyl)phenol (2a) in 87% yield at room temperature
(Entry 1). Other aluminum reagents, such as those of
trimethylaluminum reagent and tribromoaluminum reagent were
not at all effective for this rearrangement at all (Entries 2 and 3).
Moreover, no reaction proceeded in the presence of BF3·Et2O
(Entry 4). Next, we investigated the effect of the solvents (Entries
5-9). We found the reaction in toluene also proceeded and
delivered product 2a in 59% yield (Entry 5). The reaction in
dichloromethane produced the corresponding product 2a in lower
yield (Entry 6). Other polar solvents such as DMF, THF, DMSO
and CH3CN were not effective for this rearrangement (Entries 7-
10).
Table 1. Optimization of conditions for Claisen rearrangement of 1a.[a]
Ph
Here, we assume that 7-allylated benzofuran derivatives
can be synthesized by the continuous reaction of Claisen
rearrangement of o-allyloxyethynylbenzene derivatives using
Lewis acid and annulation of o-alkynylphenol (Scheme 2). In
this continuous reaction, the annulation of o-alkynylphenol is
also important. Although various annulations have been
reported, all of them required transition metal catalysts[16] or
an excessive amount of a strong base such as Cs2CO3.[17]
On the other hand, the Zhang[18] and Liu groups[19] reported
the annulation of o-alkynylphenol using a catalytic amount of
Ph
Lewis acid (1.2 equiv.)
OH
Solvent (0.1 M)
O
25 °C, Ar, 3 h
2a
1a
Entry
Lewis acid
Et2AlCl
Me3Al
Solvent
Hexane
Hexane
Hexane
Hexane
Toluene
CH2Cl2
DMF
Yield of 2a (%)[b]
87
1
2
3
4
5
6
7
8
9
10
t
Trace
base such as K2CO3 or BuOK proceeded. However, these
reactions have required harsh conditions such as high
reaction temperature. Therefore, it’s clear that research on
this reaction has been insufficient.
AlBr3
Not detected
Not detected
59
BF3·OEt2
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
39
Ar
Ar
No reaction
No reaction
No reaction
No reaction
Ar
THF
O
CH3CN
DMSO
O
OH
R
R
R
[a] Reaction conditions: 1a (0.20 mmol), Lewis acid (1.2 equiv.), solvent (2.0
mL), at 25 °C for 3 h under Ar. [b] Isolated yield.
Scheme 2. Synthetic methodology of 7-allylbenzofuran.
Herein, we report that a continuous reaction of Claisen
rearrangement
of
o-allyloxyethynylbenzenes
using
aluminum reagent and annulation in the presence of TBAF
afforded the 7-allylated benzofuran derivatives.
Results and Discussion
We initiated the investigation of Claisen rearrangement using
o-allyloxyethynylbenzene derivatives 1 as starting materials for
the synthesis of 2-allyl-6-ethynylphenol derivatives 2 (Table 1).
First, we tested three types of aluminum reagents as Lewis acids
(Entries 1-3). As a result, we found that the reaction with Et2AlCl
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Table 2. Optimization of reaction conditions for annulation of 2a.[a]
Ph
Ph
Ph
Base
O
O
OH
Solvent (0.1 M)
50 °C, Air, Time (h)
3a
4a
2a
Entry
Base (equiv.)
Cs2CO3 (1.0)
K2CO3 (1.0)
tBuOK (1.0)
TBAF (1.0)
TBAC (1.0)
TBAB (1.0)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (0.1)
TBAF (2.0)
Solvent
THF
Time (h)
16
Combined yield of 3a & 4a (%)[b]
Ratio (3a : 4a)[c]
1
25
>20 : 1
2
THF
16
Trace
-
3
THF
16
9
>20 : 1
4
THF
16
93
>20 : 1
5
THF
16
No reaction
-
6
THF
16
No reaction
-
7
THF
24
93
>20 : 1
8
CH2Cl2
Toluene
Hexane
Hexane
Hexane
24
No reaction
-
9
24
70
87
88
91
>20 : 1
10
11[d]
12[d]
24
5.1 : 1 (E/Z =13.2)
1.1 : 1 (E/Z = 13.2)
1 : >20 (E/Z = 13.3)
48
48
[a] Reaction conditions: 2a (0.1 mmol), base, solvent (1.0 mL) at 50 °C under Air. [b] Combined yield of 3a and 4a after purification. [c] Ratio was
determined by 1H NMR analysis. [d] This reaction was carried out at 80 °C.
Next, we explored the reaction conditions for the annulation
of 2-allyl-4-methyl-6-(phenylethynyl)phenol (2a) (Table 2).
Following previous reports, we tried various bases such as
Cs2CO3,[17] K2CO3[18] and tBuOK[19] for annulation. However, these
bases were not effective for this reaction at 50 °C (Entries 1-3).
Then, we tried using tetrabutylammonium halides as bases
(Entries 4-6). The reaction in the presence of TBAF proceeded
and afforded 7-allyl-2-phenyl-5-methylbenzofuran (3a) in 93%
yield (Entry 4). On the other hand, no desired product was
obtained in the case of the reaction using TBAC or TBAB as a
base (Entries 5 and 6). Moreover, we found that this annulation
was completed with a catalytic amount of TBAF and afforded the
corresponding product 2a in the same yield as in the case of using
1.0 equiv. of TBAF (Entry 7). Next, we investigated the effect of
still observed, although the ratio of isomer 4a increased. Then, we
increased the amount of TBAF to 2.0 equiv. and obtained
7-alkenylbenzofuran derivative 4a selectively in 91% yield (Entry
12). At this stage, we determined that THF is the optimal solvent
for the preparation of 7-allylbenzofuran 3a, and the hexane is
suitable for the preparation of 7-alkenylbenzofuran 4a.
Under optimized reaction conditions for each reaction
(Table 1, Entry 1 and Table 2, Entry 4), we investigated the scope
and limitations of this continuous reaction for 7-allylbenzofuran
derivatives 3 by using various o-allyloxyethynylbenzene
derivatives 1 (Table 3). When we tried using substrates 1b and
1c bearing a p- or m-tolylethynyl group, the continuous reactions
also proceeded and the corresponding 7-allylbenzofuran
derivatives 3b and 3c were obtained in good yields (Entries 2 and
3). On the other hand, the annulation of 2d bearing an
o-tolylethynyl group afforded the product 3d in slightly lower yield
(Entry 4). The yield of 2e bearing a methoxy group was relatively
lower, since an oxygen atom of the methoxy group disturbed the
coordination of the aluminum reagent to the oxygen atom of the
allyloxy moiety (Entry 5). Substrates 3f and 3g bearing a halogen
atom such as chloro and bromo groups were tolerated in this
continuous reaction (Entries 6 and 7). Claisen rearrangement of
1h afforded 2h in relatively lower yield because 1h possesses a
methoxy group. On the other hand, annulation proceeded
smoothly and gave the 7-allylbenzofuran 3h in good yield (Entry
8). In the case of using chloro-substituted benzene derivative 1i,
the solvent (Entries 8-10). As
a result, we found that
dichloromethane was not effective for this annulation (Entry 8).
On the other hand, the reaction in toluene proceeded and afforded
the a nulation 7-allylbenzofuran 3a and 7-alkenylbenzofuran 4a,
which were derived from the isomerization of the allyl moiety on
3a, was obtained in the case of using hexane (Entry 10). From
this result, fluoride anion in a non-polar solvent could abstract not
only the proton from the hydroxyl group but also from the allyl
group to cause isomerization of the allyl moiety to the internal
alkene moiety. Then, we tried to raise the reaction temperature to
70 °C and extend the time to 48 hours to promote isomerization
of 3a (Entry 11). As a result, the remaining allylbenzofuran 3a was
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Table 3. Scope and limitation.
R1
R1
R1
R2
TBAF (0.1 equiv.)
Et2AlCl (1.2 equiv.)
R2
O
R2
OH
THF (0.1 M)
Hexane (0.1 M)
25 °C, Ar, 3 h
O
50 °C, Air, 24 h
1
2
3
Entry
1
R1
Ph
R2 (1)
Yield of 2 (%)[a]
Yield of 3 (%)[a]
93 (3a)
90 (3b)
89 (3c)
78 (3d)
84 (3e)
97 (3f)
4-Me (1a)
4-Me (1b)
4-Me (1c)
4-Me (1d)
4-Me (1e)
4-Me (1f)
4-Me (1g)
87 (2a)
81 (2b)
86 (2c)
88 (2d)
66 (2e)
90 (2f)
88 (2g)
74 (2h)
81 (2i)
2
p-MeC6H4
m-MeC6H4
o-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
Ph
3
4
5
6
7
93 (3g)
96 (3h)
89 (3i)
8
4-OMe (1h)
4-Cl (1i)
9[b]
10
11
Ph
Ph
H (1j)
66 (2j) + 17 (2j’)
26 (2k) + 32 (2k’)
91 (3j)
Ph
5-OMe (1k)
95 (3k)
[a] Isolated yields. [b] Reaction time of annulation was shortened to 12 h.
Ph
Ph
Ph
O
Et2AlCl (1.2 equiv.)
TBAF (0.1 equiv.)
OH
Hexane (0.1 M)
THF (0.1 M)
O
(E/Z = 4.9)
25 °C, Ar, 3 h
50 °C, Air, 24 h
2l : 32%
3l : 95%
1l
Scheme 3. Synthesis of 7-allylbenzofuran derivative 3l from o-crotyloxyethynylbenzene 1l.
both reactions proceeded smoothly (Entry 9). Claisen
rearrangement of 1j and 1k, bearing no substituent at the
p-position of the allyloxy group, delivered not only o-allylphenols
2j and 2k but also p-allylphenols such as 4-allyl-2-
(phenylethynyl)phenol (2j’) and 4-allyl-5-methoxy-2-
(phenylethynyl)phenol (2k’) as side products, respectively
(Entries 10 and 11). Then, we performed Claisen rearrangement
of 1k at 10 °C to suppress the side product 2k’. However, this
reaction afforded 2k in only 20% yield along with 25% yield of 2k’.
From this result, we concluded that the selectivity of the product
was not related to the reaction temperature. Then, we conducted
annulations of both 2j and 2k. As a result, we could obtain
benzofurans 3j and 3k in excellent yields. Furthermore, we tested
crotyloxy compound 1l (Scheme 3). Claisen rearrangement of 1l
also afforded o-allylphenol product 2l bearing a branch-type allyl
group in 32% yield. Because some other unidentified compounds
derived from decomposition were also produced in this reaction,
the yield of allylated product 2l was reduced. The following
annulation of 2l proceeded smoothly and produced the
benzofuran 3l possessing a branch-type of allyl moiety in
excellent yield. Moreover, we attempted to use a cinnamyloxy
compound 1m (Scheme 4). Although starting material 1m was
consumed completely in this reaction, unidentified complex
mixtures were produced instead of the target allylated product.
Ph
Et2AlCl (1.2 equiv.)
Complex
mixtures
Hexane (0.1 M)
O
Ph
25 °C, Ar, 3 h
1m
Scheme 4. Claisen rearrangement of o-cinnamyloxyethynylbenzene 1m.
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10.1002/ejoc.201801800
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O3 (Babbling)
CH2Cl2 (0.05 M)
-78 °C, Air, 5 min
On the other hand, we also tried a one-pot reaction of this
continuous reaction. As a first attempt, a catalytic amount (0.1
equiv.) of TBAF was added to the reaction mixture of Claisen
rearrangement. As a result, this one-pot reaction afforded only
phenol product 2a because a catalytic amount of TBAF could not
cleave the O-Al bond derived from the Claisen rearrangement.
Then, we increased the amount of TBAF to 2 equiv. From this
one-pot reaction, we could obtain 7-allylbenzofuran 3a in 78%
yield (Scheme 5a). Moreover, 7-alkenylbenzofuran 4a was
obtained in good yield via the same one-pot reaction by raising
reaction temperature and extending reaction time of annulation
using TBAF (Scheme 5b). These results indicated that both
(1)
(2)
Ph
Ph
O
O
Me2S
CHO
4a (E/Z = 13.6)
6 : 86%
Scheme 7. Ozonolysis of 4a for the preparation of 7-formylbenzofuran 6.
Conclusions
7-allylbenzofuran
3 and 7-alkenylbenzofuran 4 could be
In summary, we found that 7-allylated benzofuran derivatives 3
could be provided by continuous reaction of Claisen
synthesized via a one-pot reaction by control of the reaction
a
temperature and the time in annulation.
rearrangement using Et2AlCl and annulation in the presence of a
catalytic amount of TBAF from o-allyloxyethynylbenzene
derivative 1. We also demonstrated that 7-alkenylbenzofuran
derivative 4 could be obtained by conducting annulation under
heating conditions. Moreover, these continuous reactions could
be achieved in a one-pot reaction and afford the corresponding
7-allylbenzofurans 3 and 7-alkenylbenzofurans 4 selectively
through control of the reaction temperature and time in annulation.
Furthermore, we demonstrated that 7-allylbenzofuran 3a and
7-alkenylbenzofuran 4a were converted to benzofuran derivatives
Et2AlCl (1.2 equiv.)
TBAF (2.0 equiv.)
40 °C, Air, 12 h
3a
78%
1a
1a
(a)
(b)
Hexane (0.1 M)
25 °C, Ar, 3 h
Et2AlCl (1.2 equiv.) TBAF (2.0 equiv.)
Hexane (0.1 M)
4a
86%
(E/Z = 13.6)
25 °C, Ar, 3 h
80 °C, Air, 48 h
bearing
a formyl group. Therefore, various 7-substituted
Scheme 5. One-pot reaction of 1a.
benzofuran derivatives could be synthesized by following to this
synthetic method.
Finally, we demonstrated the transformations of products 3a
and 4a to 7-substituted benzofuran derivatives bearing a formyl
group. As for 3a, we conducted Pd-catalyzed allylic C-H
oxygenation of 3a according to the report of the Jiang group[20]
and succeeded in transforming it to 7-(2-formylvinyl)benzofuran
derivative 5 in good yield (Scheme 6).
Experimental Section
General information: Melting points were measured with an As
ONE micro melting point instrument. 1H and13C NMR spectra
were recorded with a Bruker DPX-300 NMR (300 MHz) and
Bruker AVANCE III-400M (400 MHz). Chemical shifts are given in
ppm downfield from TMS with chloroform as an internal standard.
MS (EI) spectra were recorded with a Shimadzu GCMS-QP2010
Plus mass spectrometer. The stream of ozone was generated by
the ozone generator named as an OZONE WAVE PRO SOW-
10000R. Unless otherwise noted, all reagents were used without
further purification.
H2O (1.5 equiv.)
DDQ (2.0 equiv.)
PdCl2 (10 mol%)
Ph
Ph
O
O
DCE (0.2 M)
50 °C, Ar, 2 h
CHO
3a
5 : 91%
Procedure for the preparation of starting material 1:
o-Allyloxyethynylbenzenes 1a, 1h-1k and 1m were prepared
according to our previous reported literature.[8a] For the
preparation of 1b-1g and 1l, 1-allyloxy-2-(bromoethynyl)-4-
Scheme 6. Pd-catalyzed allylic C-H oxygenation of 3a for the preparation of
7-(2-formylvinyl)benzofuran 5.
methylbenzene,[8a]
N,N’-(1,2-ethanediylidene)bis-1-
and bis(N-methyl-N-
glyoxal[21]
Moreover, we carried out the oxidative cleavage of
7-alkenylbenzofuran derivative 4a. As a result, we succeeded in
converting it to 7-formylbenzofuran derivative 6 in good yield via
ozonolysis (Scheme 7). Since the formyl group could be
transformed to various substituents, this synthetic methodology
could potentially lead to various 7-substituted benzofuran
derivatives.
pyrrolidinamine
phenylhydrazone)[21] were prepared according to our previous
reported literature.
1-Allyloxy-4-methyl-2-((p-tolyl)ethynyl)benzene
(1b):
1-Allyloxy-2-(bromoethynyl)-4-methylbenze (0.5017 g, 2.0
mmol), p-tolylboronic acid (0.6078 g, 4.0 mmol), K3PO4
(0.8491 g, 4.0 mmol), CuI (19.04 mg, 0.10 mmol) and glyoxal
bis(N-methyl-N-phenylhydrazone) (26.65 mg, 0.10 mmol) in
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
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i-PrOH (8 mL) at 50 °C under an Ar atmosphere was stirred.
After 24 h, the reaction was quenched with distilled water.
The solution was extracted with ethyl acetate, washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate (v/v = 40/1)) to afford
NMR (300 MHz, CD2Cl2): d = 7.48 (d, J = 7.6 Hz, 1H), 7.31
(d, J = 2.4 Hz, 1H), 7.25-7.23 (m, 2H), 7.21-7.14 (m, 1H),
7.05 (ddd, J = 8.4, 2.4, 0.7 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H),
6.11 (ddt, J = 17.4, 10.4, 5.1 Hz, 1H), 5.48 (ddd, J = 17.4, 3.3,
1.8 Hz, 1H), 5.29 (ddd, J = 10.4, 3.3, 1.5 Hz, 1H), 4.60 (ddd,
J = 5.1, 1.8, 1.5 Hz, 2H), 2.52 (s, 3H), 2.28 (s, 3H) ppm; 13C
NMR (75 MHz, CD2Cl2): d = 157.8, 141.1, 134.3, 134.2, 132.3,
130.97, 130.94, 130.2, 128.9, 126.3, 124.2, 117.9, 113.6,
113.2, 92.8, 90.8, 70.3, 21.4, 20.8 ppm; EI-MS m/z (rel
intensity) 262 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C19H18O+H [M + H]+ 263.1430, found 263.1430.
1
1b in 82% yield (0.4321 g, 1.65 mmol) as a yellow oil; H
NMR (300 MHz, CDCl3): d = 7.44 (d, J = 8.0 Hz, 2H), 7.31 (d,
J = 2.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.07 (ddd, J = 8.4,
2.2, 0.7 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.09 (ddt, J = 17.2,
10.6 ,4.9 Hz, 1H), 5.53 (ddd, J = 17.2, 3.4 ,1.5 Hz, 1H), 5.29
(ddd, J = 10.6, 3.4, 1.8 Hz, 1H), 4.61 (ddd, J = 4.9, 1.8 ,1.5
Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 156.9, 138.1, 133.7, 133.2, 131.4, 130.0, 129.9,
129.0, 120.6, 117.0, 112.9, 112.6, 93.4, 85.2, 69.4, 21.5, 20.3
ppm; EI-MS m/z (rel intensity) 262 (M+, 100); HRMS (ESI-
Orbitrap) m/z calcd for C19H18O+H [M + H]+ 263.1430, found
263.1431.
1-Allyloxy-2-((4-methoxyphenyl)ethynyl)-
4-methylbenzene
(1e):
1-Allyloxy-2-(bromoethynyl)-4-
g, 2.0 mmol,), 4-
methylbenzene
(0.5022
methoxyphenylboronic acid (0.6082 g, 4.0 mmol), K3PO4
(0.8488 g, 4.0 mmol), CuI (19.08 mg, 0.10 mmol) and glyoxal
bis(N-methyl-N-phenylhydrazone) (26.68 mg, 0.10 mmol) in
i-PrOH (8 mL) at 50 °C under an Ar atmosphere was stirred.
After 24 h, the reaction was quenched with distilled water.
The solution was extracted with ethyl acetate, washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane/toluene (v/v = 1/1)) to afford 1e in
1-Allyloxy-4-methyl-2-((m-tolyl)ethynyl)benzene
(1c):
1-Allyloxy-2-(bromoethynyl)-4-methylbenzene (0.5019 g, 2.0
mmol), m-tolylboronic acid (0.4080 g, 3.0 mmol), K3PO4
(0.8488 g, 4.0 mmol), CuI (19.10 mg, 0.10 mmol) and glyoxal
bis(N-methyl-N-phenylhydrazone) (26.62 mg, 0.10 mmol) in
i-PrOH (8 mL) at 50 °C under an Ar atmosphere was stirred.
After 24 h, the reaction was quenched with distilled water.
The solution was extracted with ethyl acetate, washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate (v/v = 40/1)) to afford
1
62% yield (0.3446 g, 1.24 mmol) as a colorless oil; H NMR
(300 MHz, CDCl3): d = 7.48 (dt, J = 8.4, 2.2 Hz, 2H), 7.30 (d,
J = 2.2 Hz, 1H), 7.05 (ddd, J = 8.4, 2.2, 0.7 Hz, 1H), 6.87 (dt,
J = 8.4, 2.2 Hz, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.10 (ddt, J =
17.2, 10.6, 4.9 Hz, 1H), 5.52 (ddd, J = 17.2, 3.4, 1.8 Hz, 1H),
5.29 (ddd, J = 10.6, 3.4, 1.5 Hz, 1H), 4.61 (ddd, J = 4.9, 1.8,
1.5 Hz, 2H), 3.83 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3): d = 159.4, 156.9, 133.6, 133.3, 133.0, 130.1,
129.8, 117.0, 115.9, 113.9, 113.2, 112.7, 93.2, 84.6, 69.6,
55.3, 20.3 ppm; EI-MS m/z (rel intensity) 278 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C19H18O2+H [M + H]+
279.1380, found 279.1378.
1
1c in 68% yield (0.3556 g, 1.36 mmol) as a yellow oil; H
NMR (300 MHz, CDCl3): d = 7.36-7.33 (m, 2H), 7.31 (d, J =
2.2 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H),
7.05 (ddd, J = 8.4, 2.2, 0.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H),
6.09 (ddt, J = 17.2, 10.6, 4.9 Hz, 1H), 5.52 (ddd, J = 17.2, 3.4,
1.8 Hz, 1H), 5.29 (ddd, J = 10.6, 3.4, 1.5 Hz, 1H), 4.61 (ddd,
J = 4.9, 1.8, 1.5 Hz, 2H), 2.34 (s, 3H), 2.27 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3): d = 157.0, 137.8, 133.8, 133.2, 132.1,
130.03, 130.02, 128.9, 128.6, 128.1, 123.5, 117.0, 112.9,
112.7, 93.4, 85.6, 69.5, 21.2, 20.3 ppm; EI-MS m/z (rel
intensity) 262 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C19H18O+H [M + H]+ 263.1430, found 263.1431.
1-Allyloxy-2-((4-chlorophenyl)ethynyl)-4-methylbenzene
(1f): 1-Allyloxy-2-(bromoethynyl)-4-methylbenzene (0.5018
g, 2.0 mmol), 4-chlorophenylboronic acid (0.6260 g, 4.0
mmol), K3PO4 (0.8486 g, 4.0 mmol), CuI (0.10 mmol, 19.02
mg) and glyoxal bis(N-methyl-N-phenylhydrazone) (0.10
mmol, 26.58 mg) in i-PrOH (8 mL) at 50 °C under an Ar
atmosphere was stirred. After 24 h, the reaction was
quenched with distilled water. The solution was extracted
with ethyl acetate, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/toluene (v/v =
4/1)) to afford 1f in 80% yield (0.4514 g, 1.60 mmol) as a
1-Allyloxy-4-methyl-2-((o-tolyl)ethynyl)benzene
(1d):
1-Allyloxy-2-(bromoethynyl)-4-methylbenzene (0.5022 g, 2.0
mmol), m-tolylboronic acid (0.5439 g, 4.0 mmol), K3PO4
(0.8489 g, 4.0 mmol), CuI (19.05 mg, 0.10 mmol) and glyoxal
bis(N-methyl-N-phenylhydrazone) (26.58 mg, 0.10 mmol) in
i-PrOH (8 mL) at 50 °C under an Ar atmosphere was stirred.
After 24 h, the reaction was quenched with distilled water.
The solution was extracted with ethyl acetate, washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane/ethyl acetate (v/v = 50/1)) to afford
1
white solid; mp 70-71 °C; H NMR (300 MHz, CDCl3): d =
7.46 (dt, J = 8.6, 2.2 Hz, 2H), 7.33-7.29 (m, 3H), 7.08 (ddd, J
= 8.4, 2.2, 0.7 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.09 (ddt, J
= 17.2, 10.6, 4.9 Hz, 1H), 5.52 (ddd, J = 17.2, 3.3, 1.8 Hz,
1H), 5.30 (ddd, J = 10.6, 3.3, 1.5 Hz, 1H), 4.61 (ddd, J = 4.9,
1.8, 1.5 Hz, 2H), 2.28 (s, 3H) ppm; 13C NMR (75 MHz,
1
1d in 79% yield (0.4120 g, 1.57 mmol) as a colorless oil; H
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
CDCl3): d = 157.4, 134.3, 134.1, 133.6, 133.1, 130.8, 130.5,
129.0, 122.7, 117.5, 113.0, 112.9, 92.4, 87.4, 69.9, 20.7 ppm;
EI-MS m/z (rel intensity) 282 (M+, 100); HRMS (APCI-
Orbitrap) m/z calcd for C18H15OCl [M]+ 282.0806, found
282.0802.
Z-isomer), 159.2 (E- and Z-isomer), 136.4 (E- and Z-isomer),
130.7 (E-isomer), 130.07 (Z-isomer), 130.02 (E-isomer),
129.1 (Z-isomer), 128.3 (E- and Z-isomer), 125.4 (E-isomer),
125.0 (Z-isomer), 124.77 (Z-isomer), 124.73 (E-isomer),
113.0 (E-isomer), 112.9 (Z-isomer), 69.3 (E-isomer), 64.4 (Z-
isomer), 20.2 (E- and Z-isomer), 17.8 (E-isomer), 13.4 (Z-
isomer) ppm; EI-MS m/z (rel intensity): 190 (M+, 4); HRMS
(APCI-Orbitrap) m/z calcd for C12H14O2+H [M + H]+ 191.1067,
1-Allyloxy-2-((4-bromophenyl)ethynyl)-4-methylbenzene
(1g): 1-Allyloxy-2-(bromoethynyl)-4-methylbenzene (0.5021
g, 2.0 mmol), 4-bromophenylboronic acid (0.8035 g, 4.0
mmol), K3PO4 (0.8486 g, 4.0 mmol), CuI (19.05 mg, 0.10
mmol) and glyoxal bis(N-methyl-N-phenylhydrazone) (26.67
mg, 0.10 mmol) in i-PrOH (8 mL) at 50 °C under an Ar
atmosphere was stirred. After 24 h, the reaction was
quenched with distilled water. The solution was extracted
with ethyl acetate, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/ethyl acetate
(v/v = 40/1)) to afford 1g in 85% yield (0.5560 g, 1.70 mmol)
found
191.1066.
Second
step:
2-Crotyloxy-5-
methylbenzaldehyde (E/Z = 4.7) (1.6174 g, 8.5 mmol) and
CBr4 (5.6376 g, 17.0 mmol) were added into CH2Cl2 (57 mL)
in a reaction container. The mixture was stirred at 0 °C under
Ar atmosphere. After 10 minutes, PPh3 (8.9183 g, 34.0 mmol)
was added into the reaction mixture gradually and the
mixture was stirred at room temperature. After 24 h, hexane
was added into reaction mixture. The mixture was stirred at
room temperature. After 10 minutes, the mixture was filtered
using celite and silica to remove Ph3P=O, concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography to afford 2-crotyloxy-1-(2,2-
dibromovinyl)-4-methylbenzene (E/Z = 4.9) in 87% yield
1
as a white solid; mp 69-70 °C; H NMR (300 MHz, CDCl3): d
= 7.46 (dt, J = 8.6, 2.2 Hz, 2H), 7.39 (dt, J = 8.6, 2.2 Hz, 2H),
7.30 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.4, 2.2 Hz, 1H), 6.79
(d, J = 8.4 Hz, 1H), 6.09 (ddt, J = 17.2, 10.6, 4.9 Hz, 1H),
5.52 (ddd, J = 17.2, 3.2, 1.8 Hz, 1H), 5.30 (ddd, J = 10.6, 3.2,
1.5 Hz, 1H), 4.61 (ddd, J = 4.9, 1.8, 1.5 Hz, 2H), 2.28 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): d = 156.9, 133.7, 133.1,
132.9, 131.5, 130.4, 130.0, 122.6, 122.1, 117.1, 112.4, 112.3,
92.1, 87.1, 69.3, 20.3 ppm; EI-MS m/z (rel intensity) 326 (M+,
100); HRMS (APCI-Orbitrap) m/z calcd for C18H15OBr [M]+
326.0301, found 326.0296.
1
(2.5586 g, 7.39 mmol) as a yellow oil; H NMR (300 MHz,
CDCl3): d = 7.59 (s, 1H: E- and Z-isomer), 7.50 (s, 1H: E- and
Z-isomer), 7.07 (d, J = 7.7 Hz, 1H: E- and Z-isomer), 6.76 (d,
J = 8.2 Hz, 0.17H: Z-isomer), 6.75 (d, J = 8.4 Hz, 0.83H: E-
isomer), 5.86-5.65 (m, 2H: E- and Z-isomer), 4.58 (d, J = 4.9
Hz, 0.34H: Z-isomer), 4.43 (d, J = 5.7 Hz, 1.66H: E-isomer),
2.29 (s, 3H: E- and Z-isomer), 1.76-1.71 (m, 3H: E- and Z-
isomer) ppm; 13C NMR (CDCl3): d = 153.7 (E- and Z-isomer),
133.0 (E- and Z-isomer), 130.16 (E- and Z-isomer), 130.10
(E-isomer), 129.5 (E- and Z-isomer), 129.4 (E- and Z-isomer),
128.3 (Z-isomer), 126.0 (E-isomer), 125.7 (Z-isomer), 124.51
(E-isomer), 124.45 (Z-isomer), 112.1 (E-isomer), 112.0 (Z-
isomer), 89.3 (E- and Z-isomer), 69.4 (E-isomer), 64.5 (Z-
isomer), 20.6 (E- and Z-isomer), 17.9 (E-isomer), 13.4 (Z-
isomer) ppm; EI-MS m/z (rel intensity): 344 (M+, 16); HRMS
(APCI-Orbitrap) m/z calcd for C13H14O2Br2O+H [M + H]+
344.9484, found 344.9480. Third step: 2-Crotyloxy-1-(2,2-
dibromovinyl)-4-methylbenzene (E/Z = 4.9) (1.0382 g, 3.0
mmol), phenylboronic (0.7312 g, 6.0 mmol), K3PO4 (2.5476
g, 12.0 mmol), CuI (57.0 mg, 0.30 mmol) and glyoxal bis(N-
methyl-N-phenylhydrazone) (58.5 mg, 0.30 mmol) in EtOH
(12 mL) at 60 °C under an Ar atmosphere was stirred. After
24 h, the reaction was quenched with distilled water. The
solution was extracted with ethyl acetate, washed with brine,
dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane/toluene (v/v = 4/1)) to afford
1-crotyloxy-4-methyl-2-(phenylethynyl)benzene (1l) (E/Z =
1-Crotyloxy-4-methyl-2-(phenylethynyl)benzene
(1l):
This compound was synthesized in three steps. First step:
5-Methylsalicylaldehyde (1.2254 g, 9.0 mmol,) and K2CO3
(1.8657 g, 13.5 mmol) were added into DMF (13.5 mL) in a
reaction container. The mixture was stirred at room
temperature. After 10 minutes, crotylchloride (1.31 mL, 13.5
mmol) were added into the reaction mixture gradually. The
mixture was stirred at 50 °C. After 18 h, the reaction was
quenched with distilled water and ethyl acetate. The solution
was extracted with ethyl acetate, washed with saturated
NaCl aq., dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate
(v/v
=
20/1))
to
afford
2-crotyloxy-5-
methylbenzaldehyde (E/Z = 4.7) in 98% yield (1.6731 g, 8.79
1
mmol) as a yellow oil; H NMR (300 MHz, CDCl3): d = 10.48
(s, 0.82H: E-isomer), 10.47 (s, 0.18H: Z-isomer), 7.63 (d, J =
2.2 Hz, 1H: E- and Z-isomer), 7.33 (dd, J = 8.5, 2.3 Hz,
0.18H: Z-isomer), 7.32 (dd, J = 8.6, 2.3 Hz, 0.82H: E-isomer),
6.89 (d, J = 8.5 Hz, 0.18H: Z-isomer), 6.88 (d, J = 8.6 Hz,
0.82H: E-isomer), 5.94-5.67 (m, 2H: E- and Z-isomer), 4.69
(d, J = 6.0 Hz, 0.36H: Z-isomer), 4.56 (dt, J = 6.0, 1.2 Hz,
1.64H: E-isomer), 2.30 (s, 3H: E- and Z-isomer), 1.77 (dq, J
= 6.0, 1.2 Hz, 2.46H: E-isomer), 1.73 (dq, J = 6.0, 1.2 Hz,
0.54H: Z-isomer) ppm: 13C NMR (CDCl3): d = 190.0 (E- and
1
4.9) in 76% yield (0.5640 g, 2.27 mmol) as a yellow oil; H
NMR (300 MHz, CDCl3): d = 7.55-7.52 (m, 2H: E- and Z-
isomer), 7.36-7.30 (m, 4H: E- and Z-isomer), 6.80 (d, J = 8.4
Hz, 0.17H: Z-isomer), 6.79 (d, J = 8.4 Hz, 0.83H: E-isomer),
5.96-5.71 (m, 2H: E- and Z-isomer), 4.68 (d, J = 4.6 Hz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
0.34H: Z-isomer), 4.53 (dt, J = 5.1, 1.3 Hz, 1.66H: E-isomer),
2.27 (s, 3H: E- and Z-isomer), 1.76-1.73 (m, 3H: E- and Z-
isomer) ppm; 13C NMR (75 MHz, CDCl3): d = 157.2 (E- and
Z-isomer), 133.8 (E- and Z-isomer), 131.5 (E- and Z-isomer),
130.1 (E- and Z-isomer), 129.97 (Z-isomer), 129.90 (E- and
Z-isomer), 129.6 (E-isomer), 128.2 (E- and Z-isomer), 128.1
(Z-isomer), 127.9 (E-isomer), 126.1 (E-isomer), 125.9 (Z-
isomer), 123.8 (E- and Z-isomer), 112.89 (E- and Z-isomer),
112.84 (E- and Z-isomer), 93.1 (E- and Z-isomer), 86.1 (E-
and Z-isomer), 69.7(E-isomer), 60.1 (Z-isomer), 20.3 (E- and
Z-isomer), 17.8 (E-isomer), 13.5 (Z-isomer) ppm; EI-MS m/z
(rel intensity) 262 (M+, 57); HRMS (ESI-Orbitrap) m/z calcd
for C19H18O+H [M + H]+ 263.1430, found 163.1430.
m/z (rel intensity) 262 (M+, 100); HRMS (ESI-Orbitrap) m/z
calcd for C19H18O+H [M + H]+ 263.1430, found 263.1429.
2-Allyl-4-methyl-6-((m-tolyl)ethynyl)phenol (2c) (Table 3,
Entry 3): Following the general procedure using 1-allyloxy-
4-methyl-2-((m-tolyl)ethynyl)benzene (1c) (52.2 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v =40/1)) to afford the desired
compound 2c (44.7 mg, 0.170 mmol) in 86% yield as a yellow
1
oil; H NMR (300 MHz, CDCl3): d = 7.35-7.31 (m, 2H), 7.25
(t, J = 7.5 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 1.5
Hz, 1H), 6.93 (d, J = 1.5 Hz, 1H), 6.01 (ddt, J = 16.9, 10.2,
6.6 Hz, 1H), 5.79 (s, 1H), 5.13-5.06 (m, 2H), 3.40 (d, J = 6.6
Hz, 2H), 2.36 (s, 3H), 2.25 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 152.2, 138.2, 136.4, 132.1, 131.8, 129.63,
129.55, 129.3, 128.6, 128.4, 125.6, 122.3, 115.7, 109.1, 96.1,
83.3, 34.3, 21.2, 20.4 ppm; EI-MS m/z (rel intensity) 262 (M+,
100); HRMS (ESI-Orbitrap) m/z calcd for C19H18O+H[M + H]+
263.1430, found 263.1429.
General
procedure
for
1
Claisen rearrangement:
o-Allyloxyethynylbenzene
(0.20 mmol) was dissolved in
hexane (2.0 mL, 0.1 M) under an Ar atmosphere. Et2AlCl
(0.24 mmol) in hexane (0.23 mL, 1.05 M) was added slowly
to reaction solution with stirring at room temperature. The
reaction mixture was stirred at 25 °C. After 3 h, the reaction
was quenched with 2 M HCl aq. The solution was extracted
with diethyl ether, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was
purified by silica gel chromatography to afford the
2-Allyl-4-methyl-6-((o-tolyl)ethynyl)phenol (2d) (Table 3,
Entry 4): Following the general procedure using 1-allyloxy-
4-methyl-2-((o-tolyl)ethynyl)benzene (1d) (52.7 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2d (46.2 mg, 0.176 mmol) in 88% yield as a
yellow oil; 1H NMR (300 MHz, CDCl3): d = 7.50 (d, J = 7.5 Hz,
1H), 7.29-7.17 (m, 3H), 7.14 (d, J = 1.5 Hz, 1H), 6.96 (d, J =
1.5 Hz, 1H), 6.03 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.80 (s,
1H), 5.16-5.08 (m, 2H), 3.42 (d, J = 6.6 Hz, 2H), 2.53 (s, 3H),
2.28 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 152.1,
139.8, 136.4, 131.83, 131.81, 129.6 (2C), 129.4, 128.7,
125.7, 125.6, 122.4, 115.7, 109.3, 94.8, 87.5, 34.3, 21.0, 20.4
ppm; EI-MS m/z (rel intensity) 262 (M+, 100); HRMS (ESI-
Orbitrap) m/z calcd for C19H18O+H [M + H]+ 263.1430, found
263.1429.
o-allylphenol product 2.
2-Allyl-4-methyl-6-(phenylethynyl)phenol (2a) (Table 1,
Entry 1): Following the general procedure using 1-allyloxy-
4-methyl-2-(phenylethynyl)benzene
(1a) (49.5 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2a (43.0 mg, 0.173 mmol) in 87% yield as yellow
1
oil; H NMR (300 MHz, CDCl3): d = 7.54-7.50 (m, 2H), 7.38-
7.34 (m, 3H), 7.12 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 1.6 Hz,
1H), 6.02 (ddt, J = 16.7, 10.4, 6.6 Hz, 1H), 5.80 (s, 1H), 5.14-
5.06 (m, 2H), 3.40 (d, J = 6.6 Hz, 2H), 2.26 (s, 3H) ppm; 13
C
NMR (75 MHz, CDCl3): d = 152.2, 136.4, 131.9, 131.5, 129.7,
129.4, 128.6, 128.5, 125.6, 122.5, 115.7, 109.0, 95.8, 83.6,
34.3, 20.4 ppm; EI-MS m/z (rel intensity): 248 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C18H16O+H [M + H]+
249.1274, found 249.1273.
2-Allyl-6-((4-methoxyphenyl)ethynyl)-4-methylphenol
(2e) (Table 3, Entry 5): Following the general procedure
using
1-allyloxy-2-((4-methoxyphenyl)ethynyl)-4-
methylbenzene (1e) (55.4 mg), the residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate (v/v
= 40/1)) to afford the desired compound 2e (36.6 mg, 0.131
2-Allyl-4-methyl-6-((p-tolyl)ethynyl)phenol (2b) (Table 3,
Entry 2): Following the general procedure using 1-allyloxy-
4-methyl-2-((p-tolyl)ethynyl)benzene (1b) (52.0 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2b (41.9 mg, 0.160 mmol) in 81% yield as a
yellow oil; 1H NMR (300 MHz, CDCl3): d = 7.41 (d, J = 7.9 Hz,
2H), 7.16 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 1.8 Hz, 1 H), 6.92
(d, J = 1.8 Hz, 1H), 6.01 (ddt, J = 16.7, 10.4, 6.6 Hz, 1H),
5.80 (s, 1H), 5.13-5.06 (m, 2H), 3.39 (d, J = 6.6 Hz, 2H), 2.37
(s, 3H), 2.25 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d =
152.1, 138.9, 136.4, 131.7, 131.4, 129.6, 129.3, 129.2, 125.4,
119.4, 115.6, 109.1, 96.0, 82.9, 34.3, 21.5, 20.4 ppm; EI-MS
1
mmol) in 66% yield as a white solid; mp 66-67 °C; H NMR
(300 MHz, CDCl3): d = 7.46 (dt, J = 9.0, 2.2 Hz, 2H), 7.10 (d,
J = 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.89 (dt, J = 9.0, 2.2
Hz, 2H), 6.01 (ddt, J = 16.8, 10.4, 6.6 Hz, 1H), 5.79 (s, 1H),
5.13-5.06 (m, 2H), 3.83 (s, 3H), 3.39 (d, J = 6.6 Hz, 2H), 2.25
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 159.9, 152.1,
136.5, 133.0, 131.5, 129.5, 129.3, 125.4, 115.6, 114.6, 114.1,
109.3, 95.9, 82.2, 55.3, 34.3, 20.4 ppm; EI-MS m/z (rel
intensity) 278 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C19H18O2+H [M + H]+ 279.1380, found 279.1379.
2-Allyl-6-((4-chlorophenyl)ethynyl)-4-methylphenol (2f)
(Table 3, Entry 6): Following the general procedure using
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
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1-allyloxy-2-((4-chlorophenyl)ethynyl)-4-methylbenzene (1f
)
Hz, 1H), 5.15-5.08 (m, 2H), 3.40 (d, J = 6.6 Hz, 2H) ppm; 13
NMR (75 MHz, CDCl3): d = 153.0, 135.4, 131.6, 130.7, 129.1,
128.8, 128.6, 127.8, 124.8, 121.9, 116.6, 110.7, 97.1, 82.1,
34.1 ppm; EI-MS m/z (rel intensity) 268 (M+, 100); HRMS
(ESI-Orbitrap) m/z calcd for C17H13OCl+H [M + H]+ 269.0728,
found 269.0732.
C
(56.9 mg), the residue was purified by flash chromatography
on silica gel (hexane/ethyl acetate (v/v = 40/1)) to afford the
desired compound 2f (51.2 mg, 0.181 mmol) in 90% yield as
a yellow oil; 1H NMR (300 MHz, CDCl3): d = 7.44 (dt, J = 8.6,
2.1 Hz, 2H), 7.34 (dt, J = 8.6, 2.1 Hz, 2H), 7.10 (d, J = 1.8 Hz,
1H), 6.95 (d, J = 1.8 Hz, 1H), 6.01 (ddt, J = 17.1, 10.8, 6.6
Hz, 1H), 5.71 (s, 1H), 5.06-5.13 (m, 2H), 3.39 (d, J = 6.6 Hz,
2H), 2.25 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 152.3,
136.4, 134.7, 132.7, 132.1, 129.7, 129.5, 128.8, 125.7, 121.0,
115.8, 108.7, 94.6, 84.7, 34.3, 20.4 ppm; EI-MS m/z (rel
intensity) 282 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C18H15OCl+H [M + H]+ 283.0884, found 283.0879.
2-Allyl-6-(phenylethynyl)phenol
(phenylethynyl)phenol (2j’) (Table 3, Entry 10): Following
the general procedure using 1-allyloxy-2-
(2j)
+
4-Allyl-2-
(phenylethynyl)benzene (1j) (47.1 mg), the residue was
purified by flash chromatography on silica gel (hexane/ethyl
acetate (v/v = 40/1)) to afford the desired compound 2j (31.0
mg, 0.132 mmol) in 66% yield along with side product 2j’ (8.0
2-Allyl-6-((4-bromophenyl)ethynyl)-4-methylphenol (2g)
(Table 3, Entry 7): Following the general procedure using
1-allyloxy-2-((4-bromophenyl)ethynyl)-4-methylbenzene
mg,
0.034
mmol)
in
17%
yield.
2-Allyl-6-
(phenylethynyl)phenol (2j); Yellow oil; 1H NMR (300 MHz,
CDCl3): d = 7.56-7.51 (m, 2H), 7.40-7.35 (m, 3H), 7.31 (dd, J
= 7.7, 1.6 Hz, 1H), 7.12 (ddd, J = 7.5, 1.6, 0.7 Hz, 1H), 6.86
(t, J = 7.7 Hz, 1H), 6.02 (ddt, J = 17.6, 9.5, 6.6 Hz, 1H), 5.95
(d, J = 0.4 Hz, 1H), 5.14-5.07 (m, 2H), 3.44 (d, J = 6.6 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3): d = 154.3, 136.3, 131.5,
131.0, 129.6, 128.8, 128.5, 125.9, 122.4, 120.2, 115.8, 109.3,
96.2, 83.3, 34.3 ppm; EI-MS m/z (rel intensity) 234 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C17H14O+H [M + H]+
235.1117, found 235.1117. 4-Allyl-2-(phenylethynyl)phenol
(
1g)
(65.2 mg), the residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate (v/v =
40/1)) to afford the desired compound 2g (57.4 mg, 0.175
mmol) in 88% yield as a yellow oil; 1H NMR (300 MHz,
CDCl3): d = 7.49 (dt, J = 8.5, 1.8 Hz, 2H), 7.37 (dt, J = 8.5,
1.8 Hz, 2H), 7.10 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H),
6.01 (ddt, J = 17.6, 9.3, 6.6 Hz, 1H), 5.72 (s, 1H), 5.06-5.13
(m, 2H), 3.39 (d, J = 6.6 Hz, 2H), 2.25 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d = 152.2, 136.3, 132.9, 132.1, 131.7,
129.7, 129.5, 125.6, 122.9, 121.4, 115.8, 108.6, 94.6, 84.8,
34.3, 20.4 ppm; EI-MS m/z (rel intensity) 326 (M+, 99); HRMS
(ESI-Orbitrap) m/z calcd for C18H16OBr+H [M + H]+ 327.0379,
found 327.0380.
(
2j’); Yellow oil; 1H NMR (300 MHz, CDCl3): d = 7.55-7.51 (m,
2H) , 7.39-7.35 (m, 3H), 7.25 (d, J = 2.2 Hz, 1H), 7.09 (dd, J
= 8.4, 2.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 5.95 (ddt, J =
17.4, 9.5, 6.6 Hz, 1H), 5.72 (br, 1H), 5.11-5.04 (m, 2H), 3.32
(d, J = 6.6 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d = 154.9,
137.4, 131.9, 131.6, 131.4, 130.9, 128.8, 128.5, 122.4, 115.9,
114.7, 109.4, 96.2, 83.2, 39.1 ppm; EI-MS m/z (rel intensity)
234 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C17H14O+H [M + H]+ 235.1117, found 235.1117.
2-Allyl-4-methoxy-6-(phenylethynyl)phenol (2h) (Table 3,
Entry 8): Following the general procedure using 1-allyloxy-
4-methoxy-2-(phenylethynyl)benzene (1h) (53.2 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2h (39.3 mg, 0.149 mmol) in 74% yield as a brown
2-Allyl-3-methoxy-6-(phenylethynyl)phenol (2k) + 4-Allyl-
5-methoxy-2-(phenylethynyl)phenol (2k’) (Table 3, Entry
11): Following the general procedure using 1-allyloxy-5-
1
oil; H NMR (300 MHz, CDCl3): d = 7.55-7.50 (m, 2H), 7.39-
7.35 (m, 3H), 6.82 (d, J = 3.1 Hz, 1H), 6.74 (d, J = 3.1 Hz,
methoxy-2-(phenylethynyl)benzene (1k) (53.1 mg), the
1H), 6.00 (ddt, J = 17.0, 9.4, 6.6 Hz, 1H), 5.63 (s, 1H), 5.14-
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2k (13.9 mg, 0.053 mmol) in 26% yield along with
side product 2k’ (17.1 mg, 0.065 mmol) in 32% yield. 2-Allyl-
3-methoxy-6-(phenylethynyl)phenol (2k); Yellow oil; 1H NMR
(300 MHz, CDCl3): d = 7.52-7.47 (m, 2H), 7.36-7.31 (m, 3H),
7.29 (d, J = 8.6 Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 5.98 (ddt, J
= 17.2, 9.9, 6.2 Hz, 1H), 5.94 (s, 1H), 5.03 (ddd, J = 17.2, 3.5,
1.5 Hz, 1H), 4.99 (ddd, J = 9.9, 3.5, 1.3 Hz, 1H), 3.82 (s, 3H),
3.45 (dt, J = 6.2, 1.5 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3):
d = 159.1, 155.2, 136.1, 131.4, 129.9, 128.4, 128.4, 122.7,
114.5, 114.0, 103.2, 102.4, 95.1, 83.6, 55.8, 27.4 ppm; EI-
MS m/z (rel intensity) 264 (M+, 100); HRMS (ESI-Orbitrap)
m/z calcd for C18H16O2+H[M + H]+ 265.1223, found 265.1223.
4-Allyl-5-methoxy-2-(phenylethynyl)phenol (2k’); Yellow oil;
1H NMR (300 MHz, CDCl3): d = 7.53-7.50 (m, 2H), 7.39-7.34
5.08 (m, 2H), 3.76 (s, 3H), 3.40 (d, J = 6.6 Hz, 2H) ppm; 13
C
NMR (75 MHz, CDCl3): d = 152.7, 148.8, 136.0, 131.5, 128.8,
128.5, 127.1, 122.3, 118.3, 116.1, 112.9, 109.2, 96.0, 83.6,
55.7, 34.5 ppm; EI-MS m/z (rel intensity) 264 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C18H16O2+H [M + H]+
265.1223, found 265.1222.
2-Allyl-4-chloro-6-(phenylethynyl)phenol (2i) (Table 3,
Entry 9): Following the general procedure using 1-allyloxy-
4-chloro-2-(phenylethynyl)benzene
(
1i
)
(53.7 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 2i (43.4 mg, 0.161 mmol) in 81% yield as a brown
1
oil; H NMR (300 MHz, CDCl3): d = 7.55-7.51 (m, 2H), 7.41-
7.36 (m, 3H), 7.28 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 2.4, 0.4
Hz, 1H), 5.98 (ddt, J = 17.6, 9.5, 6.6 Hz, 1H), 5.91 (d, J = 0.4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
(m, 3H), 7.17 (s, 1H), 6.52 (s, 1H), 5.97 (ddt, J = 17.6, 9.5,
6.6 Hz, 1H), 5.78 (s, 1H), 5.08-5.02 (m, 2H), 3.82 (s, 3H),
3.29 (d, J = 6.6 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d =
159.1, 156.6, 136.8, 132.0, 131.4, 128.42, 128.37, 122.8,
121.1, 115.5, 100.7, 97.6, 95.1, 83.3, 55.5, 33.3 ppm; EI-MS
m/z (rel intensity) 264 (M+, 100); HRMS (ESI-Orbitrap) m/z
calcd for C18H16O2+H [M + H]+ 265.1223, found 265.1223.
(m, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 6.12 (ddt, J
= 17.0, 10.0, 6.8 Hz, 1H), 5.22 (ddd, J = 17.0, 3.2, 1.5 Hz,
1H), 5.12 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H), 3.69 (d, J = 6.8 Hz,
2H), 2.41 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 155.6,
151.8, 136.1, 132.5, 130.7, 129.1, 128.7, 128.3, 125.6, 124.8,
123.0, 118.7, 116.1, 101.3, 34.1, 21.3 ppm; EI-MS m/z (rel
intensity) 248 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C18H16O+H [M + H]+ 249.1274, found 249.1274.
2-(But-3-en-1-yl)-4-methyl-6-(phenylethynyl)phenol (2l)
(Scheme 3): Following the general procedure using
7-Allyl-5-methyl-2-(p-tolyl)benzofuran (3b) (Table 3,
Entry 2): Following the general procedure using 2-allyl-4-
methyl -6-((p-tolyl)ethynyl)phenol (2b) (26.3 mg), the residue
was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 250/1)) to afford the desired
compound 3b (23.6 mg, 0.090 mmol) in 90% yield as a white
1-crotyloxy-4-methyl-2-(phenylethynyl)benzene
(
1l
)
(52.5
mg), the residue was purified by flash chromatography on
silica gel (hexane/ethyl acetate (v/v = 40/1)) to afford the
desired compound 2l (16.7 mg, 0.064 mmol) in 32% yield as
1
a yellow oil; H NMR (300 MHz, CDCl3): d = 7.55-7.50 (m,
1
2H), 7.38-7.34 (m, 3H), 7.10 (d, J = 2.0 Hz, 1H), 6.95 (d, J =
2.0 Hz, 1H), 6.07 (ddd, J = 17.2, 10.4, 6.2 Hz, 1H), 5.82 (br,
1H), 5.14-5.06 (m, 2H), 3.91-3.82 (m, 1H), 2.26 (s, 3H), 1.35
solid; mp 76-77 °C; H NMR (300 MHz, CDCl3): d = 7.74 (d,
J = 8.2 Hz, 2H), 7.25-7.20 (m, 3H), 6.90 (s, 1H), 6.88 (s, 1H),
6.12 (ddt, J = 17.0, 9.9, 6.8 Hz, 1H), 5.21 (ddd, J = 17.0, 3.2,
(d, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3): d = 151.7, 1.5 Hz, 1H), 5.12 (ddd, J = 9.9, 3.2, 1.3 Hz, 1H), 3.69 (d, J =
142.2, 131.5, 130.9, 129.5, 129.38, 129.41, 128.6, 128.5,
122.5, 113.3, 109.1, 95.8, 83.7, 36.4, 20.5, 19.1 ppm; EI-MS
m/z (rel intensity) 262 (M+, 100); HRMS (ESI-Orbitrap) m/z
calcd for C19H18O+H [M + H]+ 263.1430, found 263.1428.
6.8 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H) ppm; 13C NMR (75
MHz, CDCl3): d = 155.9, 151.6, 138.3, 136.1, 132.4, 129.4,
129.2, 128.0, 125.3, 124.7, 122.9, 118.6, 116.1, 100.5, 34.0,
21.39, 21.35 ppm; EI-MS m/z (rel intensity) 262 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C19H18O+H [M + H]+
263.1430, found 263.1423.
Procedure for Claisen rearrangement of 1m (Scheme 4):
1-Cinnamyloxy-2-ethynylbenzene
(1m) (62.5 mg, 0.20
mmol) was dissolved in hexane (2.0 mL, 0.1 M) under an Ar
atmosphere. Et2AlCl (0.24 mmol) in hexane (0.23 mL, 1.05
M) was added slowly to reaction solution with stirring at room
temperature. The reaction mixture was stirred at 25 °C. After
3 h, the reaction was quenched with 2 M HCl aq. The solution
was extracted with diethyl ether, washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The
residue was pathed through the silica gel chromatography
and separated some fractions. However, these fractions
included some decomposed compounds that were
unidentified by NMR analysis.
7-Allyl-5-methyl-2-((m-tolyl)ethynyl)benzofuran
(3c)
(Table 3, Entry 3): Following the general procedure using
2-allyl-4-methyl-6-((o-tolyl)ethynyl)phenol (2c) (26.6 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 250/1)) to afford the desired
compound 3c (23.7 mg, 0.090 mmol) in 90% yield as a
colorless oil; 1H NMR (300 MHz, CDCl3): d = 7.65 (d, J = 7.3
Hz, 2H), 7.32 (dd, J = 7.7, 7.3 Hz, 1H), 7.21 (s, 1H), 7.14 (d,
J = 7.7 Hz, 1H), 6.92 (s, 1H), 6.91 (s, 1H), 6.13 (ddt, J = 17.0,
10.1 and 6.7 Hz, 1H), 5.22 (ddd, J = 17.0, 3.1, 1.5 Hz, 1H),
5.13 (ddd, J = 10.1, 3.1, 1.3 Hz, 1H), 3.70 (d, J = 6.7 Hz, 2H),
2.42 (s, 3H), 2.41 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d
= 155.8, 151.7, 138.3, 136.1, 132.4, 130.6, 129.2, 129.1,
128.6, 125.5, 125.3, 123.0, 122.0, 118.6, 116.1, 101.2, 34.0,
21.5, 21.3 ppm; EI-MS m/z (rel intensity) 262 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C19H18O+H [M + H]+
263.1430, found 263.1426.
General procedure for TBAF-catalyzed annulation of 2:
o-Allylphenol derivative
2 (0.10 mmol) was dissolved in THF
(1.0 mL, 0.1 M). TBAF (0.01 mmol) in THF (10 μL, 1.0 M)
was added to reaction solution with stirring at room
temperature. The reaction mixture was stirred at 50 °C. After
24 h, the reaction was quenched with distilled water. The
solution was extracted with diethyl ether, washed with brine,
dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
7-Allyl-5-methyl-2-((o-tolyl)ethynyl)benzofuran
(3d)
(Table 3, Entry 4): Following the general procedure using
2-allyl-4-methyl-6-((o-tolyl)ethynyl)phenol (2d) (26.0 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v =250/1)) to afford the desired
compound 3d (20.3 mg, 0.078 mmol) in 78% yield as a
chromatography to afford the 7-allylbenzofuran product 3.
7-Allyl-5-methyl-2-phenybenzofuran (3a) (Table 2, Entry
7): Following the general procedure using 2-allyl-4-methyl-6-
1
colorless oil; H NMR (300 MHz, CDCl3): d = 7.84-7.80 (m,
(phenylethynyl)phenol
(2a) (24.7mg), the residue was
1H), 7.30-7.23 (m, 4H), 6.93 (s, 1H), 6.82 (s, 1H), 6.13 (ddt,
J = 17.0, 9.9, 6.7 Hz, 1H), 5.20 (ddd, J = 17.0, 3.2, 1.5 Hz,
1H), 5.11 (ddd, J = 9.9, 3.2, 1.1 Hz, 1H), 3.68 (d, J = 6.7 Hz,
2H), 2.58 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 155.5, 151.3, 136.1, 135.7, 132.4, 131.2, 130.1,
purified by flash chromatography on silica gel (hexane) to
afford the desired compound 3a (23.0 mg, 0.093 mmol) in
93% yield as a white solid; mp 57-58 °C; 1H NMR (300 MHz,
CDCl3): d = 7.86-7.82 (m, 2H), 7.46-7.41 (m, 2H), 7.36-7.30
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
129.0, 128.3, 128.0, 126.0, 125.5, 123.0, 118.7, 116.1, 105.0,
34.2, 22.0, 21.4 ppm; EI-MS m/z (rel intensity) 262 (M+, 100);
HRMS (ESI-Orbitrap) m/z calcd for C19H18O+H [M + H]+
263.1430, found 263.1430.
7-Allyl-5-methoxy-2-phenybenzofuran (3h) (Table 3,
Entry 8): Following the general procedure using 2-allyl-4-
methoxy-6-(phenylethynyl)phenol
(
2h)
(26.4 mg), the
residue was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 3h (25.4 mg, 0.096 mmol) in 96% yield as a cream
solid; mp 71-72 °C; 1H NMR (300 MHz, CDCl3): d = 7.85-7.82
(m, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 6.95
(s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.12
(ddt, J = 17.0, 10.0, 6.8 Hz, 1H), 5.22 (ddd, J = 17.0, 3.2, 1.6
Hz, 1H), 5.14 (ddd, J = 10.0, 3.2, 1.4 Hz, 1H), 3.83 (s, 3H),
3.69 (d, J = 6.8 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d =
156.2, 156.1, 148.4, 135.6, 130.6, 129.3, 128.7, 128.4, 124.7,
124.3, 116.4, 113.1, 101.7, 101.0, 55.8, 34.0 ppm; EI-MS m/z
(rel intensity) 264 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd
for C18H16O2+H [M + H]+ 265.1223, found 265.1222.
7-Allyl-5-methyl-2-(4-methoxyethynyl)benzofuran
(Table 3, Entry 5): Following the general procedure using
2-allyl-6-((4-methoxyphenyl)ethynyl)-4-methylphenol 2e
(3e)
(
)
(26.0 mg), the residue was purified by flash chromatography
on silica gel (hexane/ethyl acetate (v/v = 20/1)) to afford the
desired compound 3e (23.7 mg, 0.084 mmol) in 84% yield as
1
a white solid; mp 93-94 °C; H NMR (300 MHz, CDCl3): d =
7.77 (dt, J = 8.8, 2.7 Hz, 2H), 7.19 (s, 1H), 6.96 (dt, J = 8.8,
2.7 Hz, 2H), 6.88 (s, 1H), 6.80 (s, 1H), 6.12 (ddt, J = 17.0,
9.9, 6.8 Hz, 1H), 5.21 (ddd, J = 17.0, 3.1, 1.6 Hz, 1H), 5.12
(ddd, J = 9.9, 3.1, 1.2 Hz, 1H), 3.68 (d, J = 6.8 Hz, 2H), 3.85
(s, 3H), 2.40 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d =
159.8, 155.8, 151.5, 136.2, 132.4, 129.3, 126.2, 125.1, 123.6, 7-Allyl-5-chloro-2-phenybenzofuran (3i) (Table 3, Entry
122.8, 118.4, 116.0, 114.2, 99.7, 55.3, 34.0, 21.3 ppm; EI-MS
m/z (rel intensity) 278 (M+, 100); HRMS (ESI-Orbitrap) m/z
calcd for C19H18O2+H [M + H]+ 279.1380, found 279.1379.
9): Following the general procedure (reaction time was 12 h)
using 2-allyl-4-chloro-6-(phenylethynyl)phenol (2i) (26.7 mg),
the residue was purified by flash chromatography on silica
gel (hexane) to afford the desired compound 3i (23.7 mg,
7-Allyl-2-(4-chlorophenyl)-5-methylbenzofuran
(3f)
1
0.089 mmol) in 89% yield as a white solid; mp 63-65 °C; H
(Table 3, Entry 6): Following the general procedure using
2-allyl-6-((4-chlorophenyl)ethynyl)-4-methylphenol (2f) (28.2
mg), the residue was purified by flash chromatography on
silica gel (hexane) to afford the desired compound 3f (27.4
mg, 0.097 mmol) in 97% yield as a white solid; mp 73-74 °C;
1H NMR (300 MHz, CDCl3): d = 7.75 (dt, J = 8.6, 2.4 Hz, 2H),
7.39 (dt, J = 8.6, 2.4 Hz, 2H), 7.20 (s, 1H), 6.91 (s, 2H), 6.11
(ddt, J = 17.0, 10.0, 6.6 Hz, 1H), 5.21 (ddd, J = 17.0, 3.2, 1.4
Hz, 1H), 5.13 (ddd, J = 10.0, 3.2, 1.2 Hz, 1H), 3.68 (d, J = 6.6
Hz, 2H), 2.41 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): d =
154.5, 151.7, 136.0, 134.0, 132.7, 129.2, 128.91, 128.89,
125.93, 125.91, 123.0, 118.8, 116.2, 101.7, 34.0, 21.3 ppm;
EI-MS m/z (rel intensity) 282 (M+, 100); HRMS (APPI-
Orbitrap) m/z calcd for C18H15OCl [M]+ 282.0806, found
282.0793.
NMR (300 MHz, CDCl3): d = 7.85-7.82 (m, 2H), 7.48-7.42 (m,
2H), 7.40-7.33 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.94 (s, 1H),
6.08 (ddt, J = 17.0, 10.0, 6.7 Hz, 1H), 5.23 (ddd, J = 17.0, 3.2,
1.5 Hz, 1H), 5.16 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H), 3.69 (d, J
= 6.7 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d = 156.9,
151.7, 135.1, 130.14, 130.06, 128.9, 128.8, 128.5, 124.97,
124.95, 124.3, 118.4, 116.9, 101.0, 33.8 ppm; EI-MS m/z (rel
intensity) 268 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C17H13OCl+H [M + H]+ 269.0728, found 269.0741.
7-Allyl-2-phenybenzofuran (3j) (Table 3, Entry 10):
Following the general procedure using 2-allyl-6-
(phenylethynyl)phenol (2j) (23.4 mg), the residue was
purified by flash chromatography on silica gel (hexane) to
afford the desired compound 3j (21.3 mg, 0.091 mmol) in
91% yield as a cream solid; mp 26-27 °C; 1H NMR (300 MHz,
CDCl3): d = 7.89-7.85 (m, 2H), 7.48-7.42 (m, 3H), 7.35 (tt, J
= 7.4, 2.2 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (dt, J = 7.3,
0.7 Hz, 1H), 7.02 (s, 1H), 6.13 (ddt, J = 17.0, 10.1, 6.7 Hz,
1H), 5.25 (ddd, J = 17.0, 3.2, 1.5 Hz, 1H), 5.13 (ddd, J = 10.1,
3.2, 1.3 Hz, 1H), 3.75 (d, J = 6.7 Hz, 2H) ppm; 13C NMR (75
MHz, CDCl3): d = 155.6, 153.3, 136.0, 130.6, 129.0, 128.7,
128.5, 124.9, 124.2, 123.6, 123.1, 118.9, 116.2, 101.5, 34.0
ppm; EI-MS m/z (rel intensity) 234 (M+, 100); HRMS (ESI-
Orbitrap) m/z calcd for C17H14O+H [M + H]+ 235.1117, found
235.1117.
7-Allyl-2-(4-bromophenyl)-5-methylbenzofuran
(3g)
(Table 3, Entry 7): Following the general procedure using 2-
allyl-6-((4-bromophenyl)ethynyl)-4-methylphenol (2g) (32.3
mg), the residue was purified by flash chromatography on
silica gel (hexane/ethyl acetate (v/v = 250/1)) to afford the
desired compound 3g (29.9 mg, 0.093 mmol) in 93% yield as
a yellow solid; mp 83-84 °C; 1H NMR (300 MHz, CDCl3): d =
7.68 (dt, J = 8.7, 2.3 Hz, 2H), 7.54 (dt, J = 8.7, 2.3 Hz, 2H),
7.20 (s, 1H), 6.92 (s, 2H), 6.10 (ddt, J = 17.0, 9.9, 6.8 Hz,
1H), 5.21 (ddd, J = 17.0, 3.2, 1.4 Hz, 1H), 5.12 (ddd, J = 9.9,
3.2, 1.2 Hz, 1H), 3.67 (d, J = 6.8 Hz, 2H), 2.41 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): d = 154.5, 151.8, 136.0, 132.7,
131.8, 129.6, 128.9, 126.2, 126.0, 123.1, 122.2, 118.8, 116.2,
101.8, 34.0, 21.3 ppm; EI-MS m/z (rel intensity) 326 (M+,
100); HRMS (APPI-Orbitrap) m/z calcd for C18H15OBr
[M]+326.0301, found 326.0290.
7-Allyl-6-methoxy-2-phenybenzofuran (3k) (Table 3,
Entry 11): Following the general procedure using 2-allyl-3-
methoxy-6-(phenylethynyl)phenol (2k) (26.8 mg), the residue
was purified by flash chromatography on silica gel
(hexane/ethyl acetate (v/v = 40/1)) to afford the desired
compound 3k (25.4 mg, 0.095 mmol) in 95% yield as a cream
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
solid; mp 40-41 °C; 1H NMR (300 MHz, CDCl3): d = 7.84-7.80
(m, 2H), 7.46-7.40 (m, 2H), 7.36 (d, J = 8.6 Hz, 1H), 7.31 (tt,
J = 7.3, 2.0 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H),
6.11 (ddt, J = 17.0, 9.9, 6.4 Hz, 1H), 5.15 (ddd, J = 17.0, 3.3,
1.5 Hz, 1H), 5.03 (ddd, J = 9.9, 3.3, 1.3 Hz, 1H), 3.89 (s, 3H),
3.72 (ddd, J = 6.4, 1.5, 1.3 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d = 155.3, 155.1, 154.4, 136.0, 130.8, 128.7, 128.0,
124.5, 122.9, 118.3, 115.0, 112.0, 108.0, 101.2, 56.7, 28.0
ppm; EI-MS m/z (rel intensity) 264 (M+, 100); HRMS (ESI-
Orbitrap) m/z calcd for C18H16O2+H [M + H]+ 265.1223, found
265.1220.
128.9 (Z-isomer), 128.7 (E-and Z-isomer), 128.3 (E- and Z-
isomer), 126.0 (E-isomer), 125.7 (Z-isomer), 124.8 (E- and
Z-isomer), 123.9 (E-isomer), 123.4 (Z-isomer), 121.8 (E-
isomer), 121.1 (Z-isomer), 119.3 (Z-isomer), 119.0 (E-
isomer), 101.1 (E- and Z-isomer), 21.4 (Z-isomer), 21.3 (E-
isomer), 19.3 (E-isomer), 15.4 (Z-isomer) ppm; EI-MS m/z
(rel intensity) 248 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd
for C18H16O+H [M + H]+ 249.1274, found 249.1271.
Procedure for one-pot reaction for synthesis of 3a
7-Allyl-5-methyl-2-phenybenzofuran (3a) (Scheme 5a):
1-Allyloxy-4-methyl-2-(phenylethynyl)benzene (1a) (49.7 mg,
0.20 mmol) was dissolved in hexane (2.0 mL) under an Ar
atmosphere. Et2AlCl (0.24 mmol) in hexane (0.23 mL, 1.05
M) was added slowly to reaction solution with stirring at room
temperature. The reaction mixture was stirred at 25 °C. After
3 h, TBAF (0.4 mmol) in THF (0.40 mL, 1.0 M) was added to
reaction solution with stirring at room temperature under air.
The reaction mixture was stirred at 40 °C. After 12 h, the
reaction was quenched with 2 M HCl aq. The solution was
extracted with diethyl ether, washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane)
to afford 7-allyl-5-methyl-2-phenylbenzofuran (3a) in 79%
yield (39.0 mg, 0.157 mmol) as a white solid; mp 57-58 °C;
1H NMR (300 MHz, CDCl3): d = 7.87-7.82 (m, 2H), 7.46-7.41
(m, 2H), 7.37-7.31 (m, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 6.91
(s, 1H), 6.12 (ddt, J = 17.0, 10.0, 6.8 Hz, 1H), 5.22 (ddd, J =
17.0, 3.2, 1.5 Hz, 1H), 5.13 (ddd, J = 10.0, 3.2, 1.3 Hz, 1H),
3.69 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3): d = 155.6, 152.0, 136.1, 132.5, 130.7, 129.1, 128.8,
128.3, 125.6, 123.0, 118.7, 116.1, 101.4, 34.1, 124.8, 21.3
ppm; EI-MS m/z (rel intensity) 248 (M+, 100).
7-(But-3-en-2-yl)-5-methyl-2-phenylbenzofuran
(3l)
(Scheme 3): Following the general procedure using 2-(but-
3-en-2-yl)-4-methyl-6-(phenylethynyl)phenol (2l) (26.4 mg),
the residue was purified by flash chromatography on silica
gel (hexane/ethyl acetate (v/v = 100/1)) to afford the desired
compound 3l (25.0 mg, 0.095 mmol) in 95% yield as a brown
1
solid; mp 40-41 °C; H NMR (300 MHz, CDCl3): d = 7.85 (d,
J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.35-7.31 (m, 1H),
7.22 (s, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 6.21 (ddd, J = 17.1,
10.1, 6.6 Hz, 1H), 5.19 (d, J = 17.1 Hz, 1H), 5.09 (d, J = 10.1
Hz, 1H), 4.08-3.98 (m, 1H), 2.42 (s, 3H), 1.53 (d, J = 7.1 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): d = 155.5, 151.2, 142.0,
132.5, 130.8, 129.3, 128.7, 128.6, 128.3, 124.8, 123.6, 118.6,
113.4, 101.2, 38.1, 21.4, 19.7 ppm; EI-MS m/z (rel intensity)
262 (M+, 100); HRMS (ESI-Orbitrap) m/z calcd for
C19H18O+H [M + H]+ 263.1430, found 263.1430.
Procedure for annulation of 2a for synthesis of 4a
5-Methyl-2-phenyl-7-(prop-1-en-1-yl)benzofuran (4a) (E/Z
=
13.3) (Table 2, Entry 12): 2-Allyl-4-methyl-6-
(phenylethynyl)phenol (2a) (24.7 mg, 0.10 mmol) was
dissolved in Hexane (1.0 mL). TBAF (0.2 mmol) in THF (0.2
mL, 1.0 M) was added to reaction solution with stirring at
room temperature. The reaction mixture was stirred at 80 °C.
After 48 h, the reaction was quenched with distilled water.
The solution was extracted with diethyl ether, washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel
chromatography (hexane) to afford the 5-methyl-2-phenyl-7-
(prop-1-ene-1-yl)benzofuran (4a) (E/Z = 13.3) in 91% yield
Procedure for one-pot reaction for synthesis of 4a
5-Methyl-2-phenyl-7-(prop-1-en-1-yl)benzofuran (4a) (E/Z
=
13.6)
(Scheme
5b):
1-Allyloxy-4-methyl-2-
(phenylethynyl)benzene (1a) (49.6 mg, 0.20 mmol) was
dissolved in hexane (2.0 mL) under an Ar atmosphere.
Et2AlCl (0.24 mmol) in hexane (0.23 mL, 1.05 M) was added
slowly to reaction solution with stirring at room temperature.
The reaction mixture was stirred for 3 h at 25 °C. After the
reaction, TBAF (0.4 mmol) in THF (0.4 mL, 1.0 M) was added
to reaction solution with stirring at room temperature under
air. The reaction mixture was stirred at 80 °C. After 48 h, the
reaction was quenched with 2 M HCl aq. The solution was
extracted with diethyl ether, washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (hexane)
to afford 5-Methyl-2-phenyl-7-(prop-1-en-1-yl)benzofuran
1
(22.6 mg, 0.091 mmol) as a white solid; mp 52-54 °C; H
NMR (300 MHz, CDCl3): d = 7.87-7.83 (m, 2H: E-and Z-
isomer), 7.46-7.41 (m, 2H: E-and Z-isomer), 7.32 (tt, J = 7.4,
1.2 Hz, 1H: E- and Z-isomer), 7.22 (s, 0.07H: Z-isomer), 7.18
(s, 0.93H: E-isomer), 7.05 (s, 0.07H: Z-isomer), 7.02 (s,
0.93H: E-isomer), 6.93 (s, 0.07H: Z-isomer), 6.91 (s, 0.93H:
E isomer ), 6.85-6.73 (m, 1H: E- and Z-isomer), 6.66 (dd, J =
15.9, 1.1 Hz, 1H: E-and Z-isomer), 2.43 (s, 0.21H: Z-isomer),
2.40 (s, 2.79H: E-isomer), 2.02 (dd, J = 6.5, 1.5 Hz, 2.79H:
E-isomer), 1.94 (dd, J = 7.1, 1.8 Hz, 0.21H: Z-isomer) ppm;
13C NMR (75 MHz, CDCl3): d = 155.7 (E- and Z-isomer),
150.5 (E- and Z-isomer), 132.4 (E- and Z-isomer), 130.6 (E-
and Z-isomer), 129.6 (E- and Z-isomer), 129.1 (E-isomer),
(
4a) (E/Z = 13.6) in 86% yield (42.6 mg, 0.171 mmol) as a
1
white solid; mp 52-53 °C; H NMR (300 MHz, CDCl3): d =
7.88-7.84 (m, 2H: E-and Z-isomer), 7.47-7.41 (m, 2H: E-and
Z-isomer), 7.34 (tt, J = 7.4, 1.2 Hz, 1H: E- and Z-isomer),
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10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
7.20 (s, 1H: E- and Z-isomer), 7.06 (s, 0.07H: Z-isomer), 7.03
(s, 0.93H: E-isomer), 6.96 (s, 0.07H: Z-isomer), 6.94 (s,
0.93H: E isomer ), 6.84-6.76 (m, 1H: E- and Z-isomer), 6.67
(dd, J = 15.9, 1.3 Hz, 1H: E-and Z-isomer), 2.45 (s, 0.21H: Z-
isomer), 2.42 (s, 2.79H: E-isomer), 2.02 (dd, J = 6.5, 1.5 Hz,
2.79H: E-isomer), 1.95 (dd, J = 7.1, 1.8 Hz, 0.21H: Z-isomer)
ppm; 13C NMR (75 MHz, CDCl3): d = 155.7 (E- and Z-isomer),
150.6 (E- and Z-isomer), 132.4 (E- and Z-isomer), 130.6 (E-
and Z-isomer), 129.6 (E- and Z-isomer), 129.1 (E-isomer),
128.9 (Z-isomer), 128.7 (E-and Z-isomer), 128.3 (E- and Z-
isomer), 126.0 (E-isomer), 125.7 (Z-isomer), 124.8 (E- and
Z-isomer), 123.9 (E-isomer), 123.4 (Z-isomer), 121.8 (E-
isomer), 121.2 (Z-isomer), 119.3 (Z-isomer), 119.0 (E-
isomer), 101.1 (E- and Z-isomer), 21.5 (Z-isomer), 21.3 (E-
isomer), 19.3 (E-isomer), 15.4 (Z-isomer) ppm; EI-MS m/z
(rel intensity) 248 (M+, 100).
Hz, 2H), 7.39 (dd, J = 7.4, 2.0 Hz, 1H), 7.00 (s, 1H), 2.49 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): d = 188.5, 157.4,
152.9, 132.8, 131.0, 129.7, 129.0, 128.8, 127.2, 125.6, 125.1,
120.4, 100.5, 21.1 ppm; EI-MS m/z (rel intensity) 236 (M+,
100); HRMS (ESI-Orbitrap) m/z calcd for C16H12O+H[M + H]+
237.0910, found 237.0912.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 26410109) from Japan Society for the
Promotion of Science (JSPS). We also thank a Leading
Research Promotion Program “Soft Molecular Activation” of
Chiba University for financial support.
Procedure for Pd-catalyzed allylic C-H oxygenation of 3a
for synthesis of 5 (Scheme 6)
Keywords: Oxygen heterocycles • Rearrangement • Cyclization
• Aluminum • Allylation
(E)-7-(2-Formylvinyl)-5-methyl-2-phenylbenzofuran (5)
(Scheme 6): 7-Allyl-5-methyl-2-phenylbenzofuran (3a) (49.6
mg, 0.20 mmol), PdCl2 (3.53 mg, 0.02 mmol), DDQ (90.8 mg,
0.4 mmol) and distilled water (5.5 μL, 0.30 mmol) in
dichloromethane (1 mL) at 50 °C under an Ar atmosphere
were stirred. After 2 h, the reaction was quenched and
concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/diethyl ether
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(v/v = 3/1)) to afford
5 in 91% yield (47.8 mg, 0.182 mmol) as
a yellow solid; mp 115-117 °C; 1H NMR (300 MHz, CDCl3): d
= 9.75 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.61 (d,
J = 16.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.40-7.35 (m, 2H), 7.24
(dd, J = 16.0, 7.8 Hz, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 2.43 (s,
3H) ppm; 13C NMR (75 MHz, CDCl3): d = 194.3, 156.7, 151.2,
147.8, 132.9, 131.1, 130.3, 129.8, 128.9, 128.8, 127.3, 124.9,
124,1, 118.3, 100.9, 21.1 ppm; EI-MS m/z (rel intensity) 262
(M+, 100); HRMS (ESI-Orbitrap) m/z calcd for C18H14O2+H [M
+ H]+ 263.1067, found 263.1064.
Procedure for ozonolysis of 4a for synthesis of 6
(Scheme 7)
7-Formyl-5-methyl-2-phenylbenzofuran (6) (Scheme 7):
5-Methyl-2-phenyl-7-(prop-1-en-1-yl)benzofuran (4a) (E/Z =
13.6) (24.5 mg, 0.10 mmol) was dissolved in CH2Cl2 (2.0 mL)
and cooled to -78 °C. A stream of ozone (O3) produced by an
ozone generator was passed through the solution for 1
minute. The reaction mixture was stirred for 5 min at -78 °C.
After 5 min, 10 drops of Me2S were added to the reaction
mixture to quench the reaction. After addition, the reaction
mixture was concentrated under reduced pressure. The
residue was purified by silica gel chromatography
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6
in 86% yield
1
(20.2 mg, 0.086 mmol) as a white solid; mp 120-122 °C; H
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2.0 Hz, 2H), 7.63 (s, 1H), 7.61 (s, 1H), 7.47 (dd, J = 7.4, 7.2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801800
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Oxygen heterocycles
Ar
Mild conditions
Inexpensive reagents
Ar
R
(1) Et2AlCl
Kohei Watanabe, Takashi Mino,* Chihiro
Masuda, Yasushi Yoshida, Masami
Sakamoto
O
R
One-pot operation
(2) TBAF
O
7-Allylated benzofuran
Synthesis of 7-Allylated Benzofuran
Derivative from
7-Allylated
benzofuran
derivatives
can
be
synthesized
from
o-Allyloxyethynylbenzene via Claisen
Rearrangement and TBAF-Catalyzed
Annulation
o-allyloxyethynylbenzene derivatives through two step reactions of Claisen
rearrangement in the presence of Et2AlCl and annulation using TBAF. This
continuous reaction proceeded under mild conditions by utilizing only
inexpensive reagents in one-pot operation.
This article is protected by copyright. All rights reserved.