Facile synthesis of multisubstituted benzo[b]furans via 2,3-disubstituted 6,7-furanobenzynes generated from ortho-iodoaryl triflate-type precursors

Article abstract of DOI:10.1246/cl.160951

2,3-Disubstituted 6,7-furanobenzynes were efficiently generated from ortho-iodoaryl triflate-type precursors using a silylmethyl Grignard reagent as the activator. The reactions between 6,7-furanobenzynes and unsymmetrical arynophiles proceeded in a highly regioselective manner. Since a variety of precursors were easily synthesizable from readily available 2,3-disubstituted 6-hydroxybenzofurans, this method enabled facile synthesis of a wide range of multisubstituted benzofurans, including π-extended molecules.

Full text of DOI:10.1246/cl.160951

Advance Publication Cover Page
Facile Synthesis of Multisubstituted Benzo[b]furans via 2,3-Disubstituted
6,7-Furanobenzynes Generated from ortho-Iodoaryl Triflate-type Precursors
Takamoto Morita, Yoshitake Nishiyama, Suguru Yoshida,* and Takamitsu Hosoya*
Advance Publication on the web November 16, 2016
doi:10.1246/cl.160951
© 2016 The Chemical Society of Japan
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Publication manuscripts.

Facile Synthesis of Multisubstituted Benzo[b]furans via 2,3-Disubstituted
6,7-Furanobenzynes Generated from ortho-Iodoaryl Triflate-type Precursors
Takamoto Morita, Yoshitake Nishiyama, Suguru Yoshida,* and Takamitsu Hosoya*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
(E-mail: s-yoshida.cb@tmd.ac.jp, thosoya.cb@tmd.ac.jp)
2,3-Disubstituted 6,7-furanobenzynes were efficiently
generated from ortho-iodoaryl triflate-type precursors using a
silylmethyl Grignard reagent as the activator. The reactions
between 6,7-furanobenzynes and unsymmetrical arynophiles
proceeded in a highly regioselective manner. Since a variety
of precursors were easily synthesizable from readily available
2,3-disubstituted 6-hydroxybenzofurans, this method enabled
substrates, only simple furanobenzyne precursors, particularly
2,3-unsubstituted ones, have been reported, largely limiting
the range of synthesizable benzofurans. Here we report an
efficient generation method of 2,3-disubstituted 6,7-
furanobenzynes from easily preparable ortho-iodoaryl triflate-
type precursors and their application to the synthesis of
multisubstituted benzofurans (Figure 2C).
facile synthesis of
a wide range of multisubstituted
benzofurans, including π-extended molecules.
We have recently developed an efficient method for
generating arynes such as thiazolobenzynes and
thienobenzynes from ortho-iodoaryl triflate-type precursors
by treating them with a silylmethyl Grignard reagent.10e,g
Based on these studies, we assumed that 6,7-furanobenzynes
could be generated from ortho-iodoaryl triflate-type
precursors 1. We also assumed that, in combination with
reported methods,5,6 a variety of 2,3-substituted precursors
could be prepared easily from mono-protected resorcinol in
four steps; e.g., benzofuran formation, deprotection,
iodination, and triflylation (Figure 2C).
Keywords: Aryne | Benzofuran | Grignard Reagent
Benzo[b]furan is a heterocycle often contained in a wide
range of important molecules, including bioactive natural
products, drugs, and hole-transporting materials (Figure 1).1–4
In addition to the classical method for benzofuran synthesis
based on cyclocondensation, recent approaches such as
transition-metal catalyzed reactions and extended Pummerer
reactions have enabled various benzofuran derivatives
accessible.5,6 However, transformation of simple benzofurans
to more complex ones largely depends on limited classical
reactions such as Friedel–Crafts reaction.1 Therefore, a novel
method that allows for diversification of simple benzofurans
to multisubstituted derivatives, including those fused with
another ring system, is required.
O
A
Brown and Buszek (2012)
t-Bu
6 steps
n-BuLi
O
+ isomer
t-Bu 62%
(92:8)
O
toluene
–78 °C to rt
Br
OH
O
Br
Br
O
I
Et2N
Ph
O
Me
OMe
I
O
Ia
Me
Ph
Ph
B
HO
Garg and coworkers (2016)
OH
O
BnN3
CsF
O
N
N
N
TMS
8 steps
O
Ph
benzodifuran
(BDF)
TfO
Bn
n-Bu
Eupomatenoid-5
MeCN
23 °C
O
OH
O
O
+ isomer
Amiodarone
71%
(86:14)
Figure 1. Various benzofuran derivatives.
O
Ib
C
This work
B
Arynes are highly reactive intermediates useful for
preparing diverse aromatic compounds.7–16 Pioneering works
on a furanobenzyne, which is a benzyne fused with a furan
ring, have demonstrated the potential of this species as a
synthetic intermediate of diverse benzofurans. For example,
Brown and Buszek reported that furano[4,5-c]benzyne (Ia,
6,7-furanobenzyne) could be generated from 6,7-
dibromobenzofuran by the treatment with n-butyllithium and
used it as a dienophile in the Diels–Alder reactions (Figure
2A).11a Recently, Garg and coworkers reported a fluoride-
mediated generation method of 4,5-furanobenzyne (Ib) from
ortho-silylaryl triflate-type precursor (Figure 2B).11b These
notable studies clearly demonstrated that furanobenzynes are
useful intermediates for preparing benzofuran derivatives,
which are difficult to synthesize by conventional methods.
However, probably due to the unavailability of complex
B
arynophile
TMSCH2MgCl
4 steps
A
A
O
C
O
PGO
OH
TfO
1
I
D
B
A
O
Ic
Figure 2. Synthesis of benzofuran derivatives via furanobenzynes.
(A) Transformation via 6,7-furanobenzyne (Ia) generated from 6,7-
dibromobenzofuran reported by Brown and Buszek.11a (B)
Transformation via 4,5-furanobenzyne (Ib) generated from ortho-silylaryl
triflate-type precursor reported by Garg and coworkers.11b (C)
Transformation via 2,3-disubstituted 6,7-furanobenzyne Ic generated
from ortho-iodoaryl triflate-type precursors 1.

2
Ph
Ph
1.
yield (entry 6). Notably, the regioisomer of 3a was not
obtained from the reaction under these conditions, indicating
that cycloaddition between 6,7-furanobenzyne and azide 2
proceeded selectively.
cat. Pd
Cu(OAc)2
2. BBr3; 68% (2 steps)
Ph
Ph
3. I2, morpholine
4. Tf2O, i-Pr2NEt;
88% (2 steps)
O
MeO
OH
TfO
1a
I
Table 2. Cycloadditions of 6,7-furanobenzyne
n-Bu
C6H4-4-Cl
Bn
Ph
C6H4-4-Cl
arynophile
(5.0 equiv)
TMSCH2MgCl
n-Pr
O
O
O
TfO
TfO
TfO
Ph
Ph
1b
1c
1d
I
I
I
(2.0 equiv)
Ph
Ph
THF
rt, 1 h
O
O
A
TfO
Scheme 1. Synthesis of 2,3-substituted 6,7-furanobenzyne
precursors 1.
I
B
1a
Entry Arynophile
Product
Yield (%)
Based on this idea, we firstly prepared 2,3-diphenyl-6-
Ph
methoxybenzo[b]furan
from
3-methoxyphenol
and
O
diphenylacetylene based on the palladium-catalyzed oxidative
annulation method reported by Sahoo and coworkers,5j and
derived it to ortho-iodoaryl triflate-type 6,7-furanobenzyne
precursor 1a in three steps; demethylation, regioselective
iodination, and triflylation (Scheme 1).17 Similarly, three other
2,3-disubstituted 7-iodo-6-triflyloxybenzo[b]furans 1b–d
were prepared.
Me
Ph
Me
1
2
4
5
87
Me
O
O
Me
Ph
Ph
N
Ph
6
8
7
9
82
78
O
N
Ph
Ph
Table 1. Optimization of the reaction conditions
O
t-Bu
Ph
N
3
4
5
O
N3
O
N
Ph
MeO
Ph
t-Bu
OMe
2
O
(5.0 equiv)
O
Ph
Ph
Ph
R–Mtl
(2.0 equiv)
O
Me
N
Ph
Cl
Ph
Ph
THF
Temp., 1 h
O
O
O
O
N
TfO
10
12
11
13
89
80
N
I
N
N
1a
3a
Me
Cl
Entry
R–Mtl
n-BuLi
Temp. (°C) Yield (%)a
Ph
1
2
3
4
5
6
–78
–78
–78
–40
0
25
41
OMe
OMe
Ph
i-PrMgCl·LiCl
TMSCH2MgCl
TMSCH2MgCl
TMSCH2MgCl
TMSCH2MgCl
O
63b
74
OMe
OMe
81
84b
Ph
rt
OMe
Ph
aYields based on 1H NMR analyses, unless otherwise noted. bIsolated yield.
6
7
14
16
15
17
86
88
O
OTBS
OMe
OTBS
The reaction conditions that allowed for the efficient
generation of 6,7-furanobenzyne were screened using ortho-
iodoaryl triflate 1a and methyl 4-(azidomethyl)benzoate (2) as
an arynophile (Table 1). Although the desired cycloadduct 3a
was obtained only in low yields by treatment of the mixture of
1a and 2 (5.0 equiv) in THF with n-butyllithium12a or
isopropylmagnesium chloride–lithium chloride complex12b at
Ph
NH
Ph
O
O
N
O
The optimized conditions (Table 1, entry 6) were
−78
°C
(entries
1
and
2),
treatment
with
successfully applied to the syntheses of a variety of
multisubstituted benzofurans via the 6,7-furanobenzyne
intermediate generated from the precursor 1a (Table 2). 6,7-
Ring-fused 2,3-diphenybenzo[b]furans 5 and 7 were obtained
in high yields via Diels–Alder reaction of 6,7-furanobenzyne
with 2,5-dimethylfuran (4) or N-phenylpyrrole (6),
respectively (entries 1 and 2). Cycloadditions with nitrones 8,
10 and ketene acetals 12, 14 successfully provided oxazole-
fused benzofurans 9, 11 and cyclobutene-fused benzofurans
13, 15, respectively, as a single isomer (entries 3–6).
Nucleophilic addition of secondary amine 16 to 6,7-
furanobenzyne also took place efficiently in a regioselective
(trimethylsilyl)methylmagnesium chloride afforded 3a in a
better yield (entry 3). These results were similar to those
observed in our previous studies on the generation of
thiazolobenzynes,10e thienobenzynes,10g 3-triflyoxyarynes,10b,f
and 3-(propargyloxy)benzyne,10a in which the less
nucleophilic silylmethyl Grignard reagent most effectively
triggered the generation of arynes from ortho-iodoaryl
triflates via iodine–magnesium exchange reaction. Further
improvement of the yield of 3a was achieved by performing
the reaction at a higher temperature (entries 4–6). In particular,
the reaction at room temperature afforded 3a in the highest

3
manner to afford 6-morpholinobenzofuran 17 as a sole
product (entry 7). This high regioselectivity is worthy to note
because nucleophilic amination to 3,4-cyclobutabenzyne,13
the high electronegativity of oxygen atom, the strain induced
by the fused furan ring must have contributed to enhance the
distortion of Ia.8g,10e,g,11,14–17 Furthermore, the calculated
LUMO level of Ia is lower than that of II and III, which
indicated the higher electrophilicity of furanobenzyne.
pyrrolobenzyne
(indolyne),14
thiazolobenzyne,10e
and
thienobenzyne,10g which are 4- or 5-membered-ring-fused
benzyne species similar to furanobenzyne, were reported to
furnish a mixture of regioisomers with moderate to good
selectivities.
Furanobenzyne
intermediates
were
useful
in
synthesizing novel π-extended molecules containing a 2,3-
substituted benzofuran structure as demonstrated in the short-
step synthesis of furanoanthracene 20 and benzofuran-fused
anthracene 23 (Schemes 3 and 4). Thus, 2-methylthio-3-
trifluoromethyl-6,7-furanobenzyne precursor 1e was easily
prepared from 3-(triisopropylsilyloxy)phenol and ketene
dithioacetal monoxide 18 based on Yorimitsu benzofuran
synthesis,6 followed by protodesilylation, regioselective
iodination, and triflylation (Scheme 3). Diels–Alder reaction
between 2-methylthio-3-trifluoromethyl-6,7-furanobenzyne,
generated from 1e, and 1,3-diphenylisobenzofuran (19) and
subsequent deoxygenative aromatization18 using Fe2(CO)9
furnished furanoanthracene 20 bearing methylthio and
trifluoromethyl groups. Dibenzofuran-type aryne IV19 was
also generated from the corresponding ortho-iodoaryl triflate-
type precursor 22, which was prepared from 3-dibenzofuranol
(21) through regioselective iodination and triflylation
(Scheme 4). The reaction of aryne with 19, followed by
aromatization afforded pentacyclic compound 23.
The method was successfully applied to the generation
of various 2,3-disubstituted 6,7-furanobenzynes from
precursors 1b–d (Scheme 2). For example, 2,3-di(4-
chlorophenyl)-6,7-furanobenzyne was efficiently generated
from 1b under the optimized conditions, which reacted with
azide 2 to afford 1,2,3-triazole-fused benzofuran 3b in high
yield without affecting the chloro group. 2-Phenyl-3-n-butyl-
and 2-n-propyl-3-benzyl-substituted benzofurans, 3c and 3d,
were also obtained from the corresponding 6,7-furanobenzyne
precursors 1c or 1d, respectively. In every case, formation of
regioisomer was not observed as contrasted with the case of
the reactions of 2,3-disubstituted 6,7-thienobenzynes with
azide 2, which generally afforded a small amount of
regioisomer.10g
2 (5.0 equiv)
R2
R2
TMSCH2MgCl
(2.0 equiv)
R1
Ar
R1
THF
rt, 1 h
O
O
TfO
N
N
I
N
1
3
TIPSO
O
OH
2. n-Bu4NF;
40% (2 steps)
3. I2, H2SO4
4. PhNTf2, DBU;
60% (2 steps)
1.
C6H4-4-Cl
C6H4-4-Cl Ar
n-Bu
Bn
SMe
F3C
18
Ar
Ph
Ar
n-Pr
SMe
Ph
O
O
O
O
(CF3CO)2O
N
N
N
N
N
N
N
N
N
3b
3c
71%
3d
92%
CF3
19
Ph
CF3
78%
TMSCH2MgCl
SMe
Ph
O
SMe
O
THF
rt, 1 h;
then, Fe2(CO)9
toluene, 80 °C
Scheme 2. Cycloadditions of various 2,3-disubstituted 6,7-
furanobenzynes with azide 2. Ar = 4-(MeO2C)C6H4-.
TfO
Ph
I
1e
20
45%
(2 steps)
θ6
θ6
θ1
θ2
θ7
θ7
O
S
OMe
Ia
II
III
Scheme 3. Synthesis of furanoanthracene 20 via 6,7-furanobenzyne.
θ6 = 135.2°
θ7 = 116.5°
θ1 = 134.7°
θ2 = 119.7°
θ6 = 133.6°
θ7 = 119.8°
Δθ6-7 = 18.7°
LUMO: –2.57 eV
HOMO: –6.65 eV
Δθ1-2 = 15.0°
LUMO: –2.37 eV
HOMO: –6.49 eV
Δθ6-7 = 13.8°
LUMO: –2.53 eV
HOMO: –6.49 eV
HO
O
21
O
IV
Ph
Figure 3. Optimized structures of 6,7-furanobenzyne (Ia), 3-
methoxybenzyne (II), and 6,7-thienobenzyne (III) using a DFT method
(B3LYP/6-311+G(d,p)).
1. I2, morpholine
2. Tf2O, i-Pr2NEt;
47% (2 steps)
O
19
Ph
Ph
To gain an insight into the remarkable regioselectivity
observed in the reactions of 6,7-furanobenzynes, we
optimized the structures of 6,7-furanobenzyne (Ia), 3-
methoxybenzyne (II), and 6,7-thienobenzyne (III) based on
density functional theory (DFT) at the B3LYP/6-311+G(d,p)
level of theory using the Spartan ’14 program (Figure 3).17
The optimized geometry structure of Ia agreed well with that
previously reported by Paton, Houk, Garg, and coworkers in
the same manner as our previous studies on thiazolobenzynes
and thienobenzynes.15 The difference in the calculated values
of internal angles at the aryne carbons (Δθa-b = θa – θb) in the
optimized structure of Ia is larger than those for II and III,
indicating that the structure of Ia is more distorted than II and
III, which resulted in the high regioselectivity. In addition to
TMSCH2MgCl
O
TfO
THF
rt, 1 h;
then, Fe2(CO)9
toluene, 80 °C
O
Ph
I
22
23
49%
(2 steps)
Scheme 4. Synthesis of benzofuran-fused anthracene 23 via
dibenzofuran-type aryne.
In summary, we have developed an efficient method for
generating 2,3-disubstituted 6,7-furanobenzynes from ortho-
iodoaryl triflate-type precursors. Since various precursors are
easily available from phenols, transformations via 6,7-
furanobenzynes allow for the synthesis of a diverse range of

4
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multisubstituted benzofuran derivatives, including π-extended
molecules. Further studies to expand the scope of the method,
such as generation and transformations of 4,5- and 5,6-
furanobenzynes, detailed theoretical study, and synthesis of
practical π-extended molecules are now in progress.
The authors thank Central Glass Co., Ltd. for providing
Tf2O. This work was supported by the Platform for Drug
Discovery, Informatics, and Structural Life Science of MEXT
and AMED, Japan; JSPS KAKENHI Grant Numbers
15H03118 (B; T.H.), 16H01133 (Middle Molecular Strategy;
T.H.), 26350971 (C; S.Y.), and 15H06180 (Start-up; Y.N.);
and Suntory Foundation for Life Sciences (S.Y.).
9
Supporting Information for experimental procedures and
characterization of new compounds are available
electronically on J-STAGE.
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