Two-step, practical, and diversity-oriented synthesis of multisubstituted benzofurans from phenols through Pummerer annulation followed by cross-coupling

Article abstract of DOI:10.1246/bcsj.20140241

Practical and diversity-oriented synthesis of multisubstituted benzofurans has been accomplished from simple phenols through a Pummerer annulation/cross-coupling sequence. Operationally simple and rapid reactions of phenols with ketene dithioacetal monoxides (KDMs) with the aid of trifluoroacetic anhydride provide the corresponding 2-methylsulfanylbenzo[b]furans. The scope of the reaction encompasses phenols and KDMs having a broad range of substituents. The remaining methylsulfanyl group in the annulation products is converted to various aryl groups through cross-coupling reactions that we improved specially to this end. This two-step approach to multisubstituted benzofurans is powerful enough to synthesize highly fluorescent benzofuran derivatives as well as the naturally occurring Eupomatenoid family.

Full text of DOI:10.1246/bcsj.20140241

Selected Papers
Two-Step, Practical, and Diversity-Oriented Synthesis
of Multisubstituted Benzofurans from Phenols through
Pummerer Annulation Followed by Cross-coupling
Kei Murakami,1,2 Hideki Yorimitsu,*1,3 and Atsuhiro Osuka1
1Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
2The Hakubi Center for Advanced Research, Kyoto University, Sakyo-ku, Kyoto 606-8502
3ACT-C, JST, Sakyo-ku, Kyoto 606-8502
E-mail: yori@kuchem.kyoto-u.ac.jp
Received: August 15, 2014; Accepted: September 6, 2014; Web Released: September 12, 2014
Practical and diversity-oriented synthesis of multisubstituted benzofurans has been accomplished from simple
phenols through a Pummerer annulation/cross-coupling sequence. Operationally simple and rapid reactions of phenols
with ketene dithioacetal monoxides (KDMs) with the aid of trifluoroacetic anhydride provide the corresponding 2-
methylsulfanylbenzo[b]furans. The scope of the reaction encompasses phenols and KDMs having a broad range of
substituents. The remaining methylsulfanyl group in the annulation products is converted to various aryl groups through
cross-coupling reactions that we improved specially to this end. This two-step approach to multisubstituted benzofurans is
powerful enough to synthesize highly fluorescent benzofuran derivatives as well as the naturally occurring Eupomatenoid
family.
Since a wide variety of benzofuran-containing drugs,1 natural
products,2 and organic functional materials3 have been reported,
new methodologies for constructing benzofurans have been
studied extensively in recent years.4-15 Mainly, the recent
approaches to benzofurans can be categorized into three paths
according to the starting materials (Scheme 1): a) α-arylation/
intramolecular C-O bond formation sequence from 1,2-dihalo-
genated arenes,4 b) Sonogashira/cyclization sequence from 2-
halophenols,5 and c) direct annulation of simple phenols.6-11
Although the stepwise approaches through Path a) or b) have
been regarded as the most reliable and versatile routes to
benzofurans, tedious preparations of the precursors (1,2-dihalo-
benzene derivatives or 2-halophenols) weaken their synthetic
utility, especially in synthesizing multisubstituted benzofurans.
Recent development of direct two-component annulations
has enabled straightforward syntheses of benzofurans from
Path a) Ref. 4
Intramolecular
C–O Bond
X
-Arylation
X
O
O
Formation
R
R
R
R"
R"
R"
X'
R"
R'
R'
Path b) Ref. 5
Sonogashira
Coupling
OH
OH
X
Cyclization
O
R
R"
R"
R'
Path c) Ref. 6–11
OH
Direct Annulation of Simple Phenol
O
R
R"
R"
R'
Scheme 1. Categorization of recent approaches to benzofurans.
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1349

[1. Substrate: -Ketoester]
2009, Li; 2013, Pappo
FeCl3
(tBuO)2
O
OH
+
O
O
Ar
Ar
OAlkyl
100 °C
CO2Alkyl
O
[2. Substrate: Diol]
2012, Yi
OH
R2
R2
[(C6H6)(PCy3)(CO)RuH]BF4
OH
HO
+
100 °C, > 8 h
R1
Regioselective if R1 = H
R1
R1 = R2 or H
R2 = Alkyl or Aryl
[3. Substrate: Alkene]
Pd(OAc)2
1,10-phen
Cu(OAc)2
NaOAc
2013, Maiti
OH
+
O
O
R1
or
R1
or
air, DCE
110 °C, 24 h
R1 = Alkyl or Aryl
2013, Chen
O
OH
NO2
Cs2CO3
CO2Et
+
+
CO2Et
Ar
EDG
CHCl3, r.t.
EDG
Ar OAc
[4. Substrate: Alkyne]
2006, Liu
O
OH
Zn(OTf)2
Me
OH
Ar
EDG
100 °C
Ar
EDG
2011, Wang
OH
K2CO3
PdCl2
130 °C, 6 h
O
R
R
+
110 °C, 12 h
Br
2013, Sahoo, Jiang
•
Sahoo's conditions
•
Pd/Cu(OAc)2 H2O
O
130 °C, 24–72 h
R2
R2
OH
+
R1
R1, R2 = Alkyl or Aryl
•
Jiang's Conditions
R1
Cu(OTf)2, ZnCl2, O2,
PhNO2, 120 °C, 24 h
Regioselective if R1 = Alkyl, R2 = Ar
2013, Shi
[Cp*Rh(MeCN)3](SbF6)2
Acetanilide (ligand)
Cu(OTf)2, AgPF6
O
Ar2
C12H25Me3N+Cl–
OH
Ar2
+
Ar1
decalin, 120 °C, 3 h
Ar1
S
Only two regioselective examples: Ar1 =
, Ar2 = C6F5 or Ar1 =
, Ar2 = Ph
O
O
Scheme 2. Recent examples of direct annulation of phenol to construct benzofuran frameworks (Path c).
phenols (Path c). For example, Li and Pappo reported iron-
catalyzed oxidative annulation reactions with ¢-ketoesters
(Scheme 2-1).6 While the reactions were useful and applicable
to synthesize coumestrols,2a substituents at the 3 position of
the products are strictly limited to alkoxycarbonyls. Annulation
with diols7 or alkenes8 also directly provided benzofurans
(Schemes 2-2 and 2-3). However, regioselectivity was hardly
controllable except for the reactions with terminal 1,2-diols,7
terminal alkenes,8a or specially designed alkenes.8b Alkynes are
also suitable substrates for annulation of phenols (Scheme 2-4).
Liu reported annulation of phenols with propargyl alcohols.9a
However, this Lewis acid-catalyzed annulation limits the scope
of substrates to electron-rich phenols and aryl-substituted
propargyl alcohols to afford an insufficient variety of benzo-
1350 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

2010, 2012, Our previous work: Two-step synthesis of 3-CF3-substituted benzofurans
O
TfO
SMe
Tf2O
SMe
OH
+
SMe
SMe
TfO–
CH2Cl2
–78 °C to 0 or 25 °C
30 min
CF3
CF3KDM
CF3
R"
A
Pd cat., R'ZnX
O
O
R'
SMe
R"
R"
CF3
CF3
B
C
This work: Two-step modular synthesis of a variety of benzofurans
CF3CO2
O
(CF3CO)2O
SMe
SMe
SMe
OH
+
CH2Cl2
25 °C
1 h
SMe
CF3CO2
–
R"
R
R
1
D
R = H, Alkyl, Aryl, CF3, C6F5
Pd cat., R'ZnX
or
Ni cat., R'MgBr
O
O
R'
SMe
R"
R"
R
R
E
F
Scheme 3. Our approach through direct annulation of phenol with KDM (Path c).
furans. Wang utilized addition of phenols onto 1-bromoalkynes
Product B is transformable by means of cross-coupling with
arylzinc reagents to provide 3-trifluoromethyl-2-arylbenzofuran
C. Two major drawbacks of the reaction are that the scope of
ketene dithioacetal monoxide (KDM) is limited to CF3KDM
and that cryogenic conditions are required. We therefore envi-
sioned that the development of a new Pummerer annulation,
which proceeds with a wide range of KDMs at ambient tem-
perature, would provide a practical and diversity-oriented route
to multisubstituted benzofurans.
Very recently, we communicated such general annulation to
furnish multisubstituted benzofurans E (Scheme 3, Bottom).11
Trifluoroacetic anhydride (TFAA) acts successfully as the
milder activator of KDMs to form monocationic intermediate D
having a sufficiently long lifetime, which is thus able to react
with phenol to furnish benzofuran E.19 The reactions are so
practical that neither distilled solvents, inert atmospheres, nor
low temperatures are required. Moreover, the annulation reac-
tions complete within 1 h at ambient temperature. The follow-
ing cross-coupling of E with arylmagnesium reagents under
nickel catalysis or with arylzinc reagents under palladium
catalysis can replace the methylsulfanyl group with a variety of
aryl groups, thereby increasing the diversity of multisubstituted
benzofurans. Our approach to multisubstituted benzofurans is
powerful enough to synthesize highly fluorescent molecules
and natural products. We report herein the details of our benzo-
furan synthesis, with an emphasis on the scope and reaction
mechanism of the improved Pummerer annulation.
followed by palladium-catalyzed intramolecular C-H/C-Br
coupling to lead to one-pot syntheses of 2-substituted benzo-
furans.9b Although this two-step strategy is attractive in regard
to its modularity at the 2 position and the phenolic substituents,
no substituent can be installed at the 3 position in principle.
Recently, efficient oxidative annulation reactions with simple
alkynes were reported by Sahoo,9c Jiang,9d and Shi.9e Although
the scope of these reactions is wide, the regioselectivity of
the reactions heavily depends on the electronics of the sub-
stituents of alkynes. It is additionally noteworthy that most of
the annulation reactions of phenols require harsh conditions.
Therefore, it is still difficult to achieve concise and tailor-made
syntheses of substituted benzofurans from simple phenols
under mild conditions. Development of an easy and divergent
strategy for constructing benzofuran frameworks is indispen-
sable for a rapid screening of biologically active molecules or
organic functional materials.
In 2010, we reported direct transformation of phenols into
3-trifluoromethylbenzofurans10 with CF3-substituted ketene
dithioacetal monoxide CF3KDM16 through an extended
Pummerer reaction10,16-18 (Scheme 3, Top). The reaction
accomplished metal-free, rapid, and regioselective annulation
of simple phenols. We proposed that trifluoromethanesulfonic
anhydride (Tf2O) strongly activates CF3KDM to give reactive
monocationic intermediate A, which reacts with phenols to
furnish 3-trifluoromethyl-2-methylsulfanylbenzo[b]furan B.
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1351

1b was smoothly transformed to 3-unsubstituted benzofuran 2b
in high yield (Entry 2). In addition to phenyl KDM 1a, methyl
KDM 1c and rather bulky alkyl KDM 1d also participated to
give 3-substituted benzofurans in good yields (Entries 1, 3, and
4). The reaction with 4-trifluoromethylphenyl-substituted KDM
1e afforded 2e in high yield while the yield of 2f bearing an
electron-donating substituent was moderate (Entries 5 and 6).
Other aryl groups such as 4-halophenyl, bulky 1-naphthyl, and
heteroaromatic thienyl provided 2g, 2h, and 2i in 96%, 78%,
and 85% yields, respectively (Entries 7-9). KDMs having a
perfluorinated substituent also reacted to yield the correspond-
ing products 2j and 2k (Entries 10 and 11).22
We then studied the scope of para- and ortho-substituted
phenols (Table 2). The reaction of 4-ethoxycarbonylphenol
provided 3a in 77% yield with its ester group intact and no
acid-catalyzed transesterification with the unavoidably result-
ing methanethiol by-product was observed. Thanks to the
transition-metal-free conditions, halogenated phenols such as
4-iodophenol and 4-bromophenol were also transformed
efficiently to the corresponding benzofurans 3b and 3c. The
pinacolatoboryl group in 3d was also tolerable albeit under the
acidic conditions. Naturally, further transformations through
Suzuki-Miyaura-coupling of 3d would be viable. Electron-
withdrawing trifluoromethyl or electron-donating methoxy
groups did not suppress the reaction to yield 3e and 3f.
Unfortunately, an acetyl or formyl group was not compatible
under the original conditions since the resulting trifluoroacetic
acid catalyzed dithioacetalization of the carbonyl moieties with
methanethiol to yield 3g¤ and 3h¤.23 Further optimization
revealed that an addition of K2CO3 suppressed this dithio-
acetalization to afford 3g and 3h in good yields. A bulky
triisopropylsiloxy group remained unreacted to give 3i in
high yield. Bulky substituents at the ortho position did not
hamper the reactions and 4a-4c were obtained in good to high
yields.
Results and Discussion
Synthesis of Starting Materials. Various KDMs can be
obtained from commercially available FAMSO20 in one or two
steps.21 Electronically neutral and donating aromatic aldehydes
were directly converted to aryl-substituted KDMs in high
yields via the Knoevenagel condensation (Scheme 4, Method
A).21c,21d Since Method A was not applicable to aliphatic
aldehydes, electron-deficient aromatic aldehydes, and alde-
hydes having a labile silyl protecting group, an alternative two-
step method was invented21a,21b to provide an access to a range
of KDMs on gram scales (Method B). Usually, E isomers were
obtained as major products in Method B and these E/Z
stereoisomers were separable on silica gel. The reactivity of
each isomer toward the Pummerer annulation is described in
Table 4 (vide infra).
Scope and Limitations. In contrast to the previous Tf2O-
mediated Pummerer annulation where only CF3KDM could
be used,10 the TFAA-mediated reactions of 4-tert-butylphenol
with variously substituted KDMs 1 proceeded to completion in
30 min at 25 °C in most cases (Table 1). Unsubstituted KDM
Table 1. Scope of KDMs
O
SMe
R
tBu
TFAA (1.2 equiv)
tBu
R
SMe
SMe
CH2Cl2 (0.1 M)
25 °C, 0.5 h
O
OH
1
(1.2 equiv)
2
Entry
1: R
2
Yield/%
1
2a)
3
4
5
6
7
8
9
1a: Ph
1b: H
1c: Me
2a
2b
2c
87
67
78
63
95
51
96
78
85
54
61
1d: Cyclohexyl
1e: 4-CF3C6H4
1f: 4-MeOC6H4
1g: 4-ClC6H4
1h: 1-Naphthyl
1i: 3-Thienyl
1j: C6F5
2d
2e
2f
2g
2h
2i
The regioselectivity of the reactions of meta-substituted
phenols was studied (Table 3). The reaction of 3-tert-butyl-
phenol resulted in exclusive formation of 5a in 80% yield
due to the bulky tBu substituent (Entry 1). The reaction of
3-methoxyphenol proceeded exclusively at the 6 position
(Entry 2). Unfortunately, the reactions of 3-trifluoromethyl-
and iodophenol did not show regioselectivity to yield mixtures
of 5 and 5¤ (Entries 3 and 4). We proposed that the reaction
10a),b)
11a),b)
2j
2k
c)
CF3KDM: CF3
a) 1 (1 equiv), TFAA (2 equiv), 4-tert-butylphenol (2 equiv).
b) 40 °C, 1.5 h. c) The E/Z ratio of CF3KDM was 4/1.
[Method A] Ar = Ph, 4-ClC6H4, 4-MeOC6H4, 3-thienyl, 1-naphthyl
Triton-B
(BnMe3N+OH–)
O
O
SMe
SMe
72–94%
0.95–3.9 g
+
Ar–CHO
Ar
SMe
FAMSO
SMe
THF
60 °C, 6 h
[Method B] R = 4-CF3C6H4, 4-TBSOC6H4, Me, c-Hex, C6F5
(1) BuLi
(2) R–CHO
(3) Ac2O
O
OAc O
SMe
O
tBuOK
29–70%
(Two steps)
0.96–5.4 g
SMe
SMe
R
R
tBuOH
Toluene
One-pot
SMe
FAMSO
SMe
SMe
Scheme 4. Practical and rapid syntheses of KDMs (Ref. 21).
1352 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

Table 2. Scope of para- and ortho-Substituted Phenols
Ph
R
R
SMe
SMe
1a (1.2 equiv)
TFAA (1.2 equiv)
O
OH
3
or
or
CH2Cl2 (0.1 M)
25 °C, 0.5 h
Ph
OH
O
R
R
4
O
Ph
Ph
Ph
O
I
Br
EtO
SMe
SMe
SMe
SMe
O
O
3a 77%
3b 81%
3c 87%
Ph
Ph
O
B
Ph
F3C
MeO
O
SMe
SMe
O
O
O
3e 60%a)
3f 72%
3d 76%
O
O
H
Ph
Ph
Ph
TIPSO
Me
SMe
SMe
SMe
O
O
O
3g 55%b)
3h 60%b)
3i 65%c)
Ph
Ph
Ph
SMe
SMe
SMe
O
O
O
Cl
Ph
O
Ph
4a 70%
4c 53%
4b 60%
a) 1a (1 equiv), TFAA (1.2 equiv), 4-trifluoromethylphenol (1.2 equiv). b) 1a
(1 equiv), TFAA (2 equiv), phenol (2 equiv), K2CO3 (2 equiv), 1 h. c) 1a
(1 equiv), TFAA (2 equiv), phenol (2 equiv).
Table 3. Regioselectivity of meta-Substituted Phenols
Because of the 3-methoxy group, the HOMO of 3-meth-
R
oxyphenol has a node across the 2 and 5 positions, which
indicates no reactivity at the 2 position of 3-methoxyphenol.
In contrast, judging from the HOMOs of 3-tBu, CF3, and
I-substituted phenols, the 2 and 6 positions should have similar
reactivity from an electronic viewpoint although the 2 position
of 3-tert-butylphenol is likely to be sterically shielded.
The reactions were applicable to various phenol derivatives
(Table 4). The reactions of 2-naphthol proceeded to give 6a
and 6b with perfect regioselectivity. Although the reactivity of
the more sterically congested (Z)-1e was lower than that of (E)-
1e, 6a was obtained in a good yield of 51%. Other 2-naphthols
having a triisopropylsiloxy substituent reacted with 1a to
provide 6c and 6d without loss of the TIPS group. Vanillin was
converted to the corresponding benzofuran 6e in 45% yield,
along with unaromatized 6e¤ in 22% yield, in the presence
of K2CO3. Phenolphthalein, which is mostly insoluble in di-
chloromethane, reacted in CH2Cl2/MeCN (5:1) co-solvent to
Ph
1a (1.2 equiv)
TFAA (1.2 equiv)
Ph
SMe
SMe
R
OH
CH2Cl2 (0.1 M)
25 °C, 0.5 h
O
R
O
5
5'
Entry
R
5
5:5¤
Yield/%
1
2
3
4
tBu
MeO
CF3
I
5a
5b
5c
5d
>99:1
>99:1
65:35
59:41
80
63
53
87
would take place through [3,3]-sigmatropic rearrangement,
wherein the more electron-rich ortho position predominantly
attacks the electron-deficient vinylic carbon of H (vide infra,
Scheme 5). On the basis of our proposal, these regioselectiv-
ities observed can be roughly rationalized by the Kohn-Sham
HOMO analysis of these meta-substituted phenols (Figure 1).24
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1353

(a) with TFAA
O
CF3CO2
O
SMe
SMe
SMe
SMe
(CF3CO)2O
R'
SMe
R
SMe
CF3CO2
OH
–
R
CF3CO2
–
R
H
D
R'
Relatively Stable
O
O
O
SMe
SMe
SMe
SMe
R'
–HSMe
R'
SMe
CF3CO2
R
H
R'
R
H
–
R
I
E
J
(b) with Tf2O
SMe
R
CF3
Fast
Decomposition
SMe
2TfO–
R
L
O
TfO
O
SMe
SMe
SMe
R = CF3
OH
Tf2O
SMe
3 TfO–
SMe
R
SMe
TfO–
R'
CF
R
R = CF3: A
M
R'
R
CF3: K
O
O
O
SMe
SMe
SMe
SMe
R'
–HSMe
R'
SMe
TfO–
CF3
H
R'
CF3
H
CF3
N
B
O
Scheme 5. Proposed mechanism of Pummerer annulation with a) TFAA and b) Tf2O.
reactive
(b)
reactive
(a)
OH
MeO
OH
sterically shielded
not reactive
reactive
reactive
(d)
(c)
CF3
OH
I
OH
reactive
reactive
Figure 1. Kohn-Sham HOMOs of meta-substituted phenols: (a) 3-tert-butylphenol; (b) 3-methoxyphenol; (c) 3-trifluoromethyl-
phenol; (d) 3-iodophenol.
afford 6f in 54% yield. Gratifyingly, the reaction of 1,3-di-
hydroxybenzene (resorcinol) afforded the corresponding benzo-
difuran 6g regioselectively in one shot. The positions of two
hydroxy groups are important: 2-tert-butylhydroquinone, an
arene having two hydroxy groups at the 1,4-positions, failed to
react. Alternatively, 4-siloxyphenol engaged in the Pummerer
1354 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

Table 4. Reactions of Various Hydroxyaromatics
O
R'
R
TFAA (1.2 equiv)
R
SMe
R'
SMe
CH2Cl2 (0.1 M)
25 °C, 1 h
SMe
O
OH
6
1
yield
(1.2 equiv)
(Starting Material)
CF3
OTBDMS
TIPSO
SMe
SMe
O
O
SMe
SMe
O
O
OTIPS
6c 62%c)
6d 83%a)
(6-TIPSO-2-naphthol)
6b 74%a),b)
(2-Naphthol)
6a 92%
(3-TIPSO-2-naphthol)
(51%: reaction with (Z)-1e)
(2-Naphthol)
MeS
O
O
SMe
OHC
OHC
SMe
SMe
+
SMe
O
O
O
OMe
OMe
O
6e
6e'
6f 54%e)
67%d) (6e:45%, 6e':22%)
(Phenolphthalein)
(Vanillin)
MeS
RO
O
SMe
SMe
MeS
SMe
O
O
O
O
6h (R = TIPS) 41%g)
(2-tBu-4-TIPSO-phenol)
6g 49%f)
(Resolcinol)
6j 66%a) (6i)
6j 0% (2-tBu-hydroquinone)
TBAF
6i (R = H) 96%
(6h)
SMe
O
Me Me
MeS
O
SMe
MeS
SMe
O
O
O
O
MeS
6k 60%f)
(2,7-naphthalenediol)
6l 49%f)
(2,7-naphthalenediol)
6m 40%h)
(2,6-naphthalenediol)
a) Alcohol (1 equiv), 1 (2 equiv), TFAA (2 equiv). b) E/Z ratio of 1 was 4/1. c) Alcohol (2 equiv),
1 (1 equiv) TFAA (2 equiv). d) Vanillin (2 equiv), 1a (1 equiv), TFAA (2 equiv), K2CO3 (2 equiv).
e) Phenolphthalein (1 equiv), 1a (3 equiv), TFAA (3 equiv), CH2Cl2/MeCN (5/1). f) Diol (1 equiv),
1 (3 equiv), TFAA (3 equiv). g) 1a (2.5 equiv), TFAA (3 equiv). h) Diol (2 equiv), 1a (1 equiv),
TFAA (1.5 equiv).
annulation to afford 6h, which was then deprotected with TBAF
naphthodifurans 6k-6m directly. The structures of 6k and 6m
were unambiguously determined by X-ray crystallographic
analyses.11 Finally, we performed a gram-scale synthesis of
6k to demonstrate the robustness of the Pummerer annulation
to give 5-hydroxybenzofuran 6i. The second Pummerer annu-
lation was then performed to give benzodifuran 6j. The
reactions of 2,7- or 2,6-naphthalenediol gave the corresponding
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1355

Table 5. Comparison of Acid Anhydride
Table 6. Comparison of the Reactivity
O
O
Ph
Acid Anhydride
tBu
SMe
tBu
SMe (1.2 equiv)
CF3
OMe
Ph
SMe
SMe
SMe
1a
CH2Cl2 (0.1 M)
25 °C, 0.5 h
F3C
O
OH
1e
(0.2 mmol)
(1.2 equiv)
2a
Conditions
tBu
tBu
+
+
O
SMe
SMe
Yieldb)/% Recoveryb)/%
CH2Cl2
25 °C
O
2e
O
a)
SMe
Entry Acid anhydride
pKa
2f
(2a)
(1a)
SMe
MeO
1
2
3
4
5
6
Tf2O
Ts2O
Ms2O
¹14
¹2.8
¹2.6
25
12
5
8
22
9
1f
(0.2 mmol)
Yield/%
TFAA [(CF3CO)2O] ¹0.25
87c)
0
0
Entry
1
Conditions
2e
2f
Ac2O
4.8
¹0.25
>99
92
4-tBuC6H4OH (0.2 mmol),
then TFAA (0.2 mmol), 0.5 h
4-tBuC6H4OH (0.2 mmol),
0
41
78
44
TFA [CF3CO2H]
0
a) pKa Value of the corresponding acid in water.25
b) Determined by H NMR. c) Isolated yield.
2
3
36
1
then TFAA (0.48 mmol), 0.5 h
TFAA (0.48 mmol), 0.25 h
trace
then 4-tBuC6H4OH (0.2 mmol), 0.5 h
(eq 1). Treatment of 2,6-naphthalenediol (5 mmol) with 1a
afforded 1.4 g of 6k after filtration over a pad of silica gel and
recrystallization from CH2Cl2/MeOH.
the corresponding benzofuran E. This mechanism is similar to
that of the reaction with Tf2O (Scheme 5b).10 The key of the
Pummerer annulation is the stability of monocationic inter-
mediate D, A, or K. When the reactions of KDMs bearing no
CF3 group are performed in the presence of more Lewis acidic
Tf2O, monocationic intermediate K would readily decompose
probably via dicationic intermediate L. A strongly electron-
withdrawing CF3 group would suppress the formation of a
dicationic intermediate to circumvent these decomposition
pathways.16d
HO
OH
MeS
SMe
TFAA (3 equiv)
ð1Þ
+
O
O
O
CH2Cl2
25 °C, 1 h
SMe
Ph
Filtration &
Recrystallization
SMe
1a
(3 equiv)
6k
1.4 g, 62%
(5 mmol scale)
Comparison of Activators. We compared the reactivity
of acid anhydrides as activators in the reaction of 4-tert-
butylphenol with 1a (Table 5). Employment of Tf2O afforded
2a in 25% yield and 1a was barely recovered (Entry 1). We
assumed that the monocationic intermediate that is generated
through activation of 1a with Tf2O is too unstable and has
insufficient lifetime to react with 4-tert-butylphenol due to the
strong Lewis acidity of Tf2O (pKa of TfOH is ¹14 in water).
We envisaged that the use of a less Lewis acidic activator
would give a more stable monocationic intermediate that has
enough lifetime to react with phenol before it decomposes.
While the reaction in the presence of less acidic sulfonic
anhydrides such as Ts2O or Ms2O (pKa of TsOH = ¹2.8,
MsOH = ¹2.6) gave 2a in only low yields (Entries 2 and 3),
employment of TFAA (pKa of CF3CO2H = ¹0.25) furnished
2a in 87% yield (Entry 4). Since acetic anhydride (pKa of
AcOH = 4.8) was not acidic enough to activate KDM, 1a was
recovered quantitatively (Entry 5). Interestingly, the corre-
sponding Brønsted acid CF3CO2H was ineffective for activa-
tion of 1a to promote the reaction, and 92% of 1a was
recovered (Entry 6). The careful choice of an activator is
critical in terms of the reactivity and stability of monocationic
intermediates.
We compared the reactivities of KDMs having electronically
different aryl groups (4-CF3C6H4 and 4-MeOC6H4) (Table 6).
Treatment of a 1:1 mixture of 1e and 1f (0.2 mmol each) with
4-tert-butylphenol (0.2 mmol) in the presence of 1 equiv of
TFAA (0.2 mmol) afforded a 44% yield of 2f without forma-
tion of 2e. Obviously, electron-rich 1f was selectively activated
by TFAA because of the higher nucleophilicity of its sulfoxide
oxygen. When the reaction was performed in the presence of
2.4 equiv of TFAA (0.48 mmol), both 2e and 2f were obtained
in 41% and 36% yield, respectively. We are interested in the
stability of activated 1e and 1f and the following experiment
was performed to briefly determine the lifetimes of these
activated KDMs. After treatment of 1e and 1f with TFAA (0.48
mmol) for 0.25 h, 4-tert-butylphenol (0.2 mmol) was then
added to the mixture. As a result, benzofuran 2e was obtained
exclusively in 78% yield and only a trace of 2f was obtained.
This contrastive result indicates that most of the activated 1f
decomposed within 0.25 h and that more than 78% of the
activated 1e survived for 0.25 h. We thus conclude that activa-
tion of electron-rich KDM occurs faster than that of electron-
poor KDM but that activated monocationic intermediate
derived from electron-rich KDM is less stable than that derived
from electron-poor KDM.
Mechanistic Studies.
A proposed mechanism of the
Pummerer annulation with TFAA is shown in Scheme 5a. KDM
is activated with TFAA to give relatively stable monocationic
intermediate D. Intermediate D reacts with phenol to provide
H before unproductive decomposition of D proceeds. [3,3]-
Sigmatropic rearrangement of H provides I that readily cyclizes
into J. Elimination of MeSH from J smoothly proceeds to afford
The reactivity of phenol derivatives was studied. A mixture
of 4-ethoxycarbonylphenol (0.2 mmol) and 4-methoxyphenol
(0.2 mmol) was treated with 1a (0.2 mmol) in the presence of
TFAA (0.2 mmol) to afford 3f as a major product (eq 2). The
more electron-rich and thus more nucleophilic phenol showed
higher reactivity toward the activated KDM.
1356 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

Table 7. Optimization of Cross-Coupling Reaction with
Phenylmagnesium Bromide
Ph
EtO2C
EtO2C
SMe
SMe
O
OH
(0.2 mmol)
1a (0.2 mmol)
Catalyst (10 mol%)
SMe
3a 10%
MeS
TFAA (0.2 mmol)
PhMgBr (5 equiv)
+
+
ð2Þ
O
O
O
O
CH2Cl2, 25 °C, 0.5 h
toluene (0.1 M)
100 °C, 12 h
Ph
MeO
MeO
6k
7a
iPr
O
OH
(0.2 mmol)
3f 69%
R
R
iPr
N
R
N
N
N
N
N
A deuterium labeling experiment showed a very small
kinetic isotope effect of 1.2 (eq 3), indicating that C-H bond
cleavage is not involved in the rate-determining step.18n
R
iPr iPr
Cl Pd Cl
Cl Pd Cl
Cl Ni Cl
N
N
P
Ph
Ph
Ph
Cl
Cl
Pd-PEPPSI-IMes
O
R = iPr: Pd-PEPPSI-IPr
R = 3-Pentyl: Pd-PEPPSI-IPent
[IPrNiCl2(PPh3)]
SMe
Ph
OH
SMe
Entry
Catalyst
[NiCl2(PPh3)2]
Isolated yield/%
D
(22)a)
(14)a)
(14)a)
54
cmb)
cmb)
1a
(2 equiv)
1
2
3
4
5
6
7
8c)
(93%D)
[NiCl2(dppe)]
[PdCl2(dppf)]
Pd-PEPPSI-IPr
Pd-PEPPSI-IMes
Pd-PEPPSI-IPent
[IPrNiCl2(PPh3)]
[IPrNiCl2(PPh3)]
1
Ph
TFAA (2 equiv)
ð3Þ
SMe
CH2Cl2 (0.1 M)
25 °C, 0.5 h
O
68
62 (1.5 g)
H/D
4d
79%
kH/kD = 1.2
a) Determined by H NMR. b) Complex mixture. c) 4-mmol
scale.
Ni-NHC-Catalyzed Cross-Coupling Reactions of Bulky
3-Aryl-2-methylsulfanylbenzofurans with Arylmagnesium
Reagents. We reported efficient cross-coupling reactions of
3-trifluoromethyl-2-methylsulfanylbenzofuran10b with arylzinc
reagents by using Organ’s Pd-PEPPSI-IPr catalyst.26 In the
report, we found that a newly introduced 2-aryl substituent
remarkably affects the photophysical properties of the benzo-
furans. This fact drove us to develop more efficient reactions
to transform the methylsulfanyl group at the crowded 2 posi-
tion of benzofurans. Despite its low chemoselectivity, cross-
coupling reaction with organomagnesium reagents still remains
as a highly efficient transformation27 and has been widely
applied for the syntheses of natural products28 and organic
materials.29 In this full paper, we disclose the details of
modified reaction conditions for cross-coupling reactions of
bulky 3-aryl-2-methylsulfanylbenzofurans with organomagne-
sium reagents.30-32 The optimization of the reaction conditions
The new catalytic conditions were effective for the trans-
formations of other Pummerer annulation products (Table 8).
Phenylation of 6a gave 7b in 74% yield, the structure of which
was confirmed by X-ray crystallographic analysis. Employing
the highly active catalytic system, diphenylation also proceed-
ed smoothly to afford densely phenylated π-extended difurans
7c-7f. Notably, the products were isolated by recrystallization
without silica gel column chromatography.
Rational synthesis of multisubstituted difurans was accom-
plished through our iterative Pummerer annulation/cross-
coupling strategy over 5 steps from a siloxyphenol (Table 9).34
Siloxy-substituted 2-methylsulfanylfuran 3 or 6, which is
prepared through Pummerer annulation of the corresponding
siloxyphenol, is converted through nickel-catalyzed cross-
coupling with an organomagnesium reagent. The siloxy group
on 8 is then deprotected with TBAF to give 9. Subsequent
Pummerer annulation takes place to construct the second furan
ring with KDM 1. Cross-coupling of the resulting difuran 10
with an organometallic reagent furnishes tetrasubstituted
difuran 11. For example, we firstly converted 2-methylsul-
fanylnaphthofuran 6k with 4-biphenylylmagnesium bromide
in the presence of the nickel catalyst to yield 6-siloxy-2,3-
diarylnaphthofuran 8a. Subsequent deprotection of the siloxy
group with TBAF gave 9a in 85% yield over 2 steps. The
regioselective Pummerer annulation of 9a with naphthyl-
substituted KDM 1h followed by the second nickel-catalyzed
reaction with 2-naphthylmagnesium bromide provided 11a in
51% overall yield. The tetraarylated structure of 11a was
unambiguously confirmed by X-ray crystallographic analysis.11
Another multisubstituted naphthodifuran 11b having an ester
moiety was easily synthesized from 6k in 44% overall yield
is summarized in Table 7. The reactions of bulky substrate
30b-30e
6k were sluggish with a nickel catalyst having PPh3
or
dppe30d-30f while they are known as efficient ligands for the
reactions of thioethers with Grignard reagents (Entries 1 and 2).
[PdCl2(dppf)] (dppf: 1,1¤-bis(diphenylphosphino)ferrocene)
was also less effective, which was efficient for our previously
reported transformation of 3-trifluoromethyl-2-methylsulfanyl-
benzofurans10b (Entry 3). Pd-PEPPSI-IPr showed higher cata-
lytic activity to afford 7a in 54% yield (Entry 4). Less bulky
Pd-PEPPSI-IMes or more sterically congested Pd-PEPPSI-
IPent yielded complex mixtures (Entries 5 and 6). Finally, a
nickel catalyst that has an IPr ligand33 gave the highest yield of
68% (Entry 7). A large-scale reaction was performed on a 4-
mmol scale to give 1.5 g of 7a in 62% yield, which was easily
purified through successive filtration and recrystallization
(Entry 8).
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1357

Table 8. Further Transformations
11e generally showed higher quantum yields (ΦF = 0.45-0.93)
with various substituents, which highlights the usefulness of
our iterative annulation/cross-coupling strategy for screening
of naphthodifurans toward new organic materials.
R
R
[IPrNiCl2(PPh3)] (10 mol%)
PhMgBr/THF
SMe
Syntheses of Eupomatenoids. Eupomatenoids39 were first
isolated from Eupomatia laurina in 1972,39a and were shown
to have interesting biological activities such as anticancer40a or
anti-Trypanosoma cruzi activity.40b There are several reports on
the synthesis of Eupomatenoids.41 In recent reports by Bach
et al.,41b,41c the linear syntheses of Eupomatenoids from 2,3,5-
tribromobenzo[b]furan (13), the key common intermediate was
derived from commercially available 5-bromobenzo[b]furan
(12) in three steps (Scheme 6). They elegantly installed the
three substituents, aryl, propenyl, and then methyl groups, to
tribromobenzofuran 13 in four or five steps. However, the aryl
group at the 2 position must be installed in the first step of the
synthesis. Since the Eupomatenoid family has variety on the
aryl group, late-stage arylation would be highly desirable for
diversity-oriented synthesis of Eupomatenoids.
O
O
toluene (0.1 M)
100 °C, 12 h
6
7 yield
(Starting Material)
CF3
O
7b 74%a)
(6a)
ORTEP drawing of 7b
Me Me
O
O
As a proof-of-principle, we applied the Pummerer annula-
tion/coupling strategy toward diversity-oriented synthesis of
Eupomatenoids. In contrast to Bach’s linear synthesis, our
convergent strategy includes the concise synthesis of 14 as the
key common intermediate (Scheme 7): the reaction of 4-[(E)-1-
propenyl]phenol, which is readily available from 4-hydroxy-
benzaldehyde, with methyl-substituted KDM 2d proceeded
smoothly in the presence of TFAA to give 14 in 79% yield.
Notably, the reaction was clean enough to perform further
transformation without silica gel column chromatography.
Nickel-catalyzed arylation of 14 with 3,4-methylenedioxy-
phenylmagnesium bromide furnished Eupomatenoid-3 in 79%
yield. Since methoxy moieties could not survive under the
nickel-catalyzed conditions,33e attempts to synthesize TBS-
Eupomatenoid-5 with an arylmagnesium reagent resulted in
forming a complex mixture containing a trace amount of the
expected product. We therefore achieved the synthesis of
Eupomatenoid-5 by means of the palladium/arylzinc combi-
nation of milder reactivity.10b Pd-PEPPSI-IPr-catalyzed aryla-
tion of 14 with 3-methoxy-4-siloxyphenylzinc reagent provided
TBS-Eupomatenoid-5 in 57% yield. Quantitative deprotection
with TBAF completed the synthesis of Eupomatenoid-5.
Summary. We developed the Pummerer annulation/cou-
pling strategy toward facile and diversity-oriented syntheses of
multisubstituted benzofurans. The transition-metal-free annula-
tion directly constructs benzofuran frameworks in one shot
from simple phenols and KDMs with the aid of TFAA as a
mild activator. Thanks to the conditions that are orthogonal
to transition-metal-catalyzed transformations, wide ranges of
phenols and KDMs having reactive functionalities such as boryl
and halogens are compatible. Detailed mechanistic study
revealed the reactivities of KDMs toward acid anhydrides and
of phenols with activated KDMs, supporting our plausible
mechanism. Improved nickel-catalyzed cross-coupling reac-
tions with readily available and cheap arylmagnesium rea-
gents42 were broadly applicable to the bulky benzofuranyl
thioethers. While there is a limitation in functional group
tolerability,43 this method would be a good alternative to the
reported palladium-catalyzed cross-coupling with arylzinc
reagents that needed relatively burdensome procedures for their
O
O
7c 67%b)
(6l)
7d 58%b)
(6g)
O
O
O
O
tBu
7e 87%b)
(6i)
7f 70%b)
(6m)
a) PhMgBr (2.5 equiv). b) PhMgBr (5 equiv).
employing a 4-ethoxycarbonylphenylzinc reagent under our
coupling conditions.10b,36 Triphenylene- and phenanthrene-type
difurans 11c37 and 11d38 were also systematically prepared
from 6i and 3i, respectively. The strategy provides a simple and
easy access to a variety of multisubstituted difurans via a direct
and intuitive route.
Photophysical Properties of Benzofurans.
Table 10
represents the photophysical properties of furan derivatives
7 and 11, including their absorption and emission properties
and fluorescence quantum yields. Generally, substituted furans
showed bright blue fluorescence with high quantum yields.
Benzodifurans 7d, 7e and naphthofurans 7f, 11a having tetra-
aryl groups showed mirror images of their absorption bands in
the fluorescence spectra with small Stokes shifts (See SI). In
contrast, compounds 11b-11d having an electron-withdrawing
ethoxycarbonyl moiety on an aryl group showed small overlap
between their absorption and emission bands. For comparison,
the UV-vis absorption and emission spectra of compounds 7f,
11a, and 11b having the same naphtho[2,1-b:6,5-b¤]difuran
core are shown in Figure 2. Since an electron-withdrawing
ethoxycarbonyl group is likely to have some effect on the
significantly red-shifted and broad emission spectrum of 11b,
further theoretical investigations and evaluations of the sub-
stituent effect are ongoing in our laboratory. Compared with
naphthomonofuran 7a (ΦF = 0.31), difurans 7b-7f and 11a-
1358 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

Table 9. Rational Synthesis of Difuransa)
Ni cat.
R1MgBr
R
R
R
TBAF
TIPSO
TIPSO
HO
Ar
SMe
Ar
8
R1
Ar
R1
(b)
(a)
O
O
O
3 or 6
9
Ni cat.
R3MgBr
(d1)
R
R
1
O
O
TFAA
MeS
Ar
R1
R3
Ar
R1
or
(c)
O
O
R2
R2
Pd cat.
10
11
3
•
R ZnI LiCl
Yield (from starting material)
[Product and Yield of each steps]
(d2)
O
O
O
O
EtO2C
11a: 51% (from 6k)
[9a:85%(a,b),
10a:75%(c), 11a:80%(d1)]
11b: 44% (from 6k)
[10b:46%(a–cb)), 11b:95%(d2)]
S
S
EtO2C
O
O
O
O
EtO2C
11c: 19% (from 6i)
[8c:71%(a), 10c:29%(b,cc)), 11c:90%(d2)]
11d: 42% (from 3i)
[8d:89%(a), 9d:83%(b),
10d:84%(c), 11d:67%(d2)]
a) Reaction conditions: (a) [IPrNiCl2(PPh3)] (10 mol %), R1MgBr/THF (1 M, 2.5 equiv), toluene
(0.1 M), 100 °C, 12 h; (b) TBAF/THF (1 M, 3 equiv), THF (0.1 M), 25 °C, 3 h; (c) 1 (2 equiv),
TFAA (2 equiv), CH2Cl2, 25 °C, 1 h; (d1) [IPrNiCl2(PPh3)] (10 mol %), R3MgBr/THF (1 M, 2.5
equiv), toluene (0.1 M), 100 °C, 12 h; (d2) Pd-PEPPSI-IPr (10 mol %), R3ZnI•LiCl/THF35 (1 M,
2.5 equiv), toluene/MeCN (1:1, 0.05 M), 60 °C, 12 h. b) E/Z ratio of 1d used in this reaction was
3:2. c) CH2Cl2/MeCN (5:1, 0.08 M) was used as a solvent.
preparation.38 This straightforward Pummerer annulation/
77.2 ppm for 13C. Hexafluorobenzene was used as the external
reference for 19F (¤ = ¹162.9 ppm). IR spectra were deter-
mined on a JASCO IR-810 spectrometer. Mass spectra were
determined on a Bruker micrOTOF II spectrometer. X-ray
data were taken at ¹180 °C with a Rigaku RAXIS-RAPID
diffractometer by using graphite monochromated Cu Kα radi-
ation (- = 1.54187 ¡). The structures were solved by direct
method SIR-97 and refined by SHELXL-97 program.44
Spectroscopic grade solvents were used for all spectroscopic
studies without further purification. UV-visible absorption
spectra were recorded on a Shimadzu UV-2550 spectrometer.
Fluorescence spectra were recorded on a Shimadzu RF-5300PC
spectrometer. Absolute fluorescence quantum yields were
measured by a photon-counting method by using an integration
sphere on a Hamamatsu Photonics C9920-02 spectrometer.
cross-coupling strategy enabled rational syntheses of highly
fluorescent benzofuran molecules and Eupomatenoid natural
products having furan cores. The annulation/coupling sequence
will therefore make an impact not only for pharmaceutical
chemists working on combinatorial lead-structure identification
but also for chemists who need libraries for development of
functional organic materials.
Experimental
Instrumentation and Chemicals. 1H NMR (600 MHz),
19F NMR (565 MHz), and 13C NMR (151 MHz) spectra were
taken on a JEOL ECA-600 spectrometer and were recorded
in CDCl3. Chemical shifts (¤) are in parts per million relative
to chloroform at 7.26 ppm for 1H and relative to CDCl3 at
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1359

Silica gel (Wakogel 300 mesh) was used for column chroma-
tography. Unless otherwise noted, materials obtained from
commercial suppliers were used without further purification.
Phenols were purchased from Wako Pure Chemical Industries,
Ltd. and TCI Co., Ltd. and used as received. 2-Deuteriophenol
was prepared according to the literature45 and deuterium
content was determined by APCI-MS and 1H NMR. (E)-4-
(1-Propenyl)phenol was prepared according to the literature.46
FAMSO and bis(methylsulfanyl)methane were purchased
from Wako Pure Chemical Industries, Ltd. Triton-B and
[IPrNiCl2(PPh3)] was purchased from TCI Co., Ltd. Pd-
PEPPSI-IPr was purchased from Aldrich. Toluene was distilled
over CaH2 and stored under nitrogen atmosphere. Anhydrous
THF was purchased from Wako Pure Chemical Industries, Ltd.
and stored under nitrogen atmosphere. CH2Cl2 was purchased
from Wako Pure Chemical Industries, Ltd. and used as is.
Reactions of KDMs with phenols were carried out in open air.
Transition metal-catalyzed reactions were carried out under
O
O
O
Table 10. Optical Properties of 7a-7f and 11a-11e
in CH2Cl2
O
O
O
-
max/nm
7 or 11
-em/nm
ΦF
¹1
(¾/104 M¹1 cm
)
EtO2C
7f
11a
11b
7a
312 (3.1)
348 (2.6)
330 (2.5)
310 (1.9)
383 (2.0)
317 (4.8)
343 (3.9)
303 (2.8)
343 (4.0)
381 (7.0)
363 (6.8)
325 (3.1)
311 (2.5)
397 (6.4)
378 (6.6)
329 (2.5)
315 (2.4)
374 (5.4)
328 (2.3)
315 (2.0)
390 (3.8)
310 (2.9)
368 (4.4)
344 (4.3)
386, 402
387
0.31
0.45
7b
7c
373, 402
390
0.50
0.933j
7d
7e
393
387, 408, 431
0.45
0.83
7f
406, 430
0.71
11a
447
469
0.81
0.71
11b
11c
wavelength / nm
Figure 2. UV-vis absorption (solid line) and fluorescence
spectra (dashed line) of 7f (black), 11a (red), and 11b
(blue) in CH2Cl2.
11d
11e
450
374, 391
0.62
0.78
O
O
Cross-coupling
Br
3 steps
52%
Br
Br
Br
12
13
Key Intermediate
(1) Cross-coupling
(2) Isomerization
O
Cross-
coupling
O
R
R
Me
Br
Br
Br
Eupomatenoid-3
29% from 13 (4 steps)
O
O
O
R
Me
Me
Eupomatenoid
Eupomatenoid-5
49% from 13 (5 steps)
OH
OMe
Scheme 6. Bach’s synthesis of Eupomatenoids.
1360 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

OH
EtPPh3I
BuLi
OH
O
O
TFAA
(1.2 equiv)
Me
THF
82%
SMe
H
Me
+
Me
CH2Cl2
25 °C, 1 h
O
O
14
Ref. 21a
Key Intermediate
SMe
SMe
Me
79%
69%
(2 steps)
SMe
SMe
2d
(1.2 equiv)
iPr
iPr
[IPrNiCl2(PPh3)] (10 mol%)
Ar1MgBr/THF (2.5 equiv)
O
N
N
O
iPr iPr
Me
Cl Ni Cl
Toluene, 60 °C, 12 h
O
Me
P
Ph
Ph
Ar1 =
Eupomatenoid-3
79%
Ph
O
[IPrNiCl2(PPh3)]
O
14
Pd-PEPPSI-IPr (10 mol%)
O
2
•
•
Ar ZnCl MgBrCl LiCl/THF
(2.5 equiv)
iPr
iPr
OR
OMe
N
N
Me
iPr
iPr
Me
MeCN, 60 °C, 6 h
Cl Pd Cl
TBS-Eupomatenoid-5
(R = TBDMS)
N
Ar2 =
OTBDMS
OMe
57%
TBAF
Cl
Pd-PEPPSI-IPr
Eupomatenoid-5
(R = H)
96%
Scheme 7. Syntheses of Eupomatenoids through the Pummerer annulation/coupling strategy.
nitrogen atmosphere. Note that the resulting methanethiol after
the Pummerer annulations or cross-coupling of 2-methylsulfan-
ylbenzofurans is so malodorous that the reactions and work-up
procedures should be performed in a well-ventilated fume
hood.
General Procedures. Typical Procedure for Syntheses of
Benzofurans: Preparation of 2a is representative (Table 1). In
a reaction flask, 4-tert-butylphenol (30 mg, 0.20 mmol) and 1a
(51 mg, 0.24 mmol) were dissolved in dichloromethane (2 mL).
Trifluoroacetic anhydride (33 ¯L, 0.24 mmol) was added to the
solution at 25 °C. After being stirred for 30 min, the mixture
was filtered through a pad of alumina and the filtrate was con-
centrated. Chromatographic purification on silica gel (hexane/
CH2Cl2 = 5/1) yielded 5-(tert-butyl)-2-methylsulfanyl-3-phen-
ylbenzo[b]furan (2a, 51 mg, 0.17 mmol, 87%).
in vacuo. Recrystallization from CH2Cl2/MeOH afforded the
corresponding product 7a in 68% yield (35 mg, 0.068 mmol).
Characterization Data. Compounds 2a-2k, 3a, 3c-3f,
3h-3i, 4a, 5b, 6a, 6c-6e, 6e¤, 6g, 6k, 6m, 8c, 8d, 9a, 9d, 10a-
10d, 11a-11d, 14, and TBS-Eupomatenoid-3 are reported in
the communication.11 Compounds 4d,19 7d,3j Eupomatenoid-
3,39b Eupomatenoid-539b are known compounds and showed
the identical spectra according to the literature.
5-Iodo-2-methylsulfanyl-3-phenylbenzo[b]furan
Oil. IR (neat): 2925, 1432, 1261, 1097, 964, 766, 696 cm
(3b):
¹1
;
1H NMR (CDCl3): ¤ 2.55 (s, 3H), 7.25-7.27 (m, 1H), 7.42-
7.43 (m, 1H), 7.51-7.53 (m, 2H), 7.56-7.59 (m, 3H), 7.94-
7.95 (m, 1H); 13C NMR (CDCl3): ¤ 16.80, 86.87, 112.97,
121.41, 127.94, 128.56, 128.88, 129.12, 131.17, 131.23,
133.04, 148.92, 154.96; HRMS (APCI-MS, positive): m/z =
365.9573. calcd for C15H11OIS: 365.9570 [M]+.
Typical Procedure for Ni-Catalyzed Cross-Coupling
Reactions:
Preparation of 7a is representative (Table 7,
5-Acetyl-2-methylsulfanyl-3-phenylbenzo[b]furan (3g):
1
Entry 7). Thioether 6k (45 mg, 0.10 mmol) and [IPrNiCl2-
(PPh3)] (7.8 mg, 0.010 mmol) were added to a Schlenk tube
under argon. Toluene (1 mL) and PhMgBr (0.5 mL, 0.5 mmol,
1 M in THF) were successively added to the tube and the
resulting mixture was heated at 100 °C for 12 h. The mixture
was allowed to cool to ambient temperature. The reaction was
quenched with HCl aq (1 M, 5 mL). The organic compounds
were extracted with CH2Cl2 three times. The combined organic
part was then washed with brine. The mixture was filtered
through a pad of silica gel and Na2SO4 and concentrated
Oil. IR (neat): 2925, 1688, 1251, 1090, 739 cm¹1; H NMR
(CDCl3): ¤ 2.56 (s, 3H), 2.64 (s, 3H), 7.42-7.44 (m, 1H), 7.51-
7.54 (m, 3H), 7.60-7.62 (m, 2H), 7.96-7.98 (m, 1H), 8.23
(s, 1H); 13C NMR (CDCl3): ¤ 16.92, 27.00, 111.10, 121.05,
122.94, 125.40, 128.11, 128.84, 129.01, 129.26, 131.23,
133.18, 149.65, 158.23, 197.72; HRMS (APCI-MS, positive):
m/z = 282.0700. calcd for C17H14O2S: 282.0709 [M]+.
7-Chloro-2-methylsulfanyl-3-phenylbenzo[b]furan (4b):
1
Oil. IR (neat): 2927, 1417, 933, 696 cm¹1; H NMR (CDCl3):
¤ 2.59 (s, 3H), 7.18-7.20 (m, 1H), 7.31-7.32 (m, 1H), 7.41-
Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan | 1361

7.43 (m, 1H), 7.50-7.53 (m, 3H), 7.59-7.61 (m, 2H); 13C NMR
(CDCl3): ¤ 17.02, 116.63, 118.39, 123.03, 124.06, 124.75,
127.96, 128.86, 129.21, 130.20, 131.49, 149.05, 151.40;
HRMS (APCI-MS, positive): m/z = 274.0226. calcd for
C15H11O35ClS: 274.0219 [M]+.
7.60 (m, 1H), 7.63 (m, 2H), 7.67-7.69 (m, 1H), 7.93-7.95
(m, 1H); 13C NMR (CDCl3): ¤ 16.95, 92.45, 111.05, 118.37,
122.60, 124.10, 124.33, 125.59, 126.38, 127.82, 128.56,
128.87, 129.11, 129.55, 131.43, 134.23, 136.63, 149.14,
152.52, 155.39, 169.86; HRMS (APCI-MS, positive): m/z =
611.1338. calcd for C38H27O4S2: 611.1345 [M + H]+.
7-tert-Butyl-5-(triisopropylsiloxy)-2-methylsulfanyl-3-
phenylbenzo[b]furan (6h): Oil. IR (neat): 2944, 1596, 1404,
1153, 865 cm¹1; 1H NMR (CDCl3): ¤ 1.10-1.12 (s, 18H), 1.24-
1.28 (m, 3H), 1.52 (s, 9H), 2.55 (s, 3H), 6.80 (s, 1H), 6.93
(s, 1H), 7.38-7.39 (m, 1H), 7.48-7.51 (m, 2H), 7.57-7.58
(m, 2H); 13C NMR (CDCl3): ¤ 12.87, 16.96, 18.17, 30.04,
34.50, 106.96, 114.76, 121.89, 127.42, 128.71, 129.15, 129.38,
132.43, 135.00, 147.07, 149.17, 152.17 ppm; HRMS (APCI-
MS, positive): m/z = 468.2520. calcd for C28H40O2SSi:
468.2513 [M]+.
7-Benzyloxy-2-methylsulfanyl-3-phenylbenzo[b]furan
¹1
(4c):
Oil. IR (neat): 2925, 1497, 1274, 728, 692 cm ;
1H NMR (CDCl3): ¤ 2.55 (s, 3H), 5.56 (s, 2H), 6.88-6.89 (m,
1H), 7.13-7.15 (m, 1H), 7.23-7.25 (m, 1H), 7.34-7.43 (m, 4H),
7.50-7.54 (m, 4H), 7.62-7.64 (m, 2H); 13C NMR (CDCl3):
¤ 17.47, 71.36, 109.39, 112.74, 123.43, 123.79, 127.62,
127.72, 128.20, 128.72, 128.76, 129.33, 130.45, 132.03,
137.09, 144.22, 145.44, 147.93; HRMS (APCI-MS, positive):
m/z = 346.1033. calcd for C22H18O2S: 346.1022 [M]+.
6-(tert-Butyl)-2-methylsulfanyl-3-phenylbenzo[b]furan
(5a): Solid. Mp 105-110 °C; IR (neat): 2929, 2873, 1489,
1313, 1076, 966, 825, 754, 700 cm¹1; 1H NMR (CDCl3): ¤ 1.42
(s, 9H), 2.55 (s, 3H), 7.36-7.38 (m, 1H), 7.40-7.43 (m, 1H),
7.51-7.54 (m, 2H), 7.56 (s, 1H), 7.59-7.60 (m, 1H), 7.65-7.66
(m, 2H); 13C NMR (CDCl3): ¤ 17.41, 31.82, 35.15, 107.86,
119.33, 120.99, 122.91, 125.89, 127.59, 128.72, 129.22,
132.23, 147.12, 148.85, 156.06; HRMS (APCI-MS, positive):
m/z = 296.1237. calcd for C19H20OS: 296.1229 [M]+.
7-tert-Butyl-5-hydroxy-2-methylsulfanyl-3-phenylbenzo-
[b]furan (6i):
Yellow solid. Mp 136-137 °C; IR (neat):
3421, 2955, 1421, 941, 699 cm¹1; H NMR (CDCl3): ¤ 1.52
(s, 9H), 2.56 (s, 3H), 4.78 (br, 1H), 6.75 (s, 1H), 6.88 (s, 1H),
7.36-7.38 (m, 1H), 7.46-7.49 (m, 2H), 7.55-7.56 (m, 2H);
13C NMR (CDCl3): ¤ 16.92, 29.97, 34.54, 102.48, 110.46,
121.74, 127.53, 128.74, 129.16, 129.73, 132.23, 135.68,
147.55, 149.09, 151.77; HRMS (APCI-MS, positive): m/z =
312.1188. calcd for C19H20O2S: 312.1179 [M]+.
1
6-Trifluoromethyl-2-methylsulfanyl-3-phenylbenzo[b]-
furan (5c) + 4-Trifluoromethyl-2-methylsulfanyl-3-phenyl-
benzo[b]furan (5c¤): Oil. IR (neat): 3060, 1423, 1310, 1110,
700 cm
7-tert-Butyl-2,5-di(methylsulfanyl)-3,4-diphenylbenzo-
[1,2-b;4,3-b¤]difuran (6j): Yellow solid. Mp 168-169 °C; IR
(neat): 2962, 1482, 962, 697 cm¹1; 1H NMR (CDCl3): ¤ 1.62 (s,
9H), 2.42 (s, 3H), 2.49 (s, 3H), 6.45-6.87 (m, 4H), 6.93-6.96
(m, 2H), 6.98-7.01 (m, 4H), 7.43 (s, 1H); 13C NMR (CDCl3):
¤ 16.94, 17.32, 30.13, 34.83, 104.81, 118.49, 121.02, 122.76,
123.97, 127.26, 127.33, 127.38, 127.42, 129.69, 131.80,
132.94, 133.17, 147.93, 151.39, 153.22 (Two sp2 signals were
not observed because of overlapping.); HRMS (APCI-MS,
positive): m/z = 458.1365. calcd for C28H26O2S2: 458.1369
[M]+.
¹1
;
1H NMR (CDCl3): ¤ 2.50 (s, 3H © 0.35), 2.59
(s, 3H © 0.65), 7.34-7.71 (m, 8H © 0.35 + 7H © 0.65), 7.76
(s, 1H © 0.65); 13C NMR signals are not assigned because the
signals are too complicated; 19F NMR (CDCl3): ¤ ¹59.12,
¹62.20; HRMS (APCI-MS, positive): m/z = 308.0492. calcd
for C16H11OF3S: 308.0483 [M]+.
6-Iodo-2-methylsulfanyl-3-phenylbenzo[b]furan (5d) +
4-Iodo-2-methylsulfanyl-3-phenylbenzo[b]furan
Oil. IR (neat): 2924, 1406, 1094, 961, 695 cm
(5d¤):
¹1
;
1H NMR
(CDCl3): ¤ 2.48 (s, 3H © 0.41), 2.54 (s, 3H © 0.59), 6.99-7.01
(m, 1H © 0.41), 7.36-7.68 (m, 7H), 7.86 (s, 1H © 0.59);
13C NMR (CDCl3): ¤ 16.89, 16.95, 84.04, 88.14, 111.13,
120.30, 121.22, 122.31, 124.66, 125.67, 127.92, 128.27,
128.35, 128.86, 129.14, 129.24, 130.33, 130.73, 131.39,
132.20, 132.25, 134.78, 148.37, 150.78, 155.10, 156.02;
HRMS (APCI-MS, positive): m/z = 365.9591. calcd for
C15H11OIS: 365.9575 [M]+.
3-(4-tert-Butyldimethylsiloxyphenyl)-2-methylsulfanyl-
naphtho[2,1-b]furan (6b): Oil. IR (neat) 2928, 1497, 1251,
908, 802, 780 cm¹1; 1H NMR (CDCl3): ¤ 0.33 (s, 6H), 1.07 (s,
9H), 2.48 (s, 3H), 7.02-7.04 (m, 2H), 7.31-7.34 (m, 1H), 7.39-
7.43 (m, 3H), 7.65-7.66 (m, 1H), 7.73-7.75 (m, 1H), 7.82-7.84
(m, 1H), 7.91-7.92 (m, 1H); 13C NMR (CDCl3): ¤ ¹4.10,
18.08, 18.47, 25.91, 112.19, 120.32, 122.57, 123.38, 124.55,
125.95, 126.04, 126.18, 127.97, 129.02, 130.92, 131.71,
147.44, 153.41, 155.77 (One sp2 signal was not observed
because of overlapping.); HRMS (APCI-MS, positive):
m/z = 421.1662. calcd for C25H29O2SSi: 421.1652 [M + H]+.
3,3-Bis[5-(2-methylsulfanyl-3-phenylbenzo[b]furanyl)]-2-
3,4-Dimethyl-2,5-di(methylsulfanyl)naphtho[2,1-b:7,8-b¤]-
difuran (6l): Solid. Gradually decomposed from 99 °C; IR
1
(neat): 2924, 1373, 1256, 899, 816 cm¹1; H NMR (CDCl3):
¤ 2.48 (s, 6H), 2.50 (s, 6H), 7.55 (d, J = 9.0 Hz, 2H), 7.71
(d, J = 9.0 Hz, 2H); 13C NMR (CDCl3): ¤ 13.03, 17.75, 110.86,
121.51, 121.99, 123.68, 126.36, 128.19, 147.44, 155.47;
HRMS (APCI-MS, positive): m/z = 328.0580. calcd for
C18H16O2S2: 328.0586 [M]+.
2,3,4,5-Tetraphenylnaphtho[2,1-b:7,8-b¤]difuran
(7a):
Yellow solid. Mp >250 °C. IR (neat): 1382, 960, 757, 692
1
cm¹1; H NMR (CDCl3 at 60 °C): ¤ 6.59-6.60 (m, 4H), 6.83-
6.86 (m, 4H), 6.99-7.02 (m, 2H), 7.24-7.30 (m, 10H), 7.72-
7.74 (m, 2H), 7.89-7.91 (m, 2H); 13C NMR (CDCl3 at
60 °C): ¤ 111.08, 121.90, 121.98, 123.03, 126.16, 127.02,
127.90, 128.24, 128.32, 128.91 (2C), 129.35, 132.20, 132.65,
150.87, 154.70; HRMS (APCI-MS, positive): m/z = 512.1753.
calcd for C38H24O2: 512.1771 [M]+; UV-vis (CH2Cl2): -max
(¾ [M¹1 cm¹1]) = 312 (3.1 © 104) nm; Fluorescence (CH2Cl2,
-
ex = 280 nm): -max = 386, 402 nm, ΦF = 0.31.
benzofuran-1(3H)-one (6f): Yellow solid. Mp 101-115 °C;
3-(4-Trifluoromethylphenyl)-2-phenylnaphtho[2,1-b]-
¹1
IR (neat): 1763, 1459, 1097, 962 cm
;
1H NMR (CDCl3):
furan (7b): Yellow solid. Mp 144-145 °C; IR (neat): 1619,
1327, 1103, 805 cm¹1; 1H NMR (CDCl3): ¤ 7.28-7.33 (m, 4H),
7.41-7.52 (m, 4H), 7.71-7.76 (m, 3H), 7.79-7.80 (m, 1H),
¤ 2.52 (s, 6H), 7.26-7.28 (m, 2H), 7.34-7.37 (m, 2H), 7.41-
7.46 (m, 6H), 7.49-7.50 (m, 4H), 7.53-7.55 (m, 1 H), 7.59-
1362 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan

7.84-7.86 (m, 2H), 7.94-7.96 (m, 1H); 13C NMR (CDCl3):
¤ 112.41, 118.26, 122.94, 123.26, 124.44 (q, J = 271 Hz),
124.66, 126.44, 126.48, 126.52, 126.60, 128.24, 128.39,
128.76, 129.33, 130.57, 130.65 (q, J = 32 Hz), 131.18,
131.36, 139.06, 150.68, 151.80; 19F NMR (CDCl3): ¤ ¹63.49;
HRMS (APCI-MS, positive): m/z = 388.1076. calcd for
7.63-7.64 (m, 2H); 13C NMR (CDCl3): ¤ 105.18, 111.75,
113.50, 117.55, 127.12, 127.76, 128.53, 128.57, 129.12,
129.80, 130.80, 131.24, 132.94, 149.22, 151.70, 151.84;
HRMS (APCI-MS, positive): m/z = 286.0988. calcd for
C20H14O2: 286.0986 [M]+.
2-Methylsulfanyl-3,4,5-triphenylbenzo[1,2-b;4,3-b¤]-
difuran (10e): Solid. Mp 181-182 °C. IR (neat): 3064, 1502,
C25H15OF3: 388.1070 [M]+; UV-vis (CH2Cl2):
-
max
(¾ [M¹1 cm¹1]) = 310 (1.9 © 104), 330 (2.5 © 104), 348
1228, 757, 688 cm¹1; H NMR (CDCl3): ¤ 2.42 (s, 3H), 6.86-
1
(2.6 © 104) nm; Fluorescence (CH2Cl2, -ex = 280 nm): -max
387 nm, ΦF = 0.45.
=
6.90 (m, 4H), 6.95-7.01 (m, 6H), 7.20-7.21 (m, 3H), 7.30-7.32
(m, 2H), 7.49-7.55 (m, 2H); 13C NMR (CDCl3); ¤ 17.17,
108.08, 119.04, 121.44, 122.21, 124.16, 127.26, 127.66,
127.86, 128.11, 128.33, 128.36, 129.76, 130.33, 131.07,
133.39, 133.73, 149.07, 151.39, 151.79, 152.94 (Two sp2
signas were not observed because of overlapping.); HRMS
(APCI-MS, positive): m/z = 463.1707. calcd for C34H20O2:
463.1693 [M]+.
3,4-Dimethyl-2,5-diphenylnaphtho[2,1-b:7,8-b¤]difuran
(7c):
Yellow solid. Gradually decomposed around 174-
185 °C. IR (neat): 1381, 906, 810, 687 cm¹1; 1H NMR (CDCl3):
¤ 2.80 (s, 6H), 7.36-7.38 (m, 2H), 7.51-7.54 (m, 4H), 7.65-7.66
(m, 2H), 7.77-7.78 (m, 2H), 7.95-7.97 (m, 4H); 13C NMR
(CDCl3): ¤ 14.27, 110.89, 114.69, 122.54, 125.09, 126.48,
126.56, 127.84, 128.57, 128.87, 131.58, 151.11, 153.69; HRMS
(APCI-MS, positive): m/z = 388.1466. calcd for C28H20O2:
388.1458 [M]+; UV-vis (CH2Cl2): -max (¾ [M¹1 cm¹1]) = 317
2,3,4,5-Tetraphenylbenzo[1,2-b;4,3-b¤]difuran
(11e):
Yellow solid. Mp >250 °C. IR (neat): 3049, 1411, 754, 690
¹1
cm
;
1H NMR (CDCl3): ¤ 6.89-6.92 (m, 4H), 6.97-6.98
(4.8 © 104), 383 (2.0 © 104) nm; Fluorescence (CH2Cl2, -ex
350 nm): -max = 373, 402 nm, ΦF = 0.50.
=
(m, 4H), 7.03-7.05 (m, 2H), 7.16-7.18 (m, 6H), 7.23-7.26
(m, 2H), 7.58 (s, 2H); 13C NMR (CDCl3): ¤ 108.34, 119.14,
122.97, 127.03, 127.70, 127.96, 128.30, 128.59, 130.37,
131.10, 134.23, 151.28, 151.77; HRMS (APCI-MS, positive):
m/z = 463.1707. calcd for C34H20O2: 463.1693 [M]+; UV-vis
(CH2Cl2): -max (¾ [M¹1 cm¹1]) = 344 (4.3 © 104) nm; Fluores-
cence (CH2Cl2, -ex = 300 nm): -max = 374, 391 nm, ΦF =
0.78.
7-tert-Butyl-2,3,4,5-tetraphenylbenzo[1,2-b;4,3-b¤]difuran
(7e): Yellow solid. Mp >250 °C; IR (neat): 2957, 1445, 1068,
687 cm¹1; 1H NMR (CDCl3): ¤ 1.70 (s, 9H), 6.89-7.04 (m, 9H),
7.15-7.25 (m, 11H), 7.54 (s, 1H); 13C NMR (CDCl3): ¤ 30.28,
34.92, 105.53, 118.92, 120.87, 123.29, 126.80, 126.85, 127.53,
127.70, 127.75, 127.80, 128.26, 128.37, 128.58, 128.60,
130.39, 130.45, 131.30, 132.27, 134.27, 134.54, 149.53,
150.82, 151.20, 151.53 (Two sp2 signals were not observed
because of overlapping.); HRMS (APCI-MS, positive): m/z =
519.2306. calcd for C38H30O2: 519.2319 [M]+; UV-vis
(CH2Cl2): -max (¾ [M¹1 cm¹1]) = 343 (4.0 © 104) nm; Fluores-
cence (CH2Cl2, -ex = 280 nm): -max = 393 nm, ΦF = 0.45.
This work was supported by Grants-in-Aid from MEXT
(Nos.: 24106721 “Reaction Integration” and 25107002 “Sci-
ence of Atomic Layers”) and from JSPS (Nos.: 24685007
(Young Scientists (A)) and 26620081 (Exploratory Research)).
K.M. acknowledges JSPS for financial support.
2,3,7,8-Tetraphenylnaphtho[2,1-b:6,5-b¤]difuran
(7f):
Supporting Information
Solid. Mp >250 °C. IR (neat): 3060, 1559, 1389, 809, 691
1
cm¹1; H NMR (CDCl3): ¤ 7.24-7.27 (m, 6H), 7.51-7.61 (m,
UV-visible and fluorescence spectra, crystallographic data,
and NMR spectra. This material is available electronically on
J-STAGE.
18H); 13C NMR (CDCl3): ¤ 111.74, 119.59, 120.89, 124.82,
125.67, 126.48, 127.99, 128.45, 128.56, 129.70, 130.88,
131.04, 135.07, 150.39, 150.74 (One sp2 signal was not
observed because of overlapping.); HRMS (APCI-MS, posi-
tive): m/z = 512.1770. calcd for C38H24O2: 512.1771 [M]+;
UV-vis (CH2Cl2): -max (¾ [M¹1 cm¹1]) = 311 (2.5 © 104),
325 (3.1 © 104), 363 (6.8 © 104), 381 (7.0 © 104) nm; Fluores-
cence (CH2Cl2, -ex = 350 nm): -max = 387, 408, 431 nm, ΦF =
0.83.
References
1
a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893. b) B. L. Flynn, G. S. Gill, D. W. Grobelny, J. H.
Chaplin, D. Paul, A. F. Leske, T. C. Lavranos, D. K. Chalmers,
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5-Triisopropylsiloxy-2,3-diphenylbenzo[b]furan
(8e):
1H NMR
¹1
Oil. IR (neat): 2923, 1497, 1197, 909, 696 cm
;
(CDCl3): ¤ 1.13-1.15 (m, 18H), 1.27-1.32 (m, 3H), 6.92-6.94
(m, 1H), 7.01 (s, 1H), 7.30-7.34 (m, 3H), 7.40-7.44 (m, 2H),
7.48-7.53 (m, 4H), 7.66-7.67 (m, 2H); 13C NMR (CDCl3):
¤ 12.83, 18.15, 109.70, 111.34, 117.69, 117.75, 127.21, 127.70,
128.44, 128.55, 129.10, 129.82, 130.99, 133.13, 149.39,
151.49, 152.33 (One sp2 signal was not observed because of
overlapping.); HRMS (APCI-MS, positive): m/z = 442.2322.
calcd for C29H34O2Si: 442.2323 [M]+.
2
a) A. L. Ososki, E. J. Kennelly, Phytother. Res. 2003, 17,
845. b) K. Baba, K. Takeuchi, F. Hamasaki, M. Kozawa, Chem.
Pharm. Bull. 1985, 33, 416. c) K. Baba, K. Takeuchi, F. Hamasaki,
M. Kozawa, Chem. Pharm. Bull. 1986, 34, 595. d) K. Baba, K.
Takeuchi, M. Doi, M. Inoue, M. Kozawa, Chem. Pharm. Bull.
1986, 34, 1540. e) K. Yoshikawa, S. Bando, S. Arihara, E.
Matsumura, S. Katayama, Chem. Pharm. Bull. 2001, 49, 327.
f) M. Takasugi, S. Nagao, S. Ueno, T. Masamune, A. Shirata, K.
Takahashi, Chem. Lett. 1978, 1239.
5-Hydroxy-2,3-diphenylbenzo[b]furan (9e):
(neat): 3319 (br), 1466, 1148, 759, 691 cm
Oil. IR
1H NMR
¹1
;
(CDCl3): ¤ 4.63 (br, 1H), 6.84-6.86 (m, 1H), 6.89-6.90 (m,
1H), 7.29-7.33 (m, 3H), 7.39-7.41 (m, 2H), 7.45-7.49 (m, 4H),
3
a) K. Nakahara, C. Mitsui, T. Okamoto, M. Yamagishi, H.
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Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
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© 2014 The Chemical Society of Japan

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23 Without addition of K2CO3, dithioacetals 3g¤ and 3h¤ were
obtained in low yields.
MeS SMe
MeS SMe
Ph
Ph
Me
H
SMe
SMe
O
O
3g'
3h'
24 The structures of 3-tert-butylphenol, 3-methoxyphenol, and
3-trifluoromethylphenol were optimized and the orbital was
obtained at the B3LYP/6-31G(d) level and the structure of 3-
iodophenol was optimized and the orbitals were obtained at the
B3LYP/6-31G(d) (C, H, O) + LANL2DZ(I) level by using the
Gaussian 09 program: M. J. Frisch, G. W. Trucks, H. B. Schlegel,
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25 For the comparison of pKa values, see the following
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b) http://www.chem.wisc.edu/areas/reich/pkatable/index.htm.
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38 The regioselectivity of the reaction of 9d with 1i to afford
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shown below. The structure of intermediate 10e was unambigu-
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34 Concept of rational and sequential installation of substitu-
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MeS
O
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O
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11e: 40% (from 3i)
[8e:78%(a), 9e:94%(b),
10e:67%(c), 11e:81%(d1)]
ORTEP drawing of 10e
10e
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42 A variety of arylmagnesium reagents are commercially
available and are cheaper than the corresponding arylzinc reagent.
For instance, a PhMgBr solution in THF costs 6,000 yen for 50
mmol while a PhZnBr solution in THF costs 22,500 yen for 25
mmol from Aldrich).
43 A disadvantage of the nickel-catalyzed reactions is low
functional group tolerability. For instance, the IPr/Ni catalyst can
often cleave the C(sp2)-O bonds of anisole derivatives. In such
cases, the Pd-PEPPSI-IPr/ArZnX system is the better option
because alkoxy groups are compatible under the milder conditions.
We recommend employing a readily available arylzinc reagent that
was prepared from the corresponding aryl bromide, Mg metal,
LiCl, and ZnCl2 (Ref. 35b).
36 Recent examples of cross-coupling of sulfides with organo-
zincs: a) L. Melzig, A. Metzger, P. Knochel, J. Org. Chem. 2010,
75, 2131. b) M. E. Angiolelli, A. L. Casalnuovo, T. P. Selby,
Synlett 2000, 905. c) I. Ghosh, P. A. Jacobi, J. Org. Chem. 2002,
67, 9304. d) W. P. Roberts, I. Ghosh, P. A. Jacobi, Can. J. Chem.
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h) A. Metzger, L. Melzig, P. Knochel, Synthesis 2010, 2853. i) L.
Melzig, A. Metzger, P. Knochel, Chem.®Eur. J. 2011, 17, 2948.
j) T. Koshiba, T. Miyazaki, H. Tokuyama, T. Fukuyama, Hetero-
cycles 2009, 77, 233. For cross-coupling of sulfonium salts: k) J. F.
Hooper, A. B. Chaplin, C. González-Rodríguez, A. L. Thompson,
A. S. Weller, M. C. Willis, J. Am. Chem. Soc. 2012, 134, 2906. l) J.
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37 During the synthesis, 10c was obtained along with 10c¤
after the Pummerer annulation. Treatment of 10c¤ in TFA/CH2Cl2
as a solvent at 25 °C for 0.5 h afforded 10c in 77% yield.
S
1i (2 equiv)
TFAA (2 equiv)
44 SHELXL-97 and SHELXS-97, program for refinement of
crystal structures from diffraction data, University of Goettingen,
Goettingen (Germany); G. M. Sheldrick, T. R. Schneider, Methods
Enzymol. 1997, 277, 319.
45 C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131,
4194.
CH2Cl2/MeCN (5/1)
25 °C, 1 h
O
O
HO
O
MeS
10c 10%
TFA/CH2Cl2
(1/1, 0.05 M)
25 °C, 0.5 h
+
77%
S
46 S. Lin, M. A. Ischay, C. G. Fry, T. P. Yoon, J. Am. Chem.
Soc. 2011, 133, 19350.
MeS
MeS
O
O
10c' 25%
1366 | Bull. Chem. Soc. Jpn. 2014, 87, 1349–1366 | doi:10.1246/bcsj.20140241
© 2014 The Chemical Society of Japan