Gold-Catalyzed Dimeric Cyclization of Isoeugenol and Related 1-Phenylpropenes in Ionic Liquid: Environmentally Friendly and Stereoselective Synthesis of 1,2,3-Trisubstituted 2,3-Dihydro-1 H -indenes

Article abstract of DOI:10.1055/s-0035-1561604

Gold-catalyzed dimerization of isoeugenol and related 1-phenylpropenes in ionic liquid enabled environmentally friendly, stereoaselective synthesis of 1,2,3-trisubstituted 2,3-dihydro-1H-indenes. Dimerization of isoeugenol or isohomogenol afforded diisoeu

Full text of DOI:10.1055/s-0035-1561604

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
A
special topic
N. Morita et al.
Special Topic
Synthesis
Gold-Catalyzed Dimeric Cyclization of Isoeugenol and Related
1-Phenylpropenes in Ionic Liquid: Environmentally Friendly and
Stereoselective Synthesis of 1,2,3-Trisubstituted 2,3-Dihydro-
1H-indenes
MeO
Nobuyoshi Morita*
Rie Mashiko
MeO
RO
RO
Dai Hakuta
Daisuke Eguchi
Shintaro Ban
OMe
AuCl (2 mol%)
R = H, Me
AgOTf (2 mol%)
H, Me = 79%
OMe
OR
Yoshimitsu Hashimoto
Iwao Okamoto
Osamu Tamura*
[EMIM][NTf2]
MeO
MeO
MeO
OMe
Showa Pharmaceutical University, Machida, Tokyo 194-8543,
Japan
morita@ac.shoyaku.ac.jp
tamura@ac.shoyaku.ac.jp
OMe
MeO
OMe
39%
OMe
R1
Received: 30.01.2016
Accepted after revision: 09.03.2016
Published online: 20.04.2016
diisoeugenol (2)
1
R2
R3
R1 = H, R2 = OMe, R3 = OH, R4 = H
2
3
diisohomogenol (4)
R1 = H, R2 = OMe, R3 = OMe, R4 = H
DOI: 10.1055/s-0035-1561604; Art ID: ss-2016-c0078-st
R1
R2
diasarone (6)
R1 = OMe, R2 = H, R3 = OMe, R4 = OMe
R4
Abstract Gold-catalyzed dimerization of isoeugenol and related 1-
phenylpropenes in ionic liquid enabled environmentally friendly, stereo-
selective synthesis of 1,2,3-trisubstituted 2,3-dihydro-1H-indenes. Di-
merization of isoeugenol or isohomogenol afforded diisoeugenol or di-
diisosafrole (8)
R4
R
1 = H, R2, R3 = -OCH2O-, R4 = H
R3
isohomogenol,
respectively,
with
α-configuration,
whereas
Figure 1 Structures of 1,2,3-trisubstituted 2,3-dihydro-1H-indenes
dimerization of α-asarone furnished diasarone with γ-configuration.
Key words gold-catalyzed dimerization, ionic liquid, addition, cycliza-
tion, 1,2,3-trisubstituted 2,3-dihydro-1H-indenes
R
R
R
R
R
R
R
R
Lignans and neolignans show tremendous structural di-
versity,1 and dimers of phenylpropanoid units (C6–C3) form
a huge family of secondary metabolites in nature. Among
them, polyfunctionalized 2,3-dihydro-1H-indenes2 such as
diisoeugenol (2),2a,3 diisohomogenol (4),2b diasarone (6),4
and diisosafrole (8)5 form an important group, within
which four diastereomers are possible, namely α-(1,2-cis-
2,3-trans), β-(1,2-cis-2,3-cis), γ-(1,2-trans-2,3-trans), and
δ-(1,2-trans-2,3-cis) (Figure 1 and Figure 2). The α-diaste-
reomers of diisoeugenol (2) and its derivatives exhibit vari-
ous biological properties, including cytotoxic,5 anti-inflam-
matory,6 antioxidant,7 spasmolytic, hypertensive, and
thromboxane formation-inhibitory activities,8 while the γ-
diastereomer of diisoeugenol (2) protects perfumes from
deterioration.9 Because of the potential utility of these ac-
tivities, and inadequate supplies of the compounds from
natural sources, development of synthetic methods for
1,2,3-trisubstituted 2,3-dihydro-1H-indenes has attracted
much interest.
α
β
γ
δ
Figure 2 Four stereoisomers of 1,2,3-trisubstituted 2,3-dihydro-1H-in-
denes
Reported syntheses of 2,3-dihydro-1H-indene deriva-
tives can be mainly divided into two groups: (i) dimeriza-
tion of related 1-phenylpropenes10–12 and (ii) intra-/inter-
molecular coupling reaction of 1-phenylpropan-1-ols and
1-phenylpropenes.13,14 Most dimerizations of 1-phenylpro-
penes require the use of a toxic and volatile halogenated
solvent (CH2Cl2 or CHCl3) and a hazardous, corrosive re-
agent (H2SO4, HCl, or CF3CO2H). Recently, Kouznetsov’s
group developed the first green protocol for the large-scale
preparation of γ-diisoeugenol (2) and related 2,3-dihydro-
1H-indenes using PEG-400, a commercially available and
easily degradable solvent, or silica-supported sulfuric acid
(SiO2-OSO3H) as a reusable heterogeneous system.10a On the
other hand, most coupling reactions of 1-phenylpropan-1-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
N. Morita et al.
Special Topic
Synthesis
ol derivatives and 1-phenylpropenes require a stoichiomet-
ric amount of reagents (BF3·OEt2, SnCl4, or ZnCl2). The re-
placement of these potentially hazardous solvents and stoi-
chiometric reagents with environmentally benign solvents
and sustainable reagents is thus an important issue for
green chemistry. Here, we report a gold-catalyzed, environ-
mentally friendly, stereoselective synthesis of 2,3-dihydro-
1H-indenes in ionic liquid.15
Initially, we investigated various catalyst systems for di-
merization of isoeugenol (1) in dichloroethane, despite its
environmental unsuitability (Table 1). Gold(I) catalyst, AuCl
(2 mol%), failed to afford the desired diisoeugenol (2) (Table
1, entry 1), whereas cationic gold species generated from
AuCl (2 mol%) and AgOTf (2 mol%) afforded α-diisoeugenol
(α-2) in 76% yield with high stereoselectivity (entry 2).
Next, the effect of the counter anion of silver was examined
(entries 3–6). Combined use of AuCl (1 mol%) and AgOTf (1
mol%) furnished α-2 in high yield with good selectivity (en-
try 3). Gold(III) catalyst, AuBr3 (2 mol%), afforded diisoeuge-
nol (2) in good yield, though with limited selectivity (entry
7). Various counter anions of silver catalysts with AuBr3 (1
mol%) failed to provide a dramatic improvement in α-selec-
tivity (entries 8–11). Taking into account both yield and ste-
reoselectivity, combined use of AuCl (1 mol%) and AgOTf (1
mol%) appeared to be the best catalyst system for obtaining
α-diisoeugenol (α-2).
We next examined the use of ionic liquids in the
AuCl/AgOTf-catalyzed dimerization of isoeugenol (1) (Fig-
ure 3 and Table 2). The reaction in [EMIM][(MeO)2PO2] or
[EMIM][MeCO2] did not proceed at all (Table 2, entries 1
and 2). The reaction in [EMIM][HSO4] or [EMIM][BF4] selec-
tively furnished α-diisoeugenol (2) in moderate yield, but
the reaction time was long (Table 2, entries 3 and 4). In con-
trast, the reaction in [EMIM][NTf2] smoothly proceeded to
afford α-diisoeugenol (2) in better yield with good selectiv-
ity (entry 5). Further improvement was achieved by in-
creasing the amounts of AuCl and AgOTf. Thus, the reaction
of isoeugenol (1) in the presence of AuCl (2 mol%) and
AgOTf (2 mol%) in [EMIM][NTf2] gave diisoeugenol (2) in
79% yield with 9:1 α-selectivity (entry 6). In addition, the
large-scale preparation of α-diisoeugenol (α-2) was also
achieved from 1.0 g (6.1 mmol) of isoeugenol (1), affording
the product α-2 in 74% yield. Surprisingly, gold(I) catalyst
itself, AuCl (2 mol%) in [EMIM][NTf2] smoothly catalyzed
dimerization of isoeugenol (1), furnishing α-diisoeugenol
(2) in good yield (Table 2, entry 7), although AuCl (2 mol%)
was completely inactive in dichloroethane (Table 1, entry
1). Lee’s group reported various advantages of ionic liquids
for catalytic reactions, including formation of more reactive
catalysts or stabilization of reactive intermediates and tran-
sition states.16 Although the reason for the high activity of
AuCl in ionic liquid [EMIM][NTf2] (Table 2, entry 7) remains
unclear, two possibilities can be considered. The first is that
an active gold species, AuNTf2 might be generated by anion
Table 1 Optimization of Reaction Conditions for the Gold-Catalyzed
Dimerization of Isoeugenol (1) in Dichloroethane
MeO
cat.
ClCH2CH2Cl
HO
r.t., time
1
MeO
HO
MeO
HO
+
OMe
OMe
OH
OH
α-2
γ-2
Entry
1
Cat. (mol%)
AuCl (2)
Time (h)
Yield (%)
nda
Ratio α/γ
20
8
2
AuCl (2)/AgOTf (2)
AuCl (1)/AgOTf (1)
AuCl (1)/AgNTf2 (1)
AuCl (1)/AgBF4 (1)
AuCl (1)/AgPF6 (1)
AuBr3 (2)
76
10:1
10:1
8:1
3
20
20
24
24
8
80
4
61
5
trace
trace
80
6
7
4:1
6:1
6:1
8
AuBr3 (1)/AgOTf (3)
AuBr3 (1)/AgNTf2 (3)
AuBr3 (1)/AgBF4 (3)
AuBr3 (1)/AgPF6 (3)
8
84
9
3
80
10
11
24
24
trace
trace
a Not detected.
exchange between chloride ion of the gold catalyst and NTf2
ion of the ionic liquid, [EMIM][NTf2]. The second possibility
would be the formation of reactive gold species bearing the
NHC ligand,17 which could be generated from the ethylme-
thylimidazolium cation of [EMIM][NTf2].
EMIM = ethylmethylimidazolium
X = (MeO)2PO2
X = MeCO2
X = HSO4
X = BF4
[EMIM][(MeO)2PO2]
[EMIM][MeCO2]
[EMIM][HSO4]
[EMIM][BF4]
N
N
Me
Et
X
X = NTf2
[EMIM][NTf2]
Figure 3 Ionic liquids as solvents
Next, the recycling of the gold-catalyst system in ionic
liquid for dimerization of 1 was investigated (Table 3). After
extraction of the product of the 1st run with diethyl ether
(Table 3, entry 1), remaining AuCl (2 mol%) and AgOTf (2
mol%) in ionic liquid [EMIM][NTf2] was directly used for the
2nd run; however, the yield of dimerization product 2 was
low (entry 2). Since it was thought that the catalyst might
have been deactivated by diethyl ether, increased amounts
of catalysts were used. When 6 mol% of AuCl and 6 mol% of
AgOTf were used in ionic liquid, the 2nd and the 3rd reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
N. Morita et al.
Special Topic
Synthesis
Table 2 Optimization of Dimerization in Ionic Liquids
Next, the gold-catalyzed dimerization of other related
1-phenylpropenes, isohomogenol (3) and α-asarone (5), in
ionic liquid was examined (Schemes 1 and 2). Treatment of
isohomogenol (3) with AuCl (2 mol%) and AgOTf (2 mol%)
in [EMIM][NTf2] afforded diisohomogenol (4) with α-con-
figuration in good yield (Scheme 1). On the other hand,
gold-catalyzed dimerization of α-asarone (5) surprisingly
furnished γ-diasarone (6) in moderate yield (Scheme 2).
AuCl (1 mol%)
MeO
AgOTf (1 mol%)
ionic liquid
HO
r.t., time
1
MeO
HO
MeO
HO
AuCl (2 mol%)
+
MeO
AgOTf (2 mol%)
OMe
OMe
[EMIM][NTf2]
MeO
r.t., 3 h
OH
OH
3
α-2
γ-2
MeO
MeO
MeO
MeO
Entry
Ionic liquid
Time
Yield (%)
Ratio α/γ
1
[EMIM][(MeO)2PO2]
[EMIM][MeCO2]
[EMIM][HSO4]
[EMIM][BF4]
11 d
11 d
10 d
9 d
nra
nr
+
2
OMe
OMe
3
44
34
60
79
73
8:1
8:1
9:1
9:1
4:1
OMe
79% (α-4/γ-4 = 8:1)
OMe
4
5
[EMIM][NTf2]
[EMIM][NTf2]
[EMIM][NTf2]
4.5 h
6b
7c
4.5 h
4.5 h
Scheme 1 Gold-catalyzed dimerization of isohomogenol (3)
OMe
a No reaction.
b With AuCl (2 mol%)/AgOTf (2 mol%).
c With AuCl (1 mol%).
AuCl (2 mol%)
MeO
AgOTf (2 mol%)
MeO
OMe
[EMIM][NTf2]
r.t., 16.5 h
OMe
MeO
OMe
tions afforded the dimerization product 2 in 78 and 57%
yield, respectively, although longer reaction periods were
required (entries 3–5, runs 1–3).
5
39%
MeO
OMe
γ-6
Scheme 2 Gold-catalyzed dimerization of α-asarone (5)
Table 3 Recycling of Gold-Catalyzed Dimerization Reaction in Ionic
Liquid
To confirm the stereochemistry of the synthesized 2,3-
dihydro-1H-indenes, α-diisoeugenol (2), α-diisohomogenol
1
(4), and γ-diasarone (6), their H NMR spectra were com-
MeO
1
pared with the reported data (Table 4).11c,14b,e The H NMR
cat.
spectra of the synthesized 2,3-dihydro-1H-indenes 2 and 4
were identical with those reported for α-2 and α-4 in both
chemical shifts and coupling constants,18 while the 1H NMR
spectrum of synthesized γ-diasarone (6) was consistent
with the reported spectrum18 of γ-6.
[EMIM][NTf2]
HO
r.t., time
1
MeO
HO
MeO
HO
+
A plausible mechanistic model for gold-catalyzed di-
merization of isoeugenol (1) in ionic liquid is shown in
Scheme 3. Gold species could coordinate to the double
bond19 of isoeugenol (1), forming gold-quinone methide
complex A. The gold center of complex A would coordinate
to the double bond of another 1, inducing addition reaction
to complex A to afford intermediate B bearing an electron-
rich aromatic ring and an electron-deficient ring. Cycliza-
tion takes place between the aromatic ring and benzylic po-
sition in complex B to furnish gold intermediate C, which
undergoes aromatization and deauration to provide di-
isoeugenol (2) with α-configuration (1,2-cis-2,3-trans). The
first carbon–carbon bond formation (addition step, A → B)
OMe
OMe
OH
OH
α-2
γ-2
Entry
Run
Cat. (mol%)
Time (h) Yield (%) Ratio α/γ
1
2
3
4
5
1
2
1
2
3
AuCl (2)/AgOTf (2)
4.5
24
79
7
9:1
–
AuCl (6)/AgOTf (6)
2.5
6
82
78
57
9:1
9:1
8:1
9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
N. Morita et al.
Special Topic
Synthesis
Table 4 Comparison of 1H NMR Spectra of 2,3-Dihydro-1H-indenes 2, 4, and 6 in CDCl3
OMe
1
1
MeO
RO
2
2
CH3
CH3
OMe
3
3
MeO
OMe
MeO
MeO
OR
α−Diisoeugenol: R = H
α−Diisohomogenol: R = Me
OMe
γ−Diasarone
Chemical shifts, δ
Dimer
H-1
2.91
H-2
2.46
H-3
3.74
CH3
α-diisoeugenol (α-2)a
γ-diisoeugenol (γ-2)b
α-2 (synthesized)
α-diisohomogenol (α-4)a
γ-diisohomogenol (γ-4)c
α-4 (synthesized)
γ-diasarone (γ-6)c
γ-6 (synthesized)
Coupling constants
Dimer
1.03
1.15
1.03
1.05
1.15
1.05
1.17
1.17
2.69
2.91
2.94
2.69
2.94
2.67
2.68
2.00
2.46
2.47
2.00
2.47
2.07
2.07
3.65
3.74
3.79
3.65
3.79
4.27
4.29
J
1,2 (Hz)
7.5
J2,3 (Hz)
α-diisoeugenol (α-2)a
α-2 (synthesized)
α-diisohomogenol (α-4)a,c
α-4 (synthesized)
γ-diasarone (γ-6)c
γ-6 (synthesized)
9.5
7.5
9.6
7.2
9.5
7.2
9.9
4.2
4.3
3.6
3.9
a See ref. 11c.
b See ref. 14b.
c See ref. 14e.
would be important to control the stereochemistry of α-di-
isoeugenol (2). In the addition step, π–π stacking between
the electron-rich and electron-deficient rings in A would
make the orthogonal approach favorable, leading to forma-
tion of 1,2-cis-diisoeugenol (2) (Figure 4). Cyclization pro-
ceeds again with π–π stacking in intermediate B to form a
five-membered ring with α-configuration (1,2-cis-2,3-
trans) (Figure 4). The dimerization of isohomogenol (3)
would proceed in a similar manner, affording diisohomoge-
nol (4) with α-configuration. In the case of dimerization of
α-asarone (5), the orthogonal approach suffers from severe
steric hindrance due to the additional methoxy group on
the rings and hence addition reaction may proceed via an
extended approach A′ leading to B′ with 1,2-trans stereo-
chemistry (Figure 5). Intermediate B′ cyclizes at the ortho-
position of the aromatic group and propenyl group to pro-
vide C′, constructing the γ-configuration (1,2-trans-2,3-
trans) of γ-diasarone (6) after aromatization and deaura-
tion.
OMe
Au+
1
MeO
HO
MeO
Au
OH
+
HO
1
A
Au
Au
MeO
HO
MeO
HO
MeO
HO
H
+
HO
MeO
MeO
OMe
OH
OH
B
C
2
Scheme 3 Plausible mechanism of gold-catalyzed dimerization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
N. Morita et al.
Special Topic
Synthesis
Hz. IR spectra were recorded on a Shimadzu FTIR-8200A spectrome-
ter. Mass spectra were recorded on Jeol JMS-D300 and HX110 spec-
trometers. Merck silica gel 60 (1.09385) and Merck silica gel 60 F254
were used for column chromatography and TLC, respectively.
electron-rich
aromatic ring
electron-deficient
ring
A
π−π stacking
π−π stacking
OMe
OMe
HO
HO
HO
H
H
H
HO
H
Gold(III)-Catalyzed Dimerization of 1-Phenylpropenes 1, 3, and 5
to 2,3-Dihydro-1H-indenes 2, 4, and 6 in Ionic Liquid; General Pro-
cedure
Me
Me
MeO
MeO
H
electron-rich
aromatic ring
Au
Me
Me
Au
1
electron-deficient
ring
B
Gold catalyst (2 mol% of AuCl) and silver catalyst (2 mol% of AgOTf)
were added at r.t. to a solution of 1-phenylpropene (1, 3, or 5) in
[EMIM][NTf2] and the mixture was stirred at the same temperature.
After complete consumption of the 1-phenylpropenes (the reaction
was monitored by TLC), the product was extracted with Et2O and the
solvent was removed in vacuo. The crude product was subjected to
column chromatography on silica gel (hexane–EtOAc, 2:1) to give the
corresponding 2,3-dihydro-1H-indenes 2, 4, and 6, respectively.
interaction of gold and double bond
α-2
Figure 4 Mechanisms of addition and cyclization for construction of α-
2
OMe
MeO
A'
OMe
OMe
MeO
MeO
OMe
H
H
α-Diisoeugenol (2)
OMe
H
Me
H
MeO
OMe
Isoeugenol (1; 102 mg, 0.622 mmol), AuCl (3.5 mg, 0.015 mmol, 2
mol%), and AgOTf (3.6 mg, 0.014 mmol, 2 mol%) in [EMIM][NTf2] (1
mL) furnished α-diisoeugenol (2) (80.0 mg, 79%, α/γ = 9:1) as a color-
less solid; mp 179–180 °C.11c
A'
Me
Au
MeO
MeO
Au
Me
5
Me
5
disfavored
favored
IR (KBr): 3649, 3364, 2872, 1596, 1499, 1375, 1339, 1288, 1261, 1227,
1207, 1151, 1088, 1059, 1034, 866, 845, 818, 773, 760 cm–1
.
MeO
MeO
OMe
Me
OMe
1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.5 Hz, 3 H), 1.03 (d, J = 6.9
Hz, 3 H), 1.38 (ddq, J = 13.5, 6.3, 4.5 Hz, 1 H), 1.70 (ddq, J = 13.2, 7.8,
5.4 Hz, 1 H), 2.46 (ddq, J = 9.6, 7.2, 6.9 Hz, 1 H), 2.91 (ddd, J = 8.7, 7.5,
5.4 Hz, 1 H), 3.74 (d, J = 9.6 Hz, 1 H), 3.82 (s, 3 H), 3.90 (s, 3 H), 5.46 (s,
1 H), 5.49 (s, 1 H), 6.47 (d, J = 0.6 Hz, 1 H), 6.61 (d, J = 1.8 Hz, 1 H), 6.65
(dd, J = 8.4, 1.8 Hz, 1 H), 6.77 (s, 1 H), 6.84 (d, J = 8.4 Hz, 1 H).
MeO
OMe
H
H
OMe
H
H
MeO
Au Me
OMe
Me
Au
OMe
B'
Me
MeO
13C NMR (75 MHz, CDCl3): δ = 12.7, 14.2, 22.8, 49.0, 49.7, 56.4, 56.6,
57.2, 107.9, 111.1, 111.4, 114.4, 121.9, 136.2, 139.1, 139.6, 144.5,
145.0, 145.6, 146.9.
HRMS (FAB): m/z [M + H]+ calcd for C20H24O4: 328.1675; found:
328.1670.
MeO
B'
OMe
MeO
MeO
OMe
Me
H
MeO
OMe
H H
MeO
H
OMe
MeO
Au Me
OMe
α-Diisohomogenol (4)
Isohomigenol (3; 104 mg, 0.581 mmol), AuCl (2.6 mg, 0.011 mmol, 2
mol%), and AgOTf (3.3 mg, 0.013 mmol, 2 mol%) furnished α-diisoho-
mogenol (4) (82.0 mg, 79%, α/γ = 8:1) as a colorless solid; mp 107–
108 °C.11c
MeO
OMe
γ-6
C'
Figure 5 Reaction mechanism for construction of γ-6
IR (KBr): 2957, 2831, 1606, 1514, 1464, 1418, 1261, 1217, 1155, 1140,
1096, 1028, 991, 854, 758 cm–1
.
In summary, we have developed a gold-catalyzed di-
merization reaction of isoeugenol (1) and related 1-phenyl-
propenes 3 and 5 in ionic liquid and accomplished an envi-
ronmentally friendly stereoselective synthesis of 1,2,3-tri-
substituted 2,3-dihydro-1H-indenes. Dimerization of
isoeugenol (1) and isohomogenol (3) gave the α-dimerized
products, whereas α-asarone (5) afforded the γ-product.
AuCl/AgOTf in [EMIM][NTf2] solution could be recycled for
further dimerization reaction of isoeugenol (1). We are now
pursuing further applications of this environmentally be-
nign and sustainable catalyst system.
1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.5 Hz, 3 H), 1.05 (d, J = 7.2
Hz, 3 H), 1.40 (ddq, J = 13.5, 6.3, 4.5 Hz, 1 H), 1.72 (ddq, J = 13.5, 7.8,
6.0 Hz, 1 H), 2.47 (ddq, J = 9.6, 7.5, 7.2 Hz, 1 H), 2.94 (ddd, J = 8.7, 7.2,
5.4 Hz, 1 H), 3.73 (s, 3 H), 3.79 (d, J = 9.9 Hz, 1 H), 3.80 (s, 3 H), 3.88 (s,
3 H), 3.90 (s, 3 H), 6.44 (s, 1 H), 6.65 (d, J = 2.1 Hz, 1 H), 6.71 (dd, J =
8.4, 2.4 Hz, 1 H), 6.81 (s, 1 H), 6.83 (d, J = 7.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 12.2, 13.7, 22.4, 48.5, 49.5, 55.8, 55.8,
55.9, 56.0, 56.9, 108.0, 108.1, 110.9, 111.3, 120.7, 136.6, 138.0, 139.4,
147.5, 147.6, 148.1, 148.8.
HRMS (FAB): m/z [M + H]+ calcd for C22H28O4: 356.1988; found:
356.1975.
γ-Diasarone (6)
1H and 13C NMR spectra were recorded on a Jeol JNM-AL300 spec-
trometer at r.t. with TMS as an internal standard (CDCl3 solution).
Chemical shifts were recorded in ppm, and coupling constants (J) in
α-Asarone (5; 100 mg, 0.481 mmol), AuCl (2.4 mg, 0.010 mmol, 2
mol%), and AgOTf (2.3 mg, 0.0090 mmol, 2 mol%) furnished γ-diasa-
rone (6) (39.0 mg, 39%) as a colorless solid; mp 99–100 °C.11d
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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IR (KBr): 2955, 2836, 1603, 1508, 1464, 1437, 1396, 1337, 1319, 1232,
1205, 1178, 1119, 1082, 1036, 980, 885, 866, 841, 814, 781, 737 cm–1
(10) For dimerization with catalysts, see: (a) Kouznetsov, V. V.;
Merchan Arenas, D. R. Tetrahedron Lett. 2009, 50, 1546.
(b) Gonzalez-de-Castro, A.; Xiao, J. J. Am. Chem. Soc. 2015, 137,
8206.
(11) For dimerization with Brønsted acid, see: (a) Davis, M. C.;
Guenthner, A. J.; Groshens, T. J.; Reams, J. T.; Mabry, J. M.
J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 4127. (b) Alvarez-
Thon, L.; Carrasco-Altamirano, H.; Espinoza-Catálan, L.;
Gallardo-Araya, C.; Cardona-Villada, W.; Ibañez, A. Acta Crystal-
logr. 2006, E62, o2000. (c) Al-Farhan, E.; Keehn, P. M.; Stevenson,
R. J. Chem. Res., Synop. 1992, 100. (d) Al-Farhan, E.; Keehn, P. M.;
Stevenson, R. J. Chem. Res., Synop. 1992, 36.
.
1H NMR (300 MHz, CDCl3 ): δ = 0.98 (t, J = 7.5 Hz, 3 H), 1.17 (d, J = 6.9
Hz, 3 H), 1.54–1.42 (m, 1 H), 1.84 (ddd, J = 10.5, 7.5, 2.7 Hz, 1 H), 2.07
(ddq, J = 9.6, 7.2, 2.7 Hz, 1 H), 2.68 (dt, J = 9.0, 3.6 Hz, 1 H), 3.38 (s, 3
H), 3.64 (s, 3 H), 3.83 (s, 3 H), 3.85 (s, 3 H), 3.85 (s, 3 H), 3.88 (s, 3 H),
4.29 (d, J = 3.9 Hz, 1 H), 6.38 (s, 1 H), 6.43 (s, 1 H), 6.55 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 11.8, 22.0, 26.7, 47.7, 49.9, 52.4, 55.5,
56.1, 56.6, 56.7, 56.8, 59.9, 97.0, 97.9, 113.0, 127.0, 127.6, 139.2,
139.7, 142.7, 147.5, 151.2, 152.0, 152.2.
HRMS (FAB): m/z [M + H]+ calcd for C24H32O6: 416.2199; found:
416.2189.
(12) For dimerization with silica-supported acids or solid acids, see:
(a) Alesso, E.; Torviso, R.; Erlich, M.; Finkielsztein, L.; Lantaño,
B.; Moltrasio, G.; Aguirre, J.; Vázquez, P.; Pizzio, L.; Cáceres, C.;
Blanco, M.; Thomas, H. Synth. Commun. 2002, 32, 3803.
(b) Alesso, E. N.; Aguirre, J.; Lantaño, B.; Finkielsztein, L.;
Moltrasio, G. Y.; Vázquez, P. G.; Pizzio, L. R.; Caceres, C.; White,
M.; Thomas, H. J. Molecules 2000, 5, 414. For other examples,
see: (c) Grigor’eva, N. G.; Talipova, R. R.; Korzhova, L. F.;
Vosmerikov, A. V.; Kutepov, B. I.; Dzheimilev, U. M. Russ. Chem.
Bull. 2009, 58, 59. (d) Madhavan, D.; Murugalakshmi, M.;
Lalitha, A.; Pitchumani, K. Catal. Lett. 2001, 73, 1. (e) Benito, A.;
Corma, A.; García, H.; Primo, J. Appl. Catal., A 1994, 116, 127.
(13) For intramolecular coupling reaction of 1-phenylpropan-1-ols
with 1-phenylpropenes, see: Sarnpitak, P.; Trongchit, K.;
Kostenko, Y.; Sathalalai, S.; Gleeson, M. P.; Ruchirawat, S.;
Ploypradith, P. J. Org. Chem. 2013, 78, 8281.
Acknowledgment
This research was supported by grants from the Platform Project for
Supporting Drug Discovery and Life Science Research (Platform for
Drug Discovery, Informatics, and Structural Life Science) of the Minis-
try of Education, Culture, Sports, Science (MEXT), and the Japan
Agency for Medical Research and Development (AMED).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561604.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(14) For intermolecular coupling reaction of 1-phenylpropan-1-ols
with 1-phenylpropenes, see: (a) Li, H.-H. Chin. Chem. Lett. 2015,
26, 320. (b) Lantaño, B.; Aguirre, J. M.; Ugliarolo, E. A.; Benegas,
M. L.; Moltrasio, G. Y. Tetrahedron 2008, 64, 4090. (c) Pizzio, L.
R.; Vázquez, P. G.; Cáceres, C. V.; Blanco, M. N.; Alesso, E. N.;
Torviso, M. R.; Lantaño, B.; Moltrasio, G. Y.; Aguirre, J. M. Appl.
References
(1) For reviews on lignans and neolignans, see: (a) Saleem, M.; Kim,
H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22, 696.
(b) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23,
1207. (c) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75.
(2) In earliest researches, 2,3-dihydro-1H-indene derivatives were
originally thought to be derivatives of cyclobutane or 9,10-dihy-
droanthracene. The skeletons of 2,3-dihydro-1H-indenes were
first proposed by Baker et al. in 1940, and MacMillan et al.
assigned the correct stereochemical structure for the dimers
derived from (E)-isosafrole and isohomogenol in 1969:
(a) Baker, W.; Enderby, J. J. Chem. Soc. 1940, 1094.
(b) MacMillan, J.; Martin, I. L.; Morris, D. J. Tetrahedron 1969, 25,
905.
Catal.,
A 2005, 287, 1. (d) Lantaño, B.; Aguirre, J. M.;
Finkielsztein, L.; Alesso, E. N.; Brunet, E.; Moltrasio, G. Y. Synth.
Commun. 2004, 34, 625. (e) Alesso, E.; Torviso, R.; Lantaño, B.;
Erlich, M.; Finkielsztein, L. M.; Moltrasio, G.; Aguirre, J. M.;
Brunet, E. ARKIVOC 2003, : 283. (f) Angle, S. R.; Arnaiz, D. O.
J. Org. Chem. 1992, 57, 5937.
(15) For gold-catalyzed reactions in ionic liquids, see: (a) Lempke, L.;
Fischer, T.; Bell, J.; Kraus, W.; Rurack, K.; Krause, N. Org. Biomol.
Chem. 2015, 13, 3787. (b) Cui, D.-M.; Ke, Y.-N.; Zhuang, D.-W.;
Wang, Q.; Zhang, C. Tetrahedron Lett. 2010, 51, 980. (c) Neaţu, F.;
Pârvulescu, V. I.; Michelet, V.; Gênet, J.-P.; Goguet, A.; Hardacre,
C. New J. Chem. 2009, 33, 102. (d) Aksin, Ö.; Krause, N. Adv.
Synth. Catal. 2008, 350, 1106. (e) Ambrogio, I.; Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007, 1775. (f) Liu, X.;
Pan, Z.; Shu, X.; Duan, X.; Liang, Y. Synlett 2006, 1962.
(16) (a) Lee, J. W.; Shin, J. Y.; Chun, Y. S.; Jang, H. B.; Song, C. E.; Lee,
S.-g. Acc. Chem. Res. 2010, 43, 985. (b) Park, B. Y.; Ryu, K. Y.;
Park, J. H.; Lee, S.-g. Green Chem. 2009, 11, 946. (c) Kim, J. H.;
Lee, J. W.; Shin, U. S.; Lee, J. Y.; Lee, S.-g.; Song, C. E. Chem.
Commun. 2007, 4683. (d) Song, C. E.; Jung, D.-u.; Choung, S. Y.;
Roh, E. J.; Lee, S.-g. Angew. Chem. Int. Ed. 2004, 43, 6183.
(e) Song, C. E.; Shim, W. H.; Roh, E. J.; Lee, S.-g.; Choi, J. H. Chem.
Commun. 2001, 1122. (f) Song, C. E.; Shim, W. H.; Roh, E. J.; Choi,
J. H. Chem. Commun. 2000, 1695.
(3) Puxeddu, E. Gazz. Chim. Ital. 1909, 39, 131.
(4) (a) Saxena, D. B. Phytochemistry 1986, 25, 553. (b) Bohlmann, F.;
Gracza, L. Arch. Pharm. (Weinheim) 1982, 315, 474.
(5) (a) Atsumi, T.; Tonosaki, K.; Fujisawa, S. Arch. Oral Biol. 2006, 51,
913. (b) Atsumi, T.; Murakami, Y.; Shibuya, K.; Tonosaki, K.;
Fujisawa, S. Anticancer Res. 2005, 25, 4029.
(6) Murakami, Y.; Shoji, M.; Hirata, A.; Tanaka, S.; Yokoe, I.;
Fujisawa, S. Arch. Biochem. Biophys. 2005, 434, 326.
(7) Ko, F.-N.; Liao, C.-H.; Kuo, Y.-H.; Lin, Y.-L. Biochim. Biophys. Acta
1995, 1258, 145.
(8) Lin, C.-H.; Kuo, Y.-H.; Lin, Y.-L.; Teng, C.-M. J. Pharm. Pharmacol.
1994, 46, 54.
(9) Danilova, L. I.; Ivanova, I. Ya.; Kozlova, Z. G.; Kore, S. A.; Livshits,
A. G.; Osipova, V. P.; Tsepalov, V. F.; Shlyapintokh, V. Ya. Patent
SU No. 224741, 1968.
(17) (a) Clement, N. D.; Cavell, K. J. Angew. Chem. Int. Ed. 2004, 43,
3845. (b) McGuinness, D. S.; Cavell, K. J.; Yates, B. F. Chem.
Commun. 2001, 355. (c) Mathews, C. J.; Smith, P. J.; Welton, T.;
White, A. J. P.; Williams, D. J. Organometallics 2001, 20, 3848.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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N. Morita et al.
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(d) Xu, L.; Weiping, C.; Xiao, J. Organometallics 2000, 19, 1123.
(e) Herrmann, W. A.; Elison, M.; Fischer, J.; Köcher, C.; Artus, G.
R. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2371.
and related 1,2,3-trisubstituted 2,3-dihydro-1H-indenes. More-
over, Lantaño et al. also showed similar tendency of chemical
shifts (ppm) and coupling constants (J values) for α-, β- and γ-
configuration for various types of 1,2,3-trisubstituted 2,3-
dihydro-1H-indenes with NMR experiments (see Ref. 14b).
(19) (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (b) De Graaf, P. W.
J.; Boersma, J.; van der Kerk, G. J. M. J. Organomet. Chem. 1976,
105, 399.
(18) Stereochemical assignments of diisohomogenol (4) and related
1,2,3-trisubstituted 2,3-dihydro-1H-indenes were conducted by
MacMillan et al. with 1H NMR spectra and comprehensive
double irradiation experiments (see ref. 2b). They had shown
chemical shifts (ppm) and coupling constants (J values) for the
α-, β-, and γ-configuration for three of the diisohomogenol (4)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G