Intramolecular electrophilic aromatic substitution of α-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes

Article abstract of DOI:10.1016/j.tet.2006.03.092

Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF₃·OEt₂ induces an intramolecular electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms o

Full text of DOI:10.1016/j.tet.2006.03.092

Tetrahedron 62 (2006) 5717–5724
Intramolecular electrophilic aromatic substitution
of a-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes
Takashi Jobashi,a Atsushi Kawai,a Satomi Kawai,a Katsuya Maeyama,a Hideaki Oike,a
Yasuhiko Yoshidab and Noriyuki Yonezawaa,
*
aDepartment of Organic and Polymer Materials Chemistry, Tokyo University of Agriculture & Technology, Koganei,
Tokyo 184-8588, Japan
bDepartment of Applied Chemistry, Graduate School of Engineering, Toyo University, Kawagoe, Saitama 350-8585, Japan
Received 27 February 2006; revised 18 March 2006; accepted 23 March 2006
Available online 27 April 2006
Abstract—Treatment of a-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF3$OEt2 induces an intramolecular
electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms of the indene formation have been
elucidated on the basis of the reaction behaviors of b-deuterated a-methylcinnamaldehyde and the NMR studies of the reaction mixture. The
transformation process involves successive reactions, i.e., alkoxylation of the carbonyl carbon of a-alkylcinnamaldehydes to form acetals,
elimination of alkoxide from the acetals to give alkoxycarbenium ion and g-alkoxyallyl cation, and intramolecular electrophilic arylation
to afford the indene ring structure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
or low chemoselective one-pot preparations,18 except for
a recent report of Pd-complex catalyzed intramolecular
cyclization of alkynylbenzaldehyde dialkyl acetals to form
dialkoxyindenes.19
Indene derivatives are frequently found in natural products
and widely employed as medicinal compounds.1–5 In accor-
dance with this, indene derivatives have attracted organic
and pharmaceutical chemists. One of the conventional ap-
proaches toward producing the indene framework is acid-
mediated cyclodehydration reaction of aryl ketones.6–8
Some 1-phenylallyl cations also undergo the intramolecular
cyclization to afford the corresponding indenes.9–12 In these
cases, the cyclization proceeds via electrophilic aromatic
substitution mechanisms. While various substituted indenes
have so far been prepared by these methods, synthesis of
1-indenols and 1-alkoxyindenes through the electrophilic
aromatic substitution process has not been reported.
Recently, transition metal catalyzed coupling reactions of
alkynes with ortho-carbonylated arylhalides13 or arylboron
compounds14 have been developed as an effective method for
the preparation of 1-indenols. The transition metal catalyzed
annulation reaction has also been applied for the construction
of indenes.15,16 Nevertheless, an efficient and practical
means to construct 1-alkoxyindene frameworks has been an
ongoing challenge. Almost all of the syntheses of 1-alkoxy-
indenes are performed via multi step transformations5,17
During the study on the acid mediated oxidative crossed
aldol type reaction of aliphatic ethers with benzaldehyde di-
methyl acetal giving a,b-unsaturated carbonyl compounds,20
we have found that several ethers afford 1-alkoxy-2-alkyl-
indenes in place of a,b-unsaturated carbonyl compounds.21
Our preliminary study indicated that the produced a,b-unsat-
urated carbonyl compounds may be further transformed to
1-alkoxy-2-alkylindenes during the reaction.
In consequence, we have investigated the above reaction
aiming at the development of the efficient one-pot synthesis
of 1-alkoxyindenes to reveal the structural requirements and
the activation process. In this paper, the reaction features, the
scope and limitations, and the reaction mechanisms of the
transformation of a-alkylcinnamaldehydes into 1-alkoxy-
indenes are discussed.
2. Results and discussion
2.1. The reaction behaviors and characterization of the
products
Keywords: 1-Alkoxy-2-alkylindene; a-Alkylcinnamaldehyde; Alkoxyla-
tion; Intramolecular electrophilic arylation; Acetal.
We have recently reported that the BF3 mediated reaction of
bis(b-alkylethyl) ethers with benzaldehyde dimethyl acetal
* Corresponding author. Tel.: +81 42 388 7053; fax: +81 42 388 7291;
e-mail: yonezawa@cc.tuat.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.092

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T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
affords 1-alkoxy-2-alkylindenes.21 As some kinds of ali-
phatic ethers yield a,b-unsaturated carbonyl compounds in
the presence of benzaldehyde dimethyl acetal and BF3 ether-
ates, a,b-unsaturated carbonyl compounds were obviously
regarded as the precursors for the 1-alkoxyindene formation
reaction.20,21 However, the treatment of BF3$OEt2 against
a-methylcinnamaldehyde (1) did not afford any indenes
(Scheme 1, Route 1). In this case, aldehyde 1 was recovered.
In contrast, addition of trimethyl orthoformate [HC(OMe)3
(2)] to this reaction system has been found to accomplish
the transformation affording 1-methoxy-2-methylindene
(3a) in a good yield (Scheme 1, Route 2). These facts dem-
onstrate that a-methylcinnamaldehyde (1) by itself is not the
direct precursor of 1-methoxyindene 3a, but has a capability
to form 1-methoxy-2-methylindene (3a) with the aid of
HC(OMe)3 (2).
Among the acidic mediators employed, BF3$OEt2 afforded
1-methoxy-2-methylindene (3a) in the highest yield (Entry
3). Acidic mediators except BF3$OEt2 gave aldehyde 1
and/or unidentified products that have broad signals of aro-
matic ring protons and alkyl group ones in 1H NMR spectra
(Entries 6–10), though triflic acid also gave 1-methoxy-
indene 3a in a good yield (Entry 11). These by-products are
probably composed of some kinds of polymeric compounds
formed via cationic polymerization of 1-alkoxyindene22
and/or a-methylcinnamaldehyde (1)23 produced in the early
stage of the reaction.
2.2. Effect of the alkoxylating agent
Generally, treatment of orthoester against aldehyde in the
presence of acidic mediator is known to give acetal.24 In
other words, acetals of a-alkylcinnamaldehydes were con-
sidered to be the actual precursors of the 1-alkoxyindenes
in this transformation. In fact, when a-methylcinnam-
aldehyde dimethyl acetal (4) was treated with BF3$OEt2 in
the absence of HC(OMe)3 (2), 1-methoxy-2-methylindene
(3a) was also formed in a good yield (Scheme 2). Therefore,
1-alkoxyindenes must be produced via the acetal of a-alkyl-
cinnamaldehyde or at least its equivalent.
BF OEt
Route 1
BF3•OEt2
HC(OMe)3
•
3
2
O
Me
OMe
Ph
1
H
3a
2
Me
Route 2
60%
Scheme 1.
Table 1 shows the results of the reaction of a-methylcinna-
maldehyde (1) with HC(OMe)3 (2) in the presence of several
acidic mediators.
OMe
BF3•OEt2
CH2Cl2
°
25 C, 3 h
Me
OMe
OMe
Ph
3a
68%
4
Me
Scheme 2.
Table 1. Reaction of a-methylcinnamaldehyde (1) with HC(OMe)3 (2) in
the presence of several acidic mediatorsa
Acetals are also synthesized by the reaction of aldehyde with
alcohol or thiol.24 Therefore, alcohols and thiols are ex-
pected to react with aldehyde 1 affording the corresponding
indenes. Table 2 shows the results of the reaction using other
hydroxy compounds 5 or thiophenol (6). When MeOH (5a)
Acidic
O
mediator
HC(OMe)3
Me
OMe
Ph
H
+
CH2Cl2
2
1
3a
Me
25 °C, 3 h
Entry
2/1
(mol/mol)
Acidic
mediator
Acidic mediaor/1
(mol/mol)
NMR
yield/%b
Table 2. Reaction of a-methylcinnamaldehyde (1) with hydroxy com-
pounds 5 or thiophenol (6) in the presence of BF3$OEt2
a
1
2
3
4
5
6
7
8
1
2
4
4
4
4
4
4
4
4
4
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OEt2
BF3$OMe2
AlCl3
SnCl4
ZnCl2
H2SO4
CF3SO3H
1
1
1
0.5
2
1
1
1
1
60
72
79
37
74
57
8
O
Hydroxy
+
compounds 5
or PhSH 6
Ph
H
1
Me
BF3•OEt2
Me
OR1
°
25 C, 3 h
5
3
9
10
11
32
35
68
3e: R1 = PhCH2
3b: R1 = i-Pr
3c: R1 = t-Bu
3d: R1 = Ph
1
1
3f: R1 = PhCH CH
Me
3h:
2
2
3g: R1 = BrCH2CH2
SPh
a
Reaction conditions: a-methylcinnamaldehyde (1), 0.5 mmol; CH2Cl2,
2.5 mL; 25 ꢀC, 3 h.
Determined by 1H NMR spectrum with the use of nitrobenzene as internal
standard.
b
Entry 5 or 6
5 or 6/1 BF3$OEt2/1
(mol/mol) (mol/mol)
3
NMR
yield/%b
1c
2
3
4
5
6
7
8
9
MeOH 5a
5a
i-PrOH 5b
t-BuOH 5c
PhOH 5d
PhCH2OH 5e
PhCH2CH2OH 5f 10
BrCH2CH2OH 5g 10
PhSH 6
4
10
10
10
10
10
1
10
10
10
10
10
10
10
10
3a Trace
3a 69
3b 54
In the presence of one equimolar amount of BF3$OEt2, the
treatment of a-methylcinnamaldehyde (1) with four equi-
molar amounts of HC(OMe)3 (2) afforded 1-methoxyindene
3a in a high yield (79%, Entry 3). However, the reaction was
retarded with the decrease in the amount of HC(OMe)3 (2)
(Entries 1 and 2). In addition, the use of catalytic amount
of BF3$OEt2 resulted in a lower yield of 1-methoxyindene
3a (Entry 4), while the treatment with excess amount of
BF3$OEt2 afforded 1-methoxyindene 3a in a comparative
yield (Entry 5).
3c
3d
3e
0
0
0
3f 56
3g 30
3h 59
10
a
Reaction conditions: aldehyde 1, 0.5 mmol; 25 ꢀC, 3 h.
Determined by 1H NMR spectrum with the use of nitrobenzene as internal
standard.
b
c
Reaction conditions: aldehyde 1, 0.5 mmol; CH2Cl2, 2.5 mL; 25 ꢀC, 3 h.

T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
5719
Table 3. Reaction of a-alkylcinnamaldehydes with HC(OMe)3 (2) in the
presence of BF3$OEt2
was treated with a-methylcinnamaldehyde (1) as an alterna-
tive alkoxylating agent under the same conditions as for or-
thoester 2, 1-methoxyindene 3a was slightly obtained (Entry
1). On the other hand, manipulation with excess amounts of
BF3$OEt2 and MeOH (5a) to a-methylcinnamaldehyde (1)
without solvents gave 1-alkoxyindene 3a in a good yield
(Entry 2). Furthermore, some primary alcohols 5f and 5g
(Entries 7 and 8) and secondary alcohol 5b (Entry 3) also
gave the corresponding 1-alkoxy-2-methylindenes (3f, 3g,
and 3b) under the same conditions. However, t-BuOH
(5c), phenol (5d), and benzyl alcohol (5e) did not yield
1-alkoxyindenes, which suggests that large steric hindrance
and/or the low nucleophilicity of the hydroxy compounds
prevent alkoxylation of the carbonyl group of a-methyl-
cinnamaldehyde (1) (Entries 4–6). On the other hand, the
reaction of thiophenol (6) with a-methylcinnamaldehyde
(1) gave 2-methyl-1-phenylthioindene (3h) (Entry 9). Hence,
some alcohols and thiols show lower reactivity than
orthoester, but have a sufficient potential to give indene
derivatives in this system.
a
O
BF3•OEt2
CH2Cl2
R2
Me
OMe
+ HC(OMe)3
Ar
H
2
Me
Ar¼
Entry
1
Aldehyde
Product
NMR
yield/%b
Me
OMe
4-MeOC6H4
4-MeC6H4
3-MeC6H4
9
3k Trace
MeO
Me
OMe
2
3
10
11
3l 82
Me
Me
5-Me 3m
Me
75c
7-Me 3n
OMe
Me
4
2-MeC6H4
12
3o 90
Me
OMe
2.3. Structural requirements of a-alkylcinnamaldehydes
To clarify the structural requirements of the starting alde-
hydes, simple and several substituted cinnamaldehydes
were employed for the reaction with HC(OMe)3 (2) in the
presence of BF3$OEt2 (Schemes 3 and 4). When cinnamalde-
hyde (7) was treated with HC(OMe)3 (2), indene 3i was not
obtained at all (Scheme 3). In contrast, a-ethylcinnamalde-
hyde (8) afforded the corresponding 1-alkoxyindene (3j)
(Scheme 4). Aldehydes 1 and 8 have an a-alkyl substituent
in common, which is considered to be essential for the
formation of 1-alkoxyindenes.
Me
OMe
5
6
4-ClC6H4
3-ClC6H4
4-NO2C6H4
13
14
15
3p Trace
Cl
Cl
5-Cl 3q
Me
OMe
57d
7-Cl 3r
Me
OMe
7
3s 0 (33)e
O2N
a
Reaction conditions: aldehyde, 0.5 mmol; HC(OMe)3 (2), 2 mmol;
BF3$OEt2, 0.5 mmol; CH2Cl2, 2.5 mL; 25 ꢀC, 3 h.
Determined by 1H NMR spectrum with the use of nitrobenzene as internal
standard.
b
O
BF3•OEt2
HC(OMe)3
Ph
H
+
CH2Cl2
2
c
d
e
Indene 3m:indene 3n¼59:16.
7
3i
25
°
C, 3 h
OMe
Indene 3q:indene 3r¼43:14.
Reaction was undertaken in ClCH2CH2Cl instead of CH2Cl2 at reflux.
Scheme 3.
matic ring moiety. This probably caused the side reactions
to give unknown products resulting in diminishment of the
yield of the corresponding 1-methoxyindene (3k) to a trace
amount.
O
Et
OMe
BF3•OEt2
CH2Cl2
HC(OMe)3
Ph
H
+
2
3j
70%
8
Et
°
25 C, 3 h
Scheme 4.
On the other hand, m-substituted a-methylcinnamaldehydes
11 and 14 afforded 5- and 7-substituted indenes (Entries 3
and 6). In these cases, 5-substituted ones were produced
preferentially compared to 7-substituted ones. This behavior
is probably due to the steric effect of the substituent of
aromatic ring.
Table 3 shows the results of the reaction of several a-methyl-
cinnamaldehydes that have a substituent in the aromatic
ring in the presence of BF3$OEt2 and HC(OMe)3 (2).
When methylated or m-chlorinated a-methylcinnamalde-
hydes (10–12 and 14) were allowed to react with HC(OMe)3
(2), the corresponding 1-alkoxyindenes (3l–3o, 3q, and 3r)
were obtained in high yields (Entries 2–4 and 6). In contrast,
p-methoxylated and p-chlorinated a-methylcinnamalde-
hydes (9 and 13) afforded 1-alkoxyindenes 3k and 3p,
respectively, in low yields (Entries 1 and 5). In the case of
the reaction of a-methyl-p-nitrocinnamaldehyde (15) with
HC(OMe)3 (2) at room temperature, the nitrated 1-alkoxy-
indene (3s) was not obtained, while the manipulation at
higher temperature gave 1-alkoxyindene 3s in a moderate
yield (Entry 7). p-Methoxylated aldehyde 9 is considered
to be highly active against electrophilic attack on the aro-
2.4. Reaction mechanisms
The plausiblereactionpathwayfortheformationof1-alkoxy-
indenes is elucidated on the basis of the results of the follow-
ing two experimental approaches. First is the reaction of
a partially deuterated a-methylcinnamaldehyde. Second is
the analysis of the 13C NMR spectral change of the reaction
solution.
The reaction of b-deuterated a-methylcinnamaldehyde (16)
with MeOH (5a) in the presence of BF3$OEt2 afforded

5720
T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
3-deuterio-1-methoxy-2-methylindene (3t) (Scheme 5). In
this case, 1-deuterio-1-methoxy-2-methylindene (3u) was
not obtained at all. As the cyclization proceeds via carbon–
carbon bond formation between the carbonyl carbon and the
ortho-carbon of aromatic ring, this result indicates that
the alkoxylation occurs at the carbonyl carbon of a-alkyl-
cinnamaldehyde during the formation of 1-alkoxyindenes.
In other words, this conversion does not proceed via Michael
type alkoxylation product but via acetal or its equivalent.
The results agree with the formation of 1-alkoxyindene
3a from a-methylcinnamaldehyde dimethyl acetal (4)
described in the previous section.
In addition, this result also means that the alkoxylating agent
does not attack via SN20 type displacement against the
alkoxy group in the formed 1-alkoxyindene. On the other
hand, Wadia’s group has reported that 1-chloroindenes are
formed via the reaction of a,b-unsaturated carbonyl com-
pounds with hydrogen chloride.7 In their paper, 1-chloro-
indene is proposed to be formed by SN20 attack of the
chloride ion against the hydroxy group of the indenol inter-
mediate that is formed via intramolecular electrophilic
aromatic substitution of the a,b-unsaturated carbonyl
compound. In contrast, the 1-alkoxyindenes in the trans-
formation reaction presented here are inertness against
nucleophilic substitution and the alkoxy group attached on
the indene ring retains throughout the transformation.
D
O
MeOH 5a
BF3•OEt2
Ph
H
2.5. Determination of intermediates with the aid of
NMR study of the reaction mixture
25
°
C, 3 h
16
Me
D
D
>95%-d
OMe
Me
Me
OMe
The intermediatesof thisreactionare determinedasmethoxy-
carbenium ion 17 and g-alkoxyallyl cation 18 by NMR spec-
traof reaction solutions. Figure1showsthe13C NMRspectral
change of the reaction solution of a-methylcinnamaldehyde
3t
20% >95%-d
3u
0%
Scheme 5.
Figure 1. 13C NMR spectra of the reaction solution of a-methylcinnamaldehyde (1) with HC(OMe)3 (2) and BF3$OEt2, and the related reaction solutions in
CDCl3 at rt.

T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
5721
(1) with HC(OMe)3 (2) in the presence of BF3$OEt2 and the
3. Conclusion
spectraof therelated solutions. Afteradditionofan equimolar
amount of BF3$OEt2 to the solution of a-methylcinnam-
aldehyde (1) and an equimolar amount of HC(OMe)3 (2),
a-methylcinnamaldehyde (1) and HC(OMe)3 (2) are rapidly
consumed and an intermediate and methyl formate
(HCOOMe) are generated (Fig. 1, 10 min). Then, the inter-
mediate disappears and 1-methoxy-2-methylindene (3a)
appears and increases with passage of time (Fig. 1, 10–
60 min). The intermediate has the broad signals of methoxy,
carbonyl, and two alkenyl carbons and the sharp signals of
methyl and some aromatic carbons (marked by arrows in
the spectrum). Those signals except that at around 50 ppm
due to the methoxy carbon are essentially identical to those
of the solutions of the mixture of a-methylcinnamaldehyde
(1) and BF3$OEt2 (Fig. 1). This behavior means that the
electron structure of the reaction intermediate should be a
homologue of the BF3-coordinated complex of a-methyl-
cinnamaldehyde (1). Thus, the intermediates are proposed
as methoxycarbenium ion 17 and its resonance structure as
g-methoxyallyl cation 18.
We have found the reaction of a-alkylcinnamaldehyde with
alkoxylating agents to afford 1-alkoxy-2-alkylindenes. The
scope and limitation and the reaction mechanisms have
also been elucidated. This reaction has sufficient potential
for the novel preparative synthesis of indene skeleton com-
pounds by one pot operation.
4. Experimental
4.1. General
Trimethyl orthoformate (2), alcohols 5, thiophenol (6),
boron trifluoride etherates, nitrobenzene, CH2Cl2, and
ClCH2CH2Cl were purchased and purified according to the
method in the literature.25 Other acidic mediators were em-
ployed as received. a-Alkylcinnamaldehydes were synthe-
sized by the same method as in the literature.26 Acetal 4
was synthesized by the same method as in the literature.27
Distillation of indene derivatives was carried out by Kugel-
¨
rohr distillation. Boiling point was determined by the tem-
perature of the furnace. H NMR spectra were recorded on
2.6. Plausible reaction pathway
1
The plausible pathway of the reaction of a-methylcinnam-
aldehyde (1) with alkoxylating agents to form 1-methoxy-
2-methylindene (3a) is shown in Scheme 6 on the basis of
the consideration described above. In this pathway, a-meth-
ylcinnamaldehyde (1) is transformed into the corresponding
acetal (4) through the coordination of BF3 to the carbonyl
oxygen and the nucleophilic attack of alkoxylating agent,
i.e., orthoester 2 and alcohol 5a. Then, elimination of an
alkoxide group from acetal 4 with the aid of BF3 affords the
resonancehybridofalkoxycarbeniumions17andg-methoxy-
allyl cations 18. These cations presumably produce small
amounts of the corresponding geometrical isomers. The
sterically crowded geometrical isomers thus formed are cer-
tainly liable to intramolecular electrophilic aromatic substi-
tution ring closure to yield 1-methoxy-2-methylindene (3a).
In this ring closure transformation, the a-alkyl group of
a-substituted cinnamaldehydes probably assists the forma-
tion of the precursory isomers of the alkoxycarbenium ion/
g-alkoxyallyl cation. When cinnamaldehydes have no a-alkyl
groups, formation of the sterically unfavorable geometrical
isomer is strictly prevented. In this consequence, cinnam-
aldehyde (7) does not afford 1-alkoxyindenes because of
the lack of a-alkyl group that destabilize the precursor.
a JEOL JNM-LA500 (500 MHz) or a JEOL JNM-AL300
(300 MHz) spectrometer using Me4Si (1H, d 0.00) as an in-
ternal standard. 13C NMR spectra were recorded on a JEOL
JNM-LA500 (125 MHz) or a JEOL JNM-AL300 (75 MHz)
spectrometer using CDCl3 (13C, d 77.0) as an internal stan-
dard. IR spectra were recorded on a JASCO FTIR-5300.
High-resolution mass spectra (HRMS) were recorded on
a JEOL MStation JMS-700.
4.1.1. 3-Chloro-a-methylcinnamaldehyde (14). Aldehyde
14 was synthesized from 3-chlorobenzaldehyde and propa-
nal by the same method of the literature.25 Isolated yield
50% [distillation], pale yellow oil. Bp 130–132 ꢀC
1
(10 mmHg). H NMR (300 MHz, CDCl3) d 9.59 (1H, s),
7.50 (1H, s), 7.34–7.45 (3H, m), 7.20 (1H, s), 2.07 (3H,
s) ppm. 13C NMR (75 MHz, CDCl3) d 195.2, 147.8, 139.4,
136.7, 134.6, 129.9, 129.6, 129.4, 127.9, 10.9 ppm. IR
(neat) n 1675, 1630, 1606, 1450, 1114, 900 cmꢁ1. Anal.
Calcd for C10H9ClO: C, 66.49; H, 5.02. Found: C, 66.64;
H, 4.97.
4.2. Typical procedure for the reaction of a-alkylcinnam-
aldehyde with alkoxylating agent in the presence of
acidic mediator
OMe
O
HC(OMe)3 2 or MeOH 5a
BF3•OEt2
OMe
H
Method A: BF3$OEt2 (0.5 mmol, 0.071 g) was added to
the solution of a-alkylcinnamaldehyde (0.5 mmol) and
HC(OMe)3 (2 mmol, 0.21 g) in CH2Cl2 (2.5 mL) and stir-
ring at 25 ꢀC for 3 h. The solution was quenched with water
(20 mL) and extracted with CH2Cl2 (20 mLꢂ3). The com-
bined extracts were washed with saturated aqueous NaCl
(15 mLꢂ3), dried over Na2SO4, filtered, and concentrated
under reduced pressure.
Me
Me
1
4
BF3
BF3OMe
−
OMe
OMe
Me
Me
17
18
Method B: BF3$OEt2 (5 mmol, 0.710 g) was added to the
mixture of a-alkylcinnamaldehyde (0.5 mmol) and alkoxy-
lating agent (5 mmol) and stirring at 25 ꢀC for 3 h. The
solution was quenched with water (20 mL) and extracted
with CH2Cl2 (20 mLꢂ3). The combined extracts were
Me
− H
Me
OMe
Me
OMe
H
3a
OMe
18
Scheme 6.

5722
T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
washed with saturated aqueous NaCl (15 mLꢂ3), dried
over Na2SO4, filtered, and concentrated under reduced
pressure.
1583, 1477, 1377, 1024, 750, 700 cmꢁ1. HRMS m/z (EI)
calcd for C16H14S (M)+ 238.0816, found 238.0790.
4.2.6. 2-Ethyl-1-methoxyindene (3j).21 Isolated yield 48%
[method A, column chromatography (silica gel, hexane/
ethyl acetate¼5:1 v/v) and distillation], pale yellow oil.
4.2.1. 1-Methoxy-2-methylindene (3a).17,21 Isolated yield
45% [method A, silica gel column chromatography (hexane/
ethyl acetate¼5:1 v/v) and distillation], pale yellow oil. Bp
1
Bp 100–102 ꢀC (8 mmHg). H NMR (300 MHz, CDCl3)
1
92–94 ꢀC (8 mmHg). H NMR (500 MHz, CDCl3) d 7.42
d 7.42 (1H, d, J¼7.2 Hz), 7.23 (1H, t, J¼7.5 Hz), 7.14
(1H, d, J¼7.5 Hz), 7.12 (1H, t, J¼7.5 Hz), 6.46 (1H, s),
4.95 (1H, s), 3.07 (3H, s), 2.25–2.50 (2H, m), 1.21
(3H, t, J¼6.6 Hz) ppm. 13C NMR (75 MHz, CDCl3) d
152.1, 143.8, 141.8, 128.4, 126.7, 124.6, 123.8, 120.3,
83.8, 51.8, 21.5, 12.4 ppm. IR (KBr) n 1722, 1618,
1460, 1319, 1203, 1103, 1082, 752, 734 cmꢁ1. HRMS
m/z (EI) calcd for C12H13O (MꢁH)+ 173.0966, found
173.0925.
(1H, d, J¼7.5 Hz), 7.23 (1H, t, J¼7.5 Hz), 7.14 (1H, d,
J¼7.5 Hz), 7.12 (1H, t, J¼7.5 Hz), 6.45 (1H, s), 4.86 (1H,
s), 3.05 (3H, s), 2.03 (3H, s) ppm. 13C NMR (125 MHz,
CDCl3) d 145.8, 143.8, 141.7, 128.7, 128.3, 124.6, 123.7,
120.1, 84.8, 51.8, 14.1 ppm. IR (neat) n 1720, 1626, 1606,
1464, 1373, 1321, 1207, 1107, 1080, 752 cmꢁ1. HRMS
m/z (EI) calcd for C11H11O (MꢁH)+ 159.0810, found
159.0766.
4.2.2. 1-Isopropoxy-2-methylindene (3b). Isolated yield
34% [method B, silica gel column chromatography (toluene)
and distillation], pale yellow oil. Bp 110–113 ꢀC (8 mmHg).
1H NMR (300 MHz, CDCl3) d 7.40 (1H, d, J¼7.2 Hz), 7.18
(1H, t, J¼7.2 Hz), 7.05–7.08 (2H, m), 6.34 (1H, s), 4.79 (1H,
s), 3.78 (1H, sept, J¼6.0 Hz), 2.04 (3H, s), 1.24 (3H, d,
J¼6.0 Hz), 1.18 (3H, d, J¼6.0 Hz) ppm. 13C NMR
(75 MHz, CDCl3) d 147.0, 143.8, 143.1, 127.9, 127.2,
124.3, 123.3, 119.8, 83.4, 70.2, 23.4, 23.2, 14.1 ppm. IR
(KBr) n 1720, 1618, 1460, 1381, 1302, 1107, 1070, 750,
702 cmꢁ1. HRMS m/z (EI) calcd for C13H16O (M)+
188.1201, found 188.1201.
4.2.7. 1-Methoxy-2,6-dimethylindene (3l). Isolated yield
38% [method A, column chromatography (silica gel, hex-
ane/ethyl acetate¼5:1 v/v) and distillation], pale yellow
oil. Bp 99–102 ꢀC (8 mmHg). 1H NMR (300 MHz,
CDCl3) d 7.10–7.15 (2H, m), 7.00 (1H, s), 6.39 (1H, s),
4.82 (1H, s), 3.03 (3H, s), 2.32 (3H, s), 2.00 (3H, s) ppm.
13C NMR (75 MHz, CDCl3) d 144.7, 142.1, 137.1, 136.8,
128.9, 128.8, 124.8, 119.7, 84.8, 51.8, 21.4, 14.0 ppm. IR
(neat) n 1722, 1610, 1512, 1450, 1377, 1091, 817 cmꢁ1
.
HRMS m/z (EI) calcd for C12H14O (M)+ 174.1046, found
174.1012.
4.2.8. 1-Methoxy-2,5-dimethylindene (3m). Isolated yield
25% [method A, column chromatography (silica gel, tolu-
ene) and distillation], pale yellow oil. Bp 103–106 ꢀC
4.2.3. 2-Methyl-1-(2-phenylethoxy)indene (3f). Isolated
yield 34% [method B, silica gel column chromatography
(toluene) and distillation], yellow oil. Bp 140–145 ꢀC
1
(8 mmHg). H NMR (300 MHz, CDCl3) d 7.29 (1H, d,
1
(6 mmHg). H NMR (300 MHz, CDCl3) d 7.05–7.30 (9H,
J¼7.5 Hz), 6.96 (1H, s), 6.93 (1H, d, J¼7.5 Hz), 6.39 (1H,
s), 4.83 (1H, s), 3.02 (3H, s), 2.37 (3H, s), 2.02 (3H,
s) ppm. 13C NMR (75 MHz, CDCl3) d 146.0, 144.1, 138.8,
138.1, 128.6, 125.2, 123.5, 121.1, 84.6, 51.6, 21.5,
14.1 ppm. IR (neat) n 1724, 1608, 1462, 1379, 1265, 1120,
808 cmꢁ1. HRMS m/z (EI) calcd for C12H14O (M)+
174.1046, found 174.1012.
m), 6.38 (1H, s), 4.86 (1H, s), 3.53 (2H, t, J¼7.5 Hz), 2.83
(2H, t, J¼7.5 Hz), 1.92 (3H, s) ppm. 13C NMR (75 MHz,
CDCl3) d 146.1, 143.6, 142.1, 139.0, 128.9, 128.8, 128.3,
128.2, 126.1, 124.5, 123.6, 120.0, 84.4, 65.3, 36.7,
14.0 ppm. IR (KBr) n 1722, 1602, 1454, 1282, 1078, 750,
700 cmꢁ1. HRMS m/z (EI) calcd for C18H18O (M)+
250.1358, found 250.1286.
4.2.9. 1-Methoxy-2,7-dimethylindene (3n). Isolated yield
8% [method A, column chromatography (silica gel, toluene)
and distillation], colorless oil. Bp 101–102 ꢀC (8 mmHg).
1H NMR (300 MHz, CDCl3) d 7.34 (1H, t, J¼7.5 Hz),
7.14 (1H, t, J¼7.5 Hz), 6.95 (1H, d, J¼7.5 Hz), 6.90 (1H,
d, J¼7.5 Hz), 6.43 (1H, s), 4.93 (1H, s), 2.91 (3H, s), 2.39
(3H, s), 2.02 (3H, s) ppm. 13C NMR (75 MHz, CDCl3)
d 145.2, 139.0, 134.7, 133.5, 128.8, 128.6, 126.5, 117.6,
84.4, 50.4, 22.6, 14.0 ppm. IR (neat) n 1724, 1608, 1448,
1277, 1087, 825, 704 cmꢁ1. HRMS m/z (EI) calcd for
C12H14O (M)+ 174.1046, found 174.1052.
4.2.4. 1-(2-Bromoethoxy)-2-methylindene (3g). Isolated
yield 15% [method B, silica gel column chromatography
(toluene) and distillation], yellow oil. Bp 123–127 ꢀC
1
(6 mmHg). H NMR (300 MHz, CDCl3) d 7.43 (1H, d,
J¼6.9 Hz), 7.24 (1H, t, J¼6.9 Hz), 7.10–7.15 (2H, m),
6.45 (1H, s), 4.98 (1H, s), 3.40–3.53 (4H, m), 2.07 (3H,
s) ppm. 13C NMR (75 MHz, CDCl3) d 145.3, 143.5, 141.5,
128.9, 128.6, 124.8, 123.7, 120.2, 84.3, 64.1, 31.3,
14.1 ppm. IR (KBr) n 1722, 1601, 1460, 1379, 1277, 1109,
754 cmꢁ1. HRMS m/z (EI) calcd for C12H13BrO (M)+
252.0150, found 252.0900.
4.2.10. 1-Methoxy-2,4-dimethylindene (3o). Isolated yield
50% [method A, column chromatography (silica gel, tolu-
ene) and distillation], pale yellow oil. Bp 104–108 ꢀC
4.2.5. 2-Methyl-1-phenylthioindene (3h). Isolated yield
41% [method B, silica gel column chromatography (toluene)
and distillation], pale yellow oil. Bp 138–142 ꢀC (6 mmHg).
1H NMR (300 MHz, CDCl3) d 7.48 (1H, d, J¼7.5 Hz), 7.44
(1H, d, J¼7.5 Hz), 7.27 (1H, t, J¼7.5 Hz), 7.19 (1H, t,
J¼7.5 Hz), 7.05–7.16 (5H, m), 6.36 (1H, s), 4.43 (1H, s),
2.17 (3H, s) ppm. 13C NMR (75 MHz, CDCl3) d 145.9,
144.9, 143.7, 132.8, 132.5, 128.3, 128.2, 127.4, 127.3,
124.4, 123.9, 120.1, 56.3, 15.0 ppm. IR (KBr) n 1720,
1
(8 mmHg). H NMR (300 MHz, CDCl3) d 7.05–7.20 (3H,
m), 6.55 (1H, s), 4.85 (1H, s), 3.03 (3H, s), 2.33 (3H, s),
2.04 (3H, s) ppm. 13C NMR (75 MHz, CDCl3) d 145.1,
142.4, 141.7, 141.6, 129.6, 126.8, 124.6, 121.2, 85.1, 51.7,
18.0, 14.1 ppm. IR (neat) n 1720, 1601, 1448, 1099,
761 cmꢁ1. HRMS m/z (EI) calcd for C12H14O (M)+
174.1046, found 174.1012.

T. Jobashi et al. / Tetrahedron 62 (2006) 5717–5724
5723
Katzenellenbogen, J. A. J. Med. Chem. 1989, 32, 2163–2171;
(d) Watanabe, N.; Ikeno, A.; Minato, H.; Nakagawa, H.;
Kohayakawa, C.; Tsuji, J. J. Med. Chem. 2003, 46, 3961–3964.
2. Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Mura-
kami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno,
M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani,
M. J. Med. Chem. 1996, 39, 3636–3658.
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Chem. 1998, 41, 2175–2179.
4. Reggio, P. H.; Basu-Dutt, S.; Barnett-Norris, J.; Castro, M. T.;
Hurst, D. P.; Seltzman, H. H.; Roche, M. J.; Gilliam, A. F.;
Thomas, B. F.; Stevenson, L. A.; Pertwee, R. G.; Abood,
M. E. J. Med. Chem. 1998, 41, 5177–5187.
5. Clive, D. L. J.; Yu, M. Chem. Commun. 2002, 2380–2381.
6. (a) Koo, J. J. Am. Chem. Soc. 1953, 75, 2000–2001; (b) Saito,
S.; Sato, Y.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1994,
116, 2312–2317.
7. Karmarkar, P. G.; Chinchore, V. R.; Wadia, M. S. Synthesis
1981, 228–229.
8. Roussel, C.; Rajoharison, H. G.; Bizzari, L.; Shaimi, L. J. Org.
Chem. 1988, 53, 683–685.
9. Canevet, J. C.; Graff, V. Tetrahedron 1978, 34, 1935–1942.
10. (a) Olah, G. A.; Asensio, G.; Mayr, H. J. Org. Chem. 1978, 43,
1518–1520; (b) Anke, L.; Weyerstahl, P. Chem. Ber. 1985, 118,
613–619.
4.2.11. 5-Chloro-1-methoxy-2-methylindene (3q). Iso-
lated yield 19% [method A, column chromatography (silica
gel, toluene) and recrystallization (hexane)], colorless nee-
1
dle. Mp 32.5–34 ꢀC. H NMR (300 MHz, CDCl3) d 7.31
(1H, d, J¼7.2 Hz), 7.10 (1H, s), 7.08 (1H, d, J¼7.2 Hz),
6.39 (1H, s), 4.82 (1H, s), 3.02 (3H, s), 2.03 (3H, s) ppm.
13C NMR (75 MHz, CDCl3) d 147.9, 145.5, 139.9, 134.2,
127.8, 124.5, 124.4, 120.5, 84.2, 51.8, 14.1 ppm. IR (KBr)
n 1724, 1601, 1460, 1278, 1103, 898, 823, 698 cmꢁ1
.
HRMS m/z (EI) calcd for C11H10ClO (MꢁH)+ 193.0420,
found 193.0376. Anal. Calcd for C11H11ClO: C, 67.87; H,
5.70. Found: C, 67.66; H, 5.77.
4.2.12. 7-Chloro-1-methoxy-2-methylindene (3r). Isolated
yield 5% [method A, column chromatography (silica gel,
1
toluene)], pale yellow oil. Bp 115–118 ꢀC (8 mmHg). H
NMR (300 MHz, CDCl3) d 7.17 (1H, t, J¼8.1 Hz), 7.05
(1H, d, J¼8.1 Hz), 7.01 (1H, d, J¼8.1 Hz), 6.41 (1H, s),
4.97 (1H, s), 3.01 (3H, s), 2.03 (3H, s) ppm. 13C NMR
(75 MHz, CDCl3) d 146.9, 146.0, 142.1, 138.0, 130.2,
127.9, 125.5, 118.5, 88.4, 51.5, 13.9 ppm. IR (KBr) n
1730, 1601, 1458, 1280, 790, 758, 702 cmꢁ1. HRMS m/z
(EI) calcd for C11H11ClO (M)+ 194.0498, found 194.0470.
4.2.13. 1-Methoxy-2-methyl-6-nitroindene (3s). Isolated
yield 10% [method A, column chromatography (silica gel,
toluene) and distillation], yellow oil. Bp 120–123 ꢀC
11. Singh, G.; Ila, H.; Junjappa, H. Synthesis 1986, 744–747.
12. (a) Padwa, A.; Blacklock, T. J.; Loza, R. J. Am. Chem. Soc.
1981, 103, 2404–2405; (b) Padwa, A.; Blacklock, T. J.; Loza,
R. J. Org. Chem. 1982, 47, 3712–3721; (c) Steinmetz, M. G.;
Meyes, R. T. J. Am. Chem. Soc. 1985, 107, 2111–2121.
13. (a) Liebeskind, L. S.; Gasdaska, J. R.; McCallum, J. S.;
Tremont, S. J. J. Org. Chem. 1989, 54, 669–677; (b) Quan,
L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc. 1999,
121, 3545–3546; (c) Gevorgyan, V.; Quan, L. G.; Yamamoto,
Y. Tetrahedron Lett. 1999, 40, 4089–4092; (d) Vicente, J.;
1
(8 mmHg). H NMR (300 MHz, CDCl3) d 8.23 (1H, s),
8.20 (1H, d, J¼8.1 Hz), 7.24 (1H, d, J¼8.1 Hz), 6.55 (1H,
s), 4.91 (1H, s), 3.12 (3H, s), 2.13 (3H, s) ppm. 13C NMR
(75 MHz, CDCl3) d 151.4, 147.7, 147.3, 142.8, 129.4,
123.8, 123.6, 119.7, 83.2, 51.8, 12.5 ppm. IR (neat)
n 1725, 1602, 1456, 1375, 1086, 812 cmꢁ1. HRMS m/z
(EI) calcd for C11H11NO3 (M)+ 205.0739, found 205.0725.
4.2.14. 3-Deuterio-1-methoxy-2-methylindene (3t).21 Iso-
lated yield 8% [method B, column chromatography (silica
gel, hexane/ethyl acetate¼5:1 v/v) and distillation], pale
´
´
´
Abad, J.-A.; Lopez-Pelaez, B.; Martınez-Viviente, E. Organo-
metallics 2002, 21, 58–67; (e) Rayabarapu, D. K.; Yang, C.-H.;
Cheng, C.-H. J. Org. Chem. 2003, 68, 6726–6731.
14. (a) Shintani, R.; Okamura, K.; Hayashi, T. Chem. Lett. 2005,
34, 1294–1295; (b) Matsuda, T.; Makino, M.; Murakami, M.
Chem. Lett. 2005, 34, 1416–1417.
1
yellow oil. Bp 93–96 ꢀC (7 mmHg). H NMR (300 MHz,
CDCl3) d 7.42 (1H, d, J¼7.5 Hz), 7.23 (1H, t, J¼7.5 Hz),
7.14 (1H, d, J¼7.5 Hz), 7.12 (1H, t, J¼7.5 Hz), 4.86 (1H,
s), 3.05 (3H, s), 2.03 (3H, s) ppm. 13C NMR (75 MHz,
CDCl3) d 145.7, 143.8, 141.8, 128.6 (t, JCD¼28 Hz),
128.3, 124.6, 123.7, 120.1, 84.8, 51.7, 14.0 ppm. IR (KBr)
n 1720, 1626, 1606, 1464, 1373, 1321, 1207, 1107, 1080,
752 cmꢁ1. HRMS m/z (EI) calcd for C11H11DO (M)+
161.0951, found 161.0925.
15. (a) Halterman, R. L.; Zhu, C. Tetrahedron Lett. 1999, 40, 7445–
7448; (b) Xi, Z.; Guo, R.; Mito, S.; Yan, H.; Kanno, K.;
Nakajima, K.; Takahashi, T. J. Org. Chem. 2002, 68, 1252–
1257.
16. (a) Lautens, M.; Mancuso, J. Org. Lett. 2002, 4, 2105–2108; (b)
Lautens, M.; Mancuso, J. J. Org. Chem. 2004, 69, 3478–3487;
(c) Lautens, M.; Marquardt, T. J. Org. Chem. 2004, 69, 4607–
4614.
Acknowledgements
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Pincock, J. A. Can. J. Chem. 1988, 66, 2888–2893; (b) Pin-
cock, J. A.; Young, I. S. Can. J. Chem. 2003, 81, 1083–1095.
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We acknowledge Central Glass Co., Ltd for providing us
triflic acid.
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