Dehydrogenative nucleophilic addition of aliphatic ether to benzaldehyde dimethyl acetal mediated by ether-boron trifluoride (1/1) affording 1-alkoxy-2-alkylindenes or α,β-unsaturated carbonyl compounds specifically

Article abstract of DOI:10.1246/bcsj.79.627

The R₂O·BF₃-mediated dehydrogenative crossed aldol condensation reaction of acyclic aliphatic ethers with benzaldehyde dimethyl acetal to give specifically indene derivatives or α,β- unsaturated carbonyl compounds has been found. When the ethers have bis(β-alkylethyl) ether structures, dehydrogenative formation of enol ether equivalents followed by successive crossed aldol addition to acetal-originated electrophile and intramolecular electrophilic aromatic substitution reactions give annulation products of 1-alkoxy-2-alkylindenes. When the ether has two β- and one or more α-hydrogens, α,β-unsaturated carbonyl compounds are obtained. The structural correlation between deuterated starting materials and the obtained products, the structural requirements for ethers, and the distinct substrate specificity have revealed the reaction routes and mechanisms.

Full text of DOI:10.1246/bcsj.79.627

Ó 2006 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 79, No. 4, 627–633 (2006)
627
Dehydrogenative Nucleophilic Addition of Aliphatic Ether
to Benzaldehyde Dimethyl Acetal Mediated by Ether–Boron
Trifluoride (1/1) Affording 1-Alkoxy-2-alkylindenes
or ꢀ,ꢁ-Unsaturated Carbonyl Compounds Specifically
Takashi Jobashi,1 Katsuya Maeyama,1 Keiichi Noguchi,2
ꢀ1
Yasuhiko Yoshida,3 and Noriyuki Yonezawa
1Department of Organic and Polymer Materials Chemistry, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-8588
2Instrumentation Analysis Center, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-8588
3Department of Applied Chemistry, Graduate School of Engineering, Toyo University,
2100 Kujirai, Kawagoe 350-8585
Received October 11, 2005; E-mail: yonezawa@cc.tuat.ac.jp
The R2O BF3-mediated dehydrogenative crossed aldol condensation reaction of acyclic aliphatic ethers with benz-
ꢁ
aldehyde dimethyl acetal to give specifically indene derivatives or ꢀ,ꢁ-unsaturated carbonyl compounds has been found.
When the ethers have bis(ꢁ-alkylethyl) ether structures, dehydrogenative formation of enol ether equivalents followed
by successive crossed aldol addition to acetal-originated electrophile and intramolecular electrophilic aromatic substitu-
tion reactions give annulation products of 1-alkoxy-2-alkylindenes. When the ether has two ꢁ- and one or more ꢀ-hydro-
gens, ꢀ,ꢁ-unsaturated carbonyl compounds are obtained. The structural correlation between deuterated starting materials
and the obtained products, the structural requirements for ethers, and the distinct substrate specificity have revealed the
reaction routes and mechanisms.
We have been investigating the acid-mediated decarbonyl-
ative diarylation reaction of ꢀ-alkoxy- and ꢀ-oxocarboxylic
acids, where the ꢀ-carbon of the carboxylic acids act as equiv-
alents of those of highly activated aldehydes or ketones.1
During the course of the investigation, we have unexpectedly
found that diethyl ether (Et2O, 2a) reacts with benzaldehyde
that some aliphatic ethers yield similarly ꢀ,ꢁ-unsaturated
carbonyl compounds. A part of the results have been reported
preliminarily.2 Recently, we have found that the reaction of
dipropyl ether [(n-Pr)2O, 2d] with acetal 1 affords a pair of
annulation products, 1-methoxy-2-methylindene (6a)3 and 2-
methyl-1-propoxyindene (7a), in place of ꢀ,ꢁ-unsaturated car-
bonyl compounds (Scheme 1, Route 2). We have ascertained
that several ethers also undergo this unique annulation. The
production of indene derivatives 6 and 7, and ꢀ,ꢁ-unsaturated
carbonyl compound 3 from ethers accompanies distinct speci-
ficity.
In this paper, we wish to report and discuss the overall reac-
tion behavior, the structural requirements, and the reaction
mechanisms in the specific transformation of aliphatic ethers
with benzaldehyde dimethyl acetal into indene derivatives
and ꢀ,ꢁ-unsaturated carbonyl compounds.
dimethyl acetal (1) in the presence of Me2O BF3 to afford cin-
namaldehyde (3a) (Scheme 1, Route 1). We have ascertained
ꢁ
H2
2a
2 O
OMe
OMe
O
Me2O•BF3
Ph
OMe
H
Ph
1
Route 1
3a
OH
+
+
Ph
Ph
4
5
Results and Discussion
The Reaction Behaviors of Aliphatic Ethers 2 with Benz-
aldehyde Dimethyl Acetal (1) in the Presence of Me O
2 O
H2
Me2O•BF3
2d
Á
acetal (1) with/without Et2O (2a) in the presence of R2O BF3
2
Me
Me
7a OPr
+
BF3. The results of the reaction of benzaldehyde dimethyl
ꢁ
6a
OMe
Route 2
are shown in Table 1.
The reaction of acetal 1 with Et2O (2a) in the presence of
+
4 + 5
Me2O BF3 afforded cinnamaldehyde (3a) and benzyl methyl
ether (4) with the evolution of H2 (Entry 1). On the other hand,
ꢁ
Scheme 1.
Published on the web April 7, 2006; DOI: 10.1246/bcsj.79.627

628 Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
Dehydrogenative Nucleophilic Addn. of Ether
benzaldehyde (8) did not react with Et2O (2a) (Entry 2). Fur-
thermore, the reaction of benzaldehyde dimethyl acetal (1)
on the condition that benzaldehyde dimethyl acetal (1) and
Me2O BF3 are present. The existence of acetal is apparently
crucial to accomplish this transformation.
Table 2 shows the results of the reaction of several aliphatic
ethers 2 with benzaldehyde dimethyl acetal (1) in the presence
ꢁ
with Me2O BF3 in the absence of Et2O (2a) gave no adducts
(Entry 3). In contrast, acetal 1 reacted with Et2O BF3 yielding
ꢁ
ꢁ
cinnamaldehyde (3a) without the addition of Et2O (2a). Con-
sequently, Et2O (2a) is proved to form cinnamaldehyde (3a)
of Me2O BF3.
ꢁ
When Et2O (2a), diisopropyl ether [(i-Pr)2O, 2b], or methyl
1-phenylethyl ether (2c) was allowed to react with acetal 1,
ꢀ,ꢁ-unsaturated carbonyl compounds 3a–3c were formed with
the evolution of H2. At the same time, formation of benzyl
methyl ether (4) and/or benzyl alcohol (5) was observed
(Entries 1–3).2
Table 1. Reaction of Benzaldehyde Dimethyl Acetal (1)
with/without Et2O (2a) in the Presence of R2O BF3
2
;a)
ꢁ
Et2O 2a
R2O•BF3
H2
O
OMe
OMe
OMe
+
Ph
H
Ph
Ph
1
In contrast to the production of ꢀ,ꢁ-unsaturated carbonyl
compounds 3, some kinds of ethers have been found to yield
annulated products specifically under the same conditions.
As shown in Entries 4–6 of Table 2, the treatment of (n-Pr)2O
(2d), dibutyl ether [(n-Bu)2O, 2e], or diisopentyl ether (2f)
with acetal 1 did not yield ꢀ,ꢁ-unsaturated carbonyl com-
pounds 3. Instead, mixtures of pairs of homologues of indene
derivatives, i.e. 1-methoxyindenes 6 and 1-(ꢁ-alkylethoxy)-
indenes 7, were obtained. In these reactions, H2 was formed
with benzyl methyl ether (4) and benzyl alcohol (5). Unlike
the reaction of the acyclic ethers, treatment of THF (2g) with
acetal 1 did not give ꢀ,ꢁ-unsaturated carbonyl compounds 3 or
indene derivatives 6 and 7 (Entry 7).
3a
4
Product
distribution/%cÞ
Acetal or 2a/
equivalent mmol
bÞ
Entry
R2O BF3 H2
ꢁ
3a
4
8
1
2
3
4
1
PhCHO (8) 20 Me2O BF3
20 Me2O BF3
þ
12
—
—
43
16
—
2
72
100
98
ꢁ
ꢂ
ꢁ
1
1
0
0
Me2O BF3
Et2O BF3
ꢂ
ꢁ
þ
40
17
ꢁ
a) Reaction conditions: acetal 1 or benzaldehyde (8), 2 mmol;
R2O BF3, 12 mmol; CH2Cl2, 20 mL; 25 ꢃC, 3 h, under a N2
atmosphere. b) Evolution of H2 was confirmed by gas detector
tube; GASTEC Corporation, Gas Detector Tube No. 30; sign
plus denotes evolution of H2 and minus denotes not. c) Calcu-
ꢁ
The formation of the indene skeleton has been confirmed
by the X-ray crystal structure determination of 1,2-dibromo-
1
lated on the basis of H NMR spectrum.
aÞ
Table 2. Reaction of Aliphatic Ethers 2 with Benzaldehyde Dimethyl Acetal (1) in the Presence of Me2O BF3
ꢁ
Product distribution/%cÞ
bÞ
Entry
12
Ether 2
H2
ꢀ,ꢁ-Unsaturated carbonyl compounds or indene derivatives
4
5
8
O
O
2O
2a
þ
19
9
52
12
8
Ph
H
Ph
H
3a'
3a
O
22
þ
31
8
2
59
Ph
Ph
O
2b2
3b
O
32;d)
þ
þ
þ
þ
ꢂ
27
14
34
18
35
24
0
10
11
5
59
9
Ph
O
Ph
Ph
2c
3c
31
Me
Me
OMe
O
16
20
11
4
2d 2
2e
7a
6a
6b
6c
MeCH2CH2O
Et
O
Et
OMe
2
5
45
33
6
EtCH2CH2O 7b
iPr
iPr
OMe
6
16
76
O
2
iPrCH2CH2O
7c
2f
O
72
—
0
2g
a) Reaction conditions: benzaldehyde dimethyl acetal (1), 0.5 mmol; ether 2, 5 mmol; Me2O BF3, 3 mmol; 25 ꢃC, 3 h,
ꢁ
in the N2 atmosphere. b) Evolution of H2 was confirmed by gas detector tube; GASTEC Corporation, Gas Detector
Tube No. 30; sign plus denotes evolution of H2 and minus denotes not. c) Calculated on the basis of 1H NMR spectrum.
d) CH2Cl2 (5 mL) was added as solvent.

T. Jobashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
629
OMe
Me2O•BF3
D
+
2b
Ph
OMe
12
>95%-d
O
D
O
D
+
11
+
Ph
D
Ph
Ph
13
14
Fig. 1. X-ray crystal structure of 1,2-dibromo-3-methoxy-
2-methylindane (9).
40%
34%
>95%-d
26%
>95%-d
>95%-d
Scheme 3.
OMe
Me2O•BF3
H
D
R2
3b +
+ 8
18%
R2
1 +
Ph
D
11
38%
>95%-d
R1
R'
2 O
R1
10
>95%-d
44%
O
15
O
2
2
R' = CHR2CH2R1
Scheme 2.
Scheme 4.
3-methoxy-2-methylindane (9), which was obtained as the
dibrominated adduct of one of the products in the reaction of
(n-Pr)2O (2d) with acetal 1 (Fig. 1).
OMe
OMe
15
There have been several reports on the preparation of indene
derivatives.4–7 However, formation of 1-alkoxyindenes by an-
nulation between acetal and ether has never been reported.
The Reaction Mechanisms of the Dehydrogenative
Transformation of Aliphatic Ethers into Enol Ether Equiv-
alents. As described above, distinct specificity is observed in
the formation reaction of 1-alkoxy-2-alkylindenes 6 and 7 or
ꢀ,ꢁ-unsaturated carbonyl compounds 3 from aliphatic ethers
2 and benzaldehyde dimethyl acetal (1). In the first place,
the acyclic ether structure is required to form these products.
When the alkyl group of the ether has a bis(ꢁ-alkylethyl) ether
skeleton [(R1CH2CH2)2O], 1-alkoxyindene derivatives 6 and 7
are obtained predominantly. On the other hand, Et2O (2a) or
ꢀ-substituted ethyl ethers 2b and 2c gave ꢀ,ꢁ-unsaturated car-
Ph
Ph
OMe
Ph
1
16
R'
Indene derivatives 6/7
or
OMe O
α,β-Unsaturated
R2
carbonyl compounds 3
R1
17
Scheme 5.
ether (11) (Scheme 2). This result indicates that the ꢀ-hydro-
gen (deuterium) of the ethers is oxidatively eliminated as a
hydride (deuteride), and a part of the hydrides (deuterides)
react with acetal 1 to form benzyl methyl ether (4 and 11).
In addition, when ꢀ-deuterated acetal 12 was allowed to
react with ether 2b, a ꢁ-deuterated ꢀ,ꢁ-unsaturated carbonyl
compound 13 and ꢀ-monodeuterated benzyl methyl ether
(11) were obtained (Scheme 3). This result shows that the
hydride source in this reaction is ether 2b. The ꢀ-hydrogen
of the acetal does not function as a hydride source in contrast
to the acid-mediated Cannizzaro reaction.9
Consequently, saturated aliphatic ethers 2 are certainly trans-
formed dehydrogenatively into enol ether equivalent species
like structure 15 (Scheme 4). The enol ether equivalent readily
reacts with the electrophiles such as alkoxycarbenium ion 16
to afford 1-alkoxy-2-alkylindenes 6 and 7, or ꢀ,ꢁ-unsaturated
carbonyl compounds 3 via precursors 17 (Scheme 5).
For the dehydrogenative transformation of aliphatic ethers
to enol ether equivalents depicted in Scheme 4, there are two
possible routes (Scheme 6). One is the hydride abstraction from
ether 2 by alkoxycarbenium ion 16, followed by proton release
giving benzyl methyl ether (4) and an enol ether equivalent
species (Route 1). The other is the hydride abstraction by dis-
sociated free BF3 followed by proton release (Route 2).
Because the evolution of H2 indicates that the reaction of a
hydride and a proton advances in this system, direct capture of
hydride from alkyl ether 2 by alkoxycarbenium ion 16 to give
benzyl methyl ether (4) shown in Route 1 (Scheme 6) is incon-
bonyl compounds 3 in the Me2O BF3-mediated reaction with
acetal 1.
ꢁ
ꢀ,ꢁ-Unsaturated carbonyl compounds are generally synthe-
sized by crossed aldol-type condensations. Actually, treatment
of benzaldehyde dialkyl acetals with vinyl ethers in the pres-
ence of Lewis acids affords cinnamaldehyde homologues.8
Consequently, the formation of ꢀ,ꢁ-unsaturated carbonyl com-
pounds 3a–3c from acetal 1 and aliphatic ethers 2a–2c indi-
cates that ethers are oxidized to enol ether equivalents in the
early stages of this transformation system. In this course, H2,
benzyl methyl ether (4), and benzyl alcohol (5) are surely
yielded by the action of hydride species formed in this oxida-
tion step. As formation of indene derivatives from ethers ac-
companies the evolution of H2, and the formation of benzyl
methyl ether (4) and benzyl alcohol (5), indene derivatives
are yielded presumably via at least a partially common reac-
tion pathway, i.e. oxidative transformation of ethers into enol
ether equivalents.
The proposed mechanism is supported by the results of the
reaction of deuterated substrates. The Me2O BF3-mediated
ꢁ
reaction of ꢀ-deuterated diisopropyl ether [bis(1-deuterio-1-
methylethyl) ether, 10] with acetal 1 in the presence of Me2O
BF3 has been found to afford a non-deuterated ꢀ,ꢁ-unsaturated
carbonyl compound 3b and ꢀ-monodeuterated benzyl methyl
ꢁ

630 Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
Dehydrogenative Nucleophilic Addn. of Ether
D
D
2d
Me2O•BF3
R2
OMe
D
OMe
− 4
Route 1
+
Me
Me
R1
R'
Ph 16
Ph
OMe
O
12
19
20
OMe
OPr
9%
>95%-d
>95%-d
R2
H
27%
>95%-d
R1
− H
BF3
D
OR'
OR'
Me
OH
2
H
+
+
+
+
11
32%
14
18
MeO−BF3
Ph
D
22
11%
21
0%
Route 2
R2
21%
>95%-d >95%-d >95%-d
R1
R'
− Hydride complex
− MeOH•BF3
O
Scheme 7.
15
Scheme 6.
indenes 21. Therefore, the 1-positioned carbons of the indene
rings in compounds 6 and 7 surely originate in the ꢀ-carbon of
the employed ether. Consequently, the methoxy group on the
1-positioned carbon of the indene ring in products 6a–6c nec-
essarily originates in the methoxy group of acetal 1. Further-
more, the reaction behavior of ꢀ-deuterated benzaldehyde di-
methyl acetal (12) also indicates that the interchange of the
alkoxy group occurs during the generation of the indene ring
structure and that the SN20-type interchange of the alkoxy
groups never occurs after formation of the indene skeletons.
The Reaction Pathway of the Specific Formation of 1-
Alkoxy-2-alkylindenes or ꢀ,ꢁ-Unsaturated Carbonyl Com-
pounds. On the basis of the reaction behaviors described
above, the interpreted reaction pathway for formation of 1-
alkoxy-2-alkylindenes 6 and 7, and ꢀ,ꢁ-unsaturated carbonyl
compounds 3 from acyclic ether 2 and acetal 1 is demonstrated
in Scheme 8.
sistent with the formation of H2. In addition, if the reaction
proceeded via Route 1, the sum of benzyl methyl ether (4) and
benzyl alcohol (5) should be always larger than the amount of
1-alkoxy-2-alkylindenes 6 and 7 or ꢀ,ꢁ-unsaturated carbonyl
compounds 3. From this point, the product distribution shown
in Entries 2–6 of Table 2 reconfirms the favor of Route 2.
In Route 2, dissociated free BF3 abstracts a hydride from
aliphatic ether 2. This hydride abstraction is probably achieved
in cooperation with proton abstraction by BF3-methoxide com-
plex (18) that is formed from the reaction of dissociated BF3
and acetal 1. As a result of abstraction of a proton and hydride,
MeOH BF3 and the hydride complex are formed. The hydride
ꢁ
complex thus formed in situ reacts with a proton source to gen-
erate H2, or attacks an alkoxycarbenium ion to form benzyl
methyl ether (4). In addition, benzyl alcohol (5) probably
yields after formation of benzyl methyl ether (4) via cleavage
of the carbon–oxygen linkage.
At the early stage of this transformation, ethers 2 and acetal
1 afford aldol equivalent 17 and the hydride complex with the
Consequently, transformation of ether 2 probably undergoes
via Route 2. The distinguished difference in reactivity of acetal
1 and benzaldehyde (8) strongly supports the involvement of
BF3-methoxide complex (18), which is only formed from ace-
tal 1 (Table 1, Entries 1 and 2).
To the best of our knowledge, the transformation of aliphat-
ic ethers into enol ether equivalents has never been reported.
As the only one related reaction, Arulraj and Alphonse have
reported the self-condensation of benzaldehyde dialkyl acetals
aid of Me2O BF3. If the intermediate 17 does not have poten-
ꢁ
tial to form indene derivatives 6 and 7, only (E)-alkoxycarbe-
nium ion 26 or ꢂ-alkoxyallyl cation 260 forms, resulting in for-
mation of ꢀ,ꢁ-unsaturated carbonyl compound 3 by work-up
treatment. On the other hand, when aldol equivalent 17 is
formed from bis(ꢁ-alkylethyl) ethers 2d–2f and acetal 1, inter-
mediate 17 is further transformed into (E)- and (Z)-alkoxycar-
benium ions 26 and 27, or their resonance hybrid as ꢂ-alkoxy-
allyl cations 260 and 270 via elimination of methanol. During
the equilibrium among carbenium ions 17, 26, and 27, and ace-
tals 23, 24, and 25, an appreciable amount of the intermediates
should exchange their alkoxy group with the methoxy group of
acetal 1. The subsequent intramolecular electrophilic aromatic
substitution of the generated (Z)-alkoxycarbenium ion 27 or its
resonance hybrid 270 affords 1-alkoxy-2-alkylindenes 6 and 7,
which have either of two alkoxy groups, i.e. those originated in
acetal 1 (R0 ¼ Me) or bis(ꢁ-alkylethyl) ethers 2d–2f (R0 ¼
R1CH2CH2).
The ꢁ-alkyl group (R1) of the ethers 2d–2f is considered
to destabilize the (E)-form ion 26/260 and to drive the equi-
librium between (E)-form ions 26 and 260, and (Z)-form ions
27 and 270 toward the latter. Furthermore, the absence of sub-
stituents at the ꢀ-carbon in the ethers 2d–2f (R2 ¼ H) is con-
sidered to be significant for the progress of the intramolecular
electrophilic attack of the oxonium carbon of (Z)-cations 27
and 270.
catalyzed by Et2O BF3, where cinnamaldehyde derivatives are
ꢁ
formed via disproportionative crossed aldol condensation of an
alkoxycarbenium ion formed from the acetal and an enolate
equivalent also generated from the alkoxy moiety in the ace-
tal.10 In their report, the carbon source of cinnamaldehyde
derivatives is limited to acetals, and the possibility of ether
to react is never considered.
The Reaction Mechanisms for Formation of Two Types
of Indene Derivatives. The formation of mixtures of pairs of
homologues having different alkoxy groups at the 1-position,
i.e. 2-alkyl-1-methoxyindenes 6a–6c and 2-alkyl-1-(alkyl-
ethoxy)indenes 7a–7c (Entries 4–6 in Table 2), suggests that
this annulation accompanies the interchange of the 1-alkoxy
groups. However, the Me2O BF3-mediated reaction of ꢀ-
ꢁ
deuterated benzaldehyde dimethyl acetal (12) with (n-Pr)2O
(2d) afforded 1-alkoxy-3-deuterio-2-methylindenes 19 and 20
(Scheme 7), and did not give 1-alkoxy-1-deuterio-2-methyl-

T. Jobashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
631
R2
R2
OMeOCHR2CH2R1
R1
R1
OCHR2CH2R1
OMe
Ph
R2
R1 17
2O
2
15
OMe
OMe
R2 = H
ii
i
Ph
Ph
Ph
1
16
OMeOR'
OR'
23
− MeOH
Ph
R1
OR'
R1
OR'
24
Ph
R'O OR'
R1
25
− MeOH
i
ii
R2 = H i ii
R2 = H
R1
O
R1
OR'
OR'
R2
R2 = H
H2O
Ph
Ph
R2
Ph
Ph
Ph
R2
27
27'
R1
OR'
26'
26
OR'
R1
R1
3
R' = Me or R1CH2CHR2
i: 1, − 16
R1
OR'
- H
R1
OR'
Scheme 8.
ii: BF3, − R'O−BF3
6/7
H
The ethers that afford ꢀ,ꢁ-unsaturated carbonyl compounds
3, i.e. Et2O (2a), (i-Pr)2O (2b), and methyl 1-phenylethyl ether
(2c), have a ꢁ-unsubstituted ethyl ether structure or ꢀ-substi-
tuted one. The former structure (ether 2a; R1 ¼ R2 ¼ H) pre-
dominantly makes the (E)-isomer of the intermediates like
species 24 and 26, which is far more stable than the (Z)-iso-
mer. The intermediates formed from the latter ethers 2b/2c
(R2 ¼ H) have the structure of ketone acetals, which is rather
unstable compared with those of the corresponding aldehyde
acetals 23/24/25 (R2 ¼ H). For these reasons, the transforma-
tion of these ethers presumably terminates before cyclization,
giving 1-alkoxy-2-alkylindenes 6 and 7. As a supporting ex-
perimental result, the reaction of bis(1-methylpropyl) ether
(R1 ¼ R2 ¼ Me), an ꢀ-alkyl-substituted ether, with acetal 1
has been found to give a complex mixture containing a small
amount of the corresponding ꢀ,ꢁ-unsaturated carbonyl com-
pound 3 without indene derivatives 6 and 7 on the basis of
dinarily unique. Furthermore, the specific domino oxidation-
crossed aldol condensation-electrophilic aromatic substitution
type annulation is also a unique behavior of such conventional
molecules.
Experimental
General. Aliphatic ethers 2, R2O BF3, and CH2Cl2 were pur-
ꢁ
chased and purified according to the method in the literature.11
Acetals 1 and 12 were synthesized according to the method in the
literature.12 Ether 10 was synthesized by the same method in the
literature13 from 2-deuterio-2-propanol. Distillation of indene de-
rivatives was carried out by Kugelrohr distillation. Boiling points
¨
were determined by the temperature of the furnace. 1H NMR spec-
tra were recorded on a JEOL JNM-LA500 (500 MHz) or a JEOL
JNM-AL300 (300 MHz) spectrometer using Me4Si (1H, ꢃ 0.00) as
an internal standard. 13C NMR spectra were recorded on a JEOL
JNM-LA500 (125 MHz) or a JEOL JNM-AL300 (75 MHz) spec-
trometer using CDCl3 (13C, ꢃ 77.0) as an internal standard. IR
spectra were recorded on a JASCO FT/IR-5300. High-resolution
mass spectra (HRMS) were recorded on a JEOL MStation JMS-
700. X-ray diffraction measurements were carried out on a Rigaku
Rapid.
1
the H NMR spectra.
Conclusion
We have found the BF3-mediated transformation reaction
of aliphatic ethers and benzaldehyde dimethyl acetal to yield
1-alkoxy-2-alkylindenes or ꢀ,ꢁ-unsaturated carbonyl com-
pounds with distinct specificity. The transformation is initiated
by dehydrogenative generation of enol ether equivalents from
The Reaction of Aliphatic Ether 2 with Acetal 1 in the Pres-
ence of Me O BF . Me2O BF3 (3 mmol, 0.342 g) was added to
Á
2
3
ꢁ
a mixture of ether 2 (5 mmol) and acetal 1 (0.5 mmol, 0.076 g) and
the solution was stirred at 25 ꢃC for 3 h. The solution was quench-
ed with water (20 mL) and then extracted with CH2Cl2 (20 mL ꢄ
3). The combined extracts were washed with saturated aqueous
NaCl (15 mL ꢄ 3), dried over Na2SO4, filtered, and concentrated
under reduced pressure.
aliphatic ethers with the aid of Me2O BF3 and benzaldehyde
ꢁ
dimethyl acetal. The enol ether equivalents readily afford ꢀ,ꢁ-
unsaturated carbonyl compound precursors, which further give
1-alkoxyindene derivatives on the condition that the struc-
tural requirements are satisfied. Otherwise, the inert enol ether
equivalent intermediates formed in situ yield ꢀ,ꢁ-unsaturated
carbonyl compounds. The function of aliphatic ethers as enol
ether equivalents for carbon–carbon bond formation is extraor-
1-Methoxy-2-methylindene (6a).3
Indene derivative 6a
was isolated by column chromatography (silica-gel, hexane:ethyl
acetate = 5:1 v/v) and distillation (15%, pale yellow oil). bp
1
92–94 ꢃC (8 mmHg). H NMR (500 MHz, CDCl3) ꢃ 7.42 (1H, d,

632 Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
Dehydrogenative Nucleophilic Addn. of Ether
J ¼ 7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14 (1H, d, J ¼ 7:5 Hz),
7.12 (1H, t, J ¼ 7:5 Hz), 6.45 (1H, s), 4.86 (1H, s), 3.05 (3H, s),
2.03 (3H, s) ppm. 13C NMR (125 MHz, CDCl3) ꢃ 145.8 (C), 143.8
(C), 141.7 (C), 128.7 (CH), 128.3 (CH), 124.6 (CH), 123.7 (CH),
120.1 (CH), 84.8 (CH), 51.8 (CH3), 14.1 (CH3) ppm. IR ꢄ (neat):
gel, hexane:ethyl acetate = 5:1 v/v) and distillation (4%, pale
yellow oil). bp 128–130 ꢃC (7 mmHg). 1H NMR (300 MHz,
CDCl3) ꢃ 7.43 (1H, d, J ¼ 7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14
(1H, d, J ¼ 7:5 Hz), 7.12 (1H, t, J ¼ 7:5 Hz), 6.42 (1H, s), 5.10
(1H, s), 3.3–3.1 (2H, m), 2.68 (1H, sep, J ¼ 6:6 Hz), 1.68 (1H,
t, J ¼ 6:6 Hz), 1.46–1.40 (2H, m), 1.26 (3H, d, J ¼ 6:6 Hz),
1.20 (3H, d, J ¼ 6:6 Hz), 0.85 (3H, d, J ¼ 6:6 Hz), 0.83 (3H, d,
J ¼ 6:6 Hz) ppm. 13C NMR (75 MHz, CDCl3) ꢃ 157.2 (C), 143.4
(C), 142.6 (C), 128.2 (CH), 125.1 (CH), 124.6 (CH), 123.7 (CH),
120.4 (CH), 82.3 (CH), 62.8 (CH2), 39.1 (CH2), 27.3 (CH), 24.8
(CH), 23.5 (CH3), 22.8 (CH3), 22.4 (CH3), 20.7 (CH3) ppm. IR
ꢄ (KBr): 1718, 1618, 1460, 1201, 1105, 1082, 752 cmꢂ1. HRMS
m=z (EI) calcd for C17H24O (M)þ 244.1827, found 244.1889.
3-Deuterio-1-methoxy-2-methylindene (19). Indene deriva-
tive 19 was isolated by column chromatography (silica-gel,
hexane:ethyl acetate = 5:1 v/v) and distillation (8%, pale yellow
1720, 1626, 1606, 1464, 1373, 1321, 1207, 1107, 1080, 752 cmꢂ1
.
HRMS m=z (EI) calcd for C11H11O ðM ꢂ HÞþ 159.0810, found
159.0766.
2-Ethyl-1-methoxyindene (6b). Indene derivative 6b was iso-
lated by column chromatography (silica-gel, hexane:ethyl ace-
tate = 5:1 v/v) and distillation (19%, pale yellow oil). bp 101–
102 ꢃC (8 mmHg). 1H NMR (300 MHz, CDCl3) ꢃ 7.42 (1H, d, J ¼
7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14 (1H, d, J ¼ 7:5 Hz), 7.12
(1H, t, J ¼ 7:5 Hz), 6.46 (1H, s), 4.95 (1H, s), 3.07 (3H, s), 2.5–
2.2 (2H, m), 1.21 (3H, t, J ¼ 6:6 Hz) ppm. 13C NMR (75 MHz,
CDCl3) ꢃ 152.1 (C), 143.8 (C), 141.8 (C), 128.4 (CH), 126.7
(CH), 124.6 (CH), 123.8 (CH), 120.3 (CH), 83.8 (CH), 51.8
(CH3), 21.5 (CH2), 12.4 (CH3) ppm. IR ꢄ (KBr): 1722, 1618,
1460, 1319, 1203, 1103, 1082, 752, 734 cmꢂ1. HRMS m=z (EI)
calcd for C12H13O ðM ꢂ HÞþ 173.0966, found 173.0925.
1-Methoxy-2-(1-methylethyl)indene (6c). Indene derivative
6c was isolated by column chromatography (silica-gel, hexane:
ethyl acetate = 5:1 v/v) and distillation (12%, pale yellow oil).
bp 108–110 ꢃC (9 mmHg). 1H NMR (300 MHz, CDCl3) ꢃ 7.42
(1H, d, J ¼ 7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14 (1H, d, J ¼
7:5 Hz), 7.12 (1H, t, J ¼ 7:5 Hz), 6.44 (1H, s), 5.05 (1H, s), 3.07
(3H, s), 2.69 (1H, sep, J ¼ 6:6 Hz), 1.22 (3H, d, J ¼ 6:6 Hz), 1.20
(3H, d, J ¼ 6:6 Hz) ppm. 13C NMR (75 MHz, CDCl3) ꢃ 156.5 (C),
143.6 (C), 141.8 (C), 128.3 (CH), 126.7 (CH), 124.7 (CH), 123.8
(CH), 120.4 (CH), 82.7 (CH), 51.8 (CH3), 27.3 (CH), 23.3 (CH3),
20.6 (CH3) ppm. IR ꢄ (KBr): 1720, 1618, 1466, 1205, 1107, 1080,
752, 734 cmꢂ1. HRMS m=z (EI) calcd for C13H16O (M)þ
188.1201, found 188.1198.
2-Methyl-1-propoxyindene (7a). Indene derivative 7a was
isolated by column chromatography (silica-gel, hexane:ethyl ace-
tate = 5:1 v/v) and distillation (3%, pale yellow oil). bp 111–
114 ꢃC (8 mmHg). 1H NMR (500 MHz, CDCl3) ꢃ 7.43 (1H, d,
J ¼ 7:5 Hz), 7.22 (1H, t, J ¼ 7:5 Hz), 7.13 (1H, d, J ¼ 7:5 Hz),
7.11 (1H, t, J ¼ 7:5 Hz), 6.42 (1H, s), 4.89 (1H, s), 3.13–3.11 (2H,
m), 2.05 (3H, s), 1.56 (2H, sext, J ¼ 7:3 Hz), 0.90 (3H, t, J ¼ 7:3
Hz) ppm. 13C NMR (125 MHz, CDCl3) ꢃ 146.4 (C), 143.6 (C),
142.5 (C), 128.2 (CH), 128.1 (CH), 124.5 (CH), 123.6 (CH),
120.1 (CH), 84.4 (CH), 66.1 (CH2), 23.4 (CH2), 14.2 (CH3), 10.7
(CH3) ppm. IR ꢄ (neat): 1718, 1604, 1462, 1319, 1205, 1170,
1105 cmꢂ1. HRMS m=z (EI) calcd for C13H16O (M)þ 188.1201,
found 188.1197.
1
oil). bp 93–96 ꢃC (7 mmHg). H NMR (300 MHz, CDCl3) ꢃ 7.42
(1H, d, J ¼ 7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14 (1H, d, J ¼
7:5 Hz), 7.12 (1H, t, J ¼ 7:5 Hz), 4.86 (1H, s), 3.05 (3H, s), 2.03
(3H, s) ppm. 13C NMR (75 MHz, CDCl3) ꢃ 145.7, 143.8, 141.8,
128.6 (t, JCD ¼ 28 Hz), 128.3, 124.6, 123.7, 120.1, 84.8, 51.7,
14.0 ppm. IR ꢄ (KBr): 1720, 1626, 1606, 1464, 1373, 1321, 1207,
1107, 1080, 752 cmꢂ1. HRMS m=z (EI) calcd for C11H11DO (M)þ
161.0951, found 161.0925.
3-Deuterio-2-methyl-1-propoxyindene (20). Indene deriva-
tive 20 was isolated by column chromatography (silica-gel,
hexane:ethyl acetate = 5:1 v/v) and distillation (3%, pale yellow
oil). bp 112–115 ꢃC (8 mmHg). 1H NMR (300 MHz, CDCl3) ꢃ
7.43 (1H, d, J ¼ 7:5 Hz), 7.22 (1H, t, J ¼ 7:5 Hz), 7.13 (1H, d,
J ¼ 7:5 Hz), 7.11 (1H, t, J ¼ 7:5 Hz), 4.89 (1H, s), 3.20–3.01 (2H,
m), 2.05 (3H, s), 1.62–1.51 (2H, m), 0.90 (3H, t, J ¼ 7:3 Hz) ppm.
13C NMR (75 MHz, CDCl3) ꢃ 146.3, 143.6, 142.5, 128.2 (t,
JCD ¼ 28 Hz), 128.1, 124.5, 123.6, 120.0, 84.4, 66.1, 23.3, 14.1,
10.7 ppm. IR ꢄ (KBr): 1718, 1604, 1462, 1319, 1205, 1170, 1105
cmꢂ1. HRMS m=z (EI) calcd for C13H15DO (M)þ 189.1264, found
189.1229.
Synthesis of 1,2-Dibromo-3-methoxy-2-methylindane (9).
Bromine (4.5 mmol, 0.719 g) was dropped into a solution of 1-
methoxy-2-methylindene (6a) (4.5 mmol, 0.720 g) in CH2Cl2 (40
mL) at 0 ꢃC and stirred for 1 h. The brownish colored solution im-
mediately turned colorless. The solution was quenched with water
(50 mL) and extracted with CH2Cl2 (40 mL ꢄ 3). The combined
extracts were washed with saturated aqueous NaCl (30 mL ꢄ 3),
dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. One of the isomers was isolated by repeated silica-gel col-
umn chromatography (first, hexane:CHCl3 = 1:1 v/v; second, tol-
uene) of the obtained crude products. The isolated dibromoindane
9 was purified by recrystallization (hexane) three times (8%, col-
orless prism). mp 56.5–57 ꢃC.
1,2-Dibromo-3-methoxy-2-methylindane (9): 1H NMR (300
MHz, CDCl3) ꢃ 7.5–7.3 (4H, m), 5.73 (1H, s), 4.52 (1H, s), 3.80
(3H, s), 2.26 (3H, s) ppm. 13C NMR (75 MHz, CDCl3) ꢃ 141.7,
140.2, 129.4, 128.9, 125.2, 124.5, 88.6, 75.9, 60.4, 60.3, 29.0
ppm. IR ꢄ (KBr): 1712, 1462, 1356, 1201, 1105, 1089 cmꢂ1. Anal.
Calcd for C11H12Br2O: C, 41.28; H, 3.78%. Found: C, 41.28; H,
3.78%.
1-Butoxy-2-ethylindene (7b). Indene derivative 7b was iso-
lated by column chromatography (silica-gel, hexane:ethyl ace-
tate = 5:1 v/v) and distillation (5%, pale yellow oil). bp 120–
123 ꢃC (7 mmHg). 1H NMR (300 MHz, CDCl3) ꢃ 7.42 (1H, d, J ¼
7:5 Hz), 7.23 (1H, t, J ¼ 7:5 Hz), 7.14 (1H, d, J ¼ 7:5 Hz), 7.12
(1H, t, J ¼ 7:5 Hz), 6.43 (1H, s), 4.96 (1H, s), 3.2–3.1 (2H, m),
2.5–2.2 (2H, m), 1.55–1.45 (2H, m), 1.40–1.32 (2H, m), 1.25
(3H, t, J ¼ 7:9 Hz), 0.88 (3H, t, J ¼ 7:9 Hz) ppm. 13C NMR (75
MHz, CDCl3) ꢃ 152.8 (C), 143.6 (C), 142.5 (C), 128.2 (CH),
126.1 (CH), 124.6 (CH), 123.7 (CH), 120.2 (CH), 83.3 (CH), 64.2
(CH2), 32.3 (CH2), 21.6 (CH2), 19.4 (CH2), 13.9 (CH3), 12.5
(CH3) ppm. IR ꢄ (KBr): 1716, 1616, 1466, 1203, 1170, 1107,
1080, 752, 736 cmꢂ1. HRMS m=z calcd for C15H20O (M)þ
216.1514, found 216.1491.
X-ray Crystal Structure Analysis. Diffraction measurements
were carried out on a Rigaku AFC5R detector diffractometer
equipped with graphite-monochromated Cu Kꢀ radiation (ꢅ ¼
ꢀ
1:5418 A).
1-(3-Methylbutoxy)-2-(1-methylethyl)indene (7c). Indene
derivative 7c was isolated by column chromatography (silica-
1,2-Dibromo-3-methoxy-2-methylindane (9): The crystal suits
for structure analysis measured 0:3 ꢄ 0:2 ꢄ 0:2 mm3. Indane 9

T. Jobashi et al.
Bull. Chem. Soc. Jpn. Vol. 79, No. 4 (2006)
633
crystallized in the monoclinic unit cell, space group C2=c, a ¼
e) P. G. Karmarkar, V. R. Chinchore, M. S. Wadia, Synthesis
1981, 228. f) A. Padwa, T. J. Blacklock, R. Loza, J. Org. Chem.
1982, 47, 3712. g) M. G. Steinmetz, R. T. Meyes, J. Am. Chem.
Soc. 1985, 107, 2111. h) L. Anke, P. Weyerstahl, Chem. Ber.
1985, 118, 613. i) G. Singh, H. Ila, H. Junjappa, Synthesis 1986,
744. j) C. Roussel, H. G. Rajoharison, L. Bizzari, L. Shaimi,
J. Org. Chem. 1988, 53, 683. k) S. Saito, Y. Sato, T. Ohwada,
K. Shudo, J. Am. Chem. Soc. 1994, 116, 2312.
ꢃ
ꢀ
19:558ð5Þ, b ¼ 9:050ð3Þ, c ¼ 14:333ð3Þ A, ꢁ ¼ 113:315ð16Þ ,
ꢀ 3
V ¼ 2329:8ð11Þ A , Z ¼ 8, Dcalcd ¼ 1:825 Mg mꢂ3, ꢅ ¼ 1:5418
A, ꢆ ¼ 8:550 mmꢂ1, Fð000Þ ¼ 1248. Data were collected for
ꢀ
4:92 < ꢇ < 67:00ꢃ. The structure was solved by a direct method
(SIR92)14 and refined by least squares against F2 to R1 ¼
0:0630 (wR2 ¼ 0:1476) and Sgoof ¼ 1:052. All hydrogen atoms
were added with a fixed distance by the SHELXL-97 program.15
Crystallographic data for the structures of 1,2-dibromo-3-
methoxy-2-methylindane (9) in this paper have been deposited
with the Cambridge Crystallographic Data Centre: Deposition
number CCDC-277928. Copies of the data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
5
a) L. S. Liebeskind, J. R. Gasdaska, J. S. McCallum, S. J.
Tremont, J. Org. Chem. 1989, 54, 669. b) L. G. Quan, V.
Gevorgyan, Y. Yamamoto, J. Am. Chem. Soc. 1999, 121, 3545.
c) V. Gevorgyan, L. G. Quan, Y. Yamamoto, Tetrahedron Lett.
1999, 40, 4089. d) D. K. Rayabarapu, C.-H. Cheng, Chem.
Commun. 2002, 942. e) D. K. Rayabarapu, C.-H. Yang, C.-H.
Cheng, J. Org. Chem. 2003, 68, 6726. f) K.-J. Chang, D. K.
Rayabarapu, C.-H. Cheng, Org. Lett. 2003, 5, 3963. g) K.-J.
Chang, D. K. Rayabarapu, C.-H. Cheng, J. Org. Chem. 2004,
69, 4781.
Supporting Information
1
Figures S1–S9 show H and 13C NMR spectra of indene deriv-
6
a) M. Lautens, J. Mancuso, Org. Lett. 2002, 4, 2105. b) M.
atives 6, 7, 19, and 20 and dibromoindane 9 in PDF format. This
material is available free of charge on the web at: http://www.csj.
jp/journals/bcsj/.
Lautens, J. Mancuso, J. Org. Chem. 2004, 69, 3478. c) M.
Lautens, T. Marquardt, J. Org. Chem. 2004, 69, 4607. d) T. Miura,
M. Murakami, Org. Lett. 2005, 7, 3339. e) R. Shintani, K.
Okamura, T. Hayashi, Chem. Lett. 2005, 34, 1294. f) T. Matsuda,
M. Makino, M. Murakami, Chem. Lett. 2005, 34, 1416.
References
7
M. E. Bos, W. D. Wulff, R. A. Miller, S. Chamberlin, T. A.
Brandvold, J. Am. Chem. Soc. 1991, 113, 9293.
a) B. M. Mikhailov, G. S. Ter-Sarkisyan, Zh. Obshch.
1
a) N. Yonezawa, Y. Tokita, T. Hino, H. Nakamura, R.
Katakai, J. Org. Chem. 1996, 61, 3551. b) N. Yonezawa, T. Hino,
Y. Tokita, K. Matsuda, T. Ikeda, Tetrahedron 1997, 53, 14287.
c) N. Yonezawa, T. Hino, M. Shimizu, K. Matsuda, T. Ikeda,
J. Org. Chem. 1999, 64, 4179. d) N. Yonezawa, T. Hino, T.
Kinuno, T. Matsuki, T. Ikeda, Synth. Commun. 1999, 29, 1687.
e) N. Yonezawa, T. Hino, T. Ikeda, Recent Res. Dev. Synth.
Org. Chem. 1998, 1, 213. f) N. Yonezawa, T. Hino, K. Matsuda,
T. Matsuki, D. Narushima, M. Kobayashi, T. Ikeda, J. Org. Chem.
2000, 65, 941. g) A. Kameda, H. Nishimori, S. Omura, M. Koike,
T. Hino, T. Jobashi, K. Maeyama, N. Yonezawa, Nippon Kagaku
Kaishi 2002, 211. h) T. Jobashi, T. Hino, K. Maeyama, H. Ozaki,
K. Ogino, N. Yonezawa, Chem. Lett. 2005, 34, 860.
8
Khim. 1959, 29, 1642. b) S. M. Makin, G. A. Ermakova, O. A.
Shavrygina, A. P. Pleshkova, V. N. Voznesenskii, Zh. Org. Khim.
1979, 15, 1852.
9 Y. Okuda, T. Morimoto, Y. Fujita, Nippon Kagaku Kaishi
1972, 1442.
10 a) I. Alphonse, S. J. Arulraj, Indian J. Chem. 1985, 199.
b) I. Alphonse, S. J. Arulraj, J. Indian Chem. Soc. 1986, 820.
11 W. L. F. Armarego, D. D. Perrin, Purification of Labora-
tory Chemicals, 4th ed., Butterworth-Heinemann, Oxford, 1996.
12 S. G. Davies, C. L. Goodfellow, J. Chem. Soc., Perkin
Trans. 1 1990, 393.
2
T. Jobashi, M. Takano, T. Hino, K. Maeyama, K. Fugami,
H. Ozaki, K. Ogino, N. Yonezawa, Chem. Lett. 2004, 33, 1246.
a) S. Kapur, N. C. Mathur, K. McManus, A. L. Pincock,
13 J. Hoffner, M. J. Schottelius, D. Feichtinger, P. Chen,
J. Am. Chem. Soc. 1998, 120, 376.
14 SIR92: A. Altomare, M. C. Burla, M. Camalli, M.
Cascarano, C. Giacovazzo, A. Guagliardi, G. J. Polidori, J. Appl.
Crystallogr. 1994, 27, 435.
3
J. A. Pincock, Can. J. Chem. 1988, 66, 2888. b) J. A. Pincock,
I. S. Young, Can. J. Chem. 2003, 81, 1083.
4
a) J. Koo, J. Am. Chem. Soc. 1952, 75, 2000. b) J. C.
15 G. M. Sheldrick, SHELXL-97 Program for Crystal Deter-
mination and Refinement, University of Gottingen, Germany,
1997.
Canevet, V. Graff, Tetrahedron 1978, 34, 1935. c) G. A. Olah,
G. Asensio, H. Mayr, J. Org. Chem. 1978, 43, 1518. d) A. Padwa,
T. J. Blacklock, R. Loza, J. Am. Chem. Soc. 1981, 103, 2404.
¨