Direct Synthesis of Indanes via Iron-Catalyzed Dehydrative Coupling/Friedel–Crafts Cyclization of Two Different Alcohols

Article abstract of DOI:10.1002/ejoc.201801573

We report herein a novel iron-catalyzed cascade dehydrative coupling/Friedel–Crafts cyclization of two different alcohols, providing a variety of indanes, which are ubiquitous substructures found in natural products, pharmaceuticals, and functional materi

Full text of DOI:10.1002/ejoc.201801573

A Journal of
Accepted Article
Title: Direct Synthesis of Indanes via Iron-Catalyzed Dehydrative
Coupling/Friedel–Crafts Cyclization of Two Different Alcohols
Authors: Masahiro Sai
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
COMMUNICATION
Direct Synthesis of Indanes via Iron-Catalyzed Dehydrative
Coupling/Friedel–Crafts Cyclization of Two Different Alcohols
Masahiro Sai*[a]
Abstract: We report herein
a
novel iron-catalyzed cascade
activation of a hydroxy group and a double bond must be
accomplished by a single catalyst even in the presence of
excess H2O, which often deactivates Lewis acids. Herein, we
demonstrate the feasibility of this concept by realizing direct
iron-catalyzed synthesis of indanes via cascade dehydrative
coupling/Friedel–Crafts cyclization of two different alcohols.
dehydrative coupling/Friedel–Crafts cyclization of two different
alcohols, providing a variety of indanes, which are ubiquitous
substructures found in natural products, pharmaceuticals, and
functional materials. Importantly, the developed approach is highly
atom-economic and environmentally benign, as it employs readily
available alcohols as substrates and generates water as the only
byproduct.
Friedel–Crafts cyclization of 3-aryl-1-propyl cations to indanes
Friedel–Crafts
R
cyclization
R
R'
3-aryl-1-propyl
cations
Introduction
R'
indanes
In view of the widespread occurrence of the indane scaffold in
natural products/pharmaceuticals[1] and functional materials,[2]
much effort has been directed at the development of efficient
indane synthesis methods.[3] One of such methods relies on the
intramolecular Friedel–Crafts[4] cyclization of 3-aryl-1-propyl
cations that can be generated by activating the C–O bond of 3-
aryl-1-propanols[5] or the C=C bond of allylarenes[6] in acidic
conditions. However, the above substrates are not easily
accessible, which has inspired the search for alternative
approaches such as the in situ generation of 3-aryl-1-propyl
cations in the acid-promoted dehydrative coupling of benzylic
alcohols with olefins.[7] Although the above protocol provides
access to a variety of indanes with different substitution patterns,
it generally requires stoichiometric amounts of Lewis acids,[7a–7e]
and successful catalytic examples remains scarce.[7f–7h]
Furthermore, the preparation of olefins is sometimes problematic,
particularly when they are unstable, volatile, or highly elaborated.
Thus, it is highly desirable to develop a new catalytic synthesis
of indanes from easily available starting materials.
Recently, we have reported new synthetic transformations of
unsaturated alcohols involving alcohol C–O bond cleavage by
Lewis acids.[8] Based on the results of these studies, we
attempted to directly assemble the indane skeleton from two
different alcohols, since alcohols are more stable, less volatile,
and more readily available than olefins. In order for this
approach to be successful, one needs to chemoselectively
generate carbocations and olefins from two different alcohols via
Lewis acid-catalyzed C–O bond cleavage and then couple these
in situ generated partners to provide allylarenes, which
subsequently undergo Lewis acid-catalyzed Friedel–Crafts
cyclization to indanes (Scheme 1). Accordingly, the dual
This Work
OH
[Fe]
Ar1
Ar2
R1
Ar1
Ar2
R1
R3
R2
dehydrative
coupling
Friedel–Crafts
cyclization
R3
diarylmethanols
R2
Ar2
–H2O
[Fe]
R1
Ar1
Ar2
indanes
OH
R1
Ar1
[Fe]
R3
R1
R2
R3
allylarenes
–H2O
R3
Ar1
R2
R2
H
alcohols
Ar2
3-aryl-1-propyl
cations
Scheme 1. Iron-catalyzed direct synthesis of indanes from two different
alcohols.
Results and Discussion
Initially, we aimed to identify the appropriate catalyst and
reaction conditions for the synthesis of indane 2a by the reaction
of benzhydrol 1a with tert-butyl alcohol (Table 1) and started by
testing a Ga(OTf)3/PhCF3 system, which was shown to be highly
effective for the C–O bond cleavage in our previous study.[8b]
Although this system showed high catalytic activity for the initial
dehydrative coupling to afford olefins 3 and 4,[9,10] the desired
indane 2a was obtained in only 10% yield (entry 1). Next,
representative Lewis acids were examined.
Almost no
conversion was observed in the presence of BF3·Et2O and AlCl3
(entries 2 and 3), while the catalytic activities of In(OTf)3 and
Sc(OTf)3 were similar to that of Ga(OTf)3 (entries 4 and 5). To
enhance Friedel–Crafts cyclization, soft Lewis acids such as
Cu(OTf)2 and AgOTf were employed, but olefin 3 was again
obtained as the major product (entries 6 and 7). Further catalyst
screening showed that Fe(OTf)3 was particularly effective in
promoting indane formation, delivering 2a in 76% yield (entry
8).[11] The high catalytic activity of Fe(OTf)3 toward indane
formation would be attributed to its strong Lewis acidity, which
allowed Friedel–Crafts cyclization to occur even in the presence
of excess H2O. We next investigated the effect of solvent and
reaction temperature on Fe(OTf)3-catalyzed indane formation,
[a]
Dr. M. Sai
Research Foundation ITSUU Laboratory
C1232 Kanagawa Science Park R & D Building, 3-2-1 Sakado,
Takatsu-ku, Kawasaki, Kanagawa 213-0012, Japan
E-mail: msai@itsuu.or.jp
http://itsuu.or.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
COMMUNICATION
showing that poor yields were observed at 80 ˚C in PhCF3 and
diarylmethanols bearing aryl groups with largely different
electron densities and discovered that diarylmethanols with one
electron-rich aryl group exclusively generated single
regioisomers (2c–2e). In these cases, direct functionalization of
the indane skeleton was achieved because cyclization involved
the more electron-rich aromatic ring. In the case of 2e,
cyclization occurred with exclusive regioselectivity at the
sterically less hindered ortho-position of the more electron-rich
aryl ring. Unfortunately, the reactions of diarylmethanols bearing
highly electron-rich aryl groups such as anisole and benzofuran
residues afforded complex product mixtures. The reaction of
diarylmethanols with one electron-deficient aryl group also
afforded indanes 2f–2j in high yields with exclusive
regioselectivities, although longer reaction times and higher
at 85 ˚C in DCE (entries 9 and 10).
Accordingly, high
temperature was determined to be of key importance for indane
formation, while the yield of 2a was reduced to 51% when the
reaction was carried out in toluene at 115 ˚C (entry 11).[12] The
yield of 2a was increased to 82% in PhCF3 (with almost
complete consumption of 3 and 4) as the reaction time was
extended to 4 h (entry 12). At this point, it should be noted that
the previous method[7] of 2a synthesis involves the use of
gaseous and flammable 2-methylpropene instead of tert-butyl
alcohol and is therefore clearly inferior to the approach
described herein.
Table 1. Optimization of reaction conditions.[a]
catalyst loadings were required.
Heterocyclic compounds
Me
showed modest reactivities (2k and 2l), and mono- and
triarylmethanols could also be employed (2m and 2n).
Me
Me
Ph
Me
Ph
tBuOH (4 equiv.)
catalyst (5 mol-%)
Me
OH
Ph
solvent, T [˚C], 2 h
Ph
Ph
1a
Ph
Ph
Me
tBuOH (4 equiv.)
Me
2a
3
4
OH
Fe(OTf)3 (5 mol-%)
R1
R2
Ar
R2
PhCF3, 105 ˚C, 4 h
Yield [%][c]
R1
1
Ar
Entry
Catalyst
Solvent[b]
T [˚C]
indanes 2
1a
0
2a
3
4
6
0
0
6
5
7
20
1
7
7
3
0
Me
Me
1
Ga(OTf)3
BF3·Et2O
AlCl3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
DCE
105
105
105
105
105
105
105
105
80
10
0
80
0
Me
Me
Me
Me
2
95
93
0
Ph
Ph
Me
3
0
0
Me
Me
Me
2b
2b'
82%
(2b/2b' = 2.6:1)[a]
4
In(OTf)3
Sc(OTf)3
Cu(OTf)2
AgOTf
12
17
11
7
75
67
73
62
11
81
88
36
4
2c, 84%
5
0
Me
Me
Me
Me
Me
Me
6
0
Me
Ph
Ph
Ph
7
0
O
OMe
O
Me
2d, 86%
8
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
0
76
6
2e, 75%[b]
complex mixture
Me
9
0
Me
Me
Me
Me
Me
10
11
12[d]
85
0
4
toluene
PhCF3
115
105
0
51
82[e]
F
Cl
Br
2f, 92%
(6 h)
2g, 88%
2h, 97%
(6 h)
0
(6 h)
Me
Me
Me
Me
Me
Me
[a] Reaction conditions: 1a (0.25 mmol), tBuOH (1.0 mmol), and catalyst (5
mol-%) in solvent (3 mL) for 2 h. [b] PhCF3 (bp 102 ˚C), DCE (bp 83 ˚C), and
toluene (bp 111 ˚C). [c] Determined by 1H NMR (400 MHz) analysis of the
crude reaction mixture. [d] Run for 4 h. [e] Isolated yield.
NTs
Ph
MeO2C
F3C
2j, 90%[d]
2k, 38%[b]
2i, 85%[c]
(12 h)
(12 h)
With the optimal conditions in hand, we explored the
substrate scope of indane synthesis (Scheme 2), focusing on
the use of unsymmetrical diarylmethanols in view of the scarcity
of successful examples of regioselective indane synthesis from
such compounds.[7d,7e,7h] First, phenyl(4-tolyl)methanol 1b was
reacted with tert-butyl alcohol under iron catalysis, resulting in a
2.6:1 mixture of two regioisomers, 2b and 2b′. To improve
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Me
S
2l, 68%[b]
2m, 42%[b]
2n, 79%
regioselectivity,
we
examined
various
unsymmetrical
Scheme 2. Iron-catalyzed regioselective synthesis of indanes. Reaction
conditions: 1 (0.25 mmol), tBuOH (1.0 mmol), and Fe(OTf)3 (5 mol-%) in
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
COMMUNICATION
PhCF3 (3 mL) at 105 ˚C for 4 h. Isolated yield is shown. [a] Determined by 1H
NMR (400 MHz) analysis of the crude reaction mixture. [b] In DCE at 85 ˚C. [c]
With 20 mol-% Fe(OTf)3. [d] With 10 mol-% Fe(OTf)3.
time intervals. The dehydrative coupling reaction was quite fast,
and olefin 3 was obtained in 81% yield after 0.5 h. However, as
the reaction proceeded, the yield of 3 significantly decreased,
and indane 2a was obtained as the major product. Moreover,
treatment of 3 with Fe(OTf)3 led to the formation of indane 2a in
92% yield, i.e., 3 was the intermediate leading to the formation
of 2a.
To further demonstrate the utility of the developed method,
we tried the diastereoselective synthesis of indanes (Scheme 3).
Treatment of 1a with 1-phenylethanol under standard conditions
resulted in a 1.4:1 cis/trans mixture of 1,3-disubstituted indane
2o. In contrast, the reaction with 1-phenylpropanol smoothly
proceeded in DCE at 85 ˚C, presumably because of the Thorpe–
Ingold effect, providing a single diastereomer of the 1,2,3-
1. Dehydrative coupling process (NMR yields)
tBuOH (4 equiv.)
Fe(OTf)3 (5 mol-%)
Ph
Ph
OH
Ph
OH
Ph
OtBu
O
Ph
trisubstituted indane 2p in 86% yield.[13]
The excellent
PhCF3, 60 ˚C, 1 h
Ph
Ph
Ph
Ph
Ph
1a
diastereoselectivity of this reaction was ascribed to the relative
stabilities of possible cationic intermediate conformers.
1a
5
6
22%
53%
27%
Specifically, conformer
A
was more stable than other
tBuOH (4 equiv.)
Fe(OTf)3 (5 mol-%)
Me
Me
Ph
conformers, as the steric interaction between the methyl group
and the phenyl group therein was avoided. Thus, cyclization
preferentially involved conformer A to diastereoselectively afford
2p.[14] The reaction with 1,2-diphenylethanol afforded 2q as a
single diastereomer in 95% yield, which highlighted the
applicability of our method to the diastereoselective synthesis of
1,2,3-trisubstituted indanes.
OR
Ph
5: R = CHPh2
6: R = tBu
PhCF3, 105 ˚C, 0.5 h
Ph
Ph
3
82% from 5
83% from 6
2. Friedel–Crafts cyclization process
Me
tBuOH (4 equiv.)
Fe(OTf)3 (5 mol-%)
Me
Me
Ph
Me
Ph
Me
OH
Ph
Ph
Ph
PhCF3, 105 ˚C
Ph
Ph
OH
Ph Ph
OH
Ph
Ph
Fe(OTf)3 (5 mol-%)
PhCF3, 105 ˚C, 4 h
1a
2a
3
4
Ph
Ph
Me
(2 equiv.)
NMR Yield [%]
Ph
Ph
1a
Time [h]
Entry
2a
5
3
4
8
1
0
2o, 52%
9%
1
2
3
0.5
2
81
11
4
(cis/trans = 1.4:1)
76
82[a]
Ph
Me
4
OH
Ph
OH
Fe(OTf)3 (5 mol-%)
DCE, 85 ˚C, 1 h
[a] Isolated yield.
Me
Ph
Ph
Ph
Me
Me
Me
Ph
Me
H
1a
(2 equiv.)
Fe(OTf)3 (5 mol-%)
PhCF3, 105 ˚C, 1 h
Me
Ph
2p, 86%
Ph
Ph
Ph
3
2a
92%
A
favored
Ph
Scheme 4. Control experiments.
Ph
OH
OH
Fe(OTf)3 (5 mol-%)
DCE, 85 ˚C, 1 h
Ph
Ph
Ph
Ph
Ph
On the basis of these results, a plausible indane formation
mechanism is illustrated in Scheme 5. Initially, the C–O bond of
1a is cleaved by Fe(OTf)3 to generate the benzyl cation A, while
the simultaneous activation of the tert-butyl alcohol C–O bond
1a
(2 equiv.)
2q, 95%
Scheme 3. Diastereoselective synthesis of 1,2,3-trisubstituted indanes.
affords 2-methylpropene.
Subsequently, A, which is in
equilibrium with dimer 5 and tert-butyl ether 6, undergoes
dehydrative coupling with 2-methylpropene to provide olefin 3.
Under harsh reaction conditions (PhCF3, 105 ˚C), the double
bond of 3 is activated by Fe(OTf)3, and the thus generated
tertiary carbocation B undergoes intramolecular Friedel–Crafts
cyclization to give indane 2a and regenerate Fe(OTf)3.
To gain insight into the reaction mechanism, several control
experiments were conducted (Scheme 4). First, iron-catalyzed
dehydrative coupling of 1a with tert-butyl alcohol was performed
in PhCF3 at 60 ˚C. In this case, dimer 5 (53% yield) and tert-
butyl ether 6 (27% yield) were obtained.[15] Exposure of 5 and 6
to standard conditions for 0.5 h furnished olefin 3 in 82 and 83%
yields, respectively, which indicated that these ethers are the
principal intermediates of dehydrative coupling.
Next, we
conducted the reaction of 1a with tert-butyl alcohol in PhCF3 at
105 ˚C and monitored the product distribution at appropriate
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
COMMUNICATION
Me
Me
[Fe]
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[Fe] + H2O
Me
tBuOH
Me
[Fe]-OH
[Fe]
OH
Ph
[Fe]
[Fe]-OH
Me
Me
dehydrative
coupling
Ph
Ph
Ph
Ph
Ph
Ph
3
1a
A
B
+ H2O
–[Fe]
–H2O
Friedel–Crafts
cyclization
tBuOH
1a
Ph
[Fe]
Me
Me
OtBu
[Fe]
O
Ph
Ph
Ph
Ph
Ph
Ph
6
5
2a
+ H2O
+ H2O
[Fe] = Fe(OTf)3
[2]
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Scheme 5. A plausible mechanism.
Conclusions
We have developed
a novel regioselective synthesis of
functionalized indanes via iron-catalyzed cascade dehydrative
coupling/Friedel–Crafts cyclization of two different alcohols,
showing that the employed catalytic system is also applicable to
the diastereoselective synthesis of 1,2,3-trisubstituted indanes.
This method allows using inexpensive, stable, and easily
available alcohols as starting materials and generates water as
the only byproduct. Thus, the reaction offers a highly atom-
economic and environmentally friendly procedure for the
synthesis of the indane skeleton.
[3]
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[4]
[5]
Experimental Section
General procedure: In a glovebox, Fe(OTf)3 (6.3 mg, 0.0125 mmol) was
charged in an oven-dried vial equipped with a stirring bar. Outside the
glovebox, to the vial was added a solution of benzylic alcohol 1 (0.25
mmol) and tert-butyl alcohol (74.1 mg, 1.0 mmol) in PhCF3 (3 mL). The
resulting mixture was stirred in a pre-heated oil bath (105 ˚C) for 4 h.
The reaction mixture was cooled to room temperature, diluted with Et2O,
filtered through a short pad of activated alumina, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (hexane/EtOAc) to give the corresponding product 2.
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Acknowledgements
[6]
We are grateful to Prof. Shuji Akai (Osaka University) for his
kind and helpful discussions. We also thank Prof. Masayuki
Inoue (The University of Tokyo), Prof. Takeo Kawabata (Kyoto
University), Prof. Tomohiko Ohwada (The University of Tokyo),
Dr. Mitsuaki Ohtani (ITSUU Laboratory), and Dr. Kin-ichi Tadano
(ITSUU Laboratory) for helpful discussions.
Keywords: Alcohols • Iron • C-C coupling • Cyclization •
[7]
Indanes
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
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actual catalyst, it is difficult to explain why only Fe(OTf)3 exhibits high
catalytic activity for indane formation.
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[11] When the reaction was conducted with 15 mol-% TfOH in PhCF3 at 105
˚C for 4 h, indane 2a was formed in 80% NMR yield. Accordingly, the
possibility that TfOH produced from Fe(OTf)3 and tBuOH or H2O
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10.1002/ejoc.201801573
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
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A novel iron-catalyzed cascade
dehydrative coupling/Friedel–Crafts
cyclization of two different alcohols to
indanes has been developed. This
approach is highly atom-economic
and environmentally benign, as it
employs readily available alcohols as
substrates and generates only water
as byproduct.
Indane Synthesis
Masahiro Sai*
Page No. – Page No.
Direct Synthesis of Indanes via Iron-
Catalyzed Dehydrative
Coupling/Friedel–Crafts Cyclization
of Two Different Alcohols
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