Synthesis of highly substituted indene derivatives by Br?nsted acid catalyzed Friedel-Crafts reaction of homoallylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2014.05.027

An efficient synthetic method to prepare highly substituted indenes in moderate to excellent yields that relies on Br?nsted acid catalyzed Friedel-Crafts reaction of homoallylic alcohols under mild conditions is described.

Full text of DOI:10.1016/j.tetlet.2014.05.027

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Synthesis of highly substituted indene derivatives by Brønsted acid
catalyzed Friedel–Crafts reaction of homoallylic alcohols
Xiaoxiang Zhang a,b, , , Wan Teng Teo b, , Weidong Rao b, Dik-Lung Ma c, Chung-Hang Leung d,
⇑
Philip Wai Hong Chan b,
⇑
a College of Chemical Engineering, Jiangsu Key Lab of Biomass-based Green Fuels and Chemicals, Nanjing Forestry University, Nanjing 210037, China
b Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
c Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
d State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method to prepare highly substituted indenes in moderate to excellent yields that
Received 28 January 2014
Revised 27 April 2014
Accepted 8 May 2014
Available online xxxx
relies on Brønsted acid catalyzed Friedel–Crafts reaction of homoallylic alcohols under mild conditions is
described.
Ó 2014 Published by Elsevier Ltd.
Keywords:
Brønsted acid
Homoallylic alcohols
Homogeneous catalysis
Friedel–Crafts reaction
Indene derivatives
Indenes are important synthetic targets in organic chemistry
because of the prevalence of the structural ring motif in many
natural products, biologically active pharmaceutical agents, and
functional materials.1–3 They are also useful as ligands in the
development of olefin polymerization reactions.4 It is therefore
not surprising to find a myriad of elegant methods for their synthe-
sis being established over the years.1,5–11 This has included syn-
thetic strategies such as CÀH bond activation,5 CÀC bond
cleavage,6 [3+2] cycloadditions,7 thermal cascade,8 and skeletal
rearrangements mediated by a variety of transition metals and
Lewis and Brønsted acid and base catalysts.9–11
Metal-free mediated methods for indene synthesis that have
made use of unsaturated alcohols as electrophilic precursors have
often relied upon the allylic, benzylic, or propargylic derivatives of
the substrate.11,12 To our knowledge, a synthetic approach to
indene derivatives from other members of the unsaturated alcohol
family of compounds such as homoallylic alcohols, by contrast, has
not been explored. Added to this, the benzofused ring forming
transformations typically required a stoichiometric amount of
the catalyst. The cyclization of 3-iodoprop-2-en-1-ols to 3-iodoind-
enes mediated by BF3ÁEt2O has, thus far, remained the one and only
example whereby the Lewis acid is employed in a catalytic
amount.11c In this context and as part of an ongoing program
exploring the scope of unsaturated alcohols in organic synthesis,13
our discovery that p-TsOHÁH2O can affect the Friedel–Crafts
reaction of readily accessible homoallylic alcohols of the type 1 is
reported herein (Scheme 1). This provides a convenient synthetic
route to a variety of substituted indene derivatives 2 in moderate
to excellent yields.
We began by examining the cycloisomerization of 2-methyl-
1,1-diphenylbut-3-en-1-ol 1a by a variety of Brønsted acids to
establish the reaction conditions (Table 1). This initially revealed
that subjecting 0.3 mmol of 1a in 1,2-dichloroethane to 10 mol %
of p-TsOHÁH2O at reflux for 0.5 h gave 1,2-dimethyl-3-phenyl-1H-
indene 2a in 99% yield (entry 1). A comparable product yield was
⇑
Corresponding authors. Tel.: +86 25 85427024; fax: +86 25 85418873 (X.Z.);
tel.: +65 6316 8760; fax: +65 6791 1961 (P.W.H.C.).
E-mail addresses: s070038@hotmail.com (X. Zhang), waihong@ntu.edu.sg
(P.W.H. Chan).
Scheme 1. Synthetic strategy for the synthesis of highly substituted indenes from
These authors contributed equally to this work.
homoallylic alcohols.
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X. Zhang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
with 1,4-dioxane as the solvent (entries 6 and 8–11). On the other
Optimization of the reaction conditionsa
hand, the analogous reaction with 10 mol % of BF3ÁEt2O as the cat-
alyst gave a product yield of 75% (entry 12). On the basis of the
above results, reaction of 1a with 5 mol % of p-TsOHÁH2O in 1,2-
dichloroethane at reflux for 0.5 h was deemed to provide the opti-
mum conditions.
With the optimized catalytic conditions in hand, we next
explored their generality for a series of homoallylic alcohols 1b–
1r and the results are summarized in Table 2. Reactions of homo-
allylic alcohols 1 bearing an electron-withdrawing group at the
para position of both phenyl rings gave the corresponding substi-
tuted indenes 2b–d in good to excellent yields of 88–98% (entries
1–3). Similarly, the analogous reactions of substrates where the
two phenyl rings contained a pendant electron-donating group at
the para position (1e and 1f) afforded the corresponding substi-
tuted indenes 2e and 2f in 90% and 82% yields, respectively (entries
4 and 5). Starting alcohols in which one of the aryl groups was
replaced by a methyl substituent, as in 1g–1k, were found to be
well tolerated, providing the corresponding indene products 2g–
2k in 58–79% yield (entries 6–10). The presence of a phenyl instead
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
1
p-TsOHÁH2O
p-TsOHÁH2O
p-TsOHÁH2O
p-TsOHÁH2O
p-TsOHÁH2O
p-TsOHÁH2O
p-TsOHÁH2O
Tf2NH
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
PhMe
MeCN
1,4-Dioxane
MeNO2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
0.5
0.5
20
15
15
15
15
15
0.5
15
15
12
99
99
62
94
79
2c
3d
4
5
6
7
8
e
—
68
e
—
—
—
—
e
9
TfOH
f
10
11
12
TFA
H3PO4
g
f
BF3ÁEt2O
75
a
Unless stated otherwise, all reactions were performed at reflux with a catalyst/
1a ratio of 1:10.
of a methyl group at the a-carbon center to the alcohol functional
b
Isolated yield.
group (1m,n) or a vinyl methyl ester unit (1o) in the substrate was
found to have minimal effect on the outcome of the reaction
(entries 12–14). In these reactions, the corresponding indene
derivatives 2m–2o were afforded in 72–76% yield. Tertiary alco-
hols containing N-methyl indole (1l) moiety at the carbinol carbon
c
Reaction conducted with 5 mol % of p-TsOHÁH2O.
d
Reaction conducted at room temperature.
Mixture of unknown decomposition products obtained based on TLC and 1H
e
NMR analysis of the crude reaction mixture.
f
No reaction based on TLC and 1H NMR analysis of the crude reaction mixture.
Used as an 80% solution in H2O.
g
center or in which the identity of the
a-position to the alcohol
group was a methylene carbon center (1p,q) were also examined
under the standard conditions (entries 11, 15, and 16). However,
these reactions were found to give 1,4-diene 3l and 1,3-diene 4p
in 88% and 83% yields, respectively, and for 1q, a mixture of decom-
position products.14 In our hands, the reactivity of the secondary
alcohol 1r was additionally investigated but found to result in
the recovery of the substrate in near quantitative yield (entry 17).
A tentative mechanism for the Brønsted acid catalyzed indene
forming reaction is illustrated in Scheme 2. This could involve
the activation of homoallylic alcohol 1 in the presence of Brønsted
acid to give the cationic species A. As a consequence, dehydration
obtained on decreasing the catalyst loading from 10 to 5 mol % or
repeating the reaction with toluene in place of 1,2-dichloroethane
as the solvent (entries 2 and 4). Lower yields of 62–79% were
furnished when the reaction was conducted with 10 mol % of
p-TsOHÁH2O in 1,2-dichloroethane at room temperature or in
acetonitrile or nitromethane instead of the chlorinated solvent at
reflux (entries 3, 5, and 7). In contrast, either a mixture of unknown
decomposition products or no reaction was observed in control
experiments where p-TsOHÁH2O was replaced with 10 mol % of
Tf2NH, TfOH, TFA, and H3PO4 as the catalyst or 1,2-dichloroethane
Table 2
p-TsOHÁH2O catalyzed reactions of 1b–ra
Entry
Substrate
Product
Time (h)
Yieldb (%)
1
2
2b, R = F
2c, R = Cl
20
3
98
88
3
4
5
2d, R = Br
2e, R = Me
2f, R = OMe
20
0.5
20
88
90
82
1b-1f
6
7
2g, R = Cl
2h, R = Br
14
23
64
58
8
9
10
2i, R = H
2j, R = Me
2k, R = OMe
23
14
12
60
79
77
1g-1k
11
3l
0.5
83
1l
12
13
2m, R = Br
2n, R = H
24
13
73
76
1m,n
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X. Zhang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2 (continued)
Entry
Substrate
Product
Time (h)
24
Yieldb (%)
Ph
Me
14
2o
72
1o
1p
CO2Me
15
16
4p
24
36
88d
c
—
—
—
—
—
1q
1r
e
17
3
—
a
All reactions were performed at reflux in (CH2Cl)2 with a p-TsOHÁH2O/1a ratio of 1:20.
Isolated yield.
b
c
Unknown side products obtained based on 1H NMR analysis of the crude mixture.
Obtained as a 4:1 mixture of regiosomers based on 1H NMR analysis of the crude mixture.
Recovery of starting material based on TLC and 1H NMR analysis of the crude mixture.
d
e
Scheme 4. Proposed formation of 3l.
in 85% yield, which is comparable to that formed from 1a described
in Table 1, entry 1.
As shown in Scheme 4, the preferential formation of 1,4-diene
3l could be due to a more facile 1,3-proton transfer process on for-
mation of the cationic species F from p-TsOHÁH2O mediated dehy-
dration of 1l.15 Deprotonation and re-aromatization of the
resulting iminium intermediate G might then provide the indole
side-product. In the case of 1,3-diene 4p being furnished, this could
be due to resistance to carbocation formation as a result of the
presence of the electron-withdrawing ester and a methylene moi-
Scheme 2. Proposed mechanism.
occurs to deliver the homoallylic carbonium adduct B. Deprotona-
tion of this newly formed adduct might then give 1,3-diene C,
which on re-protonation of the distal C@C bond, would provide
the internal allylic cationic intermediate D. This is the active spe-
cies that undergoes the Friedel–Crafts reaction, which upon re-aro-
matization of the ensuing Wheland intermediate E, would produce
the indene product 2.
ety at the
a
-position to the alcohol group in the adduct. Likewise,
-sub-
while the ionization of 1q might proceed, the absence of an
a
stituent to the alcohol group in the substrate might lead to the
resulting cationic species being less stable and thus more prone
to a variety of decomposition pathways before Friedel–Crafts reac-
tion can proceed. The recovery of the secondary alcohol could be
due to the potential generation of a less stable secondary carbo-
nium species being unfavorable.
In summary, we have developed an efficient approach to highly
substituted indenes from p-TsOHÁH2O catalyzed Friedel–Crafts
reaction of homoallylic alcohols. Achieved under mild conditions,
the reaction was shown to be applicable to a variety of unsaturated
alcohols. Efforts exploring the scope and synthetic applications of
this approach to the benzofused carbocyclic derivative are in pro-
gress and will be reported in due course.
The proposed involvement of 1,3-diene C was supported by the
following control experiments (Scheme 3). Treating a 1,2-dichloro-
ethane solution containing 1a with 5 mol % of p-TsOHÁH2O at room
temperature for 1 h gave 2a along with 4a as a 1:3 inseparable
mixture in 75% yield. On re-treating this mixture of compounds
to the optimized conditions of 5 mol % of p-TsOHÁH2O in 1,2-
dichloroethane at 80 °C for 0.5 h, the desired indene was afforded
p-TsOH.H2O
Ph
(5 mol %)
+
1a
2a
Ph
(CH2Cl)2
1 h, rt
Me
4a
79% yield
2a : 4a =1 : 3
p-TsOH.H2O
(5 mol %)
Acknowledgments
(CH2Cl)2
0.5 h, Δ
85% yield
This work is supported by a College of Science Start-Up Grant
from Nanyang Technological University and
a Tier 1 Grant
Scheme 3. Control experiment with 1a.
(MOE2013-T1-002-035) from the Ministry of Education of
Please cite this article in press as: Zhang, X.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.027

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X. Zhang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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a Young National Natural Science
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