Synthesis of Indenes by a BF3·OEt2-Mediated, One-Pot Reaction of Aryl Homopropargyl Alcohols, Aldehydes, and Arenes

Article abstract of DOI:10.1021/acs.orglett.8b01929

A new and efficient protocol to prepare indenes is reported. Assisted by boron trifluoride diethyl etherate, the one-pot reaction of aryl homopropargyl alcohols and aldehydes in the presence of arenes yielded indene derivatives. The reaction was studied with various substrates, which suggests a cascade reaction including a sequence of Prins, Friedel-Crafts, ring-opening reactions, and Friedel-Crafts to form three C-C bonds leading to indenes.

Full text of DOI:10.1021/acs.orglett.8b01929

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Indenes by a BF3·OEt2‑Mediated, One-Pot Reaction of
Aryl Homopropargyl Alcohols, Aldehydes, and Arenes
Trimurtulu Kotipalli and Duen-Ren Hou*
Department of Chemistry, National Central University, No. 300 Jhong-Da Road, Jhong-li, Taoyuan 32001, Taiwan
S
* Supporting Information
ABSTRACT: A new and efficient protocol to prepare indenes is reported. Assisted by
boron trifluoride diethyl etherate, the one-pot reaction of aryl homopropargyl alcohols
and aldehydes in the presence of arenes yielded indene derivatives. The reaction was
studied with various substrates, which suggests a cascade reaction including a sequence
of Prins, Friedel−Crafts, ring-opening reactions, and Friedel−Crafts to form three C−C
bonds leading to indenes.
he indene framework is frequently found in natural
products,1 pharmaceutically active compounds,2 func-
according to TLC analysis and the spectroscopic data (IR and
1H, 13C NMR) of the major product were consistent with the
reported indene derivative 3a with a 30% isolated yield.11b The
structural assignment was also confirmed by X-ray crystallog-
raphy (see the Supporting Information for the ORTEP of 3a). In
addition to the moieties of 1a and 2a, the incorporation of a
benzene molecule into product 3a was interesting and prompted
us toward further study. Several reaction factors, such as the
stoichiometry of boron trifluoride diethyl etherate, Lewis acids
and reaction time were screened. The results are summarized in
Table 1. The yields of 3a increased as the amount of BF3·OEt2
increased (entries 1−4); however, more impurities were
observed when 5 equiv of BF3·OEt2 were applied. Prolonging
the reaction time did not improve the yield (entry 5). The
reaction also proceeded to yield 3a with 10 equiv of benzene in
CH2Cl2 (entry 6) or was promoted by trimethylsilyl triflate and
T
tional molecules,3 and ligands for metal complexes.4 It is not
surprising that syntheses of indenes and their derivatives
continue to receive chemists’ attention, and many methods
have been developed to prepare this important carbocycle,5
which include the dehydration of indanols,6 intramolecular
cyclization of conjugated alkenes or alkynes,7 arene cyclization
involving various metal-catalyzed C−H activations,8 Brønsted
or Lewis acid catalyzed intramolecular Friedel−Crafts cycliza-
tion of aryl−allylic carbocations,6a,9 and various cascade
reactions using propargyl alcohols.10 Indenes have also been
prepared by Lewis acid catalyzed cycloaddition reactions of
arylidenecyclopropanes with aldehydes, acetals, or aldimines (eq
1).11 Here, we report that indene derivatives could also be
Table 1. Optimization of the Reaction Conditions
a
b
entry
Lewis acid
equiv
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
TMSOTf
TfOH
1.0
2.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
1
1
1
1
2
1
12
2
30
40
64
68
66
c
28
prepared from homopropargyl alcohols, aldehydes and arenes,
promoted by boron trifluoride diethyl etherate at room
temperature (eq 2). The reactions between homopropargyl
alcohols and aldehydes are known to form furans (eq 3)12 via
Lewis acid catalyzed Prins cyclizations.13,14 In the presence of
aromatic solvents and boron trifluoride diethyl etherate, we
found that the cascade reaction was further extended to yield
indenes.
26
19
0
d
FeCl3
12
a
Reactions were conducted with 1a (0.25 mmol), 2a (0.28 mmol) in
b
c
benzene (1 mL). Isolated yields. Reactions were conducted with 1a
(0.25 mmol), 2a (0.28 mmol), benzene (2.5 mmol) in CH2Cl2 (1
d
mL). Unidentified mixture.
Our investigation started with the reaction of 4-phenylbut-3-
yn-1-ol (1a) and benzaldehyde (2a) in benzene and the
presence of BF3·OEt2. The reaction was complete in 1 h
Received: June 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
trifluoromethanesulfonic acid; however, the yields were lower
(entries 6−8). The reaction using iron(III) chloride was
sluggish to yield a complicated mixture (entry 9). Other Lewis
acids, such as CF3CO2H, InCl3, Fe(OTf)2, and Zn(OTf)2, failed
to induce the reactions, and the starting materials were
recovered.
Table 2. Synthesis of Indene with Various Aldehydes
Various aldehydes were applied to examine the reaction scope
with this optimized reaction condition (3 equiv of BF3·OEt2 in
benzene, 0 °C to rt, Table 2). All of the para-substituted
benzaldehydes provided the desired indene products (3b−i,
entries 1−8) with moderate to good reaction yields (55−90%),
which indicate that the reaction is not sensitive to the electronic
properties of aldehydes imposed by the para-substituents. The
ortho-substituted benzaldehydes also gave satisfactory yields
(3j−l, entries 9−11), and the reaction was not deterred by the
sterically more hindered 2,6-dichlorobenzaldehyde (entry 13).
Although 3-methoxybenzaldehyde provided a fair yield (49%,
entry 12), slightly better results were observed for other 3-
alkoxy-substituted benzaldehydes (entries 14 and 15). Other
aromatic aldehydes, such as cinnamaldehyde and thiophene-2-
carbaldehyde, were also good substrates and converted to the
corresponding indenes (3q and 3r, entries 16 and 17). Aliphatic
aldehydes were compatible for this process (entries 18−21);
however, their yields decreased as the steric hindrance around
the carbaldehyde group increased. Overall, many aryl and alkyl
aldehydes could be converted to indenes by this simple, three-
component reaction with fair to good yields.
In contrast to the high tolerance of aldehydes, we found that
this reaction is sensitive to the substituents on the
homopropargyl alcohols (Table 3). The reactions of 4-(4-
chlorophenyl)-3-butyn-1-ol (1b) with three aldehydes 2d, 2j,
and 2p, provided the indenes 3bd, 3bj, and 3bp, respectively
(entries 1−3). The location of the chloro substituent was
unambiguously determined by X-ray crystallography of 3bj
(Figure 1). However, the reaction of methyl-substituted alcohol
1c gave a pair of regioisomers 3cg and 3cg′, which suggests a
competition between the phenyl and tolyl groups during the
formation of the indene moiety (vide infra). Interestingly,
alcohol 1d bearing an electron-donating methoxy group
afforded the known conjugated enone 4,15 derived from a
formal alkyne−carbonyl metathesis of 1d and benzaldehyde.16
No indene was generated from the reaction of the
homopropargyl alcohol bearing an electron-deficient p-nitro-
benzene (1e, entry 6). The inertness of aliphatic 3-pentynol (1f)
and methyl ether 1g under this condition (entries 7 and 8)
indicates that the aromatic alkynyl moiety and the hydroxyl
group are essential for the reaction.
On the basis of the above results and previous studies,12b,c
a
plausible mechanism for the formation of indenes is proposed
(Scheme 1). Boron trifluoride initiated the reaction of
homopropargyl alcohol and aldehyde to form the oxonium
cation A. The following Prins-type cyclization yielded the
exocyclic vinyl cation B, which was the electrophile for the
Friedel−Crafts reaction of benzene and the precursor of
intermediate C. The equilibrated, ring-opening rearrangement
gave the allyl carbocation D, which was intercepted by the more
electron-rich aryl group to produce thermodynamically stable
indene 3. Many aldehydes that can form oxonium cation A and
allow the following Prins-type cyclization are compatible with
this process. On the other hand, the R2 substituent has a direct
influence on the formation of vinyl cation B. Thus, the reaction
was obstructed by an electron-withdrawing R2 group, such as the
nitro group of 1e (entry 6, Table 3); however, the electron-
a
Reactions were conducted with 1a (0.25 mmol), aldehyde (0.28
b
mmol), and BF3·OEt2 (0.75 mmol) in benzene (1 mL). Isolated
yields. Reaction time: 12 h.
c
donating methoxy group seems to stabilize intermediate B well
and thwart the following Fridedel−Crafts reaction to give 4
(entry 5, Table 3). The reaction using 4-methyl-substituted 1c
proceeded but gave a mixture of regioisomers due to the
B
DOI: 10.1021/acs.orglett.8b01929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Synthesis of Indene with Substituted Alcohols
Scheme 1. Proposed Mechanism for the Formation of indene
3
Scheme 2. Reactions Conducted in Different Solvents
dimethoxybenzene gave single product 3x. The results are
consistent with the relative reactivity of the corresponding aryl
groups toward to the allyl cation in the intermediates D1 and
D2. No indene product could be found when the reaction was
carried out in bromobenzene.
In summary, a new approach to access indenes is developed
through a sequence of Prins, Friedel−Crafts, ring-opening and
Friedel−Crafts reactions including three C−C bond formations.
This method has the advantages of broad substrate scope in
aldehydes, readily available substrates and a metal-free, simple
one-pot procedure. The intermolecular Friedel−Crafts reaction
between the vinyl cations and arenes is especially attractive
because the effort needed to prepare the highly strained
arylidenecyclopropanes is circumvented. Further studies on
the tandem Prins/Friedel−Crafts reactions and their application
in synthesis are in progress.
a
Reactions were conducted with 1a (0.25 mmol), aldehyde (0.28
b
c
mmol) in benzene (1 mL). Isolated yields. Unidentified mixture.
d
Starting materials recovered.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01929.
Experimental procedures and spectral data of compounds
described herein (PDF)
Figure 1. ORTEP of 3bj.
Accession Codes
competition between the two aryl groups in the intramolecular
Friedel−Crafts-type cyclization of D to form indenes 3cg and
3cg′ (entry 4, Table 3). The issue of competition was relieved in
1a (R2 = H) and the chloro-substituted 1b (R2 = Cl), which
gives a symmetrical D or has a deactivated chlorophenyl group
for the Friedel−Crafts-type reaction, respectively.
The above mechanism was also supported by the results
obtained from the reactions performed in p-xylene or 1,4-
dimethoxybenzene/CH2Cl2 (Scheme 2). The 1H and 13C NMR
spectra indicated that the reaction in p-xylene provided a pair of
regioisomers (3w and 3w′), and the reaction in 1,4-
CCDC 1846842 and 1847193 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: drhou@ncu.edu.tw.
C
DOI: 10.1021/acs.orglett.8b01929
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
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Duen-Ren Hou: 0000-0003-1072-2915
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Ministry of Science and
Technology (MOST 106-2113-M-008-001), Taiwan. We thank
Ms. Ping-Yu Lin at the Institute of Chemistry, Academia Sinica,
Taiwan, and the Valuable Instrument Center at National Central
University, Taiwan, for mass analysis.
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