para-Toluenesulfonic Acid Catalyzed Synthesis of Indenes via a Tandem Friedel–Crafts Alkylation/Hydroarylation of Tertiary Propargylic Alcohols with Electron-Rich Arenes

Article abstract of DOI:10.1007/s10562-020-03220-0

A simple protocol to synthesize indenes efficiently by PTSA catalyzed tandem Friedel–Crafts alkylation/hydroarylation of tertiary propargylic alcohol with electron-rich arenes is described. The desired indenes were obtained regioselectively in good to ver

Full text of DOI:10.1007/s10562-020-03220-0

Catalysis Letters
https://doi.org/10.1007/s10562-020-03220-0
para‑Toluenesulfonic Acid Catalyzed Synthesis of Indenes a Tandem
Friedel–Crafts Alkylation/Hydroarylation of Tertiary Propargylic
Alcohols with Electron‑Rich Arenes
Gitumoni Kalita1 · Dipankar Paul1 · Snehadrinarayan Khatua2 · Paresh Nath Chatterjee1
Received: 23 December 2019 / Accepted: 12 April 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
A simple protocol to synthesize indenes efciently by PTSA catalyzed tandem Friedel–Crafts alkylation/hydroarylation
of tertiary propargylic alcohol with electron-rich arenes is described. The desired indenes were obtained regioselectively
in good to very good yields under mild reaction conditions. The allene intermediate was isolated to get an insight into the
mechanistic pathway of the indene forming reaction.
Graphic Abstract
Keywords PTSA · Propargylic alcohol · Electron-rich arene · Indene · Allene
1 Introduction
indenyl-based metallocenes of group 4 and 10 metals are
known for catalysing the olefn polymerization reaction
[11–13]. Due to the biological relevance of indenes, the
synthesis of indene derivatives has always attracted the
attention of organic chemists. Considering the importance
of indene moieties, various methods of indene synthesis
have been reported in literature using alkynes [14–19],
allenes [20–22], and propargylic alcohols [23–35] etc. as
the substrates in presence of Lewis acid or Brønsted acid
catalysts. Easily accessible propargylic alcohols which
involve two functional groups (alkyne and hydroxyl) have
often served as suitable starting substrates for the syn-
thesis of a variety of organic motifs [36]. In 2009, Chan
et al. reported the synthesis of indenols from propargylic
alcohols and substituted phenols using Yb(OTf)3 as the
catalyst (Scheme 1) [28]. Roy et al. reported an easy
access to indenes from propargylic alcohols and arenes in
the presence of their in-house synthesized heterobimetal-
lic catalyst [Ir(COD)(SnCl3)Cl(µ-Cl)]2 (Scheme 1) [37].
Indene scafolds are available in many natural products
and biologically active pharmaceutical compounds [1–5].
The indene motifs constitute an integral part of several
pharmaceutical compounds such as anti-tumour drug
Dichroanal B [6], anti-infammatory drug Sulindac [7,
8], estrogen receptor agonist [9, 10], etc. (Fig. 1). The
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-020-03220-0) contains
supplementary material, which is available to authorized users.
* Paresh Nath Chatterjee
paresh.chatterjee@nitm.ac.in
1
Department of Chemistry, National Institute of Technology
Meghalaya, Bijni Complex, Laitumkhrah, Shillong,
Meghalaya 793003, India
2
Centre for Advanced Studies, Department of Chemistry,
North Eastern Hill University, Shillong, Meghalaya 793022,
India
Vol.:(0123456789)
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G. Kalita et al.
Fig. 1 Biologically important
molecules bearing indene motifs
MeS
HO
OH
HO
F
OH
O
OH
CHO
Dichroanal B
Anti-tumour agent
Sulindac
Indenestrol A
Agonist of estrogen receptor
Anti-inflammatory agent
Scheme 1 Comparison of the literature with the present method
However, inert reaction conditions, difculty in synthe-
sizing the Roy’s catalyst as well as high expense (due to
iridium) makes their protocol less popular. To address
these drawbacks, we planned to develop a simple protocol
to construct the indene carbocycles from easily accessible
starting materials using commercially available Brønsted
acid catalyst. In this report, we describe a method to syn-
thesize indene derivatives via a tandem Friedel–Crafts
alkylation/hydroarylation of tertiary propargylic alcohols
with sterically bulky and electron-rich arenes/heteroarenes
in presence of commercially available and non-toxic p-tol-
uenesulfonic acid (PTSA) catalyst under air atmosphere
(Scheme 1). The reactions proceeded smoothly to give the
indenes regioselectively in good yields for a wide variety
of substrates under mild reaction conditions.
2 Results and Discussion
To achieve the optimized reaction conditions, initially we
chose 1,1,3-triphenylprop-2-yn-1-ol 1a and 1,3,5-trimeth-
oxybenzene 2a as the starting materials for the synthesis
of 1,1-diphenyl-3-(2,4,6-trimethoxyphenyl)-1H-indene
3a (Table 1). We screened several Brønsted and Lewis
acid catalysts at 80 °C using MeCN solvent to choose
an efcient catalyst for the desired reaction. Among the
screened Brønsted acids (Table 1, entries 1–3), we isolated
the desired indene 3a with highest yield (85%) in pres-
ence of PTSA catalyst regioselectively. Lewis acid cata-
lysts such as BiCl3, SnCl2.2H2O, SnCl4, FeCl3, and ZnCl2
were unable to surpass the catalytic efciency shown by
PTSA (Table 1, entries 5–9). We also used several organic
1 3

para-Toluenesulfonic Acid Catalyzed Synthesis of Indenes a Tandem Friedel–Craft…
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Time (h)
Temp. (°C)
Yield of
3a (%)b
1
2
3
4
5
6
7
8
PTSA
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeNO2
DCE
CHCl3
hexane
EtOH
chlorobenzene
THF
1
1
1
1
1
1
1
1
5
1
1
1
1
1
1
5
5
5
1
1
5
80
80
80
80
80
80
80
80
80
80
80
60
60
80
80
60
25
55
80
80
80
85
80
77
47
68
42
59
65
25
70
34
57
30
45
63
–
CF3SO3H
CF3COOH
Molecular I2
BiCl3
SnCl2·2H2O
SnCl4
FeCl3
ZnCl2
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
PTSA
9
10
11
12
13
14
15
16
17
18
19c
20d
21
MeCN
MeCN
MeCN
MeCN
MeCN
–
30
74
83
–
PTSA
No catalyst
aReaction conditions: 1a (1.0 mmol), 2a (1.1 mmol), catalyst (10 mol%), solvent (2.0 mL), Temperature 80 °C
bIsolated yields
cCatalyst (5 mol%)
dCatalyst (15 mol%)
solvents such as MeCN, MeNO2, DCE, CHCl3, hexane,
The highest yield of 3a was obtained in MeCN solvent
within 1 h (Table 1, entry 1). In particular, THF as solvent
at 60 °C did not lead to product formation (Table 1, entry
EtOH, and chlorobenzene to examine the efect of solvent
in the indene forming reaction (Table 1, entries 10–15).
1 3

G. Kalita et al.
Fig. 2 List of tertiary propargylic alcohols 1 and electron-rich arenes 2 employed in the study
16). We also examined the efect of temperature which
showed that the reaction did not yield the desired indene
at room temperature instead allene 4a was obtained in 82%
(Table 1, entry 17). When we increased the temperature to
55 °C, the reaction gave 30% yield of 3a along with 65% of
4a after 5 h (Table 1, entry 18). Further studies regarding
the formation of allene 4a is discussed later. Besides, we
have studied the efect of catalyst loading in the reaction
and found that 10 mol% loading of PTSA catalyst was
adequate for the synthesis of indene 3a (Table 1, entries
19–20). Both the starting materials, 1a and 2a, remained
unreacted in absence of catalyst (Table 1, entry 21).
in the reaction medium producing the desired indene 3l in
62% yield. We have also established the versatility of the
reaction by taking diferent types of nucleophiles such as
2b–e as the coupling partner with propargylic alcohol 1a and
in all cases, the corresponding indenes 3m–p were isolated
in good yields (62–77%). It is to be noted that, 1,3,5-tri-
methoxybenzene 2a showed superior results in the indene
formation reaction due to its higher steric bulkiness and
electron-richness in comparison to 3,5-dimethoxy toluene
2b. It is worth to mention that, when 1,2,3-trimethoxyben-
zene 2c was employed as the electron-rich arene, we iso-
lated an indene 3n that was formed by the intramolecular
hydroarylation of the incoming arene 2c. Under the standard
reaction conditions, the 1,2-disubstituted indoles 2d and 2e
reacted well with the propargylic alcohol 1a to produce the
desired indenes 3o and 3p in good yields, respectively.
While extending the substrate scope of the present reac-
tion, we had another interesting observation (Scheme 3).
In the presence of less electron-rich arene 1,3-dimethoxy-
benzene 2f the reaction with propargylic alcohol 1a did not
aford the desired indene 3q even after prolonged reaction
time and instead, it solely generated the allene product 4b
in 76% yield. Very recently, Sanz et al. have reported the
PTSA catalyzed synthesis of tetra-substituted allene 4b
from tertiary propargylic alcohol 1a at room temperature in
MeCN solvent together with the regioisomer of the allene
product [38]. In case of other less electron-rich arenes, such
as 2,6-dimethylanisole 2g, anisole 2h and mesitylene 2i,
the propargylic alcohol 1a rearranged to the α,β-conjugated
ketone 5 through Meyer-Schuster rearrangement [39, 40]
instead of producing the indene (3r–t) or allene (4c–e)
product via the coupling reaction (Scheme 3). We have also
noted that, the propargylic alcohol 1a rearranged to the α,β-
conjugated ketone 5 through Meyer-Schuster rearrangement
in presence of PTSA (10 mol%) in MeCN at 80 °C.
After achieving the optimized reaction conditions, we
explored the generality of the present method by varying
the tertiary propargylic alcohols 1 and electron-rich arenes
2 as listed in Fig. 2 for the regioselective synthesis of indene
carbocycles 3 (Scheme 2). The propargylic alcohols 1 with
pendant electron-donating and electron-withdrawing sub-
stituents on the carbinol or alkyne carbon reacted with 2a
to give the desired indenes 3 in good to very good yields
(80–87%). We observed that the propargylic alcohols with
two aryl substituents at the carbinol carbon (1a–f) gave very
good yields of their corresponding indenes (3a–f) within
1 h. We observed that, propargylic alcohol 1f containing
heteroaromatic ring (3-thienyl) at the terminal position
of the alkyne of the propargylic alcohol also yielded its
corresponding product 3f in good yield. The structure of
indene 3a was established by X-ray crystallographic analysis
(CCDC-1960285; see supplementary fle). We also tested
the efect of an aliphatic substituent at the carbinol carbon
(i.e. R′=Me) of the propargylic alcohols (1g–l) and found
that, lower yields (62–78%) were obtained for their cor-
responding indenes 3g–l after prolonged reaction time. In
general, we noticed that, the propargylic alcohols with elec-
tron-withdrawing substituents at the carbinol carbon gave
better yields of the indenes than the propargylic alcohols
with electron-donating substituents. Noteworthy is the fact
that, a heteroaromatic substituent (2-thienyl) at the carbinol
carbon of the propargylic alcohol 1l can nicely be tolerated
The outcome of the reaction between propargylic alcohol
1a and less electron-rich arene 2f in Scheme 3 gave us a
hint of the probable interplay of allene intermediate in this
reaction [37]. To get an insight into the plausible reaction
1 3

para-Toluenesulfonic Acid Catalyzed Synthesis of Indenes a Tandem Friedel–Craft…
Scheme 2 PTSA catalysed synthesis of indenes
1 3

G. Kalita et al.
Scheme 3 Efect of less electron-rich arenes in the reaction
Scheme 4 Isolation of allene intermediate 4a and its conversion to the indene product 3a
mechanism we aspired to isolate the allene intermediate.
In this regard, we put up a reaction of propargylic alcohol
1a with 1,3,5-trimethoxybenzene 2a in presence of PTSA
catalyst at room temperature in MeCN solvent and success-
fully isolated the allene intermediate 4a in 82% yield after
2 h (Scheme 4) [38]. On retreating the allene intermediate 4a
to the optimized reaction conditions of 10 mol% of PTSA in
MeCN at 80 °C for 1 h, the expected indene 3a was obtained
in 88% yield. In absence of the PTSA catalyst, the allene
intermediate remained unreacted in MeCN solvent at 80 °C
after 5 h.
Based on the above fndings and the knowledge of rel-
evant literature, the probable mechanism of formation of
indene 3 is proposed in Scheme 5. The reaction might be ini-
tiated by the activation of the propargylic alcohol 1 in pres-
ence of proton donor PTSA to form an ambident electrophile
1 3

para-Toluenesulfonic Acid Catalyzed Synthesis of Indenes a Tandem Friedel–Craft…
Scheme 5. Plausible mechanism of indene 3 formation
A. The electron-rich and sterically bulky arenes 2 would
prefer to attack the less crowded electrophilic acetylenic car-
bon centre of A via the Friedel–Crafts reaction producing
an allene intermediate 4. The allene intermediate 4 would
undergo intramolecular hydroarylation followed by rearo-
matization in the reaction conditions to provide the desired
indene derivative 3. We observed that when the electron-
rich and sterically bulky arene moiety (e.g. 2,4,6-trimeth-
oxyphenyl, 2,6-dimethoxy-4-methylphenyl, 2-methylindolyl
derivatives) in intermediate 4 has its both ortho-carbons
substituted, the aromatic/heteroaromatic ring connected to
the same allenic carbon that of the electron-rich arene (Ar′)
of the allene intermediate participates in the intramolecu-
lar hydroarylation step generating product 3a–m, 3o–p via
the rearomatization of species B (path a). In contrast, the
hydroarylation step is completed by the electron-rich and
sterically bulky arene moiety (e.g. 2,3,4-trimethoxyphe-
nyl) in intermediate 4 when it has at least one ortho-carbon
unsubstituted as in the case of formation of indene 3n via
the species Bʹ (path b). A pivotal role of the Brønsted acid
catalyst PTSA and temperature (80 °C) was noticed not only
during the Friedel–Crafts alkylation reaction but also for
the subsequent hydroarylation reaction as suggested by the
studies presented in Scheme 4.
3 Conclusion
In summary, a simple protocol is developed for the synthesis
of indene derivatives from easily accessible tertiary propar-
gylic alcohols and electron-rich arenes using commercially
available, cheap, non-toxic PTSA catalyst in our laboratory.
The reaction of a wide range of propargylic alcohols con-
taining diferent aliphatic and aromatic substituents with
structurally diferent electron-rich arenes was examined to
express the generality of the reported procedure. In the pres-
ence of less electron-rich arenes the formation of indene
did not take place from tertiary propargylic alcohol, instead
the reaction leads to the formation of allene or unsaturated
ketones (via Meyer–Schuster rearrangement). The investiga-
tion of the mechanistic pathway associated with the reaction
revealed the involvement of an allene intermediate which
was confrmed by isolating the allene intermediate. The iso-
lated allene intermediate was further converted to the desired
indene product in the presence of PTSA catalyst at 80 °C.
The methodology presented in this article could be a mean-
ingful addition to the existing methods of indene synthesis.
Further investigation of the reaction mechanism, substrate
scope and application of indene products are currently under
study in our laboratory.
1 3

G. Kalita et al.
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Acknowledgements Science and Engineering Research Board (SERB)
is gratefully acknowledged for fnancial support to P. N. C (Sanction
Order No. SB/FT/CS-115/2014; dated 24/08/2015).G. K. thanks
TEQIP III and D. P. thanks NIT Meghalaya for fnancial support. P.
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