Efficient synthesis of substituted indene derivatives

Article abstract of DOI:10.1080/00397911.2014.883634

An efficient protocol for the synthesis of new functionalized indenes 3 was successfully realized. Thus the coupling reaction of allyl acetate 2 with Grignard reagents in the presence of a catalytic amount of LiCuBr₂ at low temperature afforded pure ethyl 1-alkyl-1H-indenes-2-carboxylate 3 in good yields. Copyright

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Efficient Synthesis of Substituted Indene
Derivatives
Sonia Taktouk a , Jihène Ben Kraiem a & Hassen Amri a
a Laboratory of Selective Organic Synthesis and Biological Activity,
Faculty of Science , El Manar University , Tunis , Tunisia
Accepted author version posted online: 03 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Sonia Taktouk , Jihène Ben Kraiem & Hassen Amri (2014) Efficient
Synthesis of Substituted Indene Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:14, 2004-2011, DOI:
10.1080/00397911.2014.883634
To link to this article: http://dx.doi.org/10.1080/00397911.2014.883634
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Synthetic Communications1, 44: 2004–2011, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.883634
EFFICIENT SYNTHESIS OF SUBSTITUTED INDENE
DERIVATIVES
`
Sonia Taktouk, Jihene Ben Kraiem, and Hassen Amri
Laboratory of Selective Organic Synthesis and Biological Activity,
Faculty of Science, El Manar University, Tunis, Tunisia
GRAPHICAL ABSTRACT
Abstract An efficient protocol for the synthesis of new functionalized indenes 3 was
successfully realized. Thus the coupling reaction of allyl acetate 2 with Grignard reagents
in the presence of a catalytic amount of LiCuBr2 at low temperature afforded pure ethyl
1-alkyl-1H-indenes-2-carboxylate 3 in good yields.
Keywords Allylic acetates; ethyl 1-alkyl-1H-indenes-2-carboxylate; Grignard reagents;
indenols
INTRODUCTION
Substituted indene derivatives are valuable synthetic targets in organic[1–6] and
medicinal chemistry[7,8] because of their important biological activities[9–11] and
applications in functional materials.[12] They are also used as ligands in metallocene
complexes, used in the catalyzing olefin polymerization.[13] In addition, indene scaf-
folds occupy an important place in the carbocyclic products because of the presence
of these moieties in various natural products[14,15] and in a large number of drug can-
didates possessing potential estrogenic bioactivity. Consequently, much effort has
been devoted to the construction of the indene ring system, embodying the use of
catalysts based on transition metals,[16–20] phenyl-substituted allylic alcohols,[21,22]
the ring expansion of suitably substituted cyclopropenes,[23] the reduction=
dehydration of indanones[24] and FeCl3-mediated intramolecular olefin–cationic
cyclization of cinnamates reported very recently.[25] Although the methods men-
tioned above are quite effective in synthesizing simple indenes, some disadvantages
accompany the preparation of functionalized indenes because of long reaction
sequences and strong acidic conditions.[26] In continuation of our interest in the
Received November 21, 2013.
Address correspondence to Hassen Amri, Laboratory of Selective Organic Synthesis and Biological
Activity, Faculty of Science, El Manar University, 2092 Tunis, Tunisia. E-mail: hassen.amri@fst.rnu.tn
2004

SUBSTITUTED INDENE DERIVATIVES
2005
synthesis of carbocyclic compounds,[27] we herein report a facile two-step method-
ology for obtaining highly substituted indene derivatives by the use of new indene
esters 1 as key intermediates.
RESULTS AND DISCUSSION
Very recently, we have uncovered a straightforward protocol for the prep-
aration of new indenols derivatives 1 involving the coupling reaction of a wide var-
iety of aliphatic alcohols with 1-hydroxy-1H-indene-2-carboxylic acid in the presence
of p-toluenesulfonic acid (PTSA) as catalyst (Scheme 1). This methodology afforded
an efficient entry to a variety of new indenol-based molecular models 1,[27] identified
as potent antibacterial agent against a panel of resistant pathogens. The assessment
of radical scavenging capacity of the compounds 1 toward the stable free radical
2,2-diphenyl-1-picrylhydrazyl (DPPH) was measured and these compounds were
found to scavenge DPPH free radical efficiently.
We now report the use of bicyclic bꢀhydroxyesters 1 as ideal intermediates
in the synthesis of new multiply substituted indenes 3. In our approach, the con-
struction of indene carbocycles is based on the acetylation of indenols compounds
1 followed by the displacement reaction of allylic acetates using magnesium dialkyl
cuprates generated in situ. The retrosynthetic scheme of this approach is represented
in Scheme 2.
The starting synthetic sequence shown in Scheme 3 is based on the use of allyl acet-
ates 2, obtained from the conversion of the corresponding alcohols in the presence of
acetic anhydride in the presence of a drop of concentrated sulfuric acid as a catalyst.[28]
All reactions worked well to give the desired 1-acetoxy-1H-indene-2-carboxylates 2a–e
in moderate to good yields as shown in Table 1, whose characterization was performed
Scheme 1. Synthesis of indenols derivatives.
Scheme 2. Retrosynthetic analysis.
Scheme 3. Acetylation of bicyclic b-hydroxyesters 1.

2006
S. TAKTOUK, J. B. KRAIEM, AND H. AMRI
Table 1. Preparation of allyl acetates 2a–e from the corresponding secondary
alcohols 1
R
Product
Yielda (%)
Me
Et
2a
2b
2c
2d
2e
75
80
89
68
78
Pr
i-Pr
n-Bu
1
aYields refer to the pure isolated products characterized by H NMR, 13C NMR,
and HRMS.
Scheme 4. Organocuprates addition to acetate 2b.
1
by spectroscopic methods such as infrared (IR), H NMR, 13C NMR, and HRMS
(Scheme 3, Table 1).
In this context, several years ago it was demonstrated that the application of
various Morita–Baylis–Hillman acetates,[29–32] homologous to the allyl acetates 2,
served efficiently as useful substrates in some organic transformation protocols[31,33]
and as an outstanding intermediates for allylic amination,[34–36] organo-catalytic
allylic alkylation[30,31,33,37–41] and nucleophilic displacement.[32,42] On the basis of
these applications, it occurred to us that it would be interesting to examine the elec-
trophilic reactivity of the unprecedented 1-acetoxy-1H-indene-2-carboxylates 2a–e
toward organocuprates reagents, as such study will provide the desired indenes 3.
Indeed, we found that the conjugate addition of dialkyl organocuprates reagents,
generated in situ at low temperature from Grignard reagents in the presence of
a catalytic amount of LiCuBr2, to the allylic acetate 2b led to the corresponding ethyl
1-alkyl-1H-indenes-2-carboxylate 3a–d in moderate to good yields through an usual
displacement addition–elimination or nucleophilic SN20. The results are summarized
in Scheme 4 and Table 2.
To the best of our knowledge, this is the first report in the synthesis of various
functionalized indenes derivatives 3 from available indenol-based molecular models
1. Nowadays the procedures for preparation of indene are widely developed with the
use of expensive catalysts based on transition metals, palladium, platinum,
ruthenium, and niobium, and hence the originality and the simplicity of our protocol
in the synthesis of substituted and functionalized indenes 3.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on Bruker AMX 300 spec-
trometer working at 300 and 75 MHz respectively for the proton and 13C with CDCl3

SUBSTITUTED INDENE DERIVATIVES
2007
Table 2. Synthesis of ethyl 1-alkyl-1H-indenes-2-carboxylate 3a–d
Entry
RMgX (equiv)
Time (min)
Product 3
Yields (%)a
1
EtMgBr (2.0)
10
81
82
72
2
3
i-PrMgBr (2.5)
i-BuMgBr (2.2)
12
15
4
PhCH2MgBr (2.0)
10
75
aYields refer to the pure isolated products characterized by 1H and 13C NMR.
as solvent and Tetramethylsilane (TMS) as the internal standard. The chemical shifts
(d) and coupling constants (J) are, respectively, expressed in parts per million (ppm)
and hertz (Hz). All NMR spectra were acquired at room temperature. Assignments
of proton (1H NMR) and carbon (13C NMR) signals were secured by distortionless
enhancement by polarization transfer (DEPT) 135, nuclear Overhauser effect spec-
troscopy (NOESY), heteronuclear multiple quantum correlation (HMQC), and het-
eronuclear multiple bond correlation (HMBC) experiments. Multiplicity of peaks is
indicated by the following: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. IR
spectra were recorded on an Equinox 55 spectrophotometer. HRMS analyses were
performed with a Maldi-TOF-TOF technique on a Bruker Autoflex III Smartbeam.
All reactions were monitored by TLC, performed on Merck aluminium-backed
plates precoated with silica (0.2 mm, 60 F254), which were visualized either by
quenching of ultraviolet fluorescence (kmax ¼ 254 nm) or by charring with KMnO4
TLC dip. Flash chromatography (FC) was performed on silica gel (Merck Kieselgel
60 F254, 230–400 mesh).
General Procedure for the Synthesis of 1-Acetoxy-1H-
indene-2-carboxylic Acid Alkyl Ester 2a–e
A drop of concentrated sulfuric acid was added to a mixture of alcohol 1
(5 mmol) and acetic anhydride (25 mmol) in 40 mL of anhydrous ether cooled at
0 ꢁC under stirring in a nitrogen atmosphere. After completion of the reaction, the
mixture was hydrolyzed with ice water and extracted with ether (3 ꢂ 20 mL). The

2008
S. TAKTOUK, J. B. KRAIEM, AND H. AMRI
organic layers were washed successively with sodium hydroxide solution (1.5 M) and
brine until neutral pH then dried over MgSO4 and concentrated in vacuo. After
evaporating of the solvent, the residue was purified by silica-gel column chromato-
graphy (AcOEt=hexane, 7:3).
The spectral (1H and 13C NMR and HRMS) data of the unknown compounds
2a–e are given.
Selected Data: 1-Acetoxy-1H-indene-2-carboxylic Acid Methyl Ester 2a
1
Yield: 75% as a white solid; mp 66–68 ꢁC. IR (ATR): 1711, 1230 cmꢀ1; H
NMR (300 MHz, CDCl3): 7.67 (s, 1H); 7.49–7.32 (m, 4H); 6.65 (s, 1H); 3.82
(s, 3H); 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3): 170.9; 163.6; 144.0; 143.6;
140.1; 136.2; 129.3, 129.1, 125.0, 123.9; 74.5; 51.7; 21.0. HRMS calculated for
C13H12O4Na [MþNa]þ 255.06278; found 255.06244.
Organocuprate Addition to Acetate 2b: Typical Procedure
A solution of alkylmagnesium halide RMgX (2–2.5 equiv.) was added drop-
wise over a period of 15 min to a mixture of ethyl 1-acetoxy-1H-indene-2-carboxylate
2b (2 mmol) and a 1 M solution of LiCuBr2 (0.15 mL) diluted in dry THF (10 mL)
at ꢀ 60 ꢁC under nitrogen. After a few minutes, the reaction mixture was quenched
with saturated NH4Cl solution (10 mL) and then extracted with ether (3 ꢂ 15 mL).
The combined organic layers were dried over MgSO4, filtered, and evaporated under
reduced pressure. The crude product was purified by column chromatography on
silica gel (EtOAc=hexane, 1:9) to afford ethyl 1-alkyl-1H-indene-2-carboxylates 3a–d.
Selected Data: 1-Ethyl-1H-indene-2-carboxylic Acid Ethyl Ester 3a
Yield: 81% as a yellow oil. 1H NMR (300MHz, CDCl3): 7.69 (s, 1H); 7.48–7.29
(m, 4H); 4.30 (q, 2H, J ¼ 6.0 Hz); 3.83 (t, 1H, J ¼ 6.5 Hz); 2.18 (quintuplet, 2H,
J ¼ 6.5 Hz); 1.36 (t, 3H, J ¼ 6.0 Hz); 0.55 (t, 3H, J ¼ 6.5 Hz); 13C NMR (75 MHz,
CDCl3): 164.8; 149.3; 142.0; 141.3; 140.5; 127.5; 126.9; 123.4; 123.3; 60.2; 50.2; 23.0;
14.4; 8.6. HRMS calculated for C14H17O2 [MþH]þ 217.12175; found 217.12231.
CONCLUSION
We reported in this paper a novel method to access to recent substituted indene
esters using simple operational resources and inexpensive products. In addition, the
synthesis protocol reported here is likely to provide access to several varieties of
indene-based molecular models which can be used in the development of bioactive
compounds, ligands precursors for metallocene catalyst systems, and some
functional materials.
ACKNOWLEDGMENT
The authors thank Professor Jacques Lebreton (University of Nantes, France)
for logistical help.

SUBSTITUTED INDENE DERIVATIVES
2009
FUNDING
This work was supported by the Higher Education and Scientific Research of
Tunisia.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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