FeCl3 mediated synthesis of substituted indenones by a formal [2+2] cycloaddition/ring opening cascade of o-keto-cinnamates

Article abstract of DOI:10.1039/c5cc03040d

A novel FeCl₃ mediated formal [2+2] cycloaddition/ring opening cascade of o-keto-cinnamates was developed for the synthesis of indenones. The reaction tolerates a broad range of functional groups, including bromide, chloride, amide, acid and es

Full text of DOI:10.1039/c5cc03040d

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DOI: 10.1039/C5CC03040D
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FeCl3 Mediated Synthesis of Substituted Indenones by Formal
[2+2] Cycloaddition/Ring Opening Cascade of O-Keto-Cinnamates
Dattatraya H. Dethe*a and Ganesh M. Murhadea
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel FeCl3 mediated formal [2+2] cycloaddition/ring opening
cascade of o-keto-cinnamates was developed for the synthesis of
indenones. The reaction tolerates a broad range of functional
groups, including bromide, chloride, amide, acid and ester groups.
The use of environmentally benign, mild iron catalysis in organic
synthesis is still emerging.1 The iron catalysed/mediated reactions
has generated considerable interest in organic synthesis because of
their unique reactivity, the diversity of transformations that can be
achieved and the extremely high functional group tolerance.1 Our
interest in the iron catalysed/mediated reactions for the C-C bond
formation culminated into the discovery of new reactions.2 We
report here an interesting finding of FeCl3 mediated formation of
highly substituted indenone derivatives by formal [2+2]
cycloaddition /ring opening cascade of o-keto cinnamates. Indane
motif is found in many biologically active compounds such as (+)-
indatraline (1), a nonselective monoamine transporter inhibitor to
block the reuptake of dopamine, norepinephrine and serotonin
3(fig. 1). It is also found in naturally occurring molecules from
resvetrol family quadranglularin A (2),4a,b parthenocissin A (3)4c,d
Scheme 1: Method for synthesis of indanone derivative.
and pauciferol F (4).4e Additionally, indenone derivatives donepezil
(5)5a and indacrinone (6)5b,c have been developed as Alzheimer and
antihypertensive drugs respectively. Indenone (7) shows agonistic
activity against PPAR (γ), which is useful for the treatment of type 2
diabetes (Fig. 1).6 Indenone based compounds are also used as
intermediate in pharmaceuticals,7a-c conducting polymers,7d ligands
for metallocene complexes7e,f and in material science as discotic
liquid crystals.7g Due to their synthetic utility and application in
pharmaceuticals, variety of synthetic methods have been
developed for the synthesis of indenones. Among these,
intramolecular Friedel-Crafts8 and Nazarov cyclization9 reactions are
the most common methods found in literature. In addition to this,
number of metal catalysts has been used for the synthesis of
indenones (some of them are summarised in Scheme 1). Recently
Nakamura et. al. reported an elegant, copper-catalyzed arylative
cyclization of arylalkynes with aromatic sulfonyl chlorides for the
synthesis of polysubstituted 1H-indenes (Scheme 1, eq.-1).10
Synthesis of indenone and its derivatives was achieved by Liu et. al.
using gold-catalyzed cyclization reaction of cis-3-en-1-ynes (Scheme
1, eq.-2).11 In 2013 Hashmi et. al. developed an excellent gold-
catalyzed oxidative diyne cyclizations via 1,6-carbene transfer for
Fig 1: Representive example of natural and unnatural
indanones/indenes and its derivatives.
(a) Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur
208016,India. E-mail: ddethe@iitk.ac.in; Fax: +91-512-2597436; Tel: +91-512-
2596537‡ Electronic supplementary information (ESI) available: See
DOI: 10.1039/x0xx00000x
† This work is dedicated to Dr. J. S. Yadav on the occasion of his 65th birthday.
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the synthesis of indenones (Scheme 1, eq.-3).12 Although all these the starting material. No change in starting material VwieawsArotibclseeOrnvleinde
methods are catalytic they require super stoichiometric amount of
in presence of FeCl3 after changing solveDnOt I:fr1o0m.103C9H/C2C5lC2Ct0o30T4H0FD,
toluene or acetonitrile at room temperature as well as under reflux
condition. At this stage, it was contemplated that FeCl3 mediated
intramolecular nucleophilic attack could be facilitated by increasing
the electrophilic character of keto group, which could be achieved
by changing the R group in compound 11 from alkyl to aromatic for
Scheme 2. Work plan.
Scheme 3: Synthesis of keto-cinnamate.
Table 1. Optimization of cyclisation reaction.
Entry
Catalyst
(2 equvi.)
FeCl3
FeCl3
FeCl3
Solvent
Temp. Time
Yield
1
2
3
4
CH2Cl2
CH3CN
CH3CN
THF
r.t.
12 h
12 h
12 h
12 h
1 h
C.R.M.
N.R.
45%
N.R.
87%
r.t.
reflux
reflux
FeCl3
FeCl3
5
Toluene reflux
6
7
8
9
10
11
12
FeCl3.6H2O
Fe(OTf)3
TiCl4
CH3CN
CH3CN
Toluene reflux
Toluene reflux
CH3CN
CH2Cl2
Toluene reflux
reflux
reflux
12 h
24 h
1 h
N.R.
N.R.
N.R.
C.R.M.
N.R.
AlCl3
1 h
BF3.OEt2
BF3.OEt2
BF3.OEt2
r.t.
r.t.
24 h
12 h
12 h
C.R.M.
C.R.M.
Scheme 4. Various indenone derivatives.
further polarization of keto group. To quickly check our assumption
o-keto-cinnamate 13a was synthesized from aldehyde 12 in one
step by regioselective Horner-Wadsworth-Wittig reaction. Although
we observed complex reaction mixture after reaction of compound
13a with FeCl3 (2 equiv.) in CH2Cl2 at room temperature, to our
delight compound 13a on treatment with FeCl3 (2 equiv.) in
acetonitrile under reflux conditions was converted directly into
indenone 14a in 45% yield instead of expected indenol 9. To
improve the yield of this transformation, we examined various
catalysts as well as solvents which is summarised in table 1. Among
the catalyst screened, use of 2 equivalent FeCl3 and BF3.OEt2 in
acetonitrile at room temperature failed to generate 14a from 13a
(entry 2 and 10, Table 1) and BF3.OEt2 in CH2Cl2 at room
temperature formed complex reaction mixture (entry 12, Table 1).
FeCl3 in THF and TiCl4 in toluene reflux condition failed to generate
any product 14a and starting material 13a was recovered (entry 4
and 8, Table 1). Complex reaction mixture was observed in case of
external additive/oxidant (Scheme 1, eq.-1, 2, 3). Herein we report
the novel approach of FeCl3 mediated cascade for synthesis of
highly substituted indenones (Scheme 1, eq.-4). Recently we have
developed an olefin-cation cyclization reaction of cinnamates
(Scheme 2, eq.-1).2a On similar lines we became interested in
reaction of ortho keto-cinnamates 8 using FeCl3 to generate the
indenol derivative 9 (Scheme 2, eq.-2). Although such kind of
intramolecular attack on ketone is unprecedented in literature, we
thought of tuning the reaction conditions and substrate to take the
reaction in forward direction for the synthesis of indenol 9 (Scheme
2, eq.-2).
To begin with required keto-cinamate 11 was prepared by
regioselective Wittig reaction on aldehyde 10, using PPh3=CHCO2Et
in CH2Cl2 (scheme 3). Once keto-cinnamate 11 in hand, it was
treated with FeCl3 (2 equiv.) in CH2Cl2 at room temperature, but to
our disappointment we didn’t observe any reaction and recovered
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DOI: 10.1039/C5CC03040D
Fig 2: Ortep diagram of indenone 14o.13
AlCl3 and BF3.OEt2 under toluene reflux condition (entry 9 and 12,
Table 1). Cinnamate 14a was remained unreacted when treated
with FeCl3.6H2O and Fe(OTf)3 under acetonitrile reflux condition
(entry 6 and 7, Table 1). In the presence of other metal catalyst
(CuCl2, CuCl, CuI, NiCl2, PtCl2 and PdCl2) this reaction did not
proceed at all. Interestingly, after screening various solvent and
catalyst combination, it was found that the use of FeCl3 (2 equiv.)
and toluene as solvent under reflux condition for 1 h, leads to the
formation of 14a in 87% yield (entry 5, Table 1). Use of catalytic
amount of FeCl3 (10 mol%) afforded indenone 14a from 13a in less
than 10% yield, showing the need of stoichiometric amount of FeCl3
to effect this transformation.
Scheme 6. Plausible mechanism.
cyclization reaction, keto-cinnamate 16 was converted into
indenone 7 in 84% yield (Scheme 5). We were surprised by the
indenone product 14 formation as it requires transfer of oxygen
atom of keto group of compound 13 to form the keto group in
indenone 14. At this stage although we do not have any proof for
mechanism of this reaction, a plausible mechanism is proposed for
this transformation as shown in scheme 6. Reaction of keto-
cinnamate 17 with FeCl3 could generate conjugated enolate 19
which on further rearrangement forms oxa-bridged intermediate 21
via 20 by attack of enolate on Lewis acid activated ketone at ortho
position of aromatic ring, followed by rearomatization. Loss of
acidic proton followed by subsequent opening of bridged system
generates indenole 22, which on iron mediated oxidation affords
indenone 23.
Scheme 5. Synthesis of indenone 7.
In conclusion, we have developed a novel cascade approach for the
synthesis of highly substituted indenones using environmentally
benign and abundantly available catalyst FeCl3. It was observed that
to carry out this transformation biaryl system attached to carbonyl
carbon is necessary to increase the electrophilicity of the carbonyl
group. High functional group tolerance of this reaction allows
access to various indenones for further application in
pharmaceutical and material chemistry.
To check the substrate scope of this reaction, we prepared various
keto-cinnamates 13b-q by varying substitution on both the
aromatic rings (see supporting information for the preparation).
Keto-cinnamates 13b-q converted into respective indenone
derivatives 14b-q in good yields. As illustrated in scheme-4 it was
observed that, this reaction can tolerate different functional groups
such as bromide (14k, 14l and 14m), chloride (14f, 14o, 14q, 14r
and 14n), methoxy (14i and 14j), carboxylic acid (14b and 14d),
amide (14c, 14h, 14e and 14g) and ester (14a, 14p and 14s). Keto-
cinnamate 13r and 13s, containing naphthalene and thiophene ring
on carbonyl carbon also converted smoothly into indenone 14r and
14s in 93% and 83% yield respectively, further expanding the scope
of the reaction. The structure of indenone derivative was further
established by single crystal X-ray analysis of compound 14o (Fig.
2).13 This method was also applied for the synthesis indenone 7,
which shows agonistic activity with an EC50 value of 50 nM, and
could be useful for the treatment of type 2 diabetes.6 To begin with
compound 15 (see supporting for preparation) was subjected for
the hydrolysis of acetate using K2CO3 in MeOH at room temperature
followed by protection of resultant hydroxy group with 3-
bromopropyl benzene to furnish the required keto-cinamate 16 in
79% yield. Then using FeCl3 mediated cascade
We thank Khushbu singh and Dinesh De for crystal structure
analysis. G.M. thanks CSIR, New Delhi, for the award of a research
fellowship. Financial support from DST New Delhi is gratefully
acknowledged.
Notes and references
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13 CCDC 1035484 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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