An efficient synthesis of highly substituted indanones and chalcones promoted by superacid

Article abstract of DOI:10.1039/c4ra04763j

A superacid promoted one-pot process for the efficient synthesis of indanones is presented. This process enabled the formation of a dual C-C bond between aryl isopropyl ketones and benzaldehydes. Interestingly, when the reaction was performed between acetophenones and benzaldehydes, it was impeded just after the aldol condensation and resulted in the corresponding chalcones. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra04763j

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An efficient synthesis of highly substituted
indanones and chalcones promoted by superacid†
Cite this: RSC Adv., 2014, 4, 26662
*
Amrita Das, Alavala Gopi Krishna Reddy, Jonnada Krishna and Gedu Satyanarayana
Received 1st April 2014
Accepted 6th June 2014
DOI: 10.1039/c4ra04763j
www.rsc.org/advances
A superacid promoted one-pot process for the efficient synthesis of carbocyclic compounds are of signicant importance. Because
indanones is presented. This process enabled the formation of a dual many such carbocyclic systems are present as core structure in
C–C bond between aryl isopropyl ketones and benzaldehydes. many natural products of biological relevance. In this regard,
Interestingly, when the reaction was performed between acetophe- among many classical C–C bond forming reactions, Friedel–
nones and benzaldehydes, it was impeded just after the aldol Cras reaction is treated as one of the best method for either
condensation and resulted in the corresponding chalcones.
alkylation or acylation discovered by Friedel and Cras in 1877.1
Remarkably, in past few decades this reaction has been exten-
sively applied in the eld of organic synthesis under Brønsted/
Lewis acidic conditions.2–4 Signicantly, the Friedel–Cras
cyclization became an useful method for the synthesis of cyclic
systems via single or multiple C–C bonds formation.5
Organic synthesis in a one-pot procedure is an indispensible
technique due to its advantage of constructing more than one
bond without the need to isolate the intermediate species.
Therefore, those techniques that enable the formation of C–C
bonds in a single step, particularly, for the synthesis of
Table 1 Optimization of reaction conditions for the synthesis of
indanone 3c
Acid
(equiv.)
Solvent
(mL)
Temp.
(ꢀC)
Time
(h)
Yielda
(%)
Entry
1
2
3
TFA (5)
TFA
DCE (2)
TFA (2)
50
50
r.t.
r.t.
50
r.t.
50
50
50
50
50
50
12
12
24
24
36
24
24
24
16
16
16
36
—
—
10
30
57
—
50
85
60
—
—
61
TfOH (3)
TfOH (5)
TfOH (3)
TfOH (5)
TfOH (5)
TfOH (5)
H2SO4 (5)
p-TSA (3)
FeCl3 (3)
AlCl3 (3)
DCE (2)
DCE (2)
DCE (2)
Benzene (2)
CHCl3 (2)
DCE (2)
DCE (2)
DCE (2)
DCE (2)
DCE (2)
4
5b
6
Fig. 1 Representative examples for indanone based drugs and natural
products.
7
8
9
10
11
12b
Indian Institute of Technology (IIT) Hyderabad, Ordnance Factory Estate Campus,
Yeddumailaram
– 502 205, Medak District, Andhra Pradesh, India. E-mail:
gvsatya@iith.ac.in; Fax: +91(40) 2301 6032
a
b
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra04763j
Isolated yields of the pure products. yield calculated based on the
recovery of starting material.
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Notably, the superelectrophiles (more reactive intermediate
Because of the importance of indanone core, various acid
species) concept was introduced by Olah et al.,6 which has been mediated approaches have been reported on their synthesis.14
employed to build ring systems efficiently.3b As a part of our With this background, we envisaged that it would be feasible to
ongoing research interests on domino/sequential domino one- generate enol selectively from aryl alkyl ketone under acidic
pot transformations,7 recently, we have reported the synthesis reaction conditions. Thus the so formed enol of the ketone
of indanones using simple cinnamate esters via dual C–C bond would act as a nucleophile and attack on the electrophilic
formation promoted by superacid.8 Also, very recently, we have aldehyde group in intermolecular fashion to give the b-hydroxy
developed mild method for the controlled formation of b-diaryl ketone intermediate which in turn is liable for subsequent
esters without the subsequent intramolecular acylation to give intramolecular Friedel–Cras alkylation to furnish the target
the indanones, via Friedel–Cras Michael addition on cinna- indanones. Though, it can be realized that the intramolecular
mate esters as key step for the synthesis of chromans.9 Inda- Friedel–Cras alkylation will not be much favourable with an
nones are ubiquitous systems that are present in many natural aromatic ring directly connected to a deactivating group
products, which show good range of biological activities as well (carbonyl), the idea behind this aim is based on the use of
as in a variety of drug candidates. Representative examples of heating conditions in the presence of acid that may overcome
such compounds include neo-lignin,10 pauciorol F,11 alcyop- such hurdles. Herein, we present an efficient one-pot method
terosin N,12 and indacrinone13 (Fig. 1).
for the synthesis of highly substituted indanones via dual C–C
bond formation promoted by superacid (triic acid). On the
Table 2 Scope of superacid mediated one-pot formation of indanones 3 from various ketones 1a
a
One-pot reaction conditions for the formation of indanones 3: ketones 1 (0.25 mmol), aldehydes 2 (0.50 mmol, 2 equiv.), TfOH (1.25 mmol, 5
equiv.) and DCE (1.5 mL) at 80 ꢀC for 48 h for the formation of indanones 3a & 3b and at 50 ꢀC for 24 h for other indanones 3c–3k formation.
b
Yields in the parentheses are isolated yields of chromatographically pure products. Yields based on the recovery of the starting material 1a.
c
The reaction furnished neither the product nor the recovery of the starting material.
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Table 3 Superacid mediated indanones 4 & 40 formation from the Table 4 Scope of superacid promoted chalcones 6 formation by aldol
ketone 1b
condensation from a variety of acetophenones 5a
a
Reaction conditions for the formation of chalcones 6: ketones 5 (0.50
mmol), aldehydes 2 (1.0 mmol, 2 equiv.), TfOH (2.5 mmol, 5 equiv.) and
DCE (1.5 mL) at 50 ꢀC for 24 h for the formation of chalcones 6a–6i.
Yields in the parentheses are isolated yields of chromatographically
pure products.
as the reaction medium at 50 ꢀC were not clean (Table 1, entries
1 & 2). On the other hand, treatment of 1c with superacid (triic
acid) in DCE at ambient temperature, furnished the product 3c,
albeit in poor yield (30%) along with the recovery of the starting
other hand, we have noticed that the reaction between the
acetophenones and benzaldehydes, impeded aer aldol
condensation and gave the corresponding chalcones as the end material 1c (Table 1, entry 4). However, when benzene was used
products.
The required aryl isopropyl ketones for this study, were
as the solvent, the reaction was not clean (Table 1, entry 6).
Interestingly, the reaction in hot CHCl3, improved the product
3c yield (50%, Table 1, entry 7). Gratifyingly, treatment of 1c in
DCE at 50 ꢀC, was found to be the best and furnished 3c as an
exclusive product in good yield (85%, Table 1 entry 8). Use of
concentrated H2SO4 also proved to be good and gave the
product 3c in 70% yield (Table 1, entry 9). On the other hand,
synthesized from the corresponding benzaldehydes using
standard isopropyl Grignard addition and oxidation protocol
(see, ESI†). To nd out the best optimized reaction conditions,
the ketone 1c was chosen as model and reacted with the benzal-
dehyde 2a under different reaction conditions in the presence
of acid as promoting agent and the results are summarized in the reaction with p-TSA, led to the total recovery of starting
Table 1. Thus, the reactions of 1c with TFA either as reagent or material 1c (Table 1, entry 10). On the other hand, use of other
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Scheme 1 Possible reaction mechanism for the formation of indanone 3 and chalcone 6.
Lewis acid (FeCl3), led to unclear reaction mixtures (Table 1,
entry 11). Also the use of Lewis acid AlCl3 at 50 ꢀC resulted into have attempted the reaction between acetophenones 5 and
the product 3c in 61% yield (Table 1, entry 12). benzaldehydes 2 as well. Surprisingly, the reaction was impeded
To further check the scope and generality of the method, we
Among all screened reaction conditions, the entry 8 of Table 1 aer the aldol condensation without subsequent cyclization
turned out to be the best with respect to the yield of the product (Table 4). This may be due to thermodynamic stability of enone
3c. Therefore, these conditions were applied to the other systems systems. Moreover, to check the generality of the process, we
1a–1d to check the scope and limitations of the method. Grati- have explored the reaction between different acetophenones 5
fyingly, it was proved to be amenable and furnished the corre- and benzaldehydes 2. Gratifyingly, the reaction was found to be
sponding indanones 3a–3j with dense functionality on either of quite successful and gave the corresponding chalcones 6 in very
the aromatic rings, in good yields as shown in Table 2. It is worth good to excellent yields as shown in Table 4.
mentioning that the reaction was smooth with electron rich
The possible reaction mechanism for the formation of
aromatic ring of the ketones 1b–1d. Whereas, in case of simple indanones 3 and chalcones 6 is outlined in Scheme 1. Initially,
aromatic ketones 1a the reaction was found to be slow, as antic- the acid can activate ketone through protonation to the
ipated reaction rate depends on the electron rich nature of the carbonyl oxygen and yields the corresponding enol A. Nucleo-
aromatic ring. However, the reaction was successful by raising philic attack of the enol A to the electrophilic aldehyde carbon
temperature from 50 ꢀC to 80 ꢀC, albeit in moderate yields of the furnishes the b-hydroxy ketone intermediate B. Since the b-
products 3a and 3b (Table 2). While, further increasing the triic hydroxy ketone intermediate B can be liable for intramolecular
acid amount (10 equivalents), led to the unclear reaction mixture. Friedel–Cras alkylation in the presence of acid, it triggers to
In general, the reaction was smooth for benzaldehydes 2 with the cyclization through the intermediate C and generates the
simple to electron rich aromatic rings except 3,4,5-trimethox- nal indanone product 3. Similarly, in case of acetophenones, it
ybenzaldehyde 2g. In case of 3,4,5-trimethoxybenzaldehyde 2g, yields the corresponding b-hydroxy ketone intermediate B.
simple mono demethylation was observed from a para-methoxy However, because of the availability of b-hydrogen for hydroxyl
group to the aldehyde group. The reaction was not clean with group it prefers dehydration than cyclization and furnishes the
electron decient para-nitrobenzaldehyde 2h, where, neither the chalcone 6 products.
product nor the corresponding starting material was isolated.
While, the reaction with 3-anisyl isopropyl ketone 1b fur-
Conclusions
nished the regioisomeric mixture of indanones 4 & 40 in almost
4 : 1 ratios, in which, as expected, the major isomer was the one
where cyclization occurred at para-position to the methoxy
group and the results are as summarized in the Table 3.
In summary, we have developed an efficient one-pot method for
the synthesis of highly substituted indanones via dual C–C
bond formation promoted by superacid. Signicantly, these
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indanone systems are ubiquitous units that are present in drugs
and many biologically active natural products. Interestingly,
when acetophenones were treated with benzaldehydes in the
presence of super acid, the reaction was impeded aer aldol
condensation and furnished the chalcones. Further, applica-
tions of this method to different structurally important carbo-
cyclic compounds are under progress.
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Acknowledgements
Financial support by the Council of Scientic and Industrial
Research [(CSIR), 02(0018)/11/EMR-II], New Delhi, is gratefully
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